Clinical Trials

Date: 2017-06-12

Type of information: Publication of results in a medical journal

phase: 2-3

Announcement: publication of results in JAMA Neurology

Company: Adamas Pharmaceuticals (USA - CA)

Product: ADS-5102 (amantadine hydrochloride)

Action mechanism:

• antiparkinsonian. ADS-5102, an investigational agent, is a long-acting, extended-release capsule formulation of amantadine HCl administered once daily at bedtime.

Disease: levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) patients

Therapeutic area: Neurodegenerative diseases - Rare diseases

Country:

Trial details:

• The Phase 3 clinical program of ADS-5102 for the treatment of evodopa-induced dyskinesia comprises three placebo-controlled trials: EASED, EASE LID and EASE LID 3. These trials enrolled a total of 286 patients, of whom 122 patients received a 340 mg dose of ADS-5102 once daily before bedtime. In all three trials, change in evodopa-induced dyskinesia versus placebo was achieved at each trial's predefined treatment period as assessed by the Unified Dyskinesia Rating Scale (UDysRS): change from baseline to week 8 (EASED), week 12 and week 24 (EASE LID) and week 12 (EASE LID 3). EASE LID 2 is an open-label safety study for patients from EASED, EASE LID and EASE LID 3 and for LID patients who have undergone deep brain stimulation.

Latest news:

