Mibampator (LY451395) randomized clinical trial for agitation/aggression in Alzheimer's disease

Abstract

Background Mibampator, an AMPA receptor potentiator, was evaluated for treatment of agitation and aggression (A/A) in Alzheimer’s disease (AD). Methods Outpatients (n=132) with probable AD and A/A randomized to 12 weeks of double-blind treatment with 3 mg po mibampator or placebo were assessed using the 4-domain NPI-4-A/A derived from the Neuropsychiatric Inventory. Secondary measures included the Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia, Frontal Systems Behavior inventory (FrSBe), and ADAS-Cog. Efficacy was analyzed using mixed-effects model repeated measures from baseline to endpoint. Adverse events (AEs), labs, vital signs and ECGs were monitored. Results Baseline characteristics were comparable between groups. Both groups improved on the NPI-4-A/A, but without group differences. Among secondaries, mibampator was significantly better (p=.007) than placebo only on the FrSBe. AEs were similar between groups. One death occurred in the placebo group. Conclusion Possible explanations for no significant group differences include caregiver, drug target engagement, and design issues.

Medication development for agitation and aggression in Alzheimer disease: review and discussion of recent randomized clinical trial design

“…Mibampator (Trzepacz et al, 2013) led to better outcomes on the Frontal Systems Behaviors Scale, and memantine-NH on NPI total score (Fox et al. , 2012).…”

Progresses in treating agitation: a major clinical challenge in Alzheimer’s disease

“…While no evidence of efficacy on cognition was found in this RCT, a significant improvement on the NPS secondary measure was evident, fueling another Phase II trial to further assess the efficacy and safety of mibampator in patients with AD and clinically significant agitation/aggression symptoms [43]. In this 12-week double-blind study on 132 outpatients with probable AD and agitation/aggression, no significant benefits were observed for 3 mg of oral mibampator compared to placebo on agitation/aggression symptoms.…”

“…In this 12-week double-blind study on 132 outpatients with probable AD and agitation/aggression, no significant benefits were observed for 3 mg of oral mibampator compared to placebo on agitation/aggression symptoms. However, a secondary outcome ecological measure of behaviors associated with prefrontal cortical dysfunction was positively affected by the drug [43]. One possible reason for lack of efficacy could be ascribed to the extensive neurodegenerative damage of the frontolimbic networks at the time of study entry.…”

AMPA Receptor-Positive Allosteric Modulators for the Treatment of Schizophrenia: An Overview of Recent Patent Applications

“…There are several distinct classes of AMPA receptorpositive allosteric modulators ( Figure 3) that have been investigated in clinical studies [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52]. A summary of clinical trials reported on these compounds to date is given in Table 1, while a number of molecules have progressed to Phase II studies, disappointingly none have yet entered wider population Phase III trials.…”

“…Significant improvements at highest dose on hyperactivity and inattention indices [44] Drug-induced respiratory depression [45] CX1739 Sleep apnea No effect on mean apnea/ hypopnea index, however significantly reduced apnea time [46] ORG26576 [50] AD 200 patients Negative [51] GSK729327 Ph I 79 volunteers, 1-6 mg Completed [52] PF-4958242 Ph I Ten studies currently registered On-going [53] future science group AMPA receptor-positive allosteric modulators for the treatment of schizophrenia Review the chemistry has focused on roughly four main chemotypes as discussed in the previous section, the reasons for this are not clear however this does suggest that the chemotypes are amenable to considerable structural modification which retains activity. GlaxoSmithKline have filed extensively in this area with 12 patents in the period covered by this article, the last being in 2010 [57][58][59][60][61][62][63][64][65][66][67][68].…”