No dose-limiting toxicities were observed up to weekly subcutaneous doses of 1.2 mg/kg, with mostly mild Cytokine Release Syndrome, no cases of neurotoxicity, and no discontinuations due to adverse events.
ISB 2001 demonstrated an ORR of 83% in heavily pretreated patients treated at active doses (0.05 mg/kg and higher).
Preliminary half-life of over 10 days supports planned evaluation of less-frequent dosing schedule.
Data suggest ISB 2001 could compare favorably with approved bispecific options.
NEW YORK, Dec. 09, 2024 (GLOBE NEWSWIRE) -- New York headquartered, Ichnos Glenmark Innovation (IGI), a global fully integrated clinical-stage biotech company developing multispecifics in oncology, today presented first-time clinical data from the early dose-escalation portion of its Phase 1 study of ISB 2001 for the treatment of relapsed or refractory multiple myeloma (RRMM). ISB 2001 is an investigational trispecific TREAT antibody for the treatment of RRMM that targets BCMA and CD38 on myeloma cells and CD3 on T cells. Initial results from 20 patients treated as of October 1, 2024, demonstrated an overall response rate (ORR) of 75% (15/20) across all doses tested (0.005 to 1.2 mg/kg), with a stringent complete remission (sCR) and complete remission (CR) rate of 20%. The ORR was 83% among the 18 patients treated at active doses (0.05 mg/kg and higher doses), including sCR/CR rate of 22%. The safety profile was mild with good tolerability, comparing favorably with first-generation 1+1 bispecifics.
The data were presented today during an oral session at the 66?? American Society of Hematology (ASH) Annual Meeting in San Diego, CA.
"The data presented today on ISB 2001 highlight its remarkable effectiveness as a novel trispecific-antibody T cell engager," said Professor Hang Quach, M.D., Professor of Haematology at the University of Melbourne and Director of Haematology at St Vincent's Hospital Melbourne. "These results are among the most impressive I have seen in this patient population. ISB 2001 has the potential to revolutionize the treatment landscape for heavily pretreated patients with multiple myeloma who have exhausted currently approved therapies."
ISB 2001 was designed to enhance avidity with two binders targeting distinct myeloma-associated antigens - even at low expression levels - while offering improved safety compared to first-generation bispecific antibodies. IGI is developing ISB 2001 to meet the critical needs of RRMM patients, who have received prior T-cell directed therapies (including CAR-T cells and bispecifics).
"Early data based on only 20 patients are encouraging. ISB 2001 showed high clinical responses in a heavily pretreated and advanced patient population. Combined with a favorable safety and tolerability profile, these findings suggest ISB 2001 could represent a major advance in the treatment of RRMM in the future," said Lida Pacaud, M.D., Chief Medical Officer at IGI. "We are excited to advance the development of ISB 2001 by completing dose-escalation and moving swiftly into the dose-expansion part of the trial to establish the recommended Phase 2 dose and optimal dosing schedule."
ISB 2001 Phase 1 Dose Escalation Study Design
The Phase 1, first-in-human, open-label study is evaluating the safety and anti-myeloma activity of ISB 2001 in patients with RRMM). The study is enrolling patients with RRMM who have been treated with immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies and are refractory to, or intolerant of, established therapies known to provide clinical benefit in multiple myeloma. Patients with prior CAR-T cell therapies, bispecifics and/or prior BCMA targeted agents were eligible.
The study is being conducted in two parts: dose escalation and dose expansion. This dataset comes from patients treated in the dose escalation at six sites in the United States and Australia.
Preliminary ISB 2001 Phase 1 Dose Escalation Results
The early portion of the trial is evaluating the safety and anti-myeloma activity of ISB 2001. Twenty heavily pretreated patients with RRMM were enrolled as of October 1, 2024. These patients had received a median of 6 prior lines of therapy. Six patients (30%) had extra-medullary plasmacytomas, and 4 of the 12 patients assessed (33%) had high cytogenetic risk. Five (25%) patients were triple-refractory, 14 (70%) were penta-exposed, 2 (10%) were penta-refractory and 13 (65%) were refractory to the last therapy prior to study entry. About half of patients (n=9) had received bispecific antibodies, with other prior therapies including anti-BCMA targeted therapies (n=8), and CAR-T cell therapies (n=2).
ISB 2001 showed a favorable safety profile in patients with heavily pretreated RRMM. No dose-limiting toxicity was detected, and no adverse events led to treatment discontinuation. Grade 1 CRS was observed in 13 patients (65%), and only 2 patients (10%) experienced Grade 2. The median duration of CRS was 2 days (range: 1-8). No immune cell-associated neurotoxicity syndrome (ICANS) was observed. Injection site reactions were reported in 10 patients (50%), all Grade 1. Grade 3 infections were reported in 3 patients (15%).
In the 20 heavily pretreated patients, the ORR was 75% across all dose levels.
Responses to ISB 2001 at active doses (0.05 mg/kg or higher) were durable and deepened over time:
- The ORR was 83% among the 18 patients which included stringent Complete Responses (sCRs) in 3 patients (17%), Complete Response in 1 patient (6%), Very Good Partial Responses (VGPRs) in 9 patients (50%), and Partial Responses (PRs) in 2 patients (11%).
- The median time to first objective response was 36 days (range: 29-99).
- 16 patients (80%) remain on treatment at data cutoff.
Dose-proportional PK with long half-life of over 10 days and low immunogenicity (2/20 patients, 10% across all doses tested) support exploring less-frequent dosing than weekly subcutaneous administration.
T cell activation, proliferation and soluble BCMA reduction were observed in most patients at effective doses.
Potential Opportunity for ISB 2001
ISB 2001 was developed using IGI's proprietary BEAT® protein platform, which combines TCR interface-based heavy chain pairing and universal light chain technology to create multispecific antibodies. This innovative design can increase binding to tumor cells while minimizing on-target, off-tumor side effects and/or boost immune cell activity against tumor cells by triggering multiple signals.
"While there have been significant advancements in treatments for relapsed/refractory multiple myeloma, many patients still experience relapse. IGI designed ISB 2001 to offer a therapeutic option to patients who have previously received T-cell directed therapies including first-gen bispecific and CAR-T cell therapies," said Cyril Konto, M.D., President and CEO of IGI. "These results further validate IGI's BEAT® technology which addresses the stability and engineering bottlenecks that previously hindered the large-scale production of bispecific and multispecific antibodies."
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