FDA asks for changes in safety strategy before Ultomiris approval

Alexion seeking therapy approval for most adults with NMOSD

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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The U.S. Food and Drug Administration (FDA) has asked for modifications to the risk evaluation and mitigation strategy — known as REMS — for Ultomiris (ravulizumab) before approving the therapy for most adults with neuromyelitis optica spectrum disorder (NMOSD).

Ultomiris already is available in the U.S. for treating other diseases, but only through a restricted program called Ultomiris REMS. That program is meant to reduce the occurrence of potentially life-threatening meningococcal infections whose risk is increased with the therapy.

Meningococcal infections are caused by the Neisseria meningitidis bacterium and affect the brain and spinal cord.

The program requires prescribing physicians to be enrolled in the REMS program and to inform their patients about Ultomiris-associated increased risk of meningococcal infection, its early signs, and the need for immediate medical evaluation in the presence of those signs.

Now, in its complete response letter to Alexion, AstraZeneca Rare Disease, which markets Ultomiris, the FDA requested that Ultomiris REMS include an assessment of patients’ meningococcal vaccination status or preventive administration of antibiotics before treatment.

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Ultomiris approved in EU for adults with AQP4-positive NMOSD

No safety, efficacy concerns raised by FDA

Alexion, AstraZeneca Rare Disease is as a part of AstraZeneca that was created after the latter acquired Alexion Pharmaceuticals, the original developer of Ultomiris.

The letter comes in response to Alexion’s request to approve Ultomiris for adults who are positive for antibodies against the AQP4 protein, the most common target of NMOSD-driving self-reactive antibodies.

Alexion, AstraZeneca Rare Disease is working closely with the FDA regarding next steps for the REMS modifications and remains committed to bringing Ultomiris to people living with NMOSD in the US as quickly as possible.

The agency did not raise any concerns about the therapy’s efficacy or safety in this patient population that were shown in the Phase 3 CHAMPION-NMOSD trial (NCT04201262), whose data supported the regulatory application. No additional analyses or trials were requested.

“Alexion, AstraZeneca Rare Disease is working closely with the FDA regarding next steps for the REMS modifications and remains committed to bringing Ultomiris to people living with NMOSD in the US as quickly as possible,” AstraZeneca announced in a company press release.

The therapy was approved in Japan earlier this year, just after its approval in the European Union, for adults with NMOSD with anti-AQP4 antibodies.

Ultomiris is an antibody that blocks C5, a protein of the immune system’s complement cascade, which is essential to fight off infection but becomes overly active in NMOSD.

This overactivation contributes to the neurological damage seen in NMOSD patients, affecting mostly nerve cells in the optic (eye) nerve and spinal cord. As such, Ultomiris is expected to prevent the immune system from damaging these nerve cells, easing NMOSD symptoms.

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Therapy is similar to Soliris, but given less frequently

The therapy is Alexion’s successor to Soliris (eculizumab), an approved NMOSD treatment with a similar mechanism of action. The second-generation therapy is thought to create less of a treatment burden for some patients, as it remains active for longer in the body, thus requiring less frequent dosing. Specifically, Ultomiris is given once every eight weeks versus once every other week, as is needed with Soliris.

In the global CHAMPION-NMOSD trial, 58 adults with the disorder who were positive for anti-AQP4 antibodies were treated with Ultomiris for up to 2.5 years.

The results showed that none of them experienced a disease relapse during this period. This represented a 98.6% drop in the risk of relapse compared with patients given a placebo in a previous Soliris trial.

Moreover, clinically-important worsening in walking skills was significantly less common among Ultomiris-treated patients than in those in the external placebo group (3.4% vs. 23.4%).

The most common side effects of Ultomiris reported in the study were COVID-19 infection and joint pain. Meningococcal infectionsoccurred in two patients who had been vaccinated against such infection, but both recovered fully.

After completing the trial’s treatment phase, 56 patients chose to enter its long-term extension period, in which they are continuing treatment for up to two years or until Ultomiris is approved, whichever occurs first.

In the U.S., the therapy also is approved for other disorders associated with complement overactivation, including generalized myasthenia gravis, paroxysmal nocturnal hemoglobinuria, and atypical hemolytic uremic syndrome.