Safety, Tolerability and Efficacy of Cael-101 in AL Amyloidosis Patients Treated on a Phase 2, Open-Label, Dose Selection Study to Evaluate the Safety and Tolerability of Cael-101 in Patients with AL Amyloidosis

Background: CAEL-101 is an AL amyloid fibril reactive IgG1 monoclonal antibody with potential for therapeutic immune clearance of AL amyloid deposits in AL amyloidosis (AL) patients. Phase I study of CAEL-101 did not identify any significant toxicity at doses up to 500 mg/m² IV dosed weekly for 4 weeks as a single agent. Organ responses occurred in a majority of patients. The primary objective for this current dose escalation study (NCT04304144) is to provide a recommended phase III dose of CAEL-101 when given in combination with bortezomib, cyclophosphamide, and dexamethasone (CyBorD) for a planned randomized study in Mayo stage IIIa and IIIb AL patients.

Methods: 13 AL patients (7 heart, 3 kidney, 3 both) were enrolled in a 3+3 dose escalation safety study allowing for an additional patient in each cohort if available. Five heart patients were Mayo stage IIIa with the remaining 5 Mayo stage II. Cohort 1 (n=4), 2 (n=3), and 3 (n=6) received CAEL-101 IV at 500 mg/m², 750 mg/m² and 1000 mg/m² respectively over 2 hours, all weekly for 4 weeks then every other week for the remainder of the study. Premedication with diphenhydramine 25 mg po and acetaminophen 1 gram po were given 30 minutes prior to each CAEL-101 infusion. Pharmacokinetic and anti-drug antibody data will be reported separately. All patients were treated with CyBorD weekly, 3 of 5 weeks in the first cycle to align treatments with CAEL-101 and then 3 of 4 weeks for up to 6 cycles. Patients were permitted to receive up to 3 cycles of CyBorD immediately prior to enrollment. Only 3 of the 13 patients had hematologic measurable disease at enrollment. Hematologic and organ response data on assessable patients were evaluated per consensus criteria.

Results: With the longest follow up of 91 days and all 13 patients receiving at least 4 doses of CAEL-101, no dose limiting toxicity has been seen with 6 patients dosed at the maximum planned 1000 mg/m² dose. No infusion reactions occurred. Three significant adverse events occurred. One patient developed recurrent atrial fibrillation without rapid ventricular response at the 500 mg/m² dose level not attributed to CAEL-101. Two other patients dosed at 1000 mg/m² were hospitalized with Clostridium difficile colitis and enlarging pleural effusion not attributed to CAEL-101. Of the 3 patients with hematologic measurable disease, there have been 2 PR, and 1 that is too early to evaluate. One patient with PR had a response plateau after cycle 2 of CAEL and is the only patient off study due to need for change in anti-plasma cell therapy. Of the 7 patients currently evaluable for organ response, 2 have met organ response criteria in the 500 mg/m² cohort (1 heart by NT pro BNP and 1 kidney by 24 hour urine protein). There is ongoing monitoring of organ responses and updated data will be presented at the meeting.

Conclusions: CAEL-101 dosed at 1000 mg/m² is the recommended phase 3 dose in combination with CyBorD for upcoming randomized, double blind, phase 3 trials. Hematologic responses do not seem to be affected by concurrent use of CAEL-101 with CyBorD. Organ responses have occurred early in the course of therapy and are expected to increase over time, particularly after completion of chemotherapy and dexamethasone. Longer follow up, the ongoing exposure to CAEL-101 after the conclusion of chemotherapy and planned phase III trials will provide more data on organ response, quality of life and survival.