Discussion
The presently reported studies (3000/3001) are the last of four phase 3 trials performed to evaluate bapineuzumab immunotherapy. As in the first two U.S. trials (Studies 301 and 302), no significant differences were found in the coprimary cognitive or functional endpoints in this more global demographic [
3]. Early termination of the 3000/3001 studies could have contributed to the inability to detect a treatment effect; however, enrollment in the carrier (3001) study was complete (only the PET substudy was still recruiting), MMRM analysis was used, the treatment and placebo values were similar, and the negative results in the mITT and completer populations were consistent with studies 301/302 collectively, suggesting that the lack of clinical effect seen in these two studies was not due to early termination. There was no evidence of a clinical dose effect in the noncarrier study between the 0.5 mg/kg and 1.0 mg/kg doses. The small number of patients in the 2.0 mg/kg dose group (11 patients, 9 completers) and the reassignment of these patients to 1.0 mg/kg did not permit evaluation of the effects of higher doses.
The need for earlier intervention with amyloid-lowering therapy has been hypothesized as a potential reason for lack of clinical efficacy observed in recent phase 3 studies of bapineuzumab and of solanezumab, another anti-Aβ-targeted monoclonal antibody [
2,
3,
8,
9]. Also, a statistically significant benefit of bapineuzumab was reported in Study 301 in a mild AD subgroup (MMSE >19) of ApoE ε4 noncarriers on the functional but not the cognitive measure [
3]. On the basis of these findings, phase 3 studies in patients with mild AD and prodromal AD were initiated with solanezumab and another anti-Aβ-targeted monoclonal antibody, gantenerumab [
10]. Twenty-three percent of noncarriers and two percent of carriers who had baseline PiB-PET scans met the clinical criteria for AD dementia but did not meet the PiB-PET threshold for amyloid positivity at baseline. These patients with “suspected nonamyloid pathology” may have had some other form of dementia that could not be differentiated from AD on the basis of clinical inclusion criteria. Patients with low levels of amyloid would not be expected to benefit from an antiamyloid therapy. Inclusion of subthreshold amyloid patients was also a factor in the 301/302 bapineuzumab PiB-PET substudies (36 % and 6.5 % of those with baseline scans in the noncarrier and carrier studies, respectively) [
3]. The proportion of patients not meeting the amyloid threshold was lower in the 3000/3001 studies than in the 301/302 studies using the same threshold value, suggesting some differences in enrollment between the two sets of studies. The choice of amyloid threshold was based on the consensus of experts consulted at the time the studies were initiated, but the plot of baseline values shows a clear separation between positive and negative populations that would be robust to a range of selected thresholds. The amyloid-negative patients were included in the analyses of outcomes other than SUVr; however, it is unlikely that exclusion of the ten patients who were amyloid-negative would affect the overall study outcome. Since brain amyloid positivity was not an inclusion criterion, it is not possible to evaluate its impact on the observed cognitive and functional outcomes. Collectively, the findings from these studies indicate that amyloid assessment at screening is essential and that meeting an agreed amyloid threshold should be an inclusion criterion for future antiamyloid therapy trials.
The 3000/3001 bapineuzumab studies did not fully replicate the PiB-PET or CSF biomarker findings from Studies 301/302. In Studies 3000/3001, no significant treatment differences were seen in amyloid burden on PiB-PET or CSF p-tau (but trends were in the expected directions) (Fig.
3b), which appeared to be related to stability of the placebo groups over time. This finding differs from the results of Study 302 in ApoE ε4 carriers, in which SUVr on PiB-PET continued to increase in the placebo group with no change in the bapineuzumab group, suggesting prevention of Aβ accumulation. Significant decreases in amyloid load on PiB-PET with bapineuzumab were also reported from a phase 2 study [
6]. However, Study 301 in noncarriers showed no change in SUVr in the placebo group and no significant difference at week 71 between placebo and the bapineuzumab 0.5 mg/kg and 1.0 mg/kg groups [
3]. Mean amyloid load at baseline in amyloid-positive patients was similar between carriers and noncarriers in all four studies and between the 301/302 and 3000/3001 studies. A possible reason for lack of significance of the PiB-PET results in Studies 3000/3001 is the small number of subjects who completed each PiB-PET substudy, owing to early study termination. Only 27 patients in the current carrier study and 14 in the noncarrier study (approximately half in the bapineuzumab and half in the placebo group in each study) had an assessment at week 71, in contrast to 115 patients (75 bapineuzumab, 40 placebo) in the 302 carrier study and 39 patients (24 bapineuzumab, 15 placebo) in the 301 noncarrier study [
3]. However, the projected
p values for the PET substudies assuming full enrollment with the observed data trends suggest that full enrollment would not have changed the study conclusions. The cerebellar gray matter was used as reference region in the PET analyses, opening up another possibility that the use of the pons as reference region might have reduced the noise and thereby improved sensitivity to detect changes [
11].
