Parkinson’s disease is the second most common neurodegenerative disorder in the elderly and it affects more than two million people in the U.S. and Europe. There are more than 600,000 Parkinson’s disease patients in the U.S. who experience motor fluctuations, a condition where with disease progression patients experience both “wearing off” (where they have trouble with movement), and “dyskinesias” or uncontrolled movements. More than 400,000 of these patients in the U.S. experience in excess of one hour per day of motor fluctuations.
Disease progression and motor complications have a considerable impact on quality of life.
The majority of Parkinson’s disease patients are treated with levodopa (LD). However, LD treatment is associated with motor complications, mainly wearing “OFF” periods and LD-induced Dyskinesia.
The efficacy and adverse effects of levodopa are directly related to plasma levels of the drug. Current formulations of LD provide only limited efficacy as LD has a very short half-life of approximately 90 minutes and its absorption is confined to the upper part of the gastrointestinal tract (narrow absorption window). Consequently, stabilizing levodopa plasma levels remains a major factor for improving anti-parkinsonian control in advanced Parkinson’s disease patients.
The Accordion Pill—Carbidopa/Levodopa
The Accordion Pill Carbidopa/Levodopa (AP-CD/LD) is a gastric-retentive drug delivery system containing carbidopa and levodopa in both immediate and controlled-release modes. The innovative gastric retentive qualities of AP-CD/LD allows the controlled release LD to be released slowly in the stomach over 8 – 12 hours, allowing the body to absorb it more steadily in the upper GI tract, resulting in a more stable pharmacokinetic (PK) profile.
Phase 2 Clinical Studies of AP-CD/LD
A total of approximately 60 Parkinson’s patients took part in the various Phase II trials, during which three different dosages of AP-CD/LD were evaluated. Forty-eight Parkinson’s patients in advanced stages of the disease participated in the trial. The patients were treated with the AP-CDLD for a period of three weeks and then crossed over (randomized) for a second three-week period in which they were treated according to the optimized current marketed Carbidopa/Levodopa treatment regimen of each patient.
One study cohort of twenty-one Parkinson’s disease patients tested the efficacy and safety of AP-CD/LD 50/500 mg BID (two times per day) during 24-hour periods, in comparison to the optimized current treatment regimen. The primary end-points of the trial were the reduction of total OFF time and safety. The secondary objectives of the trial were, inter alia, extending the good ON time and reducing the daily number of doses of Levodopa. These objectives were successfully achieved with statistical significance.
Among the 18 patients who completed the trial in accordance with the study protocol, a statistically significant reduction of approximately 45% was achieved in total OFF time, from an average of 5.1 hours during 24-hour periods with their optimized current treatment to an average of 2.8 hours with the AP-CDLD (P<0.0001).
In addition, AP-CD/LD treatment demonstrated a reduction of approximately 42% in total ON time with troublesome Dyskinesia, from 1.2 hours to 0.7 hours, during 24-hour periods
The proportion of good ON time during waking hours was increased from approximately 61% to approximately 77% (P<0.0001). In addition, a statistically significant reduction in the total number of Levodopa daily doses from 5.4 to 4.0 was achieved (P<0.0001).
Phase 3 Clinical Studies of AP-CD/LD
Intec Pharma completed a global, pivotal Phase 3 clinical trial of AP-CD/LD in advanced Parkinson’s disease. The Phase 3 “ACCORDANCE” clinical trial of AP-CD/LD was a multi-center, global, randomized, double-blind, double-dummy, active-controlled, parallel-group study in adult subjects with fluctuating PD. The primary efficacy endpoint was the change from baseline to endpoint in the percent of daily OFF time during waking hours based on Hauser home diaries. The study was 90% powered to be statistically significant for a one-hour difference in OFF time.
The study was conducted at over 90 clinical sites throughout the U.S., Europe and Israel. Prior to the 13-week randomized and double-blinded portion of the study, the ACCORDANCE study had two open label periods of 6 weeks each during which all patients in these open label periods were first stabilized and then optimized on the active comparator, Sinemet®, and then on AP-CD/LD. The study enrolled 462 patients in the Sinemet titration period to provide for the 320 patients that were randomized into the 13-week, double-blinded portion of the study. All patients completing the 13-week randomized period were eligible to continue in an open-label extension study in which they receive treatment with AP-CD/LD for an additional 12 months. More than 90% of eligible patients elected to enter the OLE study.
The study showed that AP-CD/LD provided treatment for Parkinson’s disease symptoms but did not demonstrate a statistically significant reduction in OFF time over that obtained with IR-CD/LD under the conditions established in the protocol. In preliminary review, AP-CD/LD provided meaningful reduction in OFF time for those patients who were dosed at 1.6 to 2.0 times the IR-CD/LD dose, which is comparable to the ratios of other extended release LD products. Treatment-emergent adverse effects (TEAEs) observed with AP-CD/LD were generally consistent with the known safety profile of CD/LD formulations and no new safety issues were observed throughout the double-blinded study, during the gastroscopy safety sub-study or the 12-month open-label extension (OLE) study.
Intec Pharma continues to analyze the full data set and expects that such findings will help inform the strategy for AP-CD/LD moving forward in PD.
To learn more about our AP-CD/LD program in Parkinson’s disease, please contact email@example.com.