Hi, I'm Professor Quach from St. Vincent's Hospital Melbourne and the University of Melbourne, Australia. ​ At the 66th ASH annual meeting, I had the privilege of presenting the first result from a phase one first-in-human clinical study of ISB 2001, which is a first-in-class trispecific antibody targeting two markers on the myeloma cells, BCMA and CD38, while engaging the immune T-cell by binding to CD3, and in the process, causing a T-cell mediated myeloma cell death.

ISB 2001 is designed to effectively bind to myeloma cells, even when BCMA and CD38 expression levels are low. ​ It is also likely to overcome resistance caused by the downregulation of BCMA in myeloma cells that have relapsed after treatment with other BCMA-targeted therapies. ​ Additionally, ISB 2001 has a low CD3 binding affinity, which helps prevent excessive T-cell activation, reducing the risk of tumor side effects. ​

In this study, we enrolled patients with a relapsed refractory multiple myeloma who had been previously treated with at least three classes of drugs, including immunomodulatory drugs, proteasome inhibitors, and CD38 monoclonal antibodies, and who had exhausted all available treatment options. ​ ISB 2001 was administered subcutaneously once a week in a 28-day cycle, with a step-up dosing regimen on cycle one, day one and cycle one, day four, reaching the full dose by cycle one, day eight, and treatment was continued until disease progression. ​

The study aimed to evaluate nine dose levels of ISB 2001, that is, up to 2,700 microgram per kilogram. ​ The primary objectives were to assess safety, tolerability, and determining the maximum tolerated dose or the recommended phase two dose. ​ The secondary objectives included assessment of pharmacokinetics, that's how the body handles the drug, and the preliminary clinical activity. ​

At the time of the ASH presentation, we had explored dose level seven, that is, 1,200 microgram per kilogram, in a total of 20 patients. ​ There was no dose-limiting toxicity reported. ​ Remarkably, responses were observed even at low doses, as low as 50 microgram per kilogram. ​ Among the 18 patients receiving at least 50 microgram per kilogram of this drug, 83% responded to treatment. 73% achieved a very good partial response or better, with 23% achieving a complete response or better. ​ These rates and type of response, I think, are quite remarkable for a group of triple-class exposed patients. ​

Importantly, these responses were durable, with some patients maintaining responses for over nine months. ​ Responses were rapid, occurring after a median of just over one treatment cycle, and deepened with time as well. ​ One patient achieved minimal residual disease negativity thus far. ​ Notably, ISB 2001 also demonstrated activity even in patients who had received advanced therapies, including CAR T-cell therapy, bispecific antibody T-cell engagers, and other BCMA targeted therapies. ​ Among patients with prior T-cell redirection therapy, that is, prior CAR T-cell and bispecific T-cell engagers, we observed 75% overall response rate, and among patients previously treated with BCMA targeted therapies, 86% of patients responded, with deep responses also observed, and I think these types of response are really unprecedented for this group of patients to date. ​

Importantly, the safety profile of ISB 2001 was highly favorable, particularly given the heavily pretreated patient population. ​ Severe infections, that's grade three, were low, with only three of 20 patients experiencing grade three infections that included upper respiratory tract infections and pneumonia. ​ There were no treatment-related deaths or discontinuation. ​ Cytokine release syndrome, which is a side effect for T-cell engagers in general, occurred in 75% of patients, but was predominantly mild. ​ 65% of patients had grade one CRS, and importantly, there were no cases of neurological toxicity or ICANS. ​

This study is currently ongoing, with exploration of higher doses levels underway, however, these early results, to me, are amongst the most promising I've seen in this challenging group of patients to date. ​ I think that this abstract is highly relevant to the myeloma community, especially for patients, as I believe that ISB 2001 holds significant potential to address the urgent unmet need of those who've exhausted all available therapies, and this includes patients who've progressed after BCMA targeted treatments, a particularly challenging group of patients to treat at this point in time with very limited options. ​

Looking ahead, I think it would make sense to move ISB 2001 to earlier lines of treatment when the immune system is even more robust, which could potentially lead to even better responses. ​ In patients who are naive to CAR T-cells and T-cell engagers, we're already observing a 90% response rate, with 30% achieving complete responses. Moreover, ISB 2001's favorable toxicity profile opens up the possibility of combining it with other agents, exploring synergistic approaches with drugs that have different mechanisms of action, such as IMiDs, proteasome inhibitors, or even anti-CD38 monoclonal antibodies that work through natural killer cell-mediated myeloma cell healing, and given its promising clinical activity and excellent safety profile, I do think that ISB 2001 has the potential to transform the treatment landscape for multiple myeloma, particularly for those who've exhausted all other options. ​

Thank you for your attention. ​