•  • On June 12, 2017, Adamas Pharmaceuticals announced that results of its Phase 3 EASE LID clinical trial of ADS-5102 were published online in JAMA Neurology. A New Drug Application supporting ADS-5102 (amantadine) extended-release capsules for the treatment of levodopa-induced dyskinesia in people with Parkinson's disease is under review by the FDA with a Prescription Drug User Fee Act (PDUFA) action date of August 24, 2017.
• The randomized, double-blind, placebo-controlled EASE LID study met its pre-specified primary endpoint demonstrating that patients who received ADS-5102 experienced a significantly greater decrease in levodopa-induced dyskinesia at 12 weeks than those who received placebo (p=0.0009), as measured by the Unified Dyskinesia Rating Scale (UDysRS). This improvement was maintained at 24 weeks, with ADS-5102-treated patients again showing a significantly greater decrease than placebo-treated patients (p=0.0008). Additionally, the ADS-5102 group experienced significant improvements in key pre-specified, hierarchical secondary endpoints compared with the placebo group, as measured using the Parkinson's disease home diary. ADS-5102 treatment resulted in a statistically significant increase in ON time without troublesome dyskinesia and a statistically significant decrease in OFF time at 12 and 24 weeks.
• Adverse events (AEs) were reported for 89 percent of ADS-5102 patients and 60 percent of placebo patients, and most reported were mild to moderate. The most common AEs for ADS-5102 versus placebo were visual hallucinations, peripheral edema, and dizziness. No study drug-related serious AEs were reported. A total of 17 patients discontinued study treatment due to an AE (13 patients in the ADS-5102 group vs. four in the placebo group). The EASE LID trial results were previously presented at the 68th American Academy of Neurology Annual Meeting and at the 20th International Congress of Parkinson's Disease and Movement Disorders.
• • On June 8, 2017, Adamas Pharmaceuticals announced the presentation of an updated analysis of efficacy and tolerability data from EASE LID 2, the company's ongoing Phase 3 open-label, long-term safety and efficacy study of ADS-5102 (amantadine) extended-release capsules. Overall, results demonstrated that ADS-5102 was well tolerated and the treatment effect on motor complications, as measured by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Part IV score, was maintained for up to 88 weeks. Analyses of data from two subgroups of patients, those who have undergone prior deep brain stimulation (DBS) treatment and those who switched from amantadine immediate-release (IR) to open-label ADS-5102, both showed a rapid and sustained reduction in dyskinesia and OFF after introduction of ADS-5102. The analyses were presented in a poster session at the 21st International Congress of Parkinson's Disease and Movement Disorders in Vancouver, Canada.
• Expanding on previously reported 64-week data, this updated analysis demonstrated that the treatment effect of ADS-5102 on motor complications, as accessed by MDS-UPDRS, Part IV (a measurement of dyskinesia, OFF and dystonia), was durable and maintained at a constant level for up to 88 weeks. Among patients previously treated with amantadine IR, switching to open-label ADS-5102 provided a 3 point, statistically significant reduction in MDS-UPDRS Part IV at Week 8. The treatment effect experienced by patients previously treated with amantadine IR was similar to that experienced by previous placebo-treated patients, and was maintained for up to 64 weeks. Patients who have undergone prior DBS treatment and were switched to open-label ADS-5102 also demonstrated a comparable reduction in the MDS-UPDRS, Part IV. All subgroups achieved reductions in motor complications without compromising the underlying control of Parkinson's symptoms, as assessed by Parts I-III of the MDS-UPDRS.
• The safety data are consistent with the previously reported safety profile of ADS-5102 and the known safety profile of amantadine, which includes precautions and warnings related to suicidality, hallucinations and dizziness. Approximately 50% of discontinuations due to adverse events (AEs) occurred within the first month of treatment. The most common AEs, occurring in five percent or more of patients in any group, included falls, visual hallucinations, peripheral edema, constipation, livedo reticularis, nausea, dry mouth, insomnia and dizziness.
• • On April 24, 2017, Adamas Pharmaceuticals announced the presentation of two separate analyses of pooled data from the placebo-controlled Phase 3 clinical trials of ADS-5102 (amantadine) extended-release capsules at the 69th American Academy of Neurology (AAN) Annual Meeting in Boston. The pooled data results, which are consistent with the original findings from EASE LID and EASE LID 3, demonstrated that people with Parkinson's disease treated with ADS-5102 had a significant reduction in levodopa-induced dyskinesia, as measured by the Unified Dyskinesia Ratings Scale (UDysRS), and showed statistically significant reduction in OFF time, as reported by Parkinson's disease home diary data.
• ¤Platform Presentation (Primary Endpoint) - Pooled Analysis of Phase 3 Studies of ADS-5102 (amantadine) Extended-Release Capsules for Levodopa-Induced Dyskinesia: A Detailed Review of UDysRS Results The UDysRS data from EASE LID and EASE LID 3 were pooled in a pre-specified analysis. The UDysRS included both physician assessments and historical patient assessments. The pooled ADS-5102 UDysRS results showed a significant, rapid and durable reduction in levodopa-induced dyskinesia versus placebo: At Week 12, the UDysRS total score was -17.7 in the ADS-5102 group versus -7.6 in the placebo group (p < 0.0001) - an improvement in the UDysRS total score of approximately 30 percent among those treated with ADS-5102 compared to placebo treated patients. For any change from baseline in UDysRS total score, a greater proportion of patients taking ADS-5102 showed a reduction compared to placebo. Treatment effects were comparable in both the objective (physician-assessed) and historical (patient-reported) UDysRS scores, and reductions were significantly greater with ADS-5102 than with placebo (p < 0.0001 for both).
