Ultomiris Safe, Effective at Resolving Life-threatening Complications of aHUS, Trial Results Show

Ultomiris (ravulizumab-cwvz) is safe and effective at resolving acute and life-threatening complications of atypical hemolytic uremic syndrome (aHUS) in adults with thrombotic microangiopathy (TMA), Phase 3 clinical trial data shows.

Trial findings were reported in the study, “The long-acting C5 inhibitor, Ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment,” published in the journal Kidney International.

aHUS is caused by the progressive destruction of red blood cells due to  dysregulation of the complement system — a set of more than 20 blood proteins that form part of the body’s immune system. The disease often is associated with TMA, a condition in which the small blood vessels found inside the kidneys, become clogged, potentially leading to kidney failure.

Ultomiris is a monoclonal antibody (a lab-made protein) developed by Alexion Pharmaceuticals that has been designed to bind and block the activity of the complement C5 protein, which prevents the over-activation of the complement system and the destruction of red blood cells associated with aHUS.

The medication was approved in 2019 by the U.S. Food and Drug Administration (FDA) for the treatment of adults and children ages 1 month and older who have aHUS.

Compared to Soliris (eculizumab), another complement inhibitor also developed by Alexion that has been approved to treat aHUS, Ultomiris remains active for longer periods of time. For that reason, the medication can be administered less frequently while maintaining the same level of effectiveness.

“A reduction in dosing frequency without sacrificing the immediate and complete C5 inhibition and resolution of TMA is expected to improve patient quality of life by reducing infusion burden and other potential consequences of repeated venous punctures and infusions,” investigators wrote.

Researchers now have reported the findings of a Phase 3 trial (NCT02949128) called aHUS-311 that evaluated the safety and effectiveness of Ultomiris when administered by intravenous infusion in 56 adults with aHUS and TMA.

Patients received an initial loading dose of Ultomiris based on their body weight at day 1, followed by maintenance doses at day 15, and every eight weeks thereafter.

The main goal of the study was to determine the percentage of patients achieving a complete TMA response during the first 26 weeks of the trial. Patients achieved a complete TMA response when their platelet counts were normal, as were the levels of the enzyme lactate dehydrogenase (LDH, lower than 246 U/l), and they experienced a minimum of 25% improvement in kidney function. LDH is an enzyme whose levels can be used as a readout of red blood cells’ destruction.

Improvements in kidney function were evaluated based on the levels of serum creatinine. Treatment safety and additional parameters of kidney function also were evaluated.

From the 56 patients who were eligible for final analyses, 49 completed the initial portion of the trial, and seven discontinued. Study findings revealed that Ultomiris led to a fast, complete, and durable inhibition of the complement system in all patients.

The trial met its primary goal, with more than half (53.6%) of the patients attaining a complete TMA response. Nearly all patients (83.9%) saw a normalization of their platelet counts during the study, and approximately three fourths (76.8%) had normalization of their LDH levels.

More than half (58.9%) of the participants also experienced an improvement in kidney function of at least 25% during the trial. Improvements in estimated glomerular filtration rate (another measure of kidney function) also were achieved by 68.1% of the patients during the first 183 days of the study.

Safety analyses did not reveal any unexpected adverse side effects. Approximately a third (34.5%) of the patients experienced treatment-related side effects, which included headache, diarrhea, and vomiting, and more than half (51.7%) had serious serious side effects that included high blood pressure and pneumonia.

A total of four deaths occurred during the trial, but none were related to Ultomiris.

“Treatment with ravulizumab in adult patients rapidly resolved acute and life-threatening, complement-mediated TMA caused by aHUS, with immediate and complete terminal complement inhibition sustained throughout the initial evaluation period of 26 weeks. Furthermore, patients treated with ravulizumab experienced no unexpected adverse events,” the researchers wrote.

They added that the findings of this trial support the use of Ultomiris to treat adults with aHUS. A similar Phase 3 trial (NCT03131219) assessing the safety and effectiveness of the medication in children and adolescents with aHUS is ongoing.