FDA Grants Fast Track Designation to ISB 2001 in Relapsed/Refractory Multiple Myeloma

FDA

The FDA has granted fast track designation to the investigational trispecific antibody therapy ISB 2001 for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least 3 prior lines of therapy—including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody.1

ISB 2001 was engineered to exhibit enhanced avidity-based binding to BCMA and CD38 on multiple myeloma cells, as well as to CD3 on T cells, even at low target expression levels. The spatial arrangement of the binding domains, particularly the distal positioning of the CD38 and CD3 binders, contributes to the agent’s ability to minimize CD38-related off-tumor adverse effects and simultaneously maintain robust antitumor activity.2

“A growing number of patients with multiple myeloma have been heavily pretreated, have exhausted currently approved therapies, and continue to face disease progression,” Cyril Konto, MD, president and chief executive officer of the drug’s developer, Ichnos Glenmark Innovation (IGI), stated in a news release.1 “At IGI, we have long recognized the urgent need for novel treatment options—particularly for patients who have already received first-generation bispecific [antibodies] or CAR T-cell therapies. Our trispecific candidate is designed to enhance tumor targeting [and reduce] on-target, off-tumor toxicity. We are honored to receive this Fast Track designation and look forward to working closely with the FDA to advance our multispecific T-cell engager, with the goal of delivering a first-in-class therapy for patients with relapsed or refractory multiple myeloma.”

The safety, tolerability, and preclinical efficacy of the agent were evaluated in a phase 1 dose-escalation/expansion study (NCT05862012) in patients with relapsed/refractory multiple myeloma.1,2 Patients were required to have progressed on 3 or more prior lines of therapy; have received prior treatment with a CD38-targeting monoclonal antibody, IMiD, or PI; and be ineligible for regimens known to provide clinical benefit.2 Prior exposure to CAR T-cell therapy and/or bispecific antibodies, including those targeting BCMA, was permitted.

In the dose-escalation portion of the study, patients received 1 of 9 doses of ISB 2001 subcutaneously once weekly in 28-day cycles. Treatment began with 2 step-up doses on days 1 and 4 of cycle 1, followed by the full target dose starting on day 8 of cycle 1. Backfilling to each dose level was allowed.

The study’s primary objectives were assessing the safety and tolerability of ISB 2001 and determining the maximum tolerated dose and/or recommended phase 2 dose of the agent. Secondary objectives include characterization of pharmacokinetics, evaluation of immunogenicity, and assessment of preliminary clinical activity based on International Myeloma Working Group criteria using an accelerated titration design.

Early findings from the dose-escalation portion of the study, which was recently completed, were presented at the 2024 ASH Annual Meeting.1,2 Overall, ISB 2001 produced high response rates, durable responses, and had a favorable safety profile. Anti-myeloma activity was observed beginning at the 50-µg/kg dose level (dose level 3; n = 1), where a minimal residual disease–negative stringent complete response was reported at a median follow-up of 6 months (range, 2-10).2 Across dose levels 3 to 7 (1200 µg/kg; n = 18), the agent achieved a high overall response rate (ORR) of 83%, comprising a complete response rate of 22%, a very good partial response rate of 50%, and a partial response rate of 11%. The median time to first response was 36 days (range, 29-57).

Additional subgroup analyses showed ORRs of 75% and 90% among patients with (n = 8) vs without (n = 10) prior exposure to CAR T-cell or bispecific antibody therapy, respectively. Patients previously treated with BCMA-directed therapy (n = 7) and those with CD38 inhibitor–refractory disease (n = 7 each) each achieved ORRs of 86%.

Regarding safety, no dose-limiting toxicities were observed up to dose level 7 with weekly dosing. ISB 2001 was primarily associated with any-grade cytokine release syndrome (CRS 75%) and injection site reactions (60%), with no instances of immune effector cell–associated neurotoxicity syndrome. All CRS events were grade 1, excepting 2 cases of grade 2 CRS on day 1 and day 118. The median time to CRS was 3 days (range, 1-118) and the median duration of CRS was 2 days (range, 1-8). Infection and hematologic toxicity rates remained low.

Pharmacokinetic data demonstrated dose-proportional exposure and a long half-life of the drug, supporting the potential for less-frequent dosing. Evidence of T-cell activation was also observed at effective dose levels.

Complete results from the dose-escalation portion will be presented at the 2025 ASCO Annual Meeting, according to IGI.1 The dose-expansion portion of this ongoing trial is currently enrolling patients across 9 sites in the United States and Australia.

References

1. Ichnos Glenmark Innovation (IGI) receives U.S. FDA fast track designation for ISB 2001 for relapsed/refractory multiple myeloma. News Release. IGI. May 5, 2025. Accessed May 5, 2025. https://iginnovate.com/2025/05/03/ichnos-glenmark-innovation-igi-receives-usfda-fasttrack-designation-for-isb-2001-for-relapsed-refractory-multiple-myeloma
2. Quach H,Augustson B, Sia H, et al. First results of a phase 1, first-in-human, dose-escalation study of ISB 2001, a BCMAxCD38xCD3 targeting trispecific antibody in patients with relapsed/refractory multiple myeloma (RRMM). Blood. 2024;144(suppl 1):1026.doi:10.1182/blood-2024-208189