Mast Therapeutics Inc. expects to quit development of its lead candidate, vepoloxamer, after it failed to significantly outperform a placebo in shortening the duration of vaso-occlusive crisis (VOC) in the phase III trial EPIC. Shares of the San Diego-based company (NYSE MKT:MSTX) dove 79.2 percent to close at 12 cents on Wednesday as management pledged to cut costs and determine next steps, including advancement of its second asset, AIR001, for heart failure. A $10 million loan payment Mast owes Hercules Capital Inc. is under discussion.

"There may yet be cohorts which are found to be in favor of vepoloxamer, either by trend or with significance," said Mast's CEO Brian Culley, "but in light of the top-line findings, we believe those would be unlikely to support further development by Mast in sickle cell disease."

Vaso-occlusive crises are painful events for people with sickle cell disease (SCD) in which sickled red blood cells "stick" to the endothelium and to each other and leads to blocking circulation and causing tissue damage. Minimization of the episodes, which send SCD patients to the hospital nearly 70,000 times each year in the U.S., is hugely important not just to patients but everyone who pays for the average six days of hospitalization patients endure during each event.

Vepoloxamer, a purified form of a nonionic, triblock copolymer (poloxamer 188) also known as MST-188, was designed to lower the viscosity of patients' blood during such a crisis by decreasing adhesion and improving the malleability of cells, improving blood flow and thereby shortening the duration of the crisis.

During EPIC, short for "Evaluation of Purified Poloxamer 188 in Vaso-Occlusive Crisis of Sickle Cell Disease," 388 patients, ages 4 to 46, were randomized to either vepoloxamer or placebo after being hospitalized for acute pain typical of vaso-occlusive crisis who required treatment with parenteral opioid analgesia. Randomization was stratified by age, use of hydroxyurea and pain score.

The mean duration of VOC for vepoloxamer-treated patients in the intent-to-treat (ITT) group was 82 hours vs. 78 hours in the placebo group and the measure didn't reach statistically significance (p=0.09). There were also no statistically significant differences between treatment groups in the ITT population across the two secondary efficacy endpoints, rate of re-hospitalization for VOC and the occurrence of acute chest syndrome.

Prior to Wednesday's news, Piper Jaffray analyst Edward Tenthoff had forecast U.S. sales of vepoloxamer could reach more than $400 million by 2023.

Consistent with previously conducted studies, vepoloxamer was generally well tolerated with no statistically significant differences in treatment-related serious adverse events in the vepoloxamer group compared to the placebo group. No deaths occurred in the study.

Next up, said Culley, will be further analysis of EPIC's data to more fully understand the outcome and "simultaneously assess opportunities to create value from that unique clinical dataset," the product of what the company said was the largest placebo-controlled clinical trial ever completed in SCD.

In addition, the company plans to perform an interim analysis on its ongoing vepoloxamer heart failure study, though it declined to discuss the timing of that peek. "Because the connection between the drug's activity and clinical outcomes in sickle cell disease may be too difficult to detect," said Culley, "we plan to critically re-evaluate whether to continue our clinical study of vepoloxamer for heart failure or whether partnering opportunities might exist around vepoloxamer for ischemic stroke, since improvements in blood flow might be more directly measured and translatable to clinical outcomes."

Mast is also planning to continue advancing development of AIR001 for patients with heart failure with preserved ejection fraction. A 100-patient phase II study being conducted by the Heart Failure Clinical Research Network is expected to complete enrollment before the end of next year.

With just $35 million in cash on its balance sheet at June 30 and a $10 million loan repayment to Hercules triggered by announcement of EPIC's top-line results, Mast also is planning to "quickly and significantly reduce our operating expenses," said Culley. Whether the payment due Hercules can be put off or restructured, one potential topic of discussion, is unknown. Ioana Hone, Mast's director of investor relations declined to provide any specifics related to the company's ongoing discussions with Hercules.

Just weeks ago, on Sept. 9, Mast announced that it was joining the newly formed Sickle Cell Disease Coalition with what Culley said was the hope of providing the first approved medicine for intervention in VOC. On Wednesday, his team faced a different reality, summed up at the conclusion of the company's conference call: "Biotech is an unpredictable and sometimes frustrating industry," he said.


Despite EPIC's outcome, the SCD treatment space remains active, though not as lively as patients and their advocates would like. On Sept. 8, Torrance, Calif.-based Emmaus Life Sciences Inc. submitted a new drug application seeking approval for its pharmaceutical-grade L-glutamine, a treatment that demonstrated a 25 percent reduction in the median frequency of sickle cell crises in a 230-patient phase III study. (See BioWorld Today, Sept. 9, 2016.)

Another SCD player, Gaithersburg, Md.-based Glycomimetics Inc., is developing rivipansel, a pan-selectin antagonist for the treatment of VOC. Rivipansel is being evaluated in a phase III trial being conducted by Glycomimetics' strategic collaborator, Pfizer Inc.

Earlier it its journey is Cambridge, Mass.-based Imara Inc., which is taking on SCD backed by a $31 million series A round from the venture-backed orphan drug accelerator Cydan Development Inc. Imara expects to file an investigational new drug application for its phosphodiesterase 9 inhibitor, IMR-687, on its way toward starting a planned healthy volunteers study this fall and testing in patients with SCD next spring. (See BioWorld Today, April 15, 2016.)

As many as 15 additional trials targeting SCD are joining in the march, expecting to wrap up trials during the remainder of this year and into 2017. (See BioWorld Insight, July 18, 2016.)