Accordion Pill Enables Higher Optimal Doses of Levodopa Than Sinemet, Data Show

Patients with Parkinson’s disease who were treated with Accordion Pill Carbidopa/Levodopa (AP-CD/LD) tolerated a higher dose of levodopa and experienced less variability in plasma levels of this standard therapy than those on Sinemet.

Those are the top-line results from a Phase 3 clinical trial and data from a pharmacological study.

The effectiveness of levodopa may wear off with chronic treatment, resulting in the reappearance of motor complications, known as “off” periods. As this is associated with levodopa’s limited absorption in the upper gastrointestinal tract, Intec Pharma developed AP-CD/LD, which includes a gastric retention and release system to enable both immediate and controlled release. This controlled release mode prolongs the discharge of the medication into the stomach to eight to 12 hours, which may improve absorption.

The double-blind ACCORDANCE study (NCT02605434) is comparing AP-CD/LD with Merck’s Sinemet, an immediate release formulation of CD/LD. A total of 320 patients with advanced Parkinson’s were included in the double-blind part of the study (65.6% men, average disease duration 8.7 years), with the final visit occurring last May.

All eligible participants were on a daily levodopa dose within 400 and 1,300 mg and experienced at least 2.5 hours of off periods. After study completion, the patients could join a 12-month open-label safety extension study of AP‑CD/LD.

After two periods of six weeks each to stabilize and optimize patients on Sinemet and then on AP-CD/LD, the patients were assigned randomly to either approach over 13 weeks, with a two-week follow-up.

Two AP-CD/LD doses were tested: 50 mg of carbidopa, with 400 or 500 mg of levodopa, two or three times daily. Similar to the baseline percentage of daily off time, the patients’ mean age did not differ significantly between the two groups: 62.8 years in the AP-CD/LD group and 64.9 years in patients receiving IR-CD/LD.

At the recent  International Congress of Parkinson’s and Movement Disorder Society (MDS 2019),  R. Michael Gendreau, MD, PhD, Intec’s chief medical officer, presented the scientific poster “Patients Experiencing Motor Fluctuations with Parkinson’s Disease: Participant Characteristics in the ACCORDANCE Phase 3 Efficacy and Safety Trial of Accordion Pill-Carbidopa/Levodopa.” The presentation showed that patients on AP-CD/LD tolerated higher daily doses of levodopa than those taking Sinemet.

Specifically, 86.2% of patients taking AP-CD/LD achieved an optimal levodopa dose of 1,200 mg or greater, compared to only 19.7% among those on Sinemet.

Previous results from ACCORDANCE showed that, compared with Sinemet, AP-CD/LD did not provide greater reduction in daily off periods, benefits in “on” time without troublesome dyskinesia (involuntary body movements), or improved motor function scores, as assessed with the  Unified Parkinson’s Disease Rating Scale.

In a press release, Gendreau said that this lack of significant benefits of AP-CD/LD may have been due to confounding effects from patients whose dose was increased to the maximum (50/500 mg).

An analysis of lower doses showed a greater difference in mean daily off time between AP-CD/LD and IR-CD/LD in participants who were not dose-limited during the Accordion Pill titration process.

“This suggests that for many participants, AP doses higher than those available in this study may have been necessary to achieve optimal efficacy,” said Gendreau.

Also at MDS 2019, Jeffrey A. Meckler, Intec’s vice chairman and CEO, presented the study, “Pharmacokinetics of Accordion Pill-Carbidopa/Levodopa Following Multiple Doses in Patients with Parkinson’s Disease.” That presentation showed a pharmacokinetic (PK) comparison of AP-CD/LD 50/500 mg three times per day and the immediate release form (37.5/150 mg) five times daily in 12 patients. (Of note, PK refers to how a compound is absorbed, distributed, metabolized and eliminated by the body.)

After treatment with the immediate release form on day 1, the patients were instructed to take AP-CD/LD until day 8, when they returned to the clinic in the off state and received AP-CD/LD three times over 10 hours.

In line with Phase 2 findings — which also showed reduced motor fluctuations — preliminary results showed that AP-CD/LD provided less variability in levodopa’s plasma levels. Overall, as variable plasma levodopa levels have been associated with motor complications, the findings “suggest that treatment with AP-CD/LD may reduce motor complications,” the team wrote. AP-CD/LD was well-tolerated and no serious adverse side effects were reported.

“We believe the data underscored the potential of AP-CD/LD in PD while highlighting its long-term safety data,” said Meckler. “We have initiated a formal process for partnering AP-CD/LD in PD and this enhanced exposure will be important as we seek to partner AP-CD/LD for continued late-stage clinical development and commercialization in [Parkinson’s] patients.”