Science & Medicine

Momelotinib – “Things are very good.”

Is momelotinib’s proven power to knock out anemia going to be enough to earn a place in the lineup?

Momelotinib has been around.  In the early days of JAK-Stat discovery, Andrew Wilks PhD, working at the Ludwig Institute for Cancer Research in Melbourne, founded  Cytopia. There he worked on the molecule soon to be born as CYT-387.  Its first clinical trial was in 2009.

In JAK inhibition terms Momelotinib is an old, well-traveled molecule with a passport stamped originally in Australia (Cytopia) and then Canada (YMI Bioscience) before Gilead brought it to the United States in December 2012 with a half billion dollar payout.That’s when CYT-387, with those three  national stamps on its passport, was re-branded as momelotinib,  Throughout its clinical trial history, momelotinib has exhibited a near maddening spectrum of results from high effectiveness to unacceptable toxicity. Promise of an anemia benefit and inhibition of the JAK2 mutation equal to Jakafi’s swirled around its clinical trials…along with reports of toxicity and lack of efficacy. In 2014 MPNforum published an overview of the lagging development of the drug while in Gilead’s hands along with a history of its rocky road to approval.

But there is strong incentive to persevere.

Despite its blockbuster position as the only FDA approved drug for myelofibrosis — and its demonstrated ability to shrink enlarged spleens and improve patient Quality of Life — Incyte’s Jakafi has a few striking weaknesses.  It’s not generally available to patients with uncontrolled anemia and it drives down platelet levels. But mostly it’s something else.

Eventually, if you’re on Jakafi, you know it’s likely to fail.   What happens then?   You rely on this drug for life support, your sole relief from the impact of myelofibrosis, and suddenly it’s gone.

Ask Louise Haugh.  

“I was one of the first on Jakafi, starting in February 2011.  I went  down to Incyte and was very lucky to speak with a lot of people.  I still talk to Incyte people. I love them all, they saved my life for awhile.  I had a good life as a realtor for 25 years,  out among people. I loved what I did until my legs quit working and I could not cover the sites. ”  We asked her how she knew her long-term use of Jakafi wasn’t working anymore.

“I knew because I was having transfusions every four weeks, my spleen was huge.louise-haugh I just felt like I was going to die.  I did nothing, sat on a chair and slept most of the time. I used a local cancer center but got so scared I went to Penn State Hershey for a second opinion.

My hemoglobin was 7.0 , bounding around 7 for nearly a year, and my platelets were down to 54.  I was really tired,  When I went to the ER for a transfusion, the doc on duty never heard of my myelofibrois.  It’s not cancer girl, who put that idea in your head.  Eventually I saw Dr. Winton.

“The doctor at Penn State Hershey didn’t have any trials just then but he suggested I go down to Baltimore to see Dr. Carole Miller. She was an investigator on a trial  for a drug called momelotinib. To participate I had to prove Jakafi no longer worked.

” I went down two times to get on to the trial.  She talked with me told me about the trial and then I had to qualify. Two weeks later I was back but my blood was too low. I had to have an immediate transfusion so I went from her office to Hershey Medicine. The next day I went back down to Baltimore, and was enrolled in the trial  because my blood levels were  high enough. I was the last person enrolled in that trial at St. Agnes.

“The day I started the trial I was still on Jakafi.  I went from Jakafi to momelotinib and stayed down there for the entire day as they took levels. I stayed until late in the evening  When I drove home it took a little over three hours and  I did get sick. I had to pull over and I was nauseated.

