ND0701, A Novel Formulation of Apomorphine for Subcutaneous Infusion, in Comparison to a Commercial Apomorphine Formulation: 28-Day Pharmacokinetic Study in Minipigs and a Phase I Study in Healthy Volunteers to Assess the Safety, Tolerability, Pharmacokinetics and Relative Bioavailability
Subcutaneous apomorphine is used for the treatment of Parkinson’s disease (PD); however, infusion site reactions are a common adverse event (AE), which can lead to treatment discontinuation. Apomorphine formulations that are more tolerable and convenient for use are needed.
Our aim was to compare the toxicity and bioavailability of ND0701, a new concentrated formulation of apomorphine free base, with one of the commercially available apomorphine HCl formulations (APO-go®, Britannia Pharmaceuticals Ltd).
(1) Preclinical study: 16 minipigs were randomly assigned to placebo, APO-go®, and ND0701 groups, and treated for 28 days. Pharmacokinetic, clinical, and pathological assessments were performed. (2) Phase I study: 18 healthy volunteers participated in an open-label, two-sequence, randomized, three single-dose, partial crossover study to compare the pharmacokinetics, safety, and tolerability of ND0701 with APO-go® (1%).
(1) Preclinical study: No systemic toxicity was observed in apomorphine-treated minipigs, but local skin reactions were observed at the infusion sites. These effects were less frequent and less severe and recovery was more rapid for ND0701 compared with APO-go®. (2) Phase I study: Both formulations were safe and well tolerated under the conditions of the study and no severe or serious treatment-emergent AEs were reported. Infusion site nodules were reported more frequently, with higher severity, and recovered slower at APO-go®-treated sites compared with ND0701-treated sites. Bioavailability of apomorphine was comparable between the two formulations.
Based on these pilot studies, ND0701 appears to be superior to APO-go® in terms of tolerability and safety, while maintaining comparable bioavailability with APO-go®, and shows promise as a future treatment for PD.
We thank our colleagues at NeuroDerm Ltd. for fruitful discussions.
Compliance with Ethical Standards
Both studies were funded by NeuroDerm Ltd.
Conflict of interest
Abraham Nyska and Itay Perlstein served as consultants to NeuroDerm Ltd; Liat Adar, Sheila Oren, Cecile Durlach and Oron Yacoby Zeevi are employees of NeuroDerm Ltd; and Yuval Ramot has received an honorarium from NeuroDerm Ltd. Danny Fishelovitch, Giuseppe Sacco, and Rosanna Manno have no conflicts of interest to declare.
Preclinical study: All procedures in this study were conducted in compliance with the Guide for Good Laboratory Practice, Care and Use of Laboratory Animals, and with the requirements of Directive 2010/63/EU on the protection of animals used for scientific purposes. The study was approved by the RTC Animal Welfare Committee. Phase 1 clinical study: The study was approved by the appropriate Ethics Committee and the Medicines and Healthcare Products Regulatory Agency (MHRA).
All subjects included in the study have given written informed consent to participate in the study.
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