Ra Pharmaceuticals announced positive interim results from the company’s ongoing, global phase II clinical program evaluating RA101495 SC for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). Ra Pharma is a clinical stage biopharmaceutical company focusing on the development of next-generation therapeutics for the treatment of complement-mediated diseases and is developing RA101495 as a novel, subcutaneously-administered (SC) inhibitor of complement component 5 (C5).

The global, dose-finding phase II clinical program is designed to evaluate the safety, tolerability, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of RA101495 SC in patients with PNH. As of the data cut-off date of November 30, 2017, a total of 29 patients have been dosed with RA101495 SC in three cohorts:

• Eculizumab naïve: 10 patients enrolled, dosing completed
• Eculizumab switch: 16 patients enrolled, dosing ongoing
• Eculizumab inadequate responders: three patients enrolled, dosing ongoing

Eculizumab Naïve Cohort: RA101495 SC met the primary endpoint in eculizumab naïve patients (n=10). In these patients, a rapid, robust, and sustained reduction in lactate dehydrogenase (LDH) levels from baseline to the mean of weeks six to 12 (p=0.002) and near-complete suppression of complement activity were observed (See figure). Fifty percent of eculizumab naïve patients who were transfusion-dependent prior to enrollment have been transfusion-free since commencing RA101495 SC. Based on preliminary data, meaningful improvements in standard measures of quality of life, as shown by the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue score, have been observed, as well as a high level of patient satisfaction with subcutaneous self-administration based on patient surveys completed to date. Furthermore, eight of 10 subjects enrolled in the study have elected to continue treatment with RA101495 SC in a long-term extension study.

Eculizumab Switch Cohort: Interim results from the ongoing switch cohort demonstrate near complete, sustained, and uninterrupted inhibition of complement activity during and after eculizumab washout. The LDH response observed in switch patients is bimodal based on prior transfusion requirements on eculizumab. In transfusion-independent patients from this cohort (n=5), a population segment representing approximately 80% of patients on long-term eculizumab therapy, switching to RA101495 SC has been successful as indicated by stable LDH levels and no episodes of breakthrough hemolysis. Among difficult to treat eculizumab patients who were transfusion-dependent at baseline (n=11) from this cohort, breakthrough hemolysis occurred after switching in seven patients, who all reverted to eculizumab without complications.

Inadequate Responder Cohort: In the U.S.-based cohort of inadequate responders to eculizumab, who have a history of elevated LDH, 3 patients have been enrolled. LDH stabilization and relief of side effects associated with eculizumab intolerance have been observed in the first patient enrolled in this cohort.

Across all cohorts, no meaningful safety or tolerability concerns have been identified after more than 300 patient weeks of cumulative exposure. The majority of adverse events were deemed unrelated to the study drug and the most frequent study drug-related adverse event to date was headache. No meningococcal infections or thromboembolic events have been observed. Out of more than 2,000 doses administered, only seven mild (grade 1) injection site reactions have occurred among 3 patients. Full compliance with once daily subcutaneous self-administration of RA101495 SC has been observed thus far.

“These results support the potential for RA101495 to be a safe, effective, and convenient subcutaneous, self-administered therapeutic option that patients may readily adopt,” said Principal Investigator Anita Hill, M.D., Ph.D., MRCP, FRCPath, Consultant Haematologist for Leeds Teaching Hospitals NHS Trust, UK, and Lead Clinician for the National PNH Service in England. “This is evident from the meaningful and sustained LDH reduction seen in treatment naïve patients, and by maintenance of LDH control in transfusion-independent switch patients, who make up the majority of the eculizumab-treated population.”

“RA101495 has now demonstrated the potential to serve as first-line therapy for newly diagnosed patients with PNH, as well as an attractive alternative for transfusion-free patients switching from eculizumab,” said Doug Treco, Ph.D., President and Chief Executive Officer of Ra Pharma. “We believe the vast majority of PNH patients could benefit from greater access to therapy and the convenience of subcutaneous self-administration. We look forward to engaging with regulators around the world to advance into a registrational program for RA101495 in PNH. We believe the data announced today support the potential utility of RA101495 across the entire spectrum of C5-mediated diseases, including our clinical development programs in gMG, aHUS, and LN.”