2015 ASH: Dr. John Byrd Discusses ACP 196 or Acalabrutinib, a new BTK inhibitor

In this video interview with Dr. John Byrd, my treating physician at the Ohio State University, I caught up with the doctor less than an hour after he had won the well-deserved and very prestigious 2015 William Dameshek prize for recent outstanding contributions in the field of hematology. (See video at the bottom of the page)

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Dr. Byrd has brought many new therapies to CLL patients including doing some of the pivotal research on rituximab and recently ibrutinib.

So when he says he is excited by a new targeted therapy, I listen carefully.

ACP-196 or acalabrutinib is a new BTK inhibitor in clinical trials, similar to ibrutinib in its efficacy and in the way it works, but with a very focused activity and at least in this early trial, an encouragingly mild side effect profile. The median follow-up in the 61 patients studied was a little over 14 months.

These results give us reason to be hopeful that acalabrutinib will prove to be another very safe and efficacious non-chemo targeted therapy and a strong option for those of us with CLL as it now moves into larger and longer trials and in the future, as an approved therapy for CLL.

The seven trials that are open as of today using ACP-196 can be found by clicking here, including the ibrutinib versus ACP-196 that Dr. Byrd mentioned.

If you want all the details of the trial we discussed where Dr. Byrd was the lead investigator, please take a look at the paper in the NEJM.

ACP-196 is not the only new BTK inhibitor in development. Click on ONO-4059 or BGB-3111 to look at the relevant abstracts presented at ASH 2015.

Please enjoy the interview below and the obvious enthusiasm of Dr. Byrd at this propitious time for those of us with CLL.

Dr. Brian Koffman: Hi, Dr. Brian Koffman, family doctor and a CLL patient here on the last day of ASH 2015 with my treating doctor, Dr. John Byrd. Do you want to introduce yourself?

Dr. John Byrd: I’m John Byrd. I’m the director of hematology at Ohio State University

BK: Dr. Byrd, you’ve been involved in the development of a lot of the novel therapies. I think everyone knows about ibrutinib (Imbruvica), a BTK inhibitor, but you presented some very exciting data on a new BTK inhibitor that has a different profile and there are also some others here. I wonder if you could explain why patients should know about these.

JB: Who would have thought that with ibrutinib, a great drug, that we could do better. What’s been really exciting over the past several years is reliving what happened in the 90’s with CML (chronic myelogenous leukemia) where we had this great drug called Gleevec which transformed CML. People who were receiving chemotherapy, immunotherapy, or transplant…their lives were transformed to going on a pill. So that’s sort of what the last 5 years have been. We’re starting a CML-era for CLL.

What was unique to CML was after the success of Gleevec, there were several copycats, but there were also drugs that were developed that were more selective and that had safety profiles that perhaps for some patients were better. That provided an opportunity to improve on something that was already transforming.

We’re seeing that at this meeting where there were 2 molecules, one from Beijing, and a molecule that our group has been working on called ACP-196 (acalabrutinib). The paper about the trial came out in the New England Journal of Medicine at the same time as the presentation here at ASH, describing 61 patients with relapsed CLL who received this. The responses were very good.

BK: I would say they were great.

JB: Looking at the response, and the durability, the data look very, very strong. It’s non-comparative data, but it looks very strong. It’s very encouraging. There were no cases of Richter’s transformation in the first year, which is what we worry about when we do anything within high risk disease.

I believe the uniqueness of this drug, of the ONO medicine (ONO-4059), of all of the specific BTK inhibitors are potentially going to allow us to take a step forward, particularly for high-risk patients. We can dose the drug twice a day, which puts better pressure on the target BTK and maybe prevent, more rapidly growing proliferative CLL and even Richter’s from developing in some patients.

This will take what’s been a great drug, ibrutinib, and potentially move things even further forward for patients. The other neat thing about a more specific drug, which we’ve learned with Gleevec, we’ve also learned with the solid tumor cancers with combining things is, the less selective a drug is, the harder it is to combine it with other drugs.

The data with all the selective BTK inhibitors, in particular with ACP-196, we haven’t seen atrial fibrillation to any degree above what you would expect to see in an age-matched population. Less diarrhea, less bruising, no major bleeding episodes, or anything more than just bruising, generally. The side effect profile with ACP-196 is clearly more favorable. As we think of what’s the next step, for some people, being on an oral medicine long-term, and controlling their disease, that’s going to be fine. They’re going to be comfortable with that. A lot of people like the idea of taking a combination therapy, getting rid of the disease completely, with the thought that maybe it won’t come back, which we hope, or alternatively, being off therapy for a period of time and not worrying about having to take medicine. I think these second-generation medicines are going to be important in that regard because they’re going to be easier to combine with other agents that are active in CLL. I believe this is the future of CLL – combination therapy, particularly for younger patients, getting them off therapy and really thinking, for all the tools that we have, perhaps there in a subset of people, we can cure this disease.

BK: I’m going to push you back a little on the ACP-196. You mentioned that there was less atrial fibrillation, less serious bleeds, less diarrhea. What about some of the more annoying side effects like the muscle aches and pains, the arthralgias, the fatigue, and the hypertension. Nothing that should make you stop the medicine, but can be pretty annoying for some patients that are taking ibrutinib. What is your experience there?

