Category: The Pipeline Blog

Author: Michaela Price, PhD

Editors: Morgan McCullough & Kylie VanDerMolen

Today, we will be discussing Kebilidi (eladocagene exuparvovec-tneq). Kebilidi is manufactured by PTC Therapeutics, Inc. and was approved for the treatment of aromatic L-amino acid decarboxylase (AADC) deficiency. In the United States, the Food and Drug Administration (FDA) announced in November 2024 that they approved Kebilidi for the treatment of AADC deficiency in pediatric and adult patients.¹ It was previously approved as Upstaza by the European Medicines Agency, Medicinal Health Products Regulatory Agency, and the Ministry of Health to treat children with severe AADC deficiency in the European Union, United Kingdom, and Israel, respectively.² In this post, we will describe AADC deficiency, the previous standard of care therapies, and the characteristics of Kebilidi and its clinical trial, including some of the special designations under which Kebilidi’s application was approved.

Overview of Aromatic L-Amino Acid Decarboxylase Deficiency

AADC deficiency is an exceedingly rare, autosomal recessive disorder caused by pathological variants in the DOPA decarboxylase (DDC) gene.^3,4 The DDC gene encodes AADC, which is a key enzyme in the biosynthesis pathway for neurotransmitters, including serotonin, dopamine, norepinephrine, and epinephrine (Figure 1).^3-5 AADC deficiency reduces AADC enzymatic activity and thus impairs the synthesis of these neurotransmitters, which produces debilitating symptoms and severely limits patients’ quality of life.^3-5

The prevalence of AADC deficiency is difficult to measure, but the National Organization for Rare Disorders estimates it to be approximately 1-2 in 1,000,000 newborns.⁶ A 2017 study identified 117 patients with AADC deficiency worldwide.⁴ Less than 350 patients have been reported in the literature⁶ since its initial description in a 1990 twin case study.⁷ The case study described 2-month-old twins with a fairly extreme deficiency in AADC enzymatic activity with only 1% of normal levels in the liver and 1.7-7.5% of normal levels in the plasma.⁷ This was accompanied by several symptoms, including severe hypotonia, developmental delay, irritability, oculogyric crises (OGC).⁷ OGC are involuntary deviations of the eyes that may occur around the same time as involuntary movements by other parts of the face and body.³ OGC are experienced nearly universally among patients, as 98% of subjects reported experiencing OGC during their lifetime.³ Episodes can last for hours at a time and occur at a high frequency, presenting a huge challenge to individuals’ quality of life.³ Studies have shown that symptom onset usually occurs within the first year of life.^3,4 The most common initial symptoms are hypotonia, OGC, developmental delay, feeding problems, sleepiness, irritability, excessive sweating, and nasal congestion (Figure 1).³ Severe AADC deficiency has a profound impact on gross motor function to the point that patients are incapable of reaching the most basic motor milestones like controlling one’s own head.²

Figure 1. Overview of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency. AADC is an enzyme in the biosynthesis pathway of serotonin, dopamine, norepinephrine, and epinephrine.^3,4 Symptom onset typically occurs within the first year of life.^3,4 The most common initial symptoms experienced in an international cohort of subjects include hypotonia, oculogyric crises (a hallmark of AADC deficiency), developmental delay, feeding problems, and more.³ 5-HTP = 5-hydroxytryptophan; DBH = dopamine β-hydroxylase; PNMT = phenylethanolamine N-methyltransferase. The image was created by the author.

Available Treatments

Before November 2024, there were no FDA-approved treatments for AADC deficiency. However, there were three treatments that the field considered “standard of care” treatments for AADC deficiency, including dopamine agonists, monoamine oxidase inhibitors, and pyridoxal 5’-phosphate/pyridoxine.^2,3,7 

Dopamine Agonists: Dopamine agonists activate dopamine receptors. AADC deficiency severely reduces the amount of dopamine synthesized, so dopamine agonists may be useful for restoring dopamine receptor-mediated functions and compensating for the lack of naturally- synthesized dopamine. In an international cohort of patients, 83% of the subjects had been prescribed one of the following dopamine agonists: bromocriptine, pramipexole, rotigotine, and ropinirole.³ Rotigotine had the highest percentage of subjects that experienced benefits (82%), whereas pramipexole, bromocriptine, and ropinirole had significantly lower percentages of respondents that reported benefits from the medication (29%, 26%, and 13%, respectively).³ Importantly, dopamine agonists had adverse effects for a significant portion of patients. Half of the subjects reported adverse effects with rotigotine and ropinirole, whereas 38% of subjects reported adverse effects with pramipexole and 30% with bromocriptine.³ The high rate of adverse effects led to 25% of patients discontinuing their medication.³

Monoamine Oxidase Inhibitors (MAOIs): Monoamine oxidase is an enzyme that breaks down neurotransmitters, including dopamine, serotonin, and norepinephrine.⁸ MAOIs prevent the breakdown of these neurotransmitters, leading to increased neurotransmitter levels in the brain. In the context of AADC deficiency, patients may be able to naturally produce a small concentration of monoamines that would be protected by MAOIs from being broken down. Over 60% of the subjects in an international study tried an MAOI, such as selegiline and/or tranylcypromine.³ Benefits were reported by 35% of the subjects for selegiline and 18% of subjects for tranylcypromine.³ On the other hand, 27% of subjects reported adverse effects with selegiline and 6% for tranylcypromine.³ There were low medication discontinuation rates for both MAOI options (12% for selegiline, 6% for tranylcypromine).³

Pyridoxine: Pyridoxine is one of the six forms of vitamin B6 that is found in mammals.^9,10 Pyridoxine can be converted to a biologically active form of vitamin B6 like pyridoxal 5’-phosphate (PLP).^9,10 AADC is a PLP-dependent enzyme, which makes the synthesis of neurotransmitters dependent on PLP as well.¹⁰ In an international cohort of patients, 78% tried pyridoxine, but only 7% had noticeable improvement from the medication.³ None of the patients reported side effects from pyridoxine.³ These data indicate that the medication was well-tolerated, but had minimal benefits. 

