I want to walk you through, because this is a new way of thinking about treating AML, I want to walk you through a little bit about what IDH is and what IDH does and what mutant IDH does. So the normal function of isocitrate dehydrogenase is to help your cells make energy. Isocitrate dehydrogenase or IDH converts isocitrate to alpha-ketoglutarate and that’s a normal cellular process. When you have a mutation in IDH what ends up happening is that isocitrate instead of being converted to alpha-ketoglutarate, alpha-ketoglutarate ends up being converted to this substance called beta-hydroxyglutarate. Increased levels of beta-hydroxyglutarate end up causing what we think are epigenetic changes to the cell which causes a block in the ability of the cell to differentiate into a normal, healthy adult neutrophil. That’s essentially what leukaemia is, you get stuck at the myeloblast stage of differentiation, you get your myeloblasts accumulating and it causes various degrees of bone marrow failure.
The hypothesis is that if you can decrease the levels of 2HG you can release the brakes from these cells that are blocked from differentiating and you can cause that normal differentiation programme to happen, you get normal adult healthy neutrophils and the leukaemia is reversed.
These mutations come in two flavours, IDH1 and IDH2, depending on where in the cell these enzymes are located. IDH2 mutations occur in 9-13% of patients with AML and 3-6% of patients with myelodysplastic syndromes. IDH1 mutations occur in 6-10% of patients with AML and 3% of patients with MDS and these numbers, since this is a new area, these numbers are constantly being updated.
So this is, as we just talked about, a phase I first in man study. Just a little bit of the study background: AG-221 is oral, it’s given either once or twice a day in continuous 28 day cycles. The study is enrolling mutation positive hematologic malignancies, that includes relapsed or refractory AML, MDS or untreated AML. The key outcome measures are pretty standard for a phase I trial: safety and tolerability, looking at dose limiting toxicities, looking at the maximum tolerated dose and the recommended phase II dose, looking at the pharmacokinetics and pharmacodynamics and characterising the differentiation effect of this agent.
This update that we’re giving, the last update was given at the meeting of the European Haematology Association, we’ve treated an additional 38 patients for a total of 73 patients on study as of October 1st 2014. We’ve explored four additional dose cohorts with cumulative daily doses up to 300mg. We’ve initiated four expansion cohorts at the 100mg once per day level and there is in parallel dose escalation with both twice a day and once a day dosing regimens.
So these are the patient characteristics, I want to draw your attention to just some salient points. Number one, the age of the patients is 67 years which really reflects the age of patients in the United States with AML. Most of the patients had relapsed or refractory AML, 55 of them, and it was a very poor risk patient population. So 18% of the patients had had a prior bone marrow transplant, there are other characteristics of the patients that make them very, very unlikely to have responded to further efforts with regular chemotherapy.
In terms of the safety of the drug it has really been extremely well tolerated to date. A maximum tolerated dose has not been reached. The most common adverse events are nausea, fever, diarrhoea and fatigue. I just want to bring to your attention that these are all cause adverse events, these are not treatment related adverse events and these are adverse events that you typically see in patients with acute myeloid leukaemia. There has been one dose limiting toxicity which was a grade 5 hypoxia at 100mg twice a day and that was in a patient who also had unrelated fungal pneumonia and septic shock. The 30 day all-cause mortality was 4.1% and the 60 day all-cause mortality was 13.7%.
I want to draw your attention to one serious adverse event which I think is very interesting from a scientific perspective and that’s leucocytosis. Leucocytosis is when you have an elevation in white blood cells and we think that’s part of the differentiation effect of the drug. So what happens is that as you get your drug these myeloblasts start differentiating, the white blood cells go up, and all of these patients who had leucocytosis actually went on to achieve a complete remission or a partial remission.
There have been 11 deaths reported on study, two were possibly related, a sepsis and hypoxia, and one due to atrial flutter.
This is the best overall response by cumulative daily dose level and I want to draw your attention to the right hand column, which is the total column. So what you can see from this is that 15 of the patients had a complete remission or a complete remission with incomplete blood count recovery, meaning they’ve cleared their blasts from their bone marrow but their platelets have not yet reached over 100,000, their neutrophils may not have reached over 1,000 yet but they’ve had a complete remission or a complete remission with incomplete blood count recovery, that’s 15 of the patients. 10 of the patients have had a partial remission and, you know but I’ll tell you anyway, what that means is that you’ve had a 50% decrease in your blasts in your bone marrow but, this is a real partial remission, you’ve had normalisation of your neutrophil count and normalisation of your platelet count. 17 patients had stable disease and there were only 2 patients in the efficacy evaluable population, which was the population of patients with a day 28 response assessment, who had progressive disease. For an overall response rate, if you add up the complete remissions, complete remission with incomplete count recovery and the partial remissions, 56%.
This is the duration of treatment and the best overall response. So this is something that we’ve been very interested in because obviously we want this agent to last a long time. You can see that in the green are the partial remissions and in various shades of blue are the complete remissions or complete remissions with incomplete count recovery. What’s notable is that the partial remissions are staying on study for, as you can see, as long as nine months and many of them have been on for as long as six months and the complete remissions have been on for a fairly long time also. It really shows that, at least to date, the responses appear durable. In addition, what’s not shown on this slide is that the stable disease patients, those patients who haven’t had their blasts go up but their blasts have remained stable, maybe in the 10-12% range, they also many of them have been on treatment for as long as the patients who achieved partial remissions or complete remissions.
So, in conclusion, AG-221 is well tolerated in patients with advanced hematologic malignancies. The inhibition of beta-hydroxyglutarate is greater than 90% in patients with an IDH2 R140 mutation. Consistent with the preclinical models we’re seeing clear evidence of myeloblast differentiation and those myeloblasts turning into healthy adult neutrophils. The overall response rate is 56% including 6 complete remissions and the remissions appear durable to date. Dose expansion is continuing and there are the four expansion cohorts that we talked about. We think that these data provide continued validation of mutant IDH2 as a therapeutic target in AML and myelodysplastic syndromes.