Birtamimab for Amyloidosis

(AFFIRM-AL Trial)

No longer recruiting at 176 trial locations

Overseen By Karen Lai

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Prothena Biosciences Ltd.

Must be taking: Bortezomib

Must not be taking: Doxycycline, Daratumumab

Disqualifiers: Non-AL amyloidosis, Myocardial infarction, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 56

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness and safety of a new drug, birtamimab, for individuals with AL amyloidosis, a condition affecting the heart. Participants will receive either birtamimab (an experimental treatment) plus standard chemotherapy or a placebo plus standard chemotherapy to determine if the new drug offers any benefits. The trial targets those newly diagnosed with this condition who have not yet received treatment, particularly if the disease has caused heart problems. Participants must have a confirmed diagnosis of AL amyloidosis with significant heart involvement. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that participants should not have had certain treatments like plasma cell-directed chemotherapy or other investigational treatments for amyloid before joining. It's best to discuss your current medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that birtamimab is generally safe and well-tolerated by patients. In one study, patients with AL amyloidosis experienced no major safety issues with birtamimab, and most handled the treatment well over time. Another study with 302 patients reported an average treatment period of about 12 months without major safety concerns.

Overall, although some treatment goals were not achieved in certain studies, birtamimab's safety profile remained positive. This suggests that the treatment is likely safe for most people considering joining the clinical trial. ^{1 2 3 4 5}

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

Birtamimab is unique because it targets amyloid deposits directly, which distinguishes it from standard treatments like bortezomib-based chemotherapy regimens. This approach could potentially clear these harmful deposits from organs more effectively, addressing the root cause of amyloidosis rather than just managing symptoms. Researchers are excited because this mechanism offers hope for improved outcomes in patients with this challenging condition.

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

Research shows that birtamimab might benefit patients with a severe form of AL amyloidosis, known as Mayo stage IV. One study found that after 9 months, 74% of patients on birtamimab survived, compared to 49% on a placebo, suggesting it might extend life. Additionally, patients on birtamimab walked an average of 15.22 meters farther in a 6-minute walk test, indicating improved physical function. However, another study did not meet its primary objectives, resulting in mixed outcomes. In this trial, participants will receive either birtamimab plus standard chemotherapy or a placebo plus standard chemotherapy. These findings are important to consider when deciding whether to join a trial. ^{2 3 4 6 7}

Are You a Good Fit for This Trial?

This trial is for adults with Mayo Stage IV AL Amyloidosis, a condition affecting the heart due to abnormal protein deposits. Participants must be newly diagnosed, treatment-naïve with specific cardiac involvement markers, and planning first-line chemotherapy including bortezomib. Those eligible for transplants or having other conditions like multiple myeloma or recent heart issues cannot join.

Inclusion Criteria

My tests show I have advanced AL Amyloidosis with specific heart and blood markers.

My first chemotherapy will include weekly bortezomib shots.

I have been diagnosed with AL amyloidosis.

Exclusion Criteria

I am planning to have a stem cell or organ transplant.

I meet the criteria for multiple myeloma, except for one specific blood marker.

I haven't received blood products or growth factors in the last week.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Double-blind Phase

Participants are randomized to receive either birtamimab or placebo plus standard of care chemotherapy. The primary objective is to evaluate the efficacy by assessing time to all-cause mortality.

Until predefined number of events (all-cause mortality) are reached

Intravenous administration every 28 days

Open-label Extension (OLE) Phase

Eligible subjects receive open-label birtamimab treatment for long-term safety evaluation, continuing for 24 months or until commercial availability.

24 months

Intravenous administration every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Birtamimab
• Placebo
• Standard of Care Chemotherapy

Trial Overview

The study compares the effectiveness of Birtamimab plus standard chemotherapy against a placebo combined with standard chemotherapy in treating AL Amyloidosis patients at an advanced stage. It's designed to see if Birtamimab can improve patient outcomes.

