Phase 3 Trials to Support Requests for Two New gMG Therapies, UCB Says

Both zilucoplan and rozanolixizumab, UCB’s experimental therapies for generalized myasthenia gravis (gMG), safely and effectively reduced symptom severity and their impact on daily activities, while improving patients’ quality of life, top-line data from two Phase 3 trials show.

Zilucoplan works by blocking the complement system, a part of the immune system thought to be implicated in the damaging immune responses that drive MG, while rozanolixizumab reduces the time immunoglobulin G (IgG) antibodies, such as those mounting these abnormal immune responses, remain in circulation.

“Every person living with gMG is unique, so a one-size-fits-all treatment approach will never be appropriate,” Iris Loew-Friedrich, UCB’s executive vice president and chief medical office, said in a press release.

“This is why at UCB we are investigating two medicines with different [mechanisms of action],” Loew-Friedrich said, as “this unique approach means we may be able to offer physicians and patients a range of treatment options to meet the individual needs of many different patients.”

Based on the positive RAISE and MycarinG trial findings, UCB plans to file applications to regulatory agencies in the U.S., Europe, and Japan later this year seeking the approval of both therapies, given through under-the-skin injections, for adults with gMG.

These results, along with findings from a real-world smartphone data collection study, were presented through four posters at the 14th Myasthenia Gravis Foundation of America (MGFA) International Conference on Myasthenia and Related Disorders, being held in Miami, May 10–12. Poster abstracts can be found here.

The RAISE trial

In the poster, “Outcomes from Raise: A Randomized, Placebo-Controlled, Double-Blind, Phase 3 Trial of Zilucoplan In Generalized Myasthenia Gravis,” researchers provided additional data from the international Phase 3 RAISE trial (NCT04115293).

The study assessed zilucoplan’s three-month safety and effectiveness in 174 adults with gMG and antibodies against the acetylcholine receptor (AChR), the most common type of MG-causing antibody. Under-the-skin injections of either zilucoplan (0.3 mg/kg; 86 patients) or a placebo (88 patients) were self-administered daily at home.

As previously reported, top-line data showed that RAISE met both its main and secondary goals, with zilucoplan being superior to a placebo at easing symptom severity and how they affected daily activities, and improving quality of life.

In addition, a significantly higher proportion of zilucoplan-treated patients showed a three-point or greater reduction in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale and a five-point or greater reduction in the Quantitative Myasthenia Gravis (QMG) score relative to those on a placebo.

Both MG-ADL and QMG assess symptom severity — with higher scores indicating more disability — but the former also considers how symptoms impact daily activities.

Notably, all of these benefits were observed from the first week of treatment, suggesting that zilucoplan has “the potential to provide rapid, consistent disease control earlier in the disease course,” said James F. Howard, MD, RAISE’s lead investigator and a professor of neurology, medicine, and allied health at the University of North Carolina at Chapel Hill School of Medicine.

The therapy was generally well-tolerated, showing a similar rate of side effects to placebo (76.7% vs. 70.5%), and with the most common being injection site bruising, headache, diarrhea, and MG worsening.

“These findings are an encouraging sign that we may be able to meet patients’ needs effectively, with treatments that are minimally invasive and well tolerated,” Howard said.

Patients completing the trial could choose to enroll in an open-label extension study, called RAISE-XT (NCT04225871), in which all are receiving the experimental therapy for a longer period of time.

Zilucoplan was designated an orphan drug in the U.S. for treating MG, which is meant to help accelerate the therapy’s clinical development and regulatory review.

The MycarinG trial

Detailed top-line results from the international Phase 3 MycarinG study (NCT03971422) were presented in two posters.

One was titled, “Efficacy and Safety of Rozanolixizumab In Patients with Generalized Myasthenia Gravis: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase 3 Study (MycarinG),” while the other was called, “Patient-Reported and Quality of Life Outcomes from MycarinG, A Randomized, Placebo-Controlled, Double-Blind, Phase 3 Trial of Rozanolixizumab In Generalized Myasthenia Gravis.”

In the trial, 200 gMG adults with antibodies against AChR or muscle-specific kinase — the second most common target of MG — were randomly assigned to receive weekly under-the-skin injections of either one of two doses of rozanolixizumab (7 or 10 mg/kg) or a placebo for 1.5 months. About 67 patients were assigned to each group.

Results showed that, similar to zilucoplan, use of rozanolixizumab at either dose was superior to a placebo at significantly easing symptom severity and their impact on daily activities.

Several quality-of-life measures, including muscle weakness fatigability, physical fatigue, and bulbar muscle weakness, were also assessed through the MG Symptoms patient-reported outcome (PRO) measure, which was developed by UCB together with MG patients. Bulbar muscles are those needed for chewing, swallowing, and speaking.

PRO measures “help provide greater insight into disease impact and more granular detail on the effect of treatments than traditional endpoints,” UCB stated in the release.

Significant improvements in all three MG Symptoms PRO subdomains were observed with both rozanolixizumab doses relative to a placebo, further emphasizing the therapy’s benefits. Evaluation of this PRO measure is ongoing, UCB noted.

Rozanolixizumab-treated patients also showed a greater than 70% reduction in the mean maximum IgG levels, and a drop in anti-AChR antibody levels that was in line with the total IgG reduction.

The therapy was generally safe and well-tolerated, with most adverse events being mild to moderate in severity, and the most common including headache, diarrhea, fever, and nausea. Still, rozanolixizumab was associated with a higher proportion of side effects relative to a placebo (81.3–82.6% vs. 67.2%).

Vera Bril, MD, MycarinG’s lead investigator, said these results “are extremely encouraging, and demonstrate the potential of rozanolixizumab as a new, effective and flexible treatment option to help ease the day-to-day burden of this challenging disease and improve treatment outcomes for patients.”

Bril is a professor of medicine (neurology) and the director of the neuromuscular section at the University of Toronto in Canada.

An open-label extension study (NCT04650854) is currently assessing the therapy’s long-term safety and effectiveness in patients who completed previous rozanolixizumab trials.

Real-world data via smartphones

Data from a three-month observational study carried out by UCB in collaboration with the digital health company Sharecare were presented in the poster, “A Decentralized, Prospective Observational Study to Collect Real-World Data from Patients with Myasthenia Gravis Using Smartphones.”

Results showed that collecting real-world data from gMG patients through a smartphone app is feasible and may provide greater insight into the disease’s burden. Notably, this approach allowed for the identification of unique subtypes of gMG exacerbation, or worsening, with specific symptoms.

“Our gMG pipeline is supported by a holistic and integrated platform of support services and digital innovation that aims to deliver broad access to seamless and flexible services across the gMG care continuum,” said Charl van Zyl, UCB’s executive vice president of neurology and head of Europe/international markets.