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Clinician Letter to NEJM Sends Incyte Stock Tumbling

Published: 09:27 16 Oct 2011 EDT

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On Thursday October 13th, the New England Journal of Medicine (NEJM) published a letter from prominent leukemia specialist and Key Opinion Leader (KOL), Dr. Ayalew Tefferi critiquing the efficacy and long-term safety of Incyte Pharmaceutical’s first in class JAK inhibitor, ruxolitinib. That day, Incyte’s stock dropped 6.8% on twice the usual volume.

Tefferi is as experienced as they come in Myelofibrosis (MF)- the condition ruxolitinib is up for approval for. As a Principal Investigator at the prestigious Mayo Clinic, he has overseen trials from numerous companies developing treatments for MF, including Incyte. In fact, he is particularly expert in the field of JAK inhibition.

From this point of view, any insight from Tefferi should be of interest to any investor of companies working on JAK inhibitors. Publication of his letter by the NEJM only served to validate Tefferi’s analysis.

Titled “Long-Term Outcome of Treatment with Ruxolitinib in Myelofibrosis”, Tefferi’s report was based on an analysis of 51 patients who participated in the Phase I/II portion of Incyte’s trial at the Mayo Clinic, a subset of the 153 patients in that study.

The summary of this analysis was quite disheartening: rates of treatment discontinuation were high, often due to disease progression or toxicity; activity was modest and not always durable; and the drug could lead to serious adverse events. This coming from an expert who had been a part of Incyte’s Phase I/II trial.

Yet later that day after markets closed, an analyst from Leerink Swann put out a note stating in part, “We believe INCY share are trading down in response to an NEJM article by Dr. Ayalew Tefferi from the Mayo Clinic. The article discusses 51 patients with myelofibrosis treated with Ruxolitinib and notes a high drop-off rate and inconsistent durable effects. While on the surface this would appear to be problematic for Ruxolitinib's prospects, we note material omissions in the publication and are actually surprised the NEJM would publish such analysis as, in our view, it is deficient. We believe the analysis mischaracterizes Ruxolitinib's profile."

Would a prominent academic have knowingly put out an analysis that would “mischaracterize” a drug? One would hope that is not the case. The timing and type of analysis, however, is odd, and can only wonder as to the rationale behind his report.

The FDA is set to make a decision on ruxolitinib’s NDA by December 3rd, less than two months away. This report will have no impact on the FDA decision as Incyte’s Phase III trials passed with flying colors; but it casts doubt on the drug’s utility, warning of poor durability and serious adverse effects.

Tefferi’s analysis stands in sharp contrast to an article he co-authored on the full 153 patient Phase I/II study published in September 2010, also in the NEJM. In that report, the authors concluded ruxolitinib was effective and induced a durable response. While Tefferi maintained the drug had only minor effects on spleen size reduction, the 2010 article noted a strong reduction in splenomegaly. This measure became the primary endpoint of both Phase III trials.

Moreover, Tefferi indicated discontinuation rates at 1, 2, and 3 years of 51%, 72%, and 89%, respectively at the Mayo Clinic. In the full Phase I/II, only 25% of patients had dropped out at a median follow-up of greater than 14.7 months. The study population at the Mayo Clinic was obviously skewed. For a better understanding of long-term treatment with ruxolitinib, Tefferi should have dug into the complete data rather than rely on data from a single clinic.

It should also be noted that Incyte’s two completed randomized Phase III studies involving a total of over 500patients using an optimized dose of ruxolitinib demonstrated a robust and durable response. Its 48-week European trial, COMFORT-II, had a discontinuation rate of 18%.

There is no way to know what motivated Tefferi to write this letter to the NEJM. He has relationships with Incyte as well as its competitors, making it difficult to sort out any conflict of interest issues.

It will behoove a publication as prestigious as the NEJM to fully vet future articles prior to publication- even ones from such esteemed authors as Dr. Tefferi.

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