birtamimab (NEOD001) / Prothena - LARVOL DELTA

Development of a high-affinity antibody specific to the predominant λ light chain amyloid subtype for AL amyloidosis immunotherapy (ASH 2025) - P3 | "Such mixed resultsare not unexpected: birtamimab was developed against serum amyloid A and anselamimab against κ LCamyloid, but 80% of AL amyloidosis cases involve λ LCs. Ch1F10 mAb also showed significantly higher phagocytic activity than ch11-1F4mAb against λ6 Wil amyloid using human THP-1 macrophages (P<0.0001, one-way ANOVA).CONCLUSIONSWe developed the novel λ-light chain specific monoclonal antibody 1F10, which demonstrated high-affinity binding and clearance activity. Given the current lack of efficient fibril targeting therapies for thismajority patient population, the 1F10 mAb represents a promising candidate for advancing subtype-specific precision immunotherapy in AL amyloidosis."

Amyloidosis

Histologic and Molecular Correlates in Patients with AL Amyloidosis in Hematologic Remission but with Persistent Renal Disease (ASH 2023) - P2b | "While the RAIN trial closed prematurely and NEOD001 cannot be evaluated, the molecular data revealed the presence of two distinct molecular subtypes of AL nephropathy. Whether these distinct molecular subtypes reflect different stages of the disease along a continuous spectrum or are of unique prognostic entities in of themselves remains unclear. Detailed studies, of a larger cohort of patients including investigating diseased tissue at a single cell resolution can help identify the response of individual kidney cell types."

Clinical • IO biomarker • Amyloidosis • Fibrosis • Glomerulonephritis • Nephrology • Renal Disease • ABL1 • BCL2 • BRCA • CDKN1A • CXCL8 • IL15 • IL33 • TP53 • TP73

Pooled Analysis of Safety from Birtamimab Phase 1-3 Studies in Patients with Light Chain (AL) Amyloidosis (ASH 2023) - P1/2, P2, P2b, P3 | "In VITAL, newly diagnosed treatment-naïve patients with cardiac involvement received birtamimab + SoC or placebo + SoC (where SoC was a bortezomib-containing chemotherapy regimen). Birtamimab was well tolerated in patients with AL amyloidosis when administered as monotherapy and did not demonstrate additive toxicity when given with SoC chemotherapy. Rates of TEAEs in the birtamimab arm were similar to rates in the placebo arm in the PRONTO and VITAL trials. The safety and efficacy of birtamimab is being further investigated in an ongoing confirmatory Phase 3 double-blind RCT in patients with Mayo Stage IV AL amyloidosis (AFFIRM-AL; NCT04973137), which is currently enrolling."

P1 data • Retrospective data • Amyloidosis • Cardiovascular • Congestive Heart Failure • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder • Heart Failure • Pulmonary Disease

Development of anti-AL amyloidosis CAR Phagocyte Therapy (IMS 2025) - "CAEL-101(c11-1F4), a fibril-specific monoclonal antibody in Phase 3A/B trials, promotes amyloid clearance via phagocytosis. However, the use of anti-CD38 antibodies in AL amyloidosis treatment and the recent failure of Birtamimab raised concerns that antibody-dependent phagocytosis for amyloid clearance may be impaired by high serum levels of anti-CD38 antibodies competing for Fc receptor binding... We developed the first-in-class anti-AL amyloidosis CAR phagocytes using CD34+ cells and confirmed their amyloid-targeting activities both in vitro and in vivo. By bypassing serum IgG Fc competition, CAR phagocytes represent a promising novel cell therapy for AL amyloidosis."

IO biomarker • Amyloidosis • CD14 • CD34 • CD68 • CD86 • CSF1 • ITGAX • MRC1

AFFIRM-AL: A Study to Evaluate the Efficacy and Safety of Birtamimab in Mayo Stage IV Patients With AL Amyloidosis (clinicaltrials.gov) - P3 | N=208 | Terminated | Sponsor: Prothena Biosciences Ltd. | Trial completion date: Jun 2027 ➔ Jun 2025 | Recruiting ➔ Terminated; The AFFIRM-AL clinical trial did not meet its primary endpoint.

