LAM-001 for Bronchiolitis Obliterans Syndrome

(INSPO-BOS Trial)

Overseen By Steven Hays, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Steven Hays, MD

Must be taking: Standard immunosuppression

Must not be taking: Sirolimus, Everolimus

Disqualifiers: Pregnancy, Re-transplantation, Acute infection, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 10

Duration: 48 weeks

30 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Do I need to stop my current medications to join the trial?

The trial requires participants to continue their current standard immunosuppression medications, which include Prednisone, Mycophenolate or Azathioprine, and Tacrolimus or Cyclosporine. However, you must not be taking oral sirolimus or everolimus for at least 4 weeks before joining the study.

What data supports the effectiveness of the drug LAM-001 for Bronchiolitis Obliterans Syndrome?

Research shows that sirolimus, a component of LAM-001, can stabilize lung function in patients with bronchiolitis obliterans syndrome, and rapamycin, another component, helps reduce immune system activity that can lead to this condition. ^{1 2 3 4 5}

What safety information is available for the treatment LAM-001 (Sirolimus/Rapamycin) in humans?

Sirolimus, also known as Rapamycin, is used as an immunosuppressant but can have side effects on the lungs, such as causing lung inflammation and bleeding. In some cases, stopping the drug and using steroids helped improve lung function. ^{2 4 6 7 8}

How is the drug LAM-001 (Sirolimus) unique for treating Bronchiolitis Obliterans Syndrome?

LAM-001, which includes Sirolimus, is unique because it acts as an immunosuppressant that helps prevent the immune system from attacking the lungs, potentially stabilizing lung function in patients with Bronchiolitis Obliterans Syndrome. Unlike traditional treatments that only temporarily stabilize lung function, Sirolimus has anti-proliferative properties that may offer longer-term benefits. ^{1 3 4 9 10}

Research Team

Steven Hays, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for adults over 18 who've had a double lung transplant at least a year ago and are now facing chronic rejection called bronchiolitis obliterans syndrome (BOS). They should have specific lung function levels, be on standard immunosuppression, and not be taking certain drugs. Participants must use effective birth control if they can have children and cannot donate sperm or eggs during the study.

Inclusion Criteria

Your lung function has been steadily decreasing for more than 30 days.

Written informed consent 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 refrain from breast feeding or donating eggs for the duration of the study and for 90 days after the last dose of study treatment

Exclusion Criteria

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

You have had an organ transplant before, or you are waiting for another organ transplant.

You are currently experiencing acute antibody-mediated rejection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomly assigned to inhale either LAM-001 or placebo daily for 48 weeks. They will attend 10 study visits (mixture of in-person and telehealth) and undergo pulmonary function testing, bronchoscopy, lab testing, and physical examination. Weekly home spirometry monitoring is also required.

48 weeks

10 visits (mixture of in-person and telehealth)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of progression free survival and change in FEV1.

4 weeks

Treatment Details

Interventions

• Placebo
• Sirolimus

Trial Overview The trial tests LAM-001's safety and effectiveness against BOS in lung transplant recipients. Patients will either inhale LAM-001 or a placebo daily for 48 weeks while undergoing regular health checks including lung function tests, with some visits possibly via telehealth.

Participant Groups

Group I: LAM-001 Experimental Treatment 1 Intervention

Group II: Placebo Placebo Group 1 Intervention

Lactose capsule to be inhaled daily for 48 weeks via Plastiape RS01 dry powder inhaler Model 7.

Who Is Running the Clinical Trial?

Steven Hays, MD

Lead Sponsor

Trials

1

Recruited

30+

AI Therapeutics, Inc.

Industry Sponsor

Trials

7

Recruited

280+

OrphAI Therapeutics

Industry Sponsor

Trials

7

Recruited

280+

Findings from Research

In a study of 12 lung transplant recipients with chronic lung allograft rejection (OB/BOS), the addition of sirolimus to standard immunosuppressive therapy did not significantly change overall pulmonary function for the group, but some individuals experienced stabilization or improvement in their lung function.

The combination therapy of sirolimus with calcineurin inhibitors led to notable adverse effects, including a rise in serum creatinine in 75% of patients and anemia in all patients, suggesting that while sirolimus may help some, it also carries significant risks that require careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early experience with sirolimus in lung transplant recipients with chronic allograft rejection. Cahill, BC., Somerville, KT., Crompton, JA., et al.[2019]

In a porcine model of obliterative bronchiolitis (OB), the use of 40-0-(2-hydroxyethyl)-rapamycin (RAD) in combination with cyclosporine and methylprednisolone significantly prevented OB compared to traditional immunosuppressants like azathioprine, indicating a more effective strategy for managing immune responses.

The study found that T-cell activity is crucial in the development of OB, as significant immune cell influx was observed in untreated allografts leading to obliteration, while immunosuppressed allografts showed reduced immune responses and delayed epithelial damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune cells and immunosuppression in a porcine bronchial model of obliterative bronchiolitis. Maasilta, PK., Salminen, US., Lautenschlager, IT., et al.[2021]

In a retrospective study of 24 lung transplant recipients, switching to sirolimus (SIR) one year post-transplant was associated with a lower incidence of bronchiolitis obliterans syndrome (BOS) and improved survival rates compared to those who continued with other immunosuppressants.

