Weining Z. Robieson

Introduction Foslevodopa/foscarbidopa, a soluble formulation of levodopa/carbidopa (LD/CD) prodrugs for the treatment of Parkinson’s disease (PD), is administered as a 24-hour/day continuous subcutaneous infusion (CSCI) with a single infusion site. The efficacy and safety of foslevodopa/foscarbidopa versus oral immediate-release LD/CD was previously demonstrated in patients with PD in a 12-week, randomized, double-blind, phase 3 trial (NCT04380142). We report the results of a separate 52-week, open-label, phase 3 registrational trial (NCT03781167) that evaluated the safety/tolerability and efficacy of 24-hour/day foslevodopa/foscarbidopa CSCI in patients with advanced PD. Methods Male and female patients with levodopa-responsive PD and ≥ 2.5 hours of “Off” time/day received 24-hour/day foslevodopa/foscarbidopa CSCI at individually optimized therapeutic doses (approximately 700–4250 mg of LD per 24 hours) for 52 weeks. The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in normalized “Off” and “On” time, percentage of patients reporting morning akinesia, Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Parkinson’s Disease Sleep Scale–2 (PDSS-2), 39-item Parkinson’s Disease Questionnaire (PDQ-39), and EuroQol 5-dimension questionnaire (EQ-5D-5L). Results Of 244 enrolled patients, 107 discontinued, and 137 completed treatment. Infusion site events were the most common adverse events (AEs). AEs were mostly nonserious (25.8% of patients reported serious AEs) and mild/moderate in severity. At week 52, “On” time without troublesome dyskinesia and “Off” time were improved from baseline (mean [standard deviation (SD)] change in normalized “On” time without troublesome dyskinesia, 3.8 [3.3] hours; normalized “Off” time, −3.5 [3.1] hours). The percentage of patients experiencing morning akinesia dropped from 77.7% at baseline to 27.8% at week 52. Sleep quality (PDSS-2) and quality of life (PDQ-39 and EQ-5D-5L) also improved. Conclusion Foslevodopa/foscarbidopa has the potential to provide a safe and efficacious, individualized, 24-hour/day, nonsurgical alternative for patients with PD. Trial Registration Number ClinicalTrials.gov identifier NCT03781167.

Background. Nonmotor symptoms (NMS) are common in advanced Parkinson’s disease (APD) and reduce health‐related quality of life. Objective. The aim of the study was to evaluate levodopa‐carbidopa intestinal gel (LCIG) versus optimized medical treatment (OMT) on NMS in APD. Methods. INSIGHTS was a phase 3b, open‐label, randomized, multicenter study in patients with APD (LCIG or OMT, 26 weeks) (NCT02549092). Primary outcomes assessed were total NMS (NMS scale (NMSS) and PD sleep scale (PDSS‐2)). Key secondary outcomes included the Unified PD Rating Scale (UPDRS) Part II, Clinical Global Impression of Change (CGI‐C), and PD Questionnaire‐8 (PDQ‐8). Additional secondary measures of Patient Global Impression of Change (PGIC), King’s PD Pain Scale (KPPS), and Parkinson Anxiety Scale (PAS) also were evaluated. Finally, safety was assessed. Results. Out of 89 patients randomized, 87 were included in the analysis (LCIG, n = 43; OMT, n = 44). There were no significant differences in NMSS or PDSS‐2 total score changes (baseline to Week 26) between LCIG and OMT; within‐group changes were significant for NMSS (LCIG, p < 0.001; OMT, p = 0.005) and PDSS‐2 (LCIG, p < 0.001; OMT, p < 0.001). Between‐group treatment differences were nominally significant for UPDRS Part II (p = 0.006) and CGI‐C (p < 0.001) at Week 26 in favor of LCIG; however, statistical significance could not be claimed in light of primary efficacy outcomes. PGIC (Week 26) and KPPS (Week 12) scores were nominally significantly reduced with LCIG versus OMT (p < 0.001; p < 0.05). There were no significant differences in PDQ‐8 or PAS. Adverse events (AEs) were mostly mild to moderate; common serious AEs were pneumoperitoneum (n = 2) and stoma‐site infection (n = 2) (LCIG). Conclusions. There were no significant differences between LCIG versus OMT in NMSS or PDSS‐2; both LCIG and OMT groups significantly improved from baseline. AEs were consistent with the known safety profile.

Background: Results from a phase 2a study indicated that treatment with the novel α7 nicotinic acetylcholine receptor agonist ABT-126 25 mg once daily (QD) was associated with a trend for improvement in cognition in subjects with mild-to-moderate Alzheimer’s dementia (AD). A phase 2b program was designed to evaluate a broader dose range of ABT-126 as monotherapy in subjects with mild-to-moderate AD. The program consisted of a double-blind, placebo and active controlled study of ABT-126 (dose range 25–75 mg) and an open-label extension study (75 mg). Methods: The randomized double-blind study enrolled 438 subjects (Mini-Mental Status Examination score of 10–24, inclusive) not currently taking acetylcholinesterase inhibitors or memantine. Subjects received 24 weeks of ABT-126 25 mg QD (n = 77), ABT-126 50 mg QD (n = 108), ABT-126 75 mg QD (n = 73), donepezil 10 mg QD (n = 76), or placebo (n = 104). The primary endpoint was the change from baseline to week 24 in the 11-item Alzheimer's Disease Assessment Scale—Cognitive subscale (ADAS-Cog) total score. Subjects completing the double-blind study could enroll in the 28-week open-label extension study. Adverse events (AEs) and other safety parameters were monitored in both studies. Results: A total of 367 patients (83.8 %) completed the double-blind study and 349 (79.7 %) entered the open-label study. Compared with placebo, donepezil significantly improved ADAS-Cog 11-item total scores from baseline to week 24 (−2.29 ± 0.95; one-sided P = 0.008). No ABT-126 dose demonstrated a statistically significant improvement vs placebo at week 24 in the ADAS-Cog total score: ABT-126 25 mg, −0.47 ± 0.94 (P = 0.309); ABT-126 50 mg, −0.87 ± 0.85 (P = 0.153); and ABT-126 75 mg, −1.08 ± 0.94 (P = 0.127). Rates of serious AEs and discontinuations due to AEs were similar across treatment groups. The most frequently reported AEs in both studies were constipation, fall, and headache. No clinically meaningful changes were observed in other parameters. Conclusions: In the double-blind trial, donepezil significantly improved ADAS-Cog scores but no statistically significant improvement was seen with any ABT-126 dose. ABT-126 had an acceptable safety profile in subjects with mild-to-moderate AD in both studies. Trial registration: ClinicalTrials.gov NCT01527916, Registered 3 February 2012 (randomized trial). ClinicalTrials.gov NCT01676935. Registered 29 August 2012 (open-label extension study).