MPNforum Magazine

The Attack on Jakafi

by Zhenya Senyak

While medical technology advances in quantum leaps, we still pretty much treat complex illnesses the way we did in ancient times.  We relieve symptoms rather than tackle causes which often prove elusive.

Targeting myelofibrosis

Ruxolitinib, one of the genetically designed drugs targeting a mutation often present in myelofibrosis, has been effective not because it affects the disease itself, but allays the symptoms.  In MF, one of the more complex, rare and uncharted diseases, the accumulation of fibrosis in the bone marrow replaces the blood producing cells and a cascade of events follows.  Anemia and its attendant severe fatigue, is common, as is bleeding as platelet production drops.  As blood production moves out of the marrow cavity, the spleen begins to swell, crowding organsm  reducing appetite contributing to general wasting and weakness.

The discovery of the JAK2 mutation in MPNs in 2005 presented a likely target  for  drug development.  The Janus Associated Kinases, by signalling cytokines and growth factors,  are active in hematopoiesis as well as certain immune functions.  Inhibit their action, turn off the switch, and the proliferating blood lines might  calm down.

By May, 2007, Incyte-sponsored  Phase 1/2 clinical trial of ruxolitinib, a protein kinase inhibitor, opened in the US and, shortly afterward, Europe.

One fact emerged quickly. Ruxolitinib could indeed  inhibit expression of the  offending JAK2  — possibly JAK 1 as well  — without much affecting the concentration of the mutated clone in the patient’s blood. And, in many cases, the drug proved equally effective in significantly reducing spleen size and other symptoms even in those MF patients who didn’t have the JAK2 mutation.

For patients, the worsening of anemia and further reduction of platelets (thrombocytopenia) were notable, and generally manageable,  effects. The reduction of spleen size and vast improvement in quality of life tilted the risk/benefit calculation in the drug’s favor.  In 2011, ruxolitinib was approved by regulatory bodies for use in the United States and Europe and marketed as Jakafi. But the path to patients would not be easy.

It’s an old and documented complaint.

High-powered, international research and clinical trial is expensive with hundreds of millions of dollars pouring into medical and research centers for a single drug.   Sometimes, those who take large amounts of money from drug companies to perform research and clinical trials, are biased, act dishonestly, falsify data or otherwise put their patients at risk in pursuit of profit and self interest.

 But this is not a story about that kind of thing.  This is about the other side of the coin, about the corrosive effect of undermining our confidence in our doctors, institutions and our meds. There are MF patients living with painfully big spleens today because they or their physicians doubt the safety or efficacy of Jakafi.

Last week,  presentations on Jakafi at the meeting of the American Society of Clinical Oncologists (ASCO) were characterized as “..the expected relentless effort by the drug companies and their sponsor-friendly colleagues to undermine important patient safety concerns….”

These aren’t the observations of a wild-eyed radical or a cynical consumer.  This is the considered judgment of a respected hematologist and professor at a pre-eminent American institution, a man renowned for his research and compassionate patient care: Ayalew Tefferi of the Mayo Clinic.

Unnamed, but clearly one of the drug companies in the cross-hairs of his remarks:  Incyte Corporation.  And those “sponsor-friendly colleagues?” If they’re not those doctors  who performed the Incyte-sponsored research — and presented posters and  Jakafi clinical findings at ASH and at the ASCO meeting —  it’s hard to imagine who else they might be.

 So the first question we as patients need to ask ourselves is this:  Are these doctors — some of them our physicians or personal friends –really making relentless efforts to undermine patient safety concerns”…or is that  characterization just hyperbole in support of Tefferi’s serious concerns?

Here are Professor Tefferi’s complete remarks in context, submitted in response to our request for clarification of his position on Jakafi now that the results are in. (We have his permission to quote him verbatim.)

“Facts do not change with time. My views on ruxolitinib and other JAK inhibitors are based on facts from clinical trials and personal experience in using these drugs and they are comprehensively outlined in my recent reports in NEJM, Blood and  the Mayo Clinic Proceedings  Nothing has changed since other than the expected relentless effort by the drug companies and their sponsor-friendly colleagues to undermine important patient safety concerns and the therapeutic limitations of ruxolitinib. I, for one, have no interest in being a pharmaceutical sales scout and would rather spend my time and energy to seek new and better drugs for my patients. I am old enough to have seen a similar scenario in the past with the use of anagrelide in ET and PV.”

The media continues to be the message

Dr. Tefferi is recognized as a strong and frequently outspoken patient advocate, a deeply compassionate God-fearing man.  He has a large and loyal following of patients and colleagues.  His warnings and stormings can be fruitful in stimulating discussion and calling attention to potential health issues.  But in this case his actions may have unintended consequences.

It has been nine months since Tefferi first publicly voiced his concerns about Jakafi in a letter to the New England Journal of Medicine .  Reviewing outcomes for 51 Mayo Clinic patients who participated in the early ruxolitinib Phase 1/2 dosage and toxicity clinical trials over a period of 17 months — starting October, 2007 —  the data he saw was startling.  Anemia, sharp drop in platelet levels, and serious adverse affects including withdrawal symptoms.

Both the nature and size of the sample he relied on to make his case and the place and timing of its publication caused some dismay within and beyond the medical world.  Tefferi’s NEJM letter was published after the successful ruxolitinib Phase III trials , just weeks before Jakafi’s FDA approval and subsequent distribution to MF patients.  (Incyte stock declined 6.8% immediately after publication.)

Since then, Dr. Tefferi has  published  several other high profile papers and letters in the same vein.  Last month, again in the NEJM where he concludes rather than seek symptomatic relief through ruxolitinib,  patients would be better off entering clinical trial in hope of finding a better drug!  

