Advances in treatment for myelofibrosis (MF) have come by leaps and bounds in the last few years since the discovery of the activating mutation JAK2V617F in the cells of patients with myeloproliferative disorders including MF, polycythemia vera, and essential thrombocytopenia. Incyte’s (NASDAQ:INCY) JAK inhibitor, ruxolitinib (INCB018424), looks to be the first drug to reach approval for the disorder, but a slew of competitors are following suit.
MF is characterized by anemia, bone marrow fibrosis, enlarged spleens, fatigue, bone pain, and a constellation of debilitating symptoms. Current treatment is primarily palliative; the option with any curative potential is an allogenic stem cell transplant, however the procedure carries significant risk of morbidity.
Along come the JAK2 inhibitors: ruxolitinib, SB1518, TG101348, XL019, CYT387, AZD-1480, R723, LY2784544, among others based on the premise that aberrant JAK2 signaling is the causative factor in the majority of myeloproliferative disorders. Eventual research has shown this is not the case; other pathways unrelated to JAK were also involved. Even so, these compounds have shown significant efficacy to date.
Ruxolitinib and CYT387 appear to be the top contenders. Interestingly, both have similar profiles, inhibiting JAK1 and JAK2 (the JAK family consists of JAK1, JAK2, JAK3, and TYK2). TG101348, a specific JAK2 inhibitor, shows activity at high doses, but is held back by adverse effects, particularly anemia and gastrointestinal problems. This seems to afflict many of the specific JAK2 inhibitors.
Incyte’s ruxolitinib is well ahead of the pack; management anticipates a launch in myelofibrosis by the end of this year. They have completed two randomized Phase III trials: a 24 week placebo controlled US trial and a 48 week European trial comparing ruxolitinib to best of care. Only top line data was released for these trials, saving crucial data for presentation at ASCO later this June. Both trials have met their primary and secondary endpoints.
Without disclosing much information from the Phase III trial, the only useful data comes from the Phase II results. Management suggested data between the trials were on par, speaking specifically to the 15mg dose cohort from the Phase II. This suggests ruxolitinib showed an excellent safety profile, with only single digit percent grade 3-4 thrombocytopenia and anemia, with little or no non-hematologic adverse effects.
YM Biocience’s (YMI) CYT387 has shown efficacy on par with ruxolitinib, though so far only in a small, Phase I/II trial. Not only that, but it has been shown to improve anemia symptoms with an anemia response rate of 58% based transfusion independence. The mean duration of response currently stands at six months. If this holds out, the compound could potentially be best in class; it is even dosed once daily compared to the twice a day dosing for ruxolitinib.
CYT387 may have a significant advantage over its competing JAK inhibitor, but it also has some serious liabilities. Unlike ruxolitinib, CYT387 has shown some non-hematologic adverse effects- nothing as severe as TG101348, et al - but not quite as clean a toxicity profile. There are signs of both gastrointestinal and liver issues.
Another issue is time, while Incyte plans on launching its drug this year, CYT387 will likely not reach the market until 2015. Incyte is already conducting patient and physician education (though that paves the way for YM Biosciences as well) and intends on hiring managers for its sales force this quarter. In the absence of competition, ruxolitinib will likely be used in the majority of high-risk and intermediate-2 level myelofibrosis cases. 74% of patients in Incyte’s Phase II trial were from the high-risk group while 17% were from intermediate-2.
Most analysts think of ruxolitinib as a drug for alleviating constitutional symptoms such as enlarged spleens. The company is out to change this view through continued trials intended to show a disease modifying effect for the drug. Two-year overall survival of 84% from the continuing Phase II trial points to a possible improvement in survival over historical figures; high-risk patients have a median survival of about two years and intermediate-2 patients, four.
If and when CYT387 is approved, the market will not necessarily become suddenly divvied up between the two drugs as some analysts have suggested, with non-anemic patients on ruxolitinib and anemic patients on CYT387. This is because neither drug is likely to be used alone. They may be paired with prednisone, or an IMiD such as pomalidomide to boost blood cells. Or they may be used in conjunction with a stem cell transplant.
In my view, because ruxolitinib is so well tolerated and is the first to market, it will find widespread use as doctors experiment and discover the best treatment options for their patients. Still, there will be patients who do not respond to the drug or cannot tolerate it, and some patients will prefer the convenience of a once-daily drug. Market share will therefore overlap.
Only actual usage will tell which drug is truly better. Additional data at ASCO is unlikely to make that clear. For now, CYT387 and ruxolitinib simply appear to be the two best, and that’s all I need to know.