Biotech Tracker News - Prodrugs and Improved Drug Delivery for Parkinson Disease
November 14, 2002 Patients with Parkinson disease (PD) are treated with drugs that must be taken several times a day and may be difficult to swallow. Contemporary drugs also have significant adverse effects related to modulation of dopamine and related chemicals. Moreover, fluctuating blood levels of drug can cause suboptimal control of the imprecise, disordered body movements that characterize PD. Prodrugs and alternative delivery systems that seek to circumvent these therapeutic boundaries are attractive possibilities. Presentations at the Movement Disorders Society’s 7th International Congress of Parkinson’s Disease and Movement Disorders this week in Miami support both of these approaches.  Prodrugs are compounds that are processed into active drugs by metabolic processes after administration. Prodrugs often have preferable pharmacokinetic and pharmacodynamic profiles compared to active drugs, which can lead to better activity and dosing schedules.  Besides changing the formulation of the drug, developing new routes of administration can also lead to improvements. For example, transdermal delivery of medicine intends to both improve therapeutic effects and minimize adverse effects by reducing or eliminating fluctuations in the blood level of active ingredients.  Teva’s Prodrug Teva’s (NASDAQ: TEVA) etilevodopa formulation generated data suggesting that the developmental compound has the potential to address some of the drug delivery shortcomings of contemporary levodopa therapy in the management of PD. Etilevodopa is an ethyl esther levodopa prodrug.  Dr. Eldad Melamed, chair of neurology at Tel Aviv University, reviewed data from several mid-phase etilevodopa trials that, in aggregate, demonstrate that the compound’s pharmacologic profile includes evidence of its having an earlier time to therapeutic effect and a diminished proportion of dose failures compared to conventional levodopa.  A 62-patient study enrolled patients with fluctuating PD who had a propensity to have delayed times to, or frankly failed, therapeutic effects with conventional levodopa therapy. They were randomized to either etilevodopa oral solution or standard levodopa/carbidopa. Patients’ diaries showed that the delayed therapeutic effect rate was reduced by 21% for the morning dose and 17% for the post-lunch dose in the etilevodopa group versus a 9% decrease for the morning dose and no change for the post-lunch dose for standard levodopa recipients. Both differences were clinically and statistically significant (p < 0.05 for the morning dose and p < 0.01 for the post-lunch dose).  A 29-patient (26 evaluable), open-label, randomized, cross-over trial demonstrated similarly more rapid onsets of therapeutic effects of etilevodopa, compared to standard levodopa/carbidopa, administered as an oral solution, as dissolved tablets, or as tablets swallowed whole.  Outcomes of phase III studies of etilevodopa, involving 220 patients, are expected to be available “within a few months,” Dr. Melamed said. BiotechTracker modeling estimates the probability of etilevodopa’s first-tier approval at 45-55%.  Schwarz’s Patch Schwarz’s (Frankfurt: SRZG.F) transdermal rotigotine patch (the “Parkinson’s Patch”) may provide the steady state dopamine stimulation required to reduce fluctuating PD symptoms. Dr. Peter A. LeWitt described the limitations of the pulsatile effects seen with contemporary dopamine replacement therapies, and reviewed the evidence that continues to accrue indicating that this delivery system achieves a more continuous dosing, translating to greater, more consistent symptom relief. He reviewed mid-phase data from over 600 patients demonstrating the patch’s ability to shorten therapeutic response times, provide fewer periods of no relief of disordered movement, and reduce dopamine-related adversities.  Phase III clinical trials of transdermal rotigotine are ongoing, and Schwarz expects the patch to become available by the beginning of 2004. BiotechTracker estimates the probability of the rotigotine patch’s FDA approval at 50-60%.
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