For patients, this is deeply discouraging to read. What point is served by the lengthy clinical trial and FDA approval processes if, at the end, we’re told to take our chances on another and  unproven drug?

It will likely be many months before another drug is rigorously tested and approved.  Are we supposed to wait, or enter a risky experimental clinical trial, or can we trust our doctors who prescribe the FDA/EMA approved  Jakafi, proven over five years of intensive worldwide clinical trial?  

Why the New England Journal of Medicine?

Disputes over data interpretation or differences of opinion are a healthy, vital component of professional medical discourse and regularly take place at conferences, universities, medical centers and in the pages of specialized journals  But to escalate the volume and extend the contention into the public sector through the NEJM drags untrained patients into the discourse.

 The NEJM, the largest paid circulation among medical journals, has over 200,000 subscribers with selected translated articles targetting 140,000 physicians in China.  The online NEJM  “reaches between 300,000 and 400,000 readers each week…. Studies published in the Journal receive extensive coverage in the news media worldwide, reaching millions of additional health care professionals and patients each week.”

As one of the most published and honored figures in hematology worldwide, Dr. Tefferi’s objections quickly trickled down through consumer publications, social media and word of mouth.   One result: For some seriously ill, at-risk myelofibrosis patients, and their personal physicians,  Jakafi has become either a game-changing lifeline or a dangerous life-threatening gamble.

What does the data say?

As patients, we need to clear the air of confusion.

(1) Either Jakafi is a good option for us under some circumstances, or not.   

(2 Either our physicians are concerned about our health and safety or not.  

(3) Either the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have fairly evaluated robust data prior to approving this drug, or not.

What we think we know for sure about Jakafi…

Based only on proven claims, Jakafi  will not cure MF,  will not stop the progression of the disease and will likely contribute to thrombocytopenia (platelet reduction) and anemia.

But the wonder of Jakafi  is – in most cases —  it will rapidly and significantly reduce the size of our swollen spleens, improve MF symptoms across the board along with our quality of life and produce a durable response.  It is relatively safe. The jury’s still out on life extension benefits, but there are promising indications resulting from the  COMFORT crossover data. (See Verstovsek”s Therapeutic Advances in MPNs, this issue for data on safety and longevity.)

There is no other drug, JAK inhibitor or not, available to us now with any of that power.

Conclusion:  Jakafi is clearly a good option for us under some circumstances.  (Dr. Tefferi agrees with that conclusion…but he would severely limit those circumstances.)

Dr. Tefferi is passionate enough  about patient safety to have repeatedly voiced his concerns over attendant health issues.  But, as patients,  we too are concerned.  And so, we would like to believe,  are our doctors and the ruxolitinib clinical investigators. .

Finally, we know that independent and highly respected research groups in major American and European medical centers have generated reproducible, statistically significant data from long and painstaking ruxolitinib clinical trials, including the large scale double blind gold-standard COMFORT Phase III trials, before publishing their peer-reviewed reports.

 Dr. Tefferi is right. Our views, as patients, should be  based on facts. In addition to the data published by Dr. Tefferi, here are the facts presented at ASCO, including the poster specifically addressing his concerns. That poster is signed by 19 world-class colleagues.

In this issue, we’re also presenting the full 27-slide educational presentation given by Dr. Verstovsek at ASCO in Chicago last week and short notes from him on how he would treat anemia and thrombocytopenia.  We are also linking to  articles mentioned by Dr. Tefferi in his e-mail so we can  judge for ourselves, as patients,  our best options in light of all current findings

Documentary evidence:   Finally, we’re publishing Dr. Jason Gotlib’s comprehensive  PowerPoint presentation What We Know about Myelofibrosis delivered  at the MPN Research Foundation’s meeting in San Mateo, California two weeks ago.

Dr. Gotlib’s views are  well worth knowing since he is principal investigator on  YMBioscience’s CYT387 (Cytopia), another JAK inhibitor in clinical trial — a drug for which Dr. Tefferi is  the Study Chair —  and he is a ruxolitinib clinical trial principal investigator at Stanford.

As journalists, we cannot select between alternative professional opinions about a drug’s efficacy. Our job is to present the current state of knowledge of our difficult and sometimes intransigent MPNs to patients and caregivers.  As patients we need to be fully informed to participate meaningfully in our treatment.  We need all the clarity we can get, all the light of open fact-based discussion…and none of the heat.

We’ve reported results and published graphs and tables submitted to the FDA  for Jakafi in the past.  Here now  is ASCO  Poster 6624  presented just a week ago  in Chicago, “Adverse Events and the Return of Myelofibrosis Related Symptoms After Interruption or Discontinuation of Ruxolitinib Therapy.” specifically addressing Dr. Tefferi’s concerns.  Because of size constraints, it’s difficult to read  however the findings are covered in Dr. Verstovsek’s slide presentation and Dr. Gotlib’s PowerPoint presentation.  You can however click on the  poster graphic to easily see the main points and the names of those who co-authored this report.

The bet of a lifetime

As patients we deeply and truly appreciate Dr. Ayalew Tefferi’s efforts to advance our knowledge, discover therapies and protect our safety. I don’t know all the hematologists who support the COMFORT findings on Jakafi.  I’ve talked with some, exchanged views with many and know several personally. I would bet my life they wouldn’t knowingly endanger our health.

In fact, as patients, that’s exactly what we do.

Take me back to the Contents

© Zhenya Senyak and MPNforum.com, 2012. Unauthorized use and/or duplication of this material without express and written permission from this blog’s author and/or owner is strictly prohibited. Excerpts and links may be used, provided that full and clear credit is given to Zhenya Senyak and MPNforum.com with appropriate and specific direction to the original content.