International MPN News, Science & Opinion

The Pacritinib Affair – Screwed again.

We need a T shirt that says “MPN Lives Matter.”

Zhen Cropped Team Leader

Zhenya Senyak

Forget the T shirt, we need a mob to stop traffic and scream and shout at the entrance to the FDA, at the doors of Big Pharma: “MPN Lives Matter.”

Because, once again, we’re getting screwed. Another Phase III trial for a myelofibrosis drug has exploded and we’re out in the cold. Without a paddle.

Two years ago it was Sanofi, crawling out from a secret weekend meeting to pull the plug on fedratinib after botching a trial, killing and injuring MPN patients. “MPN Lives Don’t Count for Jack.”  Hundreds of MF patients left to fend for themselves, no drugs, no compensation, no apologies, no explanation.  We headed on home.. Nothing to show for our clinical trial experience except maybe some debt, some tired bones, and some bitter regrets.

Two weeks ago we saw pacritinib vanish from the the treatment landscape even as our docs were warming up their prescription pads. Finally a drug for low platelet MF patients. And then … POW! Just like that.

The FDA descended from on high, swept the table clean of pills and decreed “No more pacritinib for you.”  Once again hundreds of MF patients who were benefiting from a clinical trial drug, many sick and weak, were now out in the cold with nothing to cover their naked need for relief but some hints and rumors.

And once again the cone of silence descended over the scene. Nobody’s talking. Negotiations in progress. Confidentiality required. Privacy guaranteed. Blah Blah.  It would be a joke if it weren’t so damned insulting to all our friends who believed enough in our money grubbing clinical trial system to swallow the pills, make their appointments, get jabbed and prodded only to be told to turn in their electronic diaries, any inventory of pills, sign this release and get lost.

Last time it took MPNforum four months of intense undercover investigative work to put together the sad Sanofi story.  This time we don’t have to go much further than the printed record to figure out a likely scenario.

Let’s start with the conclusion:  There’s plenty of blame to go around but the truly nasty guys in the black hats this time are the Feds.

Even if it were really necessary to call a time out on a trial that had been completed and amply reported on, did the FDA have to mount a Secret Operation, taking doctors and patients by surprise? Why call in a SWAT team in full camo to come kicking in the doors and windows when a kinder, gentler approach would have been just as effective? This is a drug that was helping most everybody on the trial. Forcing  MF patients to go cold turkey on pacritinib was flat out cruel.  Their physicians had to violate their Hippocatic Oath.  Primum non nocere.  There was plenty of nocere in the wake of this action.

Everyone knows a sudden cessation of JAK inhibitors is going to send your spleen and symptoms through the roof. Ask Tefferi.  Ask Verstovsek. Ask your grandmother or kid sister.

This FDA full clinical hold — even if it were necessary for the safety of patients — could have been phased in gradually over several weeks easing the impact on patients.

But was it really necessary?  Let’s take a look at what we know for sure.

There were two arms to the trial:  The pacritinib group that got the pill and the Best Available Therapy group that got something else.

Last summer Dr. Ruben Mesa reported on pacritinib at the big ASCO meeting.

Conclusions: This study demonstrated PAC was well tolerated and induced significant and sustained SVR and symptom control even in patients with severe thrombocytopenia. PAC therapy resulted in RBC transfusion independence in a significant proportion of pts.Clinical trial information: NCT01773187

Pacritinib asco cropped

It was a report signed by a Who’s Who of the worlds most experienced, renowned hematologists and researchers  Very positive, no drug related serious inexplicable events.

Two months ago Dr. Alessandro Vannucchi at ASH  did the honors Same deal. Very promising. Conclusions:  Comparisons vs BAT were favorable for all patient subpopulations examined for both endpoints. These results support the use of pacritinib across all intermediate- or high risk MF pt subgroups analyzed.

Yes there were deaths on this trial.

