Ultomiris Normalizes Blood Markers, Improves Kidney Function in aHUS Patients, Phase 3 Trial Shows

Treatment with Ultomiris (ravulizumab-cwvz) normalized platelet counts, eased hemolysis  (destruction of red blood cells), and improved kidney function in a Phase 3 trial in patients with atypical hemolytic uremic syndrome (aHUS) who had not been treated with complement inhibitors.

Specifically, 53.6% of patients showed complete thrombotic microangiopathy (TMA) response — defined by hematologic (blood parameters) normalization and improved kidney function — with the Alexion therapy over the initial 26-week treatment period. Also, Ultomiris enabled immediate and complete inhibition of the complement C5 protein, which was maintained over the entire eight-week dosing interval.

Of note, uncontrolled activation of the complement system — a set of more than 20 blood proteins that are part of the body’s immune defenses — mediates TMA, which refers to blood clots in small blood vessels.

The global, multicenter trial (NCT02949128) included 56 adults to evaluate the safety and efficacy of intravenous Ultomiris. An extension period of up to two years is ongoing.

After a loading dose on day 1 that depended on the patients’ weight — 2,400 mg within 40-60 kg, 2,700 mg within 60-100 kg and 3,000 mg at or above 100 kg — the participants received higher maintenance doses (3,000 mg within 40-60 kg, 3,300 mg within 60-100 kg and 3,600 mg at or above 100 kg) on day 15 and once every eight weeks thereafter.

The primary goal was complete TMA response. TMA is characterized by reduced platelet count (thrombocytopenia), hemolytic anemia resulting from hemolysis, and acute kidney injury.

To achieve complete TMA response, participants had to show normalized platelet count and lactate dehydrogenase level — increased in people with hemolysis — as well as a minimum 25% improvement in serum creatinine (a marker of kidney function) from baseline at the same time at least once. Also, each criterion had to be met for at least 28 consecutive days.

The results demonstrated that Ultomiris provided 83.9% of the patients with reduced thrombocytopenia, 76.8% reduced hemolysis, and 58.9% improved kidney function.

“We are very pleased with these data, which demonstrate that Ultomiris can provide clinically meaningful benefits to patients with aHUS,” John Orloff, MD, Alexion’s executive vice president and head of research & development, said in a press release. “The results met the high bar of complete TMA response and provide confidence that Ultomiris has the potential to become the new standard of care for patients with aHUS.”

Alexion is “preparing regulatory submissions for Ultomiris in aHUS in the U.S., European Union, and Japan as quickly as possible,” Orloff said. Ultomiris has already received orphan drug designation for under-the-skin treatment of aHUS in the United States.

Safety results were in line with those of Phase 3 trials in patients with paroxysmal nocturnal hemoglobinuria (PNH). Similar to aHUS, chronic, and harmful, activation of the terminal complement cascade is key in PNH and anti-acetylcholine receptor antibody-positive myasthenia gravis (MG).

The most common adverse events were headache, diarrhea, and vomiting. The most frequent serious adverse events were pneumonia and hypertension. None of the four deaths that occurred was considered related to treatment with Ultomiris. Also, no case of meningococcal infection — a known risk with terminal complement inhibition — was observed. Detailed results will be presented at a future medical congress.

“I am very excited about these data and the potential for an effective new treatment option that can provide hematologic normalization and improved kidney function, including the potential to stop dialysis, when administered every eight weeks,” said Spero Cataland, MD, a study investigator and hematologist at Ohio State University Wexner Medical Center.

Ultomiris is being evaluated in an international Phase 3 study (NCT03131219) in children and adolescents with aHUS who have or have not used a complement inhibitor. Enrollment for a planned total of 23 patients is ongoing. More information about locations and contacts can be found here.

In the U.S., Ultomiris is an approved treatment for adults with PNH. Regulatory authorities in the E.U. and Japan are reviewing applications for similar approvals.

The company plans to start another Phase 3 study of Ultomiris delivered under the skin once weekly in patients with aHUS and PNH. Ultomiris’ development for patients with generalized MG and neuromyelitis optica spectrum disorder is also planned.