LAM-001 Introduction
Pulmonary Hypertension (PH)
Bronchiolitis Obliterans Syndrome (BOS)
Sarcoidosis Associated Pulmonary Hypertension (SAPH)
LAM-001 is a proprietary dry powder inhaled formulation of sirolimus, also known as rapamycin. Oral sirolimus was first approved in 1999 as a treatment for kidney transplant rejection. While there is evidence of oral sirolimus activity in several lung diseases, its known systemic side effects have limited its use in these indications.
LAM-001 is designed to deliver sirolimus directly to the lungs without the systemic exposure and concomitant toxicity seen with oral dosing. This safety profile is supported by data from both animal and early human clinical trials. Orphai Therapeutics has completed a clinical study of LAM‑001 in pulmonary hypertension (PH), is currently conducting a study in bronchiolitis obliterans syndrome following lung transplant (BOS), and plans to initiate clinical studies in PH associated with interstitial lung disease (PH‑ILD) and in sarcoidosis‑associated pulmonary hypertension (SAPH) in 2026.
Sirolimus selectively inhibits the mTOR pathway, a central regulator of how cells grow, divide, and respond to stress 1,2. Within cells, mTOR operates through two major complexes, mTORC1 and mTORC2, each controlling distinct aspects of cellular metabolism and proliferation. Sirolimus binds to the intracellular protein FKBP12, and this complex effectively suppresses mTORC1 activity, the branch of the pathway closely linked to abnormal cell growth and inflammatory signaling.
When mTOR is over activated, it drives protein synthesis and fuels the proliferative behavior of smooth‑muscle cells, endothelial cells, fibroblasts, and immune cells 3. By dampening this signaling, sirolimus exerts anti‑proliferative, anti-fibrotic and immunomodulatory effects. These properties form the biological rationale for exploring mTOR inhibition across pulmonary indications where unchecked cellular growth, inflammation, and tissue remodeling contribute to disease progression.
1. Weichhart, Thomas. “mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini Review.” Gerontology, vol. 64, no. 2, 2018, pp. 127–34.
2. Liu, Guang Y., and David M. Sabatini. “mTOR at the Nexus of Nutrition, Growth, Ageing and Disease.” Nature Reviews Molecular Cell Biology, vol. 21, no. 4, 2020, pp. 183–203.
3. Krymskaya, Vera P., et al. “mTOR Is Required for Pulmonary Arterial Vascular Smooth Muscle Cell Proliferation under Chronic Hypoxia.” FASEB Journal, vol. 25, 2011, p. 1922.
Pulmonary hypertension (PH) is a rare, progressive, life‑threatening condition characterized by structural remodeling of the lung vasculature and consequent elevated pressure in the pulmonary circulation 1,2,3. Across its diverse etiologies, including idiopathic and heritable forms, such as pulmonary arterial hypertension (PAH) as well as PH-associated with interstitial lung diseases (ILDs), the causes and progression of PH converges on vascular endothelial injury, dysregulated repair and remodeling, and pulmonary arterial smooth muscle cell hyperproliferation that leads to disease progression 4,5,6.
In both idiopathic and heritable PAH, intrinsic abnormalities in endothelial and smooth‑muscle cell function progressively narrow and obliterate the small pulmonary arteries. Even without parenchymal lung disease, this vasculopathy steadily increases pulmonary vascular resistance, strains the right heart, and ultimately leads to right‑heart failure. In patients who develop PH in the setting of fibrotic or inflammatory ILDs, vascular remodeling compounds the underlying lung injury and contributes to a particularly poor prognosis. Across this broader landscape, affecting tens of thousands of patients in the United States, idiopathic, heritable, and ILD‑associated forms of PH share a common unmet need for treatments that directly target the cellular drivers of vascular remodeling rather than primarily providing symptomatic relief and limited functional improvement.
Despite advances in therapy, PH remains a condition with substantial morbidity and mortality 7. The persistent clinical burden, limited disease‑modifying options, and high rate of progression underscore the opportunity for new therapies capable of altering outcomes in individuals with this complex vascular disease. Current treatment strategies, including vasodilators, prostacyclin analogs and agonists, endothelin receptor antagonists, and phosphodiesterase‑5 inhibitors, primarily target vasomotor tone 8. While these agents improve symptoms and functional capacity, most patients continue to experience disease progression even on combination regimens.
The mTOR pathway is a central regulator of cell growth, repair, and response to stress 9. In healthy lungs, this signaling pathway helps maintain balance in both the airways and the blood vessels 10,11. In PH, however, this regulatory network becomes uncontrolled and hyperactive.
