MPNforum Magazine

The Triumphant Return of Fedratinib

–  Zhenya Senyak

This is story for the holiday season, a story with a potentially happy ending.  But it starts with a major blow to MPN myelofibrosis patients.

First, a little background

Back in 2013, shortly before the ASH meeting in New Orleans, the FDA placed a clinical hold on Sanofi’s fedratinib (SAR302503) drug. They want to have a closer look at potential toxicity in light of reports from clinical trial sites. .  The French drug giant responded by simply shutting down the trial and withdrawing fedratinib. Patients deriving benefit from the drug were out in the cold. 

The storm of protest from patients, physicians, shareholders didn’t help. The offers to acquire the rights to the drug by groups of investors didn’t help. The combined pleas of patients and their doctors didn’t work. Eventually, a simple phone call did help.

Fedratinib, Sanofi’s myelofibrosis drug, was ready for FDA approval after years of intense clinical trial.  Results from more than 800 patients worldwide proved its efficacy.  And then, at the ASH meeting, a sudden disaster.  Reports of a sometimes deadly neurological effect started to circulate.  A brain swelling condition called Wernicke’s encephalopathy (WE).  The FDA placed a clinical hold on the trials November 13.

Five days later to the surprise and dismay of patients and principal investigators at sites everywhere, Sanofi pulled the drug completely and abruptly.

“We are deeply disappointed to have to discontinue development of fedratinib, (claimed the press release)  “especially given the needs of this difficult-to-treat patient population and the earlier promise shown for this therapy, but patient safety is our top priority and drove this decision,” said Tal Zaks, head of development and interim head of Sanofi Oncology.

And opinion

Concern for patient safety might have been better served had Sanofi taken a deep dive into the causes of the neurological disorder that triggered the FDA clinical hold… and making some provision for patient support post-trial.  The hasty retreat even prevented the gathering of valuable clinical data from patients who were steadily dosed with fedratinib,. And then what about the patients benefiting from fedratinib?  Do they continue to get the drug as promised when they signed up for the trial?

No matter how you look at it, it was a rude ending.  A little brutal in execution.  Patients were left with no options, no meds, no compensation and little advice beyond seeing their doctors to check their thiamine (B1) levels.  All this despite Sanofi’s commitment to continue to provide treatment “to patients who are deriving benefit and do not have unacceptable toxicity …..”

That’s the background and opinion… here’s the good news

From The Skype Interviews.

Serious pushback from the medical profession accelerated with a phone call from Dr. Catriona Jamieson to Dr. John Hood, both of UC San Diego.  Hood — the co-developer of federatinib at TargeGen — and Jamieson were both associated with Dr. David Cheresh’s research lab at UCSD. One of Jamieson’s patients, Theresa Blanda, learned fedratinib, a drug she had come to depend on for survival, was being withdrawn. ” I got into the clinical trial, one of the first to receive the TargeGen drug (federatinib),” Blanda said. “That went on for about five years. I did really well. I had an amazing recovery within a matter of a couple of months. Everything, spleen, liver, back to normal. I went back to work. And everything went along OK, until the drug got pulled.”

Jamieson wanted to know if Hood could help get fedratinib for Theresa Blanda on a compassionate use base. They  failed and tried again. Finally, after long delay, they succeeded/ They were notified their patient could get the drug. That was one day before Theresa Blanda died of her illness.

As reported in the San Diego Union Tribune, February 2015: “That went on for about five years.,” said Blanda,” I did really well. I had an amazing recovery within a matter of a couple of months. Everything, spleen, liver, back to normal. I went back to work. And everything went along OK, until the drug got pulled.”

The death of Theresa Blanda renewed the passionate committed campaign of Jamieson and Hood.  with the participation of MPN specialists and advisors who would soon organize as Impact Biomedicines  they fought to gain access to fedratinib.  After the recent failure of other JAK2 inhibitor drugs in clinical trial, the outlook for new, effective myelofibrosis med  is bleak. Patients and their physicians had desperate need of an alternative to the only FDA approved MFdrug, Incyte’s Jakafi.