Kebilidi Gene Therapy

Kebilidi is an adeno-associated virus serotype 2 (AAV2) vector-based gene therapy that is administered to patients in a single neurosurgical session.^1,2 During neurosurgery, surgeons deliver four infusions of Kebilidi into a brain region called the putamen.² The infused AAV contains a functional copy of the DDC gene that encodes the AADC enzyme.^2,5 Putamen cells take up the AAV and begin producing functional AADC in the putamen, leading to increased synthesis of neurotransmitters.²  

The Clinical Trial 

The safety and efficacy of Kebilidi was tested in an open-label, single-arm clinical study that enrolled 13 pediatric patients.^1,2 All clinical trial subjects were required to have a confirmed diagnosis of AADC deficiency, and analyses were completed by comparing subjects treated with Kebilidi to the natural progression of AADC deficiency in an untreated control cohort.^1,2 At baseline, all subjects had severe AADC deficiency, as exemplified by failing to achieve any gross motor milestones, having low AADC activity in the plasma, and failing to respond to therapies that were the standard of care.^1,2 The patients were treated with Kebilidi and monitored for adverse effects and changes in symptoms. One of the expedited programs that Kebilidi qualified for, the Accelerated Approval pathway, allows the product’s efficacy to be assessed using an intermediate clinical endpoint that should be able to be measured earlier than irreversible morbidity and mortality (IMM) and predict the product’s impact on IMM.^2,11,12 Treatment-induced changes in motor function can be measured early, and experts would expect early improvement in motor function to predict a long-term improvement in motor function and other long-term clinical benefits.² Therefore, motor function was measured as the intermediate clinical endpoint.^1,2 

The clinical study completed assessments to measure motor function in 12 of the 13 enrolled patients 48 weeks after receiving treatment.^1,2 The assessments demonstrated that Kebilidi had clinical efficacy since gross motor function improved in 8 of the 12 treated patients.^1,2 All 8 patients that improved reached a new gross motor milestone (full head control) on the Peabody Developmental Motor Scale second edition (PDMS-2).² Some of the patients improved dramatically. In terms of the highest motor milestone achieved, 2 patients were able to sit with or without assistance, 2 patients were able to walk backwards, and 1 patient was able to sit unassisted.² This reflects a massive improvement in motor function considering that all patients lacked head control at the beginning of the trial. The trial followed 44 untreated patients with AADC deficiency, and none of them had achieved any motor milestones at their last assessment.² Given the complete lack of improvement in untreated individuals, it was unexpected for two-thirds of the treated patients to reach new motor milestones and certainly unexpected for the improvement to be so stark.² Additional supporting data illustrated that Kebilidi increased the expression of dopamine metabolites in the cerebrospinal fluid and increased dopamine uptake in the putamen, consistent with Kebilidi’s mechanism of action.² There were some adverse reactions reported in the clinical trial, including dyskinesia (involuntary muscle movement), fever, low blood pressure, anemia, increased saliva production, insomnia, low ion levels, and procedural complications like cardiac and respiratory arrest.¹ Altogether, the FDA approved Kebilidi to treat AADC deficiency based on improved motor function (the intermediate clinical endpoint), additional supporting data, acceptable risks associated with Kebilidi considering the severity of AADC deficiency, and the lack of FDA-approved therapeutics for the disease.²

The Challenges of Pharmaceutical Development and the Need for Expedited Programs 

The Unmet Need: The available therapies described in the previous section arguably have limited benefits and often have adverse effects for patients with AADC deficiency. Prior to the development of Kebilidi, there was a clear unmet clinical need for a therapeutic to treat AADC deficiency, given the severity of the symptoms associated with the disease and the lack of available FDA-approved therapies. 

The Cost: The cost to develop a gene therapy and bring it to market is exorbitant. A recent calculation based on 25 cell and/or gene therapies estimated that research and development costs associated with the clinical development of a gene therapy would be an estimated US$1.94 billion.¹³ This is a massive financial burden that a clinical trial sponsor, the entity that is responsible for initiating the clinical trial (e.g. pharmaceutical company), would be taking on. 

The Regulatory Challenge: It is a near herculean challenge to bring a product from phase 1 clinical trials to the approval stage. One study suggests that phase 1 therapeutics have a 64-67% success rate at transitioning to phase 2, only 32-39% of phase 2 therapeutics successfully move to phase 3, 60-68% of phase 3 therapeutics will make it to a new drug application (NDA) or biologics license application (BLA), and then finally, there is a 83-86% likelihood of receiving FDA approval of the NDA or BLA.¹⁴ Suffice to say that there is significant risk associated with pharmaceutical development, and every sponsor must consider the likelihood of their product successfully navigating from phase 1 clinical trials to marketing authorization.

FDA’s Expedited Programs: The FDA has established several expedited programs that encourage the development of drugs, biologics, and medical devices that are meant to treat serious conditions where there is an unmet clinical need. The FDA defines serious conditions as those that significantly impact day-to-day functioning in a persistent, recurrent, or irreversible manner.¹⁵ These programs are extremely important for product development because they provide sponsors with benefits that ease financial and regulatory barriers. The high cost of development and the risk of failure in clinical trials make FDA’s expedited programs extremely valuable for a sponsor to acquire. PTC Therapeutics, Inc. took advantage of the financial and regulatory benefits that these expedited programs provided to develop Kebilidi to treat AADC deficiency.^1,2 Kebilidi qualified for several of the FDA programs that were launched to incentivize product development for serious disorders, including Accelerated Approval (Figure 2), Priority Review (Figure 3), an Orphan Drug Designation (Figure 4), and a Rare Pediatric Disease Priority Review Voucher (Figure 5).¹ The figures below detail the criteria required to qualify, the benefits earned by the sponsor, and the rationale for Kebilidi qualifying for each of the expedited programs.

Figure 2. Overview of the Accelerated Approval Pathway. To qualify for the Accelerated Approval pathway, the product must treat, prevent, or diagnose a condition with serious or life-threatening symptoms and fill an unmet need. In addition, the product’s efficacy should be assessed using a surrogate or an intermediate clinical endpoint that is measured earlier than and likely predicts its effect on irreversible morbidity or mortality (IMM).^2,11,12 Basing approval on a surrogate or an intermediate endpoint allows the clinical trial to be quicker and potentially smaller than it would be if the clinical trial was assessing the product’s effect on IMM.^12,15 According to the summary document, Kebilidi was approved based on an intermediate clinical endpoint (motor function) that was assessed 48 weeks after treatment and was expected to predict IMM.² The improvement in motor function was supported by additional data demonstrating increased expression of dopamine metabolites in the cerebrospinal fluid and dopamine uptake in the putamen, which show that AADC activity increased.² Additionally, Kebilidi meets the criteria for being a serious condition, and it fills an unmet need.^2,3 The image was created by the author.

