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SEATTLE -- An agent that works similarly to the approved myasthenia gravis (MG) drug eculizumab (Soliris) but with a longer dosing interval, and made by the same company, proved its mettle in a pivotal study, a researcher said here.

Rapid and sustained improvements in MG symptoms were seen in patients who took ravulizumab (Ultomiris) for 26 weeks compared with a placebo group in the so-called , said Tuan Vu, MD, of the University of South Florida in Tampa.

Like eculizumab, this agent is designed to inhibit complement activation by binding to the C5 terminal protein, Vu explained during a platform presentation at the American Academy of Neurology (AAN) annual meeting. Unlike eculizumab, though, ravulizumab can be given every 8 weeks following a brief induction phase. The older drug has to be dosed every 2 weeks.

Both drugs are made by Alexion, which sponsored CHAMPION. Eculizumab was approved for MG in 2017 and has become a standard of care in later-line treatment.

Ravulizumab, meanwhile, already , also shared with eculizumab: paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome unrelated to E. coli infection. Alexion also sees potential for the drug in various other kidney disorders (including renal injury from COVID-19) and other conditions for which eculizumab is approved.

MG has become a crowded space for drug development. A biologic drug with a totally different mechanism of action, efgartigimod (Vyvgart), came on the market last December; it targets an intracellular molecule to force elimination of IgG antibodies, including autoimmune species involved in MG. Another agent called with a similar mechanism is now in phase III testing.

It's not surprising that industry sees potential in new, more targeted therapies. Conventional therapies have been the usual suspects in autoimmune disorders: steroids and immunosuppressants, plus cholinesterase inhibitors to compensate for MG's attack on cholinergic neurons. Intravenous immunoglobulin (IVIG) may also be used.

For the phase III registration study in MG, Vu and colleagues enrolled 175 patients, who were assigned 1:1 to ravulizumab or placebo. Ravulizumab began with an initial weight-based loading dose and the first maintenance dose 2 weeks later; subsequent infusions were given every 8 weeks.

The primary efficacy endpoint was change from baseline in the MG-Activities of Daily Living (MG-ADL) score; secondary outcomes included Quantitative Myasthenia Gravis (QMG) scores, quality-of-life measures, and responder analyses.

Patient demographics and characteristics were typical of established MG. About half the sample were women, mean time from MG onset was 10 years, and patients' mean age was 57. Mean baseline scores on the MG-ADL and QMG scales were 9.0 and 14.7, respectively. For functional class, the group was split evenly between class II (mild weakness) and III (moderate), with a handful of patients at class IV (severe).

Patients in both treatment arms saw improvements in MG-ADL scores after the first dose, but the trajectory was steeper and deeper for those assigned to ravulizumab. By week 26, the end of the randomized phase, those on the active drug had a mean decline of 3.1 points, compared with 1.4 points in the placebo group (P=0.0009). QMG scores showed the same pattern, with a 2.0-point greater decline in the ravulizumab group at week 26 (also P=0.0009), as did quality-of-life measures related to MG overall and fatigue specifically.

Vu and colleagues also looked at the proportions of patients achieving certain benchmark improvements in the two symptom measures:

• At least 3-point improvement in MG-ADL: 56.7% vs 34.1% for ravulizumab and placebo, respectively
• At least 5-point improvement in QMG: 30.0% vs 11.3%, respectively

Results for more stringent definitions of response were similarly lopsided.

Adverse events were as expected for the drug, based on trials for the approved indications and on experience with eculizumab. Five patients discontinued because of adverse effects, three of whom were in the placebo group. No cases of meningitis were seen, always a concern with drugs targeting complement activation (patients had to receive meningococcal vaccination prior to study entry, which would likely also be a requirement following approval).

Alexion also sponsored a long-term, open-label extension to the study that is still ongoing. An interim report was . James F. Howard Jr., MD, of the University of North Carolina at Chapel Hill, showed data on 161 patients entering the extension (i.e., all but one of the 162 who completed the 26 weeks of CHAMPION).

Basically, improvements seen in the randomized phase were maintained in the first 34 weeks of the extension, which is projected to last up to 4 years. Patients in the original placebo group who switched to ravulizumab in the extension showed the same trajectory of benefit that the active-group had obtained. As of the data cutoff for this interim analysis, 11 patients had quit the extension; Howard did not say what their reasons were.

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