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

Abstract

Background: Bapineuzumab, a humanized monoclonal antibody, targets amyloid-β (Aβ_1-40/1 -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.

Keywords

Alzheimer’s disease amyloid burden bapineuzumab biomarker pharmacokinetics

INTRODUCTION

Bapineuzumab is a recombinant humanized monoclonal antibody targeting the N-terminus of the 42-amino acid isoform of the amyloid-beta peptide (Aβ₄₂), the major constituent of amyloid plaques [1, 2]. Bapineuzumab has been shown to reduce amyloid plaque burden and prevent plaque accumulation in platelet-derived growth factor promoter driven amyloid precursor protein (PDAPP) transgenic mice, an animal model for Alzheimer’s disease (AD) [1]. In humans, bapineuzumab has been observed to reduce cortical retention of ¹¹ C Pittsburgh compound B (PIB), a biomarker of fibrillar amyloid deposition [2, 3], and cerebrospinal fluid (CSF) concentrations of phosphorylated-tau, a biomarker of neuronal injury that is elevated in AD [4].

Bapineuzumab was investigated in two large randomized, placebo-controlled Phase III clinical studies using a regimen of 0.5 mg/kg in apolipoprotein E gene, E4 allele (APOE* E4) carriers and 0.5 or 1.0 mg/kg in noncarriers, and was administered intravenously (IV) every three months over a total of 18 months. Higher dosages of bapineuzumab were limited by a higher rate of amyloid-related imaging abnormalities associated with edema and effusion (ARIA-E) [3]. While the bapineuzumab IV Phase III studies were in progress, this study was undertaken in patients with mild to moderate AD to explore whether a longer period of administration that included a lower dosage range, using the potentially more accessible and convenient regimen of monthly subcutaneous (SC) injections, could reduce cerebral amyloid with a reduced risk of ARIA-E.

The objectives of this study were to evaluate: the effects of SC bapineuzumab 2, 7, and 20 mg, administered at monthly intervals, on change from baseline in cerebral amyloid signal as measured by positron emission tomography (PET) imaging, the incidence of ARIA-E with monthly SC bapineuzumab over this 10-fold dose range (2 to 20 mg), pharmacokinetics (PK) and pharmacodynamics (PD), immunogenicity, and other safety aspects of bapineuzumab. Before this study was completed, in August 2012 the results of the Phase III clinical trials became available, revealing a lack of efficacy in the dosage range explored. In both Study 302 (in APOE*E4 carriers) and Study 301 (in APOE*E4 noncarriers), the primary efficacy endpoints were not met, specifically, no statistically significant benefit in cognitive and functional outcome (i.e., ADAS Cog/11 or DAD total scores) was seen in the bapineuzumab-treated groups compared to subjects who received placebo; no new safety findings were identified from these studies. Following a recommendation by an independent Drug Safety Monitoring Committee that was involved in a risk-benefit assessment regarding continuation or stopping of the study, the sponsor made the decision to discontinue all ongoing clinical trials of bapineuzumab IV in August 2012. Therefore although it was unlikely that participants in the bapineuzumab SC study would receive a direct clinical benefit from treatment, the objective of evaluating the effect of SC dosing on AD biomarkers was considered important. Hence in October 2012, per protocol amendment, the duration of the SC study was shortened from a 24-month to a 12-month study after all participants completed their 12-month assessments and therefore the primary endpoint was redefined at 12 instead of 24 months.

MATERIALS AND METHODS

This randomized, double-blind, placebo-controlled, parallel-group, multicenter, Phase II study (NCT01254773) was conducted at 28 centers in United States from 16 December 2010 to 14 January 2013. This study was originally designed to test the effect of exposure to SC bapineuzumab on cerebral amyloid signal for a longer duration (24 versus 18 months in the bapineuzumab IV Phase III studies) and extending