Category: The Pipeline Blog

Writer: Mohona Sarkar

Drug shortages create disruptions in treatment plans, potentially causing life-threatening situations for the patient or the public during an epidemic or outbreak. For years, they were treated as temporary interruptions that were inconvenient, but manageable. That assumption no longer holds. Today, supply failures can be frequent, prolonged, and systemic, affecting everything from cancer therapies to basic injectable vaccines to mitigate an outbreak. Pharmaceutical supply chain is influenced by a global world, defined by pandemics, geopolitical instability, climate shocks, and highly concentrated manufacturing in a few hubs across the globe

In the United States, the Food and Drug Administration (FDA) maintains a continuously updated drug shortage database, a public record of how often supply fails to meet demand.¹ These shortages signal a deeper fragility: dependence on a small number of manufacturers, limited transparency and interactions across supply networks, and regulatory systems that intervene only after disruptions occur.

Not only do drug shortages affect treatment plans, but counterfeit or adulterated drugs circulating in the market possess a serious risk to the public. Globally, the World Health Organization estimates that at least one in ten medical products in low- and middle-income countries is substandard or falsified²—an alarming figure that translates directly into treatment failure, preventable deaths, and erosion of trust in health systems.

Despite this reality, drug supply chains are still governed by reactive and retrospective analysis for compliance. Manufacturers report problems after production falters. Regulators respond after shortages emerge. Health systems scramble once shelves are already empty. This approach may have worked when supply chains were simpler, more localized and perturbations in the global market did not cause an impediment, however with interdependent manufacturing and interconnected supply chains, a reactive approach is inadequate.

Artificial intelligence (AI) offers a way out of this cycle—but only if it is treated as essential public health infrastructure, not a corporate optimization tool.^3,4

At its core, the problem is neither a lack of regulation nor a lack of intent to integrate AI. There exists information such as data trending and analytical tools around manufacturing capacity, quality deviations, prescribing trends, epidemiological patterns, logistics disruptions, and regulatory inspections, but these factors or variables do not communicate with each other. AI’s most significant contribution lies in its capacity to integrate disparate data streams, identify complex interdependencies, and detect emerging risks before they escalate, generating predictive models that map how changes in one variable propagate through secondary and tertiary factors across the supply chain. Predictive modeling has already demonstrated this potential. Machine-learning systems that combine historical shortage data with demand patterns and external signals can forecast supply disruptions earlier and more accurately than traditional statistical approaches.⁵ Studies across pharmaceutical manufacturing and hospital pharmacy settings show that AI-driven forecasting improves early detection of demand spikes and impending shortages, enabling earlier intervention.⁶

It is indeed important to shift this dynamic from a reactive to an anticipatory strategy. Early warnings allow manufacturers to adjust production, diversify sourcing, or build inventory buffers. Regulators can prioritize inspections or expedite approvals from forecasting. Health systems can plan substitutions before patient care is compromised. None of this requires deregulation; it requires better intelligence and policy to enforce guardrails. FDA first addressed AI applications in process design, advanced process control, real-time release testing, and predicting product quality attributes, including for complex biologics such as cancer vaccines, cellular, and gene therapies.⁷ AI also addresses one of the most dangerous blind spots in global medicine: counterfeit and diverted drugs. Expansive therapies and online marketplaces have made treatments more accessible but have also introduced the risks of substandard and fraudulent therapies. Patients increasingly encounter products that look legitimate but are ineffective or unsafe. Here, too, AI offers practical tools. Computer-vision systems can detect subtle packaging deviations invisible to the human eye. Transactional analytics can flag unusual distribution patterns across borders. When paired with blockchain based traceability⁸, these technologies strengthen end-to‑end verification and help regulators focus enforcement where risk is the highest. FDA initiated a few pilot programs as part of the Drug Supply Chain Security Act to assess the blockchain and its interoperability. Such programs using AI and blockchain for counterfeit detection already show measurable improvements in supply chain transparency and oversight.⁹

Inside manufacturing facilities, AI enhances quality rather than undermining it. Predictive maintenance, real-time monitoring of critical quality attributes, and deviation trend analysis reduce the likelihood that localized failures escalate into national shortages. These tools are particularly important for advanced therapies—such as cell and gene treatments—where production is patient specific and intolerant of error. Importantly, these approaches align with existing regulatory principles, including internationally recognized quality-risk management frameworks.

Logistics in the drug supply chain can be another point of vulnerability. Vaccines, biologics, and gene therapies depend on strict temperature control where even brief cold-chain failures can render products unusable. AI driven systems that combine real-time data from multiple sources with predictive routing models can anticipate disruptions due to inclement weather, infrastructure failures, or transit delays and proactively reroute shipments before damage occurs. Evidence from vaccine and biologics distribution during Covid-19 pandemic has shown that these systems reduce temperature excursions and waste^10,11, especially during largescale public health campaigns.

For regulators, AI is not a replacement for human judgment but an augmentation tool. Natural language processing tools can analyze inspection reports, recalls, and adverse-event data at a scale no agency workforce can match, surfacing recurring manufacturing deficiencies or geographic risk areas earlier than traditional review processes. While AI has great potential to improve pharmaceutical supply chains, there are still several challenges. Poor data quality, cybersecurity threats, algorithmic bias, and “black box” models could undermine trust and produce fabricated outputs or “hallucinations”.  Furthermore, there are always economic risks around new emerging technology and the ways it can cause inequities in societies. Public policy must set clear guardrails: transparency in model validation, visibility into decision logic that can be easily queried by regulators, secure public-private data sharing frameworks, and explicit equity considerations are just a few examples. AI should serve resilience and patient safety—not merely efficiency.

The question, then, is no longer whether AI belongs in the drug supply chain. It already does. The real question is whether governments and regulators will treat it as optional—or recognize it as essential infrastructure for protecting access to safe, effective medicines. In the decade ahead, compliance alone will not secure the drug supply, but intelligent forecasting based on inter-connected data and supply chains will. The schematic given below shows how AI can integrate multiple players and variables in creating a robust supply chain.

AI disclosure

Disclosure of AI use: Claude (Anthropic, Sonnet 4.6) was used to improve grammar, brevity and sentence constructs of the draft. Anthropic was also used to generate the schematic representation given here.

References:

1. FDA Drug Shortages. Published online October 23, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/drug-shortages

2. WHO Substandard and Falsified Medical Products. December 3, 2024. https://www.who.int/news-room/fact-sheets/detail/substandard-and-falsified-medical-products

3. Majumdar K, Jain J, Mohan D. AI-Driven Optimization of Pharmaceutical Supply Chains: Enhancing Forecasting, Inventory, and Transparency. In: Proceedings of Data Analytics and Management. 2025. https://doi.org/10.1007/978-3-032-03072-6_18

4. Dzogan R. Reducing drug shortages: The power of AI in pharma supply chain management. September 13, 2024. https://pharmaphorum.com/rd/reducing-drug-shortages-power-ai-pharma-supply-chain-management

5. Zhang J, Yuyang W, Zidu W. Enhancing Supply Chain Forecasting with Machine Learning: A Data-Driven Approach to Demand Prediction, Risk Management, and Demand-Supply Optimization. J Fintech Bus Anal. 2024;2(1):1-5. doi:10.54254/3049-5768/2024.18321

6. Pall R, Gauthier Y, Auer S, Mowaswes W. Predicting drug shortages using pharmacy data and machine learning. Health Care Manag Sci. 2023;26(3):395-411. doi:10.1007/s10729-022-09627-y

7. Center for Drug Evaluation and Research. Artificial Intelligence  in Drug Manufacturing. Discuss Pap. Published online 2023. https://www.fda.gov/media/165743/download

8. Md Saifur Rahman, Nazmun Nahar, Md Hasan Imam, Mohammad Nuruzzaman Bhuyian, Md Auhidur Rahman, Mayeen Uddin Khandaker, Shams Forruque Ahmed,. A blockchain-based framework for drug security: Leveraging EdDSA to prevent counterfeiting. Array. 2025;28(100604). https://doi.org/10.1016/j.array.2025.100604.

9. Drug Supply Chain Security Act Pilot Project Progran. FDA; 2023. https://www.fda.gov/media/168307/download

10. Fusco T. Using the Cold Chain to Safely Deliver COVID-19 Vaccines. March 25, 2021. https://www.unicefusa.org/stories/using-cold-chain-safely-deliver-covid-19-vaccines

11. Advancements in Cold Chain Logistics for Pharmaceuticals. https://www.opex.com/insights/cold-chain-logistics-advancements-for-pharmaceuticals/#elementor-toc__heading-anchor-0

Writer: Julia Lanfersieck

Editor: Emily DiMaulo-Milk

Diseases of the brain are often among the most challenging to treat. This is in large part because of the blood-brain barrier (BBB), a protective layer which restricts the passage of substances from the bloodstream into the brain.

Neurons, the primary functional cells of the brain, form complex networks that communicate to regulate nearly all bodily processes including sensation, movement, cognition, and behavior. Neurons can be as long lived as the organism itself, but they have limited capacity for repair and regeneration, making them particularly vulnerable to damage. The BBB serves to shield fragile neurons from toxins, infectious agents, and other blood-borne stressors. However, this barrier also presents a significant obstacle for administering targeted therapeutics, as many compounds are unable to effectively cross into the brain.

Focused ultrasound (FUS) is an actively evolving therapeutic approach that has promise to overcome the difficulty in crossing the BBB. This could significantly enhance the ability of medications to enter into the brain and improve patient outcomes.

A Barrier to Brain Medicine

A major limitation when delivering drugs to the brain is the difficulty of crossing the BBB. The BBB is composed of a layer of tight-junction-associated endothelial cells lining brain blood vessels, together with supporting cells and transport systems that carefully control exchange between the blood and the brain¹. Small molecules, such as oxygen, can passively diffuse across this barrier. Lipid-soluble compounds, such as alcohol and caffeine, can also cross the BBB. However, the vast majority of compounds, especially large molecules, are unable to enter the brain because they cannot pass between these tightly sealed cells and are not readily transported across the BBB².

Consequently, treatments for brain conditions administered orally or intravenously typically fail to adequately penetrate the brain. Increasing the dose can sometimes raise brain exposure modestly, but this approach is limited and can substantially increase systemic side effects and treatment cost. For many neurological disorders, the BBB remains one of the most persistent barriers to effective therapy.

A New Way Through with Focused Ultrasound

A potential strategy to improve the passage of drugs across the BBB is focused ultrasound (FUS). FUS is the direct application of ultrasonic sound waves which deliver energy to a specific location within the body³. This can remove tissue to create a lesion, a process known as ablation. This technique was first published in 1955 by William and Francis Fry, who used FUS to selectively and precisely ablate a 2- to 3-microm region of the brain without damaging surrounding tissues⁴.

Over the following decades, technological advances refined FUS techniques, leading to its clinical application. In 2016, the FUS was approved by the FDA for the first time for its application to essential tremor, a neurological disorder causing involuntary shaking^5,6. For this one-time procedure, magnetic resonance imaging (MRI) is performed to identify the brain regions responsible for the tremor, and FUS is applied to ablate the target region with high precision. Clinical follow-up studies have shown great benefit, with 100% of patients experiencing an immediate reduction in symptoms and reports estimating 73% improvement of symptoms even after 5 years^7.8.

While high-intensity FUS for tissue ablation has proven efficacious, recent innovations have described the use of low-intensity FUS, which preserves tissue integrity, with exciting results. Current uses of FUS are explained further in Table 1.

FUS Intensity	Primary Use	Mechanism	Clinical Status
High intensity	Tissue ablation	Delivers concentrated ultrasonic energy to heat and destroy targeted tissue, creating a precise lesion	FDA approved for essential tremor, Parkinson’s disease-related tremor, and certain cancers9,10
Low intensity	BBB opening	Used with intravenously administered microbubbles to disrupt the BBB temporarily and locally, allowing therapeutics to enter brain tissue	In clinical trials and active preclinical development for improved drug delivery to the brain
	Neuromodulation	Applies lower-energy ultrasound to alter neural circuit activity without destroying tissue	Ongoing preclinical and early clinical research for application to addiction, depression, and other neuropsychiatric disorders11

Table 1. Use, mechanism, and clinical status of current focused ultrasound (FUS) applications.

FUS for Opening the Barrier

With low intensity FUS, tissue vibrates, but is not destroyed. This distinction led Dr. Kullervo Hynynen to propose that this technique could be applied to disrupt the BBB¹². Building on this idea, Dr. Hyneynen’s lab developed an approach to disrupt the BBB using microbubbles. Microbubbles are tiny gas-filled lipid spheres that expand and contract under ultrasonic energy. When ultrasound is applied at specific frequencies and intensities, the microbubbles oscillate, exerting mechanical stress on the endothelial lining of the vasculature and causing temporary separation of tight junctions^13,14. This disrupts the integrity of the BBB and creates openings big enough for drug molecules to pass through into the brain¹³. Importantly, FUS-mediated BBB opening is reversible, as the BBB reseals within 24 to 48 hours, reducing concerns about long-term effects and fostering confidence in the safety of this technology¹⁵.

FUS-mediated BBB disruption is also precise. In clinical applications, MRI-guided brain targeting is used to direct the ultrasound to the specific BBB region of interest. Microbubbles and the therapeutic drug are then co-administered intravenously and circulate through the vasculature. The drug is only able to cross the BBB at the precise location where FUS is applied. The specific frequency and intensity of the ultrasound are carefully optimized to maximize drug delivery while minimizing tissue damage. Further research is needed to refine these settings for different clinical scenarios, but early applications of FUS appear promising.

Applying FUS toward Alzheimer’s disease

FUS treatment is currently being investigated across a range of medical disorders and is believed to have particularly strong potential in treating Alzheimer’s disease (AD). AD is the most common neurodegenerative disorder, affecting over 50 million people worldwide and ranking as the sixth leading cause of death in the United States¹⁶. AD is characterized by progressive brain atrophy associated with the accumulation of tau and amyloid-β pathology. Symptoms include memory loss, cognitive decline, and broader behavioral and mood changes¹⁷. Despite its high prevalence and decades of research, there still is no cure for AD, and available treatments remain limited.

A central challenge in developing AD treatments is the effective delivery of large molecules, like therapeutic antibodies or viral vectors, across the BBB. FUS-mediated BBB opening offers a direct solution to this limitation.

Preclinical studies first established the versatility of this approach across multiple pathological targets. In mouse models, FUS-mediated BBB opening enhanced the delivery and efficacy of both anti-amyloid and anti-tau antibodies, demonstrating that FUS is not restricted to a single disease mechanism but can be broadly applied to the major drivers of AD pathology^18-21. Notably, the ability to improve delivery of anti-tau therapeutics highlights the potential of FUS to support emerging treatment strategies beyond more established amyloid-focused approaches.

Clinical studies have begun to translate these findings to human patients. In a small-scale clinical trial led by Dr. Ali Rezai, FUS combined with microbubbles enhanced drug delivery to the brain and increased accumulation of the anti-amyloid therapy Aducanumab compared to drug administration, indicating potential for this approach to improve therapeutic outcomes in patients^15,22,23. Although Aducanumab is now discounted, ongoing studies are evaluating FUS in combination with newer approved anti-amyloid therapies, including Lecanemab and Donanemab. These agents have demonstrated modest clinical efficacy in reducing amyloid burden and slowing cognitive decline on their own; however, FUS-mediated BBB opening may further enhance their therapeutic impact by improving brain penetration and target engagement^24,25.

As BBB permeability becomes increasingly addressable through technologies such as FUS, a critical remaining challenge is maximizing the efficacy of therapeutics once they reach the brain. This shift emphasizes the need to optimize target engagement, dosing strategies, and downstream biological effects to achieve meaningful disease modification in AD and other brain disorders.

Broader Implications and Future Directions

The potential applications for FUS-mediated BBB opening extend well beyond AD. Preclinical and clinical research evaluating FUS spans brain tumors, neurodegenerative diseases, and psychiatric conditions^13,26-29. By enabling localized and transient BBB modulation, FUS provides a flexible platform for improving the delivery of diverse therapeutic modalities, including antibodies, vectors for gene therapy, and small molecules.

Beyond therapeutics, FUS may also enable new diagnostic and monitoring approaches. BBB opening is bidirectional, meaning molecules can both be delivered to and released from the brain³⁰. In this context, post-FUS peripheral blood sampling could enable “liquid biopsy,” offering a minimally invasive strategy to monitor brain-derived biomarkers, such as amyloid levels, over the course of treatment^31,32. While still an emerging approach requiring further refinement, FUS has the potential to enhance current biomarker sampling methods.

Research into FUS is rapidly expanding. Over the last two decades, the Focused Ultrasound Foundation has supported more than 70 clinical trials and several preclinical trials aimed at advancing the clinical translation and refinement of this technology³³. Current work focuses on evaluating and improving the safety and precision of repeated BBB opening for long-term clinical use³⁴. Taken together, these advances position FUS-mediated BBB opening as a promising and adaptable platform, with continued optimization of safety, precision, and therapeutic integration remaining essential for its successful clinical translation.

Conclusion

The blood-brain barrier (BBB) is essential for protecting sensitive neurological tissue, but it is also a critical obstacle in the treatment of neurological diseases. However, low-intensity focused ultrasound (FUS) provides a controlled, non-invasive approach that transiently overcomes this barrier, which could be applied across a variety of diseases and therapeutic modalities.

With FDA-approved implications recently established for Parkinson’s disease and essential tremor, high-intensity FUS is already demonstrating clinical impact. With continued research, more FUS-based strategies may be approved in the near future, paving the way for significant improvements in the treatment of neurological diseases.

References

1. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010;37(1):13-25. doi:10.1016/j.nbd.2009.07.030

2. Laterra J, Keep R, Betz LA, Goldstein GW. Blood—Brain Barrier. Basic Neurochemistry: Molecular, Cellular and Medical Aspects 6th edition. Published online 1999. https://www.ncbi.nlm.nih.gov/books/NBK28180/

3. Fishman PS, Frenkel V. Focused Ultrasound: An Emerging Therapeutic Modality for Neurologic Disease. Neurotherapeutics. 2017;14(2):393-404. doi:10.1007/s13311-017-0515-1

4. Fry WJ, Barnard JW, Fry EJ, Krumins RF, Brennan JF. Ultrasonic lesions in the mammalian central nervous system. Science. 1955;122(3168):517-518.

