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TSR March 2016

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Pacritinib — the story behind another busted JAK2 trial…and why we should care.

I was working on the zebrafish story at the time and so missed the fast breaking pacritinib newsFebruary 4, the FDA placed a partial clinical hold on pacritinib, the CTI JAK inhibitor that was wrapping up its Phase III trial. An earlier version of the trial, PERSIST-1, had concluded  with highly positive results reported at ASCO and ASH and findings had already been submitted to the FDA.

By the time I posted the news to MPN Facebook pages, events had moved on. The FDA shut the trial down cold.  Full clinical hold.  No more pacritinib for you.

Here’s how serious it is. “Under the full clinical hold, all patients currently on pacritinib must discontinue pacritinib immediately and no patients can be enrolled or start pacritinib as initial or crossover treatment.”  Thus sayeth CTI conforming to the FDA order.

CTI BioPHarma, partnered with Baxter in this effort, is the old Cell Therapeutics. In 2012 CTI acquired the Singapore-based S*Bio and its lead drug, pacritinib.   Pacritinib is a bit long in the tooth, easily setting Guiness Book of Records for time on the JAK2 launchpad…

Here was deja-vu all over again. Two years ago we had a front row seat to witness another successful, JAK inhibitor at the end of its Phase III trial, crash and burn. Without notice, patients were booted off that Sanofi federatinib trial and a cone of silence descended over Sanofi and the FDA.  After the FDA’s shameful denial of our two Freedom of Information Act requests, it took us months to crack through and report what happened. In that one.

This is may not be the same thing. Yes there were deaths on both fedratinib and pacritinib trials and the cutoff in both was without expectation or advance notice to patients or investigators.

In the fedratinib case there was botched reporting on the Sanofi trial, a long delayed response to a deadly neurological disorder,capped by a weird secret corporate weekend where the former Sanofi managers pulled the plug. That doesn’t appear to be the case here.

According to reports from observers close to the scene, the CTI board is fighting to meet the FDA requirement to lift the hold and is reportedly determined to bring pacritinib to market. Meantime CTI has withdrawn its New Drug Application (NDA) and deferred its submission until the safety and efficacy profile of the drug has been established from the PERSIST-2 trial.

Two investigators in the PERSIST trials confirm there was no drug toxicity evident but believe deaths were a function of the ill health of patients with platelet levels below 50,000 on the trial.  (Pacritinib was positioned as the potential JAK inhibitor for thrombocytopenic MF patients who could not qualify for ruxolitinib by virtue of their low platelet levels.)

Whether CTI has the will or capacity to see this process through to a successful conclusion is an open question for now.   Its capacity has surely been diminished as its stock price tanked on announcement of the FDA hold, dropping 40% to hit a yearly low of $0.25 cents a share. And its credibility has taken a hit.

CTI might be the unintentional architect of its own distress.  A JAK inhibitor effective for MF patients with low platelets is sorely needed. On that basis,  having applied for and been granted fast track status, the company was assured it would get an expedited review on its rolling submission.

Its positive PERSIST results were submitted while PERSIST-2 was wrapping up.  When the FDA regulators saw the deaths and cardiac events in the latest data compounding those in the first submission they blew the whistle for a time out.  Another issue that may be confounding the analysis of survival curves is CTI’s rejection of its Independent Data Commission’s recommendation to curtail the crossover option permitting patients on the comparator arm of the trial to move into the pacritinib arm if their disease worsened . The crossover option may have contributed to a greater number of sick and dying patients moving into the trials pacritinib arm.

Beyond that the CTI track record with the FDA is not unblemished.

Back in 2010, CTI had another drug rejected by the FDA.   FDA regulators found fault with CTI’s (Cell Therapeutics’) development process and application for Pixuvri (pixantrone), a lymphoma drug, bluntly characterizing the data as inadequate for an approval.

Cell Therapeutics announced that pixantrone achieved the primary efficacy endpoint but the minutes of the Oncologic Drugs Advisory Committee meeting of March 22, 2010 show that this had not in fact been achieved with statistical significance.  At issue were comparator stats. “This combined with major safety concerns lead to the conclusion that the trial was not sufficient to support approval.” In April 2010 the FDA asked for an additional trial. CTI withdrew its NDA and was accepted in the European market.

There is an eerie similarity between what’s happening now in pacritinib’s stalled effort to make it through the FDA approval process and what happened two years ago when the Sanofi fedratinib trial blew up.  Both drugs seem to have been effective with most patients on the clinical trials.

So how does this all relate to the zebrafish story that kicked off this report?

There is a massive difference between the basic science uncovered in Leonard Zon’s work with zebrafish – work we desperately need if we are ever to get to the root of MPN disease – and drug companies sponsoring yet another JAK inhibitor clinical trial in hopes of marketing a product to eat Jakafi’s lunch niche by niche.

There is an undeniable naked commercialism fueling the JAK2 inhibitor search that is absent from purely scientific research. The MPNforum interview with Incyte then-CEO Paul Friedman revealed Incyte didn’t much care about myelofibrois. They were really after a rheumatoid arthritis  drug and MF was only a more convenient, more easily accessible target since it afforded fast track status. And there’s the musical chairs search for a potential money making drug.  We’ve seen the Cytopia inhibitor, picked up by YMI Bioscience and then handed off to Gilead, only to emerge as momelotinib languishing in a sluggish limbo as more profitable drug targets emerged. Money.  Perhaps if Sanofi weren’t so eager to catch Jakafi a more meticulous clinical trial process might have succeeded without death and debility.

Clinical trials are a hard, cold business.  During the same period in which the pacritinib trial crashed, Incyte quietly cancelled all its clinical trials of Jakafi in solid tumor applications, ending its Phase III pancreatic cancer study as well as studies in colorectal cancer, and breast and lung cancers.

It just didn’t work. Like the vast majority of clinical trials – 92% — it ended up in the graveyard of hope.  And all  the patients enrolled in those trials?  C’est la vie.  Sorry.  And yes, Incyte also announced, it’s releasing that oral RA drug after all…and expects another $800 million in revenues from Jakafi this year.

And those zebrafish? With their help, Nature gave up one of its most closely held secrets, the return of a cell to its earlier progenitor status. And the expression of a gene on the way to generating a deadly cancer.  No, there’s nothing for sale here. Just deeper understanding that will ultimately make a difference.

 

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