MPNforum Magazine

Energizing MPN Drug Discovery.  Can we help end the drought? 

– Zhenya Senyak  

Despite  thousands of brilliant scientists and technicians working on blood cancer drugs worldwide and several billions of drug company dollars funding development, we have very little concrete to show for it.

The three  leading new drug candidates for MPN patients have been around for years….and are still not much closer to adoption. Two – momelotinib and pacritinib —  are JAK inhibitors chasing after Jakafi’s market  — and one of them is under FDA clinical hold. Another,  ropeginterferon P1101,  is a tweaked sleeker interferon in pursuit of Pegasys. It’s simply trying to demonstrate non-inferiority.

The simple truth:   Even if they all succeed in gaining regulatory approval, we would be only marginally better off than we were. We still rely on two basic drugs, hydroxyurea and interferon in use for over half a century, neither of which is approved for MPN application. And the JAK inhibitor, Jakafi.

It has been five long years of total drought..  No new drugs for MPN patients since the FDA approval of Jakafi.  Year after year we come back from ASH empty handed.   Some hollow promises, a little chest thumping over a new candidate, and a few genuine new breakthroughs – CAL-R,  CRISPR and immunotherapy – but nothing our hematologist can prescribe.

There seems to be one basic reason for this drought.  Our inability to pool scientific findings and translate the most promising into drugs.   Drug companies are notoriously slow to adapt emerging science into costly drug development programs. And hematologists tend to be narrowly focused on clinical issues.

A case in point is CRISPR and gene therapy which surfaced in the MPN community at the San Francisco ASH meeting in 2014, shortly after the Jennifer Doudna lab went public with it.  While geneticists and molecular biologists have eagerly adopted and expanded this technology to create new animal models, new cellular repairs and even new species, there was hardly a ripple on the subject  among the thousands of papers at ASH in San Diego last week.

To this day, in the MPN community, CRISPR is more likely to describe a desired state of bacon than a revolutionary biotechnical development with relevance to medical research.

Our failure to pounce on breakthrough biotechnology can be attributed to the way we translate science into practical medical applications

No matter how a promising an MPN compound is discovered, it almost always ends up in the hands of a drug company to translate, that is produce, direct product development, sponsor clinical trials, obtain regulatory approval and take the med to market.  All that takes a partnership between the drug company and the MPN specialist. And there’s the rub.

The asymmetric relationship between drug company and hematologist creates a drug pipeline bottleneck.  The great bulk of translation machinery, the high cost process of bringing science to  market, is focused on commercially viable products.  The effort to duplicate successful products — versus exploring breakthrough scientific findings — takes up the creative and professional resources of the medical profession and drug company scientists and technicians. It also takes the time. health and blood of patients participating in clinical trials.

Pursuit of proven drugs via modified molecules makes commercial sense.  It’s not actually translation as much as composing variations on a theme..and so far it hasn’t worked.  Fedratinib, pacritinib, and momelotinib have been chasing after ruxolitinib like greyhounds after a mechanical rabbit, running in circles,. burning up money and brainpower.   Couple these activities — which have accounted for investment in large scale clinical trials involving hundreds of worldwide sites — with inevitable investigator bias and you have the ingredients for a full on drug drought.

Imagine you’re a hematologist, a principal investigator in an MPN drug trial. You are granted a large sum of money by a drug company to investigate its drug.  The funds help support you, your colleagues, your institution and your work.  You might even help design a clinical trial to test your sponsor’s drug.  Day after day, for years,  you immerse yourself in the project, interact with colleagues and patients,  and at some point collect and analyze final data.  You are invested in the success of your work. No matter how rigorously you approach your data, you want good results.  You want to move on to the next phase of clinical trial. You want professional  recognition and future  research contracts. You are biased.

That’s the kind of cowboy drug wrangling system, we have. It’s both entrepreneurial and competitive and yet risk averse and market oriented.

Truth is I have never read a paper or viewed a poster that said this drug sucks.  Just visit www.clinicaltrials.gov  and see the great mass of completed investigations that simply don’t report trial results. This failure denies us access to important data provided by patients on the study. Learning what doesn’t work saves time as we try to figure out what might work. for us – and by us I mean the whole MPN community of physicians, caregivers and patients. Energizing MPN drug discovery will require vigorous cooperative support of breakthrough science, open-minded exploration of new therapeutic options – and a firm commitment to joint development.

In theory, the MPD-Research Consortium already provides a framework for cooperative investigation and translation and in fact the MPN Research Foundation already provides financial backing for basic innovative science.   Both efforts contain the seed of our salvation: An adequately funded interdisciplinary scientific think tank wedded to a translation team of independent investigators.

Our existing infrastructure just needs to be super-charged, to be injected with more funding, more fresh thinking, more international, interdisciplinary participation by post-docs and venture capitalists.  Domination of the drug development process by a small handful of drug companies simply drains the pool of talented, skilled hematologists and stifles broad band scientific exploration.  As MPN patients we’ve seen the meager results the present system produces.

We need a new model and these times of chaos and dramatic initiatives —  when plans are in place for a cancer moonshot and biomedical technology is exploding — are ripe for change.  We need vigorous lobbying of the new US administration for passage of scientific medical research. and a summit meeting of blood cancer non-profit organizations and  medical institutions to forge a system that can expedite bringing scientific findings from the lab to the proverbial bedside.

Business as usual, depending on drug company translation and each of us  operating from our separate labs and various silos of influence can only bring about the same outcomes we have seen for years.

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