Given the data, Adamas has stated that it will forgo its originally planned second phase 3 placebo-controlled study, instead continuing its open-label extension study and engaging the FDA to discuss ADS-5102’s regulatory pathway.
Jeffrey Cohen, MD
Adamas Pharmaceuticals has announced top-line study results for ADS-5102, an investigational high-dose amantadine agent administered once-daily, in the treatment of walking impairment in patients with multiple sclerosis (MS). The data suggest the agent is associated with a significant improvement in walking speed compared to placebo.1
The phase 3 INROADS study was a 3-arm trial and featured 594 patients with MS, with a primary end point of walking speed response from baseline in the Timed 25-Foot Walk, with response defined as a ≥20% improvement after 12 weeks. All told, those taking a 274 mg dose of ADS-5102 (n = 185) showed an improvement of 21.1% compared to 11.3% with those taking placebo (n = 186; P = .01).
Additionally, those taking the lower dose of 137 mg (n = 187) experienced a response rate of 17.6%, which was still significant compared to placebo (P = .08). However, none of the secondary walking measures, including mean change in the Timed 25-Foot Walk, the Timed Up and Go, and the 2-Minute Walk at 12-week post-treatment, were significantly different for either dose.
“We are pleased that ADS-5102 shows a potential benefit for MS patients with walking impairment, for whom there is a significant unmet medical need and limited treatment options,“ Neil F. McFarlane, chief executive officer, Adamas Pharmaceuticals, said in a statement. “However, as we did not see the scale of clinical benefit we had hoped for in this study, we will fully assess the potential for ADS-5102 in MS patients before determining the extent of our continued investment in this program.”
Overall, the baseline characteristics were similar across every arm of treatment, with a mean time since diagnosis of 15.9 years, median Expanded Disability Status Scale scores at screening of 6.0, and mean Timed 25-Foot Walk at baseline between 11.5 to 12.4 seconds. Previous use of dalfampridine was reported in 52.5% of patients, while amantadine use was reported in 12.9%.
The most common adverse events (AEs) were peripheral edema, dry mouth, fall, constipation, urinary tract infection, and insomnia. In total, 20.5% of patients discontinued the study drug due to AEs in the 274 mg group, while 6.4% did so in the 137 mg group, compared to 3.8% in the placebo group. The reported AEs associated with ADS-5102 were deemed to be dose-dependent and consistent with the known safety profile of amantadine.
“Walking impairment negatively impacts many aspects of daily life for a large number of patients, and additional treatment options are needed,” said INROADS Steering Committee Chair, Jeffrey Cohen, MD, director, experimental therapeutics, Mellen Center for Multiple Sclerosis, Cleveland Clinic, in a statement. “This trial result is encouraging for the MS patient and physician community and we look forward to reviewing the full data set.”
“We will now complete our analyses of these data to fully characterize the efficacy and safety profile of ADS-5102 and the dose-response seen in this study,” Rajiv Patni, MD, Chief Medical Officer, Adamas Pharmaceuticals, said in a statement.
Previously, Adams completed a phase 2, proof-of-concept study of the therapy, in which patients treated with ADS-5102 showed a significant improvement in walking speed as assessed by the Timed 25 Foot Walk test, as well as an improvement in the Timed Up and Go. As well, the agent was generally well-tolerated.2
The phase 3 program was planned to consist of 2 phase 3 studies—1 being a pivotal efficacy and safety study, and anther being an open-label safety study. “Given these data, we will not initiate the originally planned replicate second phase 3 placebo-controlled study. We are continuing the open-label extension study and will engage with the FDA to discuss a potential regulatory pathway,” Patni added.
ADS-5102 has also been explored in dyskinesia, for which it is indicated in patients with Parkinson disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications. It is marketed under the brand name Gocovri.
Earlier this year, at the 2019 International Congress of Parkinson’s Disease and Movement Disorders, in Nice, France, safety data for the dopamine agonist was presented, including findings through 1 year after its FDA approval. Additionally, combined phase 3 data from 2 trials (NCT02136914 and NCT02274766) showed that the treatment was associated with significantly improved motor skills in 82 patients treated with the extended-release capsules compared to the 87 treated with placebo. One of those analyses of amantadine revealed the safety profile of the therapy was consistent, though adverse events (AEs) occurred more frequently in older age groups. Ultimately, these AEs were believed to be in part due to increasingly lower baseline glomerular filtration rates older patients, suggesting that clinicians should be mindful of renal function and overall morbidity and should consider lower dosing options for older patients.3
1. Adamas Announces Top-Line Results from INROADS Phase 3 Trial of ADS-5102 for Multiple Sclerosis Patients with Walking Impairment [press release]. Emeryville, CA: Adamas Pharmaceuticals; Published December 17, 2019. globenewswire.com/news-release/2019/12/17/1961609/0/en/Adamas-Announces-Top-Line-Results-from-INROADS-Phase-3-Trial-of-ADS-5102-for-Multiple-Sclerosis-Patients-with-Walking-Impairment.html. Accessed December 17, 2019.
2. Pipeline. Adamas website. Updated 2019. adamaspharma.com/pipeline. Accessed December 17, 2019.
3. Adamas Announces New Safety and Efficacy Data for GOCOVRI® in Parkinson’s Disease Patients with Dyskinesia at the Movement Disorder Society 2019 International Congress [press release]. Emeryville, CA: Adamas Pharmaceuticals; Published September 20, 2019. globenewswire.com/news-release/2019/09/20/1918502/0/en/Adamas-Announces-New-Safety-and-Efficacy-Data-for-GOCOVRI-in-Parkinson-s-Disease-Patients-with-Dyskinesia-at-the-Movement-Disorder-Society-2019-International-Congress.html. Accessed December 17, 2019.