MPNforum Magazine

The Bottom Line …

Drug discovery and development. We think of it as the product of brilliant scientific minds and skilled bench chemists. Maybe, but the driving force in these high-stakes gambles to bring a compound to market is located far from the lab and gene sequencing equipment. The action is in plush corporate boardrooms.

Last month, flush with cash and awash in operating losses, Incyte Corp (INCY, Nasdaq) elbowed aside both little biotechs and giant drug companies as it took the lead in fielding the first therapeutic drug for treatment of myelofibrosis.

Both in the U.S., where it’s going it alone and in the rest of the world where it teamed up with big pharma, Novartis – which took a share of the action by plunking down $150 million up front and providing milestone payments that could exceed $1 billion — Incyte has pulled out all the stops in its drive to market.

. The result? Ruxolitinib, the very first drug proven effective against splenomegaly and the worst of MF symptoms in controlled clinical trial, is poised to take the lion’s share of the MF market estimated at several hundred million dollars. With anticipated expansion to polycythemia vera and other blood disorders, revenues could exceed $1 billion over the next few years.

There are hurdles ahead: FDA approval, while anticipated for December of this year, is by no means assured. And then there are competing existing therapies like Revlimid, Hydroxyurea, Pegasys…and new drugs in clinical trial rumored to have fewer side effects, notably YMI’s Cytopia 387 which has reported similar results plus an effect on anemia, And then there are radically different mono- and combination therapies emerging from the genetics labs in this fast moving competitive pipeline. Once past those hurdles, Incyte, which holds a long lead over the rest of the field, faces the marketing and distribution battle for clinical acceptance.

Rolling the dice in this mega-million dollar gamble is Incyte president and CEO Paul A. Friedman, M.D., Friedman, formerly a professor of medicine and pharmacology at Harvard Medical School was president of Dupont Pharmaceutical Research Labs before taking over as Incyte CEO in 2001. And standing around the table are thousands of myelofibrosis patients and caregivers whose bottom line is not at all complicated.

Is there a Ruxo prescription pill in our near future that will improve our condition while we wait for the silver bullet that will stop MF in its tracks?

A week after Ruxo was formally unveiled in Chicago to the America Society of Clinical Oncologists, we talked to Dr. Friedman. Participating were Pamela M. Murphy, vice president, corporate communications amd Zhenya Senyak for MPNforum. This is the transcript of that interview.

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Forum: I’d like to talk to you as an MF patient, from that perspective, our concerns or hopes that 424 will help relieve the worst of the symptoms

PF: OK

Forum: As I understand it now Ruxolitinib…where does that name come from?

Pam: –the nib is part of the kinase nomenclature.. Ruxo is a product of our team and got approved

PF: The generic names are tongue twisters at best We call it Ruxo 424

Forum: As I understand it now while effective in reducing spleen size, it’s not going to slow the progression of the disease. I have no information on the reduction of the JAK2 allele burden and I think it may contribute to anemia as well as thrombocytopenia (platelet destruction) as well as blood transfusion requirements

PF: You make it sound some something no one would want to take.

Forum: Believe me I would want to take it if needed.

PF: OK all those things are true but out of context and so we should probably take them one at a time. Neither study was big enough or lasted long enough to be statistically powered to show a survival benefit. There was no way to show any kind for survival benefit that would be statistically meaningful in either pivotal trial If you look at the deaths in both trials the data favors Ruxo but it’s not close to being a P value of less than .05. In both

studies what’s called the hazard ratio was between .67 and .7 in favor of Ruxo arms, where Ruxo was administered

So we will not have a claim for survival and I certainly cannot tell you unequivocally that there is a survival advantage but if you think about the following: In causes of death with MF only 25-20 percent are conversions to AML and many more are from complications of the disease other than transformation

And when you think about what some of those things are you might think that a drug that appears to do what Ruxo does could benefit people in that regard And so since we’re anticipating the drugs approval and once it gets approval it would be impossible to do a prospective placebo involved trial to evaluate survival, we have to use some kind of surrogate way of looking at what data we have . And Dr Verstovsek at MD Anderson and one of his colleagues In Italy is attempting to do that in the longer term data we have in the Phase II study that continues to run with some patients being on the drug for four years or more.

