RAPA-501 Therapy for ALS

Recruiting at 1 trial location

Overseen By Michele Donato, M.D

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Rapa Therapeutics LLC

Disqualifiers: Uncontrolled infection, Hypertension, Cardiac pathology, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 7

Duration: 18 weeks

41 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new treatment for ALS using a patient's own immune cells that are modified to reduce inflammation. It targets ALS patients who have not progressed beyond certain limits. The goal is to see if this treatment is safe and effective.

Will I have to stop taking my current medications?

The trial allows participants to continue taking riluzole, edaravone, and sodium phenylbutyrate/taurusodial if they have been on a stable dose for at least 30 days before the screening. The protocol does not specify about other medications, so it's best to discuss your specific situation with the trial team.

What data supports the effectiveness of the RAPA-501 treatment for ALS?

Research shows that regulatory T cells (Tregs), which are part of the RAPA-501 treatment, have a neuroprotective role in ALS and can slow disease progression. Additionally, studies indicate that rapamycin, a component of the treatment, can enhance the function of Tregs and prolong survival in other conditions, suggesting potential benefits for ALS patients. ^{1 2 3 4 5}

Is RAPA-501 therapy safe for humans?

The research articles provided do not contain specific safety data for RAPA-501 therapy in humans. They focus on the use of rapamycin in animal models, which showed some toxicity in dogs but little toxicity in other protocols. However, these findings may not directly translate to human safety. ^{1 2 3 6 7}

How is the RAPA-501 treatment for ALS different from other treatments?

RAPA-501 is unique because it involves a type of cell therapy using modified T cells that are designed to regulate the immune system, potentially slowing ALS progression by targeting specific immune pathways, unlike traditional treatments that may not address these immune components. ^{1 2 3 4 8}

Research Team

Daniel Fowler, M.D.

Principal Investigator

Rapa Therapeutics LLC

Eligibility Criteria

This trial is for adults diagnosed with ALS within the last 24 months. They can still take certain ALS medications if doses have been stable for 30 days. Participants need normal kidney function, a specific range of ALSFRS-R scores, and adequate breathing capacity. Exclusions include uncontrolled hypertension, recent heart or pulmonary issues, active infections, positive HIV/Hepatitis tests, pregnancy/breastfeeding, and unwillingness to use contraception.

Inclusion Criteria

It has been over 2 weeks since my last major surgery or experimental treatment.

Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient participant at any time without prejudice to future medical care

My ALS symptoms started less than 24 months ago.

Exclusion Criteria

I have had a blood clot in my lungs within the last 6 months.

I have had heart surgery or angioplasty and will undergo a heart check.

I am of childbearing age and not willing to use contraception.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Apheresis and Cell Manufacturing

Apheresis procedure to collect cells for manufacturing the investigational product, RAPA-501 T cells

1-2 weeks

1 visit (in-person)

Treatment

Participants receive up to 4 infusions of RAPA-501 T cells, each separated by six weeks

18 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with visits at 24 and 30 weeks, followed by remote monitoring for two years

2 years

2 visits (in-person), remote monitoring

Treatment Details

Interventions

• RAPA-501

Trial Overview The RAPA-501-ALS study is testing a new therapy using patients' own modified T cells (RAPA-501) to treat ALS. It's in phase 2/3 which means it's looking at both effectiveness and safety in a larger group after initial promising results.

Participant Groups

Group I: RAPA-501 Autologous T stem cells Experimental Treatment 1 Intervention

Phase 2/3 Expansion Cohort, Single-agent RAPA-501 T stem cells 80 x 10EE6 cells per infusion (no host conditioning)

Who Is Running the Clinical Trial?

Rapa Therapeutics LLC

Lead Sponsor

Trials

6

Recruited

200+

Massachusetts General Hospital

Collaborator

Trials

3,066

Recruited

13,430,000+

Hackensack Meridian Health

Collaborator

Trials

141

Recruited

42,900+

Findings from Research

Polyclonal anti-T-cell antibody (ALS) significantly prolonged skin allograft survival in both naïve and alloantigen-primed mice, indicating its efficacy in preventing rejection.

Combining high-dose ALS with rapamycin (RAPA) or targeting specific T cell pathways can enhance graft survival, especially in alloantigen-primed mice, suggesting potential strategies for achieving tolerance in sensitized individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategies to induce marked prolongation of secondary skin allograft survival in alloantigen-primed mice. Minamimura, K., Sato, K., Yagita, H., et al.[2023]

A chimeric antigen receptor (CAR) was successfully developed for human regulatory T cells (Tregs) to target the aggregated G93A-hSOD1 protein associated with ALS, enhancing their ability to modulate the immune response in this disease.