5. Fishman PS. Thalamotomy for essential tremor: FDA approval brings FUS-based brain treatment to the clinic. J Ther Ultrasound. 2017;5:19. Published 2017 Jul 13. doi:10.1186/s40349-017-0096-9

6. Elias WJ, Lipsman N, Ondo WG, et al. A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor. N Engl J Med. 2016;375(8):730-739. doi:10.1056/NEJMoa1600159

7. Maragkos GA, Kosyakovsky J, Zhao P, et al. Patient-Reported Outcomes After Focused Ultrasound Thalamotomy for Tremor-Predominant Parkinson’s Disease. Neurosurgery. 2023;93(4):884-891. doi:10.1227/neu.0000000000002518

8. Cosgrove GR, Lipsman N, Lozano AM, et al. Magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor: 5-year follow-up results. J Neurosurg. 2022;138(4):1028-1033. Published 2022 Aug 5. doi:10.3171/2022.6.JNS212483

9. Cummins DD, Bernabei JM, Wang DD. Focused Ultrasound for Treatment of Movement Disorders: A Review of Non-Food and Drug Administration Approved Indications. Stereotact Funct Neurosurg. 2024;102(2):93-108. doi:10.1159/000535621

10. FDA Clears Focused Ultrasound System for Prostate Cancer Treatment. Oncology Times 37(22):p 37, November 25, 2015. | DOI: 10.1097/01.COT.0000475249.19383.04

11. Meng Y, Pople CB, Lea-Banks H, Hynynen K, Lipsman N, Hamani C. Focused ultrasound neuromodulation. Int Rev Neurobiol. 2021;159:221-240. doi:10.1016/bs.irn.2021.06.004

12. From Concept to Commercialization: Focused Ultrasound–Enabled Blood-Brain Barrier Opening – Focused Ultrasound Foundation. Focused Ultrasound Foundation. Published July 10, 2025. https://www.fusfoundation.org/posts/from-concept-to-commercialization-focused-ultrasound-enabled-blood-brain-barrier-opening/

13. Poon C, McMahon D, Hynynen K. Noninvasive and targeted delivery of therapeutics to the brain using focused ultrasound. Neuropharmacology. 2017;120:20-37. doi:10.1016/j.neuropharm.2016.02.014

14. Morse SV, Rimer S, Geoghegan G, et al. Biological effects of rapid short pulses of focused ultrasound for drug delivery to the brain. J Control Release. 2025;382:113646. doi:10.1016/j.jconrel.2025.113646

15. Rezai AR, D’Haese PF, Finomore V, et al. Ultrasound Blood-Brain Barrier Opening and Aducanumab in Alzheimer’s Disease. N Engl J Med. 2024;390(1):55-62. doi:10.1056/NEJMoa2308719

16. Duan, Y., Han, C., Zheng, H., Yu, J., & Luo, M. (2025). Global, regional, and national burden of Alzheimer’s disease and other dementias from 1990 to 2021: findings from the Global Burden of Disease Study 2021. Frontiers in aging neuroscience, 17, 1678212. https://doi.org/10.3389/fnagi.2025.1678212

17. Jack CR Jr, Andrews JS, Beach TG, et al. Revised criteria for diagnosis and staging of Alzheimer’s disease: Alzheimer’s Association Workgroup. Alzheimers Dement. 2024;20(8):5143-5169. doi:10.1002/alz.13859

18. Liu X, Naomi SSM, Sharon WL, Russell EJ. The Applications of Focused Ultrasound (FUS) in Alzheimer’s Disease Treatment: A Systematic Review on Both Animal and Human Studies. Aging Dis. 2021;12(8):1977-2002. Published 2021 Dec 1. doi:10.14336/AD.2021.0510

19. Ma X, Li T, Du L, Han T. Research and progress of focused ultrasound in the treatment of Alzheimer’s disease. Front Neurol. 2023;14:1323386. Published 2023 Dec 21. doi:10.3389/fneur.2023.1323386

20. Nisbet RM, Van der Jeugd A, Leinenga G, Evans HT, Janowicz PW, Götz J. Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain. 2017;140(5):1220-1230. doi:10.1093/brain/awx052

21. Janowicz PW, Leinenga G, Götz J, Nisbet RM. Ultrasound-mediated blood-brain barrier enhances delivery of therapeutically relevant formats of a tau-specific antibody. Sci Rep. 2019;9(1):9255. Published 2019 Jun 25. doi:10.1038/s41598-019-45577-2

22. Mehta, R. I., Ranjan, M., Haut, M. W., Carpenter, J. S., & Rezai, A. R. (2024). Focused Ultrasound for Neurodegenerative Diseases. Magnetic resonance imaging clinics of North America, 32(4), 681–698. https://doi.org/10.1016/j.mric.2024.03.001

23. Jeong J, Han M, Jeon S, et al. Aducanumab delivery via focused ultrasound-induced transient blood-brain barrier opening in vivo. Sci Rep. 2025;15(1):17742. Published 2025 May 22. doi:10.1038/s41598-025-02412-1

24. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med. 2023;388(1):9-21. doi:10.1056/NEJMoa2212948

25. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512-527. doi:10.1001/jama.2023.13239

26. Choi HJ, Han M, Jung B, et al. Evaluation of blood-tumor barrier permeability and doxorubicin delivery in rat brain tumor models using additional focused ultrasound stimulation. Sci Rep. 2025;15(1):6592. Published 2025 Feb 24. doi:10.1038/s41598-025-88379-5

27. Helal MM, Ibrahim AA, Beddor A, Kashbour M. Breaking Barriers in Huntington’s Disease Therapy: Focused Ultrasound for Targeted Drug Delivery. Neurochem Res. 2025;50(1):68. Published 2025 Jan 3. doi:10.1007/s11064-024-04302-w

28. Li W, Feng Y, Xu Z, et al. Precise antibody delivery to the brain via nanobubble-actuated focused ultrasound alleviates depression. Proc Natl Acad Sci U S A. 2025;122(35):e2421800122. doi:10.1073/pnas.2421800122

29. Durham PG, Butnariu A, Alghorazi R, Pinton G, Krishna V, Dayton PA. Current clinical investigations of focused ultrasound blood-brain barrier disruption: A review. Neurotherapeutics. 2024;21(3):e00352. doi:10.1016/j.neurot.2024.e00352

30. Zhu L, Nazeri A, Pacia CP, Yue Y, Chen H. Focused ultrasound for safe and effective release of brain tumor biomarkers into the peripheral circulation. PLoS One. 2020;15(6):e0234182. Published 2020 Jun 3. doi:10.1371/journal.pone.0234182

31. Zhu L, Cheng G, Ye D, et al. Focused Ultrasound-enabled Brain Tumor Liquid Biopsy. Sci Rep. 2018;8(1):6553. Published 2018 Apr 26. doi:10.1038/s41598-018-24516-7

32. Pacia CP, Zhu L, Yang Y, et al. Feasibility and safety of focused ultrasound-enabled liquid biopsy in the brain of a porcine model. Sci Rep. 2020;10(1):7449. Published 2020 May 4. doi:10.1038/s41598-020-64440-3

33. Foundation Funded Research Projects – Focused Ultrasound Foundation. Focused Ultrasound Foundation. Published September 26, 2024. Accessed April 12, 2026. https://www.fusfoundation.org/for-researchers-and-clinicians/foundation-funded-research-projects/

34. Tsai HC, Tsai CH, Chen WS, Inserra C, Wei KC, Liu HL. Safety evaluation of frequent application of microbubble-enhanced focused ultrasound blood-brain-barrier opening. Sci Rep. 2018;8(1):17720. Published 2018 Dec 7. doi:10.1038/s41598-018-35677-w

Author: Grace Stroman

Editor: Meghan Diefenbacher

Today’s article will discuss the Food and Drug Administration (FDA) approval of Optune Pax® for pancreatic cancer as a result of the PANOVA-3 study. On February 11th, 2026, Optune Pax in combination with gemcitabine and nab-paclitaxel chemotherapy was approved for adults with unresectable locally advanced pancreatic adenocarcinoma.¹ It represents the first FDA approval for this indication in nearly 30 years. The primary endpoint of the global PANOVA-3 trial was overall survival (OS) and the secondary endpoints were overall response rate (ORR), progression-free survival (PFS), pain-free survival, tumor resectability rate, and puncture-free survival.² Developed by Novocure, Optune Pax is a wearable medical device that generates low, alternating electric tumor treating fields (TTFields) which interfere with tumor proliferation.

Key points

• Novocure’s Optune Pax is a noninvasive medical device that locally delivers customizable low frequency alternating electric fields
• The PANOVA-3 phase III study indicated TTFields are safe and provide superior median OS for adults with unresectable pancreatic adenocarcinoma
• TTFields prolonged patient 1-year survival rate, 1-year PFS rate, length of pain-free survival, and time to distant PFS

What is pancreatic cancer?

In 2025, pancreatic cancer accounted for 8% of cancer deaths in the United States and is the fourth and third leading cause of cancer deaths for men and women, respectively.³ This is due to the poor 5-year survival rate of ~13%, lack of optimal screening tools for early diagnosis, and difficulty identifying high-risk populations for screening.^4-5 Pancreatic ductal adenocarcinoma represents ~80% of all pancreatic cancer cases with pancreatic neuroendocrine tumours and neuroendocrine carcinomas being the next most common.⁴ Over 80% of cases arise sporadically due to somatic mutations and familial pancreatic cancer accounts for 4-10% of cases.⁴ Risk factors for sporadic pancreatic cancer are age, chronic pancreatitis, tobacco use, Helicobacter pylori infection, and dietary habits.⁴ For unresectable locally advanced pancreatic adenocarcinoma patients in the PANOVA-3 trial, the standard of care is neoadjuvant chemotherapy cocktails (e.g.. gemcitabine and nab-paclitaxel) followed by surgery based on tumor shrinkage.^4,6 The gemcitabine and nab-paclitaxel cocktail was shown to increase median OS and PFS by 1.8 months compared to gemcitabine alone.⁷

TTFields established preclinical and clinical findings

TTFields therapy uses low frequency (100-300 kHz) alternating electric fields to disrupt cellular properties. In preclinical models, this approach was originally shown to affect actively proliferating cancer cells and slow in vivo tumor growth. By interfering with electrical forces required for chromosome alignment during mitosis, TTFields therapy halts cell proliferation and disintegrates diving cells.⁸ Further studies have shown that TTFields induce DNA damage, replication stress, and endoplasmic reticulum stress.^9-11 These forms of cellular distress can stimulate innate and adaptive immune-mediated cell death, enhance anti-PD-L1 (Programmed Death-Ligand 1) efficacy, and tumoral immune cell infiltration.^11-13 Using a preclinical pancreatic cancer model, Giladi and colleagues demonstrated enhanced TTFields efficacy when combined with gemcitabine and fluorouracil which function as DNA and nucleotide synthesis chemotherapeutic inhibitors.¹⁴ These preclinical findings have translated into the clinical setting. Novocure’s non-invasive, wearable NovoTTF-200T System TTFields therapy device is now FDA approved for glioblastoma, non-small cell lung cancer, and mesothelioma.^15-17 

PANOVA-3 study design and results

The PANOVA-3 was a global, randomized, open-label phase III trial designed to access the safety and efficacy of TTFields with gemcitabine and nab-paclitaxel as first-line therapy for adults with locally advanced pancreatic adenocarcinoma (Figure 1).² The multicenter study recruited 571 patients spanning 196 sites representing 20 countries. Patients were randomized 1:1 to receive TTFields with gemcitabine and nab-paclitaxel or gemcitabine and nab-paclitaxel alone. Novocure’s NovoTTF-200T System delivered 150 kHz TTFields with a recommended usage of ≥18 hours per day. Gemcitabine and nab-paclitaxel were infused once per day on days 1, 8, and 15 of a 28-day cycle. Patients were monitored during follow-up visits every 4 weeks and imaging was performed every 8 weeks to assess response. Treatment was terminated upon disease progression as defined by RECIST v1.1, adverse toxicity, pregnancy, consent withdrawal, or a break in compliance.

The PANOVA-3 trial reached its primary and secondary endpoints and Optune Pax was well tolerated. As the primary endpoint, the combination of TTFields, gemcitabine, and nab-paclitaxel significantly (P = 0.039) extended median patient OS to 16.2 months (95% CI, 15.0 to 18.0) compared to 14.2 months (95% CI, 12.8 to 15.4) with gemcitabine, and nab-paclitaxel treatment. TTFields therapy significantly prolonged patient 1-year survival rate (68.1% v. 60.2%), 1-year PFS rate (43.9% v. 34.1%), length of pain-free survival (15.2 v. 9.1 months), and time to distant PFS (13.9 v. 11.5 months). Other secondary endpoints including overall PFS, local PFS, ORR, tumor resectability rate, and puncture-free survival were not significantly improved with TTFields therapy. The majority of TTFields adverse events (AEs) reported were mild-to-moderate dermatological reactions to the device with 7.7% of patients experiencing ≥3 grade skin events. AEs led to 15.8% of patients discontinuing chemotherapy while AEs led to 8.4% of TTFields patients discontinuing. Finally, four patients (0.7%) died from chemotherapy-related AEs, but no patient succumbed to TTFields AEs. The PANOVA-3 study is a milestone as it represents the newest FDA approval available for patients in nearly 30 years and offers an additional few months of reduced pain for an already dismal disease outlook.

Looking ahead

Novocure’s TTFields technology is expanding into additional clinical combinatorial studies and indications. The PANOVA-4 phase II study is testing first-line TTFields with gemcitabine, nab-pactitaxel, and the PD-L1 inhibitor atezolizumab for metastatic pancreatic adenocarcinoma.¹⁸ For metastatic non-small cell lung cancer, the LUNAR-2 and LUNAR-4 studies are evaluating the safety and efficacy of TTFields with the PD-1 inhibitor pembrolizumab and platinum-based chemotherapy as first- and second-line treatment options, respectively.^19-20 For glioblastoma patients, the KEYNOTE D58 and TRIDENT studies are investigating the use of TTFields and temozolomide chemotherapy with pembrolizumab or radiation, respectively.^11-22 These ongoing studies will continue to determine the safety and efficacy of TTFields in new indications and test the clinical translatability of this new technology.

References 

1. NovoCure Ltd. Pivotal, Randomized, Open-Label Study of Tumor Treating Fields (TTFields, 150kHz) Concomitant With Gemcitabine and Nab-Paclitaxel for Front-Line Treatment of Locally-Advanced Pancreatic Adenocarcinoma. clinicaltrials.gov; 2026. Accessed March 19, 2026. https://clinicaltrials.gov/study/NCT03377491
2. Babiker HM, Picozzi V, Chandana SR, et al. Tumor Treating Fields With Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study. J Clin Oncol. 2025;43(21):2350-2360. doi:10.1200/JCO-25-00746
3. Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75(1):10-45. doi:10.3322/caac.21871
4. Pancreatic cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of Oncology. 2023;34(11):987-1002. doi:10.1016/j.annonc.2023.08.009
5. Cancer of the Pancreas – Cancer Stat Facts. SEER. Accessed March 19, 2026. https://seer.cancer.gov/statfacts/html/pancreas.html
6. Pancreatic Cancer Treatment (PDQ®) – NCI. February 10, 2026. Accessed March 19, 2026. https://www.cancer.gov/types/pancreatic/hp/pancreatic-treatment-pdq
7. Celgene. A Randomized Phase III Study of Weekly ABI-007 Plus Gemcitabine Versus Gemcitabine Alone in Patients With Metastatic Adenocarcinoma of the Pancreas. clinicaltrials.gov; 2019. Accessed April 2, 2026. https://clinicaltrials.gov/study/NCT00844649
8. Disruption of Cancer Cell Replication by Alternating Electric Fields | Cancer Research | American Association for Cancer Research. Accessed March 19, 2026. https://aacrjournals.org/cancerres/article/64/9/3288/517864/Disruption-of-Cancer-Cell-Replication-by?guestAccessKey=
9. Mumblat H, Martinez-Conde A, Braten O, et al. Tumor Treating Fields (TTFields) downregulate the Fanconi Anemia-BRCA pathway and increase the efficacy of chemotherapy in malignant pleural mesothelioma preclinical models. Lung Cancer. 2021;160:99-110. doi:10.1016/j.lungcan.2021.08.011
10. Mumblat H, Martinez-Conde A, Braten O, et al. Tumor Treating Fields (TTFields) downregulate the Fanconi Anemia-BRCA pathway and increase the efficacy of chemotherapy in malignant pleural mesothelioma preclinical models. Lung Cancer. 2021;160:99-110. doi:10.1016/j.lungcan.2021.08.011
11. Voloshin T, Kaynan N, Davidi S, et al. Tumor-treating fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor efficacy when combined with anti-PD-1 therapy. Cancer Immunol Immunother. 2020;69(7):1191-1204. doi:10.1007/s00262-020-02534-7
12. Chen D, Le SB, Hutchinson TE, et al. Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma. J Clin Invest. 2022;132(8):e149258. doi:10.1172/JCI149258
13. Kirson ED, Giladi M, Gurvich Z, et al. Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs. Clin Exp Metastasis. 2009;26(7):633-640. doi:10.1007/s10585-009-9262-y
14. Giladi M, Schneiderman RS, Porat Y, et al. Mitotic disruption and reduced clonogenicity of pancreatic cancer cells in vitro and in vivo by tumor treating fields. Pancreatology. 2014;14(1):54-63. doi:10.1016/j.pan.2013.11.009
15. Optune Gio® | FDA-approved glioblastoma (GBM) treatment. Optune Gio®. Accessed March 19, 2026. https://www.optunegio.com
16. Premarket Approval (PMA). Accessed March 19, 2026. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P230042
17. Humanitarian Device Exemption (HDE). Accessed March 19, 2026. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=H180002
18. NovoCure Ltd. PANOVA-4: Pilot, Single Arm Study of Tumor Treating Fields (TTFields, 150kHz) Concomitant With Atezolizumab, Gemcitabine and Nab-Paclitaxel as First-Line Treatment for Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC). clinicaltrials.gov; 2025. Accessed March 19, 2026. https://clinicaltrials.gov/study/NCT06390059
19. Study Details | NCT06216301 | LUNAR-2: TTFields With Pembrolizumab + Platinum-based Chemotherapy for Metastatic NSCLC | ClinicalTrials.gov. Accessed March 19, 2026. https://clinicaltrials.gov/study/NCT06216301
20. NovoCure GmbH. LUNAR-4: Pilot, Single Arm, Open-Label, Multinational Study of Tumor Treating Fields (TTFields, 150 kHz) Concomitant With Pembrolizumab for the Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC) Previously Treated With a PD-1/PD-L1 Inhibitor and Platinum-Based Chemotherapy. clinicaltrials.gov; 2025. Accessed March 19, 2026. https://clinicaltrials.gov/study/NCT06558799
21. NovoCure GmbH. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Optune® (TTFields, 200 kHz) Concomitant With Maintenance Temozolomide and Pembrolizumab Versus Optune® Concomitant With Maintenance Temozolomide and Placebo for the Treatment of Newly Diagnosed Glioblastoma (EF-41/KEYNOTE D58). clinicaltrials.gov; 2026. Accessed March 19, 2026. https://clinicaltrials.gov/study/NCT06556563
22. NovoCure Ltd. EF-32: Pivotal, Randomized, Open-Label Study of Optune® (Tumor Treating Fields, 200kHz) Concomitant With Radiation Therapy and Temozolomide for the Treatment of Newly Diagnosed Glioblastoma. clinicaltrials.gov; 2025. Accessed March 19, 2026. https://clinicaltrials.gov/study/NCT04471844

Writer: Emily DiMaulo-Milk

Editor: Joe Krzeski

            In April 2025, Moderna initiated a Phase II Clinical trial testing the investigational vaccine mRNA-1195 in patients with MS.¹ This vaccine targets the common virus, Epstein-Barr Virus (EBV), which causes “mono”.² A detailed explanation of the link between EBV and MS, as well as general background on both diseases, can be accessed at the first portion of this two-part blog post. Here, we will delve into the current standard of care for people living with MS and Moderna’s Horizon Trial.        

What are the current treatments available for Multiple Sclerosis and EBV?

            Multiple Sclerosis (MS) is a neurodegenerative autoimmune disorder which is caused by the destruction of the myelin sheath, a process called demyelination. The myelin sheath normally protects neurons from damage and enables speedy communication between neurons. Over time, as demyelination continues, the symptoms of MS can increase in severity and duration. There is currently no cure for MS, but there are many different medications available which can improve quality of life for people living with MS.³

The treatments for MS can be subdivided into two categories: treatments targeting symptoms (Table 1) and disease-modifying therapies (DMTs) (Table 2).^4,5

What are some of the therapies which target the symptoms of MS?

