Zaltenibart alone shows promise as PNH treatment in small trial
Benefits seen in hard-to-treat adults with medication's use as single therapy
Omeros’ zaltenibart (OMS906) as a single therapy has shown promise as a treatment for paroxysmal nocturnal hemoglobinuria (PNH) in a small clinical study, normalizing signs of hemolysis, or red blood cell destruction, in adults with hard-to-treat disease, according to new interim data.
The trial enrolled PNH patients who failed to respond to Ultomiris (ravulizumab), a PNH treatment approved in the U.S. and the European Union. The participants first received a combination of zaltenibart and Ultomiris, and then switched to the experimental therapy alone, according to Omeros.
Meanwhile, the company met with U.S. Food and Drug Administration (FDA) and EU regulators to discuss the Phase 2 clinical trial (NCT05972967), as well as data from nonclinical programs, in support of a Phase 3 study for zaltenibart in PNH. After both regulatory agencies agree with a proposed study design, Omeros can soon begin enrollment in that Phase 3 trial, which is expected to start early next year.
The “successful end-of-Phase-2 meetings with both FDA and European regulators together with the manufacturing of sufficient drug supply enable us to advance directly into Phase 3 PNH enrollment, planned for early 2025,” Gregory A. Demopulos, MD, Omeros’ chairman and CEO, said in a company press release.
Zaltenibart expected to work without comprising immune responses
PNH is marked by hemolysis, or the destruction of red blood cells that carry oxygen through the body. This leads to anemia and other hallmark PNH symptoms, including fatigue, dizziness, and shortness of breath. The rare disease is caused by genetic mutations that render blood cells, particularly red blood cells, vulnerable to attacks by the complement system, a group of proteins that normally work together to protect against infection.
All approved PNH therapies work to stop hemolysis by blocking complement activation. Still, suppressing this part of the immune system can increase the risk of infections.
Zaltenibart, which can be given as an under-the-skin (subcutaneous) or into-the-vein (intravenous) injection, blocks MASP-3, a protein that functions in a specific branch of the complement system called the alternative complement pathway. As such, the PNH treatment candidate is expected to stop hemolysis without compromising immune responses against infections.
In an earlier Phase 1 study, zaltenibart was well tolerated in healthy volunteers, leading to sustained inhibition of MASP-3.
A follow-up Phase 1b proof-of-concept study (NCT05889299), which enrolled 10 PNH adults with severe anemia who had never received a complement inhibitor, showed monthly doses of zaltenibart (5 mg/kg) normalized all markers of hemolysis.
Omeros then launched the Phase 2 trial to test zaltenibart in PNH patients who failed to respond to Ultomiris. The participants received one of two doses of zaltenibart (3 mg/kg or 5 mg/kg) at eight-week intervals in combination with Ultomiris. Those who responded were then switched to 5 mg/kg of zaltenibart alone, or as a monotherapy, also at eight-week intervals.
New interim data from the trial will be presented at the Annual Meeting of the American Society of Hematology (ASH) in December. The presentation will be titled “Monotherapy Treatment with Zaltenibart (OMS906), an Alternative Pathway Masp-3 Inhibitor, Improved Key Hematologic Parameters in Patients with PNH with a Suboptimal Response to Ravulizumab: Interim Results from a Phase 2 Proof-of-Concept Study.”
PNH treatment candidate well tolerated thus far in clinical studies
While 13 patients, ages 23-80, were initially enrolled, one stopped participating due to a treatment-emergent serious adverse event related to abnormal liver biomarker levels. Before zaltenibart, six patients had received a red blood cell transfusion.
During the combination phase, adding zaltenibart led to rapid and sustained responses with marked improvements in the levels of hemoglobin, the protein that carries oxygen in red blood cells, according to Omeros. At the study’s start, or baseline, mean hemoglobin levels were 9.26 grams per deciliter (g/dL), which rose by a mean of 3.39 g/dL at one month and 3.27 g/dL at 5.5 months.
After 10 responding patients (83%) switched to zaltenibart alone, the responses seen in the combination phase were sustained in the monotherapy phase. Four weeks after the first monotherapy dose at 5.5 months, the mean hemoglobin across all 10 patients was 13.31 g/dL. Immediately before the second dose at 7.4 months, the mean hemoglobin was 12.72 g/dL, and 12.36 g/dL before the third dose at about nine months in seven patients.
One month after the third dose, the mean hemoglobin levels in six patients were sustained at 12.77 g/dL at 10 months, representing a significant 3.85 g/dL increase in hemoglobin from baseline.
Five of these six patients achieved hemoglobin levels above 12 g/dL, within the normal range, with an improvement of more than 2 g/dL. Also, at 10 months, the mean absolute reticulocyte count, a sign of hemolytic anemia, normalized compared with baseline in these six patients. All but one remained transfusion-free.
Zaltenibart was well tolerated, with about half of patients (46.2%) experiencing mild to moderate treatment-related adverse events (AEs). Common AEs included headache, sore throat, fatigue, cough, and low blood platelet counts. Less frequent AEs were COVID-19, common cold, nasal congestion, bladder inflammation, joint pain, and abdominal discomfort. About 1 in 6 (15.4%) had extravascular hemolysis, which occurs outside blood vessels. No meningococcal infections or deaths were reported.
About the Author