It would be inevitable. The protocol for the trial almost demanded it. To qualify for the PERSIST trials of pacritinib you had to be really sick had failed other drugs and most of all had critically low platelets that would disqualify you from such amenities as a stem cell transplant or Jakafi. There was a low longevity bar.  To qualify for participation in this trial you were required to have at least a six month life expectancy.  

“The FDA’s February 8, 2016, letter, “says a CTI press release, ” notes the interim overall survival results from PERSIST-2 show a detrimental effect on survival consistent with the results from PERSIST-1. The deaths in PERSIST-2 in pacritinib-treated patients include intracranial hemorrhage, cardiac failure and cardiac arrest.”

We have heard that the difference in death rates between the two arms of the trial are small, but significant although no one has attributed the cause of death to the action of pacritinib.  The deaths that concern the FDA referred to the pacritinib-treated  patients presumably faring worse than patients treated with BAT drugs. Isn’t that what we would expect?

Even though there were two arms to the trial, there was an escape hatch. If you get worse, if your big spleen got bigger enough, if your low platelets got low enough, you might get the opportunity to cross over to the pacritinib arm. Otherwise you had to stay with your BAT friends for 24 weeks, then get measured to see how much worse your disease was, and you could cross over to the sunny side of the street.

It’s a recipe for confusion and disaster.

The Independent Data Monitoring Committee (IDMC) for the PERSIST trial recommended the BAT patients not be able to cross over before  24 weeks.  The reason: Survival curves and muddying the statisticl waters. How can you tell if pacritinib is better than BAT unless you set up rigid barriers?

CTI BioPharma and its partner Baxalta consulted with experts and then notified the FDA they rejected that recommendation and intended to follow the original protocol and permit cross over.  We have a good example right in this issue  about the impact the crossover rule had on patients. The effect of this decision may well have influenced the ultimate FDA action…but we won’t know that for sure until the FDA breaks its Code of Silence.

Consider someone in the BAT arm who wants to cross over but was told he is not sick enough and has to wait,  like Howard in our abandoned patient story.  After 24 weeks, he crosses over and starts taking pacritinib. He is six months older and  likely six months sicker than he was when the trial started but now he’s part of the pacritinib arm. If he dies, he dies on the pacritinib arm.

The procession of patients too sick to stay on BAT and moving on to pacritinib and those graduating after 24 weeks, older and likely weaker than when they started, changes the dynamic. The pacritinib arm is not only no longer randomly selected it is heavily weighted toward the most ill.

Understandably a look at the survival data could set off warning bells.  “Hey look there are more people dying on the pacritinib arm than the BAT arm. What’s going on? Let’s make everyone throw away their pills immediately and close up the trial.”

This is not to say those kinds of things can’t be easily unravelled and accounted for statistically  BUT it does point out the likelihood that more people died on the pacritinib than the BAT arm.  Not seeing the data but relying on the Vannucchi and Mesa reports of safety and CTI”s own account of its failure to follow the IDMC’s recommendation and reading that deaths on trial were an issue for the FDA, it’s a reasonable working hypothesis.  Until someone starts publishing the data.

Meantime, if we were counting on pacritinib for symptomatic relief despite our low platelet levels,  we’re still screwed…without many easily apparent options.

How about an X-Large  “MPN Lives Matter” T-shirt  ?

Got a comment on this story? Weigh in. And while you’re at it, let the FDA know what you think:

Contact FDA:  Toll Free (855) 543-3784,

Take me back to the Contents

© 2016, MPNforum. All rights reserved under Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License

Comments on: "The Pacritinib Affair – Screwed again." (15)

