Sembragiline in Moderate Alzheimer’s Disease: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Trial (MAyflOwer RoAD)

Abstract

Background: Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer’s disease (AD).Objective: To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD.Methods: In this Phase II study (NCT01677754), 542 patients with moderate dementia (MMSE 13–20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1 mg, 5 mg, or placebo once daily orally for 52 weeks.Results: No differences between treated groups and placebo in adverse events or in study completion. The primary endpoint, change from baseline in ADAS-Cog11, was not met. At Week 52, the difference between sembragiline and placebo in ADAS-Cog11 change from baseline was – 0.15 (p = 0.865) and 0.90 (p = 0.312) for 1 and 5 mg groups, respectively. Relative to placebo at Week 52 (but not at prior assessment times), the 1 mg and 5 mg sembragiline groups showed differences in ADCS-ADL of 2.64 (p = 0.051) and 1.89 (p = 0.160), respectively. A treatment effect in neuropsychiatric symptoms (as assessed by the difference between sembragiline and placebo on BEHAVE-AD-FW) was also seen at Week 52 only: – 2.80 (p = 0.014; 1 mg) and – 2.64 (p = 0.019; 5 mg), respectively. A post hoc subgroup analysis revealed greater treatment effects on behavior and functioning in patients with more severe baseline behavioral symptoms (above the median).Conclusions: This study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline.

Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer's dementia

“…The lower number of rasagiline‐treated participants who spontaneously reported neuropsychiatric events compared to the placebo group suggests an additional effect worthy of further study. This observation supports the finding of a potential MAO‐B inhibition effect on neuropsychiatric symptoms in AD patients reported in a phase 2 trial of sembragiline 12 …”

“…This observation supports the finding of a potential MAO-B inhibition effect on neuropsychiatric symptoms in AD patients reported in a phase 2 trial of sembragiline. 12 Our findings indicate that differences associated with rasagiline treatment may be most detectable in participants exceeding baseline thresholds of temporal tau burden, hypometabolism, and atrophy (Fig-…”

Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer's dementia

“…The lower number of rasagiline‐treated participants who spontaneously reported neuropsychiatric events compared to the placebo group suggests an additional effect worthy of further study. This observation supports the finding of a potential MAO‐B inhibition effect on neuropsychiatric symptoms in AD patients reported in a phase 2 trial of sembragiline 12 …”

“…This observation supports the finding of a potential MAO-B inhibition effect on neuropsychiatric symptoms in AD patients reported in a phase 2 trial of sembragiline. 12 Our findings indicate that differences associated with rasagiline treatment may be most detectable in participants exceeding baseline thresholds of temporal tau burden, hypometabolism, and atrophy (Fig-…”

The effects of rasagiline on cerebral glucose metabolism, cognition, and tau in a double-blind, placebo-controlled Phase II clinical trial in Alzheimer’s dementia

“…The lower number of rasagilinetreated participants (0) who spontaneously reported neuropsychiatric events (agitation, psychosis) compared to the placebo group (5) suggests an additional treatment effect that is worthy of further study. This observation supports the ndings of a potential effect of MAO-B inhibition on neuropsychiatric symptoms in AD patients reported in a Phase 2 trial of sembragiline, an MAO-B inhibitor 13 .…”

Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease

“…Although the recent failure of the reversible MAO-B inhibitor sembragiline in a clinical trial involving patients with AD is discouraging ( 30 ), our study offers plausible explanations for sembragiline’s failure. In the aforementioned clinical study, sembragiline was administered to patients with moderate to severe AD who had been taking either donepezil (5 to 10 mg daily) or rivastigmine (4.6 mg daily or 9.5 mg daily patch) for at least 6 months ( 30 ).…”

“…Although the recent failure of the reversible MAO-B inhibitor sembragiline in a clinical trial involving patients with AD is discouraging ( 30 ), our study offers plausible explanations for sembragiline’s failure. In the aforementioned clinical study, sembragiline was administered to patients with moderate to severe AD who had been taking either donepezil (5 to 10 mg daily) or rivastigmine (4.6 mg daily or 9.5 mg daily patch) for at least 6 months ( 30 ). The authors reported that, in their study, they did not observe any treatment effect because the study subjects were already receiving treatment during the study period and that the clinical efficacy of sembragiline may be noted in a monotherapy clinical trial ( 30 ).…”

Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer's dementia

“…The lower number of rasagiline‐treated participants who spontaneously reported neuropsychiatric events compared to the placebo group suggests an additional effect worthy of further study. This observation supports the finding of a potential MAO‐B inhibition effect on neuropsychiatric symptoms in AD patients reported in a phase 2 trial of sembragiline 12 …”

“…This observation supports the finding of a potential MAO-B inhibition effect on neuropsychiatric symptoms in AD patients reported in a phase 2 trial of sembragiline. 12 Our findings indicate that differences associated with rasagiline treatment may be most detectable in participants exceeding baseline thresholds of temporal tau burden, hypometabolism, and atrophy (Fig-…”

The effects of rasagiline on cerebral glucose metabolism, cognition, and tau in a double-blind, placebo-controlled Phase II clinical trial in Alzheimer’s dementia

“…The lower number of rasagilinetreated participants (0) who spontaneously reported neuropsychiatric events (agitation, psychosis) compared to the placebo group (5) suggests an additional treatment effect that is worthy of further study. This observation supports the ndings of a potential effect of MAO-B inhibition on neuropsychiatric symptoms in AD patients reported in a Phase 2 trial of sembragiline, an MAO-B inhibitor 13 .…”

Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease

“…Although the recent failure of the reversible MAO-B inhibitor sembragiline in a clinical trial involving patients with AD is discouraging ( 30 ), our study offers plausible explanations for sembragiline’s failure. In the aforementioned clinical study, sembragiline was administered to patients with moderate to severe AD who had been taking either donepezil (5 to 10 mg daily) or rivastigmine (4.6 mg daily or 9.5 mg daily patch) for at least 6 months ( 30 ).…”

“…Although the recent failure of the reversible MAO-B inhibitor sembragiline in a clinical trial involving patients with AD is discouraging ( 30 ), our study offers plausible explanations for sembragiline’s failure. In the aforementioned clinical study, sembragiline was administered to patients with moderate to severe AD who had been taking either donepezil (5 to 10 mg daily) or rivastigmine (4.6 mg daily or 9.5 mg daily patch) for at least 6 months ( 30 ). The authors reported that, in their study, they did not observe any treatment effect because the study subjects were already receiving treatment during the study period and that the clinical efficacy of sembragiline may be noted in a monotherapy clinical trial ( 30 ).…”

Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer's dementia

“…The lower number of rasagiline‐treated participants who spontaneously reported neuropsychiatric events compared to the placebo group suggests an additional effect worthy of further study. This observation supports the finding of a potential MAO‐B inhibition effect on neuropsychiatric symptoms in AD patients reported in a phase 2 trial of sembragiline 12 …”

“…This observation supports the finding of a potential MAO-B inhibition effect on neuropsychiatric symptoms in AD patients reported in a phase 2 trial of sembragiline. 12 Our findings indicate that differences associated with rasagiline treatment may be most detectable in participants exceeding baseline thresholds of temporal tau burden, hypometabolism, and atrophy (Fig-…”

The effects of rasagiline on cerebral glucose metabolism, cognition, and tau in a double-blind, placebo-controlled Phase II clinical trial in Alzheimer’s dementia

“…The lower number of rasagilinetreated participants (0) who spontaneously reported neuropsychiatric events (agitation, psychosis) compared to the placebo group (5) suggests an additional treatment effect that is worthy of further study. This observation supports the ndings of a potential effect of MAO-B inhibition on neuropsychiatric symptoms in AD patients reported in a Phase 2 trial of sembragiline, an MAO-B inhibitor 13 .…”

Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease

“…Although the recent failure of the reversible MAO-B inhibitor sembragiline in a clinical trial involving patients with AD is discouraging ( 30 ), our study offers plausible explanations for sembragiline’s failure. In the aforementioned clinical study, sembragiline was administered to patients with moderate to severe AD who had been taking either donepezil (5 to 10 mg daily) or rivastigmine (4.6 mg daily or 9.5 mg daily patch) for at least 6 months ( 30 ).…”

“…Although the recent failure of the reversible MAO-B inhibitor sembragiline in a clinical trial involving patients with AD is discouraging ( 30 ), our study offers plausible explanations for sembragiline’s failure. In the aforementioned clinical study, sembragiline was administered to patients with moderate to severe AD who had been taking either donepezil (5 to 10 mg daily) or rivastigmine (4.6 mg daily or 9.5 mg daily patch) for at least 6 months ( 30 ). The authors reported that, in their study, they did not observe any treatment effect because the study subjects were already receiving treatment during the study period and that the clinical efficacy of sembragiline may be noted in a monotherapy clinical trial ( 30 ).…”