How Is the Trial Designed?

Group I: Birtamimab plus Standard of Care Chemotherapy- For Double-blind Phase and OLE Phase of study Experimental Treatment 2 Interventions

Intravenous administration of 24 mg/kg birtamimab every 28 days. Drug: Standard of Care Chemotherapy. Bortezomib-containing chemotherapy regimen (e.g. cyclophosphamide, bortezomib, and dexamethasone (CyBorD)) according to the institutional standard of care. The initiation of daratumumab treatment at randomization is allowed at the discretion of the Investigator; initiation at any other time during the Double-blind Phase is prohibited. For subjects who did not initiate daratumumab at randomization during the Double-blind Phase, daratumumab may be initiated at any time during the OLE Phase at the Investigator's discretion.

Group II: Placebo plus Standard of Care Chemotherapy- For Double-blind Phase of study Placebo Group 2 Interventions

Intravenous 0.9% Saline administration as a placebo every 28 days. Drug: Standard of Care Chemotherapy. Bortezomib-containing chemotherapy regimen (e.g. cyclophosphamide, bortezomib, and dexamethasone (CyBorD)) according to the institutional standard of care. Initiation of daratumumab at randomization allowed at the discretion of the investigator.

Who Is Running the Clinical Trial?

Prothena Biosciences Ltd.

Lead Sponsor

Trials

8

Recruited

1,200+

Published Research Related to This Trial

Bortezomib plus dexamethasone (BD) shows efficacy in treating primary systemic (AL) amyloidosis, with a response observed in six out of eight evaluable patients after a median of three treatment cycles.

While BD is effective, it is associated with common adverse events such as diarrhea, thrombocytopenia, and peripheral neuropathy, indicating that careful monitoring and dosage adjustments may be necessary during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of primary systemic amyloidosis with the combination of bortezomib and dexamethasone]. Zhai, YP., Liu, HN., Yu, YP., et al.[2018]

In a study comparing two treatment regimens for AL amyloidosis, cyclophosphamide, bortezomib, and dexamethasone (CVD) showed a higher complete response rate (40.5%) compared to cyclophosphamide, thalidomide, and dexamethasone (CTD) (24.6%), indicating that CVD may be more effective in achieving deeper responses.

CVD also demonstrated superior progression-free survival (28.0 months) compared to CTD (14.0 months), suggesting that CVD may provide longer-lasting benefits for patients, although both regimens still face challenges with early mortality in AL amyloidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A matched comparison of cyclophosphamide, bortezomib and dexamethasone (CVD) versus risk-adapted cyclophosphamide, thalidomide and dexamethasone (CTD) in AL amyloidosis. Venner, CP., Gillmore, JD., Sachchithanantham, S., et al.[2021]

The combination therapy of daratumumab, cyclophosphamide, bortezomib, and dexamethasone (daratumumab-CyBorD) has become the new standard-of-care for systemic light chain (AL) amyloidosis, showing high rates of hematologic and organ response.

Recent advancements in patient selection and induction regimens have significantly reduced the mortality associated with autologous stem cell transplant (ASCT), while new treatments like venetoclax are proving effective for patients with specific genetic abnormalities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in the treatment of light chain amyloidosis. Palladini, G., Milani, P.[2023]

In a study of 49 patients with relapsed/refractory AL amyloidosis treated with daratumumab, the overall hematologic response rate was 81%, with 64% achieving a very good partial response or better, indicating strong efficacy in this challenging patient population.

Daratumumab was found to be safe and well tolerated, with no patients discontinuing treatment due to toxicity, and it demonstrated significant cardiac and renal responses (74% and 73%, respectively), supporting its use in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab for relapsed AL amyloidosis-When cumulative real-world data precedes clinical trials: A multisite study and systematic literature review. Shragai, T., Gatt, M., Lavie, N., et al.[2021]

Bortezomib treatment significantly improved overall response rates and survival outcomes in patients with AL amyloidosis, based on a meta-analysis of eight studies involving 617 participants.

Patients who received bortezomib, especially those pretreated before undergoing high-dose melphalan and autologous stem cell transplant, showed notably higher response rates compared to those who did not receive bortezomib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect and Safety of Bortezomib in the Treatment of AL Amyloidosis: A Systematic Review and Meta-Analysis. Jiang, F., Chen, J., Liu, H., et al.[2020]

In a phase 3 trial involving 260 newly diagnosed patients with AL amyloidosis, birtamimab did not show a significant improvement in overall survival or hospitalization rates compared to placebo, leading to the trial's early termination due to futility.

However, a post hoc analysis revealed that patients with Mayo stage IV AL amyloidosis treated with birtamimab had a significant survival advantage at 9 months, with 74% survival compared to 49% in the placebo group, suggesting potential efficacy in this high-risk population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Birtamimab plus standard of care in light-chain amyloidosis: the phase 3 randomized placebo-controlled VITAL trial. Gertz, MA., Cohen, AD., Comenzo, RL., et al.[2023]

In a phase 1a/b study involving 27 patients with systemic immunoglobulin light-chain amyloidosis, the monoclonal antibody CAEL-101 was well tolerated with no serious adverse events, indicating a favorable safety profile for this treatment.

The treatment led to a therapeutic response in 63% of patients with organ involvement, particularly improving organ function in those with cardiac issues, with a median time to response of just 3 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis. Edwards, CV., Rao, N., Bhutani, D., et al.[2023]

Citations

1.

hematologyadvisor.com

hematologyadvisor.com/news/birtamimab-misses-endpoints-in-late-stage-al-amyloidosis-trial/

Birtamimab Misses Endpoints in Late-Stage AL ...

The AFFIRM-AL trial assessing birtamimab in AL amyloidosis patients did not meet its primary endpoint of time to all-cause mortality.

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10644097/

Birtamimab plus standard of care in light-chain amyloidosis

At month 9, 74% of patients with Mayo stage IV AL amyloidosis treated with birtamimab and 49% of those given placebo survived. Overall, the rates of treatment- ...

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04973137

A Study to Evaluate the Efficacy and Safety of Birtamimab ...

A Phase 3 study to evaluate the efficacy and safety of birtamimab plus standard of care compared to placebo plus standard of care in Mayo Stage IV patients with ...

4.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/37366170/

Birtamimab plus standard of care in light-chain amyloidosis

At month 9, 74% of patients with Mayo stage IV AL amyloidosis treated with birtamimab and 49% of those given placebo survived. Overall, the ...

5.

ir.prothena.com

ir.prothena.com/investors/press-releases/news-details/2023/Prothena-Announces-Phase-3-VITAL-Clinical-Trial-Results-Published-in-Blood-Showing-Survival-Benefit-in-Patients-with-Mayo-Stage-IV-AL-Amyloidosis-Treated-with-Birtamimab/default.aspx

Prothena Announces Phase 3 VITAL Clinical Trial Results ...

Patients treated with birtamimab after 9 months demonstrated an increase in mean distance of 15.22 meters in the 6-minute walk test, compared to ...

6.

ashpublications.org

ashpublications.org/blood/article/142/Supplement%201/3409/499195/Pooled-Analysis-of-Safety-from-Birtamimab-Phase-1

Pooled Analysis of Safety from Birtamimab Phase 1-3 Studies ...

Results: The median (range) exposure to birtamimab among 302 patients pooled from the Phase 1-3 trials was 12.24 (0.03-57.72) months. Of the 302 ...

7.

arci.org

arci.org/negative-affirm-al-results/

Prothena Announces Negative AFFIRM-AL Trial Results

Though the endpoints of the trial were not met, birtamimab was considered generally safe and well-tolerated. “We share in the disappointment ...