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'JAK'ing Up Myelofibrosis; Sanofi's Phase III Data Are Solid

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By Jennifer Boggs
Managing Editor

As sales of Incyte Corp.'s approved JAK inhibitor Jakafi (ruxolitinib) begin to pick up steam, a competing myelofibrosis candidate from Sanofi SA moved a step closer to market.

The Paris-based big pharma, which gained rights to JAK drug SAR302503 in its 2010 buyout of TargeGen Inc., reported solid top-line data from the Phase III study dubbed JAKARTA, showing that both dose groups of the drug hit the primary endpoint of reducing spleen volume. The study was conducted under a special protocol assessment with the FDA, and Sanofi anticipates a regulatory filing shortly, though the firm declined to comment on exact timing.

A positive outcome had largely been expected for JAKARTA, which enrolled 289 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis and measured the proportion of patients who had reductions in spleen volume of 35 percent or greater at 24 weeks. But it will be secondary and safety data, expected to be released at an upcoming medical meeting, that will allow analysts to suss out SAR302503's potential in amid the growing number of JAK inhibitors in the myelofibrosis space.

Incyte's Jakafi, partnered with Basel, Switzerland-based Novartis AG, gets credit for blazing the trail in that indication. The companies had worked with the FDA to determine spleen reduction as a development endpoint, and that same endpoint has been used both by Sanofi for its JAKARTA study and by Cell Therapeutics Inc., which launched a Phase III study in January to test JAK inhibitor pacritinib. (See BioWorld Today, Jan. 10, 2013.)

If there has been any criticism of Incyte's drug, it is worries that Jakafi deals only with the symptoms of myelofibrosis, without really targeting the underlying disease. The Wilmington, Del.-based firm, however, has countered that somewhat with updated data from the pivotal COMFORT 1 and COMFORT 2 studies that have demonstrated an improvement in survival, news that no doubt helped to boost sales.

Jakafi revenue for 2012 totaled $136 million, with sales increasing toward the end of the year. First-quarter 2013 revenue totaled $71.1 million. The drug also is approved in Europe, where it is marketed by Novartis as Jakavi, with Incyte entitled to royalty payments.

Without detailed data, it's difficult to gauge the potential of Sanofi's drug, noted Wells Fargo Securities analyst Brian Abrahams. "Longer-term follow-up beyond the 24 weeks may be needed to tease out any differences," he wrote in a research note, adding that "clear demonstration of a survival benefit" could increase its threat to Jakafi.

Sanofi's drug is differentiated from Jakafi in that it is more selective – targeting only JAK2, while Jakafi hits both JAK1 and JAK2. Key secondary endpoints in the JAKARTA trial include the assessment of associated symptoms as measured by total symptom score using symptoms measured by the modified Myelofibrosis Symptom Assessment form diary.

Sanofi also will look at the compound's effect on reversing fibrosis in the bone marrow. In myelofibrosis, up-regulation of blood cell production causes fibrotic tissue to develop in the bone marrow, resulting from acquired mutations targeting hematopoietic stem cells.

Phase I/II data reported by San Diego-based TargeGen prior to the Sanofi buyout also showed the potential of SAR302503 to reduce white blood cell count in patients with leukocytosis and reduce mutant cells responsible for causing the disease in about two-thirds of the patients treated.

Full safety data are to be revealed later, but Sanofi said the JAKARTA study mirrored earlier trials, with the most common adverse events including anemia, diarrhea, nausea and vomiting. Anemia is the most problematic side effect and is also seen with most other JAK inhibitors, including Incyte's Jakafi.

Closely following Sanofi's SAR302503 is pacritinib, another selective JAK2 inhibitor. Seattle-based Cell Therapeutics, which acquired the drug in last year's buyout of S*BIO Pte Ltd., has noted the ability of its drug to also hit both wild-type mutation and clonal mutation V617F, with dual activity against FLT3 mutation.

At the time of the S*BIO acquisition, Cell Therapeutics CEO James Bianco said the market for myeloproliferative neoplasms could reach $7 billion in the U.S. alone, leaving plenty of room for multiple JAK products. (See BioWorld Today, April 20, 2012.)

According to Sanofi, the prevalence of myelofibrosis is not clear, though the latest research estimates put the number at about 15,000 patients in the U.S.

Earlier in development is CYT387, a JAK1/2 inhibitor developed by YM BioSciences Inc. and acquired by Gilead Sciences Inc. late last year. That drug is slated to start Phase III testing this year, but early data indicated it could be the most promising of the lot. Phase I/II results reported compelling improvements in spleen enlargement and constitutional symptoms of the disease, plus, surprisingly, a beneficial effect on anemia. (See BioWorld Today, Dec. 14, 2011.)

Patients in the placebo arm of the JAKARTA trial are allowed to cross over to SAR302503 following completion of 24 weeks of treatment or disease progression.

Sanofi also has a Phase II study under way testing SAR302503 in Jakafi-exposed patients who are either resistant or intolerant to Jakafi.