LAM-001 Introduction

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 rapamycin activity in several lung diseases, its known systemic side effects have limited its use in these indications.

LAM-001 is designed to deliver therapeutic doses of rapamycin directly to the lungs without the systemic exposures and concomitant toxicity seen with oral dosing, thus leading to a potentially safer and more acceptable treatment.  This safety profile is supported by data from both animal and early human clinical trials. OrphAI Therapeutics has initiated clinical studies of LAM-001 in the rare lung diseases Pulmonary Hypertension (PH) and Bronchiolitis Obliterans Syndrome (BOS).

LAM-001 and mTOR

Rapamycin is an inhibitor of the protein kinase mTOR (mammalian target of rapamycin). mTOR is found in two complexes within cells: mTORC1 and mTORC2. Rapamycin forms a complex with FKBP12 (FK Binding Protein-12) that can inhibit mTOR when part of an mTORC1 complex. Activation of mTORC1 in response to growth factors, nutrient and oxidative stress regulates protein synthesis through phosphorylation of the ribosomal protein S6 which contributes to its proliferative effects in immune and non-immune cells1,2.  Consequently, through the inhibition of mTOR, rapamycin has both immunosuppressive and anti-proliferative effects that contribute to its potential in several lung indications.

LAM-001 References

1 Weichhart T. mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review. Gerontology. 2018;64(2):127-134
2 LiuGY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease.Nat Rev Mol Cell Biol. 2020 Apr;21(4):183-203. doi: 10.1038/s41580-019-0199-y. Epub 2020Jan 14. Erratum in: Nat Rev Mol Cell Biol. 2020 Jan 31;: PMID: 31937935

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Pulmonary Hypertension (PH)

Pulmonary Hypertension is a type of high blood pressure that affects the blood vessels of the lungs, and is broken down into five different groups including Group 1 (Pulmonary Arterial Hypertension, or PAH) and Group 3 (Pulmonary Hypertension due to lung disease and/or hypoxia).

Pulmonary Arterial Hypertension is a rare, progressive lung disorder characterized by thickening and narrowing of the lung arteries, leading to high pulmonary blood pressure1. Disease progression is characterized by shortness of breath, fatigue, chest pain, and fainting episodes2.

All but one of the currently approved drugs for PAH act as vasodilators to treat the symptoms of PAH without addressing the underlying disease pathology in the pulmonary vasculature. While existing treatments have helped survival, most PAH patients still progress to respiratory failure, with an average life expectancy of 7 years3. Approximately 30,000 patients suffer from PAH in the US4 and there remains a need for new disease modifying treatments.

LAM-001 and PH

Rapamycin’s potential in PAH stems from its ability to both inhibit mTOR-mediated pulmonary arterial smooth muscle cell proliferation5 and to improve BMPR2-mediated endothelial cell function6. The mTOR pathway has been shown to be activated in small pulmonary arteries in PAH patients, and enhanced smooth muscle cell proliferation in vitro can be inhibited with rapamycin.  The BMPR2 signaling pathway is essential in maintaining endothelial cell integrity in the pulmonary arteries. Of note, >70% of familial PAH and 20% of sporadic PAH patients harbor BMPR2 mutations and reduced expression of BMPR2 is observed in patients without mutation. Reduced levels of BMPR2, whether genetic or sporadic, leads to endothelial cell proliferation and dysfunction and mice engineered with a knockout of BMPR2 in endothelial cells develop PAH. BMPR2 signaling can be rescued by rapamycin treatment7 and rapamycin reverses occlusion and improves lung function in an animal model of PAH8.

The potential activity of rapamycin in treating humans with PAH is supported by both human case studies and a small clinical trial with a closely related mTOR inhibitor, where improvement in lung function and 6-minute walk distance were observed over a six-month treatment period9,10.

An inhaled formulation of rapamycin that achieves therapeutic rapamycin levels in the lung with reduced systemic exposure and reduced concomitant toxicities has promise as a treatment for PAH.

OrphAI Therapeutics has been granted orphan status in the US for the treatment of PAH with LAM-001.

OrphAI Therapeutics has initiated a Phase 2a clinical trial of LAM-001 in PH Group 1 and 3 patients to test its efficacy and safety. For more information on OrphAI Therapeutics’ trial of LAM-001 in PH, click here to visit ( Identifier: NCT05798923).

