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

Prior treatment

• 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.
• Patients with cardiac sarcoidosis receiving treatment for active cardiac disease. Patients not on treatment are not excluded.
• Use of any oral mTOR inhibitor 4 weeks prior to study entry
• Major surgery within 60 days prior to start of study drug. Must have recovered from surgery.
• 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)

Other illness

• 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.
• Known significant non-PH related cardiac, hematologic, hepatic, psychiatric, renal, and/or other disease that may limit participation in the study
• Symptomatic coronary artery disease
• 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
• Subjects with underlying medical disorders with an anticipated life expectancy below 2 years (e.g. active cancer disease with localized and/or metastasized tumor)
• History of severe allergic or anaphylactic reaction or hypersensitivity to lactose excipients or sirolimus in IP
• 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
• Subjects with 3 or more of the following risk factors for LV disease:
  • BMI greater than 32
  • Systemic Hypertension being actively treated
  • Diabetes Mellitus
  • Atrial Fibrillation
• Evidence of Active HIV (assessed by viral load, if replication is detected) or HEP C
• Evidence of active or untreated latent tuberculosis
• Current Alcohol Use Disorder or testing in the 6 months to screening positive for Amphetamines, Methamphetamines, or Cocaine
• Ongoing bacterial, viral, or fungal lung infection requiring active treatment

Lab values

• Left ventricular ejection fraction (LVEF) \<50%, within the previous 6 months with Left atrial volume index greater than 45
• Pregnant (i.e. positive serum ß-human chorionic gonadotropin test or other signs of pregnancy) or breastfeeding women
• Any of the following clinical laboratory values during the Screening Period prior to Week 0 Visit:
  • 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
  • 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

Other

• Participants will be excluded from the study if they meet any of the following criteria:
• Patients with a PCWP \> 15 mm Hg determined at end exhalation by the RHC Core Lab
• Patients with an FVC \<50% of predicted during the screening visit
• Patients with severe airway obstruction as defined by 1-second forced expiratory volume (FEV1)/FVC \<50% absolute during screening visit
• DLCO \<25% predicted
• Continuous oxygen use at rest ≥6 liters per minute
• Patients unable to perform the 6-minute walk test
• Female of Reproductive Potential or male not using highly reliable contraception as defined above
• Subjects who are smoking or vaping
• Inability to comply with the protocol and/or not willing or not available for follow-up assessments
• Untreated Severe Obstructive Sleep Apnea

• Participants must satisfy all the following criteria to be enrolled in the study:
• 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
• 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
• WHO functional class (FC) II or III
• Confirmed positive sarcoidosis biopsy from any affected organ
• FVC ≥ 50% predicted
• 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.
• 6MWD ≥ 100 and ≤ 450 meters repeated twice during Screening Period and both values within 15% of each other, calculated from the highest value
• 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.
• Women of childbearing potential must satisfy the following:
  • 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.
  • 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.
  • 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
• Male participants must use highly effective forms of contraception:
  • 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.
  • Refrain from donating sperm for the duration of the study and for 90 days after the last dose of study treatment.
• Ability to adhere to the study visit schedule and understand and comply with all protocol requirements.
• Ability to understand and provide written informed consent