During a severe flare up, a person may be prescribed corticosteroids such as oral prednisone or intravenous methylprednisolone to reduce inflammation. If these treatments are ineffective, plasma exchange may instead be used to treat severe symptom flare-ups. During plasma exchange, blood is removed from the body and separated into cells and a liquid component called plasma. The original plasma is replaced with plasma from healthy donors. The filtered blood is then returned to the body. Plasma exchange takes multiple hours and typically needs to be done several times to be effective.^4,5 Anybody who meets the minimum requirements can help people living with MS by donating plasma, which can be accessed at the American Red Cross website. 

Outside of severe flare-ups, people living with MS may experience symptoms that impact their day-to-day functioning. Physical therapy can improve a host of symptoms, including bladder control, muscle strength and flexibility, and mobility. There are also accessibility tools which help people living with MS to adjust to changes in vision and physical ability. Occupational therapy can direct patients to resources and teach them how to use these tools. Outside of therapy, muscle relaxants such as baclofen (Lioresal, Gablofen) and tizanidine (Zanaflex) or onabotulinumtoxin A (Botox) can reduce muscle contractions. Onabotulismtoxin A (Botox) can also be used to treat any impairments in bladder control and reduce feelings of stiffness and involuntary muscle spasms. Dalfampridine (Ampyra) may be used to increase walking speed. Fatigue, one of the most common symptoms of MS, may be treated by stimulants such as methylphenidate (Ritalin, Concerta), though there is evidence that these medications may not be as effective as previously thought. Antidepressants such as bupropion (Wellbutrin) may be more effective and help with depressed mood, another common symptom of MS.^4,5  

Table 1: Examples of treatments for MS which aim to improve symptoms.

Treatment	Effect
Corticosteroidsprednisone, methylprednisone	Reduced inflammation during episodic flare-ups
Plasma exchange	Improvement of flare-up, used if corticosteroids are insufficient
Physical therapy	Catered to the patient and can improve many symptoms
Occupational therapy	Educates and directs patients towards accessibility tools
Muscle relaxants,Baclofen (Lioresal, Gablofen)     Tizanidine (Zanaflex)	Reduced muscle contractions
Onabotulinumtoxin A (Botox)	Reduced muscle contractions, stiffness, and spasmsImproved bladder control
Dalfampridine (Ampyra)	Increased walking speed
StimulantsMethylphenidate (Ritalin, Concerta)	Reduced fatigue, unclear effectiveness
AntidepressantsBupropion (Wellbutrin)	Reduced fatigue, improved mood

What disease-modifying therapies (DMTs) are available and how do they work?

DMTs aim to slow or block the progression of MS by reducing the occurrence of demyelination. Because of this, DMTs are most effective at the early stages of MS. However, while these DMTs can be beneficial, they often cause significant side effects and thus must be used with caution.^4,5

Demyelination in MS is driven by immune cells, called B- and T-cells, which mistakenly target the cells which make up the myelin sheath. Some DMTs broadly target inflammation, such as interferon-beta medications and glatiramer acetate, to dampen the immune response. Other DMTs aim to act directly upon immune cells. Teriflunomide (Aubagio) targets a type of metabolism that activated immune cells are particularly dependent upon.⁶ Fingolimod⁷ and Natalizumab⁸ are two different medications that both block immune cells from migrating to the brain, where demyelination occurs. One of the most widely prescribed DMTs are anti-CD20 monoclonal antibody therapies, such as Ocrelizumab and Ubituximab. Anti-CD20 monoclonal antibodies bind to B-cells, which causes other immune cells to kill the bound B-cell.^{4, 5} In many ways, this is similar to the demyelination process. However, these treatments are helpful because the cells which are depleted are those that produce the autoreactive antibodies which bind to the myelin sheath. 

Overall, MS can have many different symptoms and affect people in different ways. The symptoms of MS can be transient or persistent and new symptoms may develop as the disease progresses. There are also multiple types of medications that target the same symptom or biological event. Every treatment has different side effects and effectiveness from person to person. Therefore, patients and doctors closely work together to determine the appropriate medications on an individual basis. It may take a long time to find the best combination of medications for a person. 

Table 2: Examples of disease-Modifying Therapies (DMTs) to slow or stop the progression of MS.

Treatment	Effect
Interferon-beta medications	Broad suppression of immunity and inflammatory response
Glatiramer acetate	Broad suppression of immunity and inflammatory response
Teriflunomide (Aubagio)	Inhibition of activated immune cells by hindering their metabolism
Fingolimod, Natalizumab	Blockade of infiltration of immune cells into the brain
Anti-CD20 Monoclonal AntibodiesOcrelizumab, Ubituximab	Depletion of B-cells which drive demyelination

Are there treatments or preventatives which target Epstein-Barr Virus (EBV)?

In the previous blog post, we described the evidence for a link between MS and Epstein-Barr Virus (EBV) and background on this common virus. It is possible that any treatments which are effective against this virus would also be effective against MS. 

EBV is also the virus which causes infectious mononucleosis, or “mono,” an acute viral infection characterized by swollen lymph nodes, rash, fatigue, sore throat, and fever. Treatment for mono consists of rest, plenty of fluids, and over-the-counter antipyretics like ibuprofen. In people who are immunocompromised, acyclovir or ganciclovir may be used to prevent the uncontrolled lytic replication of herpesviruses, including Epstein-Barr Virus.² These medications work by blocking the virus from making more copies of the viral genome during the lytic phase. However, this medication is not specific to EBV and does not affect the virus during the latent phase of infection.⁹ Interestingly, anti-CD20 monoclonal antibody therapies are commonly used to treat EBV-associated B-cell Lymphomas. The virus typically infects CD20-expressing B-cells,² and the application of anti-CD20 monoclonal antibodies in people living with MS may also affect cells which are infected with EBV. 

Currently there are no EBV-specific treatments available. There have been many efforts to develop a vaccine to protect against infection with EBV, but none of them have been successful in practice.¹⁰

How would a vaccine help people already infected with EBV?

How would a vaccine against EBV work?

During an infection, specialized immune cells will develop an ability to recognize and respond to motifs which are specifically associated with the presence of a pathogen, called antigens. This is a normal part of a healthy immune response, called adaptive immunity. Adaptive immunity is extremely important for the successful resolution of an infection, and it protects against reinfection with the same pathogen. Vaccination exposes the immune system to an antigen to “train” the adaptive immune system to recognize and respond to that antigen without getting sick in the first place. There are many kinds of vaccines- some of which use strains of a pathogen which do not cause sickness and others that contain an antigen or cause the expression of antigen. However, regardless of the type of vaccine, a successful vaccination will result in the development of antibodies against and immune cells which recognize the antigen which was present in the vaccine.

Conventionally, vaccination has been used as a prophylactic, or a treatment which would prevent a person from getting infected. Vaccines against EBV have been designed for this application and have historically been unsuccessful. However, researchers have recently released the broader potential of vaccination as a method of harnessing the body’s endogenous ability to kill dangerous cells. Cancer vaccines have been successfully applied in preclinical models, where an antigen which is specific to the tumor is injected to improve the ability of the immune system to kill cancer cells.¹² Applying a vaccine against EBV to someone already infected with EBV would work in a similar way; rather than preventing someone from becoming infected with EBV, it would enable immune cells to recognize and kill cells that express an antigen associated with EBV. 

A critical consideration in vaccine design is the selection of which antigen(s) to target. Importantly, in healthy people, EBV is maintained in the deepest stage of latency, called Latency 0, where there is virtually no production of viral antigens.² It is difficult to imagine a vaccine capable of inducing immunity against cells where EBV is in Latency 0. In the lytic phase and other stages of latency, there are many EBV antigens could be used in a vaccine. During the lytic phase, the virus induces the expression of over 80 proteins.¹³ In contrast, even during the most active stage of latency, there are only 9 viral proteins which are expressed. When considering which latency proteins to target, EBNA1 would likely be excluded as a candidate antigen in a conservative approach to vaccine design. This is due to the molecular mimicry of EBNA1 and the myelin sheath, though anti-EBNA1 antibodies are detectable in people without MS, making it unclear exactly how risky vaccination with an EBNA1-based antigen would be in practice.¹⁴Besides EBNA1, there are eight other EBV latency proteins which could be targeted. These are the proteins EBNA2, EBNA-3A/B/C, and EBNA-LP, which are all expressed in the nucleus of the cell. LMP1 and LMP2A/B are expressed on the surface of the cell, which is exposed to immune cells, and thus these proteins would theoretically be prime candidates for vaccination targets, but the biological effect and structure of these proteins complicate matters.²Overall, while there are just nine EBV latency proteins which could be targeted via vaccination, currently there is no consensus on which protein is the optimal immunogenic target. 

How could a vaccine against EBV help people living with MS?

Generally, a successful vaccination against EBV would either prevent initial infection with EBV or kill cells which are infected with EBV. The mechanism of how EBV contributes to the development and progression of MS remains unclear. Therefore, it is impossible to know exactly how a vaccine against EBV would help people who already have MS. Additionally, vaccines may have different effects dependent upon which antigen(s) are selected. 

In one proposal, autoreactive antibodies against the EBV protein EBNA1 also target the myelin sheath and cause demyelination to occur. In the later stages of latency and the lytic phase, expression of EBNA1 is magnified, which would promote the activation and proliferation of immune cells which are responsive to EBNA1. Cells which make up the myelin sheath could be bystanders that are increasingly destroyed as immune cells initiate a response to EBNA1.^15,16 EBV infection may promote sustained, low-grade inflammation against many different viral antigens which promotes the development of autoimmune disease.¹⁵ Vaccination against a viral antigen which is produced during later, more active stages of latency could reduce the scale of a pro-inflammatory event by triggering a more rapid and complete response to the virus. 

Recent research using cells isolated from people with MS during a disease flare-up suggests that people with MS may have dysregulation of the lytic phase of EBV.¹⁷ Pro-inflammatory signaling proteins, called cytokines, are produced by host cells in response to the virus. If the lytic phase of EBV is important in MS progression, a vaccine which targets lytic EBV could reduce MS flare-ups or slow disease progression by reducing the scale of lytic reactivation and the associated production of pro-inflammatory cytokines. 

Another potential mechanism for the association between EBV and MS is explained by the discovery that cells infected with EBV can escape the biological processes which normally prevent the survival of immune cells that recognize self-antigen.¹⁸ These EBV-infected cells could then activate even uninfected immune cells to cause a cascade of aberrant inflammation which drives autoimmune disease. In this case, vaccination against a viral antigen would be impactful because it would kill the cells which respond to self-antigen and drive demyelination. However, if these cells are in Latency 0, it is unlikely that vaccination against EBV would be a successful treatment on its own.

While researchers don’t yet fully understand how EBV contributes to the development and progression of MS, if a vaccine against EBV proves to have therapeutic value to people living with MS, it is not critical to understand exactly how the vaccine works. In fact, there are many FDA-approved medications, including some of the treatments for MS, which are incompletely understood. Rather, scientists can continue their research to better understand and develop improved treatments for MS while people living with MS benefit from any effective and safe treatments. 

Who else could potentially benefit from a vaccine against EBV?

            EBV has been linked to many different autoimmune disorders. These include Systemic Lupus Erythematosus, Rheumatoid Arthritis, Sjögren’s syndrome, and others. However, EBV was first identified as an oncogenic virus and continues to drive the development of many cancers. These include the Burkitt Lymphoma, Diffuse Large B-Cell Lymphoma, NK/T- cell Lymphoma, Gastric Adenocarcinoma, Nasopharyngeal Cancer, and many other cancers. In fact, an estimated 1.3-1.9% of all cancers worldwide can be attributed to EBV.² Therefore, a vaccine which prevents EBV infection or selectively kills EBV-infected cells has the potential to benefit millions of people with many different diseases. 

What are the details of the ongoing Moderna clinical trials testing EBV vaccines?

Currently, Moderna is performing three different clinical trials to test two different vaccines against EBV, mRNA-1195 and mRNA-1189. In April 2025, Moderna initiated the Horizon Trial, a Phase II clinical trial testing mRNA-1195 in people with Multiple Sclerosis.¹ Simultaneously, mRNA-1195 is being tested in healthy adults in a Phase I clinical trial, the Equinox Trial, which was initiated in 2023 and is currently active but no longer recruiting.¹⁹ mRNA-1189 is being tested in the Eclipse Trial, where it is currently in Phase I/II development to adolescents aged 10-21.²⁰

What are the mRNA-1195 and mRNA-1189 vaccines?

In 2021, Moderna announced the development of the mRNA-1195 and mRNA-1189 vaccines targeting EBV. mRNA-1195 was intended to be used in people already infected with EBV while mRNA-1189 was developed as a prophylactic vaccine to prevent EBV infection. ²¹ Both vaccines are mRNA vaccines which act by inducing the expression of the antigen in a person’s cells. The most widely known application of mRNA vaccines are vaccines against COVID, such as the one developed by Moderna, though mRNA vaccines have been in clinical trials since 2013.²² mRNA-1189 and mRNA-1195 both contain antigens for five different EBV lytic proteins^23,24 and mRNA-1195 contains additional antigens from undisclosed EBV latency proteins.²⁴

The antigens contained in the vaccine, gH, gL, gB, gp42, and gp350 are expressed in cells during the lytic phase but primarily are on the surface of the virus, or the EBV envelope. EBV relies on these proteins to initially infect a cell. They bind to host proteins on the cell surface to triggere the engulfment of the virus or fusion of the EBV envelope with the cell.² Antibodies against these viral proteins physically block the interaction of these viral proteins with host proteins on the surface of the cell, thus blocking EBV from entering the cell to establish infection. 

Historically, vaccines against EBV have largely targeted the lytic protein gp350.¹⁰ However, while gp350 is abundantly expressed on the surface of EBV, it has proven to be unsuitable as a singular target for vaccination.¹⁰ This is likely because EBV infects both epithelial and immune cells, but relies on different viral/host protein interactions to enter the cell. The EBV proteins gp350 and gp42 interact with host proteins primarily expressed by immune cells and generally not expressed by epithelial cells. Resultingly, vaccination against gp350 or gp42 may protect B-cells from infection with EBV but it does not block the infection of epithelial cells. Excitingly, mRNA-1189 and mRNA-1195 also contain additional antigens against the viral proteins gH, gL, and gB. These proteins are critical for the infection of both epithelial and immune cells.² Therefore, mRNA-1189 and mRNA-1195 both improve upon the historical standard by incorporating antigens which are important for epithelial cell infection.

What are the details of the Horizon Trial for mRNA-1195 in people with MS?

The Horizon Trial is currently recruiting an estimated 180 people between the ages of 18-55 with MS who are willing to undergo vaccination with mRNA-1195. The study will assess the safety, tolerability, and efficacy of the vaccine at controlling EBV infection as well as its therapeutic potential for preventing disease relapse in people living with MS. The trial will last approximately 30 months. Each person will receive three injections with either the vaccine or a placebo in their upper arm. Two different doses of the vaccine will be tested on a 0-, 2-, and 6-month schedule. 

The efficacy of the vaccine will be determined by quantifying the in antibodies which neutralize B-cells and/or bind to the antigen of the vaccine. Both the abundance of antibodies and the change in antibody levels over time will be assessed. To determine the ability of the vaccine to block relapse, MRIs will be performed to detect the presence of new or worsening lesions in the brain and the time between MS flare-ups compared between the group which is vaccinated and the group which received the placebo. Patients will also undergo neurological exams to measure the severity of MS symptoms. The estimated primary completion date is in January, 2029.¹

Both the Equinox and Eclipse trial are estimated to reach completion later this year, in October, 2026.^{19, 20} The results of these studies, which are focused just on the safety, tolerability, and efficacy of the mRNA-1195 and mRNA-1189 vaccines, respectively, should also indicate if the Horizon trial has any promise.

Will a vaccine against EBV be effective?

Overall, while vaccination against EBV has therapeutic potential, there are many hurdles to the development of a vaccine. These include difficult decisions regarding what antigen(s) should be targeted by vaccination as well as questions of the actual efficacy of any vaccine. While the first EBV vaccine was in clinical trials over 30 years ago, so far, no EBV vaccine has been successful at preventing infection with the virus. However, a successful EBV vaccine has the potential not just to help people living with MS, but also to prevent millions of cancer cases and improve the lives of people with other autoimmune diseases, especially considering there are currently no EBV specific treatments available. Therefore, the potential benefits of an EBV vaccine make these investigations worthwhile, despite the historical difficulty in targeting this common virus.

Glossary:

Multiple Sclerosis (MS): A neurodegenerative disorder driven by autoimmune destruction of the myelin sheath. It is typically diagnosed in early adulthood. Symptoms are impaired motor and sensory function and are progressive. There is no cure for MS. 

Neurodegenerative disorder: A disease caused by destruction of neurons.

Autoimmune disorder: A disease caused by abnormal activity of the immune system negatively impacting healthy cells.

Demyelination: The destruction of the myelin sheath and the physiological change which causes MS symptoms.

Myelin Sheath: The fatty coating along the axon which protects the axon from damage and allows the electrical signal to travel quickly without degradation.

Neurons: Specialized nerve cells which sense the environment, control muscle movement, and are responsible for communication between the brain and the body.

Disease Modifying Therapies (DMTs): Treatments which aim to stop the progression of a disease by targeting the underlying cause.

Plasma: The liquid component of blood which contains soluble factors that can promote inflammation.

B-cell: A type of immune cell which produces antibodies and plays a supportive role in immunity. Also the type of cell that EBV primarily infects.

T-cells: A specialized immune cell, most well-known as the cells which monitor for dangerous cells, like a cancer cell or a virus-infected cell, by checking the proteins expressed in that cell.

Anti-CD20 Monoclonal Antibody Therapy: A treatment which is used to help people with MS as well as treat some B-cell Lymphomas, including one which are EBV-positive. These treatments target B-cells and result in their clearance by the immune system. 

Epstein-Barr Virus (EBV): A common virus which causes a lifelong infection and has been linked to many different cancers and autoimmune disorders. There are no EBV vaccines or specific treatments available.

Lytic: The phase of the viral lifecycle during which most viral proteins are produced and which, if successfully completed, results in the production of more virus. This phase is essential for the transmission of virus from person to person. 

Latent: The phase in the viral lifecycle where the virus is largely inactive. EBV spends the majority of its lifecycle in this phase.

Adaptive Immunity: An immune response which develops over a prolonged period of time that is specific to a particular antigen. The adaptive immune response blocks the same pathogen from reinfecting an organism and is also important in the effective clearance of an infection. Vaccines aim to produce an adaptive immune response.

Antigen: A substance which produces an immune response. In this context, an antigen is a component of a vaccine.

Prophylactic: A treatment which is given to prevent the development of a disease.

Latency 0: The deepest stage of EBV latency, during which there is virtually no production of viral proteins. In healthy people, the virus will persist in this stage of latency for the majority of the time.

EBNA1: A critical viral protein which enables the replication of the virus and the maintenance of the virus in a cell. Antibodies against this viral protein have been implicated in the development of MS.

Molecular mimicry: The phenomenon of a foreign antigen from an infectious agent having structural similarity to a protein normally produced in healthy cells. 

Latency proteins: In the context of EBV, the latency proteins are EBNA1, EBNA2, EBNA-3A/B/C, EBNA-LP, LMP1, LMP2A/B. 

Autoreactive: A descriptor for immune cells which recognize and react to self-antigen. They are associated with autoimmune diseases.