Trial completion date • Trial termination • Amyloidosis

COMPLEMENT AND AMYLOID SIGNATURE PROTEIN UPREGULATION IN POST- TREATMENT AL AMYLOID PROTEOMES PROVIDES NOVEL INSIGHTS INTO DISEASE BIOLOGY (EHA 2025) - "This is the first study to examine treatment related proteomic changes in AL amyloidosis. The upregulation of complement proteins in the post-treatment samples of responders suggests complement activation plays a role in amyloid plaque removal but may also represent a mechanism of tissue toxicity. The reduction in immunoglobulin proteins in the residual amyloid plaques of responders may have therapeutic implications, as both birtamimab and anselamimab target misfolded immunoglobulin light chains which are be less abundant following therapy."

Amyloidosis • APOE • IGKC • VTN

BIRTAMIMAB SAFETY IN AL AMYLOIDOSIS PATIENT SUBGROUPS: MAYO STAGE I-III VS STAGE IV AND PREVIOUSLY TREATED PATIENTS RECEIVING MONOTHERAPY VS NEWLY DIAGNOSED PATIENTS WITH CONCOMITANT STANDARD OF CARE (EHA 2025) - P2b, P3 | "In VITAL (NCT02312206), newly diagnosed treatment-naïve pts with cardiac involvement received birtamimab+SoC or PBO+SoC (bortezomib-containing regimen). Birtamimab has a consistent safety profile across Mayo Stages (MSI-III vs MSIV), in newly diagnosed and previously treated pts, and when given as monotherapy or with SoC. Within subgroups, rates of AEs were similar between birtamimab and PBO arms, suggesting that birtamimab is well tolerated. The safety and efficacy of birtamimab are being further investigated in a confirmatory Phase 3 trial in MSIV pts (AFFIRM-AL; NCT04973137)."

Clinical • Metastases • Monotherapy • Amyloidosis • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder

Unexpected and Successful ABO Incompatible Heart Transplant in a 50-year-Old Woman with AL Amyloid Cardiomyopathy (ISHLT 2025) - "She was treated with cyclophosphamide, bortezomib, dexamethasone and daratumumab and was also included in a trial with birtamimab vs placebo, with partial remision in July 2024...Induction with basiliximab was used, followed by standard treatment (tacrolimus, mycophenolate and prednisone)...She was started on methylprednisolone, five PLEX sessions and eculizumab, with clinical and histopathological improvement. The patient is currently stable under biweekly eculizumab treatment.Summary We present a successful case of accidental ABO incompatible HT in a patient with cardiac AL amyloidosis previously treated with daratumumab and the treatment scheme post-HT based on PLEX and eculizumab"

Clinical • Amyloidosis • Antibody-mediated Rejection • Cardiac Amyloidosis • Cardiomyopathy • Cardiovascular • Transplantation

Etiological Treatment of Cardiac Amyloidosis: Standard of Care and Future Directions. (PubMed, Curr Heart Fail Rep) - "The standard of care for ATTR-CA include agents capable of selectively stabilizing the precursor protein (e.g., tafamidis), whereas the plasma cell clone is the main target of chemotherapy for AL-CA...Recent data from ATTRibute-CM led to the approval of acoramidis, whereas patisiran received refusal based on the APOLLO-B trial. Novel CRISPR-Cas9-based drugs (i.e., NTLA-2001) hold great potential in the setting of ATTR-CA...However, the investigation of monoclonal antibodies targeting misfolded ATTR (e.g., PRX004, NI301A) or AL (e.g., birtamimab, anselamimab) has led to encouraging results. Various cutting-edge strategies are being tested for treatment of CA and may change the prognostic landscape of this condition in the next years."

Journal • Review • Amyloidosis • Cardiac Amyloidosis • Cardiovascular • Hematological Disorders

Prothena Reports Fourth Quarter and Full Year 2024 Financial Results, and Provides Financial Guidance and Business Highlights (Businesswire) - "PRX019: Phase 1 clinical trial expected to complete in 2026. Birtamimab: The ongoing confirmatory Phase 3 AFFIRM-AL clinical trial is being conducted under a Special Protocol Assessment (SPA) agreement with the FDA with a primary endpoint of all-cause mortality (time-to-event) at a statistical significance level of 0.10. Topline results from confirmatory Phase 3 AFFIRM-AL clinical trial expected in 2Q 2025. Coramitug: Phase 2 clinical trial has completed enrollment of approximately 99 patients with trial completion expected in 1H 2025."