Across independent laboratories and models, the data converge on a clear narrative: mTOR signaling is a key driver of pulmonary vascular remodeling, and mTOR inhibition can prevent progression and reverse established disease. Non-clinical studies show consistent effects on pulmonary artery smooth muscle cells (PASMCs) and endothelial proliferation, vascular structure, and right-heart strain 12,13,14,15, while early human experience with oral mTOR inhibitors demonstrate feasibility and biologic activity in patients with severe PH 16,17. Together, these findings support the development of mTOR-directed strategies as a promising avenue for disease-modifying therapy in PH and ILD-associated PH.
By delivering an mTOR inhibitor directly to the lungs with high local concentration and minimal systemic exposure, LAM-001 targets the hyperactive signaling that drives PASMC proliferation at its source. This localized inhibition is intended to slow, prevent or reverse the vascular smooth-muscle overgrowth that drives pulmonary arterial narrowing, thereby addressing the core mechanism of disease rather than its downstream consequences. In the PH‑ILD population, where vascular remodeling occurs alongside progressive parenchymal fibrosis, mTOR inhibition may also help blunt the fibroblast activation and matrix deposition that stiffen the lung and worsen pulmonary pressures. Together, these findings support the development of targeted, lung‑focused mTOR‑directed strategies as a promising avenue for potential disease‑modifying therapy in PH and ILD‑associated PH.
Orphai Therapeutics has been granted orphan-drug designation in the US for the treatment of pulmonary arterial hypertension.
Orphai Therapeutics has completed a Phase 2 clinical trial of LAM-001 to test its safety and efficacy as an add-on therapy for the treatment of PH and is currently planning a larger, placebo-controlled study in PH-ILD starting in 2026.
1. Humbert, Marc, et al. “2022ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension: Developed by the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS).” European Heart Journal, vol. 43, no. 38, 2022, pp. 3618–731.
2. National Institutes of Health. “Pulmonary Arterial Hypertension.” Genetic and Rare Diseases Information Center, rarediseases.info.nih.gov/diseases/7501/pulmonary-arterial-hypertension. Accessed 22 Jan 2026.
3. American Lung Association. “Learn About Pulmonary Arterial Hypertension.” American Lung Association, www.lung.org/lung-health-diseases/lung-disease-lookup/pulmonary-arterial-hypertension/learn-about-pulmonary-arterial-hypertension (lung.org in Bing). Accessed 22 Jan 2026.
4. Nathan, Steven D., et al. “Pulmonary Hypertension Due to Lung Disease and Hypoxia.” European Respiratory Journal, vol. 53, no. 1, 2019.
5. Humbert, Marc, et al. "Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives." European Respiratory Journal 53.1 (2019).
6. Hassoun, Paul M. "Pulmonary arterial hypertension." New England Journal of Medicine 385.25 (2021): 2361-2376.
7. Sharma M, Paudyal V, Syed SK, Thapa R, Kassam N, Surani S. Management of Pulmonary Arterial Hypertension: Current Strategies and Future Prospects. Life. 2025 Mar 8; 15(3): 430.
8. Spaczyńska, Monika, Susana F. Rocha, and Eduardo Oliver. "Pharmacology of pulmonary arterial hypertension: an overview of current and emerging therapies." ACS Pharmacology & Translational Science 3.4 (2020): 598-612.
9. Galiè N, Channick RN,Frantz RP, Grünig E, Jing ZC, Moiseeva O, Preston IR, Pulido T, Safdar Z,Tamura Y, McLaughlin VV. Risk stratification and medical therapy of pulmonary arterial hypertension. European Respiratory Journal. 2019 Jan 24; 53(1).
10. Weichhart, Thomas. “mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini Review.” Gerontology, vol. 64, no. 2, 2018, pp. 127–34.
11. Babicheva A, Makino A, Yuan JX. mTOR signaling in pulmonary vascular disease: pathogenic role and therapeutic target. International journal of molecular sciences. 2021 Feb21; 22(4): 2144.
12. Krymskaya, Vera, et al.“mTOR Is Required for Pulmonary Arterial Vascular Smooth Muscle Cell Proliferation under Chronic Hypoxia.” FASEB Journal, vol. 25, 2011, p. 1922.
13. Houssaini, A., et al.“Rapamycin Reverses Pulmonary Artery Smooth Muscle Cell Proliferation in Pulmonary Hypertension.” American Journal of Respiratory Cell and Molecular Biology, vol. 48, no. 5, 2013, pp. 568–77.