It was not an easy battle.  The Sanofi CEO,  Chris Viehbacher, had been fired shortly after Sanofi aborted the fedratinib trial. And the company’s oncology group had suffered other failures.  Sanofi was also reluctant to deal with an often contentious group of TargeGen investors (who had a continuing interest in the drug). All that plus the absence of a well-funded alternative kept fedratinib in the closet until 2016.   Hood — who had started a new company after Sanofi bought out TargeGen in 2010 for a reported $635 million  — cut through the confusion. He put up $250,000 of his own money for an option to acquire the rights to fedratinib provided he could raise $5 million within the next 90 days.  A Belgian group came through with the cash.

  The deal had been struck.  Impact Biomedicines — co-founders Drs. John Hood and Catriona Jamieson —  had acquired the rights to develop and market fedratinib worldwide. Sanofi got a 10% stake and the TargeGen investor interests were protected by Fortis, a third party shareholder representative company.

Maybe the most shocking finding of all in this Keystone Kops Klinical Trial:  It was all a mistake. Sanofi called it quits because of a diagnostic failure. Except for one patient, in very bad shape when she entered the trial, Wernicke’s encephalopathy probably didn’t even exist in that whole 800 person trial cohort.  In any event,  fedratinib at clinical doses has been decisively proven not to contribute to neuropathy.  Once the new company presented its independent findings, the FDA clinical hold was lifted

Despite Sanofi’s panicked response to the FDA clinical hold  — and its claim to have consulted with “expert neurologists and neuro-radiologists” — MPN investigators discovered Wernicke’s encephalopathy (WE) does not result from fedratinib clinical dosage.   At ASH 2017 Drs . Catriona Jamieson, Claire Harrison et al. reported on an independent panel reviewing the eight cases of suspected WE.  Looking at clinical records, autopsy reports and MRIs, the panel concluded the rate of WE within the trial cohort was far less than the general population. Moreover laboratory and in vitro testing demonstrated fedratinib would not prevent uptake of thiamine in mammals.  (The poster, below, reflects full data and discussion in the abstract, linked here.)

Wernicke’s, hard to diagnose, clue to chemo brain?

WE results from a thiamine deficiency. “We call it chemo brain,” said Jamieson, ” but these are likely effects of thiamine deficiency and our clinicians should be monitoring thiamine levels in all MF patients.  Among cancer patients, WE rates are as much as 10 times higher.  Hood agrees. “They call it chemo brain.  I think we have to get rid of that term and ask what is making people confused? We used to say it was cytokines but now I am thinking maybe people have lower thiamine levels. And monitoring of thiamine levels is a cheap and easy means to prevent the kind of confusion often associated with MPNs and other cancers.”  Drs. Ruben Mesa, University of Texas, San Antonio  and Dr. Claire Harrison, whose MPN practice at Guy’s and St. Thomas Hospital in London does regularly monitor thiamine, are not so sure. “We do regularly check and have not seen low levels of thiamine in our patients,” said Harrison

Fedratinib: Portrait of a Jakafi Killer?

It will be awhile before we know for sure how fedratinib performs head to head against Jakafi (ruxolitinib). On most markers in clinical trial the two drugs seem to be about equally effective in addressing MF symptoms. We have seen how Jakafi generally becomes ineffective after a time in large segments of the patient population. “I think we’ll see fedratinib as a second line drug in the beginning,” said Harrison.

Anemia and low platelets are side effects in both, although severe GI symptoms — vomiting and diarrhea — contributing to weight loss and nutritional deficits are a federatinib issue alone. “By reducing the clinical dosage to 400 mg, ” said Hood, “and changing the dosing protocol I think we have that under control. In clinical trial fedratinib was provided under fasting condition. Simply taking the drug at night, with food and providing Dramamine and immodium when necessary seems to have resolved the GI impacts. ”

We anticipate release of federatinib in early 2019,” said Hood. “We have access to the full Sanofi dataset from their years of clinical trial and won’t have to go through that. And we’ve cleared the WE FDA clinical hold hurdle. But first we have to remanufacture and get stability on the drug. So we likely can’t file the NDA (New Drug Application) until middle of 2018.”

Is federatinib superior to ruxolitinib (Jakafi)?

It’s understandable for Hood and Jamieson to be enthusiastic about federatinib. They were involved with the drug from the very beginning and fought hard and successfully to bring it back. There is no doubt about fedratinib’s efficacy but there has yet to be a head to head comparison with ruxolitinib. There could be no better objective referees than the two MPN specialists who were principal investigators in both the COMFORT (Jakafi) and JAKARTA (fedratinib) clinical trials, Dr Ruben Mesa, oncology chief at the University of Texas, San Antonio, and Dr. Claire Harrison, Guy’s and St. Thomas Hospital,

“We clearly need an alternative to Jakafi,” said Mesa, “but one common challenge with new drugs is physicians are more comfortable treating with a drug with which they have five year’s or more experience.”

