Anti-inflammatory Molecule Safely and Quickly Treats Generalized MG, Phase 2 Trial Reports

An anti-inflammatory molecule, known as the complement inhibitor zilucoplan, was seen to significantly ease disease severity in generalized myasthenia gravis (gMG) patients at its higher dose and to have a favorable safety profile, data from a Phase 2 clinical trial show.

These results informed the dose chosen — 0.3 mg/kg — for the ongoing Phase 3 RAISE trial (NCT04115293), currently enrolling up to 130 patients at  multiple locations in the United States.

The study, “Clinical Effects of the Self-administered Subcutaneous Complement Inhibitor Zilucoplan in Patients With Moderate to Severe Generalized Myasthenia Gravis:Results of a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial,” was published in JAMA Neurology.

Zilucoplan is a small molecule originally developed by Ra Pharmaceuticals, now part of UCB. It works by blocking the activity of complement 5 (C5), a protein involved in the complement system — a group of blood proteins that drive inflammation upon activation. The investigative therapy is given via daily subcutaneous (under-the-skin) injection.

In the Phase 2 clinical trial (NCT03315130) due to conclude in April, 44 people with gMG were randomized to treatment with zilucoplan at one of two doses (0.1 or 0.3 mg/kg), or to a placebo, daily for 12 weeks. All were positive for anti-acetylcholine receptor antibodies, the most common cause of MG, and all had moderate to severe gMG, as indicated by Quantitative Myasthenia Gravis (QMG) scores of at least 12 (average 18.8).

The QMG is a 13-item scale assessing muscle weakness, with each item scored from zero to three points. A total score of zero indicates no weakness, while 39 marks severe weakness.

Before starting treatment, the three groups were comparable in terms of demographic and disease-specific variables. Average ages ranged from 45.5 to 54.6 years, and over three-quarters of all participants were white. All but one patient had previously received some kind of MG treatment, the most common being Mestinon (pyridostigmine) and corticosteroids.

The trial’s primary goal (endpoint) was changes in QMG scores after 12 weeks. A significantly greater decrease in these scores — from baseline to week 12 — were seen in the 0.3 mg/kg zilucoplan group compared to the placebo group (-6.0 vs. -3.2 points).

“The onset of action was rapid, with separation of the 0.3-mg/kg arm from the placebo arm beginning after 1 week,” the researchers wrote.

The 0.1 mg/kg zilucoplan group also had significantly greater decreases in QMG scores post-treatment than did placebo, though the magnitude of the effect was less pronounced. Changes also took longer, with separation from the placebo arm occurring after about four weeks of treatment.

Secondary endpoints — including scores on the MG Activities of Daily Living (MG-ADL), the MG Composite (MGC), and the 15-item Myasthenia Gravis Quality-of-Life Revised Scale (MG-QoL15r) — showed similar results: both zilucoplan-treated groups showed significantly greater improvement than did placebo group patients.

On the MG-ADL and MCG tests, scores in the 0.3 mg/kg zilucoplan group changed with greater magnitude and more rapidly than in the 0.1 mg/kg group. This pattern reversed on the MG-QoL15r, which researchers suggested might be due to these scores being higher in lower-dose group prior to beginning treatment.

Analysis of participants’ blood suggested near complete (over 97%) inhibition of the complement system in those given zilucoplan at 0.3 mg/kg, and of 88% in patients treated at the 0.1 mg/kg dose.

“Our data suggest that maximal complement inhibition is necessary to provide rapid and pronounced disease suppression, although submaximal inhibition was still superior to placebo,” the researchers noted.

These efficacy data are similar to those from clinical trials of Soliris (eculizumab, by Alexion Pharmaceuticals), another MG treatment that inhibits C5, the study noted. Solaris was approved by the U.S. FDA and the European Commission in 2017.

While comparisons across clinical trials must be made with caution (due to differences in trial design, etc.), this is noteworthy because Soliris clinical trials were restricted to people with refractory disease — that is, those who had failed to respond to previous therapies.

“Importantly, this study provides evidence for the efficacy of C5 inhibition in a broader population of patients with moderate to severe gMG than were enrolled in the eculizumab studies, including those early in their disease course, without regard to failure of prior therapies,” the researchers wrote.

“This observation is important because in gMG, disease severity frequently peaks within the first few years after diagnosis, before all treatment options have been exhausted and before patients may be formally declared treatment refractory.”

Zilucoplan showed a favorable safety profile in this trial. Most reported were mild, considered unrelated to zilucoplan itself, and resolved without changes to the treatment. Eight serious adverse events (three in the placebo group and five in the 0.3-mg/kg group) were also reported, but none were thought related to the study drug.

“These results support our further evaluation of zilucoplan in the ongoing RAISE study, a pivotal Phase 3 trial of zilucoplan in gMG, with top-line results expected in early 2021,” Doug Treco, PhD, the president and CEO of Ra Pharmaceuticals, said in a press release.

“Given the similarity in the safety profile for both doses, as well as the more rapid and pronounced clinical effect seen with 0.3-mg/kg zilucoplan, this dose has been selected for further testing in a pivotal phase 3 study,” the researchers concluded.