Science & Medicine

Jakafi for PV- Hope or Hype?

— Zhenya Senyak

Jakafi’s push into the PV market wearing the Emperor’s New Clothes.

You know the story. An Emperor orders new clothes from a pair of scalawag weavers who claim they could weave the most magnificent fabrics. Cothes made of this cloth were not only beautiful but they would appear invisible to those unfit to wear them or unusually stupid.  And so of course the emperor struts about naked while courtiers admire his fine and colorful new robes.

Incyte’s heavily funded, aggressive, marketing campaign promoting Jakafi as a drug of choice for polycythemia vera, is based on a bizarre and deeply flawed clinical trial. With the support of investigators and willing media, Incyte hammers the message home.

CapeCod Arts

Got PV? Intervene with Jakafi.

.Worst of all, it works. The message is taken as gospel by doctors in the field.  It percolates down to the prescription pad in our doctor’s hand.  Incyte marketing impacts the fate of the MPN clone percolating in our bone marrow. 

The trial itself, RESPONSE, Phase III concluded in 2014.  To qualify for the trial patients had to be sick, with advanced PV requiring phlebotomies to manage hematocrit. And suffer from splenomegaly.  One more thing. They couldn’t tolerate hydroxyurea…or at least be resistant to it. They were divided into two groups, one got Jakafi the other got Best Available Therapy, a mixed bag of meds local investigators could theoretically prescribe.

In fact, however, 59%  of patients in the BAT arm, were given hydroxyurea…despite their known intolerance. Another 15 % in the BAT arm were placed on Watch & Wait, essentially observation.  These are patients who, on entering the trial, were on meds and required periodic phlebotomies.  With 75 % of these BAT patients getting essentially no therapy and the balance getting unproven alternates for their condition like interferon, anagreliede  and lenaliodomide., the results were a foregone conclusion. Jakafi patients did better on most scores. spleen reduction, blood counts.  And the Emperor took to the streets to brag about it to the applause of his courtiers..

This is only a partially applicable folk tale.  Jakafi may indeed confer short term benefit to PV patients who are resistant to or cannot tolerate hydroxyurea.  It’s good that we have it in our pharmacies. It’s not a cure.  It’s not going to be effective long-term.  It has side effects, both known and unknown,  And, in the United States, it costs about $13,000 a month.  FDA approval of Jakafi for PV application as a second line therapy makes it easier to get the drug covered by medical insurance.  But, like interferon and hydroxyurea, Jakafi was already available by prescription off label.  So the point of the RESPONSE “trial” appears really to be more economic than scientific.  And the fact that 112 patients had to suffer through the BAT regimen of this trial just incidental.  That may be the price of creating a drug that provides $1.3 billion a year in revenues to Incyte.

Our Patient Care study confirmed most of us are cared for by physicians or hematologists who don’t specialize in MPNs. A heavily advertised drug approved by the FDA and endorsed by a leading MPN specialist leads to Jakafi sales.  And expanded patient use

That the drug industry has seriously corrupted the American medical care system with its lavish distribution of funds and co-opting of investigators is no secret. It’s the subject of our lead article in this issue .  But our small MPN blood cancer backwater is uniquely dominated by a single company whose reach extends to physicians,  medical institutions, media, non-profits.

At ASH the kick off Cure Magazine MPN Hero event was conceived and is sponsored by Incyte.  One patient oriented media outlet streamed a video sponsored by Incyte featuring physicians funded by Incyte discussing means to extend the use of Incyte’s Jakafi through combo drugs.  And then on the exhibit floor of ASH there’s the blaring push to establish Jakafi as the go to PV drug.

It’s understandable the Incyte would make a strong bid for the PV sector of the MPN market. There are 10 times the number of PV patients as Myelofibrosis patients, a market segment Incyte already owns.  What is perplexing, however, is why so many trusted physicians, investigators and institutions jumped on board quoting the flawed RESPONSE trial statistics as justification.  (There is a new spate of longer term benefits attributed to Jakafi’ see links to abstracts, below.)

