Human Dopamine Receptor Affinity and Potency In Vitro and Dose Tolerability in Beagle Dogs In Vivo of Dexpramipexole and Pramipexole (P04.150)

Abstract

Objective: To determine and quantify the relative dopamine receptor affinity and agonism of the optical enantiomers pramipexole and dexpramipexole. Background Dexpramipexole [(6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride monohydrate (DEX)] is a new chemical entity now in Phase III development for ALS. It is the enantiomer of pramipexole (PPX), a high-affinity dopamine D2/D3 receptor agonist approved for use in Parkinson9s disease and restless legs syndrome. Design/Methods: We compared the in vitro receptor binding affinity and functional agonist potency of chirally pure DEX and PPX using human recombinant D2s and D3 dopamine receptors. To determine if observed differences in dopamine receptor affinities translated into differences in tolerability for the two enantiomers, both enantiomers were administered orally to beagle dogs in vivo, and the no-effect dose or the maximum tolerated dose were determined for each enantiomer. Results: PPX was a high-affinity ligand and a potent functional agonist at recombinant human D2s and D3 receptors, and produced multiple characteristic dopaminergic side effects in dogs at a dose of 0.0075 mg/kg. DEX was a much lower-affinity ligand and exhibited low potency agonism at each of these receptors. Further, dose tolerability of DEX was at least 10xE4 higher than that of PPX. The maximum tolerated dose of DEX was significantly reduced by spiking DEX drug substance with 0.5% PPX. Conclusions: While both enantiomers have been shown to have nonclinical neuroprotective properties independent of their dopamine receptor affinity, PPX9s use as a treatment for neurodegenerative disorders, including ALS, is restricted by dopamine-receptor mediated side effects. These data demonstrate that DEX, a candidate ALS therapeutic, has much lower functional dopamine activity than PPX, and should be tolerated at much higher clinical doses without titration; it is, therefore a valid candidate for the treatment of neurodegenerative disorders. The data furthermore underscore the importance of enantiomeric purity of DEX drug substance. Supported by: Knopp Biosciences LLC. Disclosure: Dr. Gribkoff has received personal compensation for activities with Knopp Biosciences LLC as an employee. Dr. Gribkoff holds stock and/or stock options in Knopp Biosciences, which sponsored research in which Dr. Gribkoff was involved as an investigator. Dr. Demady has received personal compensation for activities with Novartis Biologics as an employee. Dr. Ingersoll has received personal compensation for activities with Knopp Biosciences LLC as an employee. Dr. Ingersoll holds stock and/or stock options in Knopp Biosciences LLC, which sponsored research in which Dr. Ingersoll was involved as an investigator. Dr. Bozik has received personal compensation for activities with Knopp Biosciences LLC as an employee. Dr. Bozik holds stock and/or stock options in Knopp Biosciences LLC. Dr. Frantz has received personal compensation for activities with MPI Research Inc.