ABSTRACT
Background: Light-chain amyloidosis (AL-A) is a rare, severe, progressive, systemic disorder with high mortality caused by immunoglobulin (Ig) light chains that misfold and aggregate into amyloid fibrils that deposit in multiple organs, leading to progressive organ dysfunction/damage and death. Prognosis is poor for patients with cardiac involvement (characterized by high levels of cardiac troponin T and N-terminal brain natriuretic peptide). Median survival is 24 and 4 months for Mayo Stage IIIa and IIIb AL-A, respectively, based on the 2013 European Modification of the 2004 Mayo Staging system. For most patients, standard of care (SOC) is anti-plasma cell dyscrasia (PCD) therapy to suppress plasma cell proliferation, halt generation of amyloidogenic free light chains, and stop deposition of new amyloid fibrils and further organ decline. However, a critical need exists for therapies that accelerate the removal of deposited fibrils. CAEL-101 is a monoclonal antibody that binds to misfolded Ig light chains in amyloid fibrils. In Phase 1 and 2, CAEL-101 (with and without concurrent PCD SOC) was well tolerated up to 1000 mg/m 2. Preliminary Phase 2 data (NCT04304144) suggest improvements in cardiac and renal biomarkers in some patients. Objective: To evaluate the efficacy and safety of CAEL-101 versus placebo when administered concurrently with SOC anti-PCD therapy in treatment-naïve patients with cardiac AL-A, Mayo Stages IIIb (NCT04504825;Study 1) or IIIa (NCT04512235;Study 2). Methods: These international, multicenter, double-blind, randomized, phase 3 trials, initiated in 2020, are enrolling patients at over 70 sites in 14 countries. Newly diagnosed adults with AL-A stage IIIb or IIIa based on the 2013 European Modification of 2004 Mayo Staging (Wechalekar AD et al. Blood 2013;121:3420. Dispenzieri A, et al. J Clin Oncol. 2004;22:3751), measurable hematologic disease, and histopathological diagnosis of amyloidosis with cardiac involvement are eligible. Patients cannot have any other form of amyloidosis, symptomatic orthostatic hypotension, or supine systolic blood pressure <90 mmHg. Patients in Mayo Stages IIIb (N=111) and IIIa (N=267) are randomized 2:1 to receive once-weekly intravenous infusions of CAEL-101 (1000 mg/m 2) or placebo for 4 weeks, followed by maintenance dosing every 2 weeks. In these event-driven studies, treatment will continue to a minimum of 54 deaths for Study 1 and 77 deaths for Study 2 (a minimum treatment duration of 12 months is expected). Patients will receive concurrent anti-PCD therapy per the institutional protocol for SOC and will be followed to death from any cause or until end of study (Figure). The primary endpoint is overall survival (defined as the time from first dose of study drug to date of death, with censoring at last known living date), and will be analyzed via time-to-event log-rank statistics. Functional, quality of life, and echocardiography measures are targeted secondary endpoints. Results: Patient baseline characteristics and demographics are presented (Table). As of July 17, 2021, 9/13 (69.2%) patients in Study 1 and 23/39 (59%) patients in Study 2 have received at least 4 doses of CAEL-101 concurrently with anti-PCD therapy. Discussion: These ongoing trials will evaluate the efficacy and safety of CAEL-101 as first-in-class treatment to reduce amyloid burden in patients with cardiac AL-A. Notably, Study 1 (Mayo Stage IIIb) is the first randomized, placebo-controlled efficacy clinical trial to formally assess the effects of a pharmacological in this severely ill population. Because the median expected survival for Mayo Stage IIIb patients is far shorter than for Mayo Stage IIIa patients, the resulting sample size required for the Mayo Stage IIIB study is less (111 patients) than for the Mayo Stage IIIA study (267 patients). Importantly, these studies include patients identified as Stage III and IV based on the 2012 Mayo staging system (Kumar S. et al. J Clin Oncol. 2012;30:989). These trials are ongoing in a challenging environment. The approval of daratumumab i 2021 changed the landscape and modified the SOC, requiring appropriate protocol amendments. While the COVID pandemic affected all people, it had a greater impact on patients with AL amyloidosis, a rare disease that can only be treated effectively by a coordinated team of experts at centers of excellence. [Formula presented] Disclosures: Wechalekar: Alexion, AstraZeneca Rare Disease: Consultancy;Caelum Biosciences: Other: Clinical Trial Funding;Janssen: Consultancy;Celgene: Honoraria;Takeda: Honoraria;Amgen: Research Funding. Silowsky: Caelum Biosciences: Current Employment. Daniel: Caelum Biosciences: Current Employment. Harnett: Caelum Biosciences: Current Employment. Spector: Caelum Biosciences: Current Employment. Sobolov: Caelum Biosciences: Current Employment. Quarta: Alexion, AstraZeneca Rare Disease: Current Employment. Kurman: Caelum Biosciences: Other: Medical Monitor. Tulchinskiy: Caelum Biosciences: Consultancy. Bhattacharyya: Alexion, AstraZeneca Rare Disease: Current Employment. Liedtke: Karyopharm: Membership on an entity's Board of Directors or advisory committees;Kite: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees;Sanofi: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees;Pfizer: Honoraria;Oncopeptides: Membership on an entity's Board of Directors or advisory committees;Kura Oncology: Membership on an entity's Board of Directors or advisory committees;Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees;Alnylam: Membership on an entity's Board of Directors or advisory committees;Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding.