Better therapy for Parkinson's disease

Finding a soloution

Continous L-DOPA

The commonest problems associated with oral L-DOPA (dyskinesia, on/off variation, and freezing) are largely caused by the chaotic peaks and troughs in brain L-DOPA levels due to the variable absorption and short half-life of oral L-DOPA.

L-dopa plasma concentrations for patients taking L-dopa/carbidopa 100/25 mg standard-release tablets  every 2 hours. Stocchi

Surprisingly it has been shown that a constant intravenous infusion of L-DOPA will restore improvement of movement and reduce or abolish dyskinesia – even in patients in whom oral L-DOPA is know to produce troublesome on/off variation and dyskinesia.

Daily on-off charts in 6 patients. Each pair of horizontal lines indicates the extent of a waking day. Black bars denote on periods; off periods are open. Coexistent features of on and off states are shown by horizontal stripes. The top day shows a representative day during the initial assessment period. The remaining four days show the results of the four-day crossover comparison of oral and intravenous levodopa. The duration of the active infusion is shown by the bar above each intravenous day. Hardie

However life-long intravenous infusion of L-DOPA is neither practical nor tolerated. Intravenous infusion of L-DOPA results in phlebitis.

An alternative approach which is now marketed as “Duodopa” is to continously pump L-DOPA intestinal gel into the gut (jejunum) via a tube through the abdominal wall. The resulting smooth and steady plasma level of L-DOPA causes a steady increased levels of L-DOPA and dopamine in the striatum of the brain. The result (confirmed in a large double-blind, double-dummy trial) showed a very significant improvement in the patients condition (“on” time), a marked reduction in “off” time plus reduced dyskinesia and reduced pain associated with dyskinesia.  Olanow,

Continous infusion of L-DOPA therefore offers greater efficacy than any oral therapy. No other form of treatment has shown greater efficacy. However the life-long requirement to carry a pump and have a tube through the abdominal wall complicates use and limits patient uptake. Elderly patients with limited dexterity due to  Parkinson’s  may find the pump difficult to load and manage. The tube through the abdominal wall is associated with a high incidence of adverse events including blockage, dislodging and infection.

Despite these issues peak sales of L-DOPA intestinal gel reaches approximately $500 million/year.

The commercial potential for a treatment delivering  steady continous levels of L-DOPA to the striatum without the need for a pump and tube is considerable.

MaavRx's solution

MaavRx is developing a gene therapy to restore the production of L-DOPA and dopamine in the striatum of the brain. By enabling local production of L-DOPA we aim to establish a constant “platform” level of L-DOPA and dopamine. As patient do not develop symptoms of PD until the level of dopamine in their striatum falls below 30% of normal we believe we will be able to achieve local levels of L-DOPA sufficient to restore movement. Ideally this would replace the need for oral L-DOPA. However establishing a constant “platform” level of locally produced L-DOPA would reduce the amount of oral L-DOPA and thus reduce the peaks and troughs which result in on/off variation and dyskinesia.

Importantly the therapy would only need to be administered once but could last a life-time. Previous research has shown that the effect of a single administration of gene therapy to the putamen of primates was still active 15 years after administration. Sehara

Proof of concept

Previous studies with earlier prototypes of this approach have provided encouraging results. The approach was able to completely reverse the movement symptoms in the classic rat and non-human primate models of Parkinson’s disease. 

The results (below) show that the prototype induced a significant improvement of motor behaviour in the parkinsonian non-human primates.  The effect was dose-dependent, developed gradually over 3–4 months, and remained stable thereafter. The level of improvement seen at the highest treatment dose was identical to that obtained with an optimal dose of peripheral L-DOPA.

Importantly, the improvement in movement was obtained without any adverse dyskinetic effects, either with or without concomitant oral L-DOPA. Rosenblad

Behavioural recovery of parkinsonian (MPTP treated) non-human primates treated with different doses of an AAV gene therapy delivering the genes necessary for L-DOPA production in the striatum (Rosenblad et al)

Moving to patients

MaavRx believes that these and other data indicate that a gene therapy which resulted in the production of life-long steady levels of L-DOPA would represent an important advance in the treatment of patients with Parkinson’s disease – especially those beginning to develop on/off fluctations or early signs of dyskinesia despite optimum therapy.

However our view is that, the despite sucess when tested in rats and smaller primates, the prototypes lacked sufficient potency to maximise the chance of success in the much larger human brain. MaavRx therefore invested in developing a more potent product.

MaavRx has now shared key data with the US Food and Drug Administration at an “Interact” meeting. Based on this MaavRx is preparing the necessary steps to proceed to a first clinical trial.