The Current and Future Status of Pacritinib: An Expert Explains

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Topics include: Treatments and Understanding

Over the past year, the investigational oral kinase inhibitor, pacritinib, has been making headlines. In Feb 2016, the FDA put a clinical hold on the trial. Just a few months later, the FDA allowed some patients to re-enter the trial as part of a compassionate use program. Now, in January of 2017, the full clinical hold has been removed. To help patients sort through the information and to update us on the status of pacritinib, Dr. John Mascarenhas joined us from Mount Sinai Medical Center in New York City. 

To find open clinical trial sites for the PAC203 clinical trial, click here.

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Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you. 

Tamara Lobban-Jones:

Hello, and welcome, I am Tamara Lobban-Jones. Over the past year an investigational oral kinase inhibitor, pacritnib has been making some headlines. And that story continues to develop. To help patients sort through some of this information, and also to provide a status update on pacritnib, Dr. John Mascarenhas joins us from Mount Sinai Medical Center in New York City. Dr. Mascarenhas, thank you so much for joining us today on Patient Power. 

Dr. Mascarenhas:               

Thanks for having me.

Tamara Lobban-Jones:   

Okay. So in terms of a timeline, February 2016 the FDA put a full clinical hold on the trial. Just a few months later, the FDA allowed some patients to re-enter that trial as part of a Compassionate Use Program. Here we are today, January 2017, that hold has been removed. As you can imagine that can certainly be a little confusing for some patients. Can you take us through what these holds mean and, most importantly, provide us with an update on where the trial stands today? 

Dr. Mascarenhas:               

Sure. So the PERSIST trial is a randomized Phase III study. It really compliments the PERSIST-1 Study, which was also a randomized Phase III study. And the studies are evaluating a multi-kinase inhibitor, that's a JAK2 inhibitor. So they're really geared towards patients with myelofibrosis that are intermediate or high risk by scoring systems, and they're symptomatic and have the spleen that needs to be reduced. And what was unique about PERSIST-2 was it was specifically geared towards patients with low platelets.

And that's really an unmet need as I see it. And this would be offering an opportunity for patients who may not be eligible for ruxolitinib (Jakafi) commercially, or for many other trials, because their platelet count limited their ability. So that was to me the real benefit of this drug and the evaluation of the drug. It really opened up access to many patients, to a drug that was in my mind, it is very potent in improving a lot of the symptomatology and aspects of the disease. Unfortunately, in the early part of last year, 2016, the FDA was reviewing data as it was being generated from PERSIST-2, in conjunction with PERSIST-1.

And there was a concern on their part that there was an excess of death in those studies related to the drug or seemingly related to the drug, as it surrounded patients having cardiovascular issues and bleeding issues. So out of an abundance of concern for safety, which is what the FDA is interested in doing, they put a hold on the study. And that really required all the investigators, myself and many other dedicated MPN physicians, to have to, unfortunately, take their patients off the study—and, in many cases, actually stop the administration of the drug.

And many of those patients obviously were benefiting from the drug. So that was a difficult period, a very difficult period for patients and physicians alike. And what ended up happening is the FDA granted the ability to put patients, who were benefiting from the drug, who are on the PERSIST studies, to then go on to what's called Compassionate IND. Where they would be given the drug, but it’s not really a clinical trial.

The study is geared to looking at efficacy, were it in place, it was really to ensure safety, but most importantly to give access to a drug that was benefiting the patients. As long as everyone involved, patients and the physicians involved, were aware of the potential risks as assessed by the FDA of bleeding and cardiovascular events, which could lead to death in some cases. So at the time of that full clinical hold, there were actually a sufficient number of patients that we were able to get data from the PERSIST-2, to actually look and address the concerns of the FDA and try to look at some of the efficacy end points that were established at the onset of the study.

So this study is a Phase III study that's randomizing patients to either pacritnib at two doses, either 400 milligrams once a day, or 200 milligrams twice a day, versus the best available therapy, which could be anything, including ruxolitinib. And many of the patients who got the best available therapy actually received ruxolitinib, even though about half the patients had already seen ruxolitinib previous to the trial. And that sort of speaks to the fact that it's an unmet need, we do not have a plethora of active agents in this group of patients with myelofibrosis and a low platelet count. 

The efficacy end point was at 24 weeks. The proportion of patients that were randomized to the two cohort arms of pacritnib, to achieving a 35 percent reduction in their spleen volume, and a 50 percent reduction in their symptom burden. That would be considered a positive response, and you could consider it a responder. And there were fortunately enough patients that we were able to get some data out of it. And what we found was that when you looked at the cold analysis of the two groups, it met the efficacy end point for spleen reduction, but it did not, it fell short of meeting it for symptom reduction.

And that's not to say that many patients didn't benefit in both respects, they did, but statistically speaking it didn't meet the pre-assigned end point. And one could come up with many reasons why that it is. I think one major reason is we didn't have enough patients enrolled for enough time to actually have the power to show that. And I think that's a very valid reason. We probably would have met the primary end points if that was the case.

But most importantly, if you took out and you looked at the patients that were receiving the 200 milligrams twice a day dosing, which pharmacokinetics, it looks like the best way of delivering the drug. They met both primary end points. If the trial was just designed to look at them, that would have been a totally positive study. At the ASH Meeting, we presented the—at a late-breaking abstract—we presented the results of the study, and we demonstrated that the spectrum of the responses that you see with both the spleen and the symptoms were clearly superior to best available therapy in the 200 twice a day.

