A pivotal trial of Omeros Corp.'s narsoplimab, an investigational therapy for an occasional but serious complication of hematopoietic stem cell transplant (HSCT), found that just one dose was enough to deliver a beneficial effect in more than half the study's high-risk participants, meeting the study's primary endpoint. The medicine, for HSCT-associated thrombotic microangiopathy, helped 65% of participants hit a 100-day survival milestone, post-diagnosis. But Omeros held details of the study, including specifics of its FDA-agreed endpoints, close, not even revealing its final enrollment, which Chief Medical Officer Steve Whitaker called "a trade secret."
HSCT-TMA, a systemic disorder induced by endothelial cell-damaging factors associated with stem cell transplantation, occurs in both autologous and allogeneic transplants but, according to Omeros, is more common in the allogeneic population. In the U.S. and Europe, about 25,000 to 30,000 allogeneic transplants are performed annually, with an incidence of HSCT-TMA pegged at between 30% and 40%.
The primary efficacy endpoint of Omeros' single-arm open-label trial was the proportion of HSCT-TMA patients who achieved "a highly rigorous set of response criteria that requires both improvement in HSCT-TMA laboratory markers and improvement in clinical status," as indicated by improved organ function and reductions in the need for platelet or red blood cell transfusions. "Patients who did not fully meet these criteria were considered nonresponders," the company said. Omeros said 56% of all patients receiving at least one dose of narsoplimab achieved complete responder status, while 68% of patients who received the protocol-specified treatment of at least four once-weekly doses achieved complete responder status.
The trial "specifically targeted patients at risk for poor outcomes," said Whitaker, noting that one entry criterion was that patients had not responded to modification of calcineurin inhibitors, which are often implicated in transplant-associated TMA. Furthermore, "a high proportion of patients had other conditions at entry or during the study that negatively impact survival," he said.
That context framed two key secondary endpoints of the study, which also pointed to benefits for HSCT-TMA patients treated with the drug: 100-day survival following HSCT-TMA diagnosis hit 65% for all participants receiving at least one dose of the medicine and 81% of participants receiving the full four-week course.
By contrast, "the response rate in this high-risk population would be expected to be 10 percent to 15 percent with a 100-day survival rate of less than 20 percent. The response rate and 100-day survival achieved with narsoplimab in this trial demonstrate an unprecedented effect in this condition,” said Rafael Duarte, an associate professor and head of the hematology department and hematopoietic transplantation program at the University Hospital Puerta de Hierro Majadahonda in Madrid, who served as a global advisor on the stem cell transplant program.
Omeros reported that 21% of patients died during the trial "due to causes common in stem cell transplant, with no additional patients discontinuing for adverse events." The most common adverse events seen in the study were nausea, vomiting, diarrhea, hypokalemia, neutropenia and fever, all of which are common in stem cell transplant patients, it said.
Narsoplimab, formerly known as OMS-721, is a monoclonal antibody targeting mannan-binding lectin-associated serine protease-2 (MASP-2), a pro-inflammatory protein target and the effector enzyme of the lectin pathway of complement. It's based on technology licensed from the University of Leicester, Helion Biotech and the U.K. Medical Research Council. Completion of a rolling BLA filing for the candidate is expected by mid-2020, the company said.
Shares of Seattle-based Omeros (NASDAQ:OMER) climbed 6% to close at $15.24 on Wednesday.
The FDA has granted narsoplimab a breakthrough therapy designation for the treatment of HSCT-TMA, while both the U.S. regulator and the EMA have granted it orphan drug status in the indication.
Though Omeros is furthest along among the potential therapies for HSCT-TMA, it's not the only contender. Akari Therapeutics plc, of London is also developing a candidate, Coversin (nomacopan). Over the summer, Lonza Group AG agreed to manufacture and supply the medicine. Following a meeting with the FDA, the complement C5 factor inhibitor and leukotriene BLT receptor antagonist is headed into a pivotal single-arm responder-based study of its own, with similar endpoints to those outlined by Omeros.
Dublin-based Jazz Pharmaceuticals plc, has also been reported to be testing defibrotide – a deoxyribonucleic acid derivative approved as Defitelio in March 2016 for adults and children who develop hepatic veno-occlusive disease with additional kidney or lung abnormalities after they receive a stem cell transplant – for transplant-associated TMA. In May 2018, an open-label, single-arm, phase II pilot study was initiated in the U.S. to assess the drug’s effect when given as prophylaxis to patients receiving a conditioned stem cell transplant for preventing post-transplant TMA. The primary endpoint was incidence of missed doses of defibrotide. As of November, the study was expected to complete in July 2021.
As Omeros' team looks ahead, a European MAA to follow the U.S. filing is in the works, the company said. The company is also talking with U.S. and European transplant center doctors to lay the groundwork for a potential future launch.
In addition to HSCT-TMA, Omeros is advancing phase III programs testing narsoplimab in immunoglobulin A nephropathy and atypical hemolytic uremic syndrome. The company also continues to market its sole commercial product, Omidria (phenylephrine and ketorolac intraocular solution), which is approved in the U.S. for use during cataract surgery or intraocular lens replacement to maintain pupil size by preventing intraoperative miosis and to reduce postoperative pain. During the nine months ended Sept. 30, the company's Omidria revenue was $78.4 million.