ND0612 is a liquid formulation of the combined medications levodopa and carbidopa that aims to reduce motor complications in advanced Parkinson’s disease patients, such as involuntary shaking, slowness of movement, or muscle stiffness.
The investigational drug is designed to be continuously administered beneath the skin for 24 hours. The administration of ND0612 requires the use of a small pump, similar to the devices used to deliver insulin to people with diabetes.
NeuroDerm has developed two doses of ND0612: the low-dose (ND0612L) form is used to treat moderate stage Parkinson’s patients who can no longer effectively control their motor complications with oral levodopa, and a higher dose (ND0612H) for the treatment of severe Parkinson’s patients for whom oral drugs are no longer effective. ND0612H was designed to be a safer, more effective and convenient alternative to surgical treatments.
How ND0612 works
The liquid formulation of ND0612 works by maintaining steady concentrations of levodopa in the blood flow throughout the day and night. It is hoped that this will significantly improve motor and non-motor complications associated with the disease, including dyskinesia (involuntary muscle movement) and “off” periods (debilitating periods of decreased motor and non-motor functions when the effect of the medication is wearing off).
Once in the blood, levodopa travels to the brain where enzymes are able to convert it into dopamine, which exists at reduced levels in the brain of Parkinson’s disease patients. Levodopa is used in combination with another medication called carbidopa that protects levodopa against degradation from naturally-occurring enzymes before it reaches the brain.
Studies with ND0612
Completed clinical trials of ND0612L include a Phase 1 study in 36 healthy volunteers (NCT01486628); a Phase 1/2a safety and tolerability assessment of eight moderate Parkinson’s disease patients receiving a 24-hour infusion of ND0612L over the course of eight weeks (NCT01725802); and a Phase 2a, placebo-controlled study on 30 Parkinson’s patients who had motor complications. This study lasted two weeks and aimed to assess the safety and tolerability of ND0612L treatment as well as the pharmacokinetic profile of levodopa plasma concentrations (NCT01883505).
Results showed that the delivery of ND0612L under the skin was safe and tolerable, and achieved steady plasma levodopa concentrations estimated to be within the typical therapeutic range (700-900 ng/ml), and significantly reduced fluctuations of levodopa concentrations in the blood. Patients receiving ND0612L also experienced a two-hour reduction over placebo in “off” time, improved sleep, experienced better quality of life, and had global clinical improvement without an increase in troublesome dyskinesia.
NeuroDerm also designed a Phase 2a trial to test the efficacy, safety, tolerability, and pharmacokinetics of two ND0612H dosing regimens (NCT02577523). The study enrolled 38 participants who were randomized to receive either 24-hour or 14-hour infusions for 28 days.
Preliminary data from this trial shows that, for patients receiving the 24-hour infusion, there was a statistically significant reduction of the average “off”-time episodes, from 5.5 hours per day to 2.8 hours. “On”-time in the morning increased from 11 percent to 50 percent after 28 days. At 9 a.m., 75 percent of these patients had symptom relief. The final results of this trial will be presented in June 2017 at the 21st International Congress of Parkinson’s Disease and Movement Disorders in Vancouver, British Columbia, Canada.
NeuroDerm is currently recruiting patients for two clinical trials: a Phase 2 trial (NCT02726386) to determine the long-term safety and tolerability of two dosing regimens (24 or 14 hours of ND0612L infusion), and a Phase 3 trial to compare the effects of ND0612L treatment with placebo (NCT02782481).
The first study will last for a year and aims to enroll 100 participants in the U.S., Europe, Australia, and Israel. The second trial will run for a course of 16 weeks and enrolls up to 150 patients in Israel.
Adverse effects of ND0612
The most commonly reported adverse effects associated with ND0612 treatment were local skin infusion site reactions. Nearly all patients reported nodules under the skin at the infusion sites, which were generally not associated with pain. The nodules resolved spontaneously in two to three months. About half the patients reported mild and transient pain, erythema (reddening of the skin), and edema at the infusion sites, which resolved spontaneously. Other common adverse events included local bleeding at the infusion sites and headache.
Levodopa and carbidopa are known to be associated with adverse events, the most common being dyskinesia, nausea, vomiting, dizziness, low blood pressure upon rising, headache, sleeplessness, dry mouth, anxiety, and constipation. Serious side effects include hallucinations and delusions, unexpectedly falling asleep, unusual urges, high fever, and confusion related to medication withdrawal.
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