Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer's disease.

HYPOTHESIS: We hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action. KEY PREDICTIONS: We prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints). STRATEGY AND KEY RESULTS: Mild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments. INTERPRETATION: Our results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials.

ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease.

OBJECTIVE: To evaluate the safety and efficacy of crenezumab in patients with mild to moderate Alzheimer disease (AD). METHODS: In this phase 2 trial, 431 patients with mild to moderate AD 50 to 80 years of age were randomized 2:1 (crenezumab:placebo). Patients received low-dose subcutaneous crenezumab 300 mg or placebo every 2 weeks (n = 184) or high-dose intravenous crenezumab 15 mg/kg or placebo every 4 weeks (n = 247) for 68 weeks. Primary outcome measures were change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) and Clinical Dementia Rating-Sum of Boxes scores from baseline to week 73. RESULTS: The primary and secondary endpoints were not met. In an exploratory post hoc analysis, a reduction in decline on the ADAS-Cog12 was observed in the high-dose group. Separation from the placebo group on the ADAS-Cog12 was greatest in the milder subsets of AD patients and reached statistical significance in the group with Mini-Mental State Examination scores of 22 to 26. In both groups, there was a significant increase in CSF ß-amyloid1-42 levels that correlated with crenezumab CSF levels. The overall rate of adverse events was balanced between groups. One case of amyloid-related imaging abnormalities indicative of vasogenic edema or effusions was reported. CONCLUSIONS: Although prespecified criteria for testing treatment effects were not met, these data suggest a potential treatment effect in patients with mild AD treated with high-dose crenezumab. Together with the safety profile for crenezumab, these data support the exploration of crenezumab treatment at even higher doses in patients with early AD. CLINICALTRIALSGOV IDENTIFIER: NCT 01343966. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, for people with AD, crenezumab does not significantly improve cognition or function at 18 months. The study is rated Class II because <80% of enrolled patients completed the study.

A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Safety, Pharmacokinetics, and Biomarker Results of Subcutaneous Bapineuzumab in Patients with mild to moderate Alzheimer's disease.

BACKGROUND: Bapineuzumab, a humanized monoclonal antibody, targets amyloid-ß (Aß1-40/1 -42) that is believed to play a key role in the pathogenesis of Alzheimer disease (AD). OBJECTIVES: To assess the effects of monthly subcutaneous (SC) bapineuzumab versus placebo on cerebral amyloid signal in amyloid-positive patients with mild to moderate AD. The incidence of amyloid-related imaging abnormalities-edema/effusion (ARIA-E), pharmacokinetics, pharmacodynamics, immunogenicity, and other safety aspects of bapineuzumab were also evaluated. METHODS: In this multicenter, double-blind study, 146 patients were randomized (1 : 1:1 : 1) to SC bapineuzumab 2, 7, or 20 mg/month or placebo. Lack of efficacy of intravenous (IV) bapineuzumab in Phase III studies led to truncation of the treatment duration from 24 months to 12 months. Primary endpoint: change from baseline to month 12 in brain amyloid signal as measured by standardized uptake value ratio (SUVR) using florbetapir positron emission tomography (PET). RESULTS: Florbetapir PET SUVR decreased significantly (p = 0.038) from baseline to month 12 for the bapineuzumab 7 mg/month group only; reductions versus placebo were not significant for any dosage. One patient each in bapineuzumab 2 mg/month and 20 mg/month groups had ARIA-E. The percentages of patients with treatment-emergent adverse events were similar in placebo (77.8%) and bapineuzumab 2 mg/month (78.4%) group, but higher in 7 mg/month (94.4%) and 20 mg/month (89.2%) groups. CONCLUSION: Bapineuzumab SC once-monthly did not demonstrate significant treatment difference over placebo on cerebral amyloid signal at one year but was well-tolerated. There was less ARIA-E than had been expected based on prior experience with comparable exposure on IV bapineuzumab.

Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial.

IMPORTANCE: Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms. OBJECTIVES: To assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia. DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity. INTERVENTIONS: Oral avagacestat or placebo daily. MAIN OUTCOMES AND MEASURE: Safety and tolerability of avagacestat. RESULTS: Of the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures. CONCLUSIONS AND RELEVANCE: Avagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00890890.

Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease.

OBJECTIVE: To assess the safety, tolerability, and pharmacokinetic and pharmacodynamic effects of the -secretase inhibitor avagacestat in patients with mild to moderate Alzheimer disease (AD). DESIGN: Randomized, double-blind, placebo-controlled,24-week phase 2 study. SETTING: Global, multicenter trial. PATIENTS: A total of 209 outpatients with mild to moderate AD were randomized into the double-blind treatment phase. The median age of the patients was 75 years,58.9% were APOE ε4 carriers, and baseline measures of disease severity were similar among groups. INTERVENTION: Avagacestat, 25, 50, 100, or 125 mg daily,or placebo administered orally daily. MAIN OUTCOME MEASURES: Safety and tolerability of avagacestat. RESULTS: Discontinuation rates for the 25-mg and 50-mg doses of avagacestat were comparable with placebo but were higher in the 100-mg and 125-mg dose groups.Trends for worsening cognition, as measured by change from baseline Alzheimer Disease Assessment Scale cognitive subscale score, were observed in the 100-mg and125-mg dose groups. Treatment-emergent serious adverse events were similar across placebo and treatment groups. The most common reason for discontinuation was adverse events, predominantly gastrointestinal anddermatologic. Other adverse events occurring more frequentlyin patients undergoing treatment included reversibleglycosuria (without associated serum glucose changes), nonmelanoma skin cancer, and asymptomaticmagnetic resonance imaging findings. Exploratory cerebrospinal fluid amyloid isoforms and tau biomarker analysis demonstrated dose-dependent but not statistically significant reductions in a small subset of patients. CONCLUSIONS: Avagacestat dosed at 25 and 50 mg daily was relatively well tolerated and had low discontinuation rates. The 100-mg and 125-mg dose arms were poorly tolerated with trends for cognitive worsening. Exploratory cerebrospinal fluid biomarker substudies provide preliminary support for -secretase target engagement,but additional studies are warranted to better characterize pharmacodynamic effects at the 25- and 50-mg doses.This study establishes an acceptable safety and tolerability dose range for future avagacestat studies in AD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00810147