And when you look at that data and compare it to … a control group of demographically matched patients, the data is intriguing and suggestive of survival benefit. But we will not have a claim for that from the Phase III data. Just have to watch as Dr. Verstovsek and Dr. Passamonti’s data matures from Phase II to see how convincing the early intriguing results are

So that’s what I would say about your first (statement). The second one is there are symptoms that are related to the spleen depending on how big the spleen gets and there are symptoms that are related to the pro-inflammatory cytokines that MF patients often have, like interleukin 8. And by inhibiting the Janus kinases 1 and 2 we have a dramatic effect on spleen size with relief of symptoms that appear to be related completely or in part to big spleens and very rapid and dramatic and durable relief from symptoms that are due to the over active, proinflammatory cytokine pathways such as fatigue, night sweats, weight loss, poor appetite, bone pain, etc.

You are right. In inhibiting JAK2 you can cause bone marrow suppression. So the way we’ve gone about running the clinical trials, and the way we think the label will read, allows for the individual physician {to adjust} dosage for a given patient to maximize the therapeutic benefit and minimize the side effect profile which is essentially bone marrow suppression. It’s particularly important in MF patients, as you know, since the marrow is not functioning at maximum efficiency. So what we sometimes see in patients is a significant reduction in platelet count which in almost every patient can be taken care of by a dose reduction.

I think we had one patient on Ruxo and one on the placebo who had to drop out because of thrombocytopenia. That’s a trivial percentage of all the people who participated in the trial — and was the same in the European trial .. same for cytopenia in either arm, Ruxo or BAT.(Best Available Therapy)..

And then the other thing we do see is a decrease in hemoglobin that seems to become maximum about weeks 8 to 12 after you start on the drug and then interestingly there is compensation and the HG begins to go back up and by about 18-20 weeks and thereafter the HG level is slightly below the placebo level but there’s definite evidence of compensation which I think is a combination of decreasing the spleen size therefore the spleen is less of a trap for circulating red cells. Erythropoietin, which is a growth factor for red cells, goes up significantly when patients get Ruxo so that’s going to offset some of the inhibition of the JAK enzymes by Ruxo, of JAK2s specifically which is the JAK through which erythropoietin signals. And the other thing probably involved is something called Anemia Chronic Disease with high levels of systemic inflammation in diseases other than MF can be a damper on bone marrow functions. In any event some combination of those three things leads to compensation and the HG comes back to normal

What’s interesting about we presented at ASCO last week is even patients who have an onset high level anemia got the same level of splenic reduction and symptomatic benefit as those who didn’t have that happen. And the other interesting thing is when you look across the board over the six months of therapy and you look at patients who have transfusion requirements in either placebo or the Ruxo treated arm the number of units of red cells transfused per month was actually lower in the Ruxo arm than it was in the other placebo arm and so… in my opinion, the benefits outweigh these side effect issues,

Forum: What was your point about the transfusion, was it about the nature of the transfusion…?

PF: No it was fewer units of blood…so Ruxo makes more people become transfusion dependent than placebo does which would make sense because you are inhibiting erythropoietin but even in that setting when you look at transfusion dependent patients on Ruxo vs. transfusion dependent patients on placebo the number of units of blood that a patient got per month was less with Ruxo than placebo

Forum: Is that data in the final report?

PF: It’s on our website in the presentation by Dr. Verstovsek, on one of the slides

Forum: I want to talk to you about symptoms. At the ASCO meeting there was another report on the 20- MF symptoms, the Tefferi report, Vannuchi actually. It’s in the June MPNForum, 20 symptoms and their prevalence across an (MF) population ,relatively small 178 . I looked at those symptoms and wanted to know what portion would be addressed by Ruxo. For example some seem not to be. Your point about fatigue and its relation to EPO suppression does answer the primary one, the one that most of us feel –the fatigue – but depression , bone pain , loss of concentration, pruritis, headache — any effect noticeable? Those weren’t endpoints in your study, I know.