• ¤Poster Presentation (Secondary Endpoints) - Pooled Analysis of Phase 3 Studies of ADS-5102 (amantadine) Extended-Release Capsules for Levodopa-Induced Dyskinesia: A Detailed Review of PD Home Diary Results Parkinson's disease home diary data from the ADS-5102 Phase 3 EASE LID and EASE LID 3 studies were pooled to summarize the results of the secondary endpoints of ON time without troublesome dyskinesia, ON time with troublesome dyskinesia and OFF time. Results showed that patients treated with ADS-5102 reported a clinically meaningful increase in ON time without troublesome dyskinesia, due to significant reductions in both ON time with troublesome dyskinesia and OFF time, at 12 weeks compared to placebo: Treatment with ADS-5102 improved ON time without troublesome dyskinesia by approximately 40 percent compared to placebo, which represents a 2.4 hour per day increase in ON time without troublesome dyskinesia. Treatment with ADS-5102 decreased OFF time by approximately 45 percent compared to placebo, which represents a 1 hour per day decrease in OFF time. The treatment effect of ADS-5102 on OFF time was consistent across subgroups, including baseline OFF severity. Additional analyses of the pooled Parkinson's disease home diary data showed that among ADS-5102 treated patients, 52 percent reported complete resolution (0 hours) of ON time with troublesome dyskinesia compared to 23 percent of placebo treated patients. Also, these analyses showed that among ADS-5102 treated patients, 68 percent reported marked improvement ( > 2 hours) in ON time without troublesome dyskinesia compared to 40 percent of placebo treated patients.
• In the Phase 3 EASE LID and EASE LID 3 studies, the most common adverse events were consistent with the known amantadine safety profile, and most occurred between Weeks 2-4 of treatment. The majority (84 percent) of ADS-5102 treated patients did not discontinue study drug due to adverse reactions. The most common adverse reactions (? 5 percent in the active group) were visual hallucinations, dry mouth, dizziness, peripheral edema, falls, constipation, nausea, anxiety, decreased appetite, livedo reticularis, insomnia, auditory hallucinations and orthostatic hypotension.
• • On September 20, 2016, Adamas Pharmaceuticals announced the results of the EASE LID 3 study, the second Phase 3 trial of ADS-5102 extended-release capsules for the treatment of levodopa-induced dyskinesia in patients with Parkinson's disease. The trial met its primary endpoint, the reduction of the UDysRS (Unified Dyskinesia Rating Scale) total score at week 12 (p < 0.0001), reflecting a decrease in the duration, intensity and disability associated with levodopa-induced dyskinesia. In addition, a statistically significant reduction in OFF time  was observed, as measured by patient reported home diaries. A separate post hoc analysis of data from the EASE LID trial was also announced, reporting the impact LID has on activities of daily living (ADLs) of PD patients as well as the favorable effects of ADS-5102 on these ADLs. These data have been presented at the 4th World Parkinson Congress (WPC) in Portland ("Results of a Phase 3 Efficacy and Safety Study of ADS-5102 (amantadine hydrochloride) Extended-Release Capsules in Parkinson's Disease Patients with Levodopa-induced Dyskinesia (EASE LID 3)"; Abstract 1331 and "ADS-5102 (amantadine hydrochloride) Extended-Release Capsules Improves Activities of Daily Living (ADLs) in Parkinson's Disease (PD) Patients by Reducing Levodopa-induced Dyskinesia: A Post-Hoc Analysis from the Phase 3 EASE LID study"; Abstract 1233).  Abstract 1331 Primary Endpoint: ADS-5102 significantly decreased the UDysRS total score at week 12 compared with placebo. The percent reduction from the mean UDysRS total score at baseline compared to that at week 12 was 46 percent in the ADS-5102 group and 16 percent in the placebo group. Improvement in levodopa-induced dyskinesia was evident at the first post-baseline UDysRS assessment at week 2 and was maintained through week 12. Key Secondary Endpoints (PD Home Diaries): ADS-5102 increased ON time without troublesome dyskinesia by 1.9 hours per day, placebo adjusted (p=0.0168). In addition, OFF time decreased by 1.1 hours per day (p=0.0199). ADS-5102 was generally well tolerated and the types of adverse events (AEs) reported were consistent with the known safety profile of amantadine. The most common adverse events occurring in more than five percent of subjects were dry mouth, nausea, decreased appetite, insomnia, orthostatic hypotension, fall and visual hallucination. One trial subject reported two study drug related serious adverse events, but the subject stayed on study drug and completed the trial. Abstract 1233: An analysis of the UDysRS data from the EASE LID pivotal Phase 3 trial was conducted to characterize the effect dyskinesia has on ADLs for patients with PD and to evaluate the treatment impact of ADS-5102 on ADLs. The analysis included patient reported data from Part 1B of the UDysRS. The baseline data illustrate the major impact that dyskinesia has on the daily life of patients with Parkinson's disease. Seventy percent of patients reported mild to moderate impairment of activities in ‘public and social settings' as well as in ‘walking and balance' at baseline. Further analysis revealed that patients treated with ADS-5102 recorded a 7.0 point reduction from baseline in the UDysRS, Part 1B total score, compared to a 4.0 reduction for placebo. ADS-5102 was generally well tolerated and the types of AEs reported were consistent with the known safety profile of amantadine. • On February 9, 2015, Adamas Pharmaceuticals announced that results from its Phase 2/3 clinical study of ADS-5102 (EASED) have been published in the online issue of Movement Disorders. ADS-5102 is initially being developed by Adamas for the treatment of levodopa-induced dyskinesia (LID) in patients with Parkinson\'s disease.  The randomized double-blind, placebo-controlled, parallel group study evaluated 83 patients with troublesome LID. Patients were assigned to receive placebo or one of three dose levels of ADS-5102. Results from the study demonstrate that ADS-5102 significantly reduced dyskinesia, as measured by change in the Unified Dyskinesia Rating Scale (UDysRS) total score over eight weeks versus placebo at the 340 mg (p=0.005) dose level. In addition, ADS-5102 significantly increased ON time without troublesome dyskinesia by 3 hours per day, as assessed by Parkinson\'s disease patient diaries change from baseline relative to placebo at the 340 mg (p=0.008) dose level. ADS-5102 was generally well tolerated; the most common adverse events were constipation, hallucinations, dizziness, and dry mouth.
• Adamas is currently conducting three clinical trials for the treatment of LID in individuals with Parkinson's disease.

Is general: Yes