ORLANDO, Fla. – Preliminary data from a phase II test of Constellation Pharmaceuticals Inc.'s CPI-0610 in patients with myelofibrosis (MF), previewed to market adulation in November, got a full airing Monday at the American Society of Hematology (ASH) annual meeting. Updated data from the trial, called Manifest, showed that at 12 weeks, 12 out of 15 evaluable JAK inhibitor-naïve patients treated with a combination of CPI-0610 and Jakafi (ruxolitinib, Incyte Corp.) had at least a 35% reduction in spleen volume. Investigators also saw evidence of activity in ruxolitinib-resistant or -intolerant patients. 

"We believe that the opportunity for CPI-0610, at a minimum, is to be used wherever ruxolitinib is used," Constellation's CEO and president, Jigar Raythatha, said during an investor meeting call held at ASH.  

Despite the apparently positive results, company shares (NASDAQ:CNST) fell 17.3% Monday, closing at $36.14. 

Constellation is continuing to enroll patients in the trial and, based on the preliminary data, has decided to expand enrollment while starting to plan for initiation of a randomized, active-controlled, pivotal phase III trial studying the combination of CPI-0610 and ruxolitinib vs. ruxolitinib and placebo in JAK inhibitor-naïve patients with MF. The company expects to start the new trial in 2020. 

The phase III study will enroll patients with advanced, symptomatic MF with a palpable spleen into a double-blind study, with a primary endpoint of spleen volume response at 24 weeks, with a key secondary endpoint of Myelofibrosis Symptom Assessment Form scores, also at 24 weeks. 

Myelofibrosis is a bone marrow disorder in which the marrow is replaced by fibrous scar tissue. Once the marrow becomes diseased, it's unable to perform its basic hematopoietic function, leaving organs such as the spleen and liver to pick up the slack, though also leading to their enlargement. JAK inhibitors, such as ruxolitinib, help reduce spleen volume and improve symptoms of myelofibrosis, but their use has also been associated with worsening of anemia and transfusion independence, Constellation said.  

In addition to the spleen volume improvements seen so far with CPI-0610 in Manifest, 10 out of 14 evaluable JAK inhibitor-naïve patients achieved at least a 50% improvement in Total Symptom Score at 12 weeks, the company said. 

"If trends in preliminary data from Manifest in JAK inhibitor-naïve patients are confirmed with further study, CPI-0610 has the potential to transform the standard of care in these patients," said Claire Harrison, a professor of hematology at Guy's and St Thomas' NHS Foundation Trust who served as an investigator for the trial. 

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