Browsing by Author "Genge, Angela"

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    MN-166 (ibudilast) in amyotrophic lateral sclerosis in a Phase IIb/III study: COMBAT-ALS study design
    (Taylor & Francis, 2021) Oskarsson, Björn; Maragakis, Nicholas; Bedlack, Richard S.; Goyal, Namita; Meyer, Jenny A.; Genge, Angela; Bodkin, Cynthia; Maiser, Samuel; Staff, Nathan; Zinman, Lorne; Olney, Nicholas; Turnbull, John; Brooks, Benjamin Rix; Klonowski, Emelia; Makhay, Malath; Yasui, Seiichi; Matsuda, Kazuko; Neurology, School of Medicine
    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with motor neuron loss as a defining feature. Despite significant effort, therapeutic breakthroughs have been modest. MN-166 (ibudilast) has demonstrated neuroprotective action by various mechanisms: inhibition of proinflammatory cytokines and macrophage migration inhibitory factor, phosphodiesterase inhibition, and attenuation of glial cell activation in models of ALS. Early-phase studies suggest that MN-166 may improve survival outcomes and slow disease progression in patients with ALS. This article describes the rationale and design of COMBAT-ALS, an ongoing randomized, double-blind, placebo-controlled, multicenter Phase IIb/III study in ALS. This study is designed to evaluate the pharmacokinetics, safety and tolerability and assess the efficacy of MN-166 on function, muscle strength, quality of life and survival in ALS.
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    A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS
    (Taylor & Francis, 2021-05) Shefner, Jeremy M.; Andrews, Jinsy A.; Genge, Angela; Jackson, Carlayne; Lechtzin, Noah; Miller, Timothy M.; Cockroft, Bettina M.; Meng, Lisa; Wei, Jenny; Wolff, Andrew A.; Malik, Fady I.; Bodkin, Cynthia; Brooks, Benjamin R.; Caress, James; Dionne, Annie; Fee, Dominic; Goutman, Stephen A.; Goyal, Namita A.; Hardiman, Orla; Hayat, Ghazala; Heiman-Patterson, Terry; Heitzman, Daragh; Henderson, Robert D.; Johnston, Wendy; Karam, Chafic; Kiernan, Matthew C.; Kolb, Stephen J.; Korngut, Lawrence; Ladha, Shafeeq; Matte, Genevieve; Mora, Jesus S.; Needham, Merrilee; Oskarsson, Bjorn; Pattee, Gary L.; Pioro, Erik P.; Pulley, Michael; Quan, Dianna; Rezania, Kourosh; Schellenberg, Kerri L.; Schultz, David; Shoesmith, Christen; Simmons, Zachary; Statland, Jeffrey; Sultan, Shumaila; Swenson, Andrea; Van Den Berg, Leonard H.; Vu, Tuan; Vucic, Steve; Weiss, Michael; Whyte-Rayson, Ashley; Wymer, James; Zinman, Lorne; Rudnicki, Stacy A.; Neurology, School of Medicine
    To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).
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    Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy
    (Wiley, 2022) Statland, Jeffrey M.; Campbell, Craig; Desai, Urvi; Karam, Chafic; Díaz-Manera, Jordi; Guptill, Jeffrey T.; Korngut, Lawrence; Genge, Angela; Tawil, Rabi N.; Elman, Lauren; Joyce, Nanette C.; Wagner, Kathryn R.; Manousakis, Georgios; Amato, Anthony A.; Butterfield, Russell J.; Shieh, Perry B.; Wicklund, Matthew; Gamez, Josep; Bodkin, Cynthia; Pestronk, Alan; Weihl, Conrad C.; Vilchez-Padilla, Juan J.; Johnson, Nicholas E.; Mathews, Katherine D.; Miller, Barry; Leneus, Ashley; Fowler, Marcie; van de Rijn, Marc; Attie, Kenneth M.; Neurology, School of Medicine
    Introduction/aims: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD. Methods: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated. Results: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions. Discussion: Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.