AI Therapeutics is now OrphAI Therapeutics

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 Arterial Hypertension (PAH) and Bronchiolitis Obliterans Syndrome (BOS) and is planning studies in Pulmonary Sarcoidosis.

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 Arterial Hypertension (PAH)

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.

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 extend 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 treatment options.

LAM-001 and PAH

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.

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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Pulmonary Sarcoidosis

Sarcoidosis is a disease characterized by the development and accumulation of granulomas, masses or nodules of chronically inflamed tissue1. Sarcoidosis can affect any organ, but most commonly affects the lungs and skin. Typical symptoms include dyspnea, persistent cough and fatigue which can severely impact quality of life2.

Sarcoidosis affects approximately 180,000 individuals in the United States3, of which approximately 1/3 have chronic, progressive disease despite standard of care treatments4.

Sarcoidosis patients are often treated with corticosteroids and cytotoxic agents, but there is a need for new therapies with improved efficacy and safety.  

LAM-001 and Pulmonary Sarcoidosis

Recent studies in humans and in animals have implicated mTOR signaling in the pathogenesis of sarcoidosis.

Knock out of the TSC2 gene (an upstream regulator of mTOR) in mice leads to the formation of granulomas very similar to those seen in human sarcoidosis5. These studies suggest that mTOR activation and subsequent activation of inflammatory immune responses involving innate immune cells, such as monocytes, macrophages and dendritic cells, is a key contributor to sarcoidosis. Treatment of a sarcoidosis animal model with an mTOR inhibitor has been shown to resolve the granuloma formation.

In humans, there are case reports describing similar resolution of sarcoidosis with oral rapamycin6,7,8. Furthermore, studies of patients with progressive pulmonary sarcoidosis demonstrated alterations in genes affecting the mTOR pathway9 and analysis of patient tissues demonstrated activated mTOR signaling10.

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

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

LAM-001 Pulmonary Sarcoidosis References

1 Drent M, Crouser ED, Grunewald J. Challenges of Sarcoidosis and Its Management. N Engl J Med. 2021 Sep 9;385(11):1018-1032. doi: 10.1056/NEJMra2101555. PMID: 34496176.
2 Wijsenbeek, M. S., & Culver, D. A. (2015).Treatment of Sarcoidosis. Clinics in Chest Medicine, 36(4), 751–767.
3 Sarcoidosis Research Institute:
4 Soto-Gomez N, Peters JI, Nambiar AM. Diagnosis and management of sarcoidosis. American Family Physician. 2016;93(10):840-8.
5 Linke M, Pham HT, Katholnig K, Schnöller T,Miller A, Demel F, Schütz B,Rosner M, Kovacic B, Sukhbaatar N, Niederreiter B, Blüml S, Kuess P, Sexl V, Müller M, Mikula M, Weckwerth W, Haschemi A, Susani M, Hengstschläger M, Gambello MJ,Weichhart T. Chronic signaling via the metabolic checkpoint kinase mTORC1induces macrophage granuloma formation and marks sarcoidosis progression. NatImmunol. 2017 Mar;18(3):293-302. doi:10.1038/ni.3655. Epub 2017 Jan 16. PMID: 28092373.
6 Manzia TM, Bellini MI, Corona L, Toti L, Fratoni S, Cillis A, Orlando G, Tisone G. Successful treatment of systemic de novo sarcoidosis with cyclosporine discontinuation and provision of rapamune after liver transplantation. Transpl Int. 2011 Aug;24(8):e69-70. doi: 10.1111/j.1432-2277.2011.01256.x. Epub 2011Apr 19. PMID: 21504488
7 Kelleher,K. J., Russell, J., Killeen, O. G., & Leahy, T. R. (2020).Treatment-recalcitrant laryngeal sarcoidosis responsive to sirolimus. BMJ Case Reports, 13(8), e235372.
8 Gupta N, Bleesing JH, McCormack FX. Successful Response to Treatment with Sirolimus in Pulmonary Sarcoidosis. Am J Respir Crit Care Med.2020 Nov 1;202(9):e119-e120. doi:10.1164/rccm.202004-0914IM. PMID: 32730705.
9 Calender A, Lim CX, Weichhart T, Buisson A, Besnard V, Rollat-Farnier PA, Bardel C, Roy P, Cottin V, Devouassoux G, Finat A, Pinson S, Lebecque S, Nunes H, Israel-Biet D, Bentaher A, Valeyre D, Pacheco Y; in the frame of GSF (Group Sarcoidosis France). Exome sequencing and pathogenicity-network analysis of five French families implicate mTOR signalling and autophagy in familial sarcoidosis. Eur Respir J. 2019 Aug 1;54(2):1900430. doi:10.1183/13993003.00430-2019. PMID: 31023854.
10 Linke M, Pham HT, Katholnig K, Schnöller T, Miller A, Demel F, Schütz B, Rosner M, Kovacic B, Sukhbaatar N, Niederreiter B, Blüml S, Kuess P, Sexl V, Müller M, Mikula M, Weckwerth W, Haschemi A, Susani M, Hengstschläger M, Gambello MJ, Weichhart T. Chronic signaling via the metabolic checkpoint kinase mTORC1induces macrophage granuloma formation and marks sarcoidosis progression. Nat Immunol. 2017 Mar;18(3):293-302. doi:10.1038/ni.3655. Epub 2017 Jan 16. PMID: 28092373.

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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.  Limited retrospective data in humans administered oral rapamycin post lung transplant has demonstrated improved survival in both the prevention6 and treatment7 settings 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.

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 Sacher VY, Fertel D, Srivastava K, Panos A, Nguyen D, Baxter T, Shafazand S, Pham SM.  Effects of prophylactic use of sirolimus on bronchiolitis obliterans syndrome development in lung transplant recipients.  Ann Thoracic Surg. 2014.97:1; 268-274.
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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