Rotigotine polyoxazoline conjugate SER‐214 provides robust and sustained antiparkinsonian benefit

Abstract

Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's disease (PD) motor symptoms but often lead to significant motor complications including “wearing‐off” and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects. The purposes of the current study are to characterize the in vitro and in vivo pharmacokinetics of POZ conjugation of a U.S. Food and Drug Administration (FDA)‐approved DA agonist, rotigotine, and to evaluate their effects in an established rat model of PD. After determination of release profiles of several POZ‐conjugated constructs (“fast”: SER‐212; “moderate”: SER‐213; and “slow”: SER‐214) using in vitro hydrolysis, normal male Sprague‐Dawley rats were used for determination of the pharmacokinetic profile of both acute and chronic exposure. Finally, a separate group of rats was rendered hemiparkinsonian using intracranial 6‐hydroxydopamine (6‐OHDA) infusions, treated acutely with POZ‐rotigotine, and assessed for rotational behavior and antiparkinsonian benefit using the cylinder test. POZ‐rotigotine formulations SER‐213 and SER‐214 led to substantial pharmacokinetic improvement compared to unconjugated rotigotine. In addition, SER‐214 led to antiparkinsonian effects in DA‐lesioned rats that persisted up to 5 days posttreatment. Repeated weekly dose administration of SER‐214 to normal rats for up to 12 weeks demonstrated highly reproducible pharmacokinetic profiles. The continuous dopaminergic stimulation profile afforded by SER‐214 could represent a significant advance in the treatment of PD, with potential to be a viable, once‐per‐week therapy for PD patients.

Poly(2-oxazoline) based micelles with high capacity for 3rd generation taxoids: Preparation, in vitro and in vivo evaluation

“…10 to 20 times higher drug concentration in injectable formulations than the clinical alternatives of Taxol, Genexol-PM, and Abraxane. Poly(2-oxazoline)s (POx) in general have received increasing attention recently as alternatives to polyethylene glycol based systems [30-34] and first-in-man studies are expected to commence in 2015 [35,36]. Here, we combine the possibilities of our POx-based drug delivery platform for safe and efficient drug formulation and delivery with the advantages of 3 rd -generation taxoids, which can overcome multidrug resistance mechanisms.…”

Poly(2-oxazoline)s and click chemistry: A versatile toolbox toward multi-functional polymers

“…85 The use of a hydrolytically cleavable ester linker between the PAOx chain and the drug allowed for control over drug release rate. As such, sustained release of rotigotine was observed in male rats, leading to long-term anti-parkinsonian effects as well as a reduction of motor complications, which is commonly observed in therapies that cause large dopamine fluctuations.…”

Non-oral dopaminergic therapies for Parkinson’s disease: current treatments and the future

“…65 In vivo studies, using 6-hydroxydopamine (6-OHDA) lesioned rat models, showed SER-214 (slow-release conjugate) to have a prolonged RTG half-life with reduced motor complications, which was sustained over repeated dosing. 66 With these promising results, SER-214 has now Food and Drug Administration's approval to enter phase 1 study (NCT02579473) using de novo PD patients. 67 …”