MPNforum Magazine

The OTHER face of Jakafi

• • Zhenya Senyak

To paraphrase Dickens: Jakafi is the best of drugs. It is the worst of drugs. It has restored life to MPN patients, it has shortened and taken away lives. One MPN specialist loves it, One MPN specialists would never prescribe it,. It is truly the two faced Janus god of MPN drugs.

The US Government may be partially shuttered over Trump’s wall but some folks at the FDA are still on duty.

In response to our article on Jakafi and PV – and our questioning of the FDA’s role in approving Jakafi for PV after a clearly biased clinical trial — a spokesperson for the Agency sent us a note with an attached letter.

The letter was originally sent to Incyte’s Greg Taylor, Senior Director, Regulatory Affairs, on December 4, 2014. It clearly indicated the FDA’s concerns over safety of Jakafi in the PV setting and spelled out its requirement for Incyte to initiate a full clinical trial to study long-term safety issues.

“Since Jakafi^® (ruxolitinib) was approved on November 16, 2011, we have become aware of the serious risk of anemia in patients with polycythemia vera with or without splenomegaly receiving Jakafi^® (ruxolitinib) in clinical trials and the potential for unexpected serious risks of long-term therapy in these patients…

Finally, we have determined that only a clinical trial (rather than a nonclinical or observational study) will be sufficient to identify the serious risk of anemia and other unexpected serious risks with long-term use of Jakafi^® (ruxolitinib) in patients with polycythemia vera… /s/ Edvardas Kaminskas, MD Deputy Director Division of Hematology Products Office of Hematology and Oncology Products Center for Drug Evaluation and Research “

The full letter can be found here: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/202192Orig1s008ltr.pdf.

The FDA also provided a link to the NEJM paper discussing the trial. In it, the authors,Vannucchi et al., describe the nature of the trial:

Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. (Emphasis added,)

In fact. for the very great majority of patients, the “standard therapy” against which ruxolitinib was evaluated was hydroxyurea or nothing at all. Jakafi vs Unacceptable HU or nothing. What are the odds Jakafi would come out on top?

FDA approval of Jakafi for PV was qualified by subsequent requirements for additional safety testing. It was far from the full-throated endorsement it was made to seem. Incyte has agreed to run that follow-on safety clinical trial, to be completed May, 2021, with a final report submitted May, 2022. Meanwhile, Jakafi prescriptions for PV patients continue to be filled.

Janus is a two faced god. The JAK kinase is an enzyme whose two domains work together to help transcribe genes in the cellular nucleus. A mutation in the JAK2 gene produces a protein that stimulates blood production. Inhibit the gene = Reduce blood production. The JAK kinase is also intimately involved in signaling production of immune cells. Inhibit the JAK2 = Weaken the immune system.

And Jakafi is a two-faced drug.

So yes Jakafi is effective at reducing swollen spleens since blood production itself is reduced. That same reduction in blood cells shows up in anemia, reduced healthy red blood cells. And reduced production of immune cells and reduced resistance to bacterial and viral borne disease.

Incyte itself has two-faced messages. In its ASH brochure and exhibit this year promoting PV use there are Headlines:

ACHIEVED COMPLETE HEMATOLOGIC REMISSION WITH JAKAFI (RUXOLITINIB)

MORE PATIENTS ACHIEVED HCT CONTROL WITH JAKAFI

INTERVENE WITH JAKAFI TO ACHIEVE DURABLE COUNT CONTROL

In the very back of the promotional brochure you can find Important Safety Information. In smaller body type there’s a listing of hazards, a listing mandated by the FDA. Here’s a partial list (boldface added):

Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia…

Patients developing anemia may require blood transfusions…

Serious bacterial, mycobacterial, fungal and viral infections have occurred…

Tuberculosis has been reported..

Progressive multifocal leukoencephalopathy (PML) has occurred with Jakafi treatment

Increases in hepatitis B viral load…have been reported in patients with chronic hepatitis B virus

Non-melanoma skin cancers including basal cell, squamous cell and markel cell carcinoma have curred

Treatment with Jakafi has been associated with increases in total cholesterol, low density lipoprotein cholesterol and triglycerides.

The massive push by Incyte for its PV application of Jakafi at ASH San Diego last month mirrored the company’s brochure approach, headlined benefits and subdued treatment of risk:

There are clearly vital short term clinical benefits to Jakafi, notably relief from splenomegaly and resultant restoration of appetite and QOL and rapid control of counts. This short term use can prepare a patient for stem cell transplant or, perhaps, other therapies, or even clinical trial.

Through the blaring hoopla of Incyte’s announcements “FDA approves Jakafi for PV,” we never got a clear picture of how skewed the RESPONSE PV trial was. And, although eventually it appeared right there in the back of the promotional brochure, we were so relieved at the promise of benefits, we somehow missed the clear picture of real risks associated with Jakafi.

And there may be a much more lethal aspect to Jakafi therapy.

The study by Kate Newberry, Srdan Verstovsek and their MD Anderson colleagues revealed about one-third of the patients who discontinued Jakafi for one reason or another had acquired High Molecular Risk mutations in other genes. And over 60% of those mutations were in the dreaded ASLX-1 gene. Overall life expectancy for this group was under 14 months. There is substantial disagreement as to whether or not Jakafi is responsible for the acquisition of High Molecular Risk mutation… but possible clonal evolution is another factor to consider before extending this drug into new application areas that may not have the imperative requirements of myelofibrosis.

Jakafi’s approval for myelofibrosis in 2011 when no other drug was available to reduce splenomegaly and restore locomotion and quality of life, was a pure blessing. Its extension into the much larger market of polycythemia vera patients is more questionable, particularly as checkpoint inhibitors and newer genetic therapies are showing increasing promise.. Contributing to the uncertainty, there is a real lack of a side by side comparison with interferon or a fair comparison with patients who can and do tolerate hydroxyurea.

The current spurt of activity combining Jakafi with interferon or other drugs in clinical trial may yield good results or might simply be another well-funded Incyte attempt to extend its market. Incyte’s performance in the RESPONSE PV trial doesn’t instill confidence in the corporation’s focus on hard science vs effective marketing. Janus-like, combination therapy involving ruxolitinib and interferon may be highly effective and might also have as much chance of reducing the effectiveness of interferon over the long term as improving the clinical prospects of the patient in clinical trial.

The MPN patient population has paid a heavy price for the focus on JAK2 inhibition over the past decade. The sheer financial weight of Incyte’s multimillion dollar marketing and development activities and the rush of competitors for a piece of the JAK2 pie reduced funding and scientific brainpower necessary to discover safe drugs that are effective in limiting the progression of myeloproliferative neoplasm. Some of us have benefited from Jakafi but too many of us who opted for Jakafi are no longer among us.

It’s still January. Our modern celebration of New Year’s Day stems from the ancient feast of the Roman god Janus – god of beginnings. The month of January takes its name from the god Janus, depicted with two faces. One face of Janus looks back into the past, and the other forward to the future. The future, as in gene therapy.

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