The SIR group also experienced fewer viral infections and required lower doses of tacrolimus and prednisone, indicating a potential benefit in managing immunosuppression without increasing the risk of acute rejection or other complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of prophylactic use of sirolimus on bronchiolitis obliterans syndrome development in lung transplant recipients. Sacher, VY., Fertel, D., Srivastava, K., et al.[2021]

In a study involving trachea allograft rats, the combination of rapamycin (Rapa) and immature dendritic cells (imDCs) significantly inhibited the growth of lymphocytes and CD4+ T cells, which are crucial in the immune response, suggesting a strong immunosuppressive effect.

Rapa-imDC treatment not only reduced airway obliteration symptoms and T cell infiltration but also shifted the immune response by decreasing proinflammatory cytokines and increasing regulatory T cells (Tregs), indicating a potential strategy for preventing obliterative bronchiolitis after lung transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin Combined with Immature Dendritic Cells Attenuates Obliterative Bronchiolitis in Trachea Allograft Rats by Regulating the Balance of Regulatory and Effector T Cells. Dong, M., Wang, X., Liu, J., et al.[2015]

In a study of 65 lung transplant recipients, conversion to everolimus was primarily due to bronchiolitis obliterans syndrome (BOS) and renal insufficiency, with 21% of patients able to eliminate calcineurin inhibitors (CNI) from their regimen.

While renal function improved significantly in patients with renal insufficiency, the effects of everolimus on BOS were inconclusive, as forced expiratory volume (FEV1) remained stable among those with BOS after 12 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective 12-month study of conversion to everolimus in lung transplant recipients. Roman, A., Ussetti, P., Zurbano, F., et al.[2015]

In a study of 11 lung transplant patients with bronchiolitis obliterans (BOS) who did not respond to other treatments, 72% showed improvement or stabilization in lung function after being treated with rapamycin (RAPA) for an average of 15 months.

While RAPA can be effective in managing BOS, it is associated with potential adverse effects, including infections and myelosuppression, necessitating close monitoring of patients during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin in lung transplantation. Hernández, RL., Gil, PU., Gallo, CG., et al.[2013]

Sirolimus, a drug used to inhibit T and B cell proliferation, can cause serious lung-related side effects, including diffuse alveolar hemorrhage, as seen in a case involving a 33-year-old renal transplant recipient.

After stopping sirolimus and initiating a 6-month tapering steroid therapy, the patient's lung condition improved significantly, leading to full recovery of pulmonary functions without any remaining symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus-Induced Diffuse Alveolar Hemorrhage: A Case Report. Balcan, B., Simsek, E., Ugurlu, AO., et al.[2017]

Short-course rapamycin treatment significantly protects against airway epithelium loss and reduces the development of bronchiolitis obliterans (BO) in a murine model, particularly when administered from days 1 to 14 after transplantation.

Even late treatment with rapamycin (days 14 to 28) can lead to recovery of damaged epithelium and a reduction in BO, suggesting its potential as an effective therapy for preventing chronic rejection in lung transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-course rapamycin treatment preserves airway epithelium and protects against bronchiolitis obliterans. Gillen, JR., Zhao, Y., Harris, DA., et al.[2021]

The study evaluated an immunosuppressive regimen using sirolimus and tacrolimus in 49 lung transplant recipients, aiming for specific drug concentration levels, and found it effective in protecting lung allografts with an acceptable safety profile.

While 22% of patients discontinued sirolimus due to adverse effects, the regimen showed potential benefits in improving bronchiolitis obliterans syndrome (BOS) grades, with 8 out of 23 patients experiencing improvement over one year.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful use in lung transplantation of an immunosuppressive regimen aimed at reducing target blood levels of sirolimus and tacrolimus. Villanueva, J., Boukhamseen, A., Bhorade, SM.[2013]

In a study of 10 female patients with progressive lymphangioleiomyomatosis (LAM), sirolimus treatment led to a significant improvement in lung function, with an increase in FEV1 of 1.19 ml/day during therapy, compared to a loss of FEV1 of -2.30 ml/day before treatment.

While sirolimus showed promise in improving lung function in LAM patients, it was associated with serious respiratory side effects in some cases, leading to treatment discontinuation in 3 patients, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is sirolimus a therapeutic option for patients with progressive pulmonary lymphangioleiomyomatosis? Neurohr, C., Hoffmann, AL., Huppmann, P., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Early experience with sirolimus in lung transplant recipients with chronic allograft rejection. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Immune cells and immunosuppression in a porcine bronchial model of obliterative bronchiolitis. [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Effects of prophylactic use of sirolimus on bronchiolitis obliterans syndrome development in lung transplant recipients. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Rapamycin Combined with Immature Dendritic Cells Attenuates Obliterative Bronchiolitis in Trachea Allograft Rats by Regulating the Balance of Regulatory and Effector T Cells. [2015]

5. United States pubmed.ncbi.nlm.nih.gov

A retrospective 12-month study of conversion to everolimus in lung transplant recipients. [2015]

6. United States pubmed.ncbi.nlm.nih.gov

Rapamycin in lung transplantation. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Sirolimus-Induced Diffuse Alveolar Hemorrhage: A Case Report. [2017]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Short-course rapamycin treatment preserves airway epithelium and protects against bronchiolitis obliterans. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Successful use in lung transplantation of an immunosuppressive regimen aimed at reducing target blood levels of sirolimus and tacrolimus. [2013]

10. England pubmed.ncbi.nlm.nih.gov

Is sirolimus a therapeutic option for patients with progressive pulmonary lymphangioleiomyomatosis? [2022]