Linvoseltamab for Amyloidosis

(LINKER-AL2 Trial)

Recruiting at 17 trial locations

Overseen By Clinical Trials Administrator

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Regeneron Pharmaceuticals

Disqualifiers: Non-AL amyloidosis, Plasmacytosis, Myocardial infarction, others

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

Compensation: Varies

Number of Visits: Unknown

220 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is researching an experimental drug called linvoseltamab ("study drug"). This study is focused on patients who have AL amyloidosis that has returned or have failed other therapies and need to be treated again. The study consists of 2 phases (Phase 1 and Phase 2): * In Phase 1, linvoseltamab will be given to a small number of participants to study the side effects of the study drug and to determine the recommended doses of the study drug to be given to participants in Phase 2. * In Phase 2, linvoseltamab will be given to more participants to continue to assess the side effects of the study drug and to evaluate the ability of linvoseltamab to treat AL amyloidosis. The study is looking at several other research questions, including: * How many participants treated with linvoseltamab have improvement in the abnormal proteins that cause organ problems and for how long * How many participants treated with linvoseltamab have improvement in the heart or kidney and for how long * What the right dosing regimen is for linvoseltamab * What side effects may happen from taking linvoseltamab * How much linvoseltamab is in the blood at different times * Whether the body makes antibodies against linvoseltamab (which could make the drug less effective or could lead to side effects)

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

What data supports the effectiveness of the drug Linvoseltamab for treating amyloidosis?

The research suggests that targeting long-lived plasma cells, which are involved in antibody responses, can be effective in certain conditions. Although not directly related to Linvoseltamab, similar strategies using proteasome inhibitors like bortezomib have shown success in reversing harmful antibody responses in other diseases, indicating potential for plasma cell-targeting treatments. ^{1 2 3 4 5}

How is the drug Linvoseltamab different from other treatments for amyloidosis?

Linvoseltamab is unique because it is a bispecific antibody that targets both BCMA (B-cell maturation antigen) and CD3, potentially offering a novel mechanism of action compared to existing treatments like daratumumab, which targets CD38. This dual targeting approach may provide a new way to treat amyloidosis by engaging the immune system more directly. ^{6 7 8 9 10}

Research Team

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Eligibility Criteria

This trial is for adults with AL amyloidosis who have tried at least one but no more than four treatments and need more therapy. They should have a certain level of abnormal proteins in their blood, be able to perform daily activities with ease or some difficulty (ECOG score ≤2), and have good heart, liver, kidney, and blood function.

Inclusion Criteria

I have been diagnosed with AL amyloidosis.

My liver, blood, kidney, and heart are functioning well.

My blood tests show measurable disease markers.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Linvoseltamab is given to a small number of participants to study side effects and determine recommended doses

4 weeks

Phase 2 Treatment

Linvoseltamab is given to more participants to assess side effects and evaluate treatment efficacy

39 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Linvoseltamab

Trial Overview The study tests linvoseltamab in two phases: Phase 1 determines safe dosages through a small group; Phase 2 expands the testing for effectiveness against AL amyloidosis symptoms. It also examines how long improvements last, optimal dosing schedules, potential side effects, drug levels in the blood over time, and if the body resists the drug.

Participant Groups

Group I: Phase 2: Low Dose Experimental Treatment 1 Intervention

Dose Expansion: Participants will be randomized in a 1:1 ratio

Group II: Phase 2: High Dose Experimental Treatment 1 Intervention

Dose Expansion: Participants will be randomized in a 1:1 ratio

Group III: Phase 1: Cohort 2: High Dose Experimental Treatment 1 Intervention

Dose Escalation: Non-Randomized

Group IV: Phase 1: Cohort 1: Low Dose Experimental Treatment 1 Intervention

Dose Escalation: Non-Randomized

Who Is Running the Clinical Trial?

Regeneron Pharmaceuticals

Lead Sponsor

Trials

690

Recruited

948,000+

Founded

1988

Headquarters

Tarrytown, USA

Known For

Precision medicine

Top Products

Dupixent, EYLEA, Libtayo, Praluent

Leonard Schleifer

Regeneron Pharmaceuticals

Chief Executive Officer since 1988

MD and PhD in Medicine

George Yancopoulos

Regeneron Pharmaceuticals

Chief Medical Officer since 1997

MD from Harvard Medical School

Findings from Research

Monoclonal antibodies targeting specific T-cell surface antigens have shown promise in treating rheumatoid arthritis, but controlled studies have not consistently confirmed their effectiveness.

Anti-TNF alpha monoclonal antibodies have demonstrated significant clinical improvements and immediate suppression of inflammation in rheumatoid arthritis, supported by both open trials and recent controlled studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monoclonal antibody therapy of inflammatory rheumatic diseases. Breedveld, FC., van der Lubbe, PA.[2019]

Rituximab, an anti-CD20 monoclonal antibody, showed a high response rate in treating inflammatory myopathies (IM), with 75% of patients in this study and 72.5% in the literature reporting a good response, particularly in dermatomyositis cases.

The treatment was generally well tolerated, with no serious adverse events reported; however, infections, especially respiratory tract infections, were the most common side effects, indicating a need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in the treatment of dermatomyositis and other inflammatory myopathies. A report of 4 cases and review of the literature. Rios Fernández, R., Callejas Rubio, JL., Sánchez Cano, D., et al.[2017]

High-titered and sustained antibody responses to therapeutic proteins, such as enzyme replacement therapies, can lead to treatment failure and serious health complications, as these responses are often driven by long-lived plasma cells that resist standard immune suppressive treatments.