Cytokines: Compounds produced by the immune system which modulate the inflammatory response.

mRNA-1195: One of two EBV vaccines developed by Moderna and in clinical trials. mRNA-1195 contains antigens for undisclosed latency proteins and five lytic proteins which mediate the entry of EBV into a cell. This vaccine theoretically targets cells already infected with EBV if they exit Latency 0 as well as block the transmission of EBV. 

mRNA-1189: One of two EBV vaccines developed by Moderna and in clinical trials. mRNA-1189 contains antigens for five lytic proteins which mediate the entry of EBV into a cell. This vaccine theoretically blocks the transmission of EBV.

Horizon Trial: The Phase II Moderna clinical trial testing mRNA-1195 in people with Multiple Sclerosis. This trial is currently recruiting participants.

Equinox Trial: The Phase I Moderna clinical trial testing mRNA-1195 in healthy adults. This trial is active but no longer recruiting.

Eclipse Trial: The Phase I/II clinical trial evaluating mRNA-1189 in adolescents aged 10-21. This trial is active but no longer recruiting.

mRNA vaccine: A type of vaccine which contains “instructions” for a cell to produce an antigen rather than a segment of peptide, such as the Covid-19 vaccine produced by Moderna.

Lytic Proteins: In the context of EBV, there are over 80 proteins which are produced during the lytic phase. Most vaccines have targeted the lytic protein gp350, which EBV uses to attach to and then infect B-cells. mRNA-1189/1195 contain antigens for the lytic proteins gp350 and gp42, which mediate attachment and are involved in the infection of B-cells. They also contain antigens for the lytic proteins gH, gL, and gB, which mediate fusion of the EBV envelope with both epithelial cells and immune cells.

EBV envelope: A coating on the surface of the EBV virus which contains lipids (fatty chains) and proteins. During infection, the EBV envelope will fuse with membranes on the host cell which are made from the same material, allowing the core of the virus to enter into the cell and intiate infection. 

Epithelial cells: A broad term which refers to the class of cells that line the body and protect it from the environment. In the context of EBV infection, epithelial cells which are important are those of the tonsil, mouth, and stomach lining. 

References:

1. A Study to Investigate Multiple Sclerosis Relapse Prevention With mRNA-1195 Compared With Placebo in Participants Aged 18 to ≤55 Years. Clinicaltrials.gov. Published 2025. https://clinicaltrials.gov/study/NCT06735248?rank=1
2. Damania B, Kenney SC, Raab-Traub N. Epstein-Barr virus: Biology and clinical disease. Cell. 2022;185(20):3652-3670. doi:10.1016/j.cell.2022.08.026
3. Boutitah-Benyaich I, Eixarch H, Villacieros-Álvarez J, et al. Multiple sclerosis: molecular pathogenesis and therapeutic intervention. Signal Transduct Target Ther. 2025;10(1):324. Published 2025 Oct 2. doi:10.1038/s41392-025-02415-4
4. Mayo Clinic. Multiple sclerosis. Mayo Clinic. Published November 1, 2024. https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/diagnosis-treatment/drc-20350274
5. Empowering people affected by MS to live their best lives. National Multiple Sclerosis Society. Published 2025. https://www.nationalmssociety.org/managing-ms/treating-ms/treatments-and-medications
6. Bar-Or A, Pachner A, Menguy-Vacheron F, Kaplan J, Wiendl H. Teriflunomide and its mechanism of action in multiple sclerosis. Drugs. 2014;74(6):659-674. doi:10.1007/s40265-014-0212-x
7. Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol. 2010;33(2):91-101. doi:10.1097/WNF.0b013e3181cbf825
8. Selewski DT, Shah GV, Segal BM, Rajdev PA, Mukherji SK. Natalizumab (Tysabri). AJNR Am J Neuroradiol. 2010;31(9):1588-1590. doi:10.3174/ajnr.A2226
9. Kenney SC. Reactivation and lytic replication of EBV. In: Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007. Chapter 25. Available from: https://www.ncbi.nlm.nih.gov/books/NBK47442/
10. Khanna R, Cohen JI. Prophylactic and Therapeutic EBV Vaccination. Curr Top Microbiol Immunol. Published online June 7, 2025. doi:10.1007/82_2025_308
11. U.S. Department of Health and Human Services. Vaccine Basics. HHS.gov. Published April 26, 2021. https://www.hhs.gov/immunization/basics/index.html
12. Zaidi N, Jaffee EM, Yarchoan M. Recent advances in therapeutic cancer vaccines. Nat Rev Cancer. 2025;25(7):517-533. doi:10.1038/s41568-025-00820-z
13. Steven NM, Annels NE, Kumar A, Leese AM, Kurilla MG, Rickinson AB. Immediate early and early lytic cycle proteins are frequent targets of the Epstein-Barr virus-induced cytotoxic T cell response. J Exp Med. 1997;185(9):1605-1617. doi:10.1084/jem.185.9.1605
14. Vietzen H, Kühner LM, Berger SM, et al. Early identification of individuals at risk for multiple sclerosis by quantification of EBNA-1_381-452-specific antibody titers. Nat Commun. 2025;16(1):6416. Published 2025 Jul 14. doi:10.1038/s41467-025-61751-9
15. SoRelle ED, Luftig MA. Multiple sclerosis and infection: history, EBV, and the search for mechanism. Microbiol Mol Biol Rev. 2025;89(1):e0011923. doi:10.1128/mmbr.00119-23
16. Lanz TV, Brewer RC, Ho PP, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022;603(7900):321-327. doi:10.1038/s41586-022-04432-7
17. Soldan SS, Su C, Monaco MC, et al. Multiple sclerosis patient-derived spontaneous B cells have distinct EBV and host gene expression profiles in active disease. Nat Microbiol. 2024;9(6):1540-1554. doi:10.1038/s41564-024-01699-6
18. Younis S, Moutusy SI, Rasouli S, et al. Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus. Sci Transl Med. 2025;17(824):eady0210. doi:10.1126/scitranslmed.ady0210
19. A Clinical Trial of an Epstein-Barr Virus (EBV) Vaccine in Young Adults. Moderna Clinical Trials. https://trials.modernatx.com/study/?id=mRNA-1189-P101
20. A Clinical Trial of an EBV Vaccine for Healthy Adults. Moderna Clinical Trials. Published 2026. Accessed March 2, 2026. https://trials.modernatx.com/study/?id=mRNA-1195-P101
21. Moderna Reports Third Quarter Fiscal Year 2021 Financial Results and Provides Business Updates. BioSpace. Published November 4, 2021. Accessed March 2, 2026. https://www.biospace.com/moderna-reports-third-quarter-fiscal-year-2021-financial-results-and-provides-business-updates
22. Beyrer C. The long history of mRNA vaccines. publichealth.jhu.edu. Published October 6, 2021. https://publichealth.jhu.edu/2021/the-long-history-of-mrna-vaccines
23. Moderna, Inc. Form 10-K. United States Securities and Exchange Commission, 2020. https://www.sec.gov/Archives/edgar/data/1682852/000168285221000006/mrna-20201231.htm  
24. Moderna, Inc. Form 10-K. United States Securities and Exchange Commission, 2024. https://www.sec.gov/Archives/edgar/data/1682852/000168285225000022/mrna-20241231.htm

Author: Tiffany Peters

Editor: Joe Krzeski

Menopause and its associated symptoms

The definition of menopause has evolved over the past 20 years. Menopause has been defined as the moment one year after menstrual flow has stopped [1]. It can also be defined as the point of a woman’s very last period [2,3], but the actual event of a final period can be hard to predict and/or recognize for a number of reasons. Perimenopause is a years-long process characterized by anovulatory and irregular cycles, and vaginal bleeding during this time is not exclusively a symptom of menstruation [3].

Menopause generally occurs in a woman’s 50’s with a perimenopausal period of up to 7.5 years on average [1-3]. Associated symptoms typically include genito-urinary syndrome (GSM: vaginal dryness, burning, itching, and pain), sleep and mood dysregulation, changes in sexual behaviour,  and very commonly, vasomotor symptoms, which manifest as hot flashes and/or night sweats. Predictably, at least half of the global population will at some point in their lives experience menopause, though not all symptoms will occur and not all with equal severity. Treatment for menopause symptoms is considered a highly individual decision and should be decided on with substantial input from the patient regarding the level of stress menopause causes [1].

Cognitive symptoms have also been observed during perimenopause and menopause [3], though there should be a distinction noted between subjective reports from patients and objective data from standardized tests of cognitive function, with subjective reports marked by increased severity. Reduced memory, attention, and concentration have been reported, while subtle reductions in learning and processing speeds have been gleaned from testing during perimenopause, though it must be noted that these can be conflated with the common symptoms of aging regardless of sex. Sometimes, cognitive reductions are actually corrected without intervention once a patient transitions beyond perimenopause into postmenopause.

State-of-the-art therapy for menopause treatment 

On average, the most prevalent and ‘bothersome’ [1-3] of all the symptoms mentioned above are vasomotor symptoms which affect, by some estimates, up to 80% [4-6] of perimenopausal women. As menopause is the result of a natural decline over time in ovarian function and consequently in oestrogen and progesterone production, a typical course of treatment is hormone therapy (HT) [1-5] which typically includes oestrogen (and sometimes progestin) in the form of oestradiol with a dose in concordance to the intensity of the hot flashes. If needed, testosterone is administered in parallel when sexual dysfunction is a major concern for the patient. HT is associated with risks of breast, endometrial, and other cancers with tumors that express oestrogen receptors, blood clots, and cardiovascular indications; the inclusion of testosterone carries additional risks of alopecia, acne, and weight gain [2].

The overwhelming majority of current treatments for menopause associated with VMS is hormonal, with over twenty brand name treatments with oestradiol as the active ingredient existing in a multitude of forms, including pills, patches, and topical creams [7]. Non-hormonal treatments for VMS, prior to 2023 [8], consisted of repurposed drugs such as SSRIs (antidepressants such as Paroxetine [9], which in 2013 received FDA approval for treatment of VMS) or anticonvulsants [10] that were less effective and higher risk than HT. Further nonhormonal treatments for the symptoms of menopause have maintained pharmaceutical R&D interest as many patients have contra-indications that preclude the use of HT. 

Novel treatments

In 2023, Veozah (generic name fezolinetant) was introduced by Astellas Pharma as the first successful, non-hormonal, de novo drug development effort for menopause associated vasomotor symptoms. Since then, in October of 2025, Bayer Health Care Pharmaceuticals similarly enjoyed the success of an FDA stamp of approval on Lynkuet (generic name elizanetant). Through dual inhibition of neurokinin NK1 and NK3 receptors, Lynkuet blocks neurokinin B (NKB) binding, resulting in decreased stimulation of thermoregulatory warm sensitive and GnRH (gonadotropin releasing hormone) neurons (Figure 1) [8]. Veozah, in contrast, is a selective inhibitor of NK1 only. NKB, which is overexpressed in menopausal women [11] , increases activation of NK receptors on thermoregulatory neurons triggering heat defense mechanisms [12]. These mechanisms include vasodilation and sweating, which give rise to hot flashes. 

FDA approval of Lynkuet was given on the basis of three Phase III clinical trials: two twenty-six week long trials to determine efficacy with placebo control only in the first twelve weeks, and a fifty-two week long study focused on safety was conducted on 628 patients, randomized to placebo and treatment groups for the entire duration [12, 13]. Just over 1400 participants were involved across all three studies. The primary endpoints were a reduction in frequency of hot flashes for the treatment group as compared to placebo, with sleep disturbance and menopause related quality of life as secondary and exploratory endpoints. Lynkuet was found to significantly reduce VMS frequency as well as increase quality of life. Side effects included headache, fatigue, and drowsiness, with headache only observed in the Lynkuet trials. The dual inhibitory nature of Lynkuet as compared to Veozah may be responsible for Lynkuet’s more potent effect in improving sleep quality in menopausal women [14]. 

Concluding remarks

Over the past 9 years, significant progress has been made since the first in vivo human study showing that NK3 inhibition reduces hot flashes [15]. Menopause is an inevitability for 50% of the global population and results in uncomfortable symptoms for which hormonal intervention is not suitable for a sizable fraction of patients. The advent of FDA approved NK3 inhibitory drugs, first with fezolinetant, an NK3 inhibitor, in 2023 and now elinzanetant, dual NK3 and NK1 inhibitor,  in 2025 ushers in a more comfortable and approachable era of late-stage life for women.

References

1. Greendale, Gail A., Nancy P. Lee, and Edga R. Arriola. The Menopause. The Lancet 353, no. 9152 (1999): 571-80. 
2. Roberts, Helen, and Martha Hickey. Managing the Menopause: An Update. Maturitas 86 (2016/04/01/ 2016): 53-58. 
3. Thurston, Rebecca C., Holly N. Thomas, Alana J. Castle, and Carolyn J. Gibson. Menopause as a Biological and Psychological Transition. Nature Reviews Psychology 4, no. 8 (2025): 530-43. 
4. D.F. Archer, D.W. Sturdee, R. Baber, T.J. de Villiers, A. Pines, R.R. Freedman, et al., Menopausal hot flushes and night sweats: where are we now, Climacteric 14 (2011) 515–528.
5. Sassarini, Jenifer, and Richard A. Anderson. Elinzanetant: A Phase Iii Therapy for Postmenopausal Patients with Vasomotor Symptoms. Expert Opinion on Investigational Drugs 33, no. 1 (2024): 19-26.Hager, Marlene, Tal Goldstein, Victoria Fitz, and Johannes Ott. Elinzanetant, a New Combined Neurokinin-1/-3 Receptor Antagonist for the Treatment of Postmenopausal Vasomotor Symptoms.”Expert Opinion on Pharmacotherapy 25, no. 7 (2024): 783-89. 
6. FDA, Menopause: Medicines to help you. Published online 08/22/2019
7. Comninos, Alexander N., and Waljit S. Dhillo. Neurokinin 3 Receptor Antagonism for Menopausal Hot Flashes. Cell 186, no. 16 (2023): 3332-32.e1. 
8. Rahimzadeh  P, Nafissi  N, Ebrahimi  B, Faiz SHR. Comparison of the effects of stellate ganglion block and paroxetine on hot flashes and sleep disturbance in breast cancer survivors. Cancer Manag Res 2018; 10:4831–4837.
9. Guttuso  T  Jr., Kurlan  R, McDermott  MP, Kieburtz  K. Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol 2003; 101(2):337–345
10. Rance NE, Young WS. Hypertrophy and increased gene expression of neurons containing neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of postmenopausal women. Endocrinology. 1991 May;128(5):2239–2247
11. Dacks, P.A., Krajewski, S.J., Rance, N.E. (2011). Activation of neurokinin 3 receptors in the median preoptic nucleus decreases core temperature in the rat. Endocrinology 152, 4894–4905. 10.1210/en.2011-1492
12. Panay, Nick, Hadine Joffe, Pauline M. Maki, Rossella E. Nappi, JoAnn V. Pinkerton, James A. Simon, Claudio N. Soares, et al. “Elinzanetant for the Treatment of Vasomotor Symptoms Associated with Menopause: A Phase 3 Randomized Clinical Trial.” JAMA Internal Medicine 185, no. 11 (2025): 1319-27. 
13. Pinkerton, JoAnn V., James A. Simon, Hadine Joffe, Pauline M. Maki, Rossella E. Nappi, Nick Panay, Claudio N. Soares, et al. “Elinzanetant for the Treatment of Vasomotor Symptoms Associated with Menopause: Oasis 1 and 2 Randomized Clinical Trials.” JAMA 332, no. 16 (2024): 1343-54.
14. Artur Menegaz de Almeida, Paloma Oliveira, Lucca Lopes, Marianna Leite, Victória Morbach, Francinny Alves Kelly, Ítalo Barros, Francisco Cezar Aquino de Moraes, and Alexandra Prevedello. “Fezolinetant and Elinzanetant Therapy for Menopausal Women Experiencing Vasomotor Symptoms: A Systematic Review and Meta-Analysis.” Obstetrics & Gynecology 145, no. 3 (2025): 253-61. 
15. Prague, J.K., Roberts, R.,E., Comninos, A.N., Clarke, S.A., Jayasena, C.N., Nash, Z., Doyle, C., Papadopoulou, D.A., Bloom, S.R., Mohideen, P., et al. (2017). Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 389, 1809-1820.

Author: Caryssa Drinkuth

Editor: Meghan Diefenbacher

Overview of Fibrodysplasia Ossificans Progressiva (FOP):

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, debilitating genetic disorder that affects an estimated 1 in 1.14 million people living in the United States.¹ FOP is characterized by heterotopic ossification (HO), a process by which extra skeletal bone progressively and irreversibly develops in muscles, tendons, and ligaments.¹ Episodes of HO begin in early childhood, often accompanied by symptoms including swelling, pain, stiffness, and lethargy. HO generally occurs in a characteristic and progressive anatomic pattern, beginning along the upper back and neck, though flare-ups of HO may also occur across the body in response to inflammation, influenza-like illnesses, intramuscular immunizations, or blunt soft-tissue trauma from bruises or falls.^1,2 By the third decade of life, individuals with FOP are typically wheelchair bound and require assistance with daily activities^1,3. Over time, accumulation of HO masses results in permanent loss of mobility and difficulty with breathing and eating, often resulting in reduced quality of life and reduced life expectancy.⁴ Thoracic insufficiency syndrome (TIS) resulting from HO masses surrounding the chest wall, preventing proper breathing, is the leading cause of premature death in individuals with FOP, with a median life expectancy of 56 years.^3,5

Given that FOP is highly reactive to soft-tissue trauma, surgical interventions to remove HO masses are not possible, presenting a significant challenge for FOP management.⁴ In August 2023, Ipsen Biopharmaceutical’s Sohonos® (palovarotene) became the first and only FDA-approved oral treatment to block new HO formation in adult and pediatric individuals with FOP, representing a significant step forward in the treatment and management of FOP.⁶ 

Pathology:

Underlying Genetic Cause: While most genetic diseases are caused by specific mutations passed on from parent to child, the mutations causing the development of FOP emerge spontaneously in patients with no prior family history of the disease.^2,7 The cause of the spontaneous mutations is unknown and is not associated with any particular sex, race, ethnicity, or environmental factors.¹ Notably, the same single-nucleotide mutation (ACVR1^R206H) in ACVR1, a gene encoding Activin A receptor type I (also known as activin-like kinase 2 (ALK2)), is observed in approximately 97% of patients identified with FOP.^1,8

Normal BMP Signaling: ACVR1/ALK2 plays a key role in the regulation of bone morphogenic protein (BMP) signaling, essential for embryonic and postnatal bone and cartilage formation.^8,9 Under normal conditions, BMPs bind to and activate the ACVR1 receptor.⁴ The activated receptor binds to and phosphorylates (adds a phosphate group to, to “activate”) intracellular BMP-responsive transcription factors known as SMADs (SMAD1/5/8).^2,4,10 Phosphorylated SMAD(1/5/8) forms a complex with SMAD4 before entering the nucleus and acting to activate or repress the transcription of genes involved in cartilage formation (chondrogenesis) and bone formation (osteogenesis).¹⁰ In the absence of BMPs, Activin A binds to ACVR1 to block BMP signaling, preventing inappropriate cartilage or bone formation (Figure 1).^10,11 Activin A inhibition allows normal ACVR1/BMP signaling to be tightly controlled, only becoming activated at appropriate developmental or repair stages.

