Adverse events like dyskinesia, ON and OFF phenomenon, and falls, were all higher during the 4-week optimization phase than the 8-week maintenance phase.
Findings from a post-hoc analysis of the phase 3 M15-736 study (NCT04380142) assessing AbbVie’s 24-hour subcutaneous foslevodopa/foscarbidopa therapy showed higher rates of adverse events (AEs) and discontinuations during the 4-week optimization period compared with the 8-week maintenance period.
Presented at the 2023 American Academy of Neurology (AAN) Annual Meeting, held April 22-27, in Boston, Massachusetts, investigators concluded that "patient and physician training, education, and expectation setting before treatment initiation and during optimization may help reduce rates of treatment discontinuation."
Comprising of 130 adults with advanced Parkinson disease (PD), the trial randomly assigned individuals 1:1 to either 24-hour subcutaneous foslevodopa/foscarbidopa, or ABBV-951, plus oral placebo capsules for levodopa/carbidopa (LD/CD) or to oral immediate-release LD/CD plus continuous subcutaneous infusion of placebo solution. The analysis focused on 74 individuals on active treatment, who had dosing levels titrated during the 4-week optimization period, followed by a stable dose regiment during the 8-week maintenance period. Safety was assessed in all patients who received at least 1 dose of study drug.
When comparing the 4-week optimization and 8-week maintenance periods, a greater number of AEs (74.3% vs 67.9%) and treatment discontinuations because of AEs (16.2% vs 7.1%) were found in the optimization period. A greater proportion of patients experienced movement-related AEs during optimization vs maintenance, including dyskinesia (10.8% vs 0%), ON and OFF phenomenon (6.8% vs 1.8%), and falls (13.5% vs 8.9%).
Individual infusion site AEs followed a similar trend, favoring the maintenance period. This included erythema (20.3% vs 21.4%) pain (21.6% vs 8.9%), cellulitis (10.8% vs 12.5%) bruising (6.8% vs 1.8%), and nodules (5.4% vs 3.6%). Investigators concluded that the higher rates of AEs and discontinuations during optimization may have been a “result of the dose titration process and acclimation to a new drug delivery process."
After submitting a new drug application (NDA) in May 2022, AbbVie received a complete response letter from the FDA for ABBV-951, requesting additional information on the pump as part of its review. It did not request AbbVie to conduct additional efficacy and safety trials related to the drug. Using the M15-736 study as the basis for the NDA, the company did note it plans to resubmit an application as soon as possible.
Findings from the original analysis of the study showed that treatment with ABBV-951 resulted in increased ON time by 2.72 hours over a 12-week period compared to 0.97 hours for oral LD/CD. These improvements, documented using the Parkinson’s Disease Diary, were observed as early as the first week and persisted through the end of the study period. ABBV-951 also showed a good safety profile, with most of the reported AEs either mild or moderate in nature. Serious AEs occurred in 8% in the ABBB-951 group compared with 6% in the LD/CD group. Notably, there was 1 death recorded in the study, believed to be from a treatment-emergent AE while in the LD/CD group.2
If approved, this would mark AbbVie’s second major regulatory success for patients with PD in the last 8 years. In 2015, the FDA approved Duopa, the first and, to date, only treatment providing 16 continuous hours of LD/CD to help control motor fluctuations in advanced PD. The eternal suspension is administered using a small, portable pump that delivers LD/CD directly into the small intestine through a tube placed during an outpatient procedure.