Linvoseltamab for Amyloidosis

(LINKER-AL2 Trial)

Recruiting at 25 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, linvoseltamab (also known as REGN-5458, a BCMAxCD3 antibody), for individuals with AL amyloidosis, a condition where abnormal proteins accumulate in organs and cause damage. The trial aims to determine the optimal dose and assess the drug's effectiveness in reducing these harmful proteins and improving heart or kidney function. It consists of two phases: the first examines side effects and the appropriate dose, while the second evaluates the drug's effectiveness in a larger group. This trial suits those with AL amyloidosis whose previous treatments have failed. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

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.

Is there any evidence suggesting that linvoseltamab is likely to be safe for humans?

Research has shown that linvoseltamab has been tested in studies involving patients with various conditions. These studies found that linvoseltamab is generally safe, with most patients tolerating it well. Most side effects were mild or moderate.

However, side effects can occur with any treatment. Some patients experienced tiredness, fever, or low blood counts. These side effects are common in many treatments and are usually manageable.

It's important to note that this study is still in the early stages. Researchers are still learning about the safety of linvoseltamab for treating AL amyloidosis. However, past research suggests it might be safe for many people. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for amyloidosis?

Researchers are excited about Linvoseltamab for amyloidosis because it represents a novel approach compared to existing treatments like chemotherapy and stem cell transplants. Unlike these traditional options, which generally work by targeting rapidly dividing cells, Linvoseltamab is designed to selectively target and modulate specific proteins involved in the formation of amyloid deposits. This targeted mechanism potentially offers a more precise treatment, which could lead to fewer side effects and improved outcomes. Additionally, the flexibility in dosing explored in the trial phases may help tailor treatment to individual patient needs, enhancing its effectiveness and tolerance.

What evidence suggests that linvoseltamab might be an effective treatment for AL amyloidosis?

Research has shown that linvoseltamab may help treat conditions like AL amyloidosis. In earlier studies with patients who had relapsed or hard-to-treat multiple myeloma, linvoseltamab produced impressive results. About 71% of older patients responded to the treatment, and more than half experienced a complete or even better response. The drug's effects lasted several months for many patients. This trial will explore different dosages of linvoseltamab, with some participants receiving a high dose and others a low dose. While specific data for AL amyloidosis is still being gathered, the drug's previous success offers hope for its potential effectiveness in reducing the harmful proteins causing organ issues in AL amyloidosis. ^{1 2 4 6 7}

Who Is on the Research Team?

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11272139/

Linvoseltamab for Treatment of Relapsed/Refractory ... We present a phase I/II first-in-human trial evaluating the safety and efficacy of 50 mg and 200 mg doses of linvoseltamab, a B-cell maturation ...

2. onclive.com onclive.com/view/linvoseltamab-demonstrates-deep-durable-responses-in-r-r-myeloma-ahead-of-fda-action-date

Linvoseltamab Demonstrates Deep, Durable Responses in ... Patients at least 75 years of age (n = 31) achieved an ORR of 71% with a CR or better rate of 54.8%. In patients with a high-risk cytogenetics ( ...

3. ash.confex.com ash.confex.com/ash/2020/webprogram/Paper139192.html

291 REGN5458, a BCMA x CD3 Bispecific Monoclonal ... A total of 43.8% of responders had a DOR >4 months and 18.8% had a DOR >8 months. The ORR in patients with extramedullary plasmacytomas was 16.7 ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06292780?term=AREA%5BConditionSearch%5D(%22Immunoglobulin%20Light%20Chain%20Amyloidosis%22)%20AND%20AREA%5BInterventionSearch%5D(%22Antibodies,%20Bispecific%22)&rank=2

NCT06292780 | A Trial to Learn if Linvoseltamab is Safe ... A Trial to Learn if Linvoseltamab is Safe and Works in Adults With Relapsed or Refractory Systemic Light Chain Amyloidosis ( AL Amyloidosis ) (LINKER-AL2).

5. ajmc.com ajmc.com/view/linvoseltamab-shows-durable-efficacy-manageable-safety-in-r-r-multiple-myeloma

Linvoseltamab Shows Durable Efficacy, Manageable ... At 21.3 months median follow-up, linvoseltamab showed an overall survival of 71% in all comers, with 52% of patients achieving a complete ...

6. medchemexpress.com medchemexpress.com/linvoseltamab.html?srsltid=AfmBOooSCWh_Q5tpPzSlV_lAu5ElsJ8lCSPW1M3zO-1zoa4lWY-sG-qL

Linvoseltamab (REGN5458) | BCMA/CD3 Antibody Linvoseltamab (REGN5458) is a bispecific T-cell engager (BiTE) antibody that specifically binds to B cell maturation antigen (BCMA) and CD3 of T cells, ...

7. investor.regeneron.com investor.regeneron.com/static-files/67055c32-348a-4851-b6e6-b03c535af879

Safety and Preliminary Clinical Activity of REGN5458, an ... Summary. • A total of seven patients (median age 78 years) with R/R MM. (median seven lines of prior systemic therapies, all of whom failed.