PV and Jakafi — Good news, bad news.
Beyond the technical details in a clinical trial protocol stands a single question. In the Phase 3 Incyte/Novartis RESPONSE trial, the question is whether or not ruxolitinib is more effective in relieving symptoms of polycythemia patients than the best alternative therapy (BAT) drugs.
Since the efficacy of ruxo in treatment of PV is a question that was answered some time ago, it gives rise to another more basic question: Why do this study at all?
At the 2012 ASH meeting, a Phase 2 study of ruxo alone clearly demonstrated its efficacy and safety in treating patients with PV. (Here’s the Incyte PDF.) Since there are no approved drugs to treat PV, frontline treatment is usually phlebotomy to control HCT levels, supplemented by low dose aspirin. For symptomatic relief, physicians often prescribe hydroxyurea or interferon, off-label drugs. Jakafi (ruxolitinib) is another off label drug available to PV patients. These are all second line treatment options.
Going head to head with BAT drugs in the RESPONSE trials would seem to be about claiming bragging rights, a sort of King of the Hill game that is rewarded with lots of new business. For patients or prescribing physicians, however, there doesn’t seem to be much to prove. Amassing these data to get FDA approval for Jakafi in PV, however, would make a difference to insurers. You don’t deny a prescription for an FDA-approved drug, specially not when it’s the only one for the disease.
As measured by RESPONSE study endpoints– hematocrit and spleen response, mostly — the answer is an unqualified yes, ruxo is more effective than BAT drugs. With ruxolitinib, no patient was eligible for phlebotomy (hematocrit exceeded 45%) in the 32 week trial after week 8 and spleen reduction equaled the 35% figure we’re now familiar with from the Jakafi MF trials.
Jakafi seems like a slam dunk to be approved by the FDA for use in PV. Why not rejoice at a new drug about to be FDA-approved for use in our uneven battle with the ravages of polycythemia vera? For one thing, the way the Phase III trial came together appears to have provided ruxo with several advantages. And for another, FDA approval of ruxolitinib/Jakafi for PV treatment will likely make filling prescriptions for off label interferon more difficult.
A closer look at the ruxo vs. BAT face-off, raises questions. Current therapies are driven by the need to reduce thrombotic risk and relieve symptoms. One of the key drugs in this therapy, hydroxyurea (HU), has had documented success in controlling symptoms. While effective for many patients, long-term use has been implicated in progression to acute leukemia. HU has also proven ineffective or unacceptably toxic to some. Interferon has shown evidence of both symptom relief and control of the underlying disease. With its new lower dosage guidelines, interferon has proven largely free of side effects, free of cytotoxicity, and effective.
So what was actually being compared in RESPONSE?
The presentation of the RESPONSE trial (NCT01243944) results in Chicago earlier this month may not represent significant new therapeutic opportunities for patients. Jakafi was FDA approved for use in myelofibrosis in November, 2011 and available for off label prescription for PV patients. The use of ruxolitinib in polycythemia is limited for both medical and economic reasons. It is orders of magnitude more expensive than hydroxyurea and can’t claim the longer term benefits of the far less expensive interferon.
A Phase II study published in Cancer earlier this year (Verstovsek, Passamonti, et al.) clearly demonstrated the efficacy of ruxolitinib in advanced PV patients for whom hydroxyurea was not an option. Nearly all (97%) of patients responded by week 24. Spleens were no longer palpable in most cases and, except for one patient, phlebotomies were no longer necessary to maintain a healthy hematocrit.
At the ASCO meeting, the same sort of well designed and persuasive PowerPoint slides that characterized Incyte’s launch of Jakafi were presented as bulletproof evidence that ruxolitinib is more effective against PV than the Best Alternative Therapies.
But is it really more effective against the best alternative therapies…or only better than hydroxyurea for patients for whom hydroxyurea was not an option? One of the eligibility requirements to participate in the trial was: ” Subjects resistant to or intolerant of hydroxyurea.”