P3 data: top line • Trial completion date • Amyloidosis • Cardiomyopathy • CNS Disorders

New therapies to treat cardiac amyloidosis. (PubMed, Curr Opin Cardiol) - "The therapeutic landscape for ATTR-CM and AL-CM is rapidly evolving, driven by novel therapies targeting diverse mechanisms. Ongoing clinical trials promise to further refine the standard of care and improve outcomes for patients with cardiac amyloidosis."

Journal • Amyloidosis • Cardiac Amyloidosis • Cardiovascular

Prothena Reports Third Quarter 2024 Financial Results and Business Highlights (Businesswire) - "'From our wholly-owned programs we expect to complete our confirmatory Phase 3 AFFIRM-AL clinical trial evaluating birtamimab, which is being conducted under a SPA agreement with the FDA at a significance level of 0.10, in 1H 2025. We also expect to announce multiple clinical readouts from our ongoing Phase 1 ASCENT clinical trials evaluating PRX012 for Alzheimer’s disease starting in mid-2025 and continuing throughout the year. In collaboration with Roche, we expect results from the Phase 2b PADOVA clinical trial evaluating prasinezumab for Parkinson’s disease in 4Q 2024 and with Novo Nordisk, we expect results from the Phase 2 signal-detection clinical trial evaluating coramitug for ATTR amyloidosis with cardiomyopathy in 1H 2025.'"

P1 data • P2 data • P2b data • Trial completion • Alzheimer's Disease • Amyloidosis • CNS Disorders • Metabolic Disorders • Parkinson's Disease

Current and Emerging Immunotherapies for Systemic AL Amyloidosis. (PubMed, Discov Med) - "Quadruplet therapy of cyclophosphamide, bortezomib, dexamethasone and daratumumab (DaraCyborD) is the currently approved first-line induction therapy for systemic AL amyloidosis. Some patients need upfront autologous hematopoietic stem cell transplantation (HSCT) after high-dose melphalan conditioning particularly if DaraCyborD is not able to achieve complete hematologic response (CHR)...Both CAEL 101 and Birtamimab are currently being tested in phase 3 clinical trials for systemic AL amyloidosis patients with advanced cardiac involvement. This comprehensive review provides an up-to-date overview of AL amyloidosis therapy, with a particular focus on recent advances and future directions of immunotherapeutic strategies."

Journal • Review • Amyloidosis • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • Plasmacytoma • Transplantation

Health-Related Quality of Life in Patients With Mayo Stage IV Light Chain (AL) Amyloidosis Treated With Birtamimab Plus Standard of Care: Results From the VITAL Trial (IMW 2024) - "Treatment with birtamimab + SoC in patients with Mayo Stage IV AL amyloidosis was associated with significantly less decline in HRQoL versus placebo + SoC in several SF-36v2 domains."

Clinical • HEOR • Metastases • Amyloidosis • Pain

Prothena Reports Second Quarter 2024 Financial Results and Business Highlights (PRNewswire) - "Topline results from confirmatory AFFIRM-AL Phase 3 clinical trial expected between 4Q 2024 and 2Q 2025...Coramitug (formerly PRX004)...Phase 2 clinical trial has completed enrollment of approximately 99 patients with topline data expected in 1H 2025..."

P2 data • P3 data: top line • Amyloidosis • CNS Disorders • Metabolic Disorders

Pooled safety analysis from birtamimab phase 1–3 trials in patients with light chain (AL) amyloidosis (BSH 2024) - P1/2, P2, P2b, P3 | "Birtamimab was well tolerated, with a favourable safety profile as monotherapy and no evidence of additive toxicity with SoC in AL amyloidosis. AE rates in the birtamimab and placebo arms were similar in the RCTs. A confirmatory phase 3 RCT of birtamimab in patients with Mayo Stage IV AL amyloidosis (AFFIRM-AL; NCT04973137) is enrolling."

