Recent clinical trials in Alzheimer’s disease have faced numerous setbacks, not least in the failure of three recent clinical development programs of novel therapies.
Bapineuzumab, an anti-amyloid-beta monoclonal antibody, was investigated in two phase III trials of patients with mild to moderate AD (Salloway et al. N Engl J Med 2014;370:322-333). One studied treatment efficacy in carriers of the apolipoprotein E (ApoE) allele, the other of ApoE non-carriers. Both were very large studies (patients, n=2452; investigators, n=3741). The primary outcome measures were change from baseline in the 11-item ADAS-cog and the Disability Assessment for Dementia (DAD); secondary measures were PET amyloid imaging with Pittsburgh compound B (PiB-PET) and phospho-tau concentration in CSF.
At week 78, there were non-significant differences with either bapineuzumab dose (0.5 and 1 mg/kg) versus placebo in both the ApoE carrier and non-carrier studies. The 2 mg/kg dosing arm was discontinued due to amyloid-related imaging abnormalities with edema. Treatment was associated with improvements in biomarkers (PiB-PET and phospho-tau) in ApoE carriers but not in non-carriers.
Similar results were seen in two phase III trials with a second MAb, solanezumab, which binds soluble amyloid (Doody et al. N Engl J Med 2014;370:311-321). Over 2,000 patients in the EXPEDITION-1 and -2 trials received IV solanezumab 400 mg q4weeks for 18 months. At endpoint, there was no significant difference in change from baseline in ADAS-cog score or AD Cooperative Study-Activities of Daily Living (ADCS-ADL) score. The incidence of amyloid-related imaging abnormalities with edema was 0.9% with solanezumab versus 0.4% with placebo (combined data set). The incidence of amyloid-related abnormalities with hemorrhage was 4.9% and 5.6%, respectively.
In addition, the phase III trial of semagacestat, a small-molecule gamma-secretase inhibitor, was negative (Doody et al. N Engl J Med 2013;369:341-350). Subjects received semagacestat 100 or 140 mg/day or placebo. The study was terminated when ADAS-cog scores worsened in all groups (100 mg, 7.5 points; 140 mg, 7.8 points; placebo, 6.4 points). ADCS-ADL scores also worsened. Patients on active treatment had more infections, skin cancers and laboratory abnormalities, including lymphopenia, elevated cholesterol and elevated urinary pH.
Comment
Dr. Yves Bacher: The negative scans for amyloid in 36% of ApoE4 non-carriers at baseline in the bapineuzumab trial raise questions about the importance of amyloid pathology in Alzheimer’s disease and/or the value of our diagnostic criteria in relation to the clinical syndrome. Is it a question of the right target (i.e. fibrillar vs. soluble amyloid)? Or a question of timing (intervene even in pre-symptomatic stages)? The questions remain open for discussion.
We should also remain cautious about anti-amyloid interventions, especially with the worsening observed in the semagacestat trial. Our knowledge of the metabolism and pool of amyloid in vivo is more limited than we may have thought.