Bolstering its phase III push with the JAK2/FLT3 inhibitor pacritinib in the heating-up myelofibrosis (MF) space, Cell Therapeutics Inc. (CTI) began Persist-2, a study in patients with the disease and platelet counts less than or equal to 100,000 per microliter.

MF disrupts the normal production of blood cells, and causes scarring in bone marrow with anemia, weakness, fatigue, and often, an enlarged spleen and liver. In Persist-2, Seattle-based CTI expects to enroll as many as 300 patients in North America, Europe, Australia and New Zealand within 12 to 14 months, under a special protocol assessment (SPA) pact with the FDA.

The randomized, open-label, multicenter study will test pacritinib against Jakafi (ruxolitinib), Incyte Corp.’s JAK1/JAK2 inhibitor, cleared in 2011 as the only approved therapy for MF. Jakafi made $235.4 million for Incyte last year. Patients will be randomized to receive 200 mg pacritinib twice daily, 400 mg pacritinib once daily, or “best available therapy,” i.e., Jakafi. (See BioWorld Today, Nov. 17, 2011.)

Persist-2’s aim “is really to go head to head with [Jakafi] at its approved dose and schedule in patients who are thrombocytopenic, recognizing that ruxolitinib dose needs to be reduced for patients who have platelet counts of 100,000, or 75,000, or 50,000,” said CEO James Bianco. “If they’re below 50,000, you can’t administer [Jakafi].”

Handicappers are still guessing whether oral, once-daily pacritinib’s dual approach with FLT3 targeting will let the compound grab significant share from Jakafi. Seattle-based CTI in January launched Persist-1 in the broader MF population without platelet-count limits and also without the presence of JAK inhibitor. That experiment is enrolling 270 patients at clinical sites in Europe, Australia, Russia and the U.S.

Under the SPA for Persist-2, the first agreed-upon co-primary endpoint is the percentage of patients achieving a 35 percent or greater reduction in spleen volume measured by magnetic resonance imagery or computed tomography scan from baseline to 24 weeks of treatment. The second is the percentage of patients achieving a total symptom score reduction of 50 percent or greater using six key symptoms, as measured by the modified Myeloproliferative Neoplasm Symptom Assessment diary, from baseline to 24 weeks.

Bianco said the company was “quite pleased, I won’t say shocked, but pleased that we got [the SPA for Persist-2] in the first review cycle,” probably thanks to postmarketing experience with Jakafi. “People got surprised by the [latter’s] treatment-emergent myelosuppression,” he told BioWorld Today.

In order to enter Persist-2, “you have to have a large spleen, you have to have a lot of symptoms, and you have to have low platelets. So if you have those three things and you are on [Jakafi], then you are not really getting adequately controlled, or you’re developing a side effect, and tapering the dose of the drug, and the symptoms and [large] spleen are coming back.”

Bianco said MF is “not quite 100 percent like [chronic myeloid leukemia], but not too dissimilar, in that, if you want to be disease-modifying, maybe a single JAK therapy isn’t going to do it.”

A GOOD MIXER

Pacritinib originated at Singapore-based S*Bio Pte Ltd., which licensed it to CTI in April 2012 for $30 million up front and up to $132.5 million in regulatory and sales milestones. Onyx Pharmaceuticals Inc., of South San Francisco, previously had an option deal worth as much as $550 million for S*Bio, pipeline priorities caused Onyx to give up the program. (See BioWorld Today, May 5, 2011, and April 20, 2012.)

The compound’s promise led Deerfield, Ill.-based Baxter International Inc. to a potential $362 million deal with CTI last November, including an up-front sum of $60 million, of which $30 million was an equity investment.

Milestone payments could total as much as $302 million, including $112 million in clinical, regulatory and commercial launch rewards. CTI said at the time that the deal could mean $40 million in 2014. (See BioWorld Today, Nov. 18, 2013.)

Pacritinib will drive CTI’s value this year, wrote H.C. Wainwright & Co. analyst Reni Benjamin, adding that the “race to dethrone” Jakafi is led by CTI/Baxter and Gilead.

Persist-1 likely will finish enrollment in the first half of this year and report data by the second half. Persist-2 probably will finish enrolling in the first half of next year.

No wonder the MF market has proven enticing. Incyte has estimated the disease afflicts as many as 18,500 people in the U.S., putting the potential worth at about $1 billion, if the annual treatment price is between $80,000 and $90,000, according to estimates by RBC Capital Markets analyst Glenn Novarro.

Bianco said MF seems caused by multiple activating mutations, and drugs will be used in combination, though “most of the other approaches they’re talking about are going to be myelosuppressive,” like Jakafi, so that pacritinib – which isn’t – could be useful with them, too.

“One component of that may be the JAK1 inhibition in addition to JAK2 [with Jakafi],” Bianco said. “We’ve always hypothesized that there’s got to be redundancy in downstream signaling to the receptor for such important things as blood cell growth factors. It turns out that is probably going to be correct.”

Science is also finding more MF. “If you turn back the clock five or seven years, diseases that weren’t called MF were probably MF,” and tests for JAK2 is confirming more of it, he said.

Bianco likened the situation to Cheshire, Conn.-based Alexion Pharmaceuticals Inc.’s Soliris (eculizumab) for paroxysmal nocturnal hemoglobinuria. Once, researchers believed only about 150 patients might exist in the U.S.

“Now, [Alexion] is doing $1.5 billion in sales. If you do the math, they found themselves about 4,000 of those patients in the U.S., and it’s not that they’ve created a disease because they have a drug for it,” he said.

CTI’s stock (NASDAQ:CTIC) closed Monday at $3.63, down 22 cents.