BMP Signaling in FOP: In FOP, inflammatory flares, infection, or tissue damage are thought to recruit ACVR1^R206H expressing fibro/adipogenic progenitors (FAPs), the major cell type of origin in HO, to the site of injury.^12,13 In these FAPs, the ACVR1^R206H mutation causes leaky activity of ACVR1, whereby ACVR1/BMP signaling becomes activated even in the absence of BMP ligands. The ACVR1^R206Hmutation also increases ACVR1’s sensitivity to BMPs, such that lower levels of BMP ligand result in greater downstream signaling.¹⁰Furthermore, the ACVR1^R206H  mutation sensitizes ACVR1 to Activin A in a process referred to as neo-receptorization.⁸ In neo-receptorization, the normally inhibitory “stop” signal (Activin-A) flips into a stimulatory “go” signal, resulting in persistent activation of BMP signaling (Figure 1).  Both the loss of inhibition and sensitization to activation of ACVR1/BMP signaling result in inappropriate downstream changes in gene transcription, causing the FAPs to reprogram and differentiate into cartilage cells (chondrocytes), and later into bone-forming cells (osteoblasts) that form HO masses (Figure 2).^4,12,13 This process is further aggravated in a less-well-known manner by inflammation and hypoxia (low cellular oxygen levels), promoting further heterotopic bone formation in response to injury or infection.³

Diagnosis & Treatments:

Diagnostic Challenges: Because injuries exacerbate FOP, early detection and diagnosis are extremely important to avoid risky and unnecessary surgical procedures that may only worsen disease progression. Unfortunately, since FOP is an ultra-rare genetic disorder, clinicians are often unfamiliar with the disease or may attribute the symptoms to other causes, which can significantly delay clinical diagnosis and proper treatment. For instance, it takes about 5-6 years on average for patients to receive a FOP diagnosis.³ Additionally, approximately 90% of FOP patients are misdiagnosed, and a striking 67% of individuals with FOP undergo unnecessary surgical procedures that result in permanent harm or lifelong disability.¹⁴ Increasing clinician awareness of the classical features of FOP represents the most important step towards prompt clinical diagnosis. For instance, congenital malformation of the big toes, present in all individuals with FOP, is a unique and easily identifiable feature that can allow for quicker clinical diagnosis at earlier stages of the disease.^7,14Furthermore, given that the same single mutation (ACVR1^R206H ) is observed in most FOP patients, FOP is particularly suited to clinical genetic testing.¹⁴ Increased clinician awareness of the association between congenital big toe malformation and signs of early soft-tissue flare-ups or HO will be necessary to accelerate clinical diagnosis and prevent harms related to unnecessary medical procedures. 

Disease Monitoring: Monitoring FOP disease progression is a significant challenge given the lack of blood tests or adequate tissue markers to measure disease severity. The cumulative analogue joint involvement scale (CAJIS), which classifies 15 joints into categories of functional, partially functional, or nonfunctional, is a simple scoring system developed to evaluate and monitor changes in a patient’s functional mobility.³ In addition, CT-scan can be used to accurately quantify heterotopic bone volume in patients with FOP, though it cannot assess bone that is still being formed.³

Current Treatments: Current treatment approaches for individuals with FOP focus on preventing soft-tissue injury and maintaining pulmonary function through the use of deep breathing exercises.³ Anti-inflammatory drugs, including high-dose corticosteroids, are often prescribed after traumatic injury or at the start of HO flare-ups.^3,4 While approximately 31% patients with FOP reported an improvement of their symptoms following corticosteroid use, all evidence for corticosteroid treatment for FOP is anecdotal, and there are currently no clinical studies to evaluate the effects of corticosteroids on heterotopic bone volume.³

Non-Pharmacological Support: FOP progression, including pain from HO flare-ups, HO accumulation, and reduced mobility, may also diminish self-reported emotional health and quality of life in individuals with FOP.¹⁵ Psychological support and family therapy are recommended for patients and family members of patients diagnosed with FOP.¹⁶ FOP support groups, including the International Clinical Council on FOP (ICCFOP), International FOP Association (IFOPA), and country-specific support groups, provide safe spaces for individuals affected by FOP to share their experiences and challenges and connect with the global community.

Mechanism of Action:

Sohonos® (palovarotene), developed by Ipsen Biopharmaceuticals, Inc., is the first and currently only FDA-approved medication to reduce new bone formation (HO) in individuals with FOP. Palovarotene is a synthetic selective retinoic acid receptor γ (RARγ) agonist.⁴ It is well known that interactions of retinoids, biologically active vitamin A derivatives, at RARs serve an essential role in normal embryogenesis and post-natal growth. RARs are repressed in the absence of active retinoids and activated in the presence of active retinoids.⁴  Preclinical studies have revealed that RAR repression (occurring in the absence of retinoids), particularly involving RARγ, is essential for chondrogenesis.⁴ These initial preclinical findings led to the idea that the administration of a RARγ agonist, such as palovarotene, would disrupt RAR repression to prevent chondrogenesis and block HO formation in individuals with FOP. Indeed, palovarotene has been shown to reduce HO by acting on several key steps. Palovarotene is thought to primarily inhibit BMP signaling by degrading SMAD1/5/8.^4,13 By degrading SMAD1/5/8, palovarotene inhibits the ACVR1/BMP signaling pathway, reducing expression of genes necessary for chondrogenesis. Palovarotene may also interfere with the recruitment of FAPs (Figure 2).⁴ Together, these effects may serve to counter new HO formation in individuals with FOP.

Clinical Trial:

Trial Overview and Dosing: The safety and efficacy of palovarotene were tested in MOVE, a multicenter, single-arm, open-label, phase III clinical trial.^4,17 Data from participants in the MOVE trial were compared to data from FOP NHS participants who were not treated beyond the standard of care. The principal enrolled population included 99 individuals with the pathogenic ACVR1^R206H variant ≥4 years old who had not experienced flare-up symptoms for at least 4 weeks before enrollment, nor received vitamin A or synthetic oral retinoids other than palovarotene before screening.¹⁷ Participants were instructed to take 5 mg oral palovarotene daily (chronic dosing) or 20 mg daily for 4 weeks, followed by 10 mg daily for 8 weeks at the onset of HO flare-ups. Both chronic and flare-up dosing were weight-adjusted for skeletally immature participants (bone age <12 years in females and <14 years in males).¹⁷ 

Efficacy of Palovarotene: Efficacy outcomes included assessments of functional mobility on the CAJIS at baseline and every 6 months of MOVE, as well as annualized change in new HO volume assessed by whole body CT-scan from baseline to every 6 months of MOVE.^4,17At 12 months, the MOVE study was paused- statistical analyses failed to exhibit efficacy for palovarotene treatment at this timepoint. However, a review performed by the independent data safety monitoring board (DSMB) revealed that the prespecified statistical analyses were incompatible with the results of the study. Following changes to the statistical analyses, palovarotene was found to exhibit efficacy at 12 months, and the MOVE study was resumed.^4,17 Post hoc analyses at 18 months revealed a 99.4% probability of reduction in new HO formation, as well as a 60% reduction in new HO volume in MOVE participants relative to NHS subjects.^4,17 Changes in CAJIS were similar between MOVE participants and NHS participants receiving the standard of care, suggesting that measures such as CAJIS are less sensitive than volumetric measures, such as whole-body CT scan, over the short clinical study time period.¹⁷ Longer-term follow-up of CAJIS may provide additional insight. Overall, these findings demonstrated that palovarotene treatment shows clinical efficacy in reducing new HO formation, though these effects may only be partial. 

Safety of Palovarotene: Safety outcomes were particularly important given previously known effects of retinoids to impair bone growth, particularly in participants <18 years old with open epiphyseal plates (cartilaginous growth plates at the ends of children’s long bones- particularly the knees, wrists, and hands- that do not solidify into bone until 16-18 years old).¹⁷ Participants <18 years were carefully assessed for epiphyseal abnormalities via knee and hand/wrist radiography every 6 months.¹⁷ Premature physeal closure (PPC) is considered a severe adverse event (AE) and was seen in 21 out of 57 subjects <14 years old.^4,17 The severity of PPC resulted in a partial clinical hold of palovarotene dosing in subjects <14 years of age, and a final requirement restricting use of palovarotene to males >10 years old and females >8 years old, based on skeletal maturity data.^4,17 Unfortunately, the understanding of specific risk factors or mechanisms of PPC following palovarotene use in patients is extremely limited.^4,17 Extremely careful evaluation of risks and benefits must be considered when evaluating the potential use of palovarotene for any individual <18 years of age. Other AEs, consistent with retinoid use, included dry skin, lip dryness, alopecia, and rash, which were considered mild or moderate and were adequately managed with topical emollients.^4,17 Altogether, while palovarotene appears to have a favorable safety profile in adult populations, treatment in younger individuals carries significant risks. Ultimately, this raises concerns regarding the viability of this treatment for FOP, given that intervention during adolescence (before significant HO accumulation) may be critical in improving patient outcomes.

Clinical Relevance of FOP/ Evaluating the Rationale for Clinical Usage:

The FDA approval of Sohonos® (palovarotene) is a promising step forward for many individuals living with FOP. The preclinical and clinical studies leading to the development of Sohonos® have undoubtedly improved our understanding of the cellular, molecular, and physiological basis of FOP and have promoted clinical awareness of this ultra-rare disease. Unfortunately, many challenges remain.  Palovarotene exhibits some benefits for FOP patients but also has some major drawbacks. At its best, palovarotene could be beneficial for FOP patients due to its ability to partially block new HO, which could limit symptom progression or exacerbation. However, any amount of new HO in individuals with FOP has the potential to be extremely painful and disabling. At its worst, palovarotene has extreme adverse effects, including premature physeal closure in pediatric patients. Because initiating therapy early in pediatric patients with FOP is especially critical to reduce the accumulation of HO, further research will be necessary to better understand the mechanisms of both the therapeutic and adverse effects of palovarotene, particularly in children with FOP. 

Future Directions of Research/Treatments Under Development:

Although palovarotene was the first pharmacotherapy developed for FOP to reach FDA approval, other pharmacotherapies, including Regeneron Pharmaceuticals’ garetosmab (REGN2477), are currently being examined for their effectiveness in reducing FOP-related HO lesions. Garetosmab, a monoclonal antibody that binds to and blocks Activin A, was granted Orphan Drug designation by the FDA in 2017.¹⁸ A recent phase III clinical trial (OPTIMA) investigating the use of garetosmab demonstrated ≥90% reductions in new HO lesions in adults with FOP.¹⁸ A second phase III clinical trial (OPTIMA-2) examining the safety and efficacy of garetosmab in adults and children with FOP is planned to take place in 2026.¹⁸ While the safety of garetosmab is still under investigation, initial trials in adults suggest an acceptable safety profile, with no serious AEs resulting in discontinuation of garetosmab treatment.¹⁸ Preclinical findings further suggest that treatment with anti-Activin A antibodies may be more efficacious than palovarotene in reducing HO formation.¹³ Together, these emerging findings suggest that garetosmab may address some of the safety and efficacy concerns associated with palovarotene treatment, though further research will be necessary. Given this safety profile, if FDA-approved, garetosmab may be preferred for FOP treatment in pediatric patients, while palovarotene alone or a combination of both garetosmab and palovarotene may be used to block HO in adult patients with FOP.

Publication Licenses for Figures

1. Created in BioRender. Drinkuth, C. (2026) https://BioRender.com/51gpfp1
2. Created in BioRender. Drinkuth, C. (2026) https://BioRender.com/lnp5g4d

References

1. Pignolo RJ, Hsiao EC, Baujat G, Lapidus D, Sherman A, Kaplan FS. Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: estimate from three treatment centers and a patient organization. Orphanet J Rare Dis. Aug 5 2021;16(1):350. doi:10.1186/s13023-021-01983-2

2. Shore EM. Fibrodysplasia ossificans progressiva: a human genetic disorder of extraskeletal bone formation, or–how does one tissue become another? Wiley Interdiscip Rev Dev Biol. Jan-Feb 2012;1(1):153-65. doi:10.1002/wdev.9

3. Smilde BJ, Botman E, de Ruiter RD, et al. Monitoring and Management of Fibrodysplasia Ossificans Progressiva: Current Perspectives. Orthop Res Rev. 2022;14:113-120. doi:10.2147/ORR.S337491

4. Hsiao EC, Pacifici M. Palovarotene (Sohonos), a synthetic retinoid for reducing new heterotopic ossification in fibrodysplasia ossificans progressiva: history, present, and future. JBMR Plus. Jan 2025;9(1):ziae147. doi:10.1093/jbmrpl/ziae147

5. Kaplan FS, Zasloff MA, Kitterman JA, Shore EM, Hong CC, Rocke DM. Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am. Mar 2010;92(3):686-91. doi:10.2106/JBJS.I.00705

6. FDA approves first treatment for Fibrodysplasia Ossificans Progressiva. U.S. Food & Drug Administration; 2023. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-fibrodysplasia-ossificans-progressiva

7. Kartal-Kaess M, Shore EM, Xu M, et al. Fibrodysplasia ossificans progressiva (FOP): watch the great toes! Eur J Pediatr. Nov 2010;169(11):1417-21. doi:10.1007/s00431-010-1232-5

8. Wang RN, Green J, Wang Z, et al. Bone Morphogenetic Protein (BMP) signaling in development and human diseases. Genes Dis. Sep 2014;1(1):87-105. doi:10.1016/j.gendis.2014.07.005

9. Cao X, Chen D. The BMP signaling and in vivo bone formation. Gene. Aug 29 2005;357(1):1-8. doi:10.1016/j.gene.2005.06.017

10. Anwar S, Yokota T. Navigating the Complex Landscape of Fibrodysplasia Ossificans Progressiva: From Current Paradigms to Therapeutic Frontiers. Genes (Basel). Nov 30 2023;14(12)doi:10.3390/genes14122162

11. Hino K, Ikeya M, Horigome K, et al. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc Natl Acad Sci U S A. Dec 15 2015;112(50):15438-43. doi:10.1073/pnas.1510540112

12. Lees-Shepard JB, Yamamoto M, Biswas AA, et al. Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva. Nat Commun. Feb 2 2018;9(1):471. doi:10.1038/s41467-018-02872-2

13. Lees-Shepard JB, Nicholas SE, Stoessel SJ, et al. Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity. Elife. Sep 18 2018;7doi:10.7554/eLife.40814

14. Kaplan FS, Xu M, Glaser DL, et al. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics. May 2008;121(5):e1295-300. doi:10.1542/peds.2007-1980

15. Peng K, Cheung K, Lee A, Sieberg C, Borsook D, Upadhyay J. Longitudinal Evaluation of Pain, Flare-Up, and Emotional Health in Fibrodysplasia Ossificans Progressiva: Analyses of the International FOP Registry. JBMR Plus. Aug 2019;3(8):e10181. doi:10.1002/jbm4.10181

16. Kaplan FS, Al Mukaddam M, Baujat G, et al. Medical guidelines for fibrodysplasia ossificans progressiva. JBMR Plus. Nov 2025;9(11):ziaf150. doi:10.1093/jbmrpl/ziaf150

17. Pignolo RJ, Hsiao EC, Al Mukaddam M, et al. Reduction of New Heterotopic Ossification (HO) in the Open-Label, Phase 3 MOVE Trial of Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP). J Bone Miner Res. Mar 2023;38(3):381-394. doi:10.1002/jbmr.4762

18. Regeneron Announces Positive Phase 3 Trial in Adults with Ultra-Rare Genetic Disorder Fibrodysplasia Ossificans Progressiva (FOP), Demonstrating that Garetosmab Prevents Greater than 99% of Abnormal Bone Formation. 2025. https://investor.regeneron.com/news-releases/news-release-details/regeneron-announces-positive-phase-3-trial-adults-ultra-rare

Writer: Emily DiMaulo-Milk

Editor: Caryssa Drinkuth

            In April 2025, Moderna initiated a Phase II Clinical trial testing the investigational vaccine mRNA-1195 in patients with MS.¹ This vaccine targets the common virus, Epstein-Barr Virus (EBV), most well-known as the virus which causes “mono”.² In this two-part blog post, we will first explain how this widespread virus may contribute to the development and progression of MS before delving into the details of mRNA-1195 and Moderna’s Horizon Trial. 

What is Multiple Sclerosis (MS)? 

Who gets MS?

Multiple Sclerosis (MS) is a neurodegenerative disorder.³ While most neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease, are prevalent in elderly populations, MS is usually diagnosed in early adulthood, with the average age of diagnosis for MS at 32 years old.³ MS affects 2.9 million people worldwide, or nearly 1 of every 3,000 people. The prevalence of MS varies greatly from region to region due to genetic variation among people or differences in climate. The United States has the third-highest MS prevalence worldwide, and approximately 1 million people in the United States are living with MS.⁴ There has been an estimated 30% increase in the number of people living with MS globally from 2013 to 2020. Within the United States, there has been a 50% increase in MS cases during that same period.⁵ This increase may be due to improvement in diagnosis and treatments for MS; however, there is no indication that MS is being diagnosed earlier, suggesting that other factors may play a role.³

What are the symptoms of MS?

It can take years to diagnose MS after symptoms first occur. Most people with MS have the relapsing-remitting form of the disease. In this stage of the disease, symptoms can be transient and non-specific, making misdiagnosis common. Initial symptoms of MS include fatigue, numbness/tingling, muscle weakness, blurry or double vision, vertigo, issues with coordination and balance, changes in mood and behavior such as depression, impaired bladder or bowel control, and cognitive problems. The symptoms and their severity can vary greatly from person to person. Symptoms can appear over the course of days to weeks, then improve or completely disappear into remission for months or even years. Eventually, 20-40% of people with relapsing-remitting MS develop secondary-progressive MS, where the symptoms of MS are constant.⁶ Over time, symptoms can worsen, and new symptoms can develop. During late stages of MS, people who are affected may have difficulty speaking and hearing, partial or complete paralysis, difficulty chewing and swallowing food, muscle spasms, pain, and difficulty controlling emotions.⁷ While MS itself is rarely fatal, there is no cure for MS, and significant disability can arise because of the disease.³ Additionally, the early onset of MS means that those who are diagnosed with the disease will spend decades managing their symptoms. 

What changes in the body cause MS?

            In neurodegenerative disorders, the destruction of nerve cells, or neurons, causes the disease to develop. In MS, it is the neurons of the brain and spinal cord that are primarily affected.³ Neurons are responsible for communication between the brain and the body. This communication is critical for sensation, control of movement, and feelings like hunger and thirst. Additionally, neurons within the brain communicate with each other to control emotions, speech, memory, and thought. Neurons signal to each other through special chemicals called neurotransmitters.⁸

Neurons consist of a cell body and an axon. In MS, it is the axon that is affected. The axon is a long, tail-like structure with neurotransmitters at its end that are released to allow communication between neurons. The release of neurotransmitters is triggered by an electrical signal that travels along the length of the axon. This electrical signal is slow over long distances and will weaken over time.⁸ To preserve the signal and speed up communication between neurons, healthy axons are typically coated with myelin sheaths. The myelin sheath also protects neurons from damage by serving as a physical barrier. It is composed of specialized fatty cells that discontinuously wrap around the neuron, acting like insulation on a wire to prevent the loss of an electrical signal. There are gaps along the myelin sheath, and the electrical signal “jumps” across these gaps as it travels along the axon to reduce travel time.⁹

In people living with MS, abnormal activity of immune cells destroys of the myelin sheath, a process called demyelination, which exposes the axon. This means MS is also an autoimmune disorder. A damaged myelin sheath results in a leaky electrical signal, causing delayed communication between neurons. Damage at the exposed axon can result in a complete inability to transmit signal to other neurons. These disruptions in neuronal communication cause the symptoms of MS to arise. As the disease progresses, demyelination continues to occur, causing symptoms to increase in severity and duration.³ Currently, there are no treatments available that can regenerate the myelin sheath.

What causes MS to develop? 

