Innovations In Clinical Neuroscience

ISCTM Supplement 2015

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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[ V O L U M E 1 2 , N U M B E R 3 – 4 , S U P P L E M E N T A , M A R C H – A P R I L 2 0 1 5 ] Innovations in CLINICAL NEUROSCIENCE 13S may have been attributable, in part, to a large placebo response. 4 Subsequent statistical analysis after omitting data from the high placebo response clinical s ites (i.e., approximately 25% of the sites) did demonstrate that olanzapine was significantly superior to placebo in the remainder of sites, with pomaglumetad response lying midway in magnitude between the active comparator olanzapine and placebo groups on PANSS-Total score. 4 Safety concerns. During the HBBI clinical trial, the adverse event of tonic-clonic seizures were observed for the first time in humans with this agent. Prior to HBBI, seizure activity had not been seen in humans treated with pomaglumetad, although seizures were found in rodents. Extensive investigation in non-human primates failed to discern seizures, or seizure- like activity on EEG monitoring, at high exposures for up to one year. After much debate about whether to continue development of pomaglumetad as a treatment for schizophrenia, a long-term (24 week) safety study H8Y-MC-HBBR (HBBR) was designed to treat schizophrenia patients beyond the acute four-week duration limit of studies HBBD and HBBI and to include repeat EEG assessments. 5 Differences in tolerability of pomaglumetad and other standard of care agents (olanzapine, risperidone, and aripiprazole) were compared in the open label 24 week study with time to discontinuation as the primary outcome measure. The pomaglumetad treatment arm (flexible dosed at pomaglumetad 20mg, 40mg, or 80mg, twice a day) in HBBR was well tolerated, and with the longer duration of treatment in HBBR (as compared to the HBBI study), increased patient exposures, and the limited number of any additional seizures, the exposure-adjusted seizure rate on pomaglumetad directionally trended toward the seizure rate reported for currently available antipsychotic agents. Although HBBR was not a placebo- controlled study, pomaglumetad did demonstrate an acute antipsychotic effect on PANSS ratings, which in the initial weeks of treatment was comparable to the standard of care antipsychotic drugs, but which appeared to lessen over longer t reatment duration versus the comparator arm. 5 To aid in further understanding the neurobiological correlates and efficacy measures of pomaglumetad, a pharmacogenomic candidate gene analysis approach using patients enrolled in HBBD yielded two alleles of interest: 5-HT 2A (rs7330461) and neuregulin 1 receptor (rs10954863). 6 Patients in HBBD that were homozygous for the minor allele of 5-HT 2A (T/T) had a robust treatment response to pomaglumetad (i.e., approximately 30-percent reduction on PANSS rating) and homozygotes for the major allele of 5-HT 2A (A/A) showed virtually no response to treatment with pomaglumetad. Evaluating similar allelic differences in patients that participated in the HBBR study indicated that patients with the 5-HT 2A (T/T) allele also showed a beneficial response to pomaglumetad (not seen in the homozygous major allele group) while this allele may actually confer a reduced response to standard of care agents. 7 It appears that pharmacogenomic data such as these encouraged a tailored therapy strategy for pomaglumetad with potential to be added to a drug development program. Phase III trial. A path forward to Phase III was based on a better understanding of the seizure incidence associated with pomaglumetad and the potential to develop pomaglumetad as a targeted treatment for an ethnically and pharmacogenetically defined population. A Phase III monotherapy trial H8Y-MC-HBBM (HBBM) was designed to reflect this new pharmacogenomics guidance and utilize a study designed to 1) reduce the large placebo response as encountered in HBBI and 2) lead to a positive treatment trial. In addition, a proof of concept trial adding on pomaglumetad to a standard of care antipsychotic as an adjunctive treatment for negative symptoms was implemented as a parallel track to registration. Essentially, all patients in HBBM undergoing treatment with pomaglumetad would be analyzed for primary outcome scores and data would also be stratified according to r acial (e.g., white male subjects have a greater preponderance of A/A alleles) and pharmacogenomic profiles. 8 Centralized rating and elimination of placebo responders early on were also instituted in the methodology in attempt to reduce the placebo- response rate. Results from HBBM indicated that risperidone was effective in treatment of schizophrenia patients but pomaglumetad failed to separate from placebo at any dose administered, or in the racially defined group from the pharmacogenomics strategy. Adjunctive treatment of pomaglumetad to risperidone, olanzapine, quetiapine or aripiprazole for patients with prominent negative symptoms also did not separate from placebo. 9 Post-hoc analysis. The negative efficacy results of HBBM led in part to the termination of further development of pomaglumetad. A significant reason for the failure to demonstrate efficacy of pomaglumetad in Phase III may be related to methodological attempts to prevent another failed trial following the HBBI Phase IIb results. HBBM was designed to insure that neuroleptic responsive, by history, patients were recruited in an attempt to facilitate the possible signal detection of treatment response to pomaglumetad. This enrollment enrichment design unfortunately may have been detrimental to the primary outcome results. Limiting enrollment to neuroleptic responsive subjects could have biased the intent to treat population to one with a dopaminergic rather than glutamatergic pathophysiology diathesis based upon their history of dopamine antagonist responsiveness. Therefore, the non- dopamine mechanism of action of pomaglumated may not have had the opportunity to affect response in such patients. A hyperglutamatergic state has been reported to be associated with the early stage of schizophrenia. In a post-hoc analysis, utilizing the HBBM data set as well as an integrated

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