Our goal is to market a new levodopa/carbidopa orally-administered drug product with pharmacokinetics (PK) similar to that seen with direct infusion products. Currently, orally delivered levodopa products suffer from complications, possibly arising from pulsatile blood levels, typically encountered after several years. We have identified a metal that forms a coordination complex with levodopa and provides PK changes in pre-clinical models consistent with a drug that may be able to provide continuous dopaminergic stimulation (CDS) in humans.
With our initial lead in hand, this project is designed to bridge our drug discovery and drug development programs. First, data will be collected in an experiment that tests our hypothesis that metal absorption after repeated oral administration is within safe limits. Once that is established, we will perform an experiment in an alternative in vivo model to validate our initial results. Then, we will proceed to systematically modify the chemistry of the metal-levodopa complex in order to improve further key PK parameters and optimize our lead. Once we have the optimized lead product we plan to repeat the metal accumulation study and retest in the alternative model to confirm safety and efficacy before developing the product as an investigational new drug.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Having an orally-administered levodopa product that achieves CDS and minimizes the effects of pulsatile drug blood levels (more steady, less up-and-down) has the potential to significantly improve dopamine replacement therapy for Parkinson’s patients. For early stage patients, less pulsatility is expected to result in a lower incidence of dyskinesia and off-periods down the road. For late-stage patients, less pulsatility, as observed with levodopa infusion, should improve time spent with effective symptom control.
We expect to learn how to modify our lead complex to provide the best pre-clinical properties before we advance into clinical development. As we work to minimize potential risks and maximize potential benefits, we hope to learn more about how metal coordination chemistry can improve pharmaceutical properties. If our overall development program is successful, we hope to provide further evidence that CDS is critical in providing improved care for all Parkinson’s patients.
Our project has led to the selection of the final form of our lead levodopa drug, HLT-311. As a metal coordination complex, this drug exhibits a levodopa plasma profile in a pre-clinical model that is more like an infusion than the current orally administered levodopa drug product. A high degree of safety was indicated from an 18-day study in which the final form of HLT-311 showed less than 1/3 the metal absorption than an OTC product that contains the same metal. We validated our initial results with confirmed improvements over levodopa in an advanced in vivo pre-clinical model. Finally, the optimized HLT-311 was further defined to maintain the key molecular properties of the drug product after oral administration. Formulation optimization followed by later stage preclinical development work leading to an IND application will now be pursued.