This RESPONSE trial was a major effort, 160 sites identified, with a final count of 222 patients worldwide, reduced to 198 at Week 48. Novartis/Incyte showered tens of millions of dollars on medical institutions investigators, healthcare professionals, consulting organizations and marketing to shoehorn Jakafi into a stronger position in the PV “market.” And why not? Up for grabs are an estimated 20,000 patients for whom hydroxyurea doesn’t work or causes more problems than benefit. And at Jakafi’s $100,000+/year price tag that cash shower should leave the giant Drug company bathing in profit.
But was RESPONSE a fair trial after all?
There’s little doubt that, in many cases, ruxolitinib benefitted most patients on the trial, impressively in symptom control and reduction of both splenomegaly and phlebotomy requirements. On its own, replicating the Phase Two performance reported in Cancer in February 2014, these 32 and 38-week results are meaningful and impressive.
Stacking up improvement in individual symptoms against lack of improvement in a drug already proven ineffective to this patient population clouds the issue. (The BAT drugs are selected by investigators from a list that included interferon, hydoxyurea, and a few others.)
Did ruxolitinib really perform better than the BAT, the best alternative therapies investigators could come up with?
The BAT group of 117 patients were given alternative single therapies based on a provided menu in the protocol. 59% — about three out of five BAT arm patients — were given hydroxyurea.
Since qualification to participate in the trial selected for patients“resistant to or intolerant of hydroxyurea,” we could have known in advance that more than half would receive little or no benefit from HU. We asked Dr. Verstovsek why, knowing this, did investigators running the trials at various sites select hydroxyurea? “That investigators would still use hydroxyurea,” said Verstovsek, “reflects a lack of good alternative therapies.”
Another questionable element of the ruxo vs. BAT trial is the lack of weighting given the different pathways, processes and timeframes in which the drugs operate. We know Jakafi hones in on the spleen like a shark sensing blood in the water. Reduction of splenomegaly in Jakafi therapy is rapid, often within two or three weeks. Interferon, for example, percolates more slowly through the immune system and is (a) most effective in early disease states and (b) over longer time periods and (c) also reduces splenomegaly.
There’s no chance in the clinical trial process to gauge durability of the PV response to ruxolitinib in any long-term way. We do know, however, that Jakafi has stopped producing benefit for myelofibrosis patients after a period of time as alternative JAK enzymes are recruited to replace the JAK2 role in the JAK-STAT pathway. Interferon, on the contrary, builds benefit over long-term according to a boatload of patient and hematologist reports and large scale studies in Europe. A real head to head comparison would need to take timeframes into consideration, or modify claims of efficacy based on rapid onset of relief.
A frequent side effect of Jakafi is thrombocytopenia (decrease in platelets) and anemia. The side effects of interferon may be limited to occasional flu-like symptoms and exacerbated depression…although the new low dosage regimen developed by Dr. Richard Silver and his colleagues seem to avoid even those.
While ruxoitinib’s ability to restructure bone marrow is possible – Incyte has been advancing that claim backed up by bone marrow biopsy slides since ASH 2013 – its toxicity is documented.
The success of RESPONSE means we may be trading interferon, a relatively inexpensive, benign drug that has demonstrated long-term benefit approaching “cure,” for an astronomically expensive drug that produces short-term symptomatic improvement with serious and frequent side effects.
And the real cost to us, as patients and caregivers?
We stand to gain an FDA-approved second level drug that may begin to ease cytotoxic HU off its dominating position in PV-therapy. That might be a good thing. But once Jakafi is FDA-approved as a second line drug for PV, we may lose our well-defended right to substitute off-label interferon as a second-line treatment option for PV. And that’s the bad news.
Dr. Verstovsek, Principal Investigator, saw the results close-up. He gets the last word. “I think ruxolitinib is a very safe and valuable drug for a second line therapy to control signs and symptoms of disease in advanced PV.”
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