IPX203 Extended-Release Capsules Reduce ‘Off’ Time in Advanced Parkinson’s, Trial Shows

IPX203 extended-release capsules

Impax Laboratories‘ investigational carbidopa-levodopa extended-release capsules, IPX203, are better than immediate-release tablets at maintaining steady levels of levodopa in the blood, and prolonging the alleviation of motor symptoms, in people with advanced Parkinson’s disease, according to clinical data.

Based on its positive results, the company is now studying IPX203’s safety and effectiveness in people with advanced Parkinson’s in a Phase 3 study (NCT03670953). The trial is currently recruiting at many of its 65 worldwide study locations; more information can be found here.

The study, “Pharmacodynamics, Efficacy, and Safety of IPX203 in Parkinson Disease Patients With Motor Fluctuations,” was published in the journal Clinical Neuropharmacology.

Levodopa (LD), the “gold standard” treatment for Parkinson’s symptoms, works by replenishing the brain’s dopamine, which is gradually lost in people with the disease. The therapy can be used alone, or in combination with carbidopa (CD), and is available in many forms: as controlled or extended-release tablets, known as Rytary; as dispersible tablets that can be mixed with water; and as an intestinal gel, called Duodopa.

Impax now is developing a new version of extended-release CD-LD capsules, called IPX203, expected to reduce the motor complications seen with prolonged use of short-acting levodopa or other dopaminergic therapies.

These short-acting medications typically require frequent doses, so their concentrations in the body tend to fluctuate over time while patients are receiving treatment. As a result, dopamine receptors in the brain are stimulated in an intermittent fashion. 

Researchers believe this can explain why patients using levodopa for prolonged periods of time often experience motor complications, such as motor fluctuations or uncontrolled, involuntary movements, called dyskinesia. These side-effects are common, and can be very disabling.

To get around these effects, IPX203 contains carbidopa and levodopa in a ratio of 1-to-4. While that ratio is identical to marketed combinations, IPX203 is made of special beads meant to achieve the desired levels of levodopa in the blood. It is designed to first cause a quick rise of levodopa, followed by prolonged, steady concentrations “that extend beyond currently available products,” the researchers said.

Prior studies have shown that IPX203 has longer activity compared with immediate-release carbidopa-levodopa (IR CD-LD), and with extended-release CD-LD capsules.

In that open-label trial (NCT03007888), researchers compared the safety, efficacy, and pharmacodynamics — the interactions between the body and a compound — of IPX203 capsules versus immediate-release CD-LD tablets. The trial, conducted at 11 sites in the U.S., included 28 patients with advanced Parkinson’s who were experiencing motor fluctuations.

Participants were randomly assigned a two-week treatment with IR CD-LD, followed by a two-week treatment with IPX203, or vice-versa, with one week of “washout” between therapies. A washout is a period of time during a clinical study when a participant is taken off the study drug or other medication so as to eliminate its effects on treatment.  This type of study design is called a crossover.

The results showed that, after a single dose of IPX203, blood concentrations of levodopa were maintained during 4.6 hours above half of its highest (peak) concentration. The IR CD-LD only sustained comparable levels during 1.5 hours.

Importantly, data from levodopa’s levels and distribution in the body matched clinical improvements.

According to patient diaries, IPX203 treatment led to significantly less  “off” time — meaning less time when the medication is not working optimally and symptoms return — compared with therapy with IR CD-LD.

Patients reported a mean “off” time, depicted as a percentage of waking hours, of 19.3% with IPX203 versus 33.5% with IR CD-LD.

This translated into 2.3 hours less of feeling “off” with IPX203. Most of this extra time, a total 1.9 hours, was classified by patients as a period of “good on”defined as “on” time without or with nontroublesome dyskinesia.

Mean total “on” times with troublesome dyskinesia were similar during both treatments.

Pharmacodynamic assessments indicated similar outcomes in favor of IPX203 regarding motor symptoms, assessed using the MDS-UPDRS-III scale, in both single- and multiple-dosing studies.

Motor improvements were already noticed from 3 to 8 hours after the first dose of IPX203. Likewise, from day 1 to day 15, people treated with IPX203 had a 9.3-point improvement in motor scores, versus a 0.1 point change when taking IR CD-LD. Researchers note that a 4-unit improvement is considered clinically meaningful to the patient.

