Positive Results With Extended-Release Carbidopa-Levodopa

Susan Jeffrey

April 15, 2011

April 15, 2011 (Honolulu, Hawaii) — New phase 3 results show that treatment with IPX066, an investigational extended-release formulation of carbidopa-levodopa, was associated with improvements from baseline in activities of daily living and motor symptoms in patients with early Parkinson's disease (PD).

Dr. Rajesh Pahwa

"All 3 doses of IPX066 were superior to placebo in essentially all key measures," lead study author Rajesh Pahwa, MD, professor of neurology at the University of Kansas Medical Center, Kansas City, concluded. Adverse effects were consistent with other levodopa preparations, he added, and were most frequent in the 2 highest-dose groups.

Results were presented at the American Academy of Neurology 63rd Annual Meeting. Top-line results were reported by Impax Laboratories Inc in November 2010 and reported by Medscape Medical News at that time.

APEX-PD is the first of 2 pivotal phase 3 trials for this formulation. The second trial, called ADVANCE-PD, included patients with more advanced disease and motor fluctuations and compared IPX066 with immediate-release carbidopa-levodopa.

Top-line results of that trial were released March 14, 2011, and showed a 37% improvement in "off" time during waking hours compared with baseline vs a 17% improvement for patients taking immediate-release carbidopa-levodopa (P < .0001).

Both studies were supported by Impax Laboratories Inc, developers of IPX066.

Most Effective Treatment

Levodopa is the most efficacious symptomatic treatments for PD, but "one of its challenges" has been the relatively short half-life of 1.5 hours, Dr. Pahwa said. A sustained-release formulation is already available (Sinemet-CR), but, he said, "it has had its limitations, namely, that the absorption is slow, and in certain patients, this can result in a slow kick-in. It can also have varied absorption."

IPX066 contains both sustained- and immediate-release carbidopa-levodopa, so it can rapidly attain therapeutic levodopa concentrations and maintain them over time in early studies up to 6 hours.

APEX-PD enrolled 381 levodopa-naive patients with early PD and randomized them to placebo or 1 of 3 doses of IPX066: 145 mg 3 times per day, equivalent to 300 mg of levodopa; 245 mg 3 times per day, equivalent to 500 mg of levodopa; or 390 mg 3 times per day, equivalent to 800 mg of levodopa. A 4-week dose escalation was used, depending on the randomized dose; "so the drug was started slowly and titrated up."

The primary efficacy endpoint was the change from baseline in the sum of Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III, that is, activities of daily living and motor scores at week 30.

The dropout rates were 21% in the placebo group and 21% in the 245 mg 3 times per day group and 24% in the 390 mg 3 times per day group; in the placebo group, dropouts were related to lack of efficacy and in the treated groups to adverse events. "Again this was a fixed titration, so if patients could not tolerate it, they were more likely to get dropped," Dr. Pahwa said.

On the primary endpoint of UPDRS Part II plus III scores, there was a slight improvement with placebo but significant improvements from baseline with all 3 doses of IPX066, "not only at the end of the study but at all time points where it was measured, that is, weeks 4, 9, 16, 23, and, of course, week 30" (P < .001 for all comparisons).

Table. APEX-PD: Primary Endpoint

Endpoint Placebo 145 mg 3 Times per Day 245 mg 3 Times per Day 390 mg 3 Times per Day
Change from baseline in UPDRS scores (Part II and Part III) −0.6 −11.7 −12.9 −14.9

UPDRS = Unified Parkinson's Disease Rating Scale

On secondary endpoints, significant results vs placebo were seen in change from baseline in the UPDRS total score and change from baseline in individual UPDRS Part I, II, and III scores, but part IV scores did not reach significance, he noted. "Part IV includes patients when they develop motor fluctuations and when they develop dyskinesias, so Part IV, which would be showing if there were any significant complications of therapy, was not significant amongst these 3 groups."

Significant improvements were seen in the Patient Global Impression and Clinical Global Impression, and change from baseline in the quality-of-life measure Parkinson's Disease Questionnaire 39 was also significantly improved.

Serious adverse events were similar between groups and not judged to be related to the study medication, he noted. Other adverse effects included nausea, which was the most frequent concern, increasing as the dose did from 8.7% to 20.4% in the highest-dose group. Headache, dizziness, insomnia, dry mouth, abnormal dreams, constipation, and vomiting were also seen.

Dyskinesias occurred in none of the patients in the placebo group, 2.3% in the 145 mg 3 times per day group, 3.8% in the 245 mg 3 times per day group, and 5.1% in the 390 mg 3 times per day group. Other adverse effects included anxiety, depression, and orthostatic hypotension.

Goals of the Study?