In an attempt to understand the willingness of so many skilled, smart and committed medical professionals to embrace the flawed RESPONSE trial in pursuit of expanding Jakafi’s access to PV patients, we turned to a key figure in the entourage.  Dr. Srdan Verstovsek. He was co-coordinator of the RESPONSE trial and one of its a principal investigators and has been engaged with Incyte and Jakafi for a decade or more

This then is the story of an academic physician at the heart of the controversy whose generous receipts from Incyte invite suspicion of bias. And of a clinical trial designed and executed to put Jakafi at an advantage over existing drugs.  And an MPN community of patients and caregivers seemingly at the mercy of a system swollen with cash.

When it comes to Jakafi for PV I am biased.

In an MPN world where we have so few meds to relieve symptoms it’s blessing to have Jakafi available to us. Certainly for myelofibrosis but even for polycythemia vera.when hydroxyurea fails, when interferon is not appropriate.  But Jakafi comes at a cost. Not only the $13,000 or so each month but at health costs, It is not a benign drug,  It places the user at risk for thrombocytopenia, anemia and neutropenia.  It impacts our immune system and serious bacterial and viral infections have occurred.

I have several biases around Jakafi, some based on demonstrable fact, some based in perceptions of corporate greed, and some based on seeing the drug work for friends…and dramatically fail. 

It’s hard to disagree with Serge Verstovsek.

For one thing, his MPN accomplishments are legendary

Srdan Verstovsek, MD, PhD

With thick white curly hair framing a cherubic face he’s faultlessly courteous and patient. His intellect is formidable and as director of the clinical research center for myeloproliferative neoplasms at MD Anderson, his clinical experience broad.

On top of all that, he’s tall. You have to look up as he leans forward to explain, in a slightly Slavic-tinged accent, the molecular basis of a process powering an MPN event.

More than that, Dr. Srdan Verstovsek is a friend and a teacher. He gave me my first MPN genetics lecture on a break at a CR&T meeting a decade ago. I’ve turned to him many times to discuss the implications of a scientific paper or ASH presentation. He has helped many of my friends through their MPN. He, along with the MPNRF, generously supported our CREATE CRISPR seminar encouraging scientists to bring gene editing technology to bear on MPN cure.

I respect him. I like him.  And I find myself sharply disagreeing with him.

The issue is the Incyte clinical trial, the RESPONSE trial, that resulted in Jakafi being approved for second line use in polycythemia vera. It happened four years ago and only re-surfaced when we started research for this Conflict of Interest story.

There are strong reasons to revisit this story in light of the Sunshine Act and the need for transparency in addressing potential conflicts of interest. Conflict of interest and its twin competing angels  — bias and transparency — may roll off the tongue but in practice poses issues of self deception and painful choice..

Fortunately, on the financial side of things, the record is clear and simple.

We need to clear the air.  The Sunshine Act and the Medicare/Medicaid Open Payments  system are well intentioned. A first step toward exposing the rot of financial corruption that eats at the foundations of the American medical care system.  But there’s a downside as well. Typing in a physician’s name and getting an instant printout of payments received,  invites suspicion of bias.

Why are these drug companies paying all this money to physicians who are prescribing their products, investigating their new molecules? Open Payments collects and publishes all significant payments made to US physicians by drug companies. The idea is “to promote a more transparent and accountable health care system” making financial relationships between medical suppliers and health care providers available to the public.

Simply looking at that raw financial data can easily have unintended consequences and lead to needless suspicion and mistrust. Or open a deeper exploration of the marriage of science and money..