PF: So, bone pain is part of the Ruben Mesa symptom score and we had a very good statistically significant effect on bone pain. Fatigue is not part of his score but there are other ways of evaluating fatigue …and it’s pretty obvious from patient feedback that we’ve gotten that there’s a dramatic effect on fatigue. People feel much better. Pruritis is handled pretty well

The one (symptom), loss of concentration was one of the things that was done in COMFORT II . and that looked to be improved [Note: COMFORT is the Phase III, Ruxolinitib clinical trial, COntrolled MyeloFibrosis study with ORal Jak inhibiTor; COMFORT I was in the US and COMFORT II, in Europe.)

There were actually more reports on headache on Ruxo than placebo and they are mild and transient . I think they were incidental but if they ever get reported then they are reported Headache per se would probably… we don’t have data saying we improve the headache of MF but I don’t think that the reports of headache that we alluded to at ASCO that were grade one or two and were anything more than us looking at the data set and somebody having an occasional headache and reporting it

Forum: Were they dose dependent at all?

PF: They were not dose dependent … You have to report it and the incidence is higher than placebo but when I look at look at the data is looks like a casual but no causal association You can’t rule it out because that’s what the data suggests.. They’re mild and not chronic. If they even occur for one day or two days and were recorded in a diary for a six month period they would be listed when you actually did a tabulated workup of what you find.

Forum: Can I ask you about the study design itself? Specifically I’m interested in the BAT [Best Available Therapy] drugs and looked at the Claire Harrison presentation of COMFORT II and the BAT arm included totally unfamiliar drugs like nitrogen mustard…

PF: Well some of the things used in Europe aren’t really used here but I think the two most commonly used drugs were HU and high dose steroids.

Forum: Right but what was not used what hit my attention was only 4% of that group were the interferons. One of the things I most wanted to see was the comparison with Pegasys which is going through the same path, which relates to another question.

The BAT arm, to me, didn’t include enough of the current front line therapies. To some extent, if we are to make the comparison clear.not comparing alternative therapies with Ruxo strikes me as leaving a big gap in understanding how it works. Splenic reduction… I believe the endpoint was 35% or something like that? Well that’s achievable with Pegasys and in some cases with hydroxyurea as well

PF: Right. So what was used in Europe were those therapies that physicians in the trial chose to use It was not determined by us. We would have thought there would have been more interferons used but not in Europe

Pam: It’s not reimbursed there. Probably why it’s not used.

Forum: Interesting because the British standard of care — again I hate to keep quoting form the Forum — but in the lead article Claire Harrison talks about the therapies and the front line age-appropriate choices are the interferons.

PF: Right…I’m assuming that at some point that kind of study will get done and we’ll see what happens. I know there’s a lot of interest in Pegasys for PV and I guess there are some MF patients who are on it. When that study got done by Novartis there was not much being used

Forum: Richard Silver has published three papers recently. There are some strong advocates for Pegasys.

PF: I don’t doubt that but we don’t have any comment to make on that. We don’t have any experience with it.

Forum: OK, that leads to a broader question. And I’m delighted that you’re in this game but why? I don’t understand exactly. Am I missing some major point? When Incyte got started on this project, who was involved? Why enter a relatively small market where there is competition from established therapies, other JAK2 inhibitors in trial now and other genetic trials under way.. How did you see this as promising?

We looked at diseases where we thought shutting down JAK signaling would have therapeutic benefit. There’s a list and MF is on the list and we’ll get fairly dramatic results.

PF: Well there are a lot of diseases where a JAK inhibitor can work. MF frankly, we thought would be the quickest path to a first approval and that has turned out to be the case although we’re not approved yet. I don’t want to put the cart before the horse. But for something like rheumatoid arthritis where these drugs work dramatically well there’s a much longer development path, an order of magnitude more patients who have to be studied and approved therapies.
We looked at diseases where we thought shutting down JAK signaling would have therapeutic benefit. There’s a list and MF is on the list and we’ll get fairly dramatic results. We have a number of compounds. We took one and put it into RA. Ruxo we felt we would keep in the MPN and broader oncology area. We have formulated Ruxo although we don’t call it that, we call it 424, as a topical cream for mild to moderate psoriasis. So we thought there were multiple therapeutic areas into which you could go and MF is just one of them and one we felt there was an obvious unfulfilled therapeutic need. And we thought we could develop the drug the quickest So that’s kind of why we went into it.