14. Kato, F., et al.“Endothelial Cell Related Autophagic Pathways in Sugen/Hypoxia Exposed Pulmonary Arterial Hypertensive Rats.” American Journal of Physiology – Lung Cellular and Molecular Physiology, vol. 313, no. 5, 2017, pp. L899–915.
15. Paddenberg, R, et al.“Rapamycin Attenuates Hypoxia Induced Pulmonary Vascular Remodeling and Right Ventricular Hypertrophy in Mice.” Respiratory Research, vol. 8, no. 1, 2007,article 15.
16. Wessler, J. D., et al.“Dramatic Improvement in Pulmonary Hypertension with Rapamycin.” Chest, vol.138, no. 4, 2010, pp. 991–93.
17. Seyfarth, H. J., et al.“Everolimus in Patients with Severe Pulmonary Hypertension: A Safety and Efficacy Pilot Trial.” Pulmonary Circulation, vol. 3, no. 3, 2013, pp. 632–38.
Bronchiolitis Obliterans Syndrome (BOS) is the most common cause of lung transplant failure, affecting nearly 90% of lung transplant recipients. BOS manifests as increased fibrosis and inflammation leading to subsequent gradual scarring and narrowing of the small airways of the lungs, culminating in decreased airflow and difficulty breathing. The disease is progressive and eventually leads to irreversible airway obstruction and death 1,2.
There are approximately 4,000 lung transplants performed in the United States annually 3. There is no approved therapy for the treatment of BOS, and, despite current treatment of lung transplant patients with chronic immunosuppressive therapies, bronchodilators, and re-transplantation, 5-year survival is only 50-60% in large part due to BOS 4. There is a clear need for new treatments to improve lung function, survival and quality of life.
The potential for sirolimus to treat BOS is supported by both human and animal data. Retrospective data in BOS patients administered oral sirolimus post lung transplant demonstrated improvement and stabilization in lung function as measured by FEV1 5. These data are further bolstered by data in a mouse model of BOS which demonstrated that sirolimus prevented occlusion of airways via several mechanisms, including reduction in recruitment of fibrocytes, protection against airway epithelial loss and increased infiltration of immune inhibitory Treg and Breg cells 6,7,8.
LAM-001, an inhaled formulation of sirolimus that targets lung exposure with reduced systemic exposure, holds promise as a potential treatment for BOS.
Orphai Therapeutics has been granted orphan-drug designation in the US and EU for the treatment of BOS with LAM-001.
Orphai Therapeutics has an ongoing Phase 2 clinical trial of LAM-001 to test its safety and efficacy in patients who have developed BOS after lung transplantation. For more information on Orphai Therapeutics’ trial of LAM-001 in BOS, click here to visit clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT06018766).
1. Kulkarni, H. S., et al. “Bronchiolitis Obliterans Syndrome‑Free Survival after Lung Transplantation: An International Society for Heart and Lung Transplantation Thoracic Transplant Registry Analysis.” Journal of Heart and Lung Transplantation, vol. 38, no. 1, 2019, pp. 5–16.
2. American Thoracic Society. Bronchiolitis Obliterans Syndrome (BOS) Following Lung Transplant. https://www.thoracic.org/patients/patient-resources/resources/bronchiolitis-obliterans-syndrome.pdf.
3. Organ Procurement and Transplantation Network (OPTN). “Organ Transplants Exceeded 48,000 in 2024; a 3.3 Percent Increase from 2023.” OPTN, 2024.
4. Bos, S., et al. “Survival in Adult Lung Transplantation: Where Are We in 2020?” Current Opinion in Organ Transplantation, vol. 25, no. 3, 2020, pp.268–73.
5. Hernandez, R. L., et al. “Rapamycin in Lung Transplantation.” Transplantation Proceedings, vol. 37, 2005, pp. 3999–4000.
6. Zhao, Y., et al.“Rapamycin Prevents Bronchiolitis Obliterans through Increasing Infiltration of Regulatory B Cells in a Murine Tracheal Transplantation Model.” Journal of Thoracic and Cardiovascular Surgery, vol. 151, no. 2, 2016, pp. 487–96.e3
7. Gillen, J. R., et al. “Rapamycin Blocks Fibrocyte Migration and Attenuates Bronchiolitis Obliterans in a Murine Model.” Annals of Thoracic Surgery, vol. 95, no. 5, 2013, pp. 1768–75.
8. Gillen, J. R., et al. “Short‑Course Rapamycin Treatment Preserves Airway Epithelium and Protects against Bronchiolitis Obliterans.” Annals of Thoracic Surgery, vol. 96, no. 2, 2013, pp. 464–72.