The exact factors that underlie the development of MS remain incompletely understood, and it is likely that a combination of factors are responsible for the development of MS. There are certain genetic risk factors that are known to increase the risk of developing MS. People with a family history of MS and those of Northern European ancestry are more likely to develop MS. Particularly, the HLA-DR15 haplotype is a known risk factor for MS. People assigned female at birth are two to three times more likely to develop MS for reasons which remain unclear, but may be due to differences in hormones or the immune system. Other factors, like smoking and obesity, may contribute to MS development by promoting inflammation, which can worsen the demyelination process.³ Recently, there has been much interest in a common virus, Epstein-Barr Virus (EBV), which may be linked to the development of MS. 

What is Epstein-Barr Virus (EBV), and what diseases does it cause?

What is EBV? 

            EBV is a type of herpesvirus. Nearly every adult has EBV, as the virus is detectable in 90-95% of adults. Most people are familiar with one of the diseases caused by EBV, infectious mononucleosis, or “mono,” but EBV is responsible for many different diseases. The virus is typically transmitted via saliva. It infects several types of cells, but primarily infects a special type of white blood cell called a B-cell. An initial infection with EBV usually occurs in childhood and causes no recognizable symptoms. Infection later in life, during adolescence, is much more likely to cause “mono.”²

Regardless of whether symptoms appear or not, infection with EBV is lifelong. Once infected with the virus, it stays in some B-cells in a latent form, hiding as a piece of DNA that appears similar to a person’s own genetic material.² This is similar to another, more familiar herpesvirus, Varicella-Zoster Virus, or chickenpox. People who had chickenpox as a child might experience periodic episodes of shingles. This itchy, uncomfortable rash isn’t caused by a new infection with chickenpox, but rather a reactivation of the latent virus that infected them when they were a child.¹⁰This reactivation of the virus is known as the lytic phase. During this time, the virus replicates, which enables the transmission of the virus from person to person. The lytic phase can be triggered by factors like an illness, inflammation, or stress. Usually, this phase lasts only a short time, from days to weeks. Unlike chickenpox, there is currently no vaccine for EBV. There are also no EBV-specific treatments available.²

What other diseases does EBV cause?

            In addition to “mono,” EBV has been demonstrated to cause several different cancers, including B-cell Lymphomas, NK/T-cell Lymphomas, Gastric Cancer, Nasopharyngeal Cancer, and may be linked to other cancers as well. In these tumors, the virus remains in the latent state, expressing a limited number of genes. In people with impaired immune systems, such as people living with HIV or transplant recipients, EBV can cause uncontrolled growth of infected cells, a disease called post-transplant lymphoproliferative disorder. In these people, the virus can also become uncontrollably lytic, causing lesions in the tongue in a disease called Oral Hairy Leukoplakia.²

Interestingly, EBV has also been linked to several autoimmune diseases in addition to MS, such as Rheumatoid Arthritis and Systemic Lupus Erythematosus.²

How did scientists identify a link between EBV and MS?

A potential link between EBV and MS was first proposed in the 1980s. Early work had identified that people living with MS had significantly higher rates of EBV infection than the general population.¹¹ Later epidemiological studies demonstrated that infection with EBV at adolescence, as opposed to infection during early childhood, elevated the risk for developing MS.¹² EBV has also been detected in MS lesions in the brain.¹¹ However, while suggestive, this hypothesis ultimately relied on correlational data. 

More direct evidence for a link between EBV and MS was provided by a study published in the journal Sciencein 2022. This study, led by Dr. Kjetil Bjornevik, was a twenty-year-long effort involving over 10 million people who provided over 60 million blood samples. Researchers were able to determine if a person was infected with EBV using blood serum samples that were taken every six months. By analyzing the samples collected over time, the researchers were able to determine not only who was infected with the virus, but also when people who were uninfected became infected, termed seroconversion. Importantly, all these samples were taken from adults, meaning that any seroconversion represented a late-life infection with EBV.¹³

From this population, 801 people who went on to develop MS were identified, all but one of whom were infected with EBV. Being infected with EBV resulted in a 26-fold increase in developing MS. Interestingly, seroconversion was significantly more common in people who went on to develop MS compared to the control group, and increased the risk of developing MS by 34-fold. Importantly, seroconversion also consistently preceded the development of MS, suggesting viral infection was a prerequisite for the development of MS. These associations were not true for a related herpesvirus, Human Cytomegalovirus. The authors also used a panel that would recognize antibodies against hundreds of viruses to determine which viruses a person had developed an immune response against. By doing this, the authors could rule out a general association between viral infection and MS. Overall, there were similar antibodies in the serum of people who developed MS and those who did not- except for antibodies against EBV proteins, which were much higher in the group with MS.¹³ Ultimately, this paper was a landmark in demonstrating a specific link between EBV and MS.

How might EBV contribute to the development of MS?

How can the identified link between EBV and MS be explained?

Altogether, while this work tracking people’s EBV and MS status over time strengthened the argument for a link between late-life EBV infection and MS, it did not explain how EBV could contribute to the development of MS. However, at the same time, another group of researchers led by Dr. Tobias V. Lanz was investigating an EBV protein called EBNA1. Their paper was published in the journal Nature just eleven days after the Science paper and provided mechanistic evidence for a link between EBV and MS. The research published in Nature suggested that molecular mimicry of EBNA1 may explain how infection with EBV results in demyelination and, thus, the development of MS.¹⁴

What is molecular mimicry?

Autoimmune disorders are caused by immune cells killing a person’s own healthy cells because it mistakes them for cells that are dangerous. There are many kinds of immune cells, each of which has a specialized job in the multi-step process of recognizing and killing dangerous cells. Immune cells called T-cells identify dangerous cells infected with a virus by looking at a sample of the proteins being expressed in this cell, called antigens. A different kind of immune cell called B-cells support this process by producing antibodies which “flag” a cell expressing antigen so that other immune cells recognize and kill them.¹⁵

Immune cells that recognize proteins normally produced by cells- self-antigens– are autoreactive and typically killed during their development, though some survive. Cells infected with a virus start making new proteins that are different from cell proteins, called foreign antigens. If a foreign antigen is recognized by a T-cell during presentation or an antibody produced by a B-cell, the antigen will be “remembered” by these cells. Then, the next time that a foreign antigen shows up, these immune cells are ready to work together to attempt to kill cells expressing the foreign antigen.¹⁵

But what happens when a self-antigen and a foreign antigen are so similar that an immune cell can’t tell them apart?

In this case, immune cells will target not just dangerous cells, but also healthy cells that express the self-antigen. This is molecular mimicry, and it is the driving force behind many different autoimmune diseases.¹⁵

How could molecular mimicry in EBV cause MS symptoms?

In the case of EBV, the critical viral protein EBNA1 has molecular mimicry for several of the proteins that compose the myelin sheath.^{11, 14} In this model, immune cells mistake the healthy cells that make up the myelin sheath for dangerous cells infected with EBV, leading to the destruction of the myelin sheath and the development of MS. Antibodies that recognize both EBNA1 and components of the myelin sheath have been detected at high levels in patients with MS and may even serve as an early diagnostic marker. ^14,16 However, there is still much debate as to how cross-reactive antibodies against EBNA1 and the myelin sheath are generated and if they are truly the cause of MS.

Could other properties of the virus contribute to MS genesis and progression?

There are several other hypotheses that have been proposed regarding how EBV would result in the development of MS, and more than one may be true.

Another EBV protein, EBNA2, interacts with host proteins to manipulate the processes that regulate the expression of a gene. The genes with which EBNA2 interacts are abundantly autoimmune genetic risk factors- including nearly half of the genetic risk factors for MS. Therefore, EBV infection could simultaneously affect the expression of many different genes, which could have different impacts dependent upon the genetic background of the person who is infected.¹⁷

Additionally, as infection with EBV is lifelong, there will be a persistent presence of foreign antigens. This could cause continuous low-grade inflammation that broadly promotes the activity of immune cells with numerous effects, including promoting the survival and activation of autoreactive cells.¹² Consistent with this, there is evidence that activation of the lytic phase, when more EBV antigens are present, may correlate with MS symptom flare-ups.¹⁸

EBV is also known to manipulate the processes that normally select against cells that recognize self-antigens and may promote their survival. In a different autoimmune disorder that has been linked to EBV, Systemic Lupus Erythematosus, researchers found that EBV-infected cells in people living with Lupus were responsive to the self-antigen that is aberrantly targeted in patients with Lupus. Further, these EBV-infected autoreactive B-cells could initiate a cascade that caused even uninfected autoreactive T- and B-cells to activate.¹⁹ In this way, EBV can act as the “spark” for a larger inflammatory “fire.”

Is it definite that EBV causes MS?

Given that EBV is present in most people, but most people do not get MS, being infected with EBV is not sufficient to cause MS. Rather, a combination of factors, one of which is EBV, may drive the development of MS. While exceedingly rare, some patients are EBV negative yet develop MS, suggesting that EBV is not required for the development of MS. While preclinical studies have revealed that mice which are prone to autoimmune disease develop brain lesions and neurological symptoms when injected with a segment of EBNA1,²¹ as of right now, there is no direct proof of EBNA1 causing demyelination in humans. The antibodies against EBNA1 that are suspected of promoting demyelination are not always detectable in patients with MS and have also been detected in people who do not have MS,²² complicating matters. Again, there are likely other factors, such as the genetic background of the virus and person, the character of the autoreactive cells, and if the cells migrate to the brain, which dictate whether demyelination occurs. There may also be other autoreactive antibodies that are produced in response to EBV infection which have not yet been identified. Overall, while it is generally well accepted that EBV plays a role in the development of MS, it remains unclear exactly how this occurs, and why only a small proportion of people with EBV develop MS. Therefore, it is important that researchers continue their investigation in this area.

Could a vaccine against EBV protect or treat MS?

            Here, we describe the evidence for a link between the common virus EBV and the rare neurodegenerative and autoimmune disorder, MS. While there are treatments available for MS, there are no cures, and these treatments are not always effective or tolerable. Further, once demyelination occurs, the myelin sheath cannot be regenerated.³Therefore, there is a need to develop better methods to help people living with MS. In the next post, we will describe one of these attempts- a vaccine against EBV created by scientists at Moderna.¹

Glossary:

Multiple Sclerosis (MS): A neurodegenerative disorder driven by autoimmune destruction of the myelin sheath. It is typically diagnosed in early adulthood. Symptoms are impaired motor and sensory function and are progressive. There is no cure for MS. 

Neurodegenerative disorder: A disease caused by the destruction of neurons.

Neurons: Specialized nerve cells that sense the environment, control muscle movement, and are responsible for communication between the brain and the body.

Axon: The part of the neuron along which an electrical signal travels to enable communication between neurons.

Myelin Sheath: The fatty coating along the axon that protects the axon from damage and allows the electrical signal to travel quickly without degradation.

Demyelination: The destruction of the myelin sheath and the physiological change that causes MS symptoms.

Autoimmune disorder: A disease caused by abnormal activity of the immune system, negatively impacting healthy cells.

HLA-DR15: A well-established genetic risk factor for MS that affects a protein involved in antigen presentation.

Epstein-Barr Virus (EBV): A common virus that causes a lifelong infection and has been linked to many different cancers and autoimmune disorders. There are no EBV vaccines or specific treatments available.

B-cell: A type of immune cell that produces antibodies and plays a supportive role in immunity. Also, the type of cell that EBV primarily infects.

Latent: The phase in the viral lifecycle where the virus is largely inactive. EBV spends the majority of its lifecycle in this phase.

Lytic: The phase of the viral lifecycle during which most viral proteins are produced and which, if successfully completed, results in the production of more virus. This phase is essential for the transmission of virus from person to person. 

Seroconversion: The development of an antibody response, here used as a measure of going from uninfected with EBV to infected with EBV.

EBNA1: A critical viral protein that enables the replication of the virus and the maintenance of the virus in a cell. Antibodies against this viral protein have been implicated in the development of MS.

Molecular mimicry: The phenomenon of a foreign antigen from an infectious agent having structural similarity to a protein normally produced in healthy cells. 

T-cells: A specialized immune cell, most well-known as the cells that monitor for dangerous cells, like a cancer cell or a virus-infected cell, by checking the proteins expressed in that cell.

Antigens: A substance that produces an immune response. In this context, an antigen is a segment of a protein that is expressed by a cell.

Self-antigens: Antigens that are normally expressed by healthy cells in a person and  should not normally trigger a robust immune response.

Autoreactive: A descriptor for immune cells that recognize and react to self-antigen. They are associated with autoimmune diseases.

Foreign antigens: Antigens that are not normally expressed by healthy cells, but may instead be expressed by an infectious agent like a virus. 

References:

1. A Study to Investigate Multiple Sclerosis Relapse Prevention With mRNA-1195 Compared With Placebo in Participants Aged 18 to ≤55 Years. Clinicaltrials.gov. Published 2025. https://clinicaltrials.gov/study/NCT06735248?rank=1
   
2. Damania B, Kenney SC, Raab-Traub N. Epstein-Barr virus: Biology and clinical disease. Cell. 2022;185(20):3652-3670. doi:10.1016/j.cell.2022.08.026
   
3. Boutitah-Benyaich I, Eixarch H, Villacieros-Álvarez J, et al. Multiple sclerosis: molecular pathogenesis and therapeutic intervention. Signal Transduct Target Ther. 2025;10(1):324. Published 2025 Oct 2. doi:10.1038/s41392-025-02415-4
   
4. The Multiple Sclerosis International Federation, Atlas of MS, 3rd Edition; 2020
   
5. Walton C, King R, Rechtman L, et al. Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition. Mult Scler. 2020;26(14):1816-1821. doi:10.1177/1352458520970841
   
6. Mayo Clinic. Multiple Sclerosis. Mayo Clinic. Published 2024. https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269
   
7. Caring for someone with multiple sclerosis at end of life. Marie Curie. Published 2023.
   https://www.mariecurie.org.uk/professionals/palliative-care-knowledge-zone/multiple-sclerosis
   
8. Neurons: How the Brain Communicates. Mhanational.org. Published 2025. https://mhanational.org/resources/neurons-how-the-brain-communicates/
   
9. Cleveland Clinic. Myelin Sheath: What It Is, Purpose & Function. Cleveland Clinic. Published May 9, 2022. https://my.clevelandclinic.org/health/body/22974-myelin-sheath
   
10. Laing KJ, Ouwendijk WJD, Koelle DM, Verjans GMGM. Immunobiology of Varicella-Zoster Virus Infection. J Infect Dis. 2018;218(suppl_2):S68-S74. doi:10.1093/infdis/jiy403
    
11. SoRelle ED, Luftig MA. Multiple sclerosis and infection: history, EBV, and the search for mechanism. Microbiol Mol Biol Rev. 2025;89(1):e0011923. doi:10.1128/mmbr.00119-23
    
12. Biström M, Jons D, Engdahl E, et al. Epstein-Barr virus infection after adolescence and human herpesvirus 6A as risk factors for multiple sclerosis. Eur J Neurol. 2021;28(2):579-586. doi:10.1111/ene.14597
    
13. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301. doi:10.1126/science.abj8222
    
14. Lanz TV, Brewer RC, Ho PP, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022;603(7900):321-327. doi:10.1038/s41586-022-04432-7
    
15. Rojas M, Restrepo-Jiménez P, Monsalve DM, et al. Molecular mimicry and autoimmunity. J Autoimmun. 2018;95:100-123. doi:10.1016/j.jaut.2018.10.012
    
16. Vietzen H, Kühner LM, Berger SM, et al. Early identification of individuals at risk for multiple sclerosis by quantification of EBNA-1_381-452-specific antibody titers. Nat Commun. 2025;16(1):6416. Published 2025 Jul 14. doi:10.1038/s41467-025-61751-9
    
17. Hong T, Parameswaran S, Donmez OA, et al. Epstein-Barr virus nuclear antigen 2 extensively rewires the human chromatin landscape at autoimmune risk loci. Genome Res. 2021;31(12):2185-2198. doi:10.1101/gr.264705.120
    
18. Soldan SS, Su C, Monaco MC, et al. Multiple sclerosis patient-derived spontaneous B cells have distinct EBV and host gene expression profiles in active disease. Nat Microbiol. 2024;9(6):1540-1554. doi:10.1038/s41564-024-01699-6
    
19. Younis S, Moutusy SI, Rasouli S, et al. Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus. Sci Transl Med. 2025;17(824):eady0210. doi:10.1126/scitranslmed.ady0210
    
20. Jog NR, McClain MT, Heinlen LD, et al. Epstein Barr virus nuclear antigen 1 (EBNA-1) peptides recognized by adult multiple sclerosis patient sera induce neurologic symptoms in a murine model. J Autoimmun. 2020;106:102332. doi:10.1016/j.jaut.2019.102332
    
21. Vietzen H, Berger SM, Kühner LM, et al. Ineffective control of Epstein-Barr-virus-induced autoimmunity increases the risk for multiple sclerosis. Cell. 2023;186(26):5705-5718.e13. doi:10.1016/j.cell.2023.11.015

Writer: Kaitlin Kinney

Editor: Sarah Sizer

Major depressive disorder (MDD) remains one of the most common and disabling mental health conditions worldwide, with an estimated 332 million people affected globally.^1,2 While antidepressant medications and psychotherapy are effective for many individuals with MDD, approximately 30 to 40% of patients continue to experience persistent symptoms despite standard first-line treatment approaches.³ For individuals who do not respond adequately to initial therapies, additional interventions are available, including electroconvulsive therapy (ECT), ketamine-based treatments, and clinic-based neuromodulation approaches.^3,4 In patients with treatment-resistant depression, these interventions can still provide meaningful benefit, with reported response rates of approximately 40 to 70% depending on the modality, patient population, and outcome definition.^3,4

However, real-world access barriers, including time burden, treatment logistics, and insurance requirements, can limit feasibility for many patients who are resistant to first-line treatments.^5,6 Notably, transcranial magnetic stimulation (TMS), one of the most widely used neuromodulation techniques for MDD, commonly requires documentation of multiple prior antidepressant failures (often up to ~4 trials) before authorization.⁷ These barriers can delay access to effective treatment, prolong symptom burden, and widen disparities in depression care.⁸

On December 31, 2025, the FDA granted Premarket Approval (PMA) for Neurolief’s Proliv™Rx neuromodulation system (P250010).⁹ The Proliv™Rx System provides focal external Combined Occipital and Trigeminal Afferent Stimulation (eCOT-AS) and is intended as an adjunctive treatment for MDD in adults who failed to achieve satisfactory improvement from at least one previous antidepressant medication, for use at home or in the clinic.⁹

A quick refresher: why does PMA matter?

If you have spent any time reading health news headlines, you have probably seen words like “FDA cleared,” “FDA approved,” or “FDA authorized” used somewhat interchangeably. However, in the medical device world, these terms reflect distinct regulatory pathways that differ in their evidentiary requirements.

Depending on a device’s risk level and intended use, the FDA may evaluate medical devices through several pathways, including 510(k) clearance for lower-risk devices that are substantially equivalent to existing technologies, De Novo classification for novel moderate-risk devices, and Premarket Approval (PMA) for the highest-risk (Class III) devices. ¹⁰

PMA is the process the FDA uses to evaluate high-risk medical devices for safety and effectiveness. ¹⁰ Unlike 510(k) clearance or De Novo classification, which rely primarily on demonstrating equivalence to existing devices or reasonable assurance of safety and effectiveness, the PMA pathway typically requires direct clinical evidence from well-controlled studies demonstrating a device’s safety and effectiveness for its intended use. ¹⁰ While PMA approval does not mean a device will work for every individual, it reflects the FDA’s highest level of clinical evidence required for medical devices.¹⁰

In that sense, Proliv™Rx is notable not only because it introduces a new neuromodulation option for MDD, but because it did so through the Class III PMA pathway, placing it firmly within a regulated medical treatment rather than a consumer “wellness” technology.¹⁰

What is Proliv™Rx?

