Rapamycin + Rapalogs

Author: Kylie VanDerMolen
Editor: Ashley Aguillard

Today, I will be discussing rapamycin and its various analogs, called “rapalogs,” that have been developed for improved pharmacological properties and therapeutic uses. There are seven brand name rapamycin/rapalog therapeutics (five generics) that have been approved by the U.S. Food and Drug Administration (FDA) mainly as immunosuppressants or cancer/tumor inhibitors; however, there is a broad range of ongoing research to expand the use of these drugs to treat various other conditions, such as metabolic, neurodegenerative, and age-related diseases. I will start with an introduction to rapamycin and the pathophysiological significance of its target protein, mechanistic Target Of Rapamycin (mTOR). I will then cover the approved rapamycin and rapalog therapeutics, briefly touch on a category of rapamycin-related medical devices, and finally, discuss the future of this class of drugs and the ongoing studies intended to expand the range of their therapeutic use.

Introduction to rapamycin and mTOR signaling

The discovery of rapamycin dates back to a 1964 Canadian expedition to the Chilean territory of Easter Island, called Rapa Nui (Rapamycin’s namesake), from which researchers collected soil samples to study the diversity of microorganisms on the island in an effort to uncover novel natural products.¹ The Gram-positive bacterial species Streptomyces hygroscopicus was isolated and found to produce rapamycin, a molecule later determined to be an antibiotic and antifungal with immunosuppressive and antiproliferative effects on cells.^1,2 Further studies revealed that rapamycin is a potent inhibitor of a protein kinase named for this interaction – mechanistic Target Of Rapamycin (mTOR).² Protein kinases add a phosphate group to target substrates (i.e. other proteins) to alter their activity. This process is a key component of protein signaling pathways that ultimately lead to the regulation of important biological processes. mTOR exists in two complexes (mTORC1 and mTORC2), which are distinguished by their inclusion of distinct proteins (see Figure 1). Notably, rapamycin is thought to be a specific inhibitor of mTORC1 through formation of a complex with Fk506-binding protein 12 kDa (FKBP12) that disrupts the ability of mTORC1 to interact with its substrates (otherwise known as allosteric inhibition).² However, chronic treatment of some cell types with rapamycin has been proposed to also inhibit mTORC2.²

Since its initial identification as the mechanism of the valuable properties of rapamycin, mTOR signaling has become considered a key regulator of biological processes necessary for cell growth and proliferation, particularly in metabolic anabolism, or the building of complex biological molecules (macromolecules).^2,3 mTORC1 has been well-characterized as a key nutrient sensor, integrating signals about nutrient availability to navigate the generation of the building blocks of cells, such as proteins and fats. Less is known about mTORC2, but it is also thought to use similar signals to contribute to the production of macromolecules and regulation of cell proliferation and survival.² Overactive mTOR signaling can lead to over-proliferation of cells that become cancerous. The genes TSC1 and TSC2 (Tuberous Sclerosis Complex 1 and 2) encode for proteins that inhibit mTORC1, thereby regulating tumor suppression.² Because of its robust regulation of cell proliferation, inhibition of mTOR signaling has become a prominent mechanism for anti-cancer and anti-tumor therapeutics.³ Additionally, mTOR inhibitors are useful for suppressing unwanted cell proliferation that promotes rejection of organ transplants and other conditions associated with the genetic disease caused by mutations in the TSC1 and TSC2 genes.² However, inhibition of mTOR also has promising anti-aging and lifespan extending effects, which has led to ongoing clinical trials to expand their approval into treatment for age-related diseases.² The anti-aging effects of mTOR inhibition by rapamycin are, in part, attributed to its activation of a process called autophagy, which removes unwanted cellular debris and damaged proteins and organelles.⁴ These components are thought to accumulate with age and cause negative effects associated with disease.⁴ I will discuss some ongoing clinical trials and promising results in the conclusion of this post.

