It was approved by the U.S. Food and Drug Administration (FDA) in 2019 to treat adults and children with aHUS. In Europe, Ultomiris has received marketing authorization for the treatment of paroxysmal nocturnal hemoglobinuria, a disease characterized by the excessive breakdown of red blood cells.
How does Ultomiris work?
The body’s immune system uses the complement pathway to mark pathogens for targeted destruction by immune cells. In aHUS, mutations in complement pathway genes, such as CFH, MCP (CD46), and CFI, lead to the uncontrolled activation of the alternative complement pathway, leading to thrombotic microangiopathy (TMA) or blood clots in small blood vessels.
The alternative complement pathway is characterized by the cleavage of the complement protein C5 into C5a and C5b fragments. C5a is a pro-inflammatory molecule whereas C5b combines with other proteins to form a terminal membrane complex called C5b-9, which is known to promote clotting within blood vessels by aggregating platelets.
The mechanism of action of Ultomiris is similar to that of Soliris (eculizumab). Like Soliris, Ultomiris inhibits the cleavage of the complement factor C5 into C5a and C5b. This prevents the formation of the C5b-9 complex and stops clotting within blood vessels. Ultomiris does not affect the earlier components of the complement pathway so immunity from pathogens is not compromised.
Ultomiris in clinical trials
An ongoing Phase 3 clinical trial (NCT02949128), called aHUS-311, is studying the safety and efficacy of Ultomiris in 58 adolescent and adult aHUS patients, who have not been previously treated with any complement inhibitor. The trial is expected to be completed in July 2023.
Top-line results from the study showed that Ultomiris was well-tolerated and met its primary objective of achieving a complete TMA response in 53.6% of patients after an initial 26-week treatment period. A complete TMA response is characterized by reduced hemolytic anemia (loss of red blood cells) as measured by the normalization of lactate dehydrogenase (LDH) levels; reduced thrombocytopenia (low platelet count) as measured by normalization in platelet count; and better kidney function as measured by an improvement of more than 25% in serum creatinine level from baseline.
Another Phase 3 clinical trial (NCT03131219), called aHUS-312, is currently recruiting participants in the U.S., Europe, U.K., Japan, and Korea to assess the safety and efficacy of Ultomiris in children and adolescents with aHUS. The trial aims to recruit 28 patients: children younger than 18 who have not been previously treated with a complement inhibitor, or adolescents between 12 and 18 who have received complement inhibitor treatment. The trial is expected to be completed in May 2025.
Data from an interim analysis of 14 participants showed that 71% of patients met the primary goal of the trial by achieving a complete TMA response within the first 26 weeks of treatment. The results also showed that 93% of the children achieved normalization in platelet counts, 86% achieved normalization in LDH levels, and 79% showed significant improvement in kidney function.
The dosage of Ultomiris is based on the patient’s body weight. The treatment is administered once every eight weeks in adults and once every four to eight weeks in children.
The Ultomiris antibody molecule has four point mutations that help in extending the half-life of the treatment for less frequent dosing compared to Soliris, which needs to be administered once every two weeks.
Patients on Ultomiris therapy are at an increased risk of acquiring life-threatening meningococcal infections and must be immunized at least two weeks before starting therapy.
Ultomiris is only available through the FDA’s risk evaluation and mitigation strategy program, which requires a specially certified healthcare provider to evaluate whether the benefits of the therapy outweigh the risks of serious side effects.
Last updated: Feb. 12, 2020
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