BACKGROUND: AL amyloidosis is a rare, progressive, and typically fatal disease caused by both soluble and insoluble (amyloid) forms of misfolded immunoglobulin light chain (LC) proteins, with no approved treatments. Production and tissue deposition of LC aggregates result in various organ system dysfunction (most commonly cardiac and renal), causing significant morbidity and mortality. NEOD001 is an investigational humanized IGg1 designed to directly neutralize soluble toxic aggregates of misfolded LCs and promote phagocytic clearance of amyloid deposits.

AIM: To evaluate efficacy and safety of NEOD001 + standard of care (SOC) vs placebo + SOC in patients with AL amyloidosis by assessing time to all-cause mortality (ACM) or cardiac hospitalization (CH).

METHODS: This Phase 3, double-blind, placebo-controlled study randomized 260 newly diagnosed, untreated AL amyloidosis patients (stratified by Mayo stage (Kumar et al., 2012), renal stage, & 6MWD) with cardiac involvement. Patients were randomized 1:1 to 24 mg/kg IV NEOD001 + SOC or placebo + SOC every 28 days. SOC was concomitant chemotherapy with a first line bortezomib-containing regimen. Primary endpoint (PE) was time to ACM or time to centrally adjudicated CH (CH: >90 days after first study drug infusion). Futility analysis based on 103 adjudicated events favored NEOD001 but was not statistically significant (HR 0.84, 95% CI 0.57-1.204, p=0.386). The study was terminated early and post hoc analyses were performed. To our knowledge, this study was the first randomized, placebo-controlled, Phase 3 study evaluating an amyloid-targeting agent in AL amyloidosis.

RESULTS: Study arms were balanced with regard to demographics and baseline clinical characteristics. The final PE results (intent-to-treat, ITT) were consistent with the futility analysis: HR 0.835, 95% CI 0.5799-1.2011, p=0.330. Favorability of HR for NEOD001 was largely attributable to time to all-cause mortality rather than cardiac hospitalization. Study termination was the primary reason for discontinuation (majority occurring after 12 months). The 12-month study period was defined as modified ITT (mITT). Further mITT analyses by prognostic Mayo staging categories suggest benefit favoring NEOD001 for both PE (HR=0.635) and ACM (HR=0.498) in stage IV patients (n=77), who have highest risk of early mortality. Median overall survival in stage IV (mITT) was 8.3 months for placebo + SOC and was not reached (>12 months) for NEOD001 + SOC. One or more treatment-emergent adverse events (TEAEs) were experienced by 257 patients. Of the 88 NEOD001-treated patients with a serious adverse event (SAE), the majority of SAEs (95.5%) were considered not related to study drug. The most common TEAEs (fatigue, nausea, peripheral edema, constipation, and diarrhea) were similar in both arms. Overall safety results were similar within and across Mayo stages.

CONCLUSION: After study termination, further calculations supported that the VITAL study as designed would not have achieved statistical significance. No statistically significant differences between NEOD001 + SOC vs. placebo + SOC were observed for the PE. Overall, the incidence, severity, and seriousness of AEs were similar in each arm, suggesting that NEOD001 was generally safe and well tolerated. Post hoc analyses suggest a potential survival benefit of NEOD001 for AL amyloidosis patients with the highest risk of early mortality (Mayo stage IV). This population has historically been the most in need of therapy to improve outcomes, therefore additional clinical studies for NEOD001 are warranted.

Disclosures

Gertz:Ionis/Akcea: Consultancy; Alnylam: Consultancy; Annexon: Consultancy; Physicians Education Resource: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Medscape: Consultancy, Speakers Bureau; Appellis: Consultancy; Prothena Biosciences Inc: Consultancy; Spectrum: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; Johnson and Johnson: Speakers Bureau; Teva: Speakers Bureau. Cohen:Poseida Therapeutics, Inc.: Research Funding. Comenzo:Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Myself: Patents & Royalties: Patent 9593332, Pending 20170008966; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Prothena Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Du Mond:Inclin, Inc.: Employment; Prothena: Consultancy. Kastritis:Genesis: Honoraria; Prothena: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria. Landau:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Libby:Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy; Akcea: Consultancy. Liedtke:Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; BlueBirdBio: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Celator: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Merlini:University of Pavia: Employment. Sanchorawala:Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Takeda: Research Funding; Prothena: Research Funding; Celgene: Research Funding. Schönland:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wechalekar:Janssen-Cilag: Honoraria; GSK: Honoraria; Amgen: Research Funding; Celgene: Honoraria; Takeda: Honoraria. Zonder:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kinney:Prothena Biosciences Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: named inventor on multiple patents and patent applications related to NEOD001.

Author notes

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Asterisk with author names denotes non-ASH members.