Sirolimus: the first FDA approval of rapamycin

Sirolimus systemic

Rapamune

The FDA first approved rapamycin, also known by its generic name, sirolimus, under the brand name Rapamune to Wyeth-Ayerst Research (acquired by Pfizer in 2009) in 1999 as an oral solution and in 2000 as an oral tablet for the prevention of organ rejection in kidney transplant patients.⁵ When a patient receives an organ transplant, the body may recognize foreign molecules, or antigens, from the donor organ via specialized immune cells called T cells.^6,7 T cells trigger the immune response, which ultimately leads to the neutralization and destruction of cells with the foreign antigen via antibodies.⁷ This can cause organ damage and ultimately lead to organ failure.⁶ Treatment with immunosuppressive agents inhibits this immune response and significantly reduces the risk of rejection. Therefore, organ donor recipients are prescribed lifelong immunosuppressive intervention.⁶ Sirolimus effectively restricts the proliferation of immune T cells through inhibition of mTORC1, thus reducing the attack on the donor organ by the immune system.³ Pfizer later expanded the indicated use of Rapamune in 2015 when the FDA approved its use for the treatment of lymphangioleiomyomatosis (LAM).⁸ LAM is a rare, progressive disease that affects the lungs primarily, but also kidney and lymphatic system function.⁹ LAM symptoms occur due to abnormal cell growth in the affected tissues, leading to respiratory dysfunction, cysts, and tissue damage.⁹ Sirolimus combats this cell growth via inhibition of pro-growth mTORC1 signaling to help stabilize lung function. Importantly, Rapamune became the first approved treatment for this condition.⁸ The brand name drug, Rapamune, was discontinued by Pfizer in 2023 after a determination that the availability of generic sirolimus was sufficient to meet the therapeutic need in the U.S.¹⁰

Sirolimus protein-bound systemic

Fyarro

Sirolimus has also been approved for the most common area of indication for rapamycin/rapalogs – cancer treatment. Aadi Bioscience developed a sirolimus protein-bound particle for injectable suspension (albumin-bound) to treat local, advanced malignant perivascular epithelioid cell tumors (PEComa) associated with blood vessel walls that are unresectable or metastatic. This therapeutic was approved under the brand name Fyarro in 2021 by the FDA.¹¹ PEComa is a rare, aggressive connective tissue cancer that is frequently driven by mTOR overactivation caused by mutations in TSC1 and TSC2, leading to cell over-proliferation and tumor formation.¹² Fyarro utilizes a technology called nanoparticle albumin-bound (nab) particles, meaning that sirolimus molecules are attached to small particles of albumin (a naturally occurring protein in human blood).^12,13 This technique is particularly useful for therapeutics that are not very soluble in blood and those that are highly toxic, like anticancer drugs.¹³ Nab technology allows for improved drug delivery due to its natural compatibility with movement through the bloodstream. Importantly, sirolimus nab particles have significantly higher specificity, efficacy, and potency than oral mTOR inhibitors in nonclinical studies of human bladder cancer tumors in mice.^12,13

Sirolimus topical

Hyftor

The most recent FDA approval of rapamycin is a topical sirolimus (0.2%) manufactured as a gel that was developed by Nobelpharma and approved by the FDA in 2022 for the treatment of facial angiofibroma associated with Tuberous Sclerosis Complex (TSC).^14,15. TSC is a rare genetic condition caused by mutations in the TSC1 and TSC2 genes that leads to benign tumor growth in many tissues, including the brain, kidneys, eyes, and most commonly, the skin.¹⁵  These skin tumors (facial angiofibromas), while noncancerous, can lead to bleeding, nasal blockage, or other disfigurement and occur in 75-80% of TSC patients.¹⁵ Hyftor was developed as a topical, non-invasive treatment option for this symptom of TSC. This met a major unmet need in the treatment landscape for TSC-associated facial angiofibromas, as other existing interventions involve invasive procedures that often require anesthesia.¹⁵