Forum: You’re expecting NDA approval by December

PF: We filed the NDA and all indications are we’re expecting they will do an expedited review but we don’t have a guarantee of that. If they do a regular review it would be four months later . We expect December approval.

Forum: Would that then apply to RA as well?

PF: No, that’s a different compound and it’s being developed by Eli Lilly. We have a partnership with them. Right, it’s totally different but early on we did study of 424 in RA and got spectacular results. We just felt the development pathways would be cleaner if we had a different compound for RA and psoriasis then a second one for MPNs

Forum: It seems to me that the approach at Incyte was to develop a drug that had larger applications than MF. Is that true?

PF: Well we’re a small company. MF and a portion of P Vera is not small for a small company The very fact that other companies knowing that we’re way ahead are still interested in these patient populations is a testament to the fact that there are a reasonable number of people suffering from MF and late stage PV that would benefit by having a new therapy. It’s not small to us. And that’s looking at it strictly as a CEO. I’m also an MD. I’ve had the good fortune once before to be able to bring a drug to market that turned out to be spectacularly useful to people which was Sustiva for HIV

Very different patient population but people benefited greatly by combining that drug with a nucleoside. And you know to be able to do it again gives me a great sense of having done something useful and accomplished things.

PAM: And I tell you that throughout our organization we’re pretty proud that we did this. And very committed to making a difference here.

Forum: I can’t speak for a patient population but I was relieved and delighted to read the announcement and to follow the progress of this and always a little baffled by how it was taking place… because you think we’re not a small population but it feels pretty infinitesimal to me A few thousand…

PF : 20, 000. That’s that MF population, something like 18, 500

Forum: Just two more questions. One has to do with a competitor. YMI’s CYT327 appears to address spleen reduction while reducing anemia, at least that’s the way it was reported. I know it’s way behind where you guys are now. You want to say anything about it?

PF: Not really, I’d just as soon have them say what they want to say because every time I say anything it comes back to bite me. The data is very early. It’s not controlled. There are no MRI’s measuring spleen and when the “anemia benefit” was presented at ASCO last week it was not well received. They have a ways to go. It may turn out they have an advantage but what we’ve seen so far is not that convincing.

Forum: Last question. What’s next? Ruxo is another attempt at addressing the result of the signalling pathway reducing the JAK2 burden but not the cause. Is anyone going after the root causes of MPNs or MF?

PF: I think if people knew an exact target to go after they’d go after it. I think there are combination studies that can be done that could be more effective in normalizing bone marrow At this point I would say the precise etiology and pathogenesis is not crystal clear and so it would be hard to embark on something without having a target that you really were pretty sure was at the root of how the disease came to be. But I think there are combination studies that you could do … there are the HDAC inhibitors there are a number of things that make sense to try to see if those combinations might well have some benefit at the level of marrow. And it’s also not clear over a longer term that you might not see something with monotherapy.

We do see some drifting down of the allele burden but we don’t see normalization of bone marrow. I’m not optimist that that will happen. At this point I would say I don’t think the root cause of the disease is well enough known with a related target that you could go after it aggressively if you were where I am in a company So I think in the intermediate term what we have now is more ammunition with Ruxo which hopefully will be the first drug approved by the FDA and a breadth of combination therapy to see if we can get to a next better stage than where we are now.

Forum: Thank you, good to talk with you. Good luck.

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© Zhenya Senyak and MPNforum.com, 2011. Unauthorized use and/or duplication of this material without express and written permission from this blog’s author and/or owner is strictly prohibited. Excerpts and links may be used, provided that full and clear credit is given to Zhenya Senyak and MPNforum.com with appropriate and specific direction to the original content.