Figure 3. Overview of the Priority Review Designation. To qualify for Priority Review, the product must treat, prevent, or diagnose a disease that has serious or life-threatening symptoms and, if approved, be a significant improvement compared to standard therapies.¹⁶ The benefit of having a Priority Review designation is that the FDA prioritizes reviewing the application and shortens the review period to 6 months as opposed to the standard review process that normally takes 10 months.¹⁶ Kebilidi met the criteria to qualify for the priority review designation because it treats a disease that has serious symptoms, including oculogyric crises and the inability to reach basic motor milestones like head control.^2,3 In addition, Kebilidi is the first treatment to be FDA-approved to treat AADC deficiency, and its efficacy in clinical trials represents a significant improvement compared to the standard of care therapies that have minimal benefits and adverse effects.^2,3 The image was created by the author.

Figure 4. Overview of the Orphan Drug Designation. To qualify for the Orphan Drug Designation, a product must treat, prevent, or diagnose a rare disease and/or the investment required to develop the product must outweigh expected sales.¹⁷ A condition is considered rare if it affects less than 200,000 people in the United States, according to Section 526 of the Federal Food, Drug, and Cosmetic Act.¹⁷ After qualifying, the product’s sponsor will earn tax credits, fee exemptions, and potentially, market exclusivity for 7 years.¹⁸ Kebilidi met the criteria to qualify as a treatment for a rare disease.^4,6 The image was created by the author.

 

 

 

 

 

Figure 5. Overview of the Rare Pediatric Disease Designation Priority Review Voucher Program. The Rare Pediatric Disease Designation has an associated Priority Review Voucher program. To qualify for the Rare Pediatric Disease Designation, a product must treat, prevent, or diagnose a condition that has serious or life-threatening symptoms that primarily affect pediatric populations (birth to 18 years of age), and the condition must be rare.^19,20 After qualifying, the product’s sponsor will receive a Priority Review Voucher that they can use for a different product of their choice.^19,20 Kebilidi met the criteria to qualify as a treatment for a serious pediatric disease that is rare.^2-4,6 Notably, this voucher program began phasing out at the end of December 2024 and will not be available for future marketing authorization applications.¹⁹ The image was created by the author.

 

The Outlook and Impact of Kebilidi

Kebilidi will continue to be monitored for safety and efficacy long-term in treated patients with AADC deficiency. According to the public letter that PTC Therapeutics, Inc. received for approval of Kebilidi’s BLA, the sponsor must conduct postmarketing studies to corroborate Kebilidi’s clinical benefit and confirm that the intermediate endpoint (motor function) did in fact predict IMM.²¹ The postmarketing studies will be completed at the end of 2028 and the final report is due at the end of September 2029.²¹ Continued FDA approval of Kebilidi is contingent upon the confirmatory trial substantiating its long-term clinical benefit.² 

Kebilidi has the potential to have a profound impact on patients’ lives, particularly for the patients that are the most severely impacted by AADC deficiency. Before Kebilidi’s approval, these patients were limited to off-label use of medications that had minimal benefits and adverse effects. However, the FDA’s expedited programs for serious conditions eased financial and regulatory barriers associated with product development enough that it sparked the development of Kebilidi for an exceptionally rare disease, effectively changing patients’ lives for the better. 

References

1. FDA approves first gene therapy for treatment of aromatic L-amino acid decarboxylase deficiency. Press release. FDA. Published November 14, 2024. Accessed December 12, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-aromatic-l-amino-acid-decarboxylase-deficiency 
2. Kebilidi summary basis for regulatory action. FDA. Published November 13, 2024. Accessed January 16, 2025. https://www.fda.gov/media/184353/download?attachment 
3. Pearson TS, Gilbert L, Opladen T, Garcia-Cazorla A, Mastrangelo M, Leuzzi V, Tay SKH, Sykut-Cegielska J, Pons R, Mercimek-Andrews S, Kato M, Lücke T, Oppebøen M, Kurian MA, Steel D, Manti F, Meeks KD, Jeltsch K, Flint L. AADC deficiency from infancy to adulthood: Symptoms and developmental outcome in an international cohort of 63 patients. J Inherit Metab Dis. 2020;43:1121-1130. doi: 10.1002/jimd.12247
4. Wassenberg T, Molero-Luis M, Jeltsch K, Hoffmann GF, Assmann B, Blau N, Garcia-Cazorla A, Artuch R, Pons R, Pearson TS, Leuzzi V, Mastrangelo M, Pearl PL, Lee WT, Kurian MA, Heales S, Flint L, Verbeek M, Willemsen M, Opladen T. Consensus guideline for the diagnoses and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis. 2017;12:12. doi: 10.1186/s13023-016-0522-z
5. DDC gene. Medline Plus. Updated May 13, 2024. Accessed January 17, 2025. https://medlineplus.gov/genetics/gene/ddc/ 
6. Aromatic L-amino acid decarboxylase deficiency. National Organization for Rare Disorders. Updated November 14, 2024. Accessed January 16, 2025. https://rarediseases.org/rare-diseases/aromatic-l-amino-acid-decarboxylase-deficiency/ 
7. Hyland K, Clayton PT. Aromatic amino acid decarboxylase deficiency in twins. J Inher Metab Dis. 1990;13(3):301-304. doi: 10.1007/BF01799380. 
8. MAOIs (monoamine oxidase inhibitors). Cleveland Clinic. Updated August 30, 2023. Accessed January 4, 2025. https://my.clevelandclinic.org/health/treatments/25220-maois-monoamine-oxidase-inhibitors 
9. Stover PJ, Field MS. Vitamin B-6. Adv Nutr. 2015;6(1):132-133. doi: 10.3945/an.113.005207
10. Higdon J, Drake VJ, Delage B, Gregory JF. Vitamin B6. Linus Pauling Institute at Oregon State University. Updated May 2024. Accessed January 24, 2025. https://lpi.oregonstate.edu/mic/vitamins/vitamin-B6 
11. Accelerated approval. FDA. Updated February 24, 2023. Accessed December 12, 2024. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval 
12. Expedited program for serious conditions – accelerated approval of drugs and biologics guidance for industry. FDA. Published December 2024. Accessed January 24, 2025. https://www.fda.gov/media/184120/download 
13. Sabatini MT, Chalmers M. The cost of biotech innovation: Exploring research and development costs of cell and gene therapies. Pharm Med. 2023;37:365-375. doi: 10.1007/240290-023-00480-0
14. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014;32:40-51. doi:10.1038/nbt.2786
15. Expedited programs for serious conditions – drugs and biologics guidance for industry. FDA. Published May 2014. Accessed January 28, 2025. https://www.fda.gov/files/drugs/published/Expedited-Programs-for-Serious-Conditions-Drugs-and-Biologics.pdf 
16. Priority review. FDA. Updated January 4, 2018. Accessed December 12, 2024.  https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review 
17. Orphan drug act – relevant excerpts. FDA. Updated March 9, 2018. Accessed December 12, 2024. https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/orphan-drug-act-relevant-excerpts 
18. Designating an orphan product: Drugs and biological products. FDA. Updated August 12, 2024. Accessed December 12, 2024.  https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/designating-orphan-product-drugs-and-biological-products 
19. Rare pediatric disease designation and priority review voucher programs. Updated September 27, 2024. Accessed December 12, 2024.  https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/rare-pediatric-disease-designation-and-priority-review-voucher-programs 
20. Rare pediatric disease priority review vouchers guidance for industry. FDA. Published July 2019. Accessed January 24, 2025. https://www.fda.gov/media/90014/download 
21. Kebilidi accelerated BLA approval letter. FDA. Published November 13, 2024. Accessed January 16, 2025.  https://www.fda.gov/media/183536/download?attachment 

