Intec Readying for New Phase 3 Accordion Pill Study in Parkinson’s

Intec Pharma and its manufacturing partner, Lohman Therapie-Systeme (LTS) have shown an ability to manufacture the Accordion Pill Carbidopa/Levodopa (AP-CD/LD), an investigational Parkinson’s therapy, at a commercial scale, and are advancing with the production of stability lots expected to bring it into a new Phase 3 trial.

Meanwhile, Intec is looking for partners for the late-stage development and commercialization of AP-CD/LD.

“Our partnering activities for the AP-CD/LD program in Parkinson’s disease continue and there remain multiple parties with interest in this program,” Jeffrey A. Meckler, vice chairman and CEO of Intec Pharma, said in a press release.

But an agreement is taking longer than anticipated, Meckler added, “and [we] believe this is related to certain commercialization concerns as well as to the overall market environment as a result of the COVID-19 pandemic.”

Levodopa is considered the gold-standard treatment for Parkinson’s. However, several years after starting the medication, patients often begin experiencing fluctuations in their motor symptoms caused by a faster wearing off of the treatment’s effects.

Over time it can be necessary to take more frequent doses of levodopa to manage movement problems, which causes levodopa levels to fluctuate throughout the day, rather than staying stable. These fluctuations can result in levodopa-induced dyskinesia (involuntary movements).

Current levodopa formulations are only absorbed in the upper gastrointestinal tract, meaning they have a narrow absorption window, and they last for short periods in the blood — about 50% of levodopa is degraded within 90 minutes.

Intec’s lead candidate, AP-CD/LD, is designed to stabilize levodopa levels in the blood of Parkinson’s patients, with a goal of both reducing “off” periods — when levodopa wears off — and of increasing “on” periods — times when symptoms are adequately controlled — without dyskinesia.

AP-CD/LD includes both immediate and controlled-release modes, enabling a portion of its active ingredients to be released immediately after reaching the stomach, and another portion over a period of eight to 12 hours.

After showing significant reductions in total “off” time and “on” time accompanied by dyskinesia in a Phase 2 trial, AP-CD/LD entered the global ACCORDANCE Phase 3 trial (NCT02605434) and was compared directly with Merck’s Sinemet, an immediate release formulation of CD/LD.

The trial included 320 people with advanced Parkinson’s, who were randomly assigned to either AP-CD/LD or Sinemet for 13 weeks. Prior to randomization, all went through two six-week periods to stabilize and optimize them on Sinemet and then on AP-CD/LD.

ACCORDANCE’s main goal was to determine changes in total “off” time during wake hours from start to end of the 13-week randomized trial. Results showed that AP-CD/LD could treat motor symptoms, but it failed to provide greater reductions in daily off periods compared to Sinemet. It also did not extend on time without dyskinesia or improve patients’ motor scores.

A later analysis, however, suggested that the doses given in the study were not sufficient to achieve optimal efficacy — 50 mg of carbidopa, with 400 or 500 mg of levodopa, two or three times daily — and that patients who had not maxed out their dose during the optimization period did have a meaningful reduction in off periods.

Findings also showed that AP-CD/LD provided less variability in blood levels of levodopa, and that AP-CD/LD patients tolerated higher levodopa daily doses than those taking Sinemet.

With these findings, Intec began looking for a partner that would “advance [AP-CD/LD] into a final, pivotal Phase 3 study and move toward commercialization” to benefit those “suffering from the motor complications associated with the pulsatile delivery of generic [levodopa] formulations,” it said in a January letter to shareholders.

Intec and LTS have begun to manufacture commercial batches of AP-CD/LD, expected to serve as the clinical material for the next Phase 3 clinical trial, at LTS’s manufacturing facility in Andernach, Germany.

This facility is compliant with the U.S. Food and Drug Administration’s current good manufacturing practices (cGMP) requirements — which ensure products are manufactured according to quality standards — and has passed audits from all other major global regulatory agencies.

This is expected to expedite the initiation of the planned Phase 3 trial, as well as future regulatory submissions.

Intec is also working on next-generation Accordion Pill technologies that will enable the slow release of active ingredients in the stomach over a period of 24 hours, with a goal of bringing additional treatment options to Parkinson’s patients.