At a time when several papers have questioned the paucity of published trials with negative outcomes, the New England Journal of Medicine published two papers recently — and an accompanying editorial — highlighting the trial results of two experimental Alzheimer’s disease drugs that failed to meet their clinical endpoints in late stage trials.
Bapineuzumab, a humanized anti–amyloid-beta monoclonal antibody, and solanezumab, a humanized monoclonal antibody that preferentially binds soluble forms of amyloid, were both studied individually in two double-blind phase 3 trials and ultimately showed a failure to significantly improve cognition or functional ability in mild-to-moderate Alzheimer’s disease patients.
In one paper, Rachelle S. Doody, MD, PhD, professor of neurology at Baylor College of Medicine, and colleagues reported there was no significant improvement in the primary outcomes — a change from baseline to week 80 in scores on cognitive and daily living functions as measured by the Alzheimer’s Disease Assessment Scale (ADAs-cog11) and Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale (ADCS), respectively — in two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2) for solanezumab.
About 2000 patients with mild-to-moderate Alzheimer's disease were randomly assigned to receive either placebo or solanezumab (administered intravenously at a dose of 400 mg) every four weeks for a period of 18 months.
The difference between solanezumab and the placebo group from baseline was −0.8 points for the ADAS-cog11 score (95% confidence interval [CI], −2.1 to 0.5; p=0.24) and −0.4 points for the ADCS-ADL score (95% CI, −2.3 to 1.4;p=0.64) in EXPEDITION 1 and −1.3 points (95% CI, −2.5 to 0.3; p=0.06) and 1.6 points (95% CI, −0.2 to 3.3; p=0.08), respectively, in EXPEDITION 2.
In the second paper, Stephen Salloway, MD, director of neurology and the Memory and Aging Program at Butler Hospital in Providence, RI, and colleagues reported finding no significant change in the primary outcome measures — scores on the ADAS-cog11 and the Disability Assessment for Dementia (DAD) — compared with placebo in two double-blind, randomized, placebo-controlled, phase 3 trials of bapineuzumab. The first trial involved 1121 carriers of the apolipoprotein E (APOE) ε4 allele; and the other involved 1331 noncarriers. The drug or placebo was administered by intravenous infusion every 13 weeks for 78 weeks. The efficacy analysis included 1090 carriers and 1114 noncarriers. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations.
At week 78, the differences between the bapineuzumab group and the placebo group from baseline in the ADAS-cog11 and DAD scores were −0.2 (p=0.80) and −1.2 (p=0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were −0.3 (p=0.64) and 2.8 (p=0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (p=0.62) and 0.9 (p=0.55) with the 1.0-mg-per-kilogram dose. Differences between the two groups were reported using the PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers.
In the accompanying editorial, Eric Karran, PhD, the director of research for Alzheimer's Research UK, and John Hardy, PhD, FMedSci, professor of neuroscience at University College London, highlighted the value of publishing the negative findings. “…both the bapineuzumab trials and the solanezumab trials have … brought into question the interpretation placed on some biomarkers — especially the CSF level of phospho-tau but also brain volume. We advocate continuing to investigate ways to modulate Aβ [amyloid-beta] levels in the brain while accepting that we lack clarity on the roles that different forms of Aβ play in the disease.”
Neurology, the journal of the American Academy of Neurology, has issued a solicitation for well-designed and implemented negative trials. Neurology Editor-in Chief Robert A. Gross, MD, PhD, and Deputy Editor David S. Knopman, MD, wrote: “Neurology® believes it is important to advance research related to neurologic disease and that well-designed studies on important clinical topics should be published, whether or not the results are ‘positive.’…But let's be a bit more specific. Neurology wants negative studies that are themselves methodologically rigorous and, equally importantly, motivated by strong and convincing basic science.” See the full Neurology Today story on unpublished trial data: http://bit.ly/1heTZab.
Stay tuned for an extended discussion on the failed Alzheimer’s drug trials and what they mean for future research in an upcoming issue of Neurology Today. Browse Neurology Now’s archives on Alzheimer's: http://bit.ly/XNM5In.