ASCO 2025 | A Phase I, first-in-human study of ISB 2001 in R/R myeloma: dose escalation results

At this ASCO meeting I had the privilege to present an update of the Phase I first in human study of ISB 2001 in patients with relapsed/refractory multiple myeloma. ISB 2001 is a tri-specific T-cell engager that targets both CD38 and BCMA on myeloma cells while engaging T-cells via CD3. What’s characteristic about this molecule is that the dual high affinity binding to myeloma cells enhances cytotoxicity even at low antigen expression and the low affinity binding to T-cells minimizes off tumor toxicity and T-cell exhaustion. 

The presentation at ASCO focused on 35 patients who were enrolled in the dose escalation part one of the study, exploring nine doses of ISB 2001 up to 2,700 micrograms per kilogram. These were heavily pretreated patients with a median of six prior lines of therapy, all of whom were triple class exposed, 50% were triple class refractory, over 70% of patients were pentadrug exposed and almost half of the patients were considered quad-exposed, that is they also had prior BCMA targeted therapy. 

With respect to tolerability, we found quite a favorable safety profile. Hematological toxicities, severe hematological toxicities were low. So grade three or four neutropenia, anemia and thrombocytopenia occurred in 29%, 6% and 14% of patients, respectively. And grade three or four infection, both related and non-related to treatment, occurred in 29% of patients. CRS occurred in 69% of patients, but most were grade one and most were confined to the first dose of treatment. Now, such a promising safety profile is quite impressive given the heavily pre-treated patient population. 

With respect to efficacy, in the overall population, we found an overall response rate of 74% with a CR or better of 28%. But amongst the patients who received effective doses of treatment, that is between dose level three to dose level nine, we saw an overall response rate of 79% with a CR or better of 30%. And what’s important is that these responses were durable such that at data cutoff, some patients were still responding beyond 12 months and that’s with a median follow-up of around six months. The six months duration of response was in excess of 90%. Now this degree of response is quite remarkable given the degree of refractoriness of the patient population. 

What’s equally encouraging is that we also saw robust response in patients who were difficult to treat, including patients with prior CAR-T cells or T-cell engagers, patients with a prior exposure to BCMA targeted therapies, and patients who were refractory to anti-CD38 monoclonal antibody. Here we saw a response rate in the order of 71% to 73%, suggesting that ISB 2001 may overcome the resistance to these agents.

Based on part one of the study, ISB 2001 has demonstrated quite remarkable efficacy and tolerability in what is a very heavily pretreated group of patients. And amongst these patients who have no other significant available options, I think this drug can potentially transform the landscape for these patients and can offer renewed hope.

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