Author: Kylie VanDerMolen 

Editors: Morgan McCullough and Michaela Price, PhD 

Today, we will be covering the landmark Food and Drug Administration (FDA)-approvals of the first gene therapies to treat sickle cell disease. On December 8, 2023, the FDA approved Casgevy (Vertex Pharmaceuticals Inc.), the first ever approval of a CRISPR-based genome editing therapeutic, and Lyfgenia (bluebird bio Inc.), a cell-based gene therapy, to treat sickle cell disease (SCD) in patients 12 years or older with vaso-occlusive events. In this post, we will introduce sickle cell disease and the available options for its treatment, discuss CRISPR/Cas9 gene editing and the mechanisms of action for Casgevy and Lyfgenia, and conclude with an overview of the clinical and economic impact of these approvals. 

Overview of Sickle Cell Disease

Current Therapeutic Landscape

CRISPR/Cas9 Gene Editing

Mechanisms of Action

Both Casgevy and Lyfgenia are ex vivo gene therapies that utilize the patients’ own stem cells (CD34+ cells) from their blood, which are removed, edited, and infused back in via a single-dose hematopoietic stem cell transplant.¹⁵ Patients’ diseased cells are removed from their bone marrow with high-dose chemotherapy before the modified blood cells are replaced via Casgevy/Lyfgenia.¹⁵ Casgevy directly edits the DNA in patients’ CD34+ cells, where the CRISPR/Cas9 machinery is delivered via non-viral electroporation.¹⁶ The Cas9 complex targets the red blood cell-specific enhancer of the BCL11A gene, which encodes a transcription factor that suppresses transcription of the γ-globin genes after birth.^17,18 γ-globin complexes with α-globin to make up the fetal version of hemoglobin (HbF), which has been found to inhibit polymerization of HbS by reducing its concentration.^5,18 In Casgevy, the CRISPR/Cas9 machinery makes double-stranded breaks in the BCL11A gene that are repaired erroneously by NHEJ, effectively causing loss-of-function of the BCL11A transcription factor. In turn, γ-globin expression is re-activated in the patient when the cells are re-integrated, and the resultant increased level of HbF reduces red blood cell sickling.  

The mechanism of action for Lyfgenia is distinct from CRISPR/Cas9 gene editing. Lentiviral vectors remain the most popular gene delivery system for gene therapies in monogenic diseases.¹⁹ In Lyfgenia, the patients’ stem cells are transduced with a lentiviral vector that carries the sequence for the β-globin gene that encodes an amino acid substitution (T87Q).²⁰ Once the cells are re-infused into the body, the modified sequence will be integrated into the host genome of the cell, and the cell will transcribe this modified gene to make β^A-T87Q-globin.²⁰ β^A-T87Q-globin pairs with α-globin to make HbA^T87Q, which functions similarly to normal HbA while reducing levels of HbS and sterically inhibiting HbS polymerization to reduce red blood cell sickling.²⁰  

There are risks associated with both methods of gene delivery. Lentiviruses preferentially integrate into regions of active transcription in the genome, leaving a risk for insertion into places in the genome that may inappropriately alter transcription of important genes, such as silencing tumor suppressor genes or activating proto-oncogenes that then lead to the development of cancer.¹⁹ Several measures have been taken to optimize and improve safety of lentiviral vector use in the clinical setting.¹⁹ In contrast, CRISPR/Cas9 edits the genome in a precise manner and can be delivered via a non-viral method, but the risk of off-target editing remains. These complications have not been observed thus far with the use of either therapy.¹⁷ 

Clinical and Economic Significance

These innovative gene therapies hold substantial power to cure SCD, and the first approval of CRISPR/Cas9 for clinical use is monumental as a precedent for the continued treatment of diseases with genetic causes. As of March 2024, there are clinical trials utilizing CRISPR technology in 9 different disease areas, including two phase 1/2 trials to treat SCD with promising efficacy and safety data and one currently enrolling for a phase 1 trial. ²¹ 

As of August 2024, bluebird bio has started cell collection on four patients for Lyfgenia treatment in the U.S., and as of November 2024, Vertex Pharmaceuticals has started cell collection on 40 patients for Casgevy worldwide.^22,23 Bluebird has 70 qualified treatment centers for administration of the therapeutic, and Vertex has 45 treatment centers with a goal of 75 and an estimated global patient pool of 58,000. ^22,23 