The Physician, the Cash, the RESPONSE Trial

Srdan Verstovsek, MD., Director of the clinical research center for myeloproliferative neoplasms, MD Anderson,  has led research efforts in the large scale COMFORT trials that saw Incyte’s Jakafi approved as the first – and still only – FDA approved drug for control of symptoms and signs of myelofibrosis, . He has a large clinical practice, publishes often in professional and patient-oriented publications and is a featured presenter at medical meetings. He also appears to be the MPN specialist who is the single largest beneficiary of Incyte payments.

The environment in which he — and most of our docs — work is awash with money. Big Pharma shells out $8.5 billion annually to institutions and physicians to get its drugs through the pipeline and into the market? Most of that expenditure is for research associated activities but $3 billion is funneled to physicians as General Payments. (General Payments cover: consulting fees, speaking fees, travel and lodging, food, and in some cases fees paid to third parties on behalf of the physician.)

(Investigator- and institution-sponsored research are relatively exempt from the tsunami of cash lubricating the much larger drug development industry sponsored by pharmaceutical companies.)

$114,775: Disputed. Poorly designed trial: Disputed.

2014 was a big year for Dr. Verstovsek. The Novartis/Incyte RESPONSE clinical trial of Jakafi for PV was working its way through Phase IIl. including a $5 million+ effort at MD Anderson at which Verstovsek was trial investigator. He was also co-director of the RESPONSE study along with Incyte’s Mark Jones. That year, according to the CMS OpenPayment system,  Incyte made general payments to Verstovsek of $114,775. In December, based on the RESPONSE trial results, the FDA approved Jakafi as a second line med for PV patients..

But the numbers are distorted. Dr. Verstovsek never received a major portion of those payments.. Folded into General Payments charged to individual physicians are many payments made by Incyte to third parties.

For example: A payment made by Incyte to Verstovsek in the amount of $9748 is listed on OpenPayments as “Compensation for services other than consulting,” (ProPublica’s “Dollars for Docs” site lists that same payment as personal compensation for “Promotional/Speaking Other “ ) Another payment in the amount of $11,550 is charged to Verstovsek even though payment was made to a third party for editorial services. There are several other payments of greater and lesser amounts in the same category. These are funds he never received.

A spokesperson for Incyte confirmed the process through which payment to a third party for editorial assistance may appear as a general payment made to the investigator himself.  On OpenPayments itself, the detailed description provided by Incyte is specific: “These services were funded by Incyte Corporation and paid to a third party vendor to assist with the development of a publication at the direction of the authors. No payments were made directly to the authors for these editorial and or medical writing services.”

Even though this serious glitch in the raw OpenPayments data misrepresents funds directly paid to doctors by drug companies, that’s really beside the point.  On its own,  any reported amount would not indicate a financial conflict-of interest.  And in this instance it is obvious to anyone who knows Dr. Verstovsek that financial considerations played no role in his embrace of Jakafi. The reason he joined the Emperor’s parade in citing RESPONSE results may have come from other places. 

To him as to other MPN specialists, it was obvious polycythemia vera patients needed an option in the event of hydroxyurea failure. And he knew Jakafi’s capabilities could fill that need.

The more immediate and thorny issue may be bias.

The RESPONSE clinical trial, completed in 2014, was a major international clinical trial that resulted in Jakafi being approved for PV.

MPNforum reported on that trial at the time and considered it badly designed, essentially a stacked deck guaranteeing Jakafi’s superior performance over Best Available Therapies (BAT) for one simple reason. Results from the Jakafi group were compare with results from a group that received no or ineffective meds.

It is good that Jakafi is available to PV patients for whom other meds don’t work. There is little argument on that score. But the pathway to approval through a poorly designed trial contributing little to science — and much to the Sponsor’s bank account — might be cause to suspect a prevailing conflict of interest on the part of many.

AGAIN:  The RESPONSE trial results, Jakafi versus Best Available Therapy (BAT), revealed the majority of the BAT cohort (59%) had received hydroxyurea even though acceptance into the trial was dependent on those same patients being resistant to or intolerant of HU.. And a full 15% of that same group were simply observed. Thus, 75% of the 112 people in the cohort — 84 people in  the group, all PV patients with swollen spleens dependent on phlebotomy to maintain hematocrit levels, received “Best Available Therapy” that consisted of either no therapy at all or a drug known to be ineffective or worse.

