Sirolimus: how rapamycin may shape the future of treating age-related diseases.

Biomedical research faces increasing challenges, as the growing demand for new therapies, driven by rising rates of disease in current societies, outpaces the success of drug development (1). Modern societies are increasingly burdened by diseases associated with advanced age that continue to rise despite significant advancements in individuals’ lifespan. This divergence between lifespan and healthspan demonstrates an unmet need for novel therapeutics targeting age-related diseases, including neurodegenerative, metabolic or cardiovascular diseases. At the same time, it also highlights the growing importance of drug repurposing strategies as a means of accelerating therapeutic development.

A compelling example of such an approach is the repurposing of rapamycin, a natural macrolide compound, isolated in the 1970s from soil bacteria, Streptomyces hygroscopicus, on Easter Island (Rapa Nui)(2). In recent years, rapamycin has emerged as a central focus in the longevity field considering its role in modifying major cellular pathways associated with ageing. Despite its potential, it also remains a subject of ongoing clinical and scientific debate, particularly regarding its long-term use and immunosuppressive properties.

Before exploring its future potential, it is important to examine the developmental trajectory of rapamycin and how its transition into the generic market reflects broader issues in affordability and access, illustrating a unique example of how drugs of its nature display a particular complex case of the biotech social contract.

Rapamycin was developed by Wyeth under the brand name Rapamune and later became part of Pfizer following its acquisition in 2009 (3). Although initially investigated as an antifungal therapeutic (4), its anti-proliferative and immunosuppressive properties led to its use in transplant medicine. In 1999, it was approved by the FDA for the prophylaxis of organ rejection, particularly for prevention of acute rejection in renal transplant patients (5). In 2015, it was approved again as a targeted therapy for lymphangioleiomyomatosis (LAM), a rare multicystic lung disease (5, 6). It represents a unique class of molecules for its ability to inhibit a protein called the mammalian target of rapamycin kinase (mTOR), a kinase that regulates cellular responses to nutrients, stress and environmental signals, as well as autophagy (7). As a lipophilic molecule, rapamycin diffuses across the cell membrane and acts intracellularly. Thereby, it binds to FKBP12, forming a drug-protein complex that allosterically inhibits mTOR complex I (mTORC1) initially, and mTOR complex II (mTORC2) during longer exposure, resulting in the reduction of protein synthesis and cell cycle progression (7, 8).

In 2009, shortly after its patent expired, rapamycin entered the market with the generic drug, sirolimus. Early generic manufacturers included Teva Pharmaceuticals, Dr. Reddy’s Laboratories and Mylan (now Viatris), and it is currently produced by over ten major pharmaceutical companies worldwide, demonstrating a competitive generic landscape. While branded drug Rapamune previously cost approximately $1,100 — $1,400 per month, the generic version is now available for approximately $50 — $150 per month, representing a substantial reduction in the cost and an important step towards patient access to therapy. For LAM patients, the disease affects 3–8 per million women worldwide reaching up to 0.31 per million cases per year (9), while only in the U.S. approximately 28,000 renal transplants are performed each year (10). Therefore, considering that rapamycin is the first-line treatment for LAM (6), and that a considerate proportion of renal transplant patients receive it to prevent organ rejection, the introduction of rapamycin in the generic market has served a moderate but significant clinical impact, to the point where Pfizer no longer sells Rapamune in the U.S., as of December 2023 (11), due to the sufficient availability of generic alternatives that are widely available.

Despite the clinical and economic success, the use of sirolimus is not without significant limitations. A major challenge lies in its complex pharmacokinetic profile, characterised by low aqueous solubility and variable absorption, bioavailability issues that have raised concerns about its clinical effectiveness and safety standards (12). Therefore, maintenance of the therapeutic concentration requires careful dose adjustment, regular therapeutic drug monitoring and strict bioequivalence testing. This has been further complicated by issues raised about its narrow therapeutic index, as with many immunosuppressants of its kind (12). Ultimately, this need for close patient monitoring by healthcare professionals creates additional costs for hospitalisation, laboratory tests, and drug monitoring procedures which can offset the savings of the generic version over the branded name drug (12). World market availability represents an additional issue, as sirolimus products are not available in all regions across Europe and Australia due to regulatory and market differences (12).

Does sirolimus therefore fulfil the expectations of the biotech social contract? While its therapeutic complexities present challenges, they do not diminish its overall value but rather illustrate the difficulties of delivering effective therapies when targeting fundamental biological pathways such as the mTOR. Despite the additional costs associated with therapeutic monitoring, the introduction of generic sirolimus still led to a substantial cost reduction, improving accessibility significantly. In parallel, the ongoing pharmaceutical innovation continues to optimise improved formulations of the drug, while investigating its therapeutic potential across a broader range of conditions, repurposing its use.