Logistically and financially, the use of these gene therapies is still complicated. Access to facilities with the appropriate technology to administer the treatment is limited, and treatment is estimated to cost around $2-3 million per patient.^21,24 However, this is approximately consistent with the cost of lifetime treatment for SCD, which was estimated at $1.7 million in 2022 with about $44,000 of out-of-pocket costs for non-elderly patients.²⁵ In 2016, the total economic burden for SCD patients was $811 million in the United States.²⁵ An estimated 50-60% of SCD patients are on Medicaid, and the projected cost to provide gene therapy treatment to all Medicaid-insured patients with severe SCD in 10 states is $5.5 billion, which presents a significant challenge to affordability.^24,25 Bluebird reported progress toward accessible treatment, stating that more than half of Medicaid-insured SCD patients in the U.S. are in states that have affirmed Lyfgenia coverage, and nearly 20% are in states that have already authorized approval for treatment for at least one resident.²² To reduce barriers to accessing these treatments, the Centers for Medicare and Medicaid Services (CMS) has developed the Cell and Gene Therapy (CGT) Access Model, through which the federal government will negotiate lower prices for treatment with Vertex and bluebird on behalf of state Medicaid agencies.²⁴ Continued efforts to improve these genome editing therapies are driven by a push for minimizing costs while improving safety and experience, which will be key for overall reduction of lifetime medical costs and economic burden of SCD on patients and payers.²¹  

Not only are SCD gene therapies costly, but their development is also expensive. High costs of clinical trials and financial pressures from investors have led to layoffs in companies focused on CRISPR-based gene therapies.²¹ There is acknowledgement of a need for change in regulatory approaches to improve development of these therapeutics, especially for rare diseases. One solution in development for CRISPR therapies is platform technology, where all components of a treatment are packaged together, and changes are made per disease in order to reduce regulatory burden and streamline drug development.²¹ The U.S. Congress passed the Food and Drug Omnibus Reform Act (FDORA) in 2022, which includes the Platform Technology Designation Program to facilitate this development.²⁶ The balance between innovative medicine and affordability presents a constant challenge, but the overall societal benefit for curative therapies continues to drive the development of breakthrough drugs, such as Casgevy and Lyfgenia. 

References

1. Brandow AM, Liem RI. Advances in the diagnosis and treatment of sickle cell disease. J Hematol Oncol. 2022;15(1):20. doi:10.1186/s13045-022-01237-z 

2. GBD 2021 Sickle Cell Disease Collaborators. Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the Global Burden of Disease Study 2021. Lancet Haematol. 2023;10(8):e585-e599. doi:10.1016/S2352-3026(23)00118-7 

3. Sickle cell disease. NIH National Heart, Lung, and Blood Institute. Updated September 30, 2024. Accessed December 20, 2024. https://www.nhlbi.nih.gov/health/sickle-cell-disease 

4. Elendu C, Amaechi DC, Alakwe-Ojimba CE, et al. Understanding sickle cell disease: Causes, symptoms, and treatment options. Medicine (Baltimore). 2023;102(38):e35237. doi:10.1097/MD.0000000000035237 

5. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757):2018-2031. doi:10.1016/S0140-6736(10)61029-X 

6. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med. 1995;332(20):1317-1322. doi:10.1056/NEJM199505183322001 

7. Stevens DL, Hix M, Gildon BL. Crizanlizumab for the prevention of vaso-occlusive pain crises in sickle cell disease. J Pharm Technol. 2021;37(4):209-215. doi:10.1177/87551225211008460 

8. Sadaf A, Quinn CT. L-glutamine for sickle cell disease: Knight or pawn? Exp Biol Med (Maywood). 2020;245(2):146-154. doi:10.1177/1535370219900637 

9. Ali MA, Ahmad A, Chaudry H, et al. Efficacy and safety of recently approved drugs for sickle cell disease: a review of clinical trials. Exp Hematol. 2020;92:11-18.e1. doi:10.1016/j.exphem.2020.08.008 

10. Adel AM, Abushanab D, Al-Badriyeh D, Hamad A, Alshurafa A, Yassin MA. Cost-effectiveness of L-glutamine versus crizanlizumab for adults with sickle cell disease: model focused on reducing pain episode costs from Qatar’s healthcare perspective. SAGE Open Med. 2024;12:20503121231224551. doi:10.1177/20503121231224551 

11. Singh A, Irfan H, Fatima E, Nazir Z, Verma A, Akilimali A. Revolutionary breakthrough: FDA approves CASGEVY, the first CRISPR/Cas9 gene therapy for sickle cell disease. Ann Med Surg (Lond). 2024;86(8):4555-4559. doi:10.1097/MS9.0000000000002146 

12. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816-821. doi:10.1126/science.1225829 

13. Asmamaw M, Zawdie B. Mechanism and applications of CRISPR/Cas-9-mediated genome editing. Biologics. 2021;15:353-361. doi:10.2147/BTT.S326422 

14. Morshedzadeh F, Ghanei M, Lotfi M, et al. An update on the application of CRISPR technology in clinical practice. Mol Biotechnol. 2024;66(2):179-197. doi:10.1007/s12033-023-00724-z 

15. FDA approves first gene therapies to treat patients with sickle cell disease. Press release. FDA. Published December 8, 2023. Accessed December 27, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease 

16. Molaei Z, Jabbarpour Z, Omidkhoda A, Ahmadbeigi N. Exploring non-viral methods for the delivery of CRISPR-Cas ribonucleoprotein to hematopoietic stem cells. Stem Cell Res Ther. 2024;15(1):233. doi:10.1186/s13287-024-03848-4 

17. Vertex Pharamceuticals Inc. Casgevy (exagamglogene autotemcel). Mechanism of action. Published January 2024. Accessed December 27, 2024. https://www.casgevyhcp.com/sickle-cell-disease/mechanism-of-action 

18. Bauer DE, Orkin SH. Hemoglobin switching’s surprise: the versatile transcription factor BCL11A is a master repressor of fetal hemoglobin. Curr Opin Genet Dev. 2015;33:62-70. doi:10.1016/j.gde.2015.08.001 

19. Poletti V, Mavilio F. Designing lentiviral vectors for gene therapy of genetic diseases. Viruses. 2021;13(8):1526. doi:10.3390/v13081526 

20. bluebird bio. Lyfgenia (lovotibeglogene autotemcel). Mechanism of action. Published December 2023. Accessed December 27, 2024. https://www.lyfgeniahcp.com/mechanism-of-action 

21. Henderson H. CRISPR clinical trials: A 2024 update. Innovative Genomics Institute. Perspectives. Published March 13, 2024. Accessed January 2, 2025. https://innovativegenomics.org/news/crispr-clinical-trials-2024/ 

22. Dunleavy K. Bluebird stock plummets 18% with slow uptake of sickle cell disease gene therapy Lyfgenia. Fierce Pharma. Published August 14, 2024. Accessed January 2, 2025. https://www.fiercepharma.com/pharma/bluebird-making-progress-appears-trail-vertex-patient-starts-sickle-cell-disease 