  1. Elizabeth Goldstein said:

    I sent an email shortly after your first appeal to us and got an answer from the FDA that the information was
    confidential and couldn’t be shared with public. They suggested I contact the drug company if I wanted to
    know anything else. I didn’t see the drug company actually telling me anything so didn’t write to them. I
    have ET and hope it never progresses but this drug issue is serious. I was on Pegasys for 18 months
    and had every side effect listed plus a few that weren’t listed. I toughed it out because I thought it would
    heal my bone marrow and make progression less likely. After 18 months, I became so depressed that I
    couldn’t get out of bed for several weeks and then didn’t leave my house for months. I am doing better
    but still fighting the depression. I will have to go back to hydroxurea next week as Jakafi isn’t approved
    for ET and frankly, I am afraid to try a new drug now. Most people seem to do well on Pegasys so I must
    have some kind of strange genetics that just don’t work with it. I had some severe issues with hydroxurea,
    too, but at least I wasn’t depressed so am opting for the lesser of the two evils.
    I feel badly for the people who were just yanked off of a drug that was helping them and sincerely hope the
    drug will get approval eventually. The situation with drug companies in this country is much like the
    political circus we have witnessed and will continue to witness until, mercifully, we vote in November.
    Have been voting for 51 years and this is the worst election ever and still have no idea who to vote
    for because no one really appeals to me and my beliefs. I might just vote for Jack Daniels.

  2. This is a crosspost from my blog at terminalreason.com:

    As I’ve written, I was participating in a Phase III trial for a drug that held promise for this cancer: pacritinib. I write “was participating” because the trial has been halted by the FDA, and I am no longer taking the drug. This has given me a fresh perspective on clinical trials.

    I remember talking with one of the front desk staffers at the front desk of the transplant center; as seems to be the case, people remember me, and he had checked me in for my appointment a few weeks before, and remembered me. He asked me how the trial was going, and I responded with “Fine.” He then said he had been on a trial for a medication, and how important the trials were, and how they had changed: patients were not treated like “experiments”, there was little risk, and the old-fashioned view of us being “guinea pigs” was just wrong.

    I did not disagree with him at the time.

    Then on Feb 9, the FDA halted the Persist II trial, with no warning. Apparently, there were a few “adverse mortality events” – somebody died.

    Now, that sounds terrible – however, keep in mind that we’re talking about a drug trial involving high-risk patients who are terminal. Pretty much no matter what you do with that group, somebody is going to die. Consider that the deaths occurred in people who had been in the study for at least 6 months, and the first six months for anybody in this group meant NOT taking the drug: you essentially have taken a group of dying patients, given them quite possibly NO treatment for six months, and some of them died.

    Really?

    The answer, according to the FDA: immediately cease use of the drug. No matter if it was helping you; no matter how much benefit you were receiving.

    Moreover, it is well known in the hematology – oncology community that stopping a drug in this class (JAK2 inhibitors) cold-turkey can result in terrible side effects, including death. Yet that is exactly what the FDA has us doing: stopping the drug cold turkey.

    It hasn’t been easy: my pain levels have greatly increased; fevers are back; night sweats have returned; fatigue levels are greatly increased; I am unable to eat a full meal; my white blood cell counts are dropping rapidly.

    It seems to me that patients should have been given an option to either stop the drug immediately, or to taper the dosage to avoid the flare-up of symptoms.

    That the FDA chose to act with little regard to patient welfare in this matter shows, in fact, how patients in a clinical trial really are just guinea pigs.

    Another view of this can be found at MPN Forum Magazine .

    Update, 2/25/2016.

    The pain continues; it has reached the point where I am taking NSAIDs to counteract some of it, even though I know I will be gut-bleeding from them. I would say that 80% of the time, I am unable to walk upright at a normal pace; the pain is just too much.

    In the past 72 hours, I’ve started a new trick: severe chills and shakes. They come on randomly; sometimes I will have a fever, sometimes not. When the hit, my entire body goes into weird sort of spasm. As I convulse from my feet upward, the body not only tightens down, but also vibrates. It’s really difficult.

    I’m fairly sure that I’m dealing with systemic inflammation and rebounding cytokine levels from the cold-turkey stop of the Pactritinib. Any fever that I have had has not gone above 101, and starts to come down fairly quickly.

    I am supposed to visit the ER anytime I have a fever of 100.4 or above; since my immune system is not in great shape, my doctor has instituted a neutropenic protocol for me. My insurance doesn’t cover ER visits; between that fact, and the fact that I would have gone to the ER 8 times since Friday, I’ve just abandoned this protocol.

