Has Momelotinib run out of time?
It took me 32 minutes exactly to make it from the Stanley Hall parking lot opposite the Greek theater in Berkeley down to the Moscone Center Press Room. That meant driving at speed across the Bay Bridge, weaving through downtown San Francisco traffic to the colossal 5th and Mission parking garage and then schlepping a quarter mile carrying papers and recording equipment against a tide of suited rushed hematologists and a herd of idling chartered ASH buses.
Get the picture? This 11:30 AM, Monday, December 8 meeting was not something I was going to miss.
For two years, I have been trying to track down the fate of CYT-387, a JAK inhibitor developed by an Australian company, Cytopia, before being taken in hand by Canada’s YMI Bioscience in 2009 with a $14 million merger offer.
The drug completed its Phase II trials showing good efficacy, spleen reductions, and an anemia benefit with little or no thrombocytopenia, factors that had limited therapeutic applications of a competitive drug, Incyte’s ruxolitinib.
The hope was CYT-387 would an effective, affordable alternative to high-priced Jakafi.
I was with YMI’s James Smith in Atlanta ASH two years earlier when the acquisition of his company by Gilead was announced for nearly $500 million. At the time, CYT-387 looked like a real contender in the JAK2 Derby as Gilead announced the start of Phase 3 trials for the drug would start in the middle of 2013. It was interesting.
And it was personal. Two of my friends were dropped from that CYT-387 trial as their MF progressed to AML. They did not survive. But some good provisional results, symptomatic relief, had been reported in MPN social media along with neuropathies of varying severity. Gilead was reluctant to set up meetings in New Orleans so clearly access to scientists and investigators would not be easy. For over a year, little was heard from Gilead and its JAK inhibitor drug now renamed Momelotinib.
So getting a confirmed meeting with the Momelotiib project director, Dr. Susie Jun at San Francisco ASH was worth the mad dash across the Bay. I asked David Wallace. Editor of the PV Reporter, for back up in case I couldn’t make it on time and he attended the meeting as well.
By now, except for Pacritinib’s well traveled molecule Gilead’s Momelotinib might have qualified for the Guinness Book of Records for having changed more hands, in more continents, over a longer time than any other blood cancer drug without yet producing a prescribable product. And still, today, completing Phase III trials and bringing this drug to market seems to be proceeding at a glacial pace.
While Gilead struggles not to become irrelevant in face of an aggressive competitor which owns the JAK2 MF market, the obstacles seem nearly insurmountable. The primary problem: Finding new MF patients to participate in its Phase III clinical trial.
Dr. Susie Jun disagrees. Jun, a “hematologist/oncologist by training with Gilead for a couple of years” in the clinical research group, should know. “I basically lead the project team, lead the whole program.” Dr. Jun was appointed project director shortly after Gilead acquired YMI in December, 2012.
The big trial, Momelotinib vs. Ruxolitinib, head to head (NCT01969838) has an international recruitment target of 420 subjects in “about 200 sites.” So far 54 patients have been enrolled in approximately 15 active sites. That’s fewer than one-third the number YMI enrolled in its completed Phase I/II studies for the same drug four years ago. (Gilead is also recruiting for a smaller clinical trial, NCT02101268 to measure relative effectiveness of its JAK inhibitor in primary and secondary MF patients who are anemic or thrombocytopenic. That one is a Momelotinib vs. Best Available Therapy Phase III study.)
In spite of the two year lapse between completion of YMI’s legacy studies and the reporting of no new data. Jun believes Gilead has acted in all speed, rapidly opening Phase III trials. One major obstacle: Patients previously treated with a JAK inhibitor are barred from participation in the trial. In this post-Jakafi era those patients aren’t easy to come by.
”We just have to wait,” says Jun. “We wait for the newly diagnosed patients. The physician has to decide the patient is a good candidate for JAK inhibitor treatment. It’s hard to find myelofibrosis patients in the West who have not yet received a JAK inhibitor.”
Another reason for delay is an inexplicable lack of ruxolitinib. According to Dr. Jun there has been a delay in shipment of ruxolitinib causing Gilead to shut down further patient accruals for this trial until March, 2015. (We were unable to confirm any shortage of ruxolitinib from any independent source.) “We placed an order. There was a delay in delivery,” is all Gilead would say.
To further delay patient accrual in a trial that is already behind schedule — estimated primary data complete data is June, 2016 – even as the MF JAK inhibitor available market shrinks– cannot be good news. Jun believes there are offsetting factors.
Momelotinib has been shown to be equally effective as ruxolitinib without the requirement for dosage adjustment due to adverse anemia effects. And the study is open to transfusion dependent patients. As to why a drug so similar to ruxolitinib, targeting both JAK1 and JAK1, should not have these adverse effects, Dr. Jun frankly admits, “We don’t know what the mechanism of action is. We’ve been studying it.“
There might be a tradeoff for the anemia benefit.
“The ability of momelotinib to improve anemia in PMF patients clearly distinguishes it from the other JAK inhibitors,“ writes Dr. John Crispino in the MPN Research Foundation report on ASH. “…the drug treatment is associated with the development of neuropathy…and [according to a poster presented by Dr. Ayalew Tefferi], drug discontinuation did not alleviate this side effect during the time of follow-up.”
A tough assignment
When Gilead took over, YMI didn’t have the resources to open a Phase III trial. It had a drug and Phase 2 data. To overtake Incyte/Novartis’ ruxolitinib, Gilead launched a COMFORT style Phase III trial, the kind of worldwide blitz that brought Incyte FDA approval at the end of 2011.
We can only conjecture. Gilead acquired YMI and CYT-387 at the end of 2012 when Incyte had just a one year lead in serving the myelofibrosis market. It may have looked like that market – and unrelated disease sectors dependent on the JAK-STAT pathway — were in reach. But it would prove not to be…at least not in the short term
Susie Jun and her team had a rough patch of ground to cover. Getting out of the starting box, launching its critical Phase III trial of Momelotinib, required analyzing legacy data, writing up protocols, opening sites, clearing various institutional and National regulations… and, hardest of all. recruiting patients. Most patients needing a JAK inhibitor were intermediate or high risk MF and many were already on the Incyte drug. And with FDA-approved Jakafi readily available, underwritten by insurance companies and Incyte, a patient’s incentive to take a chance on clinical trial was lowered.
Except for those who didn’t qualify for ruxolitinib.
And then, just one year after the Gilead acquisition of YMI, along came Gilead’s blockbuster Hepatitis C drug, Solvadi, which went on sale late 2013 in the biggest drug launch in history, booking over $9 billion in sales in its first nine months. That kind of distraction is likely to take the wind out of a minor league drug playing catchup in a small market segment.
Just thinking out loud. Why, two years after a successful Phase II trial, has this experienced, professional crew with near unlimited funding still not produced any new data, have no projected date of completion and is fielding an underpopulated clinical trial that was having trouble accruing patients even before the ruxolitinib supply foul-up.
Today, Momelotinib is treading water until March when it says it will once again begin recruiting for its Ruxo head to head trial. Meanwhile, Pacritinib is slipping up on the inside rail and Incyte is mopping up the market with combos and variations and outreaches. And a greater threat is looming. Both immunotherapy and gene editing are moving ahead at warp speed and seem likely to overtake Momelotinib/CYT-387 long before the drug clears regulatory hurdles.
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