Omeros Corporation (NASDAQ: OMER) today announced additional positive data in the company's Phase 2 clinical trial of OMS721 for the treatment of thrombotic microangiopathies (TMAs). TMAs are a family of rare, debilitating and life-threatening disorders characterized by excessive thrombi (clots) – aggregations of platelets – in the microcirculation of the body's organs, most commonly the kidney and brain. OMS721 is Omeros' lead human monoclonal antibody in its mannan-binding lectin-associated serine protease-2 (MASP-2) program for the treatment of TMAs, including atypical hemolytic uremic syndrome (aHUS).
The Phase 2 trial is designed to enroll primarily aHUS patients but can also enroll patients with thrombotic thrombocytopenic purpura (TTP) and hematopoietic stem cell transplant (HSCT)-related TMA. The trial has fully enrolled the first and second cohorts and is currently completing the third and final planned cohort of its dose-ranging stage. In each three-patient cohort, OMS721 is dosed for four weeks. Data from the first (low-dose) cohort were released on February 19, 2015. Today the company is releasing data from its second (mid-dose) cohort and data to date from its third (high-dose) cohort.
Three patients were treated in the second or mid-dose cohort, two of whom have aHUS and one with TTP. Both patients with aHUS were on renal dialysis prior to and at the time of study enrollment. Based on the positive data from the mid-dose cohort, the high-dose cohort was initiated and an aHUS patient has already completed the study treatment period. No patient with HSCT-related TMA has yet completed dosing with OMS721. The data referenced for all patients include measures to one week following the last dose.
A rare and devastating family of disorders, TMAs are characterized by thrombi or clumps of aggregated platelets in small blood vessels, which lead to thrombocytopenia (below-normal platelet counts) and schistocytes (fragmentation in red blood cells) that can cause dangerously low oxygen levels in organs like the brain and kidney as well as anemia. Thrombotic microangiopathies are life-threatening and can occur both in children and adults. While thrombi, thrombocytopenia and schistocytes are hallmarks of TMAs, other markers of damage within the blood vessels include an elevated plasma lactate dehydrogenase (LDH) and undetectable or reduced plasma haptoglobin levels. In addition, an elevated creatinine level – a result of the kidney damage caused by thrombi – is an indicator of impaired kidney function in patients who are not on renal dialysis.
As in Alexion's clinical trials supporting both U.S. and European regulatory approval of Soliris® for the treatment of aHUS, this Phase 2 clinical trial, given the life-threatening nature of the disease, has no placebo arm. Soliris trials used change from baseline in platelet count as a primary endpoint to obtain approval for the treatment of aHUS. Similarly, the pre-specified primary endpoint in this Phase 2 trial is change from baseline in platelet count. In this trial, platelet counts in all three aHUS patients in the mid- and high-dose cohorts (two in the mid-dose and one in the high-dose cohort) were normal after the treatment period, with a statistically significant mean increase from baseline of approximately 68,000 platelets/mL (p = 0.0055).
In the mid-dose cohort, the two patients with plasma therapy-resistant aHUS demonstrated:
- 47% increase in mean platelet count, resulting in both patients having counts in the normal range
- 86% decrease in mean schistocyte count, with schistocytes disappearing in one patient
- 71% increase in mean haptoglobin with both patients reaching the normal range during treatment, one slipping slightly below normal at one week following the last dose
- 5% decrease in the mean levels of LDH, with levels in both patients remaining slightly elevated above normal range
The mid-dose-cohort patient with TTP required repeated plasma infusion therapy prior to entering the study. Laboratory parameters did not show consistent improvement, but the patient did not require plasma therapy during treatment with OMS721 and, to date, has not required it since completing treatment.
The first patient in the high-dose cohort – a plasma therapy-resistant aHUS patient with additional complicating disorders including hepatitis C, cryoglobulinemia and lymphoma – has also completed treatment with OMS721. Prior to OMS721 treatment, the patient required repeated dialysis. Throughout treatment and following completion of the OMS721 course, the patient to date has remained off dialysis. Hematological and renal parameters showed:
- 63% improvement in platelet count, returning to normal levels
- 100% decrease in schistocytes
- Haptoglobin increased from an undetectable level and normalized
- 43% decrease in LDH, resulting in a level just slightly above normal
- 24% reduction in creatinine level
As expected, patients with aHUS in the mid- and high-dose cohorts demonstrated more consistent and robust improvement in efficacy measures than patients in the low-dose cohort. As in the low-dose cohort, the drug was well tolerated by all patients in the mid- and high-dose cohorts throughout the treatment period.
There have been no confirmed clinically meaningful drug-related adverse events in any clinical trials with OMS721. To date, two clinically meaningful adverse events were considered possibly related to OMS721 when first observed because an infectious etiology could not be ruled out at diagnosis, but all cultures subsequently proved negative. Specifically, one patient in the low-dose cohort was reported as possibly having an infection (as described in the company's February 19, 2015 press release); however, all cultures were negative and no infection was identified. Another patient had significant diarrhea, but all tests for gastrointestinal pathogens were negative and the patient was receiving immunosuppressive therapy, including a drug very commonly associated with diarrhea. In addition, animal chronic toxicity studies have been completed and no notable adverse findings were observed. The FDA has cleared OMS721 for chronic dosing in clinical trials. Physician-requested compassionate use is ongoing, and all patients in the compassionate-use program are reported by their physicians to be doing well.
"We are excited by the data from this Phase 2 clinical trial with OMS721, both with respect to aHUS and TTP patients," stated Gregory A. Demopulos M.D., chairman and chief executive officer of Omeros. "Based on clinical data, we expect that we can deliver OMS721 either subcutaneously or intravenously at a frequency and dose that are both convenient and comfortable for patients while effectively eliminating lectin-pathway activity. Compassionate use in aHUS patients has begun, and we look forward to advancing to the fixed-dose stage of the trial and discussing Phase 3 trial design with the FDA later this year."