FDA Extends Review Period for Narsoplimab for HSCT-TMA

The FDA has announced that it will need more time to review the biologics license application (BLA) for narsoplimab as a potential therapeutic option in patients with hematopoietic stem cell transplant–associated thrombotic microangiopathy (HSCT-TMA).¹

This follows a response from the drug developer, Omeros Corporation, to an information request issued by the regulatory agency. The FDA classified the response as a major amendment which requires additional time to adequately review.

The new action date under the Prescription Drug User Fee Act is October 17, 2021.

“We’re pleased with our ongoing interactions with the FDA on the narsoplimab BLA,” Gregory A. Demopulos, MD, chairman and chief executive officer of Omeros, stated in a press release. “Omeros views the information provided in response to FDA’s information request as further supporting the application, and we look forward to making narsoplimab available to [patients with] HSCT-TMA and their physicians as soon as possible.”

The investigational, fully human IgG4 monoclonal antibody was has been shown to elicit complete responses (CRs), as well as lead to improved laboratory markers and encouraging 100-day survival rates in this patient population, according to findings from a phase 2 trial (NCT02222545) that had been presented during the 2020 European Hematology Association Congress.²

Narsoplimab achieved a CR rate of 54% (95% CI, 34%-72%) in the total patient population (n = 28). Among 23 patients who received treatment in accordance with study protocol, who had received 4 weeks or more of dosing, the ORR with the agent was found to be even higher, at 65% (95% CI, 43%-84%).

Eligibility criteria to the phase 2 trial called for patients to be 18 years of age at the time of screening and for them to have persistent HSCT-TMA. Anyone who previously received eculizumab (Soliris) within 3 months before screening, had a positive direct Coombs test, or active systemic bacterial or fungal infection that called for antimicrobial therapy, were excluded from the analysis.

The primary end points of the study included improvement in TMA laboratory markers of platelet count and serum lactate dehydrogenase (LDH) levels, improvement in clinical status, as well as safety and tolerability. Important secondary end points included survival and change from baseline in terms of laboratory markers.

At baseline, patients had a mean age of 48 years and 71% were male. Moreover, 96% of participants had malignant underlying disease and had undergone transplant due to this; 64% of these patients had risk factors like graft-versus-host disease, 75% had significant infection, 14% had noninfectious pulmonary complications, and 50% had neurological signs. Because 93% of patients had multiple risk factors for poor outcomes, the overall population was considered to be high risk.

Additional findings from the trial indicated that narsoplimab also resulted in a rapid increase of platelet counts in most participants; specifically, counts reached a threshold of over 20,000 per uL. Moreover, transfusion independence was defined at about 30,000 per uL (P = .001).

Most patients who received the agent also experienced a downward trend in LDH level (P = .008). Following treatment with the antibody, the majority of patients reported an improvement in haptoglobin change from baseline (P <.001). 

Additionally, the 100-day survival rate following HSCT-TMA diagnosis was 68% in all patients who were given narsoplimab; in those treated per study protocol, this rate was 83%. The 100-day survival rate was highest in a total of 15 patients who were responders to treatment; this rate was 93%.

The most commonly experienced toxicities with narsoplimab included nausea (25%), vomiting (32.1%), diarrhea (28.6%), hypokalemia (25%), neutropenia (25%), and pyrexia (25%). These toxicities were comparable to what is typically observed in patients who have previously undergone transplantation. Twenty-one percent of participants died on the trial due to transplant-associated causes.

Previously, the FDA granted narsoplimab a breakthrough therapy designation for the treatment of patients with high-risk transplant-associated TMA (TA-TMA); the agent has also received an orphan drug designation for use in patients with TA-TMA and complement-mediated TMA prevention.

Narsoplimab is currently under exploration in many phase 3 trials that are being done in other lectin pathway–associated diseases, such as IgA nephropathy (NCT03608033).

References

1. Omeros announces extension of FDA review period for narsoplimab in HSCT-TMA. News release. Omeros Corporation. May 20, 2021. Accessed May 20, 2021. https://bwnews.pr/3oEFq9j
2. Rambaldi A. Smith M, Whitaker S, et al. Narsoplimab (OMS721) for the treatment of adult hematopoietic stem cell transplant-associated thrombotic microangiopathy. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract S262.