Rapalogs – altering rapamycin for improved efficacy and expanded indications

Oral rapamycin, while efficacious in both the prevention of kidney transplant rejection and stabilization of lung function in LAM, is considered to have low and variable oral bioavailability.¹⁶ To improve its therapeutic use, researchers have generated alternate versions of this compound, called analogs, that enhance its pharmacological properties. Two analogs of rapamycin, or rapalogs, have been FDA approved – everolimus and temsirolimus. All rapalogs share the exact same chemical structure that interacts with FKBP12, except for a change to the chemical group of the carbon at the 40^th position (C40).¹⁷ These small alterations allow for improvements in the compound’s properties. Comparative pharmacokinetic studies demonstrated that everolimus has improved absorption and oral bioavailability in comparison to sirolimus, as well as improved systemic clearance.¹⁷ Additionally, everolimus and sirolimus may have differential access to tissues and organelles. For example, it’s been suggested that everolimus can affect mitochondrial function in the brain, while sirolimus cannot.¹⁸ This may allow for treatment of different indications.¹⁷ On the other hand, sirolimus is thought to have superior absorption through the skin, hence its beneficial effects as a topical gel for TSC-associated skin conditions.¹⁷ Temsirolimus has significantly better solubility and stability than sirolimus, allowing for its formulation as an intravenous injection.^17,18 This route of administration permits almost complete bioavailability by avoiding metabolism through the digestive system and liver.^17,18 Additionally, its immunosuppressive effects are minimized under a weekly injection dose schedule, allowing for reduced undesirable side effects in indications like cancer.¹⁸ These chemical advancements have allowed for expanded approvals of rapamycin and its analogs to treat more diseases with better efficacy and fewer adverse effects.

Everolimus systemic

Afinitor/Afinitor Disperz, Zortress

Everolimus is approved by the FDA for the treatment of several types of tumors, multiple TSC-associated conditions, and as an immunosuppressant for the prevention of kidney or liver transplant rejection.

Cancer
Novartis first got FDA approval for Afinitor (an oral tablet) in 2009 for the treatment of advanced kidney cancer (renal cell carcinoma (RCC)) after treatment failure with other therapeutics (sunitinib or sorafenib).^19,20. In 2011, Afinitor was approved to treat advanced progressive neuroendocrine tumors of pancreatic origin (PNET) that were locally advanced, metastatic, or unable to be resected.^19,20 This was a monumental approval as this indication had not seen a new treatment approved in nearly 30 years. Novartis subsequently gained approval to treat well-differentiated, progressive, nonfunctional gastrointestinal and lung neuroendocrine tumors (NET) with the same criteria in 2016.^19,20. Afintor was also approved to treat advanced breast cancer in 2012. Specifically, this approval is to treat hormone receptor-positive, HER2-negative breast cancer in combination with Aromasin (exemestane) for use in postmenopausal women with recurrent or progressing cancer after treatment with other therapeutics (letrozole or anastrozole).^19,20

TSC-associated conditions
In 2010, Afinitor first became approved to treat TSC-associated subependymal giant cell astrocytoma (SEGA), a slow-growing, but potentially fatal, brain tumor in TSC patients that could not be treated by surgery.^19,20 Novartis also developed a pediatric-specific dosage of Afinitor called Afintor Disperz, which is an oral suspension of everolimus, or a dissolvable tablet.^19,20 This formulation was approved for the same indication in patients 1 year and older in 2012. Afintor Disperz was also approved in 2018 to treat TSC-associated partial-onset seizures in patients 2 years and older.^19,20 Afinitor approval was expanded in 2012 for the first non-surgical intervention for TSC-associated benign kidney tumors (renal angiomyolipomas), which are highly prevalent among TSC patients (80%) and could become life-threatening.^19,20

Organ transplant
Novartis, who owns all of the FDA-approved everolimus therapeutics currently available, also gained approval in 2010 for Zortress, an everolimus oral tablet for preventing rejection of kidney transplants in adults that are not at high immunologic risk.²¹ This approval was expanded to include liver transplants in 2013, making Zortress the first immunosuppressive agent approved for liver transplant patients in over ten years.²² Novartis also has an everolimus immunosuppressant for kidney, heart, and lung transplant rejection prevention in adults with low to moderate immunological risk that was approved by the European Health Authorities in 2012, called Certican.²²

