Objective: Evaluate the long-term safety and efficacy of arbaclofen extended release (ER) tablets in patients with multiple sclerosis (MS)-related spasticity.Methods: In a 52-week, open-label, multicenter study, adults with a Total Numeric-transformed Modified Ashworth Scale (TNmAS) score ≥2 in the most-affected limb (MAL) received oral arbaclofen ER titrated over 9 days up to 80 mg/day based on tolerability. The primary objective was assessment of arbaclofen ER safety and tolerability. Secondary objectives included an assessment of efficacy using the TNmAS-MAL, the Patient Global Impression of Change (PGIC), and Expanded Disability Status Scale (EDSS).Results: Of 323 patients enrolled, 218 (67∙5%) completed 1 year of treatment. Most patients (74∙0%) achieved an arbaclofen ER maintenance dose of 80 mg/day. At least one treatment-emergent adverse event (TEAE) was reported by 148 patients (80∙4%). The most common adverse events (AEs) were (n patients [%]): muscle weakness (24 [13∙0]), urinary tract infection (21 [11∙4]), somnolence (18 [9∙8]), dizziness (16 [8∙7]), pollakiuria (12 [6∙5]), and asthenia (11 [6∙0]). Most AEs were of mild-moderate severity. Twenty-eight serious AEs were reported. No deaths occurred during the study. Overall, 14∙6% of patients discontinued due to AEs, primarily muscle weakness, MS relapse, asthenia, and nausea. Evidence of improvement in MS-related spasticity was observed across arbaclofen ER dosages.Conclusions: Arbaclofen ER treatment (up to 80 mg/day) was well-tolerated and improved spasticity in adults for 1 year.Classification of Evidence: This study provides Class II evidence that arbaclofen ER is well tolerated and reduces symptoms of spasticity in patients with MS.Trial Registration Details: Clinical Trial IdentifiersClinicalTrials.gov, NCT03319732.Funding Information: This study was sponsored by Osmotica Pharmaceuticals Inc. which is now RVL Pharmaceuticals, Inc. Declaration of Interests: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Okuda received personal compensation for consulting and advisory services from Biogen, Celgene/Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Janssen Pharmaceuticals, Novartis, Osmotica Pharmaceuticals, RVL Pharmaceuticals, Inc., TG Therapeutics, Viela Bio, Inc., and research support from Biogen and EMD Serono/Merck. Royalties received for intellectual property licensed by The Board of Regents of The University of Texas System. Dr. Kantor reports receiving consulting fees and honoraria from: AbbVie, Biogen, Bristol Myers-Celgene, Genentech, Janssen, Novartis, RVL Pharmaceuticals and Sanofi. Dr. Jaros is a paid consultant of RVL Pharmaceuticals Inc. Dr. deVries is a full-time employee of RVL Pharmaceuticals Inc. Dr. Hunter reports receiving grants or research studies from Alkermes, Adamas, Biogen, Bristol Myers-Celgene, EMD Serono, Genentech, Novartis, Sanofi; consulting fees and honoraria from: AbbVie, Biogen, EMD Serono, Genentech, Janssen, Novartis, Osmotica, Sanofi; and writing assistance from Novartis, RVL Pharmaceuticals, Sanofi, and MallinckrodtEthics Approval Statement: The study protocol was approved by the institutional review board or ethics committee at each participating study site. All patients provided written informed consent prior to enrollment

Baclofen, a racemic GABA-B (GABA(B)) receptor agonist, is commonly used for the management of multiple sclerosis-related spasticity but is associated with frequent dosing and poor tolerability. Arbaclofen, the active R-enantiomer of baclofen, exhibits 100- to 1000-fold greater specificity for the GABA(B) receptor compared with the S-enantiomer and similar to 5-fold greater potency compared with racemic baclofen. Arbaclofen extended-release tablets have a dosing interval of 12 hours and have shown a favourable safety and efficacy profile in early-phase clinical development. The current Phase 3 study was designed to evaluate the efficacy and safety of arbaclofen extended-release tablets in patients with multiple sclerosis-related spasticity. In this multicentre, double-blind, placebo-controlled study, adults with multiple sclerosis-related spasticity were randomized to arbaclofen extended-release 40 mg/day, arbaclofen extended-release 80 mg/day or placebo for 12 weeks. The co-primary end-points were the change from baseline to Week 12 in the Total Numeric-transformed Modified Ashworth Scale in the Most Affected Limb score and the Clinical Global Impression of Change score. A hierarchical testing procedure was used to evaluate the co-primary end-points; analyses for the 80 mg/day group were considered inferential only if the arbaclofen extended-release 40 mg/day and placebo groups demonstrated a statistically significant difference (P <= 0.05) for both end-points. Five hundred thirty-six patients were included in the study. At Week 12, the least squares mean change from baseline in Total Numeric-transformed Modified Ashworth Scale in the Most Affected Limb score was -1.67 (95% confidence interval: -1.97 to -1.36) and -1.28 (95% confidence interval: -1.57 to -0.99) in the arbaclofen extended-release 40 mg/day and placebo groups, respectively (least squares mean difference: -0.39; P < 0.048). Improvements were seen in the mean Clinical Global Impression of Change scores for both the arbaclofen extended-release 40 mg/day and placebo groups; however, no statistically significant difference was observed between them (least squares mean difference: -0.10; P = 0.43). Most adverse events were of mild-moderate severity. Arbaclofen extended-release 40 mg/day for 12 weeks significantly reduced multiple sclerosis-related spasticity compared with placebo and was safe and well tolerated over the 12-week treatment period. Although arbaclofen extended-release 40 mg/day improved Clinical Global Impression of Change scores, a significant difference from placebo was not observed. This 12-week multicenter, double-blind, placebo-controlled study reported by Okuda et al. assessed the efficacy and safety of arbaclofen extended-release tablets in adults with multiple sclerosis-related spasticity. Arbaclofen extended-release 40 mg significantly improved spasticity symptoms and numerically improved clinicians' impressions of patient improvement. Most adverse events were of mild-to-moderate severity.

