ISB 2001 in Relapsed/Refractory #Myeloma: Phase 1 Results | Hang Quach, MD, Cyril Konto, MD | #ASH24

I'm Professor Han Kwok. I'm from St. Vincent's Hospital in Melbourne, Australia and the University of Melbourne in Australia. I'm Cyril Conteau. I'm the President and Chief Executive Officer at ICNOS Glenmark Innovation. The study of ISB-2001 is a phase one study that's aimed to find the most optimal dose. To qualify for the study, patients must have to have had relapsed refractory multiple myeloma and have exhausted all available authorities, including the three major drug class immunomodulatory drugs, proteasome inhibitors and an anti-CD38 monoclonal antibody. The study is designed to look at nine dose level of ISB-2001 altogether. And thus far, we have completed exploring dose level seven at 1,200 microgram per kilogram in 20 patients. What was remarkable was that we started seeing responses at very low doses, at 50 microgram per kilogram at dose level three. And amongst the patients who received dose level three or more, we saw a remarkable response rate of 83%. 73% of these patients achieved a very good partial response, that is a 90% reduction in myeloma burden. About a quarter or 22% of these patients achieved a complete response. And even one patient achieved a minimal residual disease negativity, meaning the lack of cancer at very low threshold. What was remarkable was that the response was quite durable. Some patients responding more than nine months. And more importantly, even patients who have had prior bispecific antibodies and CAR T cells also responded to these agents. And amongst this group of patients, the response rate was 75%, which in my view is unprecedented. The safety profile of this drug was quite favorable in that there was no side effects leading to death and no side effects leading to discontinuation of the drug. What is important is that the severe infections, the grade three infection was remarkably low. It occurred only in three patients, which again is quite unexpected for this type of therapy. Cytokine release syndrome, which is a common side effect with these types of immune therapy, occurred in 75% of our patients. But the majority was mild, grade one. Only two patients reported moderate or grade two cytokine release syndrome. But one was doubtful because it occurred unusually late and it coincided with the COVID-19 infection. And the cytokine release syndrome was quite easily manageable with dexamethasone and tocilizumab, which is the common treatment we would use for these type of reactions. But only half of the patients needed it. And so overall, the preliminary results that we have here for ISB2001 is amongst the most promising I've seen in such a heavily pre-treated group of patients. And I think that ISB2001 has the power to transform the treatment landscape of patients with multiple myeloma. We've exhausted therapies in the immediate future, so it's exciting times for all of us. Remarkably, there was no one signal for any side effects. We had a lot of, 100% of patients had at least one adverse event. But the side effects were mild, there was no specific signal. And it was difficult to attribute causality to the drug because people with myeloma have these side effects anyway. So in fact, that was one of the surprising features, wasn't it? Yes. It's the outcome of the rational design of the molecule. We added a second binder to increase the specificity towards the myeloma cells to avoid any off-tumor side effects. And also, with the second binder, we have a tighter bind of the T cells to the myeloma cells, which prevents systemic effect of cytokines or other side effects. So really, this molecule was designed to deliver activity in a heavily set of pre-treated patients and to minimise the toxicity. Remarkably, over half of patients have had prior anti-CD30 targeted therapy. And to Cyril's point just now, the molecule is designed such that it binds to a different location of CD38 compared to the traditional monoclonal antibodies like Isotoxamab or Daratumumab. So just to give you a bit of perspective, normally when we give people the anti-CD38 monoclonal antibodies and we have to give them another drug that targets the same CD38, we will have to wait for six months for the Daratumumab or the Isotoxamab to be washed away so that the new drug has targets to bind. In this situation, there were six patients who had progressed on Daratumumab or Isotoxamab within the last six months. 100% all six of six patients responded to ISB2001. So therefore, that is clinical proof that the two targets, the two binding sites do not overlap and you can use one drug after the other immediately without waiting for the washout period. Against the outcome of the collaboration between research and clinic, we designed this binder to specifically target a different one than Daratumumab or Isotoxamab to enable immediate treatment for the clinicians and avoid any gap in therapy for the patients. Professor Quash and the team of investigators will continue to complete the dose escalation which will take us to January, February. Then we are preparing the dose expansion courts. We need to make sure that the phase two dose is the right one. So we are going to test several phase two doses and an optimal scheduling. We also noticed that this large molecule has a long half-life in patients. It's preliminary results but at the moment we believe that there is at least 10 days of half-life which should enable less frequent dosing for the patient. It's already administered subcutaneously. If we can have a maintenance treatment with three weekly or monthly frequency for the patient, I think we would do also we would help to prevent exhaustion of the T cells and that will be run in in 2025 and we will also discuss those results with the health authorities to see whether this molecule meets some criteria to accelerate the development and hopefully run into our first registration on trial with this asset in 2026. The patients who progress on T cell engages or CAR T cells presently have very poor prognosis and in this space there is a gap of unmet need. There's nothing available and I believe that for the first time we now have life after bispecific antibodies or CAR T cells and I think that it's early days. We have to wait for durability of response so more data is coming out. I would encourage that if patients want to get involved perhaps look at the information you have in your respective countries to see which centre runs the clinical trial and if you think that you fit that criteria and at this stage we're only needing patients who have had at least three prior lines of therapy and have seen the three major drug classes, imides, proteasome inhibitors and anti-CD38 and if you think you fit that criteria contact your specialist, get a referral and at least I can speak for Australia all of us will be very keen to meet you and assess you and we go from there. Likewise from the sponsor if you have any questions we have our contact us webpage on IGinnovate.com we'll be more than happy to direct the patients to the proper centre.