LAM-001 for the Treatment of Sarcoidosis Associated Pulmonary Hypertension (SAPH)

A Phase 2, Randomized, Double-Blind, Multi-Dose, Placebo-Controlled Study to Evaluate the Efficacy and Safety of LAM-001 (Inhaled Sirolimus) in Adults with Sarcoidosis Associated Pulmonary Hypertension (SAPH).

Approximately 60 participants will receive standard of care plus LAM-001 (inhaled sirolimus) 100 mcg, 200 mcg or placebo by oral inhalation once daily for the first 24 weeks of the study, with approximately 20 participants in each treatment group.

Participants who complete the first 24 weeks on treatment and appear to have a favorable benefit-risk profile will be eligible to continue receiving LAM-001 for the remainder of the study (Open-Label Extension Period) for an additional 24 weeks, for a total of up to 48 weeks on treatment.

All participants will complete evaluations during a Follow-Up Period of 4 weeks.

• Placebo (Drug): Matching placebo administered via dry powder inhalation
• LAM-001 (Drug): LAM-001 administered via dry powder inhaler
• LAM-001 (Drug): LAM-001 administered via dry powder inhaler

Primary outcomes

• Change in Pulmonary Vascular Resistance (PVR) at 24 weeks [24 weeks]: Change from baseline in PVR at 24 weeks adjudicated by the RHC core laboratory

Secondary outcomes

• Change in Six minute walk distance (6MWD) at 24 weeks [24 weeks]: Change in 6MWD at 24 weeks
• Time to Clinical Worsening (TCW) [24 weeks]: TCW (from time of randomization until study treatment discontinuation due to clinical worsening) using predefined criteria. Clinical worsening is defined as one of the following: * Death * Lung transplantation or Heart-Lung transplantation * Hospitalization related to worsening respiratory status/respiratory decompensation (>24 hours) * PH symptoms that require the addition of or increase in dose > 10% of a PH disease-specific medication * Symptomatic >10% decline from baseline FVC confirmed with repeat testing * Worsened WHO functional class AND * Symptomatic >15% decline in 6MWD from baseline directly related to the disease (at 2 consecutive visits at least 24 hours apart)
• The number of clinical worsening events at 24 weeks [24 weeks]: The number of clinical worsening events at 24 weeks
• Change in NT-proBNP at 24 weeks [24 weeks]: Change in NT-proBNP at 24 weeks
• Changes in FVC and DLCO and TLV/TLC (if available) at 24 weeks [24 weeks]: Change in FVC, TLV/TLC, and DLCO at 24 weeks
• To determine if LAM-001 treatment is safe and well tolerated compared to placebo [24 weeks]: Frequency, incidence and severity of * Adverse events (AEs) * Local and systemic adverse events of special interest (AESI) * Treatment emergent adverse events (TEAEs) * Serious adverse events (SAEs)
• To characterize the dose-response relationship of LAM-001 to identify the optimal therapeutic dose for Phase 3 [24 weeks]: PK analysis of LAM-001 (Maximum Plasma Concentration \[Cmax\])

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

Participants must satisfy all the following criteria to be enrolled in the study:

1. Patients 18-80 years (>70 requires medical monitor approval) with diagnosis of sarcoidosis based on American Thoracic Society (ATS)/World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) criteria
2. SAPH with precapillary phenotype diagnosed by mean pulmonary arterial pressure (mPAP) > 20 mmHg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, PVR ≥ 4.0 Wood units (WU) as determined by the RHC core lab
3. WHO functional class (FC) II or III
4. Confirmed positive sarcoidosis biopsy from any affected organ
5. FVC ≥ 50% predicted
6. If on background PH and anti-inflammatory sarcoidosis therapies, must be stable for at least 3 months and patient should be symptomatic despite background therapy. No new PH or anti-inflammatory sarcoidosis drugs started within 6 months. PH or sarcoidosis therapies are not required for inclusion.
7. 6MWD ≥ 100 and ≤ 450 meters repeated twice during Screening Period and both values within 15% of each other, calculated from the highest value
8. Subjects must be able to understand and be willing to sign the written informed consent form. A signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure.
9. Women of childbearing potential must satisfy the following:

   1. Have 2 negative pregnancy tests as verified by the investigator prior to starting study and must agree to ongoing monthly pregnancy testing during the study and at end of study treatment.
   2. If sexually active, must have used, and agree to continue to use, highly effective contraception without interruption, for at least 30 days prior to starting investigational product (IP), during the study (including dose interruptions), and for 90 days after discontinuation of study treatment.
   3. Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 90 days after the last dose of study treatment
10. Male participants must use highly effective forms of contraception:

    1. Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made from natural (animal) membrane (for example, polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions, and for at least 90 days following IP discontinuation, even if he has undergone a successful vasectomy.
    2. Refrain from donating sperm for the duration of the study and for 90 days after the last dose of study treatment.
11. Ability to adhere to the study visit schedule and understand and comply with all protocol requirements.
12. Ability to understand and provide written informed consent

Exclusion Criteria:

Participants will be excluded from the study if they meet any of the following criteria:

1. Patients receiving systemic immunosuppressive therapy to treat neurosarcoidosis or therapy for active neurological disease or other forms of sarcoidosis likely to impact life expectancy over the 12 months of the study. Participants with a history of neurosarcoidosis who have not required new or increased immunosuppressants in the past 6 months are not excluded.
2. Patients with cardiac sarcoidosis receiving treatment for active cardiac disease. Patients not on treatment are not excluded.
3. Left ventricular ejection fraction (LVEF) <50%, within the previous 6 months with Left atrial volume index greater than 45
4. Patients with a PCWP > 15 mm Hg determined at end exhalation by the RHC Core Lab
5. Patients with other causes of Pulmonary Hypertension including CTEPH and Group 2 PH. A CT scan with contrast within the last 3 months and/or a V/Q scan if clinically indicated are sufficient to rule out other causes of PH.
6. Patients with an FVC <50% of predicted during the screening visit
7. Patients with severe airway obstruction as defined by 1-second forced expiratory volume (FEV1)/FVC <50% absolute during screening visit
8. DLCO <25% predicted
9. Continuous oxygen use at rest ≥6 liters per minute
10. Patients unable to perform the 6-minute walk test
11. Known significant non-PH related cardiac, hematologic, hepatic, psychiatric, renal, and/or other disease that may limit participation in the study
12. Symptomatic coronary artery disease
13. Use of any oral mTOR inhibitor 4 weeks prior to study entry
14. Subjects with a medical disorder, condition, or history of such that would impair the subject's ability to participate or complete this study in the opinion of the investigator
15. Subjects with underlying medical disorders with an anticipated life expectancy below 2 years (e.g. active cancer disease with localized and/or metastasized tumor)
16. Pregnant (i.e. positive serum ß-human chorionic gonadotropin test or other signs of pregnancy) or breastfeeding women
17. Female of Reproductive Potential or male not using highly reliable contraception as defined above
18. Any of the following clinical laboratory values during the Screening Period prior to Week 0 Visit:

    1. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 3x upper limit of normal (ULN) or total bilirubin > 2 x ULN within 28 days of Week 0 Visit
    2. Estimated glomerular filtration rate < 30 mL/min/1.73 m2 (4-variable Modification of Diet in Renal Disease equation) within 28 days of Week 0 Visit or required renal replacement therapy within 90 days
19. History of severe allergic or anaphylactic reaction or hypersensitivity to lactose excipients or sirolimus in IP
20. Major surgery within 60 days prior to start of study drug. Must have recovered from surgery.
21. Subjects who are smoking or vaping
22. Subjects with history of active malignancy within the past 5 years, with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤ 2 squamous cell carcinomas of the skin
23. Concurrent use of another investigational drug or device therapy (i.e., outside of study treatment) during, or within 4 weeks of trial entry (signing of the informed consent form)
24. Inability to comply with the protocol and/or not willing or not available for follow-up assessments
25. Subjects with 3 or more of the following risk factors for LV disease:

    1. BMI greater than 32
    2. Systemic Hypertension being actively treated
    3. Diabetes Mellitus
    4. Atrial Fibrillation
26. Untreated Severe Obstructive Sleep Apnea
27. Evidence of Active HIV (assessed by viral load, if replication is detected) or HEP C
28. Evidence of active or untreated latent tuberculosis
29. Current Alcohol Use Disorder or testing in the 6 months to screening positive for Amphetamines, Methamphetamines, or Cocaine
30. Ongoing bacterial, viral, or fungal lung infection requiring active treatment