It is based on that trial that the FDA approved Jakafi  in December, 2014.

Of course there’s a role for ruxolitinib in PV.  And there are drawbacks as well.  In his presentation at ASH, Friday, November 30, 2018, Dr. Richard T. Silver presented a series of slides (below) outlining some instances when Jakafi should be used in PV, known side effects of the drug, and how effective it is in treating  polycythemia vera.

Dr. Aaron Gerds notes the weakness of the clinical trial that resulted in Jakafi’s FDA approval. In his 2017 paper in Oncology: “Two limitations of RESPONSE should be considered further. First, eligible patients were hydroxyurea-resistant/intolerant; however, 59% in the BAT group continued hydroxyurea treatment “ however he seems to justify it based on historic practices when physicians continued to prescribe HU “despite diminished benefit because of limited alternative treatment options.”

True enough but the RESPONSE BAT patients did not just have “diminished benefit” from HU. They were selected based on being “resistant to or intolerant of hydroxyurea” and 15% of the others received nothing at all except a watchful eye.

Gerd’s other objection has to do with the required spleen volume of ≥450 cm3 potentially resulting in inclusion of MF patients inappropriately diagnosed with PV.

Setting up rapid spleen reduction as a trial endpoint is a bit of a straw man. Dr. Hans Hasselbalch also objected to the spleen measurement comparison in his letter to the NEJM article on this study. Splenomegaly is not a determining feature of PV and, as the COMFORT trials demonstrated three years earlier,  a prime benefit of Jakafi is its ability to reduce spleen volumes rapidly..

Arm’s length and the suspicion of bias

While there is no reason to suspect financial conflict of interest affecting the RESPONSE trial’s coordinator, there is still a sticking point, an issue on which physicians and patients may not agree: The need to maintain an arm’s length relationship between physicians and drug companies to avoid perception of bias..

PV patients and their docs needed Jakafi to fall back on. But the method through which it was approved and the subsequent promotional onslaught is problematic. Dr. Verstovsek is a veteran of the COMFORT trials that saw Jakafi approved for myelofibrosis. He saw these data evolve over years. In his clinic he saw his patients enjoy rapidly improved QOL. He’s fully aware of Jakafi’s impact and limitations and likely wanted Jakafi for his PV patients.

However, it’s still bias when the physician asserts his patients needs over the scientist’s quest for objective evidence.

Verstovsek became a prominent advocate for Jakafi in treatment of PV, notably in the Press Release issued by Incyte in which he and his affiliations are prominently featured.

As a physician and investigator, he may firmly believes in the value of Jakafi in treatment of PV patients but here, he crosses over to the Sponsor’s side in promoting that value. (For the record, he told MPNforum he does not take sides but believes in data and that data speaks for itself.)

For a decade, along with many other academic physicians, Dr. Verstovsek has been engaged in shepherding ruxolitinib through its clinical trials, first for myelofibrosis and more recently for polycythemia. He has presented findings to professional and patient groups and authored papers in scientific journals.  It would seem inevitable to acquire at least a tinge of bias toward a molecule you have spent so much time nurturing, and which has produced such positive events in your clinic, in your professional life and in the world.

Bias in favor of patient care is the only way I can understand Verstovsek not conceding the deficits of the RESPONSE 3 trial and his participation in this Incyte press release announcing FDA approval of Jakafi for PV:

From the Incyte Press Release:  “The approval of Jakafi represents an important advance for patients with uncontrolled PV. For the first time we are able to provide these patients a treatment that has been shown to provide effective and consistent control of their blood counts and reduce spleen volume” said Srdan Verstovsek MD, PhD, Professor, Department of Leukemia, Division of Cancer Medicine, The university of Texas MD Anderson Cancer Center.”