JB: My experience there has been one where you don’t see those side effects or you see much less, or not at all. In fact, in the ACP-196 trial, there is an ibrutinib intolerant arm where people that have had very, very difficult muscle cramps that are limiting their quality of life or they’ve developed recurrent atrial fibrillation, or they did have it before where they can go off ibrutinib and go onto ACP-196. We’ve seen in that group that those ibrutinib side effects don’t occur. To me, that’s the best experiment in the individual patient that has not tolerated ibrutinib for one reason or another. It’s a life-saving drug for CLL patients. They can go onto another BTK inhibitor and have those side effects go away. That’s the other important thing of the second-generation medicine is, even for the people that are doing great on ibrutinib, and a lot of people are doing great on ibrutinib. I don’t want anyone to take away from our conversation that ibrutinib is not a phenomenal drug.

BK: and a relatively selective drug. It hits 9 enzymes and ACP-196 hits 3 enzymes. Still we have thousands of enzymes in our bodies.

JB: Absolutely. What always concerns me is seeing patients that come to us where their doctor is saying, “Ibrutinib has side effects. You’ve been treated with a lot of things. We should use bendamustine-rituximab.” These targeted drugs are so obvious for patients and are so much better than chemotherapy. Except for a very small subset of patients, we really should not be giving chemotherapy in CLL anymore. That’s probably a bold statement to say, but I really believe it strongly.

BK: You’re not the first person sitting in that chair to make that statement. There are a lot of other CLL experts saying that. I think bluntly that is the difference between some of the community hematologists who are very experienced and comfortable with FCR (fludarabine, cyclophosphamide, rituximab) and BR (bendamustine, rituximab) than some of the people who have had experience with some of the more novel agents because they have been involved in some of the research and know the potency of these new drugs in the trial drugs and they feel more comfortable giving their patients some of these new drugs. That’s why we always say you need 2 people. You need your community hematologist to be there, to be in the weeds with you handling this stuff, but you need an expert who may be on the cutting edge who knows of new trials and medications. You need both of them there.

Let me jump back one last time to ACP-196. These were relapsed/refractory patients. Did you tease out the data on high-risk 17P patients, versus the other patients, and was it similar to the good numbers we see with ibrutinib?

JB: This is a very high-risk patient population, so one-third were 17P, 70% had low counts, about half had bulky nodes. They had a median of 3 previous treatments, so it was representative of a refractory group. The first patient in the trial had had 12 or 13 previous treatments and had had an allogeneic transplant, started with a platelet count of 2 and was neutropenic.

What I think is so important and what I advocate is that clinical trials are for the patients. The patients are not for the clinical trials. It’s very important that clinical trials represent real people that have CLL. What I like about what happened with the ACP-196 trial is that I don’t believe the data are going to change because the eligibility criteria to go on the trial allow you to have low counts, which is part of CLL. CLL patients that have low counts don’t necessarily do as well, but you want to know that. You want to know the drug is safe. The safety data that is coming forth from ACP-196 is such that I am very confident that when it goes out to a big study, it’s going to be reproduced, because we have a representative CLL patient population.

There are other drugs that are being developed in CLL where they have very restrictive criteria. Say you berry-pick athletes, a term we use relative to patients that are going to do really well. You get a false signal, or better data than the drug really deserves. Also you put a lot of patients through screening where they would benefit from the drug and they’re disqualified for low counts or something else.

BK: One of the things that I hear inherent in this trial that I have personal excitement about is the fact that you’re not excluded if you’ve had a transplant. I don’t know how many papers that have that as an exclusion criteria. Some will exclude you if you’ve had a transplant in the last year, which makes sense, but if you had a transplant 5 years ago, why does that matter?

JB: So this trial didn’t have that exclusion criteria. What’s amazing about the data is we have more than 14 months of follow-up and there has been one progression with CLL. We lost one patient to pneumonia at 12 months who was responding. People are doing really, really well. The company is doing the right study, so we’re going to find out if it’s as good or better.

We’re doing a direct comparison to ibrutinib in the relapsed setting. I would say if you have relapsed CLL and you qualify for that clinical trial (It’s going to be done around the world.), and you’re eligible for it, it’s a great study because in both arms you get a great therapy.

BK: Non-chemotherapy in both arms.

JB: Two non-chemotherapy phenomenal drugs and we’re going to answer an important question, even if they’re the same, in terms of efficacy. I do believe ACP-196 will be better tolerated, but even if they have different side effect profiles, we’re going to have 2 drugs that are approved, so if you become intolerant to one, you can go on the other. I think it’s a great trial. Patients are so generous with their time in participating in trials. For patients, this is a great trial. Both options on the trial are phenomenal.

BK: Dr. Byrd, thanks so much. Thanks for what you do for me personally. Thank you for what you do for your hundreds and hundreds of patients and thanks for the research you are doing to move things forward.

JB: I’ll say the same thing. Thanks for all the work you do for patients with your website and foundation. We’re really happy that you’ve picked this up and are helping so many patients.

Dr. Brian Koffman, a well-known doctor, educator and clinical professor turned patient has dedicated himself to teaching and helping the CLL community since his diagnosis in 2005. He serves as the unpaid medical director of the CLL Society Inc.

Dr. John Byrd is the D Warren Brown Chair of Leukemia Research and Director, Division of Hematology at The Ohio State Comprehensive Cancer Center in Columbus, OH. He is a member of the Medical Advisory Board for the CLL Society.

Originally published in The CLL Tribune Q4 2015.