    The fevers and shakes seem to be reasonably well-controlled with Tylenol.

  3. I emailed the FDA and here is the reply :
    Dear Ms. Bonnie Handel,

    Thank you for writing the Division of Drug Information in the FDA’s Center for Drug Evaluation and Research. We sincerely appreciate you taking the time to write to us and share your concerns about the welfare of the people enrolled in clinical trials, such as the trial to evaluate pacritinib.

    We will share your comments with the Division of FDA involved with oncology drug products. If you are seeking additional information, you may be interested in contacting the company sponsoring the clinical trials for pacritinib, CTI BioPharma. The latest press release regarding pacritinib release by CTI BioPharma is available online.

    Best regards,

    LE | Pharmacist
    Drug Information Specialist
    Division of Drug Information | Center for Drug Evaluation and Research
    Food and Drug Administration

    For up-to-date drug information, follow the FDA’s Division of Drug Information on Twitter @FDA_Drug_Info
    This communication is consistent with 21 CFR 10.85(k) and constitutes an informal communication that represents our best judgment at this time but does not constitute an advisory opinion, does not necessarily represent the formal position of the FDA, and does not bind or otherwise obligate or commit the agency to the views expressed.

    —–Original Message—–
    From: Bonnie Handel and Bob Auwood [mailto:abbiedog2@hotmail.com]
    Sent: Sunday, February 21, 2016 10:09 PM
    To: CDER DRUG INFO
    Subject: Clinical Trials

    Clinical trials are without doubt a wonderful means to the endpoint of healing the sick.
    BUT THE WELFARE OF THE PEOPLE (people, not mere patients) ENROLLING IN THESE TRIALS NEEDS TO BE BETTER PROTECTED.
    The recently halted trial of pacritinib is an example of things going terribly wrong. I am not wise enough to judge the wisdom of halting the trial. But I do know that it was not only cruel, but HARMFUL to those who were benefitting from the drug to stop it suddenly. THEY SHOULD HAVE BEEN SLOWLY WEANED OFF IT. And there should have been better communication along with medical followup.
    Those enrolled in clinical trials are already quite ill, and to just leave them out in the cold is contrary to what I believe is good medical practice.
    There needs to be some sort of advocacy for the people enrolled in trials to make sure that not only the drug companies, but the sick are taken care of.
    Cynics have said that drug companies sponsor trials that even if they fail, do so to stimulate investment. I hope that is not true. But it does support the point that there is a need for patient advocacy.
    Thank you for your attention, and hopefully consideration
    Bonnie Handel, Myeloproliferative Neoplasm since 2010
    I hope I do not progress to the desperate state of needing to enroll in a trial.

  4. Karen Ulshafer said:

    It seems like we need an undercover investigative reporter for all these “behind the scenes, 11th hour” decisions that don’t include us, the patient. It is beginning to sound like a broken record. I am disgusted by government and big Pharma policies. As I wrote In their email, it seems as tho’ none of those FDA folks had family or friends who have suffered thru’ these myeloproliferative neoplasms symptoms or clinical trial experiences. If they could sit with a group of us and listen to our clinical symptoms, anguishes, hopes, maybe they would have a better idea of the effects they are causing by pulling the PAC in its 3rd clinical trial.
    I thought after the Sanofi debacle a couple of years ago, we started the Zeba Coalition to prevent this type of thing, or at least stepping down gradually if the CTI was to stop, so patients aren’t left out in the cold. I guess that has no effect on the FDA.
    Thank you for the up to date, altho’ sad information. Always, always helpful.

  5. Email sent to FDA…I hope someone reads it

    • Way to go, Bonnie. Over 5,000 of us read it soon after it appeared. We have gotten only stonewalling from FDA spokespeople. Now we are petitioning the FDA brass for some clarity on what seems to be bureaucratic cruelty. Why pull this drug so completely, so fast after years of positive review?

