NAPLES, FLORIDA—The newest therapies for Parkinson’s disease are actually new applications of old treatments, according to David Charles, MD, Professor and Vice-Chairman of Neurology at Vanderbilt University Medical Center in Nashville. At the 42nd Annual Meeting of the Southern Clinical Neurological Society, Dr. Charles reviewed some of the more recent developments in the Parkinson’s disease therapeutic armamentarium, including the rotigotine patch, the apomorphine pump, a levodopa–carbidopa intestinal gel, a new timed-release form of levodopa–carbidopa, and deep brain stimulation (DBS) for early-stage Parkinson’s disease. A common theme among these newer developments is continuous therapy.
Rotigotine was shown to be effective in three large randomized, double blind, placebo-controlled trials. “There really is no doubt that it offered superior efficacy when compared to placebo in early-stage Parkinson’s disease,” Dr. Charles said. In advanced-stage disease, the patch also had superior efficacy, compared with placebo. “What it did was reduce the amount of off time that patients had in a 24-hour period.” In advanced-stage disease, the dose was 4 to 16 mg; in early-stage disease, the dose was 2 to 8 mg.Rotigotine Patch The rotigotine patch (brand name, Neupro) provides continuous transdermal delivery of a dopamine agonist. It was first approved in the United States in 2007 but was recalled from the market because crystals would sometimes form in the patches. It took four years to fix the problem, but the drug is now back on the market. The product is FDA-approved as a once-daily treatment for Parkinson’s disease and restless legs syndrome. The patch is available in 2-, 4-, 6-, and 8-mg doses.
Apomorphine is available as a subcutaneous injection in the United States as a rescue therapy for patients with unexpected off periods. “Where it can be helpful,” Dr. Charles said, “is if you have someone who is beginning to have motor fluctuations and unexpected off periods that are keeping them from engaging in activities.” The autoinjector of apomorphine enables rapid uptake of the drug and quickly restores on time.
Apomorphine, which is unrelated to morphine, is a dopamine agonist that often causes nausea and vomiting. “It is not the easiest drug in the world to use,” Dr. Charles said. In Europe, apomorphine is available in a pump that is not yet FDA-approved in the United States. The pump delivers a continuous trickle of apomorphine into the subcutaneous space. “The advantage, theoretically, is that you avoid the ups and the downs that patients get with levodopa,” Dr. Charles said.
No randomized trials of the apomorphine pump have been conducted. Many open-label trials of the product have shown 50% to 82% reductions in the amount of off time per day. A large, multicenter, parallel-group, double-blind, placebo-controlled trial is ongoing. Its primary end point is reduction in the amount of off time the patient experiences.
Levodopa–Carbidopa Intestinal Gel
While the levodopa–carbidopa combination has been around for many years, a gel formulation was developed recently. The gel holds the medication in suspension and can be infused slowly and continuously through a tube into the jejunum. According to Dr. Charles, the disadvantages are the high price—about the same as DBS surgery—and a high adverse event rate. “It definitely works, though,” Dr. Charles said. The gel has been available in Europe since 2004 and received FDA approval in January 2015 for the treatment of motor fluctuations in patients with advanced-stage Parkinson’s disease. It is available through Abbvie under the brand name Duopa.
The pivotal trial showed that this therapy reduced the amount of off time by about four hours, compared with placebo, and it also increased the time without dyskinesias. “So, again, there’s the theme of continuous therapy,” Dr. Charles said. “There is something about the pulsatile nature of oral levodopa that seems to exacerbate the display of motor fluctuations and dyskinesias,” Dr. Charles commented.
Another therapy that FDA approved in January 2015 is a new timed-release formulation of levodopa–carbidopa (available through Impax Pharmaceuticals under the brand name Rytary). This formulation, Dr. Charles said, may resolve some of the absorption variability associated with older sustained-release formulations. The new preparation holds the medication in microspheres that are engineered to break down at different rates. “The capsule and a portion of the microspheres break down almost immediately, so patients will get that immediate on like they’ve taken a regular dose of levodopa,” Dr. Charles explained. The remaining microspheres dissolve later. If swallowing is a problem for the patient, the capsules can be broken apart and the contents sprinkled onto food.
This timed-release formulation has been studied in early- and late-stage Parkinson’s disease. The first studies were dose-finding and compared the drug head to head against placebo. Three doses were given—145 mg tid, 245 mg tid, and 390 mg tid—and all three doses significantly changed participants’ Unified Parkinson’s Disease Rating Scale (UPDRS) scores. Another study looking at advanced-stage patients came to similar conclusions. The timed-release formulation reduced off times and levodopa dosing frequency.
A crossover study compared Rytary with Stalevo, which is carbidopa and levodopa plus a COMT inhibitor (entacapone), a formulation intended to extend the usable life of the carbidopa–levodopa. Rytary reduced mean off time from 35% to 24%.
“This is pretty exciting because, unlike the levodopa gel, which is really going to fit into a niche of motor fluctuations in advanced patients, this [timed-release formulation] could potentially be used for patients with a new diagnosis,” Dr. Charles said.
DBS in Early Parkinson’s Disease
DBS was first approved in the United States in 1997 for essential tremor and unilateral tremor from Parkinson’s disease. The first implantation site was the ventral intermediate nucleus of the thalamus. In 2002, the indication was extended to implantation in the subthalamic nucleus and the globus pallidus interus. An indication for dystonia followed in 2003. The current indication for DBS is advanced Parkinson’s disease when symptoms are no longer adequately controlled.
The EARLYSTIM study, a large European trial that enrolled about 250 patients with mid-stage disease, was completed a few years ago. Participants in this open-label study had motor fluctuations and dyskinesias and had been on medicine for several years. The only blinded rating was the UPDRS part 3. The primary end point of the study was quality of life, which was 26% better with DBS than on pharmacologic treatment. All of the other measures were better in the DBS group as well. UPDRS part 4, which measures levodopa-associated dyskinesias, was 60% better in the DBS group and got 13% worse in the medicine group.
Dr. Charles and colleagues at Vanderbilt University recently completed a pilot trial of DBS of the subthalamic nucleus plus optimal drug therapy versus optimal drug therapy alone in 30 patients with very early-stage Parkinson’s disease. The results were encouraging, and Vanderbilt recently received FDA approval to conduct a multicenter, phase III, pivotal clinical trial in 280 patients with early stage Parkinson’s disease. Eligible patients can be on medication for no more than four years and can never have had a history of motor fluctuations or dyskinesias. “This trial will be evaluating DBS in a very early stage of Parkinson’s disease to determine if DBS is superior to medical therapy, reduces the relative risk of worsening, and suppresses the development of complications of medical therapy, such as motor fluctuations and dyskinesias,” Dr. Charles said.
—Glenn S. Williams