Objective: Evaluate the efficacy and safety of arbaclofen extended-release (ER) tablets in patients with multiple sclerosis (MS)-related spasticity.Methods: In a multicenter, double-blind, placebo-controlled study, adults with MS-related spasticity were randomized to arbaclofen ER 40 mg/day, arbaclofen ER 80 mg/day, or placebo for 12 weeks. Co-primary end points were the change from baseline to Week 12 in Total Numeric-transformed Modified Ashworth Scale in the Most Affected Limb (TNmAS-MAL) score and the Clinical Global Impression of Change (CGIC) score. A hierarchical testing procedure was used to evaluate the co-primary end points; analyses for the 80 mg/day group were considered inferential only if the arbaclofen ER 40 mg/day and placebo groups demonstrated a statistically significant difference (P≤0∙05) for both end points.Results: 536 patients were included in the study. At Week 12, the least squares (LS) mean change from baseline in TNmAS-MAL score was –1∙67 (95% confidence interval [CI]: –1∙97, –1∙36) and –1∙28 (95% CI: –1∙57, –0∙99) in the arbaclofen ER 40 mg/day and placebo groups, respectively (LS mean difference, –0∙39; P<0∙048). Improvements were seen in mean CGIC scores for both the arbaclofen ER 40 mg/day and placebo groups, however no statistically significant difference was observed between them (LS mean difference, –0∙10; P=0∙43). Most adverse events were of mild-moderate severity.Conclusions: Administration of arbaclofen ER 40 mg/day for 12 weeks significantly reduced MS-related spasticity compared with placebo. Although arbaclofen ER 40 mg/day improved CGIC scores, a significance difference from placebo was not observed.Trial Registration Details: ClinicalTrials.gov, NCT03290131. Funding Information: This study was sponsored by Osmotica Pharmaceuticals Inc. which is now RVL Pharmaceuticals, Inc. RVL Pharmaceuticals, Inc., in conjunction with the lead authors, participated in the design and interpretation of the studies. Declaration of Interests: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Okuda received personal compensation for consulting and advisory services from Biogen, Celgene/Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Janssen Pharmaceuticals, Novartis, Osmotica Pharmaceuticals, RVL Pharmaceuticals, Inc., TG Therapeutics, Viela Bio, Inc., and research support from Biogen and EMD Serono/Merck. Royalties received for intellectual property licensed by The Board of Regents of The University of Texas System. Dr. Kantor reports receiving consulting fees and honoraria from: AbbVie, Biogen, Bristol Myers-Celgene, Genentech, Janssen, Novartis, RVL Pharmaceuticals and Sanofi. Dr. Jaros is a paid consultant of RVL Pharmaceuticals, Inc. Dr. deVries is a full-time employee of RVL Pharmaceuticals, Inc. Dr. Hunter reports receiving grants or research studies from Alkermes, Adamas, Biogen, Bristol Myers-Celgene, EMD Serono, Genentech, Novartis, Sanofi; consulting fees and honoraria from: AbbVie, Biogen, EMD Serono, Genentech, Janssen, Novartis, Osmotica, Sanofi; and writing assistance from Novartis, RVL Pharmaceuticals, Sanofi, and Mallinckrodt.Ethics Approval Statement: The protocol was approved by the institutional review board or ethics committee at each participating study site. All subjects provided written informed consent prior to enrollment.