Temsirolimus systemic

Torisel

Temsirolimus, as previously mentioned, is available in a formulation of intravenous injection due to its significantly improved solubility and stability in comparison to sirolimus. Torisel, the only temsirolimus brand name drug that is FDA-approved, was granted to Pfizer in 2007 for the treatment of advanced renal cell carcinoma (RCC).²³ Torisel is one of many available treatment options for stage IV and recurrent renal cell cancer, along with the aforementioned everolimus brand name drug, Afintor. Torisel can be considered a first-line therapeutic for advanced RCC, whereas Afintor is approved for prescription after failure to treat with first-line therapies sunitib and sorafenib.²⁴

Other applications: Rapamycin-eluting stents

Of note, there are also multiple approved medical devices that elute rapamycin (sirolimus, everolimus, ridaforolimus, zotarolimus) called drug-eluting stents.²⁵ These stents are used in patients that have undergone procedures to open clogged arteries (coronary angioplasty) to help prevent their re-narrowing.²⁵ Stent placement can injure the wall of the arteries, promoting excessive smooth muscle cell proliferation and re-narrowing of the blood vessel, called restenosis.²⁶ Rapamycin inhibits this over-proliferation and allows the stent to keep the artery unblocked. The FDA approved a sirolimus-coated stent to Johnson & Johnson in 2003 (CYPHER), which has since been discontinued due to a decision by manufacturer Cordis in 2011 to focus more on other products in the cardiovascular device space.^26,27 The CYPHER stent was a pioneer in this medical device space and other drug-eluting stents and drug-coated balloons have since been developed and approved for treatment of in-stent restenosis.

The future of mTOR inhibitors in the clinic

mTOR signaling is a master regulator of many cellular and metabolic processes and is therefore very promising as a therapeutic area in a number of different diseases. Aside from its already approved indications, there is growing evidence for mTOR inhibition in protection against neurodegenerative, metabolic, and age-related diseases.² Preclinical studies suggest protection against in vivo mouse models of multiple neurodegenerative conditions, including Alzheimer’s, Parkinson’s and Huntington’s diseases, as well as spinocerebellar ataxia type 3.² The mechanism of action is likely due to the role of mTORC1 in protein synthesis and autophagy. Misfolded proteins are thought to accumulate in these diseases, causing the associated neurodegenerative damage. Suppressing protein synthesis and inducing autophagy through inhibition of mTORC1 may reduce and/or prevent the aggregation of these proteins to help treat the neurodegeneration.

As a key regulator of anabolic metabolism, metabolic conditions like diabetes and obesity are a target area for future uses of mTOR inhibitors. However, mTOR inhibition can have both positive and negative effects on metabolic disease due to its complicated signaling mechanisms.² Preclinical studies have demonstrated improved insulin sensitivity and protection against obesity induced by a high-fat-diet, but alternatively, have also shown increased blood glucose and lipid levels (hyperglycemia, hyperlipidemia) and insulin resistance, which are hallmarks of diabetes.² These effects are thought to, in part, be controlled by the length of treatment time in these models and how that relates to the inhibition of other regulatory components, like mTORC2, but the translation of these findings to human treatment is still being studied.

Lastly, rapamycin is well-known for its impacts on aging and longevity. Inhibition of mTOR signaling has been shown to extend the lifespan in numerous animal models from fruit flies and nematodes to mice.² Not only is the lifespan extended, but studies show that age-associated health decline and disease are improved with rapamycin treatment, including, but not limited to, cancer, cardiac disease and function, immune function, muscle decline, metabolic function, and neurodegeneration.^2,28,29 Over time, cells accumulate damage to DNA, organelles, and proteins, which contributes to cellular arrest and promotes aging.²⁸ This cellular aging may limit cell function across tissues and cause widespread inflammation, driving age-related decline and pathologies.²⁸ The contribution of mTOR to aging is likely diverse, as mTOR controls many biological processes related to cell function. The mechanism of action of mTOR inhibition in aging may involve its role in autophagy, protein and organelle regulation, DNA damage response, and more. However, the associated side effects, including hyperglycemia, hyperlipidemia, and immunosuppression, present a challenge to the use of rapamycin in age-associated interventions.²⁹ These are suggested to be partially mediated by unintended inhibition of mTORC2, which can occur in long-term rapamycin application, so lower, intermittent doses or analogs with mTORC1 specificity are suggested to help reduce these adverse events.²⁹

Rapamycin is an area of active study in the clinic, with ongoing trials in these promising disease areas or their expansion to indications similar to those it is already approved for (i.e. different cancers). The “miracle” drug discovery over 50 years ago continues to make its way into the clinic across a broad spectrum of diseases. Further development of analogs to improve its properties and efficacy has and will continue to benefit patients with a variety of conditions.

