Richard Levy, MD
In December, the FDA approved the JAK1/2 inhibitor ruxolitinib (Jakafi) for patients with polycythemia vera who are resistant or intolerant to hydroxyurea. The action made ruxolitinib the first agent with a specific indication for patients with polycythemia vera.
The FDA based its decision on the phase III RESPONSE trial, the full results of which were published today in The New England Journal of Medicine
RESPONSE randomized 222 patients with polycythemia vera to ruxolitinib (n = 110) or best available therapy (n = 112), which included hydroxyurea, interferon, observation, and other treatments.
Hematocrit control without phlebotomy was achieved for 60% of patients treated with ruxolitinib, compared with 20% receiving best available therapy. Spleen volume was reduced by ≥35% in 38% of patients receiving ruxolitinib compared with 1% for best available therapy.
The primary endpoint of the trial looked specifically at the number of patients who achieved hematocrit control without phlebotomy from week 8 to 32 and experienced greater than a 35% reduction in spleen volume by week 32. Overall, 21% of patients in the ruxolitinib arm met this criteria compared with 1% for best available therapy (P
The rates of grade 3/4 anemia and thrombocytopenia were higher in the ruxolitinib arm compared with best available therapy (2.0% vs 0% and 5.0% vs 4.0%, respectively). Symptom improvement by Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) favored ruxolitinib, with 49% of patients experiencing a ≥50% improvement from baseline compared with 5% for best available therapy.
For additional insight on the published RESPONSE data and the use of ruxolitnib to treat polycythemia vera, we reached out to Richard Levy, MD, executive vice president and chief drug development and medical officer at Incyte, the company that co-manufactures ruxolitinib with Novartis.
Can you discuss the RESPONSE trial and the results?
To design the trial to get a result that was clinically meaningful and acceptable to the FDA, we focused on two things. We focused on bringing the hematocrit level down below 45% and keeping it there without phlebotomies and also reduction in spleen size. The primary endpoint was a composite of those two things in the sense that to be a responder in the primary analysis, you had to be ineligible for phlebotomies and you had to have your spleen volume reduction by at least 35%.
So in that composite analysis, which is really a regulatory endpoint and not something that someone would look at as a combination in clinical practice, there’s a big difference between the groups—around 21% response rate versus about 1%. But when you look at the individual components of that, you can see that there’s about 60% of the patients who are able to maintain hematocrit control without phlebotomies in the ruxolitinib arm and just under 20% in the control arm. And the reason why there was such a big difference overall is that only less than 1% of patients actually have the spleen size reduction in the control arm.
The other important aspect to this is the frequency of clots, which is one of the major reasons why you treat patients with polycythemia vera. There have been papers published showing that if the control of the hematocrit is below 45%, you have a lower risk of clots than if you maintain a hematocrit level between 45% and 50%. We didn’t power the study to look at clots, per say, that would require a much larger and longer study and forcing patients who were not doing well on the control arm to stay on that control arm for longer periods of time. But [reducing the frequency of clots] is the underlying medical reason why the hematocrit control is so important. It’s not simply avoiding the uncomfortable and inconvenient phlebotomies.
What is the recommended dose of ruxolitinib when treating polycythemia vera?
The starting recommended dose is 10 mg BID and it was clear that patients need to be titrated based on their hematocrits. What we found was that the average dose at the end of the observation period was closer to 15 mg twice a day than it was to 10 mg, but there was a range from 5 mg up to 25 mg twice a day, so it really is individualized.
So these results led to the approval from the FDA. Can you discuss the specifics of this indication?
The indication is actually broader than the entry criteria into the RESPONSE study because the FDA and others have seen that the trial was designed around a regulatory endpoint, but the implications are greater.
So, for example, we used the ELN criteria for resistance to hydroxyurea but the indication is actually for patients who have an inadequate response, which is a broader term. But in doing a protocol, you needed a very specific set of entry criteria.