In the second of my three part interview from ASH 2013 with Dr. John Byrd from OSU, we discuss two new oral drugs, ONO-4059 and IPI-145, both in development for CLL and that both disrupt B cell signaling through different mechanisms.
Dr. Jeff Sharman has said that now that we have cracked the biology, new drug development is moving quickly. I have outlined some of this news with Dr. Wierda and in the included table of many but not all of the new pipeline drugs for CLL. This is all great stuff for us patients.
But as we noted earlier, there will be winners and losers in these battles to get all these new drugs to market. In the real world, it is not always efficacy and safety that determines which molecules will be part of our future. Market forces come into play. Not all of these drugs will make it to a nearby pharmacy.
Dr. Byrd discusses two promising “me too” drugs following in the footsteps of ibrutinib and idelalisib that, if they are successful commercially, could offer patients more choices and having more choices is a good thing.
The abstract of the Japanese pharmaceutical company, ONO’s drug ONO-4059 used as monotherapy is available here and the mouse trial in combination with obinutuzumab versus rituximab can be read here. Data from the murine model demonstrated that the combo with the newer monoclonal antibody was clearly superior, as expected.
The Phase 1 human trial with only 16 relapsed/refractory and high risk CLL patients had an impressive 70% response rate, but most of those were the easier to achieve partial remissions (PR) with a persistent lymphocytosis (high lymphocyte count). Based on our experience with other similar drugs, we would expect the initial high white counts to come down over time and many of these to eventually convert to true PR, but we need to see that data. Adverse events included neutropenia, but I always wonder how much of that is due to the prior therapies in these heavily treated groups. We need Phase 3 trials to answer those types of questions and those are a ways off. Of note was that there was only one case of diarrhea and only one infection, but the total number treated was so small.
ONO-4049 is a BTK inhibitor, as is ibrutinib. It even binds at the exact same site. How it may be different from or even possibly superior to ibrutinib is yet to be determined, but the early data demands we do our due diligence.
IPI-145 from Infinity is PI3K inhibitor with potential differences from another better known PI3Kδ (delta) inhibitor, idelalisib. At higher doses, IPI-145 blocks both δ (delta) and γ (gamma) isoforms of PI3K. This is not unusual, as many drugs have different binding characteristics at different blood levels. What this means is just conjecture until we have more research. Does it portent more efficacy or just more side effects? Or both or neither? The indirect effects on T cell function may hold the answer.
Dr. Flinn’s abstract can be viewed here. More than half of these 44 difficult to treat relapsed and refractory patients responded and results were similar for those with 17p deletion. Response was 79% if we included nodal responses. As with most of these signal inhibitors, we would also expect these results to improve over time. 20% of the patients had neutropenia and a quarter had some kind of infection, usually mild.
Therefore, for both the selfish reasons that they works and the selfless reasons that we are helping move forward necessary research, consider a trial with IPI-145 or the ONO-4059 when facing decisions about therapy.
Here is Dr. Byrd with his take from ASH 2013.
Brian Koffman 6/17/14 revised 3/17/15