The U.S., European Union, and Japan have approved the treatment for adults and children with aHUS. They also have approved it to treat paroxysmal nocturnal hemoglobinuria (PNH), a disease characterized by the excessive breakdown of red blood cells.
How does Ultomiris work?
The immune system uses the complement pathway to mark pathogens for targeted destruction. In aHUS, mutations in complement pathway genes, such as CFH, MCP (CD46), and CFI, lead to the uncontrolled activation of the alternative complement pathway. This leads 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 molecule that promotes inflammation. C5b combines with other proteins to form a terminal membrane complex called C5b-9. This promotes clotting within blood vessels by aggregating platelets.
The mechanism of action of Ultomiris is similar to that of Soliris (eculizumab) — also developed by Alexion and approved to treat aHUS. Both medications inhibit the cleavage of the complement factor C5 into C5a and C5b. In this way, they may prevent the formation of the C5b-9 complex and clots within blood vessels. Ultomiris does not affect the earlier components of the complement pathway. Therefore, it does not compromise immunity against pathogens.
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 received any complement inhibitor previously. Researchers expect to complete the trial in July 2023.
Top-line results from the study showed that patients tolerated Ultomiris well. The trial also 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 lower hemolytic anemia (loss of red blood cells) that researchers measure by: the normalization of lactate dehydrogenase (LDH) levels; reduced thrombocytopenia (low platelet count), which they measure by normalization in platelet counts; and better kidney function that they measure by an improvement of more than 25% in serum creatinine levels from baseline.
Another Phase 3 clinical trial (NCT03131219), called aHUS-312, is assessing the safety and efficacy of Ultomiris in children and adolescents with aHUS. Researchers expect to complete this trial 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. Moreover, 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. Doctors administer the treatment directly into the bloodstream once every eight weeks in adults, and once every four to eight weeks in children. Four point mutations in the sequence of Ultomiris extend its half-life. This allows the medication to remain active for longer periods of time. Therefore, patients require less-frequent dosing with Ultomiris than with Soliris, which doctors administer once every two weeks.
Alexion also is evaluating the safety and effectiveness of self-administered, weekly, under-the-skin injections of Ultomiris in adults with PNH. The company expects that these data will support regulatory submissions to health authorities seeking the approval of this formulation for both PNH and aHUS.
In the EU, doctors can prescribe Ultomiris to patients who have never used a complement inhibitor, as well as those who’ve been receiving Soliris for at least three months and are responding to it.
Patients on Ultomiris are at a higher risk of acquiring life-threatening meningococcal infections. So, they must receive an immunization at least two weeks before starting therapy.
Ultomiris is available only through the U.S. Food and Drug Administration (FDA)’s risk evaluation and mitigation strategy program. This program requires a specially certified healthcare provider to evaluate whether the benefits of the therapy outweigh the risks of serious side effects.
The FDA approved a higher dosage of Ultomiris (100 mg/mL) in September 2020. The Committee for Medicinal Products for Human Use (CHMP) also has recommended that the higher dosage be approved in the European Union. The European Commission (EC) is expected to give its final decision in November 2020.
Last updated: Oct. 30, 2020
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