Ichnos Glenmark Innovation (IGI), a clinical-stage biotech company developing multispecifics in oncology, 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 per cent (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 per cent. The ORR was 83 per cent among the 18 patients treated at active doses (0.05 mg/kg and higher doses), including sCR/CR rate of 22 per cent. The safety profile was mild with good tolerability, compared favourably with first-generation 1+1 bispecifics.
The data were presented during an oral session at the 66th 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 Hang Quach, M.D., Professor of Haematology, University of Melbourne and Director of Haematology, 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 revolutionise 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 favourable safety and tolerability profile, these findings suggest ISB 2001 could represent a major advance in treating RRMM in the future,” said Lida Pacaud, M.D., Chief Medical Officer, 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 evaluated 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 per cent) had extra-medullary plasmacytomas, and 4 of the 12 patients assessed (33 per cent) had high cytogenetic risk. Five (25 per cent) patients were triple-refractory, 14 (70 per cent) were penta-exposed, 2 (10 per cent) were penta-refractory and 13 (65 per cent) were refractory to the last therapy before study entry. About half of the 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 favourable 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 per cent), and only 2 patients (10 per cent) 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 per cent), all Grade 1. Grade 3 infections were reported in 3 patients (15 per cent).
In the 20 heavily pretreated patients, the ORR was 75 per cent 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 per cent among the 18 patients which included stringent Complete Responses (sCRs) in 3 patients (17 per cent), Complete Response in 1 patient (6 per cent), Very Good Partial Responses (VGPRs) in 9 patients (50 per cent), and Partial Responses (PRs) in 2 patients (11 per cent).
- The median time to the first objective response was 36 days (range: 29–99).
- 16 patients (80 per cent) remain on treatment at data cutoff.
Dose-proportional PK with a long half-life of over 10 days and low immunogenicity (2/20 patients, 10 per cent 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 tumour cells while minimising on-target, off-tumour side effects and/or boost immune cell activity against tumour 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, 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.”