A Phase 3, Open-Label, Multicenter Study To Evaluate Eculizumab In Adolescents With Refractory Generalized Myasthenia Gravis (S5.009)

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Objective: To evaluate eculizumab for the treatment of adolescents with refractory anti-acetylcholine receptor antibody-positive (AChR Ab+) generalized myasthenia gravis (gMG). Background: Patients with AChR Ab+ gMG have uncontrolled complement activation leading to neuromuscular junction destruction and impaired neuromuscular transmission, resulting in debilitating fatigable muscle weakness. In addition to established treatment, there remains a need for targeted therapies for MG. Eculizumab, a terminal complement C5 inhibitor, has demonstrated safety and efficacy in adults with refractory AChR Ab+ gMG. Design/Methods: A phase 3, open-label, multicenter study was conducted in adolescents 12–17 years (NCT03759366). Eculizumab was administered using a weight-based dosing regimen, with weekly induction (1–2 doses of 600 mg or 4 doses of 900 mg) followed by 2-weekly maintenance (300–1200 mg). The primary endpoint was change from baseline to week 26 in Quantitative Myasthenia Gravis (QMG) total score. Multiple secondary endpoints were assessed, including change from baseline to week 26 in MG-Activities of Daily Living (MG-ADL) total score. Pharmacodynamics and safety were also assessed. Results: Eleven adolescents (mean age 14.8±1.8 years) were enrolled, of whom six were receiving chronic intravenous immunoglobulin (IVIg). Ten patients completed the primary evaluation period. Least-square mean changes from baseline at week 26 were −5.8 (standard error [SE] 1.2; p=0.0004) for QMG total score and −2.3 (SE 0.6; p=0.0017) for MG-ADL total score. Similar changes were observed irrespective of chronic IVIg treatment. Overall, the primary and all secondary efficacy endpoint analyses met statistical significance at week 1. Improvements were sustained through week 26. Complete terminal complement inhibition was sustained throughout 26 weeks in all patients. Treatment-emergent adverse events were all mild/moderate and predominantly unrelated to eculizumab. Three patients experienced six serious adverse events (MG worsening [3], MG crisis, peritonsillar abscess, pyrexia). No meningococcal infections were reported. Conclusions: Eculizumab was efficacious and well-tolerated in adolescents with refractory AChR Ab+ gMG. Disclosure: Dr. Brandsema has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Brandsema has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech. Dr. Brandsema has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for PTC Therapeutics. Dr. Brandsema has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sarepta. Dr. Brandsema has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Brandsema has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Argenx. Dr. Brandsema has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Janssen. Dr. Brandsema has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Dyne. Dr. Brandsema has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Fibrogen. Dr. Brandsema has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda. Dr. Brandsema has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Edgewise. The institution of Dr. Brandsema has received research support from Novartis. The institution of Dr. Brandsema has received research support from Biogen. The institution of Dr. Brandsema has received research support from Alexion. The institution of Dr. Brandsema has received research support from CSL Behring. The institution of Dr. Brandsema has received research support from Pfizer. The institution of Dr. Brandsema has received research support from PTC Therapeutics. The institution of Dr. Brandsema has received research support from Sarepta. The institution of an immediate family member of Dr. Brandsema has received research support from Argenx. The institution of Dr. Brandsema has received research support from Astellas. The institution of Dr. Brandsema has received research support from Fibrogen. The institution of Dr. Brandsema has received research support from Genentech. The institution of Dr. Brandsema has received research support from Janssen. The institution of Dr. Brandsema has received research support from Scholar Rock. Dr. Ginsberg has nothing to disclose. Mr. Hoshino has nothing to disclose. The institution of Prof. Mimaki has received research support from Ministry of Education, Culture, Sports, Science and Technology. Prof. Nagata has nothing to disclose. Dr. Rao has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Avexis, Biogen, Roche, Sarepta, NSPharma, ScholarRock, Regenxbio. Dr. Rao has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for capricor . Dr. Rao has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen, Roche, Avexis . Dr. Rao has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Weiss, Paarz. Dr. Rao has stock in Pfizer . The institution of Dr. Rao has received research support from Sarepta, Alexion, NSPharma, AMO pharma . Dr. Ruzhansky has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Argenx. Dr. Ruzhansky has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Alexion. Dr. Ruzhansky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Immunovant. Dr. Ruzhansky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Ruzhansky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Akcea. Dr. Ruzhansky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam. Dr. Ruzhansky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MT. The institution of Dr. Ruzhansky has received research support from MGFA. Dr. Suresh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Anylam . Dr. Suresh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexeion. Dr. Suresh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenex. Dr. Suresh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Takeda . Dr. Suresh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Pfizer. Dr. Tiongson has nothing to disclose. Dr. Yamanouchi has nothing to disclose. Dr. Frick has received personal compensation for serving as an employee of AstraZeneca/Alexion Rare Disease. Dr. Frick has stock in AstraZeneca/Alexion Rare Disease. Dr. Hicks has received personal compensation for serving as an employee of Alexion Pharmaceuticals Inc.. Dr. Hicks has stock in Astrazeneca. Dr. Liao has received personal compensation for serving as an employee of Alexion. Dr. Howard has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for arenx BVBA. Dr. Howard has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safet

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