Monoclonal Amyloid Antibodies for the Treatment of Alzheimer’s Disease: More Disappointment
Abstract & Commentary
By Michael T. Lin, MD
Assistant Professor of Neurology and Neurosciences,
Weill Cornell Medical College
Dr. Lin reports no financial relationships relevant to this field of study.
Synopsis: Current trials with amyloid antibodies have not shown clinical benefit, but the results suggest that treating patients earlier in the course, or during the presymptomatic period, might be beneficial.
Source: Doody RS, et al. Phase 3 trials of solanezumab for mild-to-moderate
Alzheimer's disease. N Engl J Med 2014;370:311-321.
Salloway S, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate
Alzheimer's disease. N Engl J Med 2014;370:322-333.
Last year, the business press reported that two abeta-directed monoclonal antibodies, bapineuzumab and solanezumab, failed to meet their primary endpoints in clinical trials for mild-to-moderate Alzheimer’s disease (AD). Results from these trials are now formally reported in back-to-back articles in the New England Journal of Medicine. Although the overall results were negative, the trials provide information and raise important questions regarding pathophysiologic mechanisms. Subgroup analyses also provide some hope that earlier intervention may prove more effective.
The two antibodies bind different portions of the Abeta peptide and recognize different populations of Abeta aggregates. Bapineuzumab binds the N-terminal portion of the Abeta peptide and recognizes both soluble aggregates (found in interstitial fluid and cerebrospinal fluid [CSF]) and fibrillar aggregates (found in plaques and blood vessel walls). In contrast, solanezumab binds the central portion of the Abeta peptide and recognizes only soluble aggregates. Because bapineuzumab recognizes a greater range of Abeta species, a priori, it might have been imagined to have greater efficacy. That did not prove to be the case. Moreover, by interacting with fibrillar Abeta deposits in blood vessel walls, bapineuzumab could potentially increase the risk of vascular leakage, resulting in edema or hemorrhage, so-called amyloid-related imaging abnormalities (ARIA). That did prove to be the case. In the bapineuzumab trials, risk of ARIA-edema increased with dose, up to 15% risk in the highest dose arm; this arm was reassigned to a lower dose by the safety monitoring committee. In contrast, the overall risk of ARIA in subjects given solanezumab was 5%, indistinguishable from the rate in placebo.
There were two bapineuzumab trials, one involving apoE4 carriers and another involving noncarriers. Both trials were randomized, double-blind, placebo-controlled, multicenter, Phase 3 clinical trials, each with more than 1000 subjects with mild-to-moderate AD. In the carrier trial, subjects were randomized to placebo or 0.5 mg/kg IV every 13 weeks for 78 weeks. In the noncarrier trial, subjects were randomized to placebo, 0.5 mg/kg, 1.0 mg/kg, or 2.0 mg/kg IV every 13 weeks for 78 weeks. As mentioned above, the 2.0 mg/kg arm was subsequently reassigned to the 1.0 mg/kg arm and followed for safety, but not efficacy. The primary endpoints were cognition (11-item AD Assessment Scale, ADAS-cog11) and function (Disability Assessment for Dementia). Secondary endpoints included amyloid imaging using the Pittsburgh B compound (PiB-PET) and CSF phosphotau concentrations. There was no difference between placebo and any active agent arm in either trial with respect to cognition or function. However, there were changes in biomarkers. In the apoE4 carrier trial, amyloid burden increased in those given placebo, but remained stable in those given the antibody. Numbers were too small to be definitive in the noncarrier trial; of note, 36% of noncarriers who participated in the PiB-PET substudy did not show abnormal amyloid burden, raising the question of whether these patients truly had AD. With respect to CSF phosphotau levels, treatment with 0.5 mg/kg reduced phosphotau in apoE4 carriers, and treatment with 1.0 mg/kg reduced phosphotau in noncarriers. CSF tau and phosphotau are currently thought of as markers of neuronal injury, akin to troponin or creatine kinase in myocardial injury. The fact that treatment reduced phosphotau without any cognitive or functional benefit raises questions about the role of tau in the pathogenesis of the disease.
There were also two solanezumab trials, EXPEDITION 1 and EXPEDITION 2, one preceding the other. Both were randomized, double-blind, placebo-controlled, multicenter Phase 3 clinical trials, each with more than 1000 subjects with mild-to-moderate AD. In both trials, subjects were randomized to placebo or 400 mg solanezumab IV every 4 weeks for 18 months. The original primary endpoints were cognition (ADAS-cog11) and function (ADCS-ADL). In a pre-specified subgroup analysis for EXPEDITION 1, a benefit of solanezumab was observed for cognition in subjects with mild AD, but not moderate AD or in all subjects combined. On the basis of this finding, and before EXPEDITION 2 was completed, the statistical analysis plan for EXPEDITION 2 was revised (and approved by regulatory agencies) so that the primary analysis population was the subjects with mild AD, and the primary cognitive endpoint was changed to the ADAS-Cog14, which is a better measure of cognitive changes in patients with mild AD. The benefit of solanezumab in mild AD in EXPEDITION 2 did not quite reach significance for ADAS-Cog14 (P = 0.06) or ADAS-Cog11 (P = 0.05), though it did just reach significance for function (ADCS-ADL, P = 0.04). In contrast to the bapineuzumab studies, solanezumab had no effect on amyloid burden measured by 18F-florbetapir PET, and no effect on CSF tau or phosphotau levels. There was an increase in total CSF Abeta42 levels and plasma Abeta42 levels in subjects treated with solanezumab, suggesting engagement of target.
Both sets of studies were large, well-designed, well-executed studies. Although overall results were negative, comparing the two antibodies provides some information about pathogenesis and raises important questions. First, the discordance between plaque burden and clinical benefit (bapineuzumab reducing plaque burden but providing no benefit; solanezumab not reducing plaque burden but providing slight benefit in mild cases) reinforces current thinking that soluble Abeta aggregates may be the most pathophysiologically relevant species of Abeta. Second, the studies raise questions about the role of tau — bapineuzumab decreased CSF phosphotau levels but provided no clinical benefit, whereas solanezumab provided benefit in mild cases but did not change CSF tau or phosphotau levels. This clearly points to a gap in our understanding of AD pathogenesis. Third, the amyloid imaging data fit with other data that a substantial fraction of apoE4 negative subjects who clinically appear to have AD will be amyloid negative, suggesting that they do not suffer from AD. Understanding the cause of dementia in these individuals is an important area, and suggests that amyloid imaging should be used more routinely. Finally, the authors of both sets of studies conclude by postulating a larger benefit for anti-amyloid therapy if treatment were started earlier, before patients become symptomatic. This is reasonable, given increasing evidence from CSF studies and amyloid PET imaging that amyloid pathology can begin decades before symptoms appear. Given the slight benefit of solanezumab in mild AD and its relatively better safety profile, solanezumab has been selected as the agent for the upcoming A4 (anti-amyloid therapy in asymptomatic Alzheimer disease) trial, in which asymptomatic individuals with evidence of AD pathology as identified by amyloid imaging will be treated for 3 years to determine effect on subsequent cognitive decline. This trial represents an enormous investment of resources and currently represents the best hope for a therapeutic or preventive breakthrough.