Objective/Rationale:
In Parkinson’s disease (PD) therapeutics, carbidopa is used together with levodopa to prevent its breakdown. This investigation will determine whether subcutaneous carbidopa delivery will help to maintain more continuous levels of circulating levodopa. Pre-clinical research indicated that this is possible. Improving constancy of levodopa blood levels would lessen the problem of motor fluctuations in PD. This study will enroll PD patients experiencing motor fluctuations to see if the effectiveness of their oral levodopa regimen can be improved.
Project Description:
This clinical study will evaluate the safety and tolerability of a new carbidopa formulation and its effects on blood concentration of levodopa. This continuously-delivered carbidopa solution (ND-0611) will be administered subcutaneously by a patch. It will be tested with different dosage forms of oral levodopa/carbidopa. The PD subjects, whose motor fluctuations will be recorded by “on-off” diaries and other evaluations, will try the new carbidopa formulation over four weeks. On four occasions one week apart, the study participants will have repeated blood samples for the concentration of levodopa (to assess the fluctuation in its blood concentrations). The experiments will be designed to learn if the subcutaneously-administered carbidopa enhances the continuity of levodopa blood concentrations and achieves less “off” time as compared to conventional carbidopa-levodopa regimens.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Research suggests that sustaining dopamine concentrations in the brain will minimize problems associated with chronic levodopa therapy (such as motor fluctuations and dyskinesias). Current long-acting levodopa products or COMT inhibitors have limited effectiveness. Experience with continuous dopaminergic infusion therapies has shown that reducing dyskinesias and motor fluctuations can greatly improve disability and quality of life. We anticipate that continuous carbidopa delivery will provide a practical new solution for helping chronic problems of levodopa therapy.
Anticipated Outcome:
If the pre-clinical studies predict the results to be observed with ND-0611 in PD subjects, we anticipate that levodopa blood concentrations will show more continuous plasma concentrations of levodopa in the therapeutic range. As a result, the anti-Parkinsonian effects of oral levodopa dosing should be closer to the optimal range and patients would experience with less “off” time or dyskinesias.
Progress Report
In this Phase I/II safety and pharmacokinetic trial, ND0611, a solution of carbidopa was administered continuously subcutaneously as an adjunct therapy to Sinemet®, Sinemet® CR or Stalevo®, in patients with advanced Parkinson’s disease. The aim of this study was to demonstrate an improved bioavailability of orally-administered levodopa.
This double-blind, randomized, six-way crossover study met all of its primary and secondary endpoints showing meaningful, statistically significant improvement in all of the pharmacokinetic (PK) endpoints when administered with three most common oral levodopa therapies. The primary and secondary PK endpoints included levodopa half-life, the duration of levodopa concentration in excess of a threshold of 1000ng/ml in plasma, the area under the concentration time curve and levodopa trough levels. ND0611 has now been shown to improve levodopa’s bioavailability in patients with any type of oral levodopa drug used.
ND0611 was safe and well tolerated. The most common adverse events across all treatment arms including placebo, were vertigo, nausea, asthenia, back pain, myalgia, pain in extremity, headache and erythema.
ND0611 is unique as it is the first drug developed to administer carbidopa systemically; it acts directly on levodopa metabolism not only in the gastrointestinal tract; and it probably employs a different mode of action than orally administered carbidopa.
By providing a more even and continuous supply of levodopa to the brain, ND0611 has the potential to limit the motor fluctuations that many patients experience during periods when their medication wears off and could potentially improve the quality of life for people living with PD today.
November 2012