Omeros Corporation Reports Updated Results from Narsoplimab HSCT-TMA Clinical Trial and Highlights from Recent Clinical and CMC Meetings with FDA
– Results Surpass FDA-Agreed Efficacy Threshold –
In recent meetings with FDA focused on clinical as well as chemistry, manufacturing and controls (CMC) data, FDA confirmed important aspects of Omeros’ rolling Biologics License Application (BLA) for narsoplimab in HSCT-TMA. The BLA continues on its clear path to completion.
The efficacy threshold agreed with FDA, the updated results from the 28-patient trial, and highlights of the recent FDA meetings are the following:
- 15% is the FDA-agreed efficacy threshold for the primary endpoint (i.e., the complete response rate [CRR]) in the clinical trial
The CRR for the study population, and the lower limit of the 95 percent confidence interval (95% CI), significantly exceed the efficacy threshold:
- 54 percent CRR (95% CI = 34 percent to 72 percent, p-value < 0.0001) in patients who received at least one dose of narsoplimab
- 65 percent CRR (95% CI = 43 percent to 84, p-value < 0.0001) in patients who received the protocol-specified narsoplimab treatment of at least 4 weeks of dosing
As described in the
December 4, 2019press release, the FDA-agreed primary endpoint (the CRR) is the proportion of patients who fully achieve a rigorous set of response criteria, requiring both improvement in HSCT-TMA laboratory markers (platelet count and lactate dehydrogenase [LDH] levels) and improvement in clinical status comprised of organ (renal, pulmonary, gastrointestinal and neurological) function and transfusions (platelet and red blood cells). The full response criteria are provided below.
- The 100-day survival (defined as survival from the day of HSCT-TMA diagnosis) is 68 percent in all treated patients, 83 percent in patients who received at least 4 weeks of narsoplimab treatment as specified by the protocol, and 93 percent in patients who responded to narsoplimab treatment. Experts familiar with the pivotal trial data would expect a 100-day survival rate of less than 20 percent in the trial population.
- Preliminary results of the laboratory secondary efficacy endpoints (change from pre-treatment baseline for each laboratory value) continue to demonstrate meaningful improvement and meet statistical significance in platelet count, LDH and haptoglobin (p < 0.01 in all treated patients).
- The most commonly reported adverse events in the trial were diarrhea, nausea, vomiting, hypokalemia, neutropenia and fever – all common in stem-cell transplant patients.
- Six deaths occurred during the trial. These were due to sepsis, progression of the underlying disease, and graft-versus-host disease, all common causes of death in this patient population.
The treated population had multiple high-risk features that portend a poor outcome, including the persistence of HSCT-TMA despite modification of immunosuppression (which was a criterion for entry into the trial), graft-versus-host disease, significant infections, non-infectious pulmonary complications and neurological findings. Patients in the trial had a high expected mortality rate, with 93% of them having multiple risk factors.
“The efficacy and safety data from the pivotal trial with narsoplimab are encouraging,” said
Complete clinical trial data will be presented by
Recent FDA Meeting Highlights and CMC Updates
- FDA confirmed that the number of HSCT-TMA patients enrolled is sufficient for the BLA’s filing and review for approval. FDA agreed to stopping enrollment.
- FDA requested near-term manufacturing dates for narsoplimab so that FDA’s pre-approval inspections could be scheduled.
- FDA and Omeros’ reached agreement on CMC requirements for stability data and release assays.
- Omeros elected to accelerate the manufacturing schedule for a one-time set of five narsoplimab process validation and commercial lots. These lots were successfully manufactured by Omeros’ manufacturing partner Lonza, satisfy the BLA requirements and can be used for commercial sale following approval.