LAM-001 PAH References

1 American Lung Association:
2 National Institutes of Health:
3 McGoon MD, Miller DP. REVEAL: A contemporary US pulmonary arterial hypertension registry. Eur Respir Rev. 2012;21(123):8-18. doi: 10.1183/09059180.00008211
4 PulmonaryHypertension Association:
5 Krymskaya, V., Snow, J. Goncharova, E. (2011). mTOR is Required for Pulmonary Arterial Vascular Smooth Muscle Cell Proliferation Under Chronic Hypoxia. Faseb J. 25: 1922.
6 Orriols M, Gomez-Puerto MC, Ten Dijke P. BMP type II receptor as a therapeutic target in pulmonary arterial hypertension. Cell Mol Life Sci. 2017 Aug;74(16):2979-2995. doi: 10.1007/s00018-017-2510-4. Epub 2017Apr 26. Erratum in: Cell Mol Life Sci. 2017 May 23;: PMID: 28447104; PMCID:PMC5501910.
7 Spiekerkoetter E, Tian X, Cai J, Hopper RK, Sudheendra D, Li CG, El-Bizri N, Sawada H, Haghighat R, Chan R, Haghighat L, de Jesus Perez V, Wang L, Reddy S, Zhao M, Bernstein D, Solow-Cordero DE, Beachy PA, Wandless TJ, Ten Dijke P, Rabinovitch M. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest. 2013Aug;123(8):3600-13. doi: 10.1172/JCI65592. Epub 2013 Jul 15. PMID: 23867624
8 Kato F, Sakao S, Takeuchi T, Suzuki T, Nishimura R, Yasuda T, Tanabe N, Tatsumi K. Endothelial cell-related autophagic pathways in Sugen/hypoxia-exposed pulmonary arterial hypertensive rats. Am J Physiol Lung Cell Mol Physiol. 2017 Nov1;313(5):L899-L915. doi: 10.1152/ajplung.00527.2016. Epub 2017 Aug 10. PMID: 28798259.
9 Wessler Jd, Steingart Rm, Schwartz Gk, Harvey Bg, Schaffer W. (2010). Dramatic Improvement in Pulmonary Hypertension with Rapamycin. Chest. Oct; 138(4):991-3.
10 Seyfarth Hj, Hammerschmidt S, Halank M, Neuhaus P, Wirtz Hr. (2013) Everolimus in Patients with Severe Pulmonary Hypertension: A Safety And Efficacy Pilot Trial Pulm Circ. Sep; 3(3):632-8.

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Bronchiolitis Obliterans Syndrome (BOS)

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 in and subsequent gradual narrowing of the small airways of the lungs, resulting in decreased airflow and difficulty breathing. The disease is progressive and eventually leads to irreversible airway obstruction and death1,2.

There are over 2,500 lung transplants performed in the United States each year3. There is no approved therapy for the treatment of BOS, and despite current treatment of lung transplant patients with chronic immunosuppressive therapies, 5-year survival is only 50-60% in large part due to BOS4,5.  There is a clear need for new treatments to improve survival and quality of life.

LAM-001 and Bronchiolitis Obliterans Syndrome (BOS)

The potential for rapamycin to treat BOS is supported by both human and animal data.  Retrospective data in humans administered oral rapamycin post lung transplant has demonstrated improvement in both lung function, as measured by FEV16, and survival in the treatment7 of BOS.  These data are further bolstered by data in a mouse model of BOS which demonstrated that rapamycin 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 cells8,9,10.

LAM-001, an inhaled formulation of rapamycin that achieves superior lung exposure with reduced systemic exposure, holds promise as a potential treatment for BOS.

OrphAI Therapeutics has been granted orphan status in the US and EU for the treatment of BOS with LAM-001.

OrphAI Therapeutics has initiated a 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 ( Identifier: NCT06018766).

LAM-001 BOS References

1 Kulkarni HS, Cherikh WS, Chambers DC, Garcia VC, Hachem RR, Kreisel D, Puri V, Kozower BD, Byers DE, Witt CA, Alexander-Brett J, Aguilar PR, Tague LK, Furuya Y, Patterson GA, Trulock EP 3rd, Yusen RD. Bronchiolitis obliterans syndrome-free survival after lung transplantation: An International Society for Heart and Lung Transplantation Thoracic Transplant Registry analysis. J Heart Lung Transplant. 2019 Jan;38(1):5-16. doi: 10.1016/j.healun.2018.09.016. Epub 2018Sep 25. PMID: 30391193 Thomas, L., & Hachem, R.(2016).
2 Bronchiolitis Obliterans Syndrome (BOS) Following Lung Transplant. American Thoracic Society.
3 National Data - OPTN.(2021).
4 Lung Transplant - What Are the Risks of Lung Transplant? | NHLBI, NIH. (n.d.).
5 BosS, Vos R, Raemdonck DEV, Verleden GM. Survival in adult lung transplantation: where are we in 2020?.  Curr Opin Organ Transplant. 2020. June:25(3): 268-273.
6 Hernandez, R. L. et. al. (2015) Rapamycin in Lung Transplantation. Transplantation Proceedings 37 3999-4000.
7 Unpublished data
8 ZhaoY, Gillen JR, Meher AK, Burns JA, Kron IL, Lau CL. Rapamycin prevents bronchiolitis obliterans through increasing infiltration of regulatory B cells in a murine tracheal transplantation model. J Thorac Cardiovasc Surg. 2016 Feb;151(2):487-96.e3. doi: 10.1016/j.jtcvs.2015.08.116. Epub 2015Sep 7. PMID: 26481278
9 GillenJR, Zhao Y, Harris DA, Lapar DJ, Stone ML, Fernandez LG, Kron IL, LauCL. Rapamycin blocks fibrocyte migration and attenuates bronchiolitisobliterans in a murine model. Ann ThoracSurg. 2013b May;95(5):1768-75. doi:10.1016/j.athoracsur.2013.02.021. Epub 2013Apr 2. PMID: 23561805; PMCID: PMC4218735.
10 Gillen, J. R., Zhao, Y., Harris, D. A., LaPar, D. J., Kron, I. L., & Lau, C. L. (2013a). Short-course rapamycintreatment preserves airway epithelium and protects against bronchiolitis obliterans.The Annals of thoracic surgery, 96(2), 464–472.

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