Parkinson’s Disease: V1512
Summary
V1512 combines Levodopa (L-dopa) methylester, an enhanced soluble pro-drug of L-dopa, with Carbidopa. It is fully soluble in water and is presented in a patented, effervescent formulation as a potential novel treatment for Parkinson’s disease. L-dopa has been the cornerstone of Parkinson's disease treatment for four decades; however, after a period of treatment it may become less effective, and other problems such as motor complications and unwanted movements, known as dyskinesias, can emerge. There is evidence that some of these problems, such as a delay in the onset of effect of some L-dopa doses during the day, may be due to erratic absorption of the drug into the bloodstream caused by impaired functioning of the stomach and small intestine. Normal gut motility, called peristalsis, is essential for passage of food and solid dose form drugs (tablets and capsules) through the stomach to the parts of the intestine where absorption into the bloodstream takes place. V1512, being fully soluble in water, is administered in liquid form and therefore would be less susceptible to impaired gut motility as it could quickly pass through to the small intestine assisted only by gravity.
V1512 was licensed from Chiesi Farmaceutici (Chiesi) and in studies undertaken by Chiesi has been shown, in patients with motor complications leading to delayed effects or dose failures, to work more rapidly than conventional L-dopa in tablet form. It is currently marketed in Italy by Chiesi for the treatment of Parkinson's disease patients with motor complications. Vernalis owns the worldwide rights to V1512 with the exception of Italy, and is continuing to develop the product, which is ready to start Phase III trials under protocols agreed with the FDA through the SPA process.
Background
It is estimated that approximately 1.5 million people in the U.S. have Parkinson's disease, a condition that results from selective degeneration of an area of the brain called the substantia nigra, which is located towards the base of the brain in the basal ganglia. Normally these nerve cells release dopamine - a chemical that transmits signals between nerve cells (called a neurotransmitter). This central signalling pathway is essential for the fine control of movement and posture, and breakdown results in the symptoms of Parkinson’s disease namely tremor, rigidity, slow movements and postural instability. Muscle rigidity can become so severe as to result in “freezing” also referred to as “off” episodes, when patients are rendered immobile. Patients also suffer from problems relating to impaired control of blood pressure (postural hypotension) and gut motility, which can impair the absorption of food and drugs.
The disease is progressive and the signs and symptoms generally worsen over time. However, while Parkinson's disease may eventually be disabling, the disease often progresses gradually and with appropriate treatment many patients can have years of productive life after initial diagnosis.
Espicom Business Intelligence estimated the 2003 worldwide market for Parkinson’s disease therapeutics to be U.S. $2.2 billion.
Clinical Studies
There is clinical evidence that V1512 may reduce the periods when patients suffer from the debilitating "off" effects of Parkinson’s disease by providing a more reliable and reproducible method of delivering L-dopa than current therapy.
Eighteen clinical studies, including two European Phase II clinical studies and a proof-of-concept study, have been completed involving levodopa methylester alone or as part of V1512. These studies have demonstrated significant improvements in both the time to an effect and the time that patients remain in the "on" state following a dose of V1512 compared with equivalent doses of other L-dopa preparations. The side-effect profile of V1512 in these studies is almost identical to that of other L-dopa/Carbidopa products. The studies supported regulatory approval for the drug in Italy where it is now marketed by Chiesi for treatment of patients with advanced Parkinson’s disease.
Vernalis has recently completed a study in patients with advanced Parkinson's disease which compared the repeated pharmacokinetics of L-dopa and Carbidopa after equivalent, repeated doses of V1512 and Sinemet®, the most widely prescribed branded preparation of L-dopa/Carbidopa in the US.
Data from this study confirmed the improved reproducibility and reliability of L-dopa absorption from V1512 compared with standard L-dopa therapy.
It is planned to evaluate V1512 in a pivotal Phase III programme, which has been agreed with the FDA under the Special Protocol Assessment (SPA) process. Under Section 119(a) of the US FDA Modernization Act the SPA process allows a protocol to be adequately assessed by the FDA in terms of study size and design in order to determine whether the study design is adequate to form the basis of an efficacy claim in the proposed indication. A written agreement on the protocol, which occurs before the study commences, becomes part of the administrative record.