Clinical • P1 data • Amyloidosis • Cardiovascular • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder • Pulmonary Disease

AFFIRM-AL: A Study to Evaluate the Efficacy and Safety of Birtamimab in Mayo Stage IV Patients With AL Amyloidosis (clinicaltrials.gov) - P3 | N=220 | Recruiting | Sponsor: Prothena Biosciences Ltd. | N=150 ➔ 220

Enrollment change • Metastases • Amyloidosis

Novel monoclonal antibodies: A really specific therapy for light chain amyloidosis. (PubMed, Hematol Oncol) - "However, current clinical studies are investigating innovative targets, drug combinations and treatment strategies to improve therapeutic outcomes by minimizing adverse effects and refining patient prognosis in these challenging hematological conditions. In this paper, we review the state of the art regarding the use of anti-amyloid antibodies, as a revolutionary and innovative approach in the current scenario of amyloid treatment."

Journal • Review • Amyloidosis • Hematological Disorders • Rare Diseases

The mechanism of action, pharmacological characteristics, and clinical utility of the amyloid depleter birtamimab for the potential treatment of AL amyloidosis. (PubMed, Leuk Lymphoma) - P3 | "AFFIRM-AL (NCT04973137), a Phase 3 confirmatory trial of birtamimab plus standard of care in patients with Mayo Stage IV AL amyloidosis, is ongoing. This review summarizes birtamimab's mechanism of action, attributes, and potential clinical utility."

Journal • Review • Amyloidosis • Hematological Malignancies

POOLED ANALYSIS OF SAFETY FROM BIRTAMIMAB PHASE 1-3 TRIALS IN PATIENTS WITH LIGHT CHAIN (AL) AMYLOIDOSIS (EMN 2024) - No abstract available

P1 data • Retrospective data • Amyloidosis

AFFIRM-AL: A Study to Evaluate the Efficacy and Safety of Birtamimab in Mayo Stage IV Patients With AL Amyloidosis (clinicaltrials.gov) - P3 | N=150 | Recruiting | Sponsor: Prothena Biosciences Ltd. | Trial completion date: Jun 2024 ➔ Jun 2027 | Trial primary completion date: Jun 2024 ➔ Jun 2025

Metastases • Trial completion date • Trial primary completion date • Amyloidosis

A Study To Evaluate The Efficacy And Safety Of Birtamimab In Mayo Stage IV Patients With AL Amyloidosis (AFFIRM-AL) (HFSA 2023) - P3 | "Patients will receive either 24 mg/kg intravenous birtamimab or placebo every 28 days (both arms will also receive SoC, defined as concomitant chemotherapy with a first-line bortezomib-containing regimen). Birtamimab is the only investigational therapeutic in which a survival benefit has been observed in a post hoc analysis of patients with Mayo Stage IV AL amyloidosis in VITAL. AFFIRM-AL is currently enrolling.These data were previously presented at the 64th American Society of Hematology Annual Meeting and Exposition held December 10-13, 2022, in New Orleans, LA, USA."

Clinical • Metastases • Amyloidosis • Hematological Disorders

Birtamimab: a new amyloidosis treatment? (PubMed, Blood) - No abstract available

Journal • Amyloidosis

"Birtamimab Pushes the Needle in AL Amyloidosis @MorieGertz @vsanchorawala @MayoClinic @The_BMC @uoaofficial #oncology https://t.co/aRXHbsBdEf" (@OncLive)

Amyloidosis • Oncology

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 (Businesswire) - P3 | N=260 | VITAL (NCT02312206) | Sponsor: Prothena Biosciences | "The published data demonstrate that in a post hoc analysis of patients with Mayo Stage IV AL amyloidosis, a statistically significant survival benefit of 74 percent was observed for those treated with birtamimab plus standard of care (SOC) versus 49 percent in patients on placebo plus SOC at 9 months (HR 0.413, p=0.021). All participants in the clinical trial received concomitant bortezomib-containing chemotherapy regimens as part of SOC....Birtamimab is currently being studied in the confirmatory Phase 3 clinical trial, AFFIRM-AL, in patients with Mayo Stage IV AL amyloidosis; topline data is expected in 2024."

P3 data • P3 data: top line • Amyloidosis • CNS Disorders