The study found that gene-modified Tregs produced anti-inflammatory IL-10 and inhibited harmful factors like tumor necrosis factor alpha when interacting with ALS-related proteins, suggesting a promising therapeutic approach for ALS through targeted immunomodulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human CD4+CD25+ T cells expressing a chimeric antigen receptor against aberrant superoxide dismutase 1 trigger antigen-specific immunomodulation. Graber, DJ., Cook, WJ., Sentman, ML., et al.[2023]

Rapamycin (Rapa) significantly prolongs graft survival in skin allografted mice when used alongside antilymphocyte serum (ALS) and donor bone marrow cells (BMC), with up to 26% of recipients achieving indefinite graft survival with the highest dose.

Rapa can be administered flexibly, either as a single dose or spaced doses, and is effective even when given after initial signs of rejection, indicating its potential as a versatile immunosuppressive agent in transplant settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Late adjunctive therapy with single doses of rapamycin in skin-allografted mice treated with antilymphocyte serum and donor bone marrow cells. De Fazio, SR., Plowey, JM., Hartner, WC., et al.[2019]

Regulatory T cells (Tregs) are crucial for immune balance, and their dysfunction is linked to faster progression of amyotrophic lateral sclerosis (ALS), suggesting that enhancing Treg function could slow disease progression.

A new method was developed to expand Tregs from ALS patients, resulting in a significant increase in their numbers (25- to 200-fold) and restoration of their ability to regulate immune responses, paving the way for potential clinical trials using these enhanced Tregs as a therapy for ALS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A robust, good manufacturing practice-compliant, clinical-scale procedure to generate regulatory T cells from patients with amyotrophic lateral sclerosis for adoptive cell therapy. Alsuliman, A., Appel, SH., Beers, DR., et al.[2022]

Infusions of expanded regulatory T lymphocytes (Tregs) were found to be safe and well tolerated in three ALS patients, with no adverse effects reported during the study.

The treatment not only slowed disease progression in both early and later stages of ALS but also showed a correlation between increased Treg suppressive function and reduced progression rates, suggesting a potential therapeutic benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expanded autologous regulatory T-lymphocyte infusions in ALS: A phase I, first-in-human study. Thonhoff, JR., Beers, DR., Zhao, W., et al.[2022]

In a study involving canine renal allograft recipients, a combination treatment of rapamycin (Rapa) with antilymphocyte serum (ALS), donor bone marrow cells (BMC), and cyclosporine (CsA) significantly improved graft survival, with some dogs surviving over 470 days post-transplant.

The combination therapy showed reduced toxicity from Rapa, suggesting that this approach not only enhances the effectiveness of the treatment but also makes it safer for the recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of rapamycin on renal allograft survival in canine recipients treated with antilymphocyte serum, donor bone marrow, and cyclosporine. Hartner, WC., Van der Werf, WJ., Lodge, JP., et al.[2013]

A short course of rapamycin (Rapa) significantly enhances the survival of rat skin xenografts in mice treated with anti-lymphocyte serum, achieving a median survival time of 47 days.

Intrathymic injection of donor splenocytes did not improve skin graft survival in the presence of Rapa and anti-lymphocyte serum, suggesting that while Rapa is effective, the additional IT injection may not provide further benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Marked prolongation of rat skin xenografts induced by intrathymic injection of xenogeneic splenocytes and a short course of rapamycin in antilymphocyte serum-treated mice. Dono, K., Wood, ML., Ozato, H., et al.[2019]

In a small study of seven ALS patients, T-cell vaccination (TCV) combined with autologous adult neural stem cells slowed or stopped disease progression, extending median survival from 3.5 years to 6 years.

Neurological improvements were observed for at least one year post-treatment, indicating that TCV may be a safe and effective long-term therapy for ALS, as confirmed by an independent neurologist using the ALS Functional Rating Scale-Revised.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility, safety, and preliminary proof of principles of autologous neural stem cell treatment combined with T-cell vaccination for ALS patients. Moviglia, GA., Moviglia-Brandolino, MT., Varela, GS., et al.[2022]

References

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

Strategies to induce marked prolongation of secondary skin allograft survival in alloantigen-primed mice. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Human CD4+CD25+ T cells expressing a chimeric antigen receptor against aberrant superoxide dismutase 1 trigger antigen-specific immunomodulation. [2023]

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

Late adjunctive therapy with single doses of rapamycin in skin-allografted mice treated with antilymphocyte serum and donor bone marrow cells. [2019]

4. England pubmed.ncbi.nlm.nih.gov

A robust, good manufacturing practice-compliant, clinical-scale procedure to generate regulatory T cells from patients with amyotrophic lateral sclerosis for adoptive cell therapy. [2022]

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

Expanded autologous regulatory T-lymphocyte infusions in ALS: A phase I, first-in-human study. [2022]

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

Effect of rapamycin on renal allograft survival in canine recipients treated with antilymphocyte serum, donor bone marrow, and cyclosporine. [2013]

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

Marked prolongation of rat skin xenografts induced by intrathymic injection of xenogeneic splenocytes and a short course of rapamycin in antilymphocyte serum-treated mice. [2019]

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

Feasibility, safety, and preliminary proof of principles of autologous neural stem cell treatment combined with T-cell vaccination for ALS patients. [2022]