Dr. Walter Koroshetz

After the presentation, session moderator Walter Koroshetz, MD, deputy director of the National Institute of Neurological Disorders and Stroke, questioned the study design.

"I guess I'm a little confused about the goals of the study, and why you chose a placebo to compare this drug to," Dr. Koroshetz said. "One would intuitively think that you're going to see what you saw, but...I think what you'd want to know is how does it compare to regular Sinemet."

Dr. Pahwa responded that they needed a placebo group to prove that the formulation was efficacious and pointed out that the US Food and Drug Administration (FDA) often requires a placebo arm.

However, he added, "You're right, I believe that we would also like to see in future how it compares with immediate-release carbidopa-levodopa and also sustained-release carbidopa-levodopa preparations."

Dr. Koroshetz also asked whether, without the active comparator, they were certain that this formulation supplies the same amount of carbidopa as levodopa. "How do you know that these patients wouldn't have benefited from more carbidopa?" he asked.

Dr. Pahwa acknowledged that nausea might have been reduced either by more carbidopa or by a slower titration.

In an interview with Medscape, Dr. Pahwa pointed out that the APEX-PD trial aimed to show that the formulation is efficacious in early PD, "and it did show it, so it would still also be used as initiating treatment if that's what it is approved for, but the larger group might be more patients who have been on levodopa and are having motor fluctuations to even out their symptom control during the day."

However, it may also be possible that early treatment with a sustained-release formulation might prevent fluctuations later. "We don't have the answer from this short study, but the open-label follow-up on these patients might help guide us."

ADVANCE-PD Study Reported

The ADVANCE-PD study enrolled 471 subjects on a stable regimen of immediate-release carbidopa-levodopa, according to the company release in March. All were first entered into a dose-adjustment phase of immediate-release formulation followed by conversion to IPX066. They were then randomized to either the immediate-release formulation or IPX066 for the blinded portion of the study.

All those converted to IPX066 had a reduction from baseline of more than 2 hours in off time during waking hours, and the reduction was maintained in the group subsequently randomized to the sustained-release formulation for the blinded portion. In contrast, among those switched to IPX066 and then back to the immediate-release formulation for the double-blind phase, off time worsened again by 1 hour (P < .0001).

During the double-blind phase, "on" time without dyskinesia was improved by 1.9 hours with IPX066 vs 0.8 hours with the immediate-release formulation (P < .001). Improvements with the extended-release formulation were also seen on the UPDRS, Clinical Global Impression of Change, and the Patient Global Impression of Change (P < .0001 for all comparisons). Quality-of-life measures also improved.

Treatment was generally well tolerated, the statement noted, and during the double-blind portion of the trial had an adverse event rate of 43% compared with 40% for the immediate-release formulation.

The most common adverse events reported for IPX066 included insomnia, nausea, fall, dizziness, and dyskinesia (no event was associated with a >3.5% overall incidence). The rate of related serious events was comparable, with 1 subject in each treatment arm reporting a serious treatment-related adverse event in the double-blind treatment phase.

"In the ADVANCE-PD study, daily 'off time' was reduced without worsening of dyskinesia, and both patients and clinicians reported overall improvement," said Robert A. Hauser, MD, professor of neurology, molecular pharmacology, and physiology and director of the Parkinson's Disease & Movement Disorders Center at the University of South Florida, Tampa, and an ADVANCE-PD study investigator, in the company statement.

"The magnitude of benefit observed with IPX066 was clinically significant, and results indicate that PD patients should be able to enjoy improved control of their motor symptoms and a better quality of life," he added.

Dr. Hauser is expected to present full results of ADVANCE-PD at the upcoming 15th International Congress of Parkinson's Disease and Movement Disorders in Toronto, Ontario, Canada, June 5 to 9, 2011.

The Impax release notes that ADVANCE-PD and APEX-PD are the 2 phase 3 trials required by the FDA for a new drug application for approval of IPX066, and they hope to file in the fourth quarter of this year.

The APEX-PD and ADVANCE-PD trials were funded by Impax Pharmaceuticals Inc. Dr. Pahwa has received personal compensation from GlaxoSmithKline Inc, Impax, GE Healthcare, Teva Neuroscience, Medtronic Inc, Merck Serono, St. Jude Medical, and Novartis Pharmaceuticals. He has received personal compensation in an editorial capacity for the International Journal of Neuroscience and holds stock or stock options in General Electric. He has received research support from Xenoport, Novartis, Impax, Merck Serono, Allson Pharma, and Acadia. He has received compensation and/or research work has been funded, entirely or in part, by a grant to their university.

American Academy of Neurology (AAN) 63rd Annual Meeting: LBS.001. Presented April 13, 2011.