Sarcoidosis‑associated pulmonary hypertension (SAPH) is a serious complication of sarcoidosis characterized by elevated pressures in the pulmonary circulation and progressive right‑heart strain. SAPH can occur across the spectrum of sarcoidosis severity and is associated with significant functional impairment and increased mortality. The disease state arises from a combination of granulomatous inflammation, vascular remodeling, and structural changes within the lung. The resultant smooth muscle cell hyperproliferation within pulmonary arteries increases resistance to blood flow leading to growing pressure on the right side of the heart.
Patients with SAPH experience substantial morbidity, reduced exercise capacity, and a markedly higher risk of hospitalization and death compared with sarcoidosis alone. Reported outcomes include approximately 55% five‑year survival, an ~8 - 10‑fold increase in mortality versus sarcoidosis without pulmonary hypertension, and a median time of roughly six months from diagnosis to death or hospitalization in high‑risk cohorts 1,2,3. Despite this burden, no therapies are approved specifically for SAPH, and current treatment options include supportive care, immunosuppression, and off‑label use of pulmonary hypertension medications with variable benefit.
A growing body of translational research highlights the central role of mTOR signaling in granuloma biology and pulmonary vascular inflammation in this patient population. Chronic mTOR activation in macrophages is sufficient to drive granuloma formation, and mTOR inhibition reverses this pathology in non-clinical models 4. Recent small case studies across pulmonary, cardiac, cutaneous and multisystem sarcoidosis have also reported meaningful improvements with sirolimus treatment, further supporting the therapeutic potential of mTOR inhibition in patients with SAPH 5,6,7,8 .
There remains a significant unmet need for disease‑modifying therapies that address the underlying drivers of SAPH and improve outcomes for patients living with this high‑risk condition. Given the central role of mTOR activation in granuloma biology and pulmonary arterial smooth muscle cell hyperproliferation, inhaled sirolimus represents a promising therapeutic approach with the potential to directly target the mechanisms that drive SAPH.
LAM-001, an inhaled formulation of sirolimus that achieves targeted lung exposure with reduced systemic exposure, holds promise as a potential treatment for SAPH.
Orphai Therapeutics has been granted orphan drug status in the US for the treatment of sarcoidosis with LAM-001.
1 Baughman RP, Engel PJ, Taylor L, Lower EE. Survival in sarcoidosis-associated pulmonary hypertension: the importance of hemodynamic evaluation. Chest. 2010 Nov1;138(5):1078-85.
2 Parikh KS, Dahhan T, Nicholl L, Ruopp N, Pomann GM, Fortin T, Tapson VF, Rajagopal S. Clinical features and outcomes of patients with sarcoidosis-associated pulmonary hypertension. Scientific reports. 2019 Mar 11;9(1):4061.
3 Shlobin OA, Kouranos V, Barnett SD, Alhamad EH, Culver DA, Barney J, Cordova FC, Carmona EM, Scholand MB, Wijsenbeek M, Ganesh S. Physiological predictors of survival in patients with sarcoidosis-associated pulmonary hypertension: results from an international registry. European Respiratory Journal. 2020 May 14;55(5).
4 Linke M, Pham HT, Katholnig K, Schnöller T, Miller A, Demel F, Schütz B, Rosner M, Kovacic B, Sukhbaatar N, Niederreiter B. Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression. Nature immunology. 2017 Mar;18(3):293-302.
5 Baker MC, Vágó E, Liu Y, Lu R, Tamang S, Horváth-Puhó E, Sørensen HT. Sarcoidosis incidence after mTOR inhibitor treatment. In Seminars in arthritis and rheumatism 2022 Dec 1 (Vol. 57, p. 152102). WB Saunders.
6 Brown R, Macrohon-Sabaitue S, Specterman M, Asimaki A. Multisystemic, Possibly Familial Sarcoidosis Ameliorated by an mTOR Inhibitor. Case Reports. 2025 Jun 11;30(14):103633.
7 Hindré R, Besnard V, Kort F, Nunes H, Valeyre D, Jeny F. Complete response to mTOR inhibitor following JAKi failure in severe pulmonary sarcoidosis. Pulmonology. 2024 Nov 30;30(6):639-41.
8 Redl A, Doberer K, Unterluggauer L, Kleissl L, Krall C, Mayerhofer C, Reininger B, Stary V, Zila N, Weninger W, Weichhart T. Efficacy and safety of mTOR inhibition in cutaneous sarcoidosis: a single-centre trial .The Lancet Rheumatology. 2024 Feb 1;6(2):e81-91.
