Treatment with Accordion Pill-Carbidopa/Levodopa (AP-CD/LD) did not provide greater reduction in daily off periods in adults with advanced Parkinson’s disease compared with Sinemet, according to top-line results of a pivotal Phase 3 trial.
However, an ongoing analysis shows meaningful decreases in specific subgroups of patients, the team noted.
Chronic treatment with levodopa — the gold standard in Parkinson’s — may result in the reappearance of motor complications, known as “off” periods. This occurs when the therapy’s efficacy wears off, and is associated with levodopa’s limited absorption in the upper gastrointestinal tract.
To combat that, Intec Pharma designed AP-CD/LD to include a gastric retention and release system with carbidopa and levodopa, to enable release in both immediate and controlled-release modes. This controlled release mode leads to slow discharge of the medication into the stomach over eight to 12 hours, which could provide a more steady absorption.
The ACCORDANCE study (NCT02605434) is comparing the oral therapy with immediate release of CD-LD with Sinemet — marketed by Merck. Two AP-CD/LD doses were tested — 50 mg of carbidopa, with 400 or 500 mg of levodopa, two or three times a day. The trial took place at more than 90 locations in the U.S., Europe and Israel. The final visit for the last patient occurred in May.
Before the double-blind part, which lasted 13 weeks, two six-week open label periods were conducted to first stabilize and then optimize the patients on Sinemet, followed by AP-CD/LD. A total 462 participants initiated the trial, 320 of whom were randomly selected for the 13-week, double-blind portion.
In addition to assessing changes in the percent of daily off time during waking hours, the investigators evaluated differences in “on” time without troublesome dyskinesia — involuntary, jerky body movements. Researchers also assessed differences in the Unified Parkinson’s Disease Rating Scale (UPDRS), part 2 — motor experiences of daily living — and part 3, motor symptoms. Potential benefits also were assessed with the clinical global impression-improvement scale, as recorded by physicians and patients.
Participants receiving AP-CD/LD did not show significant benefits over those on Sinemet in any of these comparisons, the top-line results showed.
“We are disappointed that the ACCORDANCE study didn’t meet its target endpoints with statistical significance,” Jeffrey A. Meckler, Intec Pharma’s vice chairman and CEO, said in a press release.
Meckler also said that Intec is “pleased with the good safety profile of the AP-CD/LD, as it demonstrates for the first time the long-term safety of the Accordion Pill, which is important for future potential applications and partnerships.”
As for safety, the treatment-emergent adverse effects associated with AP-CD/LD were in line with the known safety profile of CD/LD formulations. No new safety issues were observed throughout the trial, a gastroscopy safety sub-study, or the open-label extension study. During the extension, the participants — more than 90% of those taking part in ACCORDANCE — received treatment with AP-CD/LD for an additional 12 months.
“We sincerely thank the patients, families and clinical trial sites involved in this study for their commitment to advancing research in Parkinson’s,” said Michael Gendreau, Intec’s chief medical officer.
“Upon our on-going preliminary review of the data, we have noted that certain subsets of patients performed particularly well,” Gendreau added. “We will continue to analyze the full data set and expect that such findings will help inform our strategy for AP-CD/LD moving forward.”
Results from a Phase 2 trial in 60 patients showed that treatment with the Accordion Pill reduced the variability of levodopa plasma levels, and enabled both longer on periods with or without dyskinesia, and greater reductions in off time.