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REGAIN trial: Eculizumab has missed its primary endpoint in patients with refractory generalized myasthenia gravis


New results from the REGAIN study, a global, placebo-controlled phase 3 registration trial of Eculizumab ( Soliris ) in patients with refractory generalized myasthenia gravis ( gMG ), were presented at 14th International Congress on Neuromuscular Diseases ( ICNMD ) in Toronto ( Canada ).
The primary efficacy endpoint of change from baseline in Myasthenia Gravis-Activities of Daily Living Profile ( MG-ADL ) total score, a patient-reported assessment, at week 26, did not reach statistical significance ( p=0.0698 ) as measured by a worst-rank analysis.
Results presented at ICNMD showed that 18 of 22 pre-defined endpoints and pre-specified analyses in the study, based on the primary and five secondary endpoints, achieved p-values less than 0.05.

New secondary efficacy endpoint data presented included change from baseline in Myasthenia Gravis Composite ( MGC ) score at week 26, which achieved a p-value of 0.1026, and change from baseline in the 15-item Myasthenia Gravis Quality Of Life ( MG-QOL15 ) at week 26, which achieved a p-value of 0.0281, both measured by a worst-rank analysis.
A pre-specified sensitivity analysis of the MGC and MG-QOL15 endpoints using repeated measures from baseline to week 26 achieved p-values of 0.0134 and 0.0010, respectively.

Although the REGAIN study narrowly missed its primary endpoint, the additional data suggest a magnitude of effect of Eculizumab in refractory patients with myasthenia gravis across four separate scales of disease severity.

At ICNMD, researchers reported that 18 of the study’s 22 pre-specified analyses achieved p-values less than 0.05. As previously reported, these included the first three secondary efficacy endpoints of change from baseline to week 26 in Quantitative Myasthenia Gravis ( QMG ) total score, a physician-administered assessment of MG clinical severity ( p=0.0129 ), as measured by a worst-rank analysis; the proportion of patients with at least a 3-point reduction in MG-ADL total score and no rescue therapy from baseline to week 26 ( p=0.0229 ); and the proportion of patients with at least a 5-point reduction in QMG total score and no rescue therapy from baseline to week 26 ( p=0.0018 ).
The primary efficacy endpoint of change from baseline in MG-ADL total score at week 26 did not reach statistical significance ( p=0.0698 ) as measured by a worst-rank analysis.

Several prospectively defined sensitivity analyses were conducted to validate results for the primary and secondary endpoints, including sensitivity analyses for change from baseline in MG-ADL, QMG, MGC, and MG-QOL15 using repeated measures, all of which achieved p-values less than 0.05.
The pre-specified sensitivity analyses of the primary and first secondary endpoints of MG-ADL and QMG using repeated measures had p-values of 0.0058 and 0.0006, respectively.
The pre-specified sensitivity analyses of MGC and MG-QOL15 using repeated measures at week 26 showed a mean change from baseline in MGC with eculizumab treatment at week 26 of -8.1 versus a mean change with placebo of -4.8 ( p=0.0134 ), and a mean change from baseline in MG-QOL15 with Eculizumab treatment at week 26 of -12.6 versus a mean change with placebo of -5.4 ( p=0.0010 ).

The safety of Eculizumab in this study was consistent with the Soliris labels. The most common adverse events in patients receiving Eculizumab and placebo, respectively, were: headache ( 16.1%, 19.0% ), upper respiratory tract infection ( 16.1%, 19.0% ), nasopharyngitis ( 14.5%, 15.9% ), nausea ( 12.9%, 14.3% ), and myasthenia gravis ( 9.7%, 17.5% ).
Serious adverse events were reported in 14.5% of Eculizumab patients and 28.6% of placebo patients.
Four patients receiving Eculizumab ( 6.5% ) discontinued treatment due to an adverse event. There were no discontinuations due to adverse events in the placebo arm.
Half as many patients treated with Eculizumab received rescue therapy compared with placebo ( 9.7%, 19.0% ).

The REGAIN study enrolled and treated 125 adult patients across North America, South America, Europe, and Asia. Patients had a confirmed myasthenia gravis diagnosis with positive serologic test for anti-AChR antibodies.
All patients were required to have previously failed treatment with at least two immunosuppressive agents or failed treatment with at least one immunosuppressive agent and required chronic plasma exchange or IVIg, and had an MG-ADL total score greater than or equal to 6 at study entry.
Patients were randomized 1:1 to receive Eculizumab or placebo for a total of 26 weeks. Patients initially received 900 mg of Eculizumab or placebo weekly for 4 weeks followed by 1200 mg of Eculizumab or placebo one week later, and then 1200 mg of Eculizumab or placebo every two weeks.
Patients were able to continue to receive stable dose and type of supportive immunosuppressive therapy ( IST ), but no new ISTs and no increase in IST dosage were permitted during the trial, unless patient required rescue therapy for disease worsening.
The primary efficacy endpoint of change from baseline in MG-ADL total score at week 26, as well as the three secondary endpoints that involved changes from baseline ( QMG, MGC, and MG-QOL15 ) were assessed using a worst-rank analysis.

Ninety-four percent of patients ( 117 of 125 ) from the REGAIN study continued into a phase 3 open-label extension study evaluating the safety and efficacy of Eculizumab in the treatment of patients with refractory generalized myasthenia gravis.

Eculizumab is a first-in-class terminal complement inhibitor. Soliris is approved in the U.S. ( 2007 ), European Union ( 2007 ), and other countries as the first and only treatment for patients with paroxysmal nocturnal hemoglobinuria ( PNH ) to reduce hemolysis. Soliris is also approved in the U.S. ( 2011 ), European Union ( 2011 ), and other countries as the first and only treatment for patients with atypical hemolytic uremic syndrome ( aHUS ) to inhibit complement-mediated thrombotic microangiopathy, or TMA ( blood clots in small vessels ).
Soliris is not indicated for the treatment of patients with Shiga-toxin E. coli-related hemolytic uremic syndrome ( STEC-HUS ).

Refractory generalized myasthenia gravis is an ultra-rare segment of myasthenia gravis, a debilitating, complement-mediated neuromuscular disease.
Myasthenia gravis typically begins with weakness in the ocular muscles and often progresses to the more severe and generalized form, known as gMG, to include weakness of the head, neck, trunk, limb and respiratory muscles. While most gMG patients are managed with conventional therapies, 10% to 15% of patients are considered refractory. ( Xagena )

Source: Alexion Pharmaceuticals, 2016

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