Both treatments were well-tolerated, with most treatment-emergent adverse events (TEAEs) being mild to moderate. A higher percentage of patients reported TEAEs while taking IPX203 (35.7%) compared with IR CD-LD (7.4%). The most common TEAEs were dyskinesia (five patients), dizziness (two patients), and nausea (two patients), all occurring during IPX203 treatment.

“[T]he findings support the safety and efficacy of IPX203 at the recommended doses given approximately every 7 to 8 hours,” the researchers said.

“The reduced peak-to-trough fluctuations of LD achieved with IPX203 resulted in a consolidation of [on] periods in contrast to the frequent cycles of [on] and [off] periods with IR CD-LD therapy,” they said.

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Gocovri Significantly Improves Dyskinesia and ‘Off’ Time in Parkinson’s, New Analysis Confirms


Parkinson’s disease patients treated with Gocovri (amantadine) experienced a 41 percent decrease in levodopa-induced dyskinesia compared to 14 percent of healthy people who took placebos.

That analysis of two Phase 3 trials are summarized in the study “Pooled Analyses of Phase III Studies of ADS-5102 (Amantadine) Extended-Release Capsules for Dyskinesia in Parkinson’s Disease,” published in the journal CNS Drugs.

“The results from this pooled analysis of two Phase 3 studies confirms the consistency of GOCOVRI’s benefit on dyskinesia and [off] time, as demonstrated in the individual studies across different Parkinson’s disease patient populations and all primary and secondary endpoint measures,” Lawrence W. Elmer, MD, PhD, of the University of Toledo, said in a press release. Elmer is the study’s lead author.

Researchers pooled the results of two trials — the EASE LID (NCT02136914) and the EASE LID 3 (NCT02274766 ) — that assessed the effectiveness of Adamas Pharmaceuticals’ Gocovri extended release capsules compared to placebo oral capsules in Parkinson’s disease patients with levodopa-induced dyskinesia, in which patients experience involuntary, jerky movements.

The trials’ design and eligibility criteria were the same in both Phase 3 trials, with the exception of treatment duration; in EASE LID patients underwent treatment for 25 weeks, and in EASE LID 3 the trial stopped at week 13.  Gocovri was given once every night at bedtime.

Researchers pooled the trial’s results to analyze its primary goal, which assessed changes in the Unified Dyskinesia Rating Scale (UDysRS) score from baseline to week 12.

Additional parameters included changes in the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), patient-reported Parkinson’s disease home diary data, and Clinician’s Global Impression of Change (CGI-C) in Overall PD Symptoms.

Gocovri led to a 41.1% reduction in dyskinesia from baseline to week 12 in the UDysRS score compared to 13.9% for the placebo group — a significant difference of 27.2%.

Also, dyskinesia and “off” time (period when medication is not working efficiently) also was improved, with patients achieving almost a four-hour improvement in “on” time without so-called “troublesome” dyskinesia.

By week 12, 25% of the patients treated with Gocovri had a complete resolution of off time compared to 14% in the placebo group.

Also, 68% of patients in the Gocovri group had an increase of more than two hours a day of on time without troublesome dyskinesia versus 40% in the placebo group. Moreover, 52% of patients treated with Gocovri had a complete resolution of on time with troublesome dyskinesia compared to only 23% of the placebo group.

“Patients take Gocovri once-daily at bedtime, which provides them with high amantadine concentrations upon waking and throughout the day when dyskinesia and [off] occur, and then lower concentrations in the evening when amantadine can disrupt sleep patterns. What’s most important from this pooled analysis, is that over half of patients treated with GOCOVRI reported a complete resolution of their [on] time with troublesome dyskinesia at 12 weeks,” he added.

The researchers believe these data show further evidence to support Gocovri as an adjunct to levodopa to treat both dyskinesia and off time in Parkinson’s patients with dyskinesia.

“With its demonstrated, consistent clinical efficacy, Gocovri finally provides a solution for physicians and patients needing a proven durable treatment for dyskinesia in people with Parkinson’s disease,” said Rajiv Patni, MD, chief medical officer of Adamas Pharmaceuticals, Inc.

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Source: Parkinson's News Today