Long-term Ultomiris Found to Improve Kidney Function in Adults

Adults with atypical hemolytic uremic syndrome (aHUS) continue to show improvements in kidney function, blood parameters, and quality of life after receiving Ultomiris (ravulizumab) for a median of 1.5 years, new analysis of clinical trial data suggests.

The findings were reported in the study “Long-Term Efficacy and Safety of the Long-Acting Complement C5 Inhibitor Ravulizumab for the Treatment of Atypical Hemolytic Uremic Syndrome,” published in the journal Kidney International Reports.

Developed by Alexion Pharmaceuticals, Ultomiris is an antibody-based therapy that works by blocking the activity of the C5 complement protein, preventing the overactivation of the complement system.

In aHUS, the overactivation of the complement system leads to the progressive destruction of red blood cells, which frequently results in kidney problems. One of the most common is thrombotic microangiopathy (TMA), a condition in which the small blood vessels inside the kidneys become clogged, resulting in kidney failure.

The Phase 3 aHUS-311 trial (NCT02949128) was designed to evaluate the safety and effectiveness of Ultomiris in 56 adults with aHUS and TMA.

Participants were given an initial loading dose of Ultomiris based on their body weight on day one, followed by maintenance doses on day 15 and every eight weeks thereafter. Treatment was maintained for 26 weeks.

Previous data from 49 patients who completed the 26-week treatment course showed that more than half (53.6%) attained a complete TMA response, defined as normal platelet counts, normal levels of the enzyme lactate dehydrogenase (LDH; lower than 246 units per liter), and a minimum of 25% improvement in kidney function. LDH is frequently used as a marker of red blood cell destruction, with high levels of the enzyme usually signaling some sort of tissue damage.

Nearly all patients (83.9%) saw a normalization of their platelet counts during the study, and 76.8% had normalization of their LDH levels. More than half (58.9%) experienced improvements in measures of kidney function.

In the new analysis, investigators at the University College London Hospitals in the U.K., along with colleagues at Alexion and other institutions, examined patients’ outcomes after a median follow-up of 76.7 weeks (around 1.5 years).

Of the 56 participants who participated in the original aHUS-311 trial, 49 completed the 26-week initial treatment course and enrolled in its extension phase, in which all continued to receive Ultomiris every eight weeks, at doses depending on their body weight, for up to 4.5 years.

At 52 weeks, eight participants had discontinued the study. Six of them had achieved a complete TMA response in the initial portion of the trial and were stable at the time of discontinuation.

During the extension study, four additional patients achieved a complete TMA response, increasing the overall percentage of responders from 53.6% to 61%.

Among these four patients, three had received a kidney transplant, with one of them achieving a complete TMA response before week 26, although this was only confirmed in the extension portion of the trial.

At the last follow-up, patients showed improvements in their platelet counts and LDH levels. Specifically, 85.7% of the patients reached normal platelet counts, 83.9% had normalization of their LDH levels, and 80.4% saw both normalize.

The estimated glomerular filtration rate, a kidney function test, improved significantly since the start of the trial up to day 351 of follow-up in 30 patients. In 11 others, it remained constant, and worsened in two patients.

While at the start of the trial, 29 of the 56 patients (58.1%) were on dialysis, 10 of the 44 patients (22.7%) required dialysis by day 351.

Among the 29 patients who were undergoing dialysis at the start of the trial, 17 of them stopped it during the first 26 weeks of treatment with Ultomiris and no longer required it during the extension phase.

Levels of fatigue in patients also diminished during the 351 days of follow-up.

All patients experienced at least one side effect. Treatment-related side effects were observed in 20 patients, with the most common being headache (38%), diarrhea (33%), and vomiting (31%). More than half (56.9%) experienced serious adverse events, which included high blood pressure and pneumonia (each in 5.2%). Four deaths were reported in the initial phase of the trial, but none was considered to be related to treatment. No deaths were reported during the extension phase of the study.

Overall, “this analysis of longer-term treatment with [Ultomiris] reveals that administration every 8 weeks is well tolerated and provides clinical improvement in kidney and hematologic [blood] parameters in adult patients with aHUS,” the researchers wrote.

“Continued treatment with [Ultomiris] beyond the initial 26 weeks can provide further clinical improvements as evidenced by the 4 additional patients who achieved complete TMA response during the extension period (overall, 61%) and a substantial reduction in the number and severity of [adverse events] observed,” they concluded.