New Drug Application Submitted for Continuous Subcutaneous Carbidopa/Levodopa Formulation

Thomas Hudson, MD

AbbVie has submitted a new drug application (NDA) for its investigational agent ABBV-951, a continuous 24-hour subcutaneous infusion of foslevodopa/foscarbidopa, for the treatment of motor fluctuations in patients with advanced Parkinson disease (PD).¹

For years, the combination of levodopa and carbidopa (LD/CD) has been the standard of care for symptom management in patients with PD. If approved, ABBV-951 will become the first subcutaneous delivery of the therapy, representing a potentially landscape-altering treatment option.

The NDA is based on the phase 3 M15-736 study (NCT04380142), a double-blind, double-dummy trial in which treatment with the agent 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.²

"Advanced Parkinson disease causes unrelenting challenges and uncertainty for patients and caregivers worldwide," Thomas Hudson, MD, senior vice president, research and development, chief scientific officer, AbbVie, said in a statement. "We are committed to addressing the unmet needs of those affected by the disease and recognize the urgency for a new treatment that can enable better symptom control through the continuous 24-hour administration of medication."¹

The study included 130 adult participants with advanced PD who were randomized 1:1 to either ABBV-951 solution as a continuous infusion under the skin plus oral placebo capsules for LD/CD or ABBV-951 as a subcutaneous infusion plus oral capsules containing LD/CD encapsulated tablets. At week 12, ABBV-951-treated patients showed a decrease of 2.75 hours in OFF time, with changes observed as early as the first week. In comparison, those in the oral LD/CD group demonstrated decreases of 0.96 hours during the same stretch (P = .0054).²

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ABBV-951 also showed a good safety profile, with most of the reported adverse events (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.

If approved, this would mark AbbVie’s second major regulatory success for patients with PD in the last 7 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.³

In May 2021, prior to the release of the results from M15-736, David Standaert, MD, PhD, chair of the Department of Neurology at the University of Alabama at Birmingham and a consultant for AbbVie, told NeurologyLive^®, "the big difference from a patient perspective is that the drug can be delivered by a small subcutaneous needle that’s a continuous way of delivering levodopa. The need for levodopa comes out of what happens in advanced PD, where patients develop wearing off of their medications."

He added, “about 50% of patients at 5 years will experience wearing off, and there are ways to treat wearing off with oral medications, but many times we get to the point where you cannot control the wearing off anymore.” Standaert, who is also among the investigators for the phase 3 study, asserted that the size of ABBV-951 is another of its advantages.

Additional safety data from M15-736 showed that erythema, pain, cellulitis, edema, bruising, hemorrhage, nodule, induration, infection, and pruritus, all infusion site AEs, were among the most reported (≥5%) with treatment of ABBV-951. Commonly reported AEs included dyskinesia, ON and OFF phenomenon, fall, hallucinations, balance disorder, constipation, and peripheral swelling. Although infusion site AEs were more common in the ABBV-951 group, most of them were considered non-serious, mild to moderate in severity, and were resolved with or without treatment. Notably, none of these led to systemic complications.

AEs leading to discontinuation from the study occurred in 21.6% of those on ABBV-951, compared to 1.5% in the oral LD/CD group. Hallucination and psychosis AEs, also more frequently reported in the ABBV-951 group, were non-serious and mild to moderate in severity. Additionally, there were less falls and associated injuries in the ABBV-951 group.

REFERENCES
1. AbbVie submits new drug application to US FDA for investigational ABBV-951 (foscarbidopa/foslevodopa) for the treatment of advanced Parkinson disease. News release. AbbVie. May 20, 2022. https://www.prnewswire.com/news-releases/abbvie-submits-new-drug-application-to-us-fda-for-investigational-abbv-951-foscarbidopafoslevodopa-for-the-treatment-of-advanced-parkinsons-disease-301551779.html?tc=eml_cleartime
2. AbbVie announces ABBV-951 showed improvement in controlling motor fluctuations compared to oral levodopa/carbidopa medication in pivotal phase 3 trial in patients with advanced Parkinson disease. News release. AbbVie. October 28, 2021. https://www.prnewswire.com/news-releases/abbvie-announces-abbv-951-foslevodopafoscarbidopa-showed-improvement-in-controlling-motor-fluctuations-compared-to-oral-levodopacarbidopa-medication-in-pivotal-phase-3-trial-in-patients-with-advanced-parkinsons-disease-301410482.html
3. AbbVie announces U.S. FDA approval of DUOPA (carbidopa and levodopa) enteral suspension for the treatment of motor fluctuations in patients with advanced Parkinson’s disease. News release. AbbVie. January 15, 2015. https://news.abbvie.com/news/abbvie-announces-us-fda-approval-duopa-carbidopa-and-levodopa-enteral-suspension-for-treatment-motor-fluctuations-in-patients-with-advanced-parkinsons-disease.htm