No Pills, No Surgery, No Electrodes for Parkinson's Disease?

BOSTON -- Several technologies for delivering levodopa-carbidopa in a more physiologically natural fashion than is possible with ordinary oral versions for Parkinson's disease took center stage here at neurology's leading scientific conference.

In plenary sessions and late-breaking abstract presentations at the American Academy of Neurology (AAN) annual meeting, researchers provided updates on two subcutaneous delivery systems -- one of which could gain FDA approval almost any time -- and another with a unique oral drip system.

Many neurologists see this type of treatment as a potential bridge for patients no longer controlled adequately with oral medications but whose disease is not so far advanced that surgical procedures such as thalamotomy, or implantation of deep brain stimulation systems, appear necessary. If dopaminergic stimulus could be provided continuously, instead of intermittently as is the case for oral drugs, it's believed that so-called "on" time could be prolonged and "off" time reduced, helping patients get through the day comfortably without undergoing risky surgeries.

AbbVie is the leader in the race to bring such systems to market. In fact, it already sells a continuous-delivery system for levodopa-carbidopa. Called Duopa, it pumps a levodopa-carbidopa gel directly into the intestinal tract for 16 hours per day. But it is far from non-invasive -- it requires a surgeon to create an abdominal stoma for quasi-permanent port placement.

The drawbacks being obvious, AbbVie has been pursuing an alternative: a subcutaneous delivery system temporarily named ABBV-951 that uses prodrugs for levodopa and carbidopa in liquid form. Primary results from a phase III trial were published several months ago, showing that the foslevodopa-foscarbidopa system extended "on" time without troublesome dyskinesia (a standard endpoint for Parkinson's disease drugs) by some 2 hours relative to immediate-release oral levodopa-carbidopa.

FDA approval is expected, but in late March, the agency told AbbVie that it had questions about the system's mechanical pump (though not about the system's efficacy or safety). No new clinical studies were requested and AbbVie promised to resubmit its application "as soon as possible."

The company presented several follow-up studies at the AAN meeting, including one comparing ABBV-951 with Duopa for pharmacokinetic parameters. Mean levodopa blood levels were virtually identical over 24-hour evaluations. Ratios of areas under the receiver operating characteristic curve indicated that levodopa availability was about 8% higher with the new system versus Duopa, and differences between maximum and minimum concentrations were somewhat lower.

The regulatory delay may give an alternative subcutaneous system a chance to catch up. Called ND0612, the product is under development by California-based NeuroDerm, now a unit of Mitsubishi Tanabe Pharma, and is designed to release regular liquid levodopa-carbidopa around the clock. The infusion device is placed primarily on sides of the abdomen and on the lower back.

At the AAN meeting, Alberto Espay, MD, of the University of Cincinnati, presented results from the product's pivotal phase III trial, called BouNDless. It randomized 259 Parkinson's disease patients to use ND0612 or ordinary oral levodopa-carbidopa medications for 12 weeks.

BouNDless began with two sequential run-in periods of 4-6 weeks each, beginning with standard oral therapy followed by ND0612, during which dosing regimens for the two types of treatment were optimized for each participant individually. When ND0612 was in use, patients could also receive immediate-release levodopa-carbidopa to maximize symptom control.

Of 381 patients initially enrolled, 259 completed the run-in phase -- no specific reason was given for most of the dropouts, although 6% of patients using the subcutaneous system during the run-in quit because of infusion-site reactions.

The remaining 259 were then randomized to ND0612 (plus supplementary oral medications as needed) or to standard oral levodopa-carbidopa for 12 weeks in a double-blind, double-dummy format. ND0612 provided up to 720 mg of levodopa and 90 mg of carbidopa per 24-hour period.

Mean patient age was about 64, and just under two-thirds were men. Time since initial diagnosis was 10 years, with motor fluctuations first appearing a mean 5 years previously.

Prior to the run-in, "on" time without troublesome dyskinesia averaged about 9.4 hours/day, rising to about 12 hours with ND0612 during the run-in phase. "Off" time at that point averaged 3.5 hours. After randomization, "on" time remained near that level through the 12-week treatment period among patients assigned to the subcutaneous system. The oral-therapy control group, on the other hand, saw "on" time slip back to near baseline. At week 12, the net difference in "on" time favoring ND0612 was 1.72 hours (95% CI 1.08-2.36).

"Off" time showed the reverse pattern: at week 12, it stood at 1.90 hours with oral therapy, versus 0.50 hours with ND0612 (P<0.0001). Other outcome measures, including Unified Parkinson's Disease Rating Scale part II scores and patients' and clinicians' global impressions, also significantly favored ND0612.

Infusion-site reactions remained a problem, Espay acknowledged. Some 13% of patients using the system complained of moderate irritation and one patient considered it severe. Seven patients assigned to the system dropped out because of treatment-emergent adverse effects, compared with four in the oral-therapy group. Skin irritation, he said, "is the Achilles heel of all SQ [subcutaneous] based therapies." He said rotating the application site to different parts of the body appears so far to be the best way to minimize the problem.

Preliminary results with a third approach were also reported at the AAN meeting. This involved a plastic oral appliance similar to the retainers that orthodontics patients often wear for maintenance, but with a small pump attached that drips a levodopa-carbidopa paste onto the back of the tongue, where it is then swallowed with saliva. Called DopaFuse, the system was developed by a company called SynAgile, based in Wyoming. Its chief medical officer, C. Warren Olanow, MD, formerly of the Icahn School of Medicine at Mount Sinai in New York City, presented findings from a small, 2-week phase II trial.

Like BouNDless, the trial had a somewhat complicated design. On study day 1, patients came into the clinic and received standard oral levodopa-carbidopa that day, with frequent blood sampling and clinical tests that day. On day 2, still in clinic, patients then used the DopaFuse system and underwent the same testing. On day 3, patients (also still in clinic) took one dose of regular oral medication and then used DopaFuse for the rest of the day. From day 4 to 14, patients repeated the day 3 procedure at home, and on day 15, they returned to the clinic for further testing.

Sixteen patients participated. Some patients found the device uncomfortable: a total of eight instances of abrasion or laceration inside the adjacent cheek were reported. All but one was considered mild, however, and all resolved after one day. No adverse events were considered serious and none of the patients discontinued on account of them.

Pharmacokinetic parameters indicated that the device was working as intended. Motor fluctuations while using DopaFuse on day 3 were smaller by about half relative to day 1 when patients received regular oral therapy. "On" time without severe dyskinesia was extended by about 1.5 hours relative to regular oral treatment, as was "on" time without any dyskinesia. "Off" time was reduced with DopaFuse to a corresponding degree.

The key clinical issue with all of these systems is, once approved, where they would fit in the treatment landscape. This came up after Espay's presentation when a session moderator posed the question directly. Espay responded, "The way in which we at the moment conceive this therapy is in adapting it into the early phase of advanced treatment, for individuals who are experiencing more fluctuations, for whom [conventional] dose optimization is not quite effective."

It would be an option, he added, "for individuals currently being considered for deep brain stimulation, for instance." Asked later whether one might introduce a continuous-infusion therapy earlier in the disease process, Espay agreed that it might indeed be warranted, but for now it remains only a "theoretical" possibility that needs more research. "We have not the data yet to demonstrate that it would in fact pan out," he said.