Safety evaluation of the mGluR5 antagonists AZD9272, AZD2066 AND AZD2516 in healthy volunteers and patients with neuropathic pain or major depressive disorder (WCP 2012) - May 2, 2012 - Presentation time: Tuesday, August 28; 9:45 am; P1, N=116; In healthy volunteers the CNS-related AEs increased in frequency with increasing dose and were found to be subject to tolerance development in the AZD2066 multiple ascending dose (MAD) study; AEs were more common among those receiving active drug compared to placebo
P1 data • Pain
|
|
14th World Congress on Pain, 27 – 31 Aug 2012
|
|
Body:
Aim of Investigation: To evaluate the clinical safety of mGluR5 antagonists (negative allosteric modulators) by pooling data from three drug-development projects.
Methods: The analysis is based on study data for AZD9272 administered to 116 healthy volunteers in 6 phase I studies, for AZD2066 administered to 273 healthy volunteers in 9 phase I studies and to 144 patients in 3 phase IIa studies and for AZD2516 administered to 105 healthy volunteers in 5 phase I studies. The focus is on adverse events (AE) as no other safety variables have caused concern across the three compounds. The efficacy data from the AZD2066 pain studies are reported and discussed elsewhere at this conference.
Results: For all three compounds nervous system and psychiatric AEs were more common among those receiving active drug compared to placebo. In healthy volunteers the CNS-related AEs increased in frequency with increasing dose and were found to be subject to tolerance development in the AZD2066 multiple ascending dose (MAD) study. There was a close relationship between the likelihood of developing a CNS related AE increased with increasing mGluR5 receptor occupancy in the brain as assessed by PET (see separate poster).
In the three phase IIa studies with AZD2066 the incidence of psychiatric AEs was more frequent in the active group compared to placebo: 7/62 vs 0/65 in patients with painful diabetic neuropathy, 10/42 vs 2/44 in patients with peripheral neuropathic pain with mechanical hypersensitivity (NPMH) and 9/40 vs 5/43 in patients with major depressive disorder.
Two subjects, (one healthy volunteer in the MAD study of AZD9272 and one patient in the NPMH sudy of AZD2066) developed serious psychiatric AEs and were hospitalized due to a psychotic reaction. In these two subjects the plasma concentrations of AZD9272 and AZD2066 respectively were in the same range as those in other study participants receiving the same doses. The development of mGluR5 antagonists for neuropathic pain has been stopped.
Conclusions: mGluR5 antagonists from different chemical classes have been found to cause dose-dependent CNS-related AEs and were in two individuals associated with development of acute psychotic reactions requiring hospitalization. Similar CNS-related AEs had also been reported with fenobam, an anxiolytic developed in the 70's, which was later discovered to antagonize mGluR5. These data provide support for the hypothesis that dose-dependent but tolerated CNS AEs as well as uncommon serious psychiatric AEs may be class effects.
|