Safety and Tolerability of Cael-101, an Anti-Amyloid Monoclonal Antibody, Combined with Anti-Plasma Cell Dyscrasia Therapy in Patients with Light-Chain Amyloidosis: 24-Month Results of a Phase 2 Study

Background: Light-chain (AL) amyloidosis is a rare, systemic disease caused by plasma cell dyscrasia (PCD). Immunoglobulin light chains misfold and deposit in organs as insoluble amyloid fibrils. The extent of cardiomyopathy due to amyloid deposition determines patient survival. Current therapies target PCD to halt amyloid formation but do not treat existing amyloid deposits in organs. CAEL-101 is a novel, investigational, potentially first-in-class therapy to remove amyloid fibrils from organs.

Aims: To present safety, tolerability, and biomarker data after 110 weeks of treatment with CAEL-101, administered initially with cyclophosphamide-bortezomib-dexamethasone (CyBorD) ± daratumumab.

Methods: Adult patients with AL amyloidosis (European Modification of Mayo Stage I-IIIa) and measurable hematologic disease were eligible for this ongoing, open-label, phase 2 study (NCT04304144). Other forms of amyloidosis and multiple myeloma were excluded. CAEL-101 ≤1000 mg/m² was administered with CyBorD therapy ± daratumumab as directed by the investigator. In addition to safety assessments, cardiac response was assessed by change over time in N-terminal pro-brain natriuretic peptide (NT-proBNP).

Results: Patients (N = 25; mean age 65 years; 72% male) with Mayo Stage I (n = 2; 8%), II (n = 19; 76%), and IIIa (n = 4; 16%) AL amyloidosis were enrolled to be treated with CAEL-101. All 25 patients experienced treatment-emergent adverse events (TEAEs); 6 (24%) experienced TEAEs possibly related to CAEL-101, 17 (68%) experienced ≥1 adverse event of ≥Grade 3 severity, and 15 (60%) experienced ≥1 serious adverse event. There were a total of 447 TEAEs reported of which only 67 (15%) were Grade ≥3. As of the cutoff date of 22 May 2023, 12 (48%) patients had discontinued the study due death (n = 3), patient withdrawal (n = 3), physician decision (n = 2), heart transplant (n = 2), heart and kidney transplant (n = 1), and adverse event (n = 1). The most common adverse events reported by ≥5 (20%) patients were fatigue (n = 12), anemia (n = 10), nausea (n = 10), constipation(n = 9), diarrhea (n = 9), cough (n = 8), dizziness (n = 8), insomnia (n = 7), peripheral neuropathy (n = 7), dyspnea (n = 6), hypokalemia (n = 6), rash (n = 6), and headache (n = 5), peripheral edema (n = 5), vomiting (n = 5). There were 22 cardiac-evaluable patients (baseline NT-proBNP >332 ng/L) enrolled in this trial. After 110 weeks of CAEL-101 treatment, 6 (27%) patients were cardiac responders (>30% NT-proBNP decrease and more than 300 ng/L decrease, if baseline NT-proBNP ≥650 ng/L), 7 (32%) patients were stable (neither response nor progression), and 2 (9%) patients showed cardiac disease progression (>30% increase and ≥300 ng/L increase from baseline in the absence of eGFR decline of ≥25%); data for 7 (32%) patients were missing. Cardiac response over time to 110 weeks of CAEL-101 treatment is shown in Figure).

Conclusions: Patients in this analysis have been treated for ≥24 months and CAEL-101 was generally well tolerated without evidence of organ toxicity. Long-term safety evaluation of CAEL-101 continues in this study. Most TEAEs (85%) were mild to moderate. Two phase 3 trials (NCT04504825 and NCT04512235) are in progress to study the efficacy and safety of CAEL-101 in cardiac AL amyloidosis European Modification Mayo Stages IIIa and IIIb.