Birtamimab for Amyloidosis

(AFFIRM-AL Trial)

Recruiting at 147 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

220 Participants Needed

Trial Summary

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.

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

In a clinical trial, Birtamimab showed significant improvement in survival for patients with the most severe form of amyloidosis (Mayo stage IV) at 9 months, with 74% of these patients surviving compared to 49% on placebo. This suggests Birtamimab may be beneficial for those at high risk of early mortality. ^{1 2 3 4 5}

Is Birtamimab safe for humans?

In the VITAL trial, Birtamimab was tested in patients with AL amyloidosis, and the rates of side effects were generally similar between those who received Birtamimab and those who received a placebo, suggesting it is generally safe. ^{2 3 4 6 7}

What makes the drug Birtamimab unique for treating AL amyloidosis?

Birtamimab is a unique drug for AL amyloidosis because it is a monoclonal antibody designed to neutralize toxic light chain aggregates and help remove amyloid deposits from organs through a process called phagocytosis (where cells engulf and digest particles). This approach is different from other treatments like bortezomib, which focuses on improving response rates and survival by targeting the underlying disease process. ^{1 2 4 7 8}

What is the purpose of this trial?

This trial tests birtamimab, a new drug, in patients with severe AL amyloidosis. The drug aims to clear harmful protein buildups in the body, potentially improving patient outcomes.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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 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]

References

1. China pubmed.ncbi.nlm.nih.gov

[Treatment of primary systemic amyloidosis with the combination of bortezomib and dexamethasone]. [2018]

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

Teclistamab in relapsed or refractory AL amyloidosis, a multinational retrospective case series. [2023]

3. England 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. [2021]

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

Birtamimab plus standard of care in light-chain amyloidosis: the phase 3 randomized placebo-controlled VITAL trial. [2023]

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

Advances in the treatment of light chain amyloidosis. [2023]

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

Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis. [2023]

7. India pubmed.ncbi.nlm.nih.gov

The Effect and Safety of Bortezomib in the Treatment of AL Amyloidosis: A Systematic Review and Meta-Analysis. [2020]

8. England 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. [2021]