In Studies 3000/3001, there was no effect of treatment on CSF p-tau, although there was a trend for significant reduction in the pooled bapineuzumab group in noncarriers. This finding differs from the results of the 301/302 studies. In ApoE ε4 noncarriers in the latter studies, there was no effect on CSF p-tau concentrations in the pooled bapineuzumab groups (the prespecified analysis), but exploratory analyses showed a significant reduction in CSF p-tau with bapineuzumab 1.0 mg/kg [
3]. As was the case for the PiB-PET analysis of SUVr, the results for CSF p-tau in the current studies were likely affected by the small number of patients who completed the assessments. Compared with the 301/302 studies, the number of patients in the bapineuzumab groups was less by almost half. vMRI assessments showed no significant effect of bapineuzumab treatment in any of the four studies, and rates of whole-brain volume loss were similar [
3].
Plasma Aβ
x–40 levels increased significantly in the bapineuzumab groups but not in the placebo group in the 3000/3001 studies, a result expected from anti-Aβ antibody infusion observed in other studies and an indicator of peripheral target engagement [
2,
9].
Infusions of bapineuzumab 0.5 and 1.0 mg/kg every 13 weeks were generally well-tolerated, and the safety profile was consistent with that reported in previous studies. No new or unexpected safety findings were observed [
3,
7]. ARIA-E were confirmed as dose-dependent TEAEs associated with bapineuzumab; these events increased with dose and ApoE ε4 allele number and led to discontinuation of the 2.0 mg/kg dose in all noncarrier studies [
3]. Rates of ARIA-E were three to four times higher in the placebo group of ApoE ε4 carriers than among noncarriers in the current studies, which differs from what was reported in the previous studies. This difference may have been due to increased detection because of the central image-reading of every MRI scan, suggesting a need for more intensive radiologist training to detect ARIA-E, particularly in clinical trials. Further research is needed to identify risk factors for ARIA-E and their long-term clinical course [
12]. There is growing evidence that ARIA is related to amyloid clearance from the brain [
12], which could eventually be tested by comparing PET and MRI images from the four completed bapineuzumab studies.
Study limitations
Early termination is the major limitation of both studies, as both were discontinued earlier than expected and before enrollment was complete in the noncarrier study. Premature termination led to smaller-than-expected sample sizes, particularly in the PiB-PET and CSF p-tau substudies. In addition, assuming that the PET substudy population is representative of the entire study population, a relatively high proportion of ApoE ε4 noncarriers did not meet a preestablished amyloid threshold and therefore lacked the drug target.
Competing interests
Dr. Vandenberghe (RV) discloses that a clinical trial agreement for the 3000 and 3001 studies was in place between Pfizer Inc. and University Hospitals Leuven (principal investigator, RV).
Dr. Rinne is a member of the Teva Finland Oy scientific advisory board and serves as a neurology consultant for Clinical Research Services Turku (CRST) Ltd. As a neurology consultant for CRST Ltd, he is involved in contract research with AC Immune, Merck, Otsuka Pharmaceutical Co., Roche, and TauRx Therapeutics. He has not received personal compensation from these organizations.
Dr. Boada has consulted for Araclon Biotech, Avid Radiopharmaceuticals, Bayer, Elan, Grifols, Janssen/Pfizer, Eli Lilly and Co., Neuroptix, Nutricia, Roche, Sanofi, and Servier Laboratories. She has received fees for lectures as well as funds for research from Araclon Biotech, Esteve, Grifols, Janssen, Novartis, Nutricia, Piramal, Pfizer, Wyeth, Roche, and Servier Laboratories. She has not received personal compensation from these organizations.
Dr. Katayama declares no competing interests.
Dr. Scheltens has served as a consultant to Pfizer, Novartis, Boehringer, Takeda, and Nutricia Research and has received research support from Merck and GE Healthcare. He has not received personal compensation from these organizations.
Dr. Vellas has served as a scientific board member for AstraZeneca, Eisai Co., Elan, Exhonit, GlaxoSmithKline, Eli Lilly and Co., Medivation, Meso Scale Discovery (MSD), Nestlé, Nutricia, Pfizer, Pierre Fabre Laboratories, Roche, Sanofi, Servier Laboratories, TauRx Therapeutics, and Wyeth. He has received research grants from AbbVie, AFFiRiS, Avid Radiopharmaceuticals, Bristol-Myers Squibb, Eisai Co., Elan, EnVivo Pharmaceuticals, Exhonit, Genentech, GlaxoSmithKline, Fondation IPSEN, Eli Lilly and Co., Medivation, MSD, Nutricia, Otsuka Pharmaceutical Co., Pharnext, Pfizer, Pierre Fabre Laboratories, Regeneron Pharmaceuticals, Roche, Sanofi, Servier Laboratories, TauRx Therapeutics, and Wyeth.