Particularly relevant in the context of ageing, sirolimus offers a pathway-targeted approach, with the potential to treat multiple diseases of advanced age through shared underlying molecular mechanisms. Ongoing research already explores therapeutic potential of rapamycin in autophagy-related, mitochondrial, cardiovascular and neurodegenerative diseases, inflammation, progeria, diabetes, and cancer (13, 14). Furthermore, although it was traditionally associated with immunosuppression, emerging evidence suggests that lower or intermediate dosing might modulate immune function which can actually enhance aspects of immune responsiveness (15). This highlights the significance of drug refinement and dose optimisation which ultimately maximise therapeutic benefits of drugs that have already been absorbed by the society through prior investment.

Sirolimus highlights a rather complex case of market generalisation, showing how a single drug can hold such a therapeutic potential in healthcare while simultaneously elucidating the challenges of research translation into effective and accessible therapies. Its evolving role in ageing research demonstrates the promise of drug repurposing and represents a notable example of how innovation and investment in drug discovery can have long-term impact that goes beyond their initial purpose. Should we invest in drugs with such extended potential might ultimately allow us to maximise the value of biomedical innovation by improving patient outcomes and enhancing the sustainability of the healthcare systems.

References:

1. Paul Ashigbie RS, Thierry Diagana & Jonathan Spector. Innovation in medicines for global health: a 20-year landscape analysis. Nature Reviews Drug Discovery. 2025;24:818–9.

2. Wullschleger S, Loewith R, Hall MN. TOR Signaling in Growth and Metabolism. Cell. 2006;124(3):471–84.

3. Xiao X, Dokudovskaya S. The rapamycin sTORy: 50-year journey from Easter Island to the frontiers of biology and medicine. Trends in Biochemical Sciences. 2026;51(4):320–41.

4. Sehgal SN, Baker H, Vézina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo). 1975;28(10):727–32.

5. U.S. Food and Drug Administration. Prescribing information (drug label) for NDA 021083 and 021110. Silver Spring, MD: U.S. Food and Drug Administration; 2018.

6. Pfizer Inc. Pfizer’s RAPAMUNE® (sirolimus) Becomes First FDA-Approved Treatment for Lymphangioleiomyomatosis (LAM), A Rare Progressive Lung Disease. 2015.

7. Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP. mTOR kinase structure, mechanism and regulation. Nature. 2013;497(7448):217–23.

8. Choi J, Chen J, Schreiber SL, Clardy J. Structure of the FKBP12-Rapamycin Complex Interacting with Binding Domain of Human FRAP. Science. 1996;273(5272):239–42.

9. Harknett EC, Chang WYC, Byrnes S, Johnson J, Lazor R, Cohen MM, et al. Use of variability in national and regional data to estimate the prevalence of lymphangioleiomyomatosis. QJM: An International Journal of Medicine. 2011;104(11):971–9.

10. Lentine KL, Smith JM, Lyden GR, Miller JM, Booker SE, Dolan TG, et al. OPTN/SRTR 2023 Annual Data Report: Kidney. Am J Transplant. 2025;25(2s1):S22-s137.

11. Sherman S. Statement on Pfizer’s decision on the brand drug, Rapamune, in the U.S.: The LAM Foundation; 2023 [cited 2026 4 May]. Available from: https://www.thelamfoundation.org/statement-on-pfizers-decision-on-the-brand-drug-rapamune-in-the-u-s/.

12. Kocur A, Kunicki PK, Pawiński T. Generic Medicinal Products in Immunosuppressive Therapy — Should It be a Challenge for Therapeutic Drug Monitoring? Therapeutic Drug Monitoring. 2023;45(2):173–90.

13. Mannick JB, Lamming DW. Targeting the biology of aging with mTOR inhibitors. Nature Aging. 2023;3(6):642–60.

14. Selvarani R, Mohammed S, Richardson A. Effect of rapamycin on aging and age-related diseases-past and future. Geroscience. 2021;43(3):1135–58.

15. Kell L, Jones EJ, Gharahdaghi N, Wilkinson DJ, Smith K, Atherton PJ, et al. Rapamycin Exerts Its Geroprotective Effects in the Ageing Human Immune System by Enhancing Resilience Against DNA Damage. Aging Cell. 2026;25(2):e70364.