Abstracts presented at the 60 Annual ASH Meeting in San Diego, December, 2018, all written by expert, experienced academic physicians and scientists, all demonstrate Ruxolitinib’s safety and efficacy. To see author attributions and read the entire abstract, click on the link embedded in the title.

Opdated Results from An Open-Label, Multicenter, Expanded Treatment Protocol (ETP) Phase (Ph) 3b Study Of Ruxolitinib (Rux) In Patients (Pts) With Polycythemia Vera (PV) Who Are Hydroxyurea (HU) Resistant Or Intolerant And For Whom No Alternative Treatments Are Available (Abstract #1774)

Conclusion: The observed safety profile of RUX in the ETP study was consistent with that of the RESPONSE studies. Efficacy results were close to the observed values in the RESPONSE studies. RUX Tx resulted in HCT control, hematologic remission, spleen response, and symptom reduction in this HU-resistant/intolerant pt population in need of a viable Tx option. Safety and efficacy findings from this ETP study support the use of RUX for pts with inadequately controlled PV, an unmet medical need.

Long-Term Efficacy and Safety (5 Years) in RESPONSE, a Phase 3 Study Comparing Ruxolitinib (rux) with Best Available Therapy (BAT) in Hydroxyurea (HU)-Resistant/Intolerant Patients (pts) with Polycythemia Vera (PV)

Conclusion  In HU resistant/intolerant PV pts, clinical benefits of rux treatment (Hct control and CLHM) were durable with long-term therapy. Considering that the OS findings from this analysis are confounded by extensive CO, the observed HR from this analysis represents a conservative estimate of rux benefit. The long-term safety was consistent with previous findings

Ruxolitinib for the Treatment of Inadequately Controlled Polycythemia Vera Without Splenomegaly: 156-Week Follow-Up From the Phase 3 RESPONSE-2 Study (Abstract #1754)

CONCLUSIONS

In this 156-wk follow-up, RUX provided durable Hct control and CHR in pts with PV without splenomegaly. RUX was well tolerated, with 88% of randomized pts and 79% of crossover pts still receiving RUX at the time of this analysis. AEs were consistent with previous reports, and no new safety signals were observed. Overall, findings are consistent with those from RESPONSE and support RUX as the standard of care for second-line therapy in pts with inadequately controlled PV.

Characteristics Associated with Hydroxyurea Treatment Change in Patients with Polycythemia Vera: An Analysis from the REVEAL Study (Abstract #1770)

Conclusion: Patients with PV who received HU demonstrated variation with respect to HU management. Patients who started alternative treatments after HU were younger, had higher counts, more frequent phlebotomies, and higher symptom burden before changing treatment. These data support current criteria for HU resistance/intolerance.

The final proof: the PV patient

The impact on PV patients is substantial. Jakafi has provided symptomatic relief and improvement of QOL for many patients over varying periods of time. At a cost. Jakafi is not an entirely benign drug. and has as yet still unknown longer term impacts.

I have been talked/pressured into taking this extremely expensive drug several times over the past 4 years and each time my symptoms get worse, way worse. I wish it worked for me like others but it doesn’t but everytime i see a new doctor they push for that drug and no matter how much i protest they insist, i had one doctor refuse to continue to treat me if i wouldn’t try it one more time.— MPN Patient, Anonymized

The chief risks for PV patients are thrombotic and cardiovascular events and hematologic transformation to more aggressive disease like MF and AML. For this reason cytoreductive agents like HU or Interferon may be effective.

