The abstract from the press conference was an update of the phase I study of a drug called ABT199. It’s an orally administered drug that targets the apoptotic pathway, the cell death pathway, by specifically inhibiting a molecule called Bcl-2. It does that very selectively, so it was free from some of the side effects of the less targeted drugs and we’ve now got 105 patients on the trial. The response rates are holding up very well, so the overall response rate is 77% and 23% complete remissions. The safety is looking very good, there’s a moderate frequency of low grade toxicities but tolerance is very good. The previous concern with rapid cell death and what’s called tumour lysis syndrome has been very well mitigated by a graduated step-wise dosing programme and very vigilant preventative measures. The main focus of the abstract was around two points: one is that the effectiveness is sustained across sub-groups of what otherwise are considered to be poor prognostic features, so those patients with deletion of chromosome 17p, those patients with disease refractory to fludarabine or those with an un-mutated immunoglobulin heavy chain, in each of those three subsets the overall response rate, again, is held at around 80% and, in contrast to some of the other targeted agents, the complete remission rate is between 22-29% in each of those subsets with some patients having no detectable disease by very high sensitivity MRD, minimal residual disease, testing. So with responses also being very durable with the median progression free survival of patients receiving doses at 400mg or above, which we’ve identified as being the optimal effective dose, the median progression free survival not yet reached and is currently at 59% at 18-24 months. So as a platform that’s then provided a basis for combination data that Andrew Roberts from the Walter and Eliza Hall Institute will present on Saturday afternoon which shows an even higher complete remission rate of 36% with the combination. So the single agent is very effective, very well tolerated and we now believe is deliverable with a safe schedule and the combination data is looking even more impressive.
What was this in combination with?
With the anti-CD20 antibody rituximab.
How did you select these patients?
In this study these were patients effectively with no other alternative therapies available that had a median of four prior treatments for their CLL and up to eleven prior therapies. So they were really a group of patients where conventional treatments were not suitable and not expected to have benefit. As the effectiveness of the drug in the trial has been established, physicians and patients with less adverse risk factors are enthusiastic to participate but they still need to have had CLL that’s refractory to or relapsed after prior treatment, a reasonably good performance status at two or above and good organ function, particularly renal function which is necessary to deal with the metabolic consequences of treatment. So there are some restrictions in eligibility criteria around study entry.
In terms of side effects there were some gastrointestinal side effects, so nausea and diarrhoea were relatively frequent at between 30-40% of patients but the vast majority of those were very low grade. There was only one patient of the 105 who needed to cease treatment because of that adverse effect of gastrointestinal tolerance. The other significant side effect that we saw was suppression of blood counts, particularly neutrophils, that was seen in just on one-third of patients. Usually it was early on in the treatment and, as we saw, as the CLL was cleared from the bone marrow and the strength of the normal bone marrow improved that neutropenia was relatively transient. So the average duration of grade 3 or grade 4 neutropenia was between 7-10 days and it responded to fairly low doses of growth factor injection, things like GCSF or Neupogen. Despite having a moderate degree of neutropenia infections were quite uncommon so there was only a 7% rate of infection complicating neutropenia. One of the potential concerns early on was that this drug may suppress the normal immune system, that it may have an effect lowering normal T-cells. We haven’t seen clinical concerns with opportunistic infections so, again, with on-going treatments appearing well tolerated and safe.
What will you do next?
There are a number of steps in the development pathway and I’ll talk about CLL. The drug is also being developed in other hematologic malignancies, non-Hodgkin’s lymphoma, acute myeloid leukaemia and also beginning development in solid tumours. But in CLL there has been a specific study in patients with deletion of chromosome 17p, a subset for which there is no established therapy, and the protocol has been accepted by the FDA and the EMEA as a potential registration pathway. That trial has completed recruitment. There are combination studies, as I mentioned, with rituximab and with the other anti-CD20 antibody, GA101 or obinutuzumab; they’re on-going in recruitment and there’s also combinations with chemotherapy, particularly bendamustine and rituximab together with ABT199. A randomised study comparing bendamustine and rituximab with ABT199 plus rituximab in patients with relapsed and refractory CLL, regardless of deletion 17p, has also begun recruitment and there are plans for front-line studies compared to best conventional therapies in both the elderly and unfit CLL as well as later on in young and fit patients with CLL. So there’s a very broad development pathway that’s moving quite quickly.
What would be your message to doctors watching this?
There are a number, probably the most fundamental one is that this definitively validates Bcl-2 as a valid target in hematologic malignancies and shows that this drug can selectively and potently inhibit that target. More specifically it shows that the agent has marked efficacy in CLL with very durable responses and manageable side effects and I anticipate that very soon this will lead to the drug becoming commercially available and hopefully widely available for patients in the US, Europe and Australia.