Proliv™Rx is a wearable, non-invasive brain neuromodulation system designed for prescription use under physician direction.⁹ Unlike many neuromodulation therapies that rely on repeated in-clinic administration, Proliv™Rx is indicated for use both in the clinic and at home. 

Treatment with Proliv™Rx involves daily stimulation sessions, with each session lasting approximately 20 minutes, administered according to a prescribed treatment schedule.¹¹ This at-home dosing model distinguishes Proliv™Rx from clinic-based neuromodulation approaches that often require frequent in-person visits over several weeks.

Proliv™Rx delivers external Combined Occipital and Trigeminal Afferent Stimulation (eCOT-AS), a neuromodulation approach designed to engage sensory afferent pathways arising from the trigeminal nerve (cranial nerve V) and occipital nerves.^11,12 Using controlled pulses of electrical stimulation, eCOT-AS is applied across both the facial/forehead region and the posterior scalp/upper cervical region, thereby activating two distinct peripheral sensory input pathways that transmit signals into the central nervous system (Figure 1).^11,12

Rather than directly stimulating cortical tissue, eCOT-AS is intended to modulate neural activity indirectly through ascending sensory afferent signaling. Through this mechanism, peripheral sensory inputs may influence distributed neural circuits involved in mood regulation, including circuits related to arousal and affective processing, though the precise downstream pathways and network effects remain under investigation.^11,12 

Figure 1. Trigeminal and occipital afferent pathways targeted by eCOT-AS. External Combined Occipital and Trigeminal Afferent Stimulation (eCOT-AS) engages sensory afferent pathways arising from the trigeminal nerve (via the face and forehead; left panel) and occipital nerves (via the posterior scalp and upper cervical region; right panel). These peripheral sensory inputs transmit ascending signals into the central nervous system, providing an indirect neuromodulatory route to influence higher-order neural networks involved in mood regulation. Created in BioRender. Kinney, K. (2026) https://BioRender.com/vglrgx8.

Clinical evidence supporting approval: the MOOD Study

FDA approval was supported by evidence from the MOOD Study, a multicenter, randomized, double-blind, sham-controlled clinical trial evaluating home-based eCOT-AS therapy in adults with MDD whose depression had not adequately improved after antidepressant medication.¹¹ Depressive symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HDRS-17), a widely used clinician-rated measure of depression severity in clinical research.¹¹

In the double-blind phase, active eCOT-AS demonstrated significantly greater improvement than sham at Week 8, with a mean HDRS-17 reduction of 8.6 points in the active group compared to 6.0 points in the sham group (p = 0.02).¹¹ The study also reported significantly higher remission rates in the active treatment group (21.3%) compared with sham (6.0%, p = 0.03).¹¹

The sham condition was designed to closely mimic the active intervention, helping preserve blinding and patient expectations, an important consideration in neuromodulation trials. As is common in depression studies, participants in the sham group showed meaningful symptom improvement, reflecting a substantial placebo response that can arise from factors such as treatment expectancy, structured daily routines, and increased clinical monitoring.³ Importantly, despite this robust sham response, active eCOT-AS produced significantly greater symptom improvement and remission rates, supporting a treatment effect beyond placebo.¹¹

Scaling neuromodulation beyond the clinic

One of the most distinctive aspects of Proliv™Rx is not only its neuromodulation mechanism and technology, but its potential to expand how neuromodulation care is delivered.

Historically, brain stimulation treatments for depression have been constrained by clinic-based infrastructure. For example, treatments such as TMS often require frequent in-person visits over several weeks, which can be difficult for individuals balancing transportation needs, work schedules, financial constraints, or caregiving responsibilities.^5,6,8 These real-world constraints can delay treatment initiation and contribute to inequities in access to evidence-based care.⁸

By contrast, an FDA-approved neuromodulation option designed for home use under physician direction introduces a new care delivery pathway for depression, one that may complement existing in-clinic interventions.⁹ In theory, home-based neuromodulation could reduce treatment burden, improve scalability, and expand access for individuals who may not otherwise be able to receive neuromodulation in a timely manner.

As with any emerging treatment, the broader impact of Proliv™Rx will likely depend not only on clinical efficacy, but also on its integration into real-world care. Key implementation considerations include:

• Adherence: How consistently can patients complete sessions over time at home?
• Support and monitoring: What level of clinician follow-up best supports safe and effective use?
• Coverage and access: How reimbursement models, including health insurance coverage and patient out-of-pocket costs, will support or limit broad adoption and equitable access.

Importantly, these questions reflect an opportunity rather than a limitation. While home-based neuromodulation has the potential to reduce logistical barriers associated with clinic-based care, its real-world impact will depend on how coverage policies evolve and whether reimbursement structures make these treatments accessible to patients beyond those who can afford to pay out of pocket.⁶ As home-based neuromodulation continues to mature, practical factors such as usability, monitoring, and reimbursement will be central to determining how widely and effectively these approaches can be implemented.

Where might Proliv™Rx fit in the depression treatment landscape?

The FDA indication for Proliv™Rx specifies use as an adjunctive therapy for adults with MDD who did not achieve satisfactory improvement after at least one antidepressant medication.⁹ This is a meaningful distinction in today’s treatment landscape, particularly because many interventional or neuromodulation therapies are often positioned later in care pathways, after multiple medication trials.⁷ 

From a practical standpoint, Proliv™Rx may help fill an important gap: offering a regulated, physician-directed neuromodulation option that could be introduced earlier for appropriate patients, without requiring the same degree of clinic attendance as other stimulation-based approaches. If adopted thoughtfully, this model could support more flexible, patient-centered care, especially for individuals whose depression symptoms make it difficult to sustain frequent in-person treatment schedules.

Looking ahead, Proliv™Rx also represents a broader shift in how depression treatments may evolve: toward care models that combine clinical oversight with more accessible delivery, allowing evidence-based neuromodulation to reach patients in ways that better fit real life.

As clinicians and health systems gain experience with Proliv™Rx, additional research and real-world data will be valuable for clarifying which patient subgroups benefit most, the durability of symptom improvements, how eCOT-AS integrates alongside medication management and psychotherapy, and whether home-based neuromodulation can reduce delays to care and meaningfully expand access.

Conclusion

Proliv™Rx’s PMA approval represents an important milestone in depression treatment and neuromodulation therapeutics. By introducing a physician-directed at-home neuromodulation option, this approval has the potential to broaden access for individuals who might otherwise face delays or barriers to receiving brain stimulation therapies.^9,10

Ultimately, what makes Proliv™Rx especially noteworthy is the direction it points the field: toward depression treatments that maintain medical oversight while becoming more scalable and flexible for patients. As home-based neuromodulation enters clinical practice, the next chapter will be shaped not only by efficacy, but by real-world implementation. 

References

1. World Health Organization. Depressive disorder (depression). World Health Organization. https://www.who.int/news-room/fact-sheets/detail/depression
   
2. Yan, G., Zhang, Y., Wang, S., Yan, Y., Liu, M., Tian, M., & Tian, W. (2024). Global, regional, and national temporal trend in burden of major depressive disorder from 1990 to 2019: An analysis of the global burden of disease study. Psychiatry Research, 337, 115958. https://doi.org/10.1016/j.psychres.2024.115958
   
3. McIntyre, R. S., Alsuwaidan, M., Baune, B. T., Berk, M., Demyttenaere, K., Goldberg, J. F., Gorwood, P., Ho, R., Kasper, S., Kennedy, S. H., Ly-Uson, J., Mansur, R. B., McAllister-Williams, R. H., Murrough, J. W., Nemeroff, C. B., Nierenberg, A. A., Rosenblat, J. D., Sanacora, G., Schatzberg, A. F., Shelton, R., Stahl, S.M., Trivedi, M.H., Vieta, E., Vinberg, M., Williams, N., Young, A.H., Maj, M. (2023). Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry: official journal of the World Psychiatric Association (WPA), 22(3), 394–412. https://doi.org/10.1002/wps.21120
   
4. Ruiz, A. C., Haseeb, A., Baumgartner, W., Leung, E., Scaini, G., & Quevedo, J. (2025). New insights into the mechanisms of electroconvulsive therapy in treatment-resistant depression. Frontiers in Psychiatry, 16. https://doi.org/10.3389/fpsyt.2025.1614076
   
5. Rowan, K., McAlpine, D. D., & Blewett, L. A. (2013). Access and cost barriers to mental health care, by insurance status, 1999–2010. Health Affairs, 32(10), 1723–1730. https://doi.org/10.1377/hlthaff.2013.0133
   
6. Kar, N. (2025). Challenges in managing depression in clinical practice: Result of a global survey. Pharmacoepidemiology, 4(1), 5. https://doi.org/10.3390/pharma4010005
   
7. Bastiaens, J., Brown, N., Bermudes, R. A., Juusola, J. L., Bravata, D. M., & Marton, T. F. (2024). Utilization and outcomes of transcranial magnetic stimulation and usual care for MDD in a large group psychiatric practice. BMC Psychiatry, 24(1). https://doi.org/10.1186/s12888-024-05928-4
   
8. Goldbloom, D. S., & Gratzer, D. (2019). Barriers to brain stimulation therapies for treatment-resistant depression: Beyond Cost Effectiveness. The Canadian Journal of Psychiatry, 65(3), 193–195. https://doi.org/10.1177/0706743719893584
   
9. U.S. Food and Drug Administration. Premarket approval (PMA). accessdata.fda.gov. (2025, December 31). https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?ID=P250010
   
10. Center for Devices and Radiological Health. Premarket approval (PMA). U.S. Food and Drug Administration. https://www.fda.gov/medical-devices/premarket-submissions-selecting-and-preparing-correct-submission/premarket-approval-pma
    
11. Carpenter, L. L., George, M. S., Navarro, N., Deutsch, L., & Leuchter, A. F. (2025). A novel home-based, combined occipital and trigeminal afferent stimulation therapy for major depressive disorder: Efficacy and safety results from a double-blind multicenter randomized sham-controlled study. Brain Stimulation, 18(5), 1695–1704. https://doi.org/10.1016/j.brs.2025.08.022
    
12. BrainsWay announces FDA approval of Neurolief’s Proliv^TMRx neuromodulation system for major depressive disorder (MDD). BrainsWay. (2026, January 12). https://www.brainsway.com/news_events/brainsway-announces-fda-approval-of-neuroliefs-prolivrx-neuromodulation-system-for-major-depressive-disorder-mdd/

Writer: Meghan Diefenbacher

Editor: Pari Dhayagude

The influenza virus is a respiratory pathogen that remains a significant global public health burden. Seasonal epidemics of influenza cause approximately 3-5 million cases of severe illness and 290,000-650,000 respiratory deaths worldwide.¹ Although the number of seasonal influenza virus infections initially decreased during the SARS-CoV-2 pandemic, they have rebounded to pre-pandemic levels,^2,3 and the current 2025-2026 season in the United States has been especially severe with over 120,000 hospitalizations, 5,000 deaths, and case numbers continuing to rise.⁴ Compounding the impact of seasonal influenza outbreaks is the risk of pandemics originating from zoonotic (animal-borne) influenza strains.^5,6 Over the past 100 years there have been four major influenza virus pandemics responsible for millions of deaths.⁵ Additionally, zoonotic influenza strains like H5N1 have continued to circulate and cause mass mortality in wild bird and mammal populations, domestic poultry and cattle, and sporadic high mortality infections in humans exposed to infected animals.^7,8

To mitigate the threats posed by both seasonal and pandemic influenza virus outbreaks, the development of therapeutics (drugs and vaccines) that are broadly protective against highly diverse influenza virus strains and provide long-lasting protection is urgently needed. Current vaccines are only effective against seasonal influenza strains and must be updated annually due to the rapid evolution of influenza viruses.⁹ Several FDA approved antivirals are available to treat influenza virus infections, however, they are only effective during the early stages of infection, and mutations conferring resistance to these antivirals have been documented in both laboratory and clinical settings.¹⁰ Addressing the concerns regarding the limited breadth and short-term efficacy of current influenza virus therapeutics, Cidara Therapeutics, recently acquired by Merck, developed a novel long-acting and broadly protective anti-influenza antiviral drug called CD388 which has exhibited efficacy in recent early stage clinical trials.¹¹

What is the influenza virus and how does it cause disease?

Influenza viruses are members of the Orthomyxoviridae family, distinguished by their segmented, negative-sense RNA genomes.¹² Influenza viruses are divided into four types- A (IAV), B (IBV), C (ICV), and D (IDV).¹² Only IAV, IBV, and ICV infect humans with IAV and IBV being responsible for seasonal influenza epidemics and only IAV causing past influenza pandemic outbreaks.¹²

Influenza Virus Transmission, Symptoms, and Disease Severity

Influenza viruses are primarily transmitted to uninfected people via inhalation of respiratory droplets released into the air after an infected person coughs or sneezes, or via contact with contaminated surfaces and then touching the eyes, nose, or mouth.¹ Symptoms begin to develop between 1 and 4 days post-infection, and uncomplicated cases of influenza last around one week.¹ Infections are primarily characterized by the sudden onset of fever and upper respiratory tract symptoms such as dry cough, sore throat, and a runny nose.¹ Infection can also be accompanied by other symptoms such as headaches, malaise (feeling unwell), and muscle and joint pain.¹ Although a majority of infections resolve within a week, people with pre-existing conditions (obesity, asthma, diabetes, heart disease etc.), pregnant women, the very young (<5 years old) and elderly (>65 years old), and those who are immunocompromised can develop additional complications such as bronchitis, sinus infections, viral or secondary bacterial pneumonia, exacerbation of symptoms related to pre-existing conditions, respiratory failure, and death.^1,12

Influenza Virus Particle Structure and Classification

IAV and IBV particles consist of the viral genetic material enclosed within an outer lipid envelope supported underneath by a layer of the viral matrix (M1) protein and studded with the viral surface proteins hemagglutinin (HA), neuraminidase (NA), and M2 (Figure 1).^13,14 The viral genetic material is divided into eight RNA segments in the form of ribonucleoprotein complexes (RNP) in which each segment is coated along its length by the viral nucleoprotein (NP) and associated with the viral replicase (PB2, PB1, PA) (Figure 1).^13,14 Unlike IBV, which has only two lineages (B/Victoria and B/Yamagata), IAV strains are highly diverse and are further classified into subtypes based on the identity of their HA and NA surface proteins.^12,15 There are 18 known HA subtypes and 11 known NA subtypes, and IAV strains are named based on the identities of their HA and NA subtypes (ex. A/HxNy).¹⁵

The Surface Proteins HA and NA Play a Critical Role in Influenza Virus Replication

Influenza viruses target host cells by binding to sialic acids (SAs), which are the terminal sugar molecules present within the larger carbohydrate structures attached to cell-membrane associated proteins (glycoproteins) or lipids (glycolipids).¹⁶ The binding of HA triggers the uptake of the virus into the cell (endocytosis) where its proteins direct the replication of the viral genetic material and the synthesis of additional viral proteins to form new virus particles (Figure 2).¹³ The virus particles then bud from the cell surface and are released via the activity of NA, which cleaves the SAs tethering the viral particles to the cell surface (Figure 2).¹³ The opposing activities of HA and NA need to be balanced to ensure efficient viral replication.^17,18 For instance, if HA attachment is more efficient than NA cleavage, the viruses will remain stuck on the cell surface. Conversely, if NA cleavage is more efficient than HA attachment, the SAs will be cleaved, preventing the virus from binding to and entering the host cell. Due to the essential roles of HA and NA in influenza virus attachment/entry, both HA and NA are important targets for influenza vaccine and drug development.

Importance of HA and NA in the Design of Influenza Virus Vaccines and Current Limitations

Vaccination against seasonal influenza viruses remains an essential component of the public health strategy to reduce influenza-related morbidity and mortality.¹⁹ Each year, based on the identities of circulating influenza strains, the World Health Organization (WHO) Global Influenza Surveillance and Response System (GISRS) makes recommendations for which strains to include in the vaccine.^9,20 Seasonal influenza infections are primarily caused by two IAV subtypes- A(H1N1) & A(H3N2)- and IBV, so vaccine formulations are typically quadrivalent or trivalent, meaning that they contain two IAV strains  (one of each A(H1N1) and  A(H3N2) subtype), and one or both of the IBV strains of the Victoria (B/Victoria) or Yamagata (B/Yamagata) lineages.^9,20 However, since the SARS-CoV-2 pandemic emerged in 2020, the B/Yamagata strain has not been detected in human populations, so it is now recommended that the vaccines only include IBV strains of the B/Victoria lineage.²¹ Traditionally, influenza vaccines are made by growing the selected influenza strains in eggs, harvesting the virus-containing fluid, inactivating the viruses, breaking apart the virus particles, and then separating out the viral proteins (antigens).²² The viral antigens in the vaccine stimulate the immune system to produce antibodies primarily against HA, and to a lesser extent NA, to inhibit their activities and prevent virus replication.^22–24

While vaccines play an integral role in the public health strategy to mitigate influenza virus epidemics, they exhibit several drawbacks, including limited breadth, requirements for annual updates, and variable efficacy.^9,20 Influenza vaccines protect against seasonal influenza viruses but not zoonotic strains, and must be continually updated due to the rapid evolution of influenza viruses, which acquire mutations that render vaccine-induced antibodies ineffective, a process known as antigenic drift.^9,20 Additionally, the vaccine efficacy is highly variable (varying from ~19-60% between 2009 and 2025)²⁵ and is influenced by several factors. For instance, there may be a mismatch between the influenza strains selected by WHO GISRS and those that circulate during the season.^9,20,26 Additionally, the viruses used in vaccine production can acquire mutations during production, known as egg-adaptive mutations.^9,20,26 Vaccine effectiveness is also influenced by variable vaccine uptake rates and individuals’ previous exposure and vaccination histories.^26–28 Overall, the development of a universally protective influenza vaccine that does not require annual updates remains a significant public health challenge and opens the door to alternative approaches to provide long-lasting and broad protection against influenza virus infections.

Current Benefits and Drawbacks of Contemporary NA Inhibitors for the Treatment of Influenza Infections

Out of the four FDA-approved antiviral drugs available to treat influenza virus infections, a majority (3/4) are NA inhibitors (NAIs): Zanamivir (Relenza®), Oseltamivir (Tamiflu®), and Peramivir (Rapibav®).²⁹ NA is a valuable therapeutic target not only because of its essential role in the influenza virus replication cycle, but also because the region of the NA protein that binds to and cleaves the SAs (the active site) is highly conserved throughout both IAV and IBV strains, increasing the potential breadth of antiviral activity.^30,31 Consequently, most NAIs are designed as SA analogues that bind to the active site in the place of cellular SAs and inhibit the cleavage activity of  NA .^32,33 The lack of NA activity prevents virus spread by causing the virus to cluster on the cell surface and get trapped by decoy receptors within the mucus layer of the respiratory tract.³⁰ Of the three NAIs, Oseltamivir is the most commonly used because it is available as an oral pill, whereas Zanamivir and Peramivir must be administered via inhalation and intravenously respectively.^32,33 A limitation of these NAIs is that to be effective, they must be administered within 48 hours of symptom onset, making the treatment window very narrow.³⁴ Additionally, NAI resistance mutations, although typically low in prevalence (~1% average), can inhibit the activity of these drugs and have been identified in laboratory settings, circulating strains, and in immunocompromised patients with prolonged influenza infections.^35–39 Therefore, it is of interest to develop new NAIs that are long-acting and decrease the likelihood of developing antiviral resistance.