“After that I saw Dr. Miller  every two weeks for the first three months  then I went every month. Now it’s just every three months.  And I’ve had no transfusions since being on momelotinib.  My spleen isn’t visible but sometimes I can feel it’s still there. My counts are excellent, hemoglobin 11.7, platelets 116, hematocrit 35.7 and I feel great. Except I feel so sad for my MPN friends, my heart is breaking for them.  We’ve been going through this together over the years and now I’m doing so well,

“What’s my future like?  We don’t know about the future. My cost of drugs with Jakafi was $160,000 . I was able to cover it with insurance and.Incyte Cares.  Right now momelotinib is free but when the trial ends… what is it going to be?”  [Louise, like Diane, below,  is on the Phase 2 momelotinib trial scheduled to complete data accrual in August, 2017]



The very first patient to be enrolled in Dr. Carole Miller’s momelotinib trial at St. Agnes was Cure Magazine’s MPN Hero Diane Womack Blackstock, founder of the popular Myelofibrosis Private Support Facebook group. She had been through two major JAK inhibitor trials before landing in the momelotinib trial.

Diane Blackstock and husband, Don

Diane Blackstock and husband, Don

“I was on Jakafi (in trial) for a little over 2  years (20 mg x 2 for 4 months, 15 mg x 2 the rest of the time). I needed 2 transfusions and anemia went from HGB of 11 to between 8 and 9 the rest of the time   My PLTs dropped from 450,000 to 89,000.

“My spleen originally shrank from 27 cm to 20 cm, but that only lasted about a year.  It was around 25 cm when we stopped Jakafi for Fedratinib.  I also gained 50 lbs and became diabetic and was hospitalized with a COPD attack. I also had terrible sores on my abdomen.

“Then we switched to Fedratinib for 8 months.  I needed 2 more transfusions only 6 weeks apart.  The spleen was down 2 cm to 23 cm. I was able to lose 45 lbs but still had the sores.  Again my HGB was below 9 the rest of the time.  When that trial closed, I went back on Jakafi at a lower dose, 10 mg x 2 p/d for 8 months while waiting for the phase 2 momelotinib trial to open.  I was the first person to be enrolled in the cohort at St.Agnes

“When I started momelotinib on July 25th 2014, my life improved.  After just 2 weeks the sores cleared up, and my HGB rose to 11.  My PLTs also rose to about 120,000. Within a month or two my HGB, HCT and PLTs were all in low normal ranges.  My WBCs went up a little but never went higher than 23 and settled around 17.  No blasts have shown up in peripheral blood draws for over 6 years.  (I had 1-2% blasts in 2009)

“ I still have fatigue, but not that short of breath feeling that was so severe when I was at a HGB of 8.5 or below.  My weight has been steady and my spleen fluctuates between 23-25 cm but it isn’t as wide and rarely hurts.  I only see the doctor every 3 months now.  My PLTs fluctuate.  They went over 200,000 briefly, but average between 117,000 and 159,000.

“From those I have talked to who were on it when it was CYT 387, it seems to work for about 5-7 years.  I really hope that will be true for me as I feel sure we will have a better med or combination in the next 3-5 years.

“I am in no hurry for it to be approved for my sake, since it is free while in the trial, but I wonder how many others might benefit who won’t consider a trial.  I also would like to see combination trials with it since I don’t have anemia or sores while on it.  I find it pretty amazing that we haven’t gotten even a bone chip sample from my BMBs for 4 years because my reticulin & collagen fibrosis is so severe, yet most of my counts are in low normal range.

“I’m feeling quite blessed….”

That’s a patient’s perspective.  An ASH single site investigator report reveals earlier data on efficacy and survival.

ATefferi videot ASH on Monday, December 5, four years after Gilead’s half billion dollar investment, Dr Ayalew Tefferi (Mayo Clinic) presented the clearest objective assessment to date of  the earliest momelotinib dosage and toxicity trial.

His paper “Momelotinib Therapy in Myelofibrosis: 6 years follow-up Data on Safety,, Efficacy and the Impact of Mutations on Overall and Relapse-Free Survival (Abstract 1123). His data was taken from the Mayo Clinic’s cohort of 100 patients in the Phase I/II Cytopia CYT-387 trial, November 2009-November 2010.