“What we can say is over time federatinib without question would be a second line therapy for people who are not having an optimal response to Jakafi”,  said Harrison.

“When drugs aren’t compared head to head,” said Mesa, “it becomes a struggle to establish a clear difference, whether one is better than another in specific cases. I am sure both companies will try to put their spin in either direction but over time there will be clinical trials comparing the efficacy of the two drugs in comparable patient populations.”

And a possibility for AML

Federatinib targets JAK2 and another tyrosine protein kinase, the  FLT3 gene. Mutations in FLT3 cause constitutive kinase activity promoting cell proliferation and resistance to cellular death (apoptosis) via the activation of multiple signaling pathways.  Currently, there are no FLT3 inhibitors approved by the FDA in the relapsed or refractory setting. One fedratinib clinical trial under consideration by Impact Biomedicines is efficacy against this mutation in a FLT3 mutated setting.

With hope, a clear warning for MPN patients.

The Sanofi SAR302503 fedratinib trial stands as a stark warning to patients.  Promised continuing access to the drug if it proved effective, seriously ill patients were instead turned out in the cold without any advance warning as Sanofi’s oncology management team responded to an FDA clinical hold.   We count on rigorous oversight by Institutional Review Boards, by Principal Investigators and on-site clinicians and by the FDA.  In the absence of a Patient Advocate at the trial site, clinical trials are at best human experiments in which human desires for successful outcomes prevail.  The shredded safety net that was the Sanofi trial bears mute testimony to the dangers patients face in entering clinical trial.

A better reporting and information management system might have given the principal investigators a chance to investigate these neurological disorders, cases of alleged Wernicke’s encephalopathy.  And a more closely monitored clinical oversight of patients might have avoided the nutritional deficits arising from severe gastrointestinal events.  And — mostly — a more reasoned, transparent review beyond one hectic weekend behind closed doors might well have helped 800+ patients and prevented years of work and hundreds of millions of dollars from being flushed down the tubes.

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PRODUCTION NOTES & ACKNOWLEDGEMENT

In reporting this story we relied on documents and Skype interviews with individuals key to the future of federatinib:  John Hood, Catriona Jamison, Ruben Mesa and Claire Harrison.  The latter three are world-famous MPN specialists, clinicians, researchers  and John Hood, an original TargeGen scientist, and co-founder of federatinib, is the CEO of Impact Biomedicines the company bringing federatinib to market.

I had booked those interviews before I knew how sick I had become. By the time ASH rolled around I was chemo’d out, skinny ugly and grounded by my doctor despite recent transfusions. One of the bright MPN lights, Marina Sampanes Peed, lives in Atlanta. She’s a stem cell transplant survivor and a buoyant presence on social media. She’s also smart and a dynamite writer.  We figured we could work on this story together.  Which is how she acquired her first press credentials and got to hang an ASH PRESS shingle on a lanyard around her neck

She was in Atlanta, I was back in Asheville and we were both, briefly,  in a world of ice and snow. Beyond Skype conversations and remote connections, there are key documents presented at ASH, posters and abstracts and papers, linked in this MPNforum story.

Ruben Mesa and Claire Harrison are authors on that fedratinib paper and poster at ASH. They both had been Principal Investigators, active in both Incyte’s ruxolitinib COMFORT trials and Sanofi’s JAKARTA trial of federatinib.  Their data, methodology and conclusions reviewing toxicity of federatinib are in the abstract and poster. Bottom line: fedratinib is safe.

Those are the experts and documents used to pull together this story. And then there’s all the behind the scenes backstage work that goes into even something as simple and non-commercial as an MPNforum story.

While I was recording those Skype sessions,  Marina was setting up video and photo camera angles and getting her own fix on things. You can see her barge into a frame or two of a Skype test interview. She took that photo of the Skype convo from the perspective of the interviewees.  Marina  worked with Cammy Duong, the Impact Biomedicines PR person from Boston, to make it all come together. And she took that chilling cover photo of Atlanta under ice. Her taped interview brought Dr. Richard T. Silver from Atlanta to our pages. He’s always really worth listening to. Thank you, Marina.

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