LAM-001 in Lung Transplant Recipients With Bronchiolitis Obliterans Syndrome.

The goal of this clinical trial is to learn about the safety and effectiveness of LAM-001 in patients who have developed bronchiolitis obliterans syndrome (BOS), a form of chronic rejection, after lung transplantation.

The main questions it aims to answer are:

* Is LAM-001 safe in these patients?
* Is LAM-001 effective in slowing BOS progression?

Participants will:

* Be randomly assigned to inhale either LAM-001 or placebo (a look-alike substance that contains no active drug) daily for 48 weeks
* Attend 10 study visits (mixture of in-person and telehealth) over the 48 week period
* Undergo pulmonary function testing, bronchoscopy, lab testing, and physical examination
* Submit weekly home spirometry monitoring

Researchers will compare participants assigned to LAM-001 versus placebo to see if LAM-001 is safely tolerated and to assess the effectiveness of LAM-001 on slowing BOS progression.

Chronic rejection, commonly denoted as bronchiolitis obliterans (BO), obliterative bronchiolitis (OB), or bronchiolitis obliterans syndrome (BOS), is the leading cause of death beyond the first year after lung transplantation. Whereas the development of BOS is rare within the first year after lung transplantation, annual increments of approximately 10% are recorded in subsequent years, resulting in a cumulative incidence range of 40-50% within the first five years and 70-80% within 10 years of transplantation.

No current effective treatment for BOS exists. BOS represents the leading cause of morbidity and mortality after lung transplantation, limiting 5-year survival to well below other solid organ transplants. BOS is characterized by an inexorable lung function decline despite currently available immunomodulatory treatments. Sirolimus has been shown to block T-cell proliferative effects induced by cytokines, alloantigens, and mitogens in a dose-dependent manner(4, 5). Oral sirolimus has been shown in small studies to have a beneficial impact on rapidly progressive BOS; however, administration in this patient population has been challenged by a high degree of intolerance with the side effects. The development of LAM-001 for lung transplant related BOS, conceptually a T-cell driven process against transplanted alloantigen, is based on the principal hypothesis that administration of a sirolimus dose to the rejecting lung allograft(s) by inhalation will result in improved efficacy by depositing higher drug concentrations directly within the allograft by inhalation than would be achieved by oral administration due to systemic toxicities associated with oral sirolimus. Because of known reduced systemic bioavailability of LAM-001 compared to oral sirolimus dosing, amelioration of the substantial adverse event profile compared to oral drug is expected. LAM-001 is also expected to reduce serious complication risks by obviating requirements for maintenance and augmented immune drugs used to treat BOS.

The primary objective is to assess the clinical efficacy of LAM-001 in lung transplant recipients with bronchiolitis obliterans syndrome as measured by progression free survival and change in forced expiratory volume in one second (FEV1) over a 48-week period. Another primary objective is to assess the safety and tolerability of LAM-001 in lung transplant recipients with bronchiolitis obliterans syndrome.

Secondary objectives are:

* To determine the impact of LAM-001 on genetic markers of bronchiolitis obliterans syndrome and activation of the mammalian target of rapamycin (mTOR) pathway by measuring chronic lung allograft dysfunction signature gene profiling and mTOR pathway activation in bronchoalveolar lavage fluid
* To determine whether donor-derived cell-free DNA (%ddcfDNA) will predict ongoing injury (versus cessation of BOS progression) by measuring %ddcfDNA in randomized subjects. % ddcfDNA will be correlated with clinical outcome measures of FEV1 change, death, and re-transplantation for both randomized groups.
* To determine the levels of sirolimus in the blood and bronchoalveolar lavage (BAL) fluid, the BAL as a surrogate for levels in the lung.

Eligibility Criteria:
Inclusion Criteria:

* Age \> 18 years old
* Recipient of a double pulmonary allograft at least 12 months before study entry
* Subjects with clinically diagnosed CLAD-BOS phenotype (all 3 required)

  * BOS defined as screening FEV1 between 85-51% of the baseline as defined by the 2 highest FEV1 measures at least 3 weeks apart.
  * Diagnosis within 12 months of screening visit.
  * FEV1 decline is persistent as defined by decline sustained for \> 30 days.
* Currently receiving Standard Immunosuppression. This is defined as a combination of 3 medications including Prednisone, Mycophenolate or Azathioprine, and Tacrolimus or Cyclosporine. The dosing should be stable for 4 weeks prior to screening.
* Absence of oral sirolimus or everolimus treatment for at least 4 weeks prior to screening based on the half-life and resolution of the tissue effects
* Stable enough to enable routine post-transplant bronchoscopy with BAL and biopsy when indicated
* Capable of understanding the purposes and risks of the study
* Written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study.
* Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to study entry
* Women of childbearing potential if sexually active must agree to using highly effective contraception during study and for 90 days after discontinuation of study treatment
* Women of childbearing potential must refrain from breast feeding or donating eggs for the duration of the study and for 90 days after the last dose of study treatment
* Male participants must agree to use a condom during sexual contact with a female of childbearing potential while participating in the study and for 90 days following discontinuation of investigational product use
* Male participants must refrain from donating sperm for the duration of the study and for 90 days after the last dose of study treatment

Exclusion Criteria:

* Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study.
* Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
* Patients with re-transplantation or currently listed for re-transplantation
* Patients with confirmed other causes for loss of lung function, such as acute infection, acute rejection, restrictive allograft syndrome (CLAD - RAS phenotype, see Protocol Specific Definition), etc.
* Patients with acute antibody-mediated rejection at Screening. In this context, clinically stable patients (as judged by the Investigator) with detectable donor-specific antibodies (DSA) levels at the Screening Visit are eligible for the study
* Active acute bacterial, viral, or fungal infection that has not successfully resolved in at least 4 weeks prior to the Screening Visit. Patients with chronic infection or colonization who are clinically stable as per judgement of the investigator are eligible.
* Mechanical ventilation within 12 weeks prior to the randomization
* Patient has baseline resting oxygen saturation of \< 89% on room air or use of supplemental oxygen at rest at screening
* Evidence of functional airway stenosis (i.e., bronchomalacia/ tracheomalacia, airway stents, or airways requiring balloon dilatations to maintain patency) with onset after the initial diagnosis of BOS and ongoing at Screening and/or Baseline Visit
* Known hypersensitivity to sirolimus or everolimus
* Currently enrolled in another investigational trial for obstructive chronic lung allograft dysfunction (BOS)
* Patients with chronic renal failure, defined as serum creatinine \> 2.5 mg/dL at screening, or requiring chronic dialysis
* Patients with liver disease and serum bilirubin \> 3-fold upper limit of normal range or transaminases \> 2.5 upper limit of normal range
* Patients with active malignancy within the previous 2 years, including post-transplant lymphoproliferative disorder, except for treated, localized basal and squamous cell carcinomas
* Any history of malignancy likely to result in significant disability or likely to require significant medical or surgical intervention within the next 6 months. This does not include minor surgical procedures for localized skin cancer.
* History of severe allergic reaction to lactose (patients with lactose intolerance are eligible)
* Patients with uncontrolled hypertension