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Accordion Pill Can Ease Motor Fluctuations in People with Advanced Disease, Phase 2 Data Show

Accordion Pill trial results

Oral treatment with Accordion Pill-Carbidopa/Levodopa (AP-CD/LD) lessened the variability of levodopa plasma levels and eased motor fluctuations in people with advanced Parkinson’s, according to results of a Phase 2 trial.

The study, “Pharmacokinetics and efficacy of a novel formulation of carbidopa-levodopa (Accordion Pill®) in Parkinson’s disease” appeared in the journal Parkinsonism & Related Disorders. These findings were also presented at the recent 2019 IAPRD World Congress, in Montreal.

Progressive depletion of dopamine levels in the brain results in the hallmark motor symptoms of Parkinson’s. Levodopa is the standard treatment and normally given with carbidopa to ensure delivery to the brain and conversion to dopamine.

People with advanced disease often develop motor fluctuations, characterized by a return of symptoms between levodopa doses due to the drug’s short-term effects. This is associated with levodopa’s limited absorption in the upper part of the gastrointestinal tract.

Intec Pharma’s AP-CD/LD aims to address this problem. The pill has a specific gastric retention and release system with carbidopa and levodopa, which enables release in both immediate and controlled-release modes. Controlled release enables a slow discharge into the stomach over eight to 12 hours, and potentially more steady absorption.

The multicenter, open-label Phase 2 study tested multiple doses of AP-CD/LD – 50/250 mg, 50/375 mg and 50/500 mg — twice per day in more than 60 patients. The treatment’s pharmacokinetics (PK) — its absorption, distribution, and metabolism in the body, and its excretion — and effectiveness were compared to Sinemet, an approved immediate-release (IR) combination (marketed by Merck) which contains 37.5 mg of carbidopa and 150 mg of levodopa.

Results of groups 1 to 4 — out of the six taking part in the trial — showed that all AP-CD/LD doses led to more stable plasma levels of levodopa than Sinemet, and significantly lessened levodopa’s maximum concentration by 57.1% and 66.8% in patients with and without motor fluctuations.

The 50/375 and 50/500 doses significantly reduced motor fluctuations compared to the patients’ current treatment. These doses lowered the mean daily off time — when patients experience tremors and dyskinesia, or involuntary movements — by up to 45% compared to Sinemet.

In turn, the total duration of on time (without dyskinesia) and good on time — without dyskinesia or with non-troublesome dyskinesia — were greater with these AP-CD/LD doses than with Sinemet, as were the proportions of total or good on time during waking hours. Overall, both the duration of off periods and/or on time with troublesome dyskinesia were significantly reduced with both AP-CD/LD doses.

The findings further showed that both these AP/CD-LD doses significantly improved patient and investigator ratings on the Global Clinical Impression scale of Parkinson’s severity.

Treatment-emergent adverse events associated with AP-CD/LD use were in line with the known safety profile of CD/LD formulations. No new safety issues were found throughout the trial.

“AP technology demonstrated effective controlled-release PK performance and reduced motor response fluctuations in advanced [Parkinson’s] patients,” the scientists wrote.

“Importantly, the substantially improved ON time for the AP versus IR [Sinemet] was attained without an emergence of troublesome dyskinesia,” they added.

Intec Pharma is conducting a Phase 3 study in the U.S., Europe and Israel called ACCORDANCE (NCT02605434) that will compare the safety and efficacy of AP-CD/LD and Sinemet in 462 adults with advanced Parkinson’s. Two different AP-CD/LD doses are being tested — 50 mg of carbidopa with 400 or 500 mg of levodopa, two or three times a day.

As these doses generally match those used in the Phase 2 study, the investigators expect “similar stable LD and CD plasma levels within the therapeutic range necessary for [Parkinson’s} symptom control.” Topline results are reported as likely to be released this summer.

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Accordion Pill May Help Reduce Motor Fluctuations in Parkinson’s Disease, Phase 2 Trial Shows

Accordian Pill, Parkinson's

The Accordion Pill Carbidopa/Levodopa (AP-CD/LD) administered three times a day reduced the variability of blood plasma levels of levodopa in Parkinson’s disease patients, which suggests that the treatment may help to ease motor fluctuations, a Phase 2 trial shows.

Warren Olanow, MD, professor at Mount Sinai School of Medicine, New York, and the study’s lead author shared these results in a scientific poster, titled “Pharmacokinetics of multiple doses of Accordion Pill Carbidopa/Levodopa in patients with Parkinson’s disease,” at the 2019 IAPRD World Congress, June 16–19 in Montreal, Canada.

Levodopa is the most widely used treatment for Parkinson’s motor symptoms, and is almost always given in combination with carbidopa — a molecule that ensures levodopa is safely delivered to the brain, where it is processed to generate dopamine. Low levels of dopamine in Parkinson’s patients lead to the characteristic motor impairments associated with the disease.

However, patients with advanced disease who are being treated with levodopa often develop motor fluctuations, which result from “off” periods (when symptoms return) between levodopa doses due to its short-term effects.