  6. Bob, My heart goes out to you. I was in the Sanofi trial and your words describe so vividly the pain and frustration that come when the disease is out of control. I’m fortunate that my disease is under control right now with Jakafi, but I take nothing for granted and realize that many of us probably can best hope to hang on from one new treatment to the next. I pray that you will find something that works for you very soon.

    I also posted this on FB: The risk of abruptly stopping a similar drug, whether in trials or not, was well-documented by Dr. Tefferi, Mayo Clinic, Rochester, several years ago. This was enough information for them to expect similar results here and to take similar precautions…stop the drug gradually and under medical supervision. Whoever is responsible for how this was handled should be held legally responsible for the pain and suffering these patients have had to endure. Having participated in the Sanofi trial and experienced the ups and downs of being on a “drug hold” due to low platelet counts, I can tell you that it is beyond frustrating to be halfway across the country, away from your own medical team and unsure of how to proceed, who to contact for help, not to mention dealing with insurance issues that arise when your stay has to be extended. My heart goes out to all of you who have been affected by this.

  7. This is a copy of my email to the FDA:

    Greetings.

    I sincerely hope that you, whoever you might be, are having a good day.

    As I write this note to an anonymous recipient, I’m not having such a good day.

    A few days ago, I was forced to stop taking Pacritinib cold-turkey by the FDA.

    I’m 54 years old – by our society’s standards, not an old man. Yet I find I am too tired to do anything physical. I am terribly fatigued today, and have been all week. Today might be especially bad because last night I suffered from intense pain, fevers, and night sweats.

    At least the abdominal pain from my spleen growing suddenly has stopped. I guess I should be thankful for that.

    Picking the one symptom that is the most troublesome is hard: maybe the pain, which makes it so I can barely walk? Or is it the fatigue, where I fall asleep at my desk?

    I guess I’ll go with the pain. Waking up at my desk in a puddle of drool isn’t so terrible, and it’s not like I’ve fallen asleep while driving on the freeway – not yet, anyhow.

    The night sweats aren’t that bad. That just means we have to do laundry more often.

    I’m used to the fevers, and having a mild fever doesn’t mean I go the emergency room any more – in direct contradiction to my doctor’s orders, but, my insurance doesn’t cover ER visits, and when the fevers come and go all day, well, I don’t have time or money to care for them.

    Anyhow, while you’re enjoying your day, if you could route this note to the appropriate department, and try to get me an answer to this one question, I would appreciate it: “Why did you force me to stop taking a JAK2 inhibitor cold-turkey when the entire medical community knows that this will cause terrible rebound effects?”

    Sincerely,

    Bob Wanamaker

    • As of today (Tuesday, 2/23), I have not received any acknowledgement of receipt from the FDA to my email. Just great.

      • Maybe let the FDA Ombudsman know? (301) 796-8530: ombuds@oc.fda.gov FDA Office of the Ombudsman Laurie Lenkel, Director

        There’s a new FDA chief coming, Dr. Robert Califf, which might not change the FDA’s approach to patient issues. (From the NYT: “In a statement, Dr. Michael Carome, director of the Public Citizen’s Health Research Group, said the Senate should reject the nomination due to Califf’s ties to pharmaceutical companies and medical device manufacturers (something TIME reported on in February): “During his tenure at Duke University, Califf racked up a long history of extensive financial ties to multiple drug and medical device companies, including Amgen, AstraZeneca, Eli Lilly, Johnson & Johnson, Merck Sharp & Dohme and Sanofi-Aventis, to name a few,” Carome said.”)

  8. Michelle Hemmes said:

    Sent an email.

    • Great, thank you. We need many more. Your email is logged so Don’t be discouraged if you get a response like this: “The FDA cannot discuss products in development and cannot confirm or deny the existence of an IND. This information is confidential under federal law and FDA regulations.” It’s their basic stonewall firewall.

  9. Tricia Ramos said:

    Thank you for such a well written article your passion, digging to expose the truth and for encouraging patients to call the FDA.
    MPN lives DO matter. Society needs to take note!

  10. Email sent to FDA

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