Tefferi’s report underscores momelotinib’s mixed record on trial.  His results may be both encouraging and sobering but have only limited applicability to contemporary patient outcomes.  His study is based on the earliest Phase I dose and toxicity trial  during the 2009-2010 period. At that time a safe, tolerable and effective dose had not yet been determined. And although we don’t have full baseline data to assess the condition of participating patients, in that pre-Jakafi era there were no FDA-approved drugs to slow or ease the impacts of myelofibrosis, As a result we can assume a number of patients enrolled in that clinical trial (NCT 00935987) were at end stage disease.

Tefferi reported in a median 3.2 year period, of the 100 patients reviewed, 70 died and 14 advanced to acute myeloid leukemia. Of the 30 living patients, 12 remained on the CYT-387 study and five opted for a stem cell transplant.   More revealing might be the report’s efficacy totals. About half of all 100 patients on the trial showed clinical improvement (57%), anemia improvement (44%), spleen response (43%) and 57% of all those who were transfusion dependent when they went on trial became independent.

Here is his concluding statement: “Momelotinib therapy in MF patients provides effective palliation in terms of anemia, splenomegaly and constitutional symptoms,. However, less than 20%of treated patients enjoy durable long-term benefit and almost half experience drug-related and mostly irreversible peripheral neuropathy. Long-term survival and durability of response were superior in patients with type 1-likemutations and inferior in those with ASXL1/SRSF2 mutations or unfavorable karyotype.

Hepcidin — the secret sauce in momelotinib.

Gilead, according to a company spokesperson, is taking its momelotinib clinical trial results to the FDA to “discuss next steps.”  By the summer of 2017 we’ll begin to have the results of this current transfusion-dependent study and can expect a report at ASH 2017.  Whether or not results are robust enough for Gilead to proceed with an application for FDA approval, some underlying science is likely to percolate into myelofibrosis therapy. Like expanded understanding of hepcidin.

The little known hormone, hepcidin, is responsible for our iron metabolism.  Hepcidin regulates dietary iron absorption from the gut, controls iron recycling from dying red blood cells, and manages iron transport from hepatocytes into plasma for blood production.  It’s the body’s traffic cop to keep our RBCs iron rich and hold anemia at bay.

Saturday morning, at the San Diego Convention Center, Gilead scientists Matthew Warr et al,  presented a paper:  “Preclinical Modeling of ACVR1- Dependent Hepcidin Production and Anemia bymomelotinib-ash16-poster Momelotinib.(Abstract 1967)”

The key finding: Block the enzyme receiving the hepcidin hormone and you improve anemia,  A kinase is a receptor enzyme that enables a process. That ACVR1 is a bone receptor kinase — ActiVin A Receptor type 1 —  key to regulating the production of hepcidin in  liver cells (hepatocytes).  Block ACVR1and you increase the release of iron locked up in cells and stimulate production of red blood cells. The Gilead paper demonstrates that, in their rat study,  increased dosage of momelotinib increases inhibition of hepcidin and improves anemia.

It’s a finding sure to impact MF drug development as anemia and RBC transfusion dependence are a debilitating hallmark of advancing myelofibrosis.

Whether or not momelotinib will be able to capitalize on its scientific efforts remains to be seen.

Is momelotinib going to be the next JAK inhibitor approved for myelofibrosis?

” We certainly need something says Dr. Carole Miller, carole-millerdirector of The Cancer Institute, St. Agnes Hospital/ Ascension Health in Baltimore. “It may not change the progression of disease or change the marrow fibrosis, but it can make a difference in quality of life and possibly longevity.

“We see it in MF patients entering clinical trial today.  In my experience,these patients on the momelotinib trial are generally not as sick because while they have failed Jakafi, they are generally starting on second line therapy before they are allowed to get as sick as patients were before the initial Jakafi trial.

“Given this, second line drugs in this disease have had a harder path to approval,  When Jakafi fails we clearly need a backup and I think at this point momelotinib is further along that path.”



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Comments on: "Momelotinib – “Things are very good.”" (1)

  1. Richard Mentzer said:

    Excellent article. I’m a Myelofibrosis patient still trying to get the right JAKAFI balance. Now better understand where in my progression I might benefit from momelotinib.

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