References

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9. Khaddour K, Sankari A, Shayuk M. Lymphangioleiomyomatosis. In: StatPearls [Internet]. 2023. Accessed March 19, 2025. https://www.ncbi.nlm.nih.gov/books/NBK534231/#:~:text=Lymphangioleiomyomatosis%20(LAM)%20is%20a%20primary,tumors%20with%20visceral%20organ%20involvement.

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11. U.S. Food & Drug Administration. FDA approves sirolimus protein-bound particles for malignant perivascular epithelioid cell tumor. November 23, 2021. Accessed March 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sirolimus-protein-bound-particles-malignant-perivascular-epithelioid-cell-tumor

12.   Aadi Bioscience, Inc. Fyarro (sirolimus protein-bound particles for injectable suspension (albumin-bound)). Accessed March 19, 2025. https://www.fyarrohcp.com/

13.   Microfluidics. Nanoparticle albumin bound (nab) drug delivery technology. Accessed March 19, 2025. https://www.microfluidics-mpt.com/applications/nanoparticle-albumin-bound-nab-drug-delivery

14.   Nobelpharma America. FDA approves Nobelpharma’s HYFTOR^TM (sirolimus topical gel) 0.2%. April 4, 2022. Accessed March 19, 2025. https://www.prnewswire.com/news-releases/fda-approves-nobelpharmas-hyftor-sirolimus-topical-gel-0-2-301516272.html

15.   Nobelpharma. Hyftor (sirolimus topical gel) 0.2%. Accessed March 19, 2025. https://www.hyftor.com/

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19.   Novartis. Afinitor (everolimus) tablets. Accessed March 19, 2025. https://www.afinitor-hcp.com/

20.   Drugs.com. Afinitor FDA approval history. Accessed March 19, 2025. https://www.drugs.com/history/afinitor.html

21.   National Kidney Foundation. Novartis receives US FDA approval for Zortress® (everolimus) to prevent organ rejection in adult kidney transplant recipients. April 22, 2010. Accessed March 19, 2025. https://www.kidney.org/press-room/national-kidney-foundation-news-2#:~:text=East%20Hanover%2C%20NJ%20(April%2022,%2Dto%2Dmoderate%20immunologic%20risk.

22.  Novartis. Novartis drug Zortress® is first in over a decade approved by FDA to prevent organ rejection in adult liver transplant patients. February 15, 2013. Accessed March 19, 2025. https://www.novartis.com/us-en/news/media-releases/novartis-drug-zortress-first-over-decade-approved-fda-prevent-organ-rejection-adult-liver-transplant-patients

23.   Pfizer. Torisel (temsirolimus). Accessed March 20, 2025. https://www.pfizermedicalinformation.com/torisel

24.  National Cancer Institute. Renal cell cancer treatment (PDQ). Accessed March 20, 2025. https://www.cancer.gov/types/kidney/hp/kidney-treatment-pdq#_385

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26.  Abizaid A. Sirolimus-eluting coronary stents: a review. Vasc Health Risk Manag. 2007;3(2):191-201. doi:10.2147/vhrm.2007.3.2.191

27.   Johnson & Johnson. Cordis announces discontinuation of nevo^TM sirolimus-eluting coronary stent. June 15, 2011. Accessed March 20, 2025. https://www.jnj.com/media-center/press-releases/cordis-announces-discontinuation-of-nevo-sirolimus-eluting-coronary-stent

28.  Walters HE, Cox LS. mTORC Inhibitors as broad-spectrum therapeutics for age-related diseases. Int J Mol Sci. 2018;19(8):2325. doi:10.3390/ijms1908232529.  

29. Mannick JB, Lamming DW. Targeting the biology of aging with mTOR inhibitors. Nat Aging. 2023;3(6):642-660. doi:10.1038/s43587-023-00416-y