23. Becker Z. Vertex’s Casgevy breaks ground with 1st commercial patient infusions as company readies another major launch. Fierce Pharma. Published November 5, 2024. Accessed January 2, 2025. https://www.fiercepharma.com/pharma/vertex-casgevy-breaks-ground-commercial-market-first-patient-infusions-company-prepares 

24. Hassanein N. New way for states to cover pricey gene therapies will start with sickle cell disease. States Newsroom: Stateline. Published March 14, 2024. Accessed January 2, 2023. https://stateline.org/2024/03/14/new-way-for-states-to-cover-pricey-gene-therapies-will-start-with-sickle-cell-disease/#:~:text=The%20two%20gene%20therapy%20treatments,%243.1%20million%20per%20patient%2C%20respectively  

25. Johnson KM, Jiao B, Ramsey SD, Bender MA, Devine B, Basu A. Lifetime medical costs attributable to sickle cell disease among nonelderly individuals with commercial insurance. Blood Adv. 2023;7(3):365-374. doi:10.1182/bloodadvances.2021006281  

26. Liermann A, McCombs C. Feedback on FDA’s platform technology designation program includes addressing post-approval changes. American Society of Gene + Cell Therapy. Policy & Advocacy. Published September 23, 2024. Accessed January 2, 2025. https://www.asgct.org/publications/news/september-2024/feedback-on-fda-s-platform-technology-designation#:~:text=The%20Platform%20Technology%20Designation%20Program,platforms%20across%20drug%20development%20programs 

Authors: Chip Norwood & Oleg Kolupaev

Today, we are here with another post covering kinase inhibitors specifically related to cancer. We will cover several topics within this post, including: 1) the impact of cancer on human health, 2) a general overview of kinase inhibitors, 3) types of kinase inhibitors, and 4) clinical and commercial significance of these therapeutics.

Impact of Cancer on Human Health

According to the National Cancer Institute (NCI) analysis in 2018, an estimated 1.8 million new cases of cancer will be diagnosed in the United States (US) and 609,000 people will die from this disease.¹ The national expenditure for cancer care in the US alone in 2017 was $147.3 billion, which is expected to continually rise. Hence, it is no surprise that efforts toward finding a suitable solution to this disease have been made over many decades. Indeed, the scientific community has made significant strides and a multitude of therapies have been developed, for example, chemotherapy. Chemotherapy uses small molecules to combat cancer cells through a variety of mechanisms.

Introduction to Protein Kinases

            Protein kinases catalyze phosphorylation of various substrates (e.g. proteins) that usually contain tyrosine, serine, and threonine (Scheme 1).^2-5 Specifically, the terminal phosphate of adenosine triphosphate (ATP) is transferred to tyrosine, threonine, and serine within substrates. Subsequently, this resultant phosphorylation initiates a plethora of events within the cell, for example, phosphorylation could mark a protein for degradation.

Scheme 1. General transformation performed by protein kinases.

Dysregulation of kinases has been found to play a major role in the development of cancer (i.e., tumor cell proliferation and survival).⁵ So, the elucidation of the intricate role of kinases in the progression of cancer spurred the development of inhibitors of these proteins.

Types of Protein Kinase Inhibitors

Mostly, kinases are targeted at the binding site of its endogenous ligand ATP. There is high conservation in this binding site among all kinases; that is, the conserved DFG (apartate-phenylalanine-glycine) and APE (alanine-proline-glutamate) motifs at the start and end of the activation loop.^2-5  This activation loop can adopt a large number of conformations which yield the protein either catalytically active or inactive. Substrate binding is either allowed or inhibited based on the position of the activation loop, which is sometimes referred to either the DFG-in or DFG-out confirmation, respectively.

Inhibitors have been categorized based on their binding to kinases. We’ll go over type I–III inhibitors, their binding modes to kinases, and a historical timeline of FDA-approved kinase inhibitors.

Type I & II Inhibitors

Type I inhibitors are directly competitive with ATP and recognize a conformation of the kinase which can facilitate phosphorylation. Typically, these inhibitors consist of a heterocycle which occupies the purine binding site that interacts with hydrophobic region II and II (e.g., Figure 2A). Several examples of type I inhibitors include Bosutinib, Gefitinib, Vandetanib, and Erlotinib (Figure 2B).

Figure 2. A. ABL1 in complex with the type I ATP-competitive inhibitor PD166326.⁵ B. Select FDA-approved type I kinase inhibitors.

In contrast, type II inhibitors bind the inactive conformation of kinases or DFG motif oriented “out” (Figure 3A). These inhibitors possess a motif that further extends into an allosteric site form hydrogen bonding interaction with conserved residues including DFG. Examples of FDA-approved type II inhibitors include Sorafenib, Imatinib, and Ponatinib (Figure 3B).

Figure 3. A. ABL1 in complex with the type II ATP-competitive inhibitor Imatinib.⁵ B. Select FDA-approved type II kinase inhibitors.

Type III Inhibitors

These inhibitors typically have the most selectivity for a specific kinase due to occupying an allosteric site unique to the kinase it inhibits.⁴ This is an area of intense research which has culminated in two FDA-approved drugs Trametinib and Cobimetinib (Figure 4).

Figure 4. Select FDA-approved type III kinase inhibitors.

Protein Kinase Inhibitor Market

Protein kinases are key components of signaling pathways orchestrating a variety of processes inside the cells: from cell cycle to differentiation to metabolism. This class of enzymes is also often dysregulated in malignant cell transformation, autoimmune, and inflammatory conditions making them a promising target for drug development.

Since the historic approval of BCR-ABL inhibitor imatinib (Gleevec), more than 70 drugs targeting a diverse array of protein kinases have been developed over the past 20 years. The total size of this market in 2018 was estimated to be $46.4 billion and was expected to grow 4% annually. More than half of the approved protein kinase inhibitors on the market target a subclass known as tyrosine kinases. About 1/3 of the drugs were designed to inhibit activity of receptor tyrosine kinases (EGFR, PDGFR, HER2) and 2/3 target non-receptor tyrosine kinases (BCR-ABL, BTK, JAK).