Proteasome inhibitors like bortezomib have shown promise in reversing harmful antibody responses in certain conditions, suggesting that further clinical trials are needed to assess their safety and efficacy in managing antibody-mediated adverse effects and autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A role for plasma cell targeting agents in immune tolerance induction in autoimmune disease and antibody responses to therapeutic proteins. Rosenberg, AS., Pariser, AR., Diamond, B., et al.[2016]

In a study involving 218 patients with refractory rheumatoid arthritis, intravenous TNFR55-IgG1 showed significant improvement in symptoms as early as one day after the first infusion, with maximum effects observed two weeks later.

The treatment was well tolerated, with mostly mild to moderate side effects, but the efficacy declined over time due to the development of antibodies against the drug, which increased its clearance from the body.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapy of refractory chronic polyarthritis with tumor necrosis factor alpha receptor fusion proteins (TNFR55-IgG1)--results of double-blind placebo-controlled studies over 3 months]. van de Putte, LB., Sander, O., Rau, R.[2019]

Rituximab, a chimeric monoclonal antibody targeting the CD20 molecule on B-cells, has shown efficacy in treating rheumatoid arthritis, indicating its potential as a therapeutic option for this condition.

Recent evidence suggests that rituximab is generally safe for use in rheumatoid arthritis patients, although monitoring for potential side effects is still important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Rituximab treatment of rheumatoid arthritis: new evidence]. Nasonov, EL.[2018]

Daratumumab, an anti-CD38 immunotherapy, has shown significant efficacy in treating newly diagnosed systemic light-chain (AL) amyloidosis by improving hematologic and organ response rates, suggesting it may become a new standard of care.

In relapsed or refractory cases, daratumumab alone or in combination therapies has also demonstrated promising results, highlighting the potential of targeting CD38 on plasma cells for effective treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab in the Treatment of Light-Chain (AL) Amyloidosis. Palladini, G., Milani, P., Malavasi, F., et al.[2021]

In a case study of a 95-year-old patient with systemic immunoglobulin light-chain (AL) amyloidosis, traditional chemotherapy treatments showed poor effectiveness, highlighting the challenges of treating this condition in very elderly patients.

The anti-CD38 antibody daratumumab demonstrated the best hematologic response with minimal side effects, suggesting it could be a safer and more effective treatment option for AL amyloidosis in older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Interest of daratumumab in refractory AL amyloidosis in a 96-year-old patient]. Vial, G., Lafargue, A., Mercié, P., et al.[2022]

Daratumumab, an anti-CD38 monoclonal antibody, has demonstrated significant clinical efficacy in treating systemic light-chain amyloidosis, showing high rates of hematologic response that correlate with improved organ function.

While anti-amyloid therapies have shown promise in preclinical studies, there is currently no confirmed evidence of their effectiveness in improving patient outcomes in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monoclonal Antibody Therapies in Systemic Light-Chain Amyloidosis. Godara, A., Palladini, G.[2021]

A study of 48 patients with systemic light-chain amyloidosis (AL) revealed that nearly all clonal plasma cells expressed high levels of the CD32B receptor, suggesting a potential target for therapy.

The humanized 2B6 monoclonal antibody, which specifically targets CD32B, shows promise as a novel treatment option for improving outcomes in patients with AL, as it effectively binds to the majority of plasma cells involved in the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD32B is highly expressed on clonal plasma cells from patients with systemic light-chain amyloidosis and provides a target for monoclonal antibody-based therapy. Zhou, P., Comenzo, RL., Olshen, AB., et al.[2021]

In the phase III ANDROMEDA trial, subcutaneous daratumumab combined with bortezomib, cyclophosphamide, and dexamethasone significantly improved the rate of complete hematological response in patients with newly diagnosed systemic AL amyloidosis compared to the standard treatment alone.

This combination therapy not only produced rapid and deep responses but also resulted in better progression-free survival and higher rates of cardiac and renal responses at 6 and 12 months, while maintaining an acceptable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Newly Diagnosed Systemic Light Chain Amyloidosis. Blair, HA.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Monoclonal antibody therapy of inflammatory rheumatic diseases. [2019]

2. Italy pubmed.ncbi.nlm.nih.gov

Rituximab in the treatment of dermatomyositis and other inflammatory myopathies. A report of 4 cases and review of the literature. [2017]

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

A role for plasma cell targeting agents in immune tolerance induction in autoimmune disease and antibody responses to therapeutic proteins. [2016]

4. Germany pubmed.ncbi.nlm.nih.gov

[Therapy of refractory chronic polyarthritis with tumor necrosis factor alpha receptor fusion proteins (TNFR55-IgG1)--results of double-blind placebo-controlled studies over 3 months]. [2019]

5. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Rituximab treatment of rheumatoid arthritis: new evidence]. [2018]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Daratumumab in the Treatment of Light-Chain (AL) Amyloidosis. [2021]

7. France pubmed.ncbi.nlm.nih.gov

[Interest of daratumumab in refractory AL amyloidosis in a 96-year-old patient]. [2022]

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

Monoclonal Antibody Therapies in Systemic Light-Chain Amyloidosis. [2021]

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

CD32B is highly expressed on clonal plasma cells from patients with systemic light-chain amyloidosis and provides a target for monoclonal antibody-based therapy. [2021]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Newly Diagnosed Systemic Light Chain Amyloidosis. [2022]