This limited effectiveness is associated with the restricted absorption of levodopa in the upper part of the gastrointestinal tract, meaning that it has a short period of absorption.

Intec Pharma’s AP-CD/LD was designed to address this problem. The pill has a specific gastric retention and release system containing carbidopa and levodopa which allows the therapy to be released in both immediate and controlled-release modes.

Controlled release enables a slow discharge of the therapy in the stomach over eight to 12 hours, potentially allowing for more steady absorption in the upper gastrointestinal tract, where levodopa is absorbed.

The Phase 2 study (NCT03576638) evaluated the pharmacokinetic (PK) profile (a compound’s processing inside the body) of AP-CD/LD compared to Sinemet (an approved combination of immediate-release carbidopa-levodopa, marketed by Merck) in 12 Parkinson’s patients.

Participants received either an AP-CD/LD capsule — containing 50 mg of carbidopa with 500 mg of levodopa — three times a day, or they were given an immediate-release Sinemet tablet — consisting of 37.5 mg of carbidopa and 150 mg of levodopa — five times a day.

Blood samples were collected pre-dose, and then at 30-minute intervals post-dose over 16 hours and again at 24 hours post-dose.

The study’s main objective was to assess the variability in the blood concentration of levopoda between four and 16 hours after dosing.

The results showed that patients treated with AP-CD/LD three times a day had less variability in the concentration of levopoda in their blood compared with those given Sinemet given five times a day. Treatment with AP-CD/LD was found to be safe as there were no reports of adverse events.

As decreasing the fluctuations in blood levopoda levels is linked with reduced motor complications, “these preliminary results suggest that treatment with AP-CD/LD may reduce motor complications compared with standard [immediate-release]-CD/LD treatment in advanced [Parkinson’s disease] patients,” the researchers wrote.

“These PK results are important as they confirm our expectations that AP-CD/LD 50/500 [three times per day] reduces levodopa variability in [Parkinson’s disease] patients, which we expect will translate to a reduction in motor fluctuations in these patients,” Jeffrey A. Meckler, vice chairman and CEO of Intec Pharma said in a press release.

Intec Pharma is also conducting a Phase 3 trial, named ACCORDANCE (NCT02605434), to compare the safety and efficacy of AP-CD/LD and Sinemet in hundreds of adults with advanced Parkinson’s.

“We are eagerly awaiting the top-line results from our Phase 3 ACCORDANCE trial in the July/August time frame and these positive PK data support our belief that AP-CD/LD treatment could provide Parkinson’s disease patients with a better baseline [levodopa] therapy to reduce motor complications,” Meckler added.

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FDA Approves Generic Version of Sinemet for Parkinson’s Treatment, Company Says

Sinemet generic

The U.S. Food and Drug Administration (FDA) has approved a generic equivalent to Sinemet (carbidopa/levodopa) for the treatment of Parkinson’s disease, according to a press release.

The oral therapy, produced by India-based Alembic Pharmaceuticals, will be available as extended-release tablets containing either 50 mg of carbidopa and 200 mg of levodopa, or 25 mg of carbidopa and 100 mg of levodopa.

Sinemet, marketed by Merck, was approved by the FDA in 2014 and is sold as controlled-release tablets in three different strengths: 25 mg of carbidopa and 100 mg of levodopa; 10 mg of carbidopa and 100 mg of levodopa; or 25 mg of carbidopa and 250 mg of levodopa.

People with Parkinson’s have low levels of the neurotransmitter dopamine in the brain. Neurotransmitters are substances produced in response to nerve signals that act as chemical messengers. Direct administration of dopamine cannot be used to increase its levels because it is unable to reach the brain due to the blood-brain barrier, a thin membrane that protects the central nervous system (brain and spinal cord) from the circulatory blood system.

Levodopa and carbidopa act to increase dopamine levels in the brain. Levodopa, a molecule involved in the chemical reaction that produces dopamine, has the ability to cross the blood-brain barrier.

Meanwhile, Carbidopa inhibits enzymes known as decarboxylases that would degrade levodopa, ensuring it reaches the brain. However, carbidopa cannot cross the blood-brain barrier, which allows decarboxylases in the brain to then convert the levodopa to dopamine. Using carbidopa together with levodopa enables the use of lower doses of levodopa, which decreases its side effects, including nausea and vomiting.

The carbidopa and levodopa extended-release tablets also are approved for treatment of postencephalitic parkinsonism, a progressive neurodegenerative disease with clinical features of Parkinson’s, likely caused by an infection, and for people with Parkinson’s symptoms following intoxication by carbon monoxide or manganese.

Brief exposure to air pollution, including to carbon monoxide, has been suggested to increase the risk of Parkinson’s disease and other neurological diseases.

Exposure to the metal manganese may trigger the development of Parkinson’s by promoting the release from nerve cells of the alpha-synuclein protein. The clustering of this protein causes inflammation and neurodegeneration.

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