Historically, most protein kinase inhibitors were developed for oncology indications; however, development and repurposing of these drugs for inflammatory diseases and other conditions have been pursued. It is almost impossible to capture all the developments in this market in our short article. Here, we would like to provide two snapshots of the state of the market and competition for (1) receptor tyrosine kinase inhibitors of epithelial growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) and (2) non-receptor tyrosine kinase inhibitors of Bruton’s tyrosine kinase (BTK) in several non-Hodgkin lymphomas.

Receptor TKI of EGFR in Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the second most common form of cancer among women and men in the US. There are two major types of lung cancer: non-small cell lung cancer (NSCLC, 84%) and small cell lung cancer (SCLC, 13%). To further stratify these two, groups clinicians use histology characteristics and biomarker expression of the tumor cells for categorization. Mutations in KRAS, EGFR, ALK, or BRAF are found in more than half of all lung cancers and play an important role in tumor biology. These mutated proteins serve as biomarkers in selection of targeted therapies.

EGFR was one of the early targets for tyrosine kinase inhibitors in solid tumors, including NSCLC. Two EGFR inhibitors were approved for NSCLC patients by the FDA in the early 2000s: Iressa (gefitinib) marketed by AstraZeneca and Terceva (erlotinib) marketed by Roche. Both drugs are still being used in clinic today and are listed as ‘recommended’ for NSCLC patients with EGFR mutations in National Comprehensive Cancer Network (NCCN) guidelines. Second-generation of EGFR inhibitors reached the market in 2010. Boehringer Ingelheim’s Gilotrif (afatinib) and Pfizer’s Vizimpro (dacomitinib) both offered improved progression-free and overall survival compared to first-generation drugs.

In 2018 AstraZeneca’s third-generation inhibitor Tagrisso (osimertinib) was approved as a first-line treatment for metastatic NSCLC with mutated EGFR based on a FLAURA phase III clinical trial. The study demonstrated improved overall survival compared to the Iressa and Terceva. Having secured a ‘preferred’ status for late-stage NSCLC harboring EGFR mutations, AstraZeneca is conducting clinical trials to expand Tagrisso’s indication for the treatment of patients at the earlier stages of the disease.

In the market, Tagrisso absolutely dominates the mutated EGFR TKI category for NSCLC. Major competitors are monoclonal antibody therapies in combination with legacy TKIs, or chemotherapy, as evidenced by the recent approval of Eli Lilly’s anti-angiogenic drug Cyramza (ramucirumab) in combination with Terceva.

Figure 5. Sales of EGFR inhibitors in NSCLC.

Non-receptor TKI in NHL

Non-Hodgkin lymphoma (NHL) is one of the most common lymphomas. According to the American Cancer Society it contributes to about 4% of all cancer cases in the US. BTK inhibition represents a targeted approach to treat several subtypes of  B-lymphoid NHL, namely: mantle cell lymphoma (MCL), chronic lymphoblastic leukemia (CLL), marginal zone lymphoma (MZL), Waldelstrom microglobulemia (WM).

The first BTK inhibitor Imbrubica (ibrutinib) was approved by the FDA for an aggressive subtype of NHL – mantle cell lymphoma in 2013. Subsequently, Abbvie/J&J expanded the drug’s therapeutic window for the most common subtype of NHL – CLL (2014) and later for WM and MZL. Today, Imbruvica is listed as a preferred drug for these indications in NCCN guidelines. This position in the clinic propelled the drug to blockbuster status with $7.24 billion in sales in 2019.

Several competing BTK inhibitors have emerged for MZ and CLL/SLL indications in recent years. These second-generation agents demonstrated a more favorable safety profile, particularly low rate of heart-related side effects in late-stage clinical trials.

AstraZeneca has received an FDA approval for Calquence (acalabrutinib) for MCL treatment in 2017. The label was expanded in November of 2019 to include treatment of patients with CLL after successful ASCEND and ELEVATE phase III clinical trials. AstraZeneca reported $162 million in sales for Caquence in 2019 and $193 million in the first half of 2020. Analysts expect sales for the drug to grow as the company continues to get approvals outside of the US. If clinical trials go well with Caquence in patients with CLL, AstraZeneca’s drug can potentially replace Imbruvica as a ‘preferred’ treatment. This event could further accelerate sales after 2021.

Competition in this treatment area will grow fierce once BeiGene’s Brukinsa enters the CLL/SLL market. Currently, the drug is approved for use as a second-line treatment for relapsed/refractory MCL in the US. The drug is being studied as a front-line therapy for patients with CLL/SLL and WM in late-stage clinical trials.

Figure 6. Sales of Imbruvica and Caquence.

References:

1. Cancer Statistics. https://www.cancer.gov/about-cancer/understanding/statistics (accessed Aug 15, 2020)
2. Non-Hodgkin Lymphomas Statistics. https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/key-statistics.html (accessed Aug 15, 2020)
3. Lung Cancer Statistics. https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html (accessed Aug 15, 2020)
4. Kinase Inhibitors: The Road Ahead. Rev. Drug Discov. 2018, 17, 353–376.
5. My Journey from Tyrosine Phosphorylation Inhibitors to Targeted Immune Therapy as Strategies to Combat Cancer. PNAS 2019, 116, 11579-11586.
6. Properties of FDA-Approved Small Molecule Protein Kinase Inhibitors: A 2020 Update. Res. 2020, 152, 104609.
7. Targeting Cancer with Small Molecule Kinase Inhibitors. Rev. Cancer 2009, 9, 28–39.

8. Kinase Inhibitors Market. https://www.transparencymarketresearch.com/kinase-inhibitors.html (accessed Aug 15, 2020)

9. The top 20 drugs by global sales in 2019. https://www.fiercepharma.com/special-report/top-20-drugs-by-global-sales-2019 (accessed Aug 14, 2020)

10. Non-small Lung Cancer. NCCN Clinical Practice Guidelines. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf (accessed Aug 7, 2020)

11. Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. N Engl J Med 2018; 378, 113-125.

12. Review of Bruton tyrosine kinase inhibitors for the treatment of relapsed or refractory mantle cell lymphoma. Curr. Oncology, 2019, 26(2), e233–e240

13. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol,  2020, 38 (25), 2849-2861.

14. ELEVATE TN: Phase 3 Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone Vs O Plus Chlorambucil (Clb) in Patients (Pts) with Treatment-Naive Chronic Lymphocytic Leukemia (CLL). Blood, 2019,134 (Supplement_1), 31.