“I have been taking Jakafi since February 1, 2018. Hydroxyurea did not work well for me because of all the side effects. Especially itching and many other problems I won’t go into right now. I have never had an enlarged spleen. I’m not real good at understanding all parts of a blood test but I do keep track of my hemoglobin and platelets and try to learn more about the rest of the tests. I read articles and keep up with information on MPN & jakafi internet sites. I tell my doctor I feel normal taking jakafi. It definitely has improved the quality of my life. That doesn’t mean I think I’m cured because sometimes I get very concerned/ scared about what’s next or when is jakafi going to stop working. I exercise everyday and I try to eat healthy foods so I will not gain weight. It isn’t easy. I love to eat! I take yoga classes and I started meditating last year. I was diagnosed in February 2016 by my primary care physician” — Renee Lundy, MPN Patient.

Perhaps more importantly, for patients with uncontrolled PV, Jakafi may successfully mask symptoms for a time while the underlying disease progresses and the time for a successful stem cell transplant runs out

“By the end of January of 09 I had to start on Hydroxyurea; I still had to have phlebotomies at different intervals,…and it was just too frequent, and this made me even sicker…In November 2012 I was feeling even worse, and a bmb showed a very minute fibrosis; this meant that I could start on the very new drug called Jakavi (which at the time was for MF diagnosis only)…Initially I felt great on Jakavi, everything was suddenly much better, I actually bought a new flat in another town, planned for a holiday in Santorini (my dream place)…But, then the anemia started, and it took about one year on Jakavi until my body settled in an ok, and sort of balanced, state….Now, on Jakavi, I am actually having an ok life. Yes, I’m tired, I’m having symptoms, but not nearly as bad. I don’t need phlebotomies any more, which for me is a very big deal.”…Bente Evadatter, MPN Patient (Edited)

Is Dr. Srdan Verstovsek biased…or just convinced?  Is Jakafi approval for PV good for MPN patients?  There is nothing definitive in all this,

Serge Verstovsek believes Jakafi is a good second line drug for polycythemia, a useful med to have in the physician’s toolbox. He’s undoubtedly right about that. His endorsement of the drug in a corporate news release, his presentation of the flawed trial’s findings at patient or professional meetings remains, to 83% of surveyed MPN patients, unacceptable. (See Patient Survey in Conflict of Interest article in this issue.)  Any breaching of an arm’s length relationship with a Sponsor encourages suspicion of bias.

Jakafi approval for FDA — even limited to instands of HU failure — has a clear downside. Once approved it can be prescribed and covered by medical insurance for unlimited PV application,  perhaps shortcircuiting more effective therapies like Pegasys or the soon to be approved Ropegintron,  Beyond short term effects, increased risk of infection, lack of durability and as yet still unclear long term health impacts, there’s the ironic problem of effectiveness. For some, Jakafi can relieve signs and symptoms PV thus masking the continual progression and possible transformation of the underlying disease. This improvement in quality of life is of inestimable value…but can prove to be deceptive.

Bottom line? Having Jakafi available when all else fails is a good thing,.  And as Verstovsek’s patients universally attest, he’s a damned good doctor and his biases are hard won in the lab and the clinic. When he examines his patients he brings to bear his experience, skill and knowledge. .

Despite our sharp disagreement about the RESPONSE trial and his role as a spokesperson in Incyte venues, when in need of medical advice he’s one guy I’d like to see sitting opposite me in his consulting room. Wearing a white coat, of course.

 

Take me back to the Contents

© 2018, MPNforum. All rights reserved under Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License

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Comments on: "Jakafi for PV- Hope or Hype?" (2)

  1. G Culverhouse said:

    Jakafi causes anemia.
    BottomLine.

  2. Patricia Cooper said:

    “For some, Jakafi can relieve signs and symptoms PV thus masking the continual progression and possible transformation of the underlying disease. This improvement in quality of life is of inestimable value…but can prove to be deceptive.” First, for many, this is a life-changing drug. Second, just as with any course of treatment, nothing can replace your doctor’s knowledge and ongoing monitoring of your condition. Finally, I know of no other treatment that reduces the JAK 2 allele burden at this time. Mine has been reduced by 60% since starting treatment on Jakafi in 2012.

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