And it looks superior to me when you combine both arms. So in my mind, this was a positive study. It met its end point, even though it was abruptly stopped. And even though we didn't have all of the patients and the full complement of data, we were still able to show that the drug is clearly active and does benefit patients. Now, what about the concern about the FDA? That was also addressed. Thankfully, when we were able to look at all the mature data, and the follow-up, we were able to see very clearly that there was no increase in death in the patients who got the study drug pacritnib.

So there were patients who died, unfortunately, on pacritnib, from disease-related complaints, and from various reasons, but there were also a similar proportion of patients who died in best available therapy. And that, unfortunately, is the natural history of the disease as well. We had a Kaplan-Meier curve that demonstrated the survival curve, which is commonly shown in Phase III studies. We were trying to compare two groups of patients. And what that curve showed us was the curves intermingled. 

They were super imposable basically, which means there really wasn’t a difference in a survival, meaning there wasn’t an increase in death, in the pacritnib, that really concerned the FDA. We even did some extensive analysis at adverse events of interest, like bleeding, like cardiovascular events. And the numbers are very low, but to just summarize it, there wasn’t at the end of the day, a very clear difference in the two groups of patients, in terms of bleeding, in terms of bleeding that's significant and leads to death, or cardiovascular events that lead to death.

There wasn’t a really a significant difference between the two arms. And thankfully the numbers were very low. And those can be issues that can affect a patient with myelofibrosis, even if they're not on pacritnib, or any therapy for that matter. So I think that the data spoke for itself. And it was quite convincing that the drug is both efficacious, particularly when given 200 milligrams twice a day. And it meets safety parameters that are acceptable for this cohort of patients with low platelets, in terms of concerns about bleeding or cardiovascular events. 

Also importantly, when we looked at the adverse event table, sort of the adverse events that one would expect with this drug, which are gastrointestinal majorly, were low grade, easily managed and mostly occurred in the first month. We rarely had reasons for a patient to discontinue. So it looked like a very reasonable drug, with a reasonable toxicity profile, and not one that really truthfully increased the risk of death, when the final analysis was done. And that was very reassuring, very gratifying. I think that was the reason why the presentation was granted this status of late-breaking abstract, which is really an honor. 

It really shows that ASH appreciated the potential for this drug. And in doing so, I do think that the FDA, when presented with the final results, and that was done at the ASH meeting, but most importantly in formal conversations with CTI BioPharma, who makes pacritnib, and the FDA, who was in agreement that there clearly is a benefit to this drug, and that it should be evaluated longer and further. And that's why this month of January, the FDA agreed to withdraw the hold and allow for further development of the drug.

And in doing so, I think the company, which gets a lot of credit for sticking to it and not jumping ship. The company has developed a randomized space to study that they’ll be unfolding shortly, which will explore the 200 milligrams dose, and a lower dose, and try to work out some of the kinks of concerns about bleeding, and toxicity and efficacy. And what I'm hoping is that that trial will accrue and will reflect what we saw in PERSIST-1, which was an active drug. And even in some cases you get improvements in blood counts, which is typically not what you see with ruxolitinib.

And that it can be delivered safely. My grand wish would be that it would be eventually commercially available to all the patients that don’t have access to a tertiarycenter or to the trial.

Tamara Lobban-Jones:   

Right. Well, let’s talk about that new trial PAC203. What is it, and what type of patient could benefit from it? 

Dr. Mascarenhas:               

So it's going to be a randomized Phase III study with the idea of looking again at efficacy of the drug, but also characterizing the toxicity and the safety of the drug. The particulars of the trial will come out soon. And to be frank with you, I don't remember all the specifics. But basically it's a patient with—it's going to be a trial that's open to patients with primary and post-ET, post-PV-related myelofibrosis with low platelets that are in need of treatment, and perhaps wouldn’t be eligible for ruxolitinib in therapy because of platelets or previous exposure. And in some ways, it's just adding upon the data that we already have from the PERSIST studies.

Tamara Lobban-Jones:   

Dr. Mascarenhas, given the ups and downs of the trial patients feel more confident about the therapy?

Dr. Mascarenhas:               

Yeah, that's a very valid concern, and I appreciate that. I mean, I think if I were a patient on the other side, and maybe not privy to all the medical nuances and information, I think I would—if it was myself or my loved one, I’d also be concerned, or curious, or question, the safety aspect of it. I think to me what's reassuring is the FDA, which is an organization that's dedicated to ensuring patient’s safety, has reviewed the mature data, and now has removed that hold. 

To me that demonstrates the FDA’s confidence in moving forward, because if they were not confident, they wouldn’t do that. And they wouldn’t take that chance and risk bad outcomes or patient safety for any reason. They're really dedicated to ensuring that for the patient. So to me that's reassuring in itself. But I think any patients that have questions beyond that really need to sit down with their treating hematologist, or ideally with an MPN specialist, and review what their particular case in a personalized manner, you know, what is the potential benefit to risk in me?

And I think that, hopefully in conjunction with the FDA’s decision to remove the hold, would allow patients to have that confidence, if they were to decide to move forward with enrolling in that study. I totally appreciate where a patient could be fearful of that.

Tamara Lobban-Jones:

Dr. Mascarenhas, thank you so much for joining us today and for your continued commitment to the MPN community.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you. 

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Page last updated on July 13, 2017