15. BeiGene nabs landmark FDA nod for Brukinsa, kicking off challenge against blockbuster Imbruvica. https://www.fiercepharma.com/marketing/beigene-nabs-landmark-fda-nod-for-brukinsa-kicking-off-challenge-against-blockbuster (accessed Aug 15, 2020)

Authors: Chip Norwood & Oleg Kolupaev

Today, our first-ever The Pipeline Blog post will cover the antiviral drug Remdesivir. This therapeutic has received a lot of attention from the media and researchers across the globe to treat COVID-19. Herein, we detail several topics related to Remdesivir, including its discovery, mechanism of action, clinical data, and commercialization.

According to the World Health Organization (WHO), COVID-19 which is caused by the SARS-CoV-2 viral strain has affected over 2 million people globally. This virus has been extremely detrimental worldwide resulting in 435,000 deaths. Due to these facts, a spur of research was initiated to discover effective tests and therapeutics to diagnose and treat the current pandemic. Remdesivir (GS-5734) was developed by Gilead Sciences and discovery stemmed from a collaboration between Gilead, U.S. Centers for Disease Control and Prevention (CDC), and the U.S. Army Medical Research Institute of Infectious Disease (USAMRIID). The primary purpose of this collaboration was to identify therapeutic agents for RNA-based viruses that had global pandemic potential (e.g., SARS).

Like other viruses in the coronavirus family, SARS-CoV-2 is an enveloped virus covered in a plethora of spike proteins which are utilized to avoid the host’s immune system and assist in cell-binding/entry. In detail, SARS-CoV-2 utilizes the receptor angiotensin-converting enzyme 2 (ACE2) for cell entry and infection. Viral entry into the host cell initiates a cellular cascade which eventually leads to translation and RNA replication, packaging, and virion release. Remdesivir targets the translation and RNA replication stage of the virus by inhibiting the RNA-dependent RNA polymerase (RdRp). This results in chain termination and decreased viral RNA production.

The mechanism of action of Remdesivir is dictated by its chemical structure which is composed of two key components including the prodrug (highlighted blue, see below) and nucleoside (highlighted black, see below). The prodrug segment of this drug allows for better cell-permeability. Subsequently, Remdesivir undergoes several key intracellular transformations, including: 1) cleavage of the ester via an esterase, 2) cleavage of the phosphorylamine group via phosphoramidase, and 3) phosphorylation via nucleoside-phosphate kinase. The resultant active metabolite is shuttled to be incorporated into the growing RNA chain and initiate chain termination.

Remdesivir was forwarded to clinical studies due to its promising activity against SARS-CoV-2. Two separate studies found that recovery speeds increased (i.e., 11 vs. 15 days) with Remdesivir treatment in comparison to the control group. Based on these results, Remdesivir has been granted emergency use authorization by the FDA. A variety of phase 2–3 clinical trials are underway with adult or pediatric patients investigating either Remdesivir alone or in combination with other drugs such as the anti-inflammatory agent Baricitinib. In June, Gilead, the maker of Remdesivir, announced a phase I clinical trial of an inhalable formulation of the drug that could be administered outside of a hospital setting.

Several additional antiviral drugs that operate through similar mechanisms of action are being investigated as well, namely, Favipiravir and EIDD-2801.

Favipiravir (Avigan) was developed by Fujifilm Pharmaceuticals for influenza aimed at patients with new influenza strains with pandemic potential. The mechanism of action for Favipiravir is believed to be like Remdesivir by targeting RdRp in SARS-CoV-2. Two clinical trials are underway in the US which are sponsored by Fujifilm Pharmaceuticals and Stanford University examining the time intervals of viral clearance in the upper airways of patients. Moreover, in Russia, Favipiravir has been granted emergency use status by the Ministry of Health of the Russian Federation due to positive results obtained from initial clinical studies. DCGI, an Indian drug regulator, also approved Favipiravir for treating patients with mild-to-severe symptoms of COVID-19.

EIDD-2801 is a broad-spectrum antiviral agent that was developed by Emory University which is orally bioavailable. This compound was found to be active against SARS-CoV-2 and other RNA viruses after being evaluated by researchers at Vanderbilt and UNC-Chapel Hill. Additionally, a study in MERS- and SARS-infected mice found that EIDD-2801 reduced the pathogenesis of these viruses when administered. In March 2020, this compound was licensed to Ridgeback Biotherapeutics for phase 1 clinical trials, soon after, Merck and Ridgeback Biotherapeutics signed a strategic collaboration for Merck to commercialize EIDD-2801 and its derivatives.

In conclusion, more time must pass to reveal the effectiveness of antiviral drugs at combating this terrible pandemic. Development of orally bioavailable drugs with a safe profile will be a huge step forward and will be extremely beneficial to patients. In addition, vaccines are currently being pursued as well, which opens another window of opportunity.

References & Further Reading:

1. Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS Cent. Sci. 2020, 6, 672–683.
2. Antiviral Therapy in Management of COVID-19: a Systematic Review on Current Evidence. Archive of Academic Emergency Medicine 2020, 8, e45.
3. Approved antiviral drugs over the past 50 years. Microbiol. Rev. 2016, 29, 695–747.
4. Remdesivir for 5 or 10 days in patients with severe COVID-19. Engl. J. Med. 2020, DOI: 10.1056/NEJMoa2015301.
5. Remdesivir for the treatment of COVID-19 — Preliminary report. Engl. J. Med. 2020, DOI: 10.1056/NEJMoa2007764.
6. Coronavirus (COVID-19) Update: FDA issues emergency use authorization for potential COVID-19 treatment. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment (accessed June 22, 2020)
7. Oral Favipiravir compared to placebo in subjects with mild COVID-19; Study of the use of Favipiravid in hospitalized subjects with COVID-19. https://clinicaltrials.gov/ct2/results?term=favipiravir&cond=COVID-19&cntry=US&draw=2&rank=1#rowId0 (accessed June 22, 2020).
8. Russians claim to have an effective treatment for the coronavirus, which hospitals will start using this month. https://www.cnbc.com/2020/06/01/russia-approves-drug-to-treat-covid-19-hospitals-to-use-in-june.html. (accessed June 22, 2020).
9. COVID-19 First in human study to evaluate safety, tolerability, and pharmacokinetics of EIDD-2801 in healthy volunteers. https://clinicaltrials.gov/ct2/show/NCT04392219 (accessed June 22, 2020).
10. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Science Transl. Med. 2020, 12, eabb5883.