Weekly Ultomiris Injections May Be as Effective as Infusions, Phase 3 Data Suggest

Self-administering Ultomiris (ravulizumab) as weekly under-the-skin injections may be as safe and effective in preventing overactivation of the complement system as standard intravenous infusions (given directly into the bloodstream), according to interim data from a Phase 3 clinical trial.

Excessive activation of the complement system — a set of more than 20 blood proteins that form part of the body’s immune system — is associated with a number of diseases, including atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH).

While the ongoing trial is comparing the two formulations of Ultomiris (marketed by Alexion Pharmaceuticals) only in PNH patients, this finding and upcoming one-year safety data are meant to support regulatory submissions to health authorities seeking the approval of the under-the-skin (subcutaneous) formulation for both PNH and aHUS.

Filings to the U.S. Food and Drug Administration and European Medicines Agency (EMA) are expected by early autumn 2021.

“These data demonstrate that subcutaneous Ultomiris may offer the same benefits of immediate, complete and sustained complement inhibition as the intravenous formulation, while also providing an additional treatment choice for those who would rather self-administer their medicine,” John Orloff, MD, Alexion’s executive vice president and head of research and development, said in a press release.

“Delivered via a rapid, patient-friendly delivery device, subcutaneous Ultomiris is an example of Alexion’s continued commitment to innovating for patients. It has the potential to be the first subcutaneous treatment option for both PNH and aHUS and may also offer improved quality of life for patients,” Orloff added.

Ultomiris is a monoclonal antibody (a lab-made protein) designed to block the activity of the complement C5 protein, and prevent the overactivation of the complement system and the destruction of red blood cells seen in aHUS and PNH patients.

While its mechanism of action is similar to Soliris (eculizumab) — another C5 inhibitor developed by Alexion and approved for aHUS and PNH — Ultomiris remains active for longer periods of time, requiring less frequent administration.

Ultomiris, whose dose is dependent on a person’s weight, is delivered intravenously every eight weeks, or every four weeks for pediatric patients weighing less than 20 kgs (about 44 lbs), following a loading dose.

The therapy is approved to treat adults and children ages 1 month and older with aHUS in the U.S., for adults and children with aHUS weighing at least 10 kgs in the European Union, and for adults with PNH in the U.S., European Union, and Japan.

The ongoing, global Phase 3 clinical trial is evaluating the safety, pharmacokinetics (uptake, distribution, and elimination in the body), pharmacodynamics (the drug’s effects on the body), and effectiveness of Ultomiris’ weekly subcutaneous formulation (Ultomiris SC) in adults with PNH in comparison with its intravenous form (Ultomiris IV).

It recruited 136 adults with clinically stable disease who were previously treated with Soliris for at least three months prior to enrollment. Participants, divided into two groups — those weighing 40–60 kgs (88.2–132.3 lbs), and those with 60–100 kgs (132.3–220.5 lbs) — were randomly assigned to either an Ultomiris SC or Ultomiris IV regimen for 71 days (over two months).

All participants were given an initial weight-based intravenous loading dose on day one. On day 15, patients in the subcutaneous group began a once-weekly and self-administered fixed-dose of Ultomiris, while those in the intravenous group were given a single infusion of the therapy.

Ultomiris’ subcutaneous dose was delivered through a patient-friendly device with a pre-filled cartridge that adheres to the body and allows self-administration with a push of a button. The device, called SmartDose preloaded device, was developed in collaboration with West Pharmaceutical Services to provide patients with a more flexible Ultomiris treatment option.

Newly released data showed that the trial met its primary goal, with Ultomiris SC regimen showing non-inferior mean trough therapy levels in the blood compared with Ultomiris IV. Trough therapy levels refer to the levels found immediately before the next dose is administered.

In addition, C5 levels were maintained below the target threshold in all participants, and mean levels of the lactate dehydrogenase enzyme — which are unusually high in people with red blood cell destruction — remained stable and below the normal upper limit.

Preliminary safety data were consistent with the known safety profile of Ultomiris, with no unexpected safety findings and no withdrawals due to adverse events in either group. There were no reports of serious adverse events related to the device, meningococcal infections — a known risk with this type of complement inhibition — or antibodies against the therapy.

Of the 135 patients who completed treatment, 134 chose to enter the study’s extension period, in which all will be treated weekly with Ultomiris SC for up to an additional 182 weeks (nearly three and a half years).

The trial’s secondary goals, including safety, immune responses, pharmacokinetics and pharmacodynamics parameters, quality of life, device performance, and effectiveness measures, will continue to be assessed.