Date: 2016-07-07
Type of
information: Presentation of results at a congress
phase: 3
Announcement: presentation of results of the 14th International Congress on Neuromuscular Diseases (ICNMD) in Toronto
Company: Alexion Pharmaceuticals (USA - CT)
Product: Soliris® (eculizumab)
Action
mechanism:
- monoclonal antibody. Eculizumab is a recombinant humanized monoclonal IgG2/4 antibody that specifically binds to the complement protein C5, inhibiting its cleavage by the C5 convertase which prevents the generation of the terminal complement complex C5b-9.
Disease: refractory generalized myasthenia gravis (MG)
Therapeutic
area: Rare diseases - Genetic diseases - Neuromuscular diseases
Country: Argentina, Australia, Belgium, Brazil, Canada, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Italy, Japan, Republic of Korea, The Netherlands, Spain, Sweden, Turkey, UK, USA
Trial
details:
- The REGAIN study is a randomized, double-blind, placebo-controlled, multicenter trial evaluating the safety and efficacy of eculizumab in patients with refractory generalized myasthenia gravis. The study enrolled and treated 125 adult patients across North America , South America , Europe , and Asia . Patients had a confirmed MG 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 ?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 and the first secondary endpoint of change from baseline in QMG total score at week 26 were assessed using a worst-rank score analysis.The trial is a multinational, double-blind, parallel-group, placebo-controlled study with the primary objective to assess the efficacy of eculizumab compared to placebo on patients’ motor function, as measured by the improvement in MG- Activities of Daily Living (MG-ADL) score at 26 weeks. Secondary endpoints include safety and tolerability as well as additional efficacy measures. Patient screening has commenced in this study. Recruitment is open to adults with a diagnosis of refractory generalized MG, with an MG-ADL total score of at least 6 demonstrating continued muscle weakness despite treatment. (NCT01997229)
Latest
news:
- • On July 7, 2016, Alexion Pharmaceuticals announced that researchers presented 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), at the Hot Topics session of the 14th International Congress on Neuromuscular Diseases (ICNMD) in Toronto . As previously reported, the study's 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 < 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.
| P-values Less Than 0.05 Achieved in 18 of 22 Pre-specified Analyses |
|
Outcome
Measure
|
|
|
Primary / Secondary Endpoints |
|
|
Sensitivity Analyses |
|
|
Worst-Rank
ANCOVA
|
|
|
Responder
Analysis
|
|
|
Repeated
Measures
at Week 26
(IST as a Covariate)
|
|
|
Change from
Baseline at Week
26 or
LOCF ANCOVA |
|
|
Worst-Rank ANCOVA
Sensitivity
|
| MG-ADL |
|
|
0.0698 |
|
|
0.0229 |
|
|
0.0058 (0.0077) |
|
|
0.0390 |
|
|
0.0800 |
| QMG |
|
|
0.0129 |
|
|
0.0018 |
|
|
0.0006 (0.0007) |
|
|
0.0032 |
|
|
0.0169 |
| MGC |
|
|
0.1026 |
|
|
N/A* |
|
|
0.0134 (0.0168) |
|
|
0.0406 |
|
|
0.1084 |
| MG-QOL15 |
|
|
0.0281 |
|
|
N/A* |
|
|
0.0010 (0.0009) |
|
|
0.0152 |
|
|
0.0328 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
- *N/A: Not applicable; not a pre-specified analysis
At ICNMD, Dr. Howard reported that 18 of the study's 22 pre-specified analyses achieved p-values < 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 < 0.05. As previously reported, 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).
Additional results from the study, including detailed outcomes from the MG-ADL and QMG responder analyses, were presented at ICNMD.
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%).
- • On June 6, 2016, Alexion Pharmaceuticals announced topline results from the REGAIN study, a Phase 3 registration trial of eculizumab (Soliris®) in patients with refractory generalized myasthenia gravis. In the study, 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. The first prospectively defined secondary efficacy endpoint of change from baseline in Quantitative Myasthenia Gravis (QMG) total score, a physician-administered assessment of MG clinical severity, with eculizumab treatment compared to placebo at week 26, achieved a p-value of 0.0129 as measured by a worst-rank analysis. In addition, the second and third prospectively defined secondary efficacy endpoints of responder status in MG-ADL and QMG achieved p-values < 0.05: 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 with eculizumab treatment compared to placebo achieved a p-value of 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 with eculizumab treatment compared to placebo achieved a p-value of 0.0018.
Pre-specified sensitivity analyses were prospectively defined to validate results for the primary and first secondary endpoints. Three of the four prospectively defined sensitivity analyses around the primary endpoint of MG-ADL achieved p-values < 0.05, including the sensitivity analysis for change from baseline in MG-ADL using repeated measures, which showed a mean change with eculizumab treatment at week 26 of -4.2 versus a mean change with placebo at week 26 of -2.3 and achieved a p-value of 0.0058. Additionally, all four prospectively defined sensitivity analyses around the first secondary endpoint of QMG achieved p-values < 0.05, including the sensitivity analysis for change from baseline in QMG using repeated measures, which showed a mean change with eculizumab treatment at week 26 of -4.6 versus a mean change with placebo at week 26 of -1.6 and achieved a p-value of 0.0006.
Alexion continues to analyze the data from the REGAIN study, and results will be presented on July 7, 2016 , during the Hot Topics session at the 14th International Congress on Neuromuscular Diseases (ICNMD) in Toronto .
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%), myasthenia gravis (9.7%, 17.5%), and nausea (12.9%, 14.3%). 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.
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 gMG.
- • On April 24, 2014, Alexion Pharmaceuticals has announced the initiation of a single, multinational, placebo-controlled trial to evaluate the safety and efficacy of eculizumab (Soliris®) in patients with refractory generalized myasthenia gravis. Refractory gMG is an ultra-rare segment of myasthenia gravis in which patients have largely exhausted conventional therapy and continue to suffer profound muscle weakness throughout the body, resulting in slurred speech, impaired swallowing and choking, double vision, upper and lower extremity weakness, disabling fatigue, shortness of breath due to respiratory muscle weakness, and episodes of respiratory failure.
- This trial is based on preliminary evidence from a Company-sponsored Phase 2 pilot study in a small group of 14 patients that evaluated the safety and efficacy of eculizumab in the treatment of refractory generalized MG.2 In the pilot study, 86% (6/7) of patients receiving a 16-week course of eculizumab therapy achieved at least a 3-point reduction in the total Quantitative Myasthenia Gravis (QMG) score, compared to 57% (4/7) of patients treated with placebo. Similarly, 86% (6/7) of patients in the eculizumab arm had at least a 2-point improvement in MG-ADL, compared to 57% (4/7) in the placebo arm; the mean change in MG-ADL was -4.1 points in the eculizumab-treated patients. Since a 2-point change in MG-ADL is considered clinically meaningful,3 the 4.1-point change in the pilot study suggests a robust treatment effect. Eculizumab therapy was well tolerated in the study.
Is
general: Yes