Dr. Tuchman has received honoraria and research funding from Pfizer, Janssen, Merck, AstraZeneca, and Amgen.
Dr. Gass declares no competing interests.
Dr. Fiebach declares no competing interests.
Dr. Hill is an employee of IXICO plc and holds stock and share options in IXICO plc. Through IXICO, he has provided services to Pfizer, Janssen Alzheimer Immunotherapy Research & Development, Bristol-Myers Squibb, Eli Lilly and Co., Teva, Roche, MedImmune, GlaxoSmithKline, Kyowa Hakko Kirin Co., Green Valley, Eisai Co., VirtualScopics, and ENKAM Pharmaceuticals. Dr. Hill holds non-study-related patents in image data management and image analysis. Also, through IXICO, he has received research grant support from the European grant sources Innovative Medicines Initiative and FP7, also including in the United Kingdom the Technology Strategy Board and the Medical Research Council.
Dr. Lobello is an employee of Pfizer Inc. and an owner of Pfizer Inc. stock.
Dr. Li is an employee of Pfizer Inc. and an owner of Pfizer Inc. stock.
Dr. McRae is an employee of Pfizer Inc. and an owner of Pfizer Inc. stock.
Dr. Lucas is an employee of Pfizer Inc. and an owner of Pfizer Inc. stock.
Dr. Evans is an employee of Pfizer Inc. and an owner of Pfizer Inc. stock.
Dr. Booth is an employee of Pfizer Inc. and an owner of Pfizer Inc. stock.
Mr. Luscan is an employee of Pfizer Inc. and an owner of Pfizer Inc. stock.
Dr. Wyman was an employee of Pfizer Inc. at the time these studies were conducted and is an owner of Pfizer Inc. stock.
Dr. Hua is an employee of Pfizer Inc. and an owner of Pfizer Inc. stock.
Dr. Yang is an employee of Pfizer Inc.
Dr. Brashear is an employee of Janssen Alzheimer Immunotherapy Research & Development.
Dr. Black was an employee of Pfizer Inc. at the time these studies were conducted and is an owner of Pfizer Inc. stock.
All authors declare that they have no nonfinancial competing interests.
Authors’ contributions
RV contributed to collection of data; provided technical assistance; supervised personnel; contributed drugs, reagents, equipment, or participants; and contributed to drafting and/or revision of the manuscript. JOR contributed to study conduct, collection of data, interpretation of the data, and drafting and/or revision of the manuscript. MB contributed to study conduct, interpretation of the data, and drafting and/or revision of the manuscript. SK contributed to study conduct, interpretation of the data, and drafting and/or revision of the manuscript. PS contributed to data acquisition, supervised patient recruitment and enrollment, and edited and approved the manuscript. BV contributed to the acquisition, analysis, and interpretation of data as well as drafting and/or revision of the manuscript. MT contributed to the design of the studies; acquisition, analysis, and interpretation of the data; and drafting and/or revision of the manuscript. AG was a central MRI reader for safety in the bapineuzumab studies and contributed to interpretation of the data and drafting and/or revision of the manuscript. JBF was a central MRI reader for safety in the bapineuzumab studies and contributed to interpretation of the data and drafting and/or revision of the manuscript. DH contributed to the acquisition, analysis, and interpretation of data; drafting and/or revision of the manuscript for content; and study supervision and coordination. KL contributed to study supervision and coordination, analysis and interpretation of the data, and drafting and/or revision of the manuscript. DL carried out the primary statistical analysis for the 3000/3001 studies. He contributed to the study design, analysis and interpretation of the data, and drafting and/or revision of the manuscript. TM contributed to the design, analysis, and interpretation of data as well as drafting and/or revision of the manuscript. PL contributed to the study design; study supervision and coordination; acquisition, analysis, and interpretation of the data; and drafting and/or revision of the manuscript. IE contributed to the study design, analysis and interpretation of the data, and drafting and/or revision of the manuscript. KB contributed to study supervision and coordination and drafting and/or revision of the manuscript. GL contributed to acquisition, analysis, and interpretation of the data; study supervision and coordination; and drafting and/or revision of the manuscript. BTW contributed to study supervision and coordination, analysis and interpretation of the data, and drafting and/or revision of the manuscript. LH conducted protocol amendment and investigator’s brochure updates and also contributed to data collection and review and to drafting and/or revision of the manuscript. LY contributed to the study design, analysis and interpretation of the data, and revision of the manuscript. HRB contributed to study concept and design; acquisition, analysis, and interpretation of data; drafting and/or revision of the manuscript; and study supervision and coordination. RSB contributed to the study design; acquisition, analysis, and interpretation of the data; and drafting and/or revision of the manuscript. All authors read and approved the final manuscript.