This is a clinical trial that we are describing the results for the first time. It’s called the VIALE-A Clinical trial which is a randomised study of azacitidine with or without venetoclax. Just as a bit of background into why this clinical trial came to be, the average AML patient is older – the average age is about 68-72 years – and the majority of our older patients with AML get lower intensity treatment strategies which are somewhat effective but responses are usually fairly low, 30-40%, and the overall survival is, on average, under a year. So we have desperately needed new treatments for our older AML patient population.
We did a phase I study that showed that when you add venetoclax, the BCL2 inhibitor, to azacitidine we see responses in the 60-70% range with survival extending up beyond a year. So this is really the confirmatory phase III study to try to show and prove that this combination really is effective and more effective than giving azacitidine alone, which is often the standard. So this was a large, multicentre, international phase III clinical trial. 431 patients were randomised and evaluated to either azacitidine with venetoclax or azacitidine with a placebo; it was a placebo-controlled trial. The primary endpoint was overall survival with key secondary endpoints of response and transfusion independence and many other clinically important endpoints for our AML population.
The average age of the patients that were enrolled was 76, so it really did represent a trial that was treating older patients with AML. About a quarter had secondary AML, meaning that it came from an antecedent immunologic disorder like MDS or was therapy related to a solid tumour, perhaps. The average follow-up for this study was about 20 months so we did have a good degree of follow-up on these patients. The primary endpoint, as I mentioned, was overall survival. We were trying to see if this combination improved responses to azacitidine alone and what we saw was indeed that, was azacitidine led to an average overall survival of about 10 months, which is exactly what we would expect based on our historical expectations and the combination improved that by up to 14.7 months with a hazard ratio of 0.66, meaning a 34% reduction in the risk of death, so really clinically meaningful.
When we talk about responses, as opposed to a response rate of about 20% with azacitidine alone, again what we would expect, we saw a complete remission rate of about 37%. Then when you look at the CR rate, including CR with incomplete count recovery, that went from 30% up to 66%, so a doubling of response rates and that was seen across the board, even people with higher risk genomic features, cytogenetics, regardless of age. So meaningful improvements in responses, no matter who you were, and the responses were durable too.
In terms of safety, the main safety signal with this combination is cytopenias. So we expect to see low counts with leukaemia patients, that’s just how this cancer manifests itself – our patients are requiring transfusions a lot – and when their immune system is low and they are neutropenic they have a high risk of infections. So we did see an increased risk of neutropenia and neutropenic related fevers with the combination, particularly in the early cycles, which was easily managed with mitigation techniques including holding therapy for a week or two to allow full count recovery, giving GCSF if needed, delaying dose reducing cycles, and I’ll go into that in the talk I give about some of these mitigation strategies to make sure people are tolerating the combination well.
The combination does lead to improvements in transfusion independence. So patients are not coming to the hospital or the clinic as often and getting transfusions of platelets and blood as often. The other thing that I didn’t mention that’s important to say with this combination is the responses really happen early. So, with azacitidine alone we’re used to seeing patients respond after about 4-6 cycles and so we continue them on treatment and their counts are low because they still have leukaemia and it just takes a long time for these lower intensity therapies to work. With the combination, though, we’re seeing responses on average within one cycle. So one of the most important things for using this combination is to make sure to do a bone marrow at the end of the first cycle to see if your patient is already in a remission, which there’s a good chance they already are. If they are then you hold therapy for a week or two for the counts to fully recover, for their bone marrow to fully heal and then you start the next cycle. That has been the most important intervention that helps patients tolerate this really well.
So that really is the very brief overview of this clinical trial which really is a transformative change in our standard of care, showing that adding this oral therapy, venetoclax, to azacitidine really improves not only responses but also transfusion independence, time to remission and, most importantly, the survival of our patients.