Background: Immediate-release (IR) amantadine has been used for treatment of levodopa induced dyskinesia (LID). The immediate-release/extended-release (IR/ER) amantadine formulation OS320 (OSMOLEX ER (R)) contains an IR outer layer and ER core for once-daily dosing. Objective: Report individual and pooled results for the similarly designed double-blind, placebo-controlled ALLAY-LID I and II trials, assessing IR/ER-amantadine for LID. Methods: PD patients with LID were randomized to IR/ER-amantadine 193 mg, 258 mg, or placebo. Primary endpoint was Unified Dyskinesia Rating Scale (UDysRS) score change from baseline to Day 98. Secondary outcome was ON time without troublesome dyskinesia based on diaries. Exploratory outcomes were other diary states (including OFF), MDS-UPDRS Parts II + III and Fatigue Severity Scale. Results: Overall, 222 individuals enrolled (N = 87 ALLAY-LID I, N = 135 ALLAY-LID II); both trials terminated early for sponsor's decision. While ALLAY-LID I did not meet its primary endpoint, a significant reduction in UDysRS scores versus placebo was observed in ALLAY-LID II for both 193 mg and 258 mg doses. In the pooled analysis, placebo-adjusted UDysRS score differences were 5.5 [ 9.8, 1.2], p = 0.012 and 5.2 [ 9.5, 0.9], p = 0.017, respectively. IR/ER-amantadine 258 mg significantly increased time spent ON without troublesome dyskinesia in ALLAY-LID II and pooled analysis. Reductions in ON time with dyskinesia supported the primary outcome. There was no effect on OFF time or other outcomes. Overall, 13.3% (193 mg), 18.7% (258 mg) and 11.1% (placebo) discontinued for adverse events, most commonly hallucinations (4.0%, 10.7%, and 1.4%, respectively). Conclusions: IR/ER-amantadine significantly reduced LID in ALLAY-LID II but not in ALLAY-LID I; post-hoc pooled data also indicated a positive treatment effect on LID.

An extended-release formulation of amantadine (Osmolex ER™, Osmotica Pharmaceutical US LLC) was approved in February 2018 to treat Parkinson’s disease and drug-induced extrapyramidal reactions in adults. To determine the pharmacokinetic profile of extended-release amantadine in subjects with varying degrees of renal impairment. Adults with normal renal function (creatinine clearance > 89 mL/min/1.73 m2), moderate renal impairment (creatinine clearance 30–59 mL/min/1.73 m2), or severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2) received a single 129-mg dose (160 mg amantadine hydrochloride) of extended-release amantadine. Blood and urine samples for pharmacokinetic analysis were taken at scheduled intervals. A two-compartment pharmacokinetic population model was employed to determine optimum extended-release amantadine dosing in subjects with renal impairment. Following a single oral dose of the 129-mg extended-release amantadine tablet, amantadine plasma concentration increased slowly, reaching a peak at approximately 11 h. Amantadine elimination was reduced in subjects with renal impairment. Renal clearance decreased from 10,965 to 2618 mL/h in subjects with severe renal impairment compared to those with normal renal function. Pharmacokinetic modeling and simulation methods were used to recommend the oral administration of 129-mg extended-release amantadine tablets at intervals of 24, 48, 72, 96, 120, or 168 h depending on the degree of renal function. Renal impairment was associated with reduced amantadine clearance. Based on pharmacokinetic modeling and simulations, dose regimens were recommended for subjects with impaired renal function to provide systemic amantadine exposure similar to subjects with normal renal function taking a once-daily extended-release amantadine tablet.

Introduction In February 2018, OS320-an amantadine extended-release (ER) tablet formulation with once-daily morning administration-was approved for the treatment of Parkinson's disease and drug-induced extrapyramidal reactions in adults. The purpose of this study was to describe three phase 1 studies that assessed the pharmacokinetics (PK) and bioavailability of amantadine ER in healthy adult volunteers. Methods Study 1 was an open-label, four-treatment, single-dose, crossover study comparing amantadine ER 129, 193, and 258 mg tablets with an equivalent dose of immediate-release (IR) amantadine 40 mg/5 mL syrup. Study 2 was an open-label, single-dose, crossover food-effect study with amantadine ER 258 mg. Study 3 was an open-label, multiple-dose, crossover study comparing amantadine ER and amantadine IR syrup. Results Amantadine ER displayed a steady release of amantadine, with the peak amantadine concentration occurring at ~ 7.5 h postdose or in the middle of the day (following a morning dose) with steady-state administration. Administration of amantadine ER 258 mg with a high-fat meal did not affect amantadine bioavailability. Amantadine plasma exposure increased proportionally with increasing doses, and at steady state, amantadine exposure from an amantadine ER 258-mg tablet was bioequivalent to twice-daily 129-mg amantadine IR syrup. Conclusion The PK profile of amantadine ER 129-mg, 193-mg, and 258-mg tablets allows for once-daily dosing in the morning; the 24-h average amantadine plasma concentration is equivalent to that for the same daily dose of IR amantadine administered twice daily. Funding Osmotica Pharmaceutical US LLC.