What is the mechanism of action of CD388 against influenza NA and how does it provide broad and long-lasting protection against influenza virus infections?

Cidara Therapeutics’ (acquired by Merck) anti-influenza drug CD388 was developed as part of the company’s Cloudbreak® platform portfolio of drugs. The Cloudbreak® platform drugs are designed as conjugates of small molecule or peptide drugs and antibody fragments (Fc) that exhibit disease-specific, targeted drug activity and can be modified to stimulate the host immune response.⁴⁰

CD388 contains two major features: an antibody fragment backbone and multiple conjugates of the NAI Zanamivir (Figure 3).⁴¹ The antibody fragment backbone serves as the platform for the binding of multiple Zanamivir dimers (groups of two) and is engineered with mutations that increase the stability and overall half-life of CD388 in the body (Figure 3).⁴¹

CD388 exerts its antiviral activity through Zanamivir, which prevents NA from cleaving sialic acids and facilitating the release of virus particles from the cell surface (Figure 4).^41,42 This prevents the virus from spreading to new tissues by causing the aggregation of virus particles (Figure 4).⁴¹ The dimeric nature and presence of multiple copies of Zanamivir in CD388 allow it to inhibit the activity of multiple adjacent NA proteins within a virus particle as well as NA proteins in neighboring viruses, thereby increasing neuraminidase inhibition and causing further virus aggregation (Figures 3,4).⁴¹

CD388 exhibits several advantages including broad antiviral activity against influenza strains, a lower likelihood of developing antiviral resistance, and its long-acting antiviral activity. As CD388 contains Zanamivir which already has broad anti-influenza activity due to targeting the highly conserved NA active site, CD388 also exhibits broad antiviral activity against both seasonal and pandemic IAV strains and IBV strains.⁴¹ In preclinical studies, CD388 exhibited potent antiviral activity against a diverse panel of IAV and IBV strains in cells and protection against virus replication, weight loss, and disease in mouse models.⁴¹ An advantage of CD388 relative to other available NAIs is its low likelihood of developing antiviral resistance, and the maintenance of antiviral activity against influenza strains with NAI resistance mutations.⁴¹ For instance, even after multiple rounds of passaging the virus in cells in the presence of CD388, only a few resistance mutations were identified which only marginally increased virus replication in the presence of the drug.⁴¹ Additionally, CD388 continued to provide protection against influenza strains with known NAI mutations in mouse models.⁴¹ The authors hypothesized that CD388 increased the barrier for antiviral resistance due to its multivalent nature (its ability to bind to and inhibit the activity of multiple NAs simultaneously) which results from the dimerization of the associated Zanamivir and the presence of many Zanamivir dimers throughout the antibody fragment.^41,42 Finally, the engineered antibody fragment promotes stability and prolongs antiviral activity in vivo.⁴¹ In preclinical studies, the authors found the half-lives of CD388 were 106 hours (~4 days) in mice and 364 hours (~15 days) in cynomolgus macaques.⁴¹ Additionally, CD388 was maintained at sufficient levels up to one week post treatment and continued to provide protection against weight loss and death in mouse models.⁴¹ The stability of CD388 has the potential to lower the overall number of doses required to provide sufficient protection against influenza virus replication.

The Early Stage NAVIGATE Clinical Trial Demonstrates the Efficacy of CD388 as a Long-Acting Antiviral for the Prevention of Seasonal Influenza Virus Infections

NAVIGATE Clinical Trial Results

In June 2025, encouraging results were released from the Phase 2b randomized, double-blind, and placebo controlled NAVIGATE clinical trial (NCT06609460)⁴³ which evaluated the safety, tolerability, and efficacy of CD388 for the prevention seasonal influenza infections in healthy, unvaccinated adults (18-64 years old).^11,43 The participants received subcutaneous (SC) doses of either 450mg, 300mg, or 150mg of CD388 or the placebo and were evaluated for influenza-like illness (ILI) as the primary endpoint and presence of fever (37.8°C or 37.2°C) as the secondary endpoint after 24 weeks.^11,43 ILI was defined as a positive influenza RT-PCR test from a nasal swab sample, the new onset of a fever (>38°C), and the new onset of at least two respiratory symptoms (nasal congestion, sore throat, cough) or one respiratory symptom and one systemic symptom (headache, feeling feverish, body aches/pains, fatigue).^11,43 After 24 weeks, the 450mg, 300mg, and 150mg doses of CD388 were 76.1%, 61.3%, and 57.7% effective at preventing ILI respectively.¹¹ Additionally, the 450mg, 300mg, and 150mg doses of CD388 were 76.1%, 55.3%, and 54.7% effective at preventing new onset fever >37.8°C respectively, and 71.1%, 49.6%, and 46.5% effective at preventing new onset fever >37.2°C respectively.¹¹ In all groups CD388 was well tolerated and treatment did not lead to any adverse events.¹¹ The finding that a single dose of CD388 protected against ILI and fever for 24 weeks is encouraging as it presents CD388 as an additional option alongside vaccines for long-acting, seasonal protection against influenza.

Upcoming Clinical Trials for CD388 and Future Directions

ANCHOR Clinical Trial

The NAVIGATE clinical trial demonstrated that CD388 was effective at preventing ILI in unvaccinated, healthy adults, so the Phase 3 ANCHOR clinical trial (NCT07159763) was initiated to determine whether CD388 could also benefit patients with pre-existing conditions who are at the highest risk of developing complications from influenza virus infections.⁴⁴ The participants will receive 450mg of CD388 or a placebo and will be evaluated for ILI from 8 days post-treatment through 24 weeks post-treatment.⁴⁴ The study will also evaluate the safety and tolerability of CD388, measure plasma concentrations of CD388 over time, and determine whether any anti-CD388 antibodies that may interfere with its activity are produced during the study.⁴⁴ If CD388 also provides significant protection against ILI in patients with high risk of developing complications from influenza virus infections, it could significantly reduce the burden of influenza-related hospitalizations and deaths in these groups. Furthermore, it would offer an additional option for patients who cannot be vaccinated or tolerate other anti-influenza antiviral therapies.

Future Directions for Influenza Therapeutic Development

Due to its long-acting nature and efficacy against diverse influenza virus strains, CD388 fills a unique niche in between traditional antivirals and vaccines with the potential to provide season-long protection against the rapidly evolving seasonal influenza strains and potentially pandemic influenza strains. Alongside the development of CD388, influenza vaccine and antiviral development continue to progress. Novel vaccine production platforms (mRNA vaccines, virus-like particles, nanoparticles etc.) have the potential to increase production efficiency, decrease the number of mutations introduced during the production process, and allow for the incorporation and targeting of novel, more highly conserved viral antigens (M1, M2, NP) or multiple HA and NA antigens from diverse influenza strains to develop a more universally protective influenza vaccine.^9,45 In the influenza antiviral space, novel small molecule antivirals and monoclonal antibodies that target more conserved regions of HA and NA, small molecules that inhibit the activity of more highly conserved viral proteins (M2, viral replicase (PB2, PB1, PA), and NP), antiviral therapies combining antivirals targeting different viral proteins, and antivirals targeting host factors required for viral replication have the potential to increase the breadth of antiviral activity and decrease the risk of antiviral resistance.⁴⁶  Complementing next-generation influenza vaccines and antivirals, CD388, with its long-acting and broadly protective anti-influenza activity, serves as an additional tool in the influenza virus therapeutic arsenal to help mitigate the significant public health burden of both seasonal and future pandemic influenza virus outbreaks.

References

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2. Jing S, Wang H. Infectivity and fatality of influenza in pre- and post-COVID-19 pandemic year. PLOS Comput Biol. 2025;21(7):e1013229. doi:10.1371/journal.pcbi.1013229

3. Giovanetti M, Ali S, Slavov SN, Azarian T, Cella E. Epidemiological Transitions in Influenza Dynamics in the United States: Insights from Recent Pandemic Challenges. Microorganisms. 2025;13(3):469. doi:10.3390/microorganisms13030469

4. CDC. Weekly US Influenza Surveillance Report: Key Updates for Week 52, ending December 27, 2025. FluView. January 8, 2026. Accessed January 10, 2026. https://www.cdc.gov/fluview/surveillance/2025-week-52.html

5. Ryu S, Cowling BJ. Human Influenza Epidemiology. Cold Spring Harb Perspect Med. 2021;11(12):a038356. doi:10.1101/cshperspect.a038356

6. Abdelwhab EM, Mettenleiter TC. Zoonotic Animal Influenza Virus and Potential Mixing Vessel Hosts. Viruses. 2023;15(4):980. doi:10.3390/v15040980

7. CDC. H5 Bird Flu: Current Situation. Avian Influenza (Bird Flu). December 12, 2025. Accessed January 6, 2026. https://www.cdc.gov/bird-flu/situation-summary/index.html

8. Simancas-Racines A, Reytor-González C, Toral M, Simancas-Racines D. H5N1 Avian Influenza: A Narrative Review of Scientific Advances and Global Policy Challenges. Viruses. 2025;17(7):927. doi:10.3390/v17070927

9. Mokalla VR, Gundarapu S, Kaushik RS, Rajput M, Tummala H. Influenza Vaccines: Current Status, Adjuvant Strategies, and Efficacy. Vaccines. 2025;13(9):962. doi:10.3390/vaccines13090962

10. Batool S, Chokkakula S, Song MS. Influenza Treatment: Limitations of Antiviral Therapy and Advantages of Drug Combination Therapy. Microorganisms. 2023;11(1):183. doi:10.3390/microorganisms11010183

11. Inc CT. Cidara Therapeutics Announces Positive Topline Results from its Phase 2b NAVIGATE Trial Evaluating CD388, a Non-Vaccine Preventative of Seasonal Influenza. GlobeNewswire News Room. June 23, 2025. Accessed January 8, 2026. https://www.globenewswire.com/news-release/2025/06/23/3103267/0/en/Cidara-Therapeutics-Announces-Positive-Topline-Results-from-its-Phase-2b-NAVIGATE-Trial-Evaluating-CD388-a-Non-Vaccine-Preventative-of-Seasonal-Influenza.html

12. Uyeki TM, Hui DS, Zambon M, Wentworth DE, Monto AS. Influenza. Lancet Lond Engl. 2022;400(10353):693-706. doi:10.1016/S0140-6736(22)00982-5

13. Carter T, Iqbal M. The Influenza A Virus Replication Cycle: A Comprehensive Review. Viruses. 2024;16(2):316. doi:10.3390/v16020316

14. Krammer F, Smith GJD, Fouchier RAM, et al. Influenza. Nat Rev Dis Primer. 2018;4(1):3. doi:10.1038/s41572-018-0002-y

15. Liu WJ, Wu Y, Bi Y, et al. Emerging HxNy Influenza A Viruses. Cold Spring Harb Perspect Med. 2022;12(2):a038406. doi:10.1101/cshperspect.a038406

16. Zhao C, Pu J. Influence of Host Sialic Acid Receptors Structure on the Host Specificity of Influenza Viruses. Viruses. 2022;14(10):2141. doi:10.3390/v14102141

17. de Vries E, Du W, Guo H, de Haan CAM. Influenza A Virus Hemagglutinin–Neuraminidase–Receptor Balance: Preserving Virus Motility. Trends Microbiol. 2020;28(1):57-67. doi:10.1016/j.tim.2019.08.010

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Author: Grace Stroman

Editor: Tiffany Ko

Today’s article will discuss the Food and Drug Administration (FDA) approval of durvalumab for gastric (GC) and gastroesophageal junction adenocarcinoma (GEJC) as a result of the multinational MATTERHORN study. On November 25th, 2025 durvalumab (Imfinzi) in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) standard of care chemotherapy was approved for neoadjuvant and adjuvant treatment in adults with resectable GC and GEJC.¹ The MATTERHORN trial primary endpoint was event-free survival (EFS) and secondary endpoints were overall survival (OS) and pathological complete response (pCR).² Developed by AstraZeneca, durvalumab is an FDA approved immune-checkpoint inhibitor that targets programmed death-ligand 1 (PD-L1) to enhance tumor clearance, and is the first immunotherapy approved for GC/GEJC with a demonstrated OS survival benefit when combined with standard of care.

Key points

• MATTERHORN is the first global phase III study demonstrating superior EFS by combining an immunotherapy agent, durvalumab, and chemotherapy standard of care for localized, early-stage GC/GEJC.
• EFS was not reached for durvalumab plus FLOT therapy while OS and pCR favor durvalumab but are not mature.
• Durvalumab is an FDA approved PD-L1 antibody for multiple solid cancers and promotes T-cell mediated tumor clearance. 

What is gastric cancer?

Stomach cancer, including GC and GEJC, is the sixth most common and seventh leading cause of cancer related deaths globally in 2022 making it a health-care challenge.³ The highest number of cases occur in Asian, South American, and eastern European populations and is twice as prevalent in males than females.³ However, early-onset (i.e., <50 years of age) sporadic GC is rising in females and is attributed to behavioral, nutritional, microbial, and environmental factors mirroring a trend observed in other gastrointestinal cancers.^4-6 GC is divided into two anatomic subsites with unique molecular subtypes and risk factors.⁷ Upper stomach GC and GEJC, where the esophagus and stomach intersect, is linked with Helicobacter pylori infection, obesity, and gastroesophageal reflux. Lower stomach GC is associated with chronic H. pylori infection, alcohol, tobacco use, and a high-sodium diet.^7,8

Current treatment paradigms and clinical trial learning points

GC/GEJC patients generally undergo surgery and chemotherapy. In east Asia, standard treatment involves adjuvant chemotherapy regimens following stomach and surrounding lymph node resection.⁸ These chemotherapies vary based on tumor staging and can include S-1 (tegafur, gimeracil, and oteracil), CAPOX (capecitabine and oxaliplatin), SOX (S-1 and oxaliplatin), or docetaxel and S-1.⁸ FLOT neoadjuvant chemotherapy prior to surgery is standard of care for operable cancers outside of Asia.⁸ However, cancer recurrence is common (~60%) after curative resection and the 5-year OS rate is 25% worldwide.⁹ Therefore, additional therapeutic intervention is recommended for stage IB or higher.^10,11 Radiotherapy and chemoradiotherapy are generally no longer recommended after the ESOPEC trial demonstrated adjuvant FLOT superiority over chemoradiation with carboplatin and paclitaxel for resectable GC and GEJC.¹² As a result, surgery with neoadjuvant and adjuvant FLOT remains the primary treatment paradigm for resectable GC/GEJC.

Looking beyond chemotherapies, targeted therapy and immunotherapy regimens have been investigated but have faced clinical setbacks. Phase II trials targeting human epidermal growth factor receptor 2 using trastuzumab and pertuzumab showed improved pCR rates but did not establish a clear survival benefit over placebo.^13-15 Additionally, immunomodulating antibodies against programmed cell death protein 1 (PD-1) (i.e., pembrolizumab, nivolumab) or cytotoxic T-lymphocyte associated protein 4 (CTLA-4) (i.e., ipilimumab) combined with chemotherapy did not demonstrate enhanced clinical efficacy over chemotherapy alone.^16-18 The phase II DANTE trial was the first to demonstrate improved histopathological regression over placebo when combining the PD-L1 antibody atezolizumab plus FLOT in neoadjuvant resectable esophagogastric adenocarcinoma.¹⁹

MATTERHORN study design and results

Despite previous immunotherapy setbacks, investigation of durvalumab, an FDA approved anti-PD-L1 antibody, was evaluated in the MATTERHORN trial for treatment of GC/GEJC. Durvalumab received FDA approval for multiple solid cancers and several indications including non-small cell lung, small-cell lung, hepatocellular carcinoma, bile duct and gallbladder, and endometrial cancers.^20-24 Moreover, elevated PD-L1 is detected in ~50% of GC and is correlated with poor prognosis underscoring the clinical potential of anti-PD-L1 therapy.²⁵ The randomized, double-blind, phase III MATTERHORN (NCT04592913) study sought to address the efficacy of durvalumab in combination with FLOT in the neoadjuvant and adjuvant settings. The trial enrolled previously untreated, non-metastatic, and resectable stage II-IVa GC/GEJC and measured EFS, OS, and pCR. The global study spanned 156 locations across North and South America, Europe, and Asia and enrolled 474 patients in both study arms. Participants were generally well balanced in each study arm by age, demographic, sex, and cancer type, however, the trial organizers recognized that Black patients were underrepresented.²

The study was designed to administer durvalumab or placebo in combination with FLOT before and after surgery and measure EFS, OS, and pCR (Figure 1). FLOT chemotherapy plus durvalumab or placebo was administered for a total of 4 cycles- 2 cycles of neoadjuvant therapy and 2 cycles of adjuvant therapy. After the last cycle, durvalumab or placebo was administered every 4 weeks. Patients underwent surgery 4-8 weeks after they received their final neoadjuvant dose, and adjuvant dosing began 4-12 weeks after surgery. Treatment continued until 1 year from the start of adjuvant therapy, 12 total cycles of adjuvant therapy, or withdrawal of study consent or participating investigator. The study was not designed to determine if durvalumab therapy had an effect in the neoadjuvant or adjuvant phases. The primary endpoint measured was EFS, defined as disease progression, recurrence, or death. The main secondary endpoints were OS from study randomization to death and pCR, defined by the lack of viable tumor cells in the resected origin or lymph node tissues. Additional secondary endpoints were disease-free survival, metastasis-free survival, disease-specific survival, and health-related quality of life. Finally, analyses were performed on subgroups within the participants including sex, age, geographic region, lymph-node status, PD-L1 expression, tumor location, Eastern Cooperative Oncology Group score, histologic type, and microsatellite instability status.²

The primary endpoint indicated that durvalumab performed significantly better than placebo, but the secondary endpoints require more data points to make definitive calls. The median EFS was not reached in the durvalumab arm and was 32.8 months for the placebo arm. At 24 months, the EFS rates were 67% for durvalumab and 59% for placebo. Both the OS and pCR endpoints have not been reached for either study arm, however, the data are trending to favor the addition of durvalumab. The OS rate was 76% with durvalumab and 70% with placebo at 24 months, and the pCR rate was 19% with durvalumab compared to 7% with placebo. As the study continues to mature and follow secondary endpoints, these analyses will be reevaluated and finalized. All subgroups tested also tended to favor durvalumab plus FLOT over placebo, although not all analyses were significant due to patient subgroup size. Importantly, the addition of durvalumab did not raise any additional safety concerns beyond FLOT standard of care.²

Mechanism of durvalumab

Durvalumab is a human monoclonal antibody selective for PD-L1 and blocks the interaction between PD-L1 and PD-1, thereby enhancing effector T-cell function for tumor cell clearance. One mechanism by which tumors can evade immune system elimination is through the upregulation of PD-L1, a regulator of T-cell activation.²⁶ Binding between tumor PD-L1 and T-cell PD-1 shuts down T-cell activation thereby blocking tumor elimination. Durvalumab can be used as a monotherapy or in synergy with chemotherapeutics.²⁷ The development of monoclonal antibodies against the checkpoint proteins PD-L1, PD-1, and CTLA-4 provide an avenue to modulate the immune system and override disease microenvironment signals.²⁶

Ongoing GC/GEJC trials

Looking ahead, additional clinical trials and therapeutic modalities are being investigated to improve GC/GEJC outcomes. These include targeted kinase inhibitors, antibodies (i.e., monoclonal, antibody-drug conjugates, bispecific), and T-cell therapies (i.e., chimeric antigen receptors, bispecific engagers).⁸

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