“The non clinical sections of our BLA have been submitted, our CMC campaign is progressing well with process validation and commercial lots already manufactured, and our pivotal trial is complete,” stated
In addition to its HSCT-TMA program, Omeros is enrolling its narsoplimab Phase 3 clinical trials for immunoglobulin A (IgA) nephropathy and atypical hemolytic uremic syndrome (aHUS). Narsoplimab has been granted, for both HSCT-TMA and IgA nephropathy, FDA’s breakthrough therapy designation as well as orphan drug designations from FDA and the
Primary Efficacy Endpoint
To be considered a responder, a patient must achieve the primary endpoint of complete HSCT-TMA response defined by improvement in laboratory markers and improvement in clinical status.
Criteria for improvement in laboratory markers are LDH less than 1.5 x upper limit of normal AND improvement of platelet count measures:
- For patients with baseline platelet count ≤20,000/μL, response requires tripling over baseline platelet count, a post-baseline platelet count >30,000/μL, and freedom from platelet transfusion
- For patients with baseline platelet count >20,000/ μL, response requires: an increase in platelet count by ≥50%, a post-baseline platelet count >75,000 /μL, and freedom from platelet transfusion
Criteria for improvement in clinical status requires at least one of the following:
- Renal response – requires >40% reduction in creatinine, or normalization of creatinine and >20% reduction in creatinine, or discontinuation of renal replacement therapy
- Pulmonary response – requires extubation and discontinuation of ventilator support, or discontinuation of non-invasive mechanical ventilation (continuous positive pressure ventilation)
Gastrointestinal response – applicable only to patients with biopsy-proven gastrointestinal HSCT-TMA and requires improvement in gastrointestinal function as determined by the
Mount Sinai Acute GVHD International Consortium(MAGIC) criteria
- Neurological response – requires improvement in reversible neurological conditions (e.g., cessation of seizures), or stabilization of irreversible neurological conditions (e.g., stability of neurological deficits following stroke without further deterioration or subsequent strokes)
- Freedom from transfusion – only applicable if patient was undergoing transfusion at baseline
Omeros is an innovative biopharmaceutical company committed to discovering, developing and commercializing small-molecule and protein therapeutics for large-market as well as orphan indications targeting complement-mediated diseases, disorders of the central nervous system and immune-related diseases, including cancers. In addition to its commercial product OMIDRIA® (phenylephrine and ketorolac intraocular solution) 1%/0.3%, Omeros has multiple Phase 3 and Phase 2 clinical-stage development programs focused on complement-mediated disorders and substance abuse. In addition, the company has a diverse group of preclinical programs including GPR174, a novel target in immuno-oncology that modulates a new cancer immunity axis recently discovered by Omeros. Small-molecule inhibitors of GPR174 are part of Omeros’ proprietary G protein-coupled receptor (GPCR) platform through which it controls 54 new GPCR drug targets and their corresponding compounds. The company also exclusively possesses a novel antibody-generating platform.
Hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) is a significant and often lethal complication of stem cell transplants. This condition is a systemic, multifactorial disorder caused by endothelial cell damage induced by conditioning regimens, immunosuppressant therapies, infection, GvHD, and other factors associated with stem cell transplantation. Endothelial damage, which activates the lectin pathway of complement, plays a central role in the development of HSCT-TMA. The condition occurs in both autologous and allogeneic transplants but is more common in the allogeneic population. In
Narsoplimab, also known as “OMS721,” is an investigational human monoclonal antibody targeting mannan-binding lectin-associated serine protease-2 (MASP-2), a novel pro-inflammatory protein target and the effector enzyme of the lectin pathway of complement. Importantly, inhibition of MASP-2 does not appear to interfere with the antibody-dependent classical complement activation pathway, which is a critical component of the acquired immune response to infection. Omeros controls the worldwide rights to MASP-2 and all therapeutics targeting MASP-2.
Phase 3 clinical programs are in progress for narsoplimab in hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), in immunoglobulin A (IgA) nephropathy, and in atypical hemolytic uremic syndrome (aHUS). The FDA has granted narsoplimab breakthrough therapy designations for HSCT-TMA and for IgA nephropathy; orphan drug status for the prevention (inhibition) of complement-mediated thrombotic microangiopathies, for the treatment of HSCT-TMA and for the treatment of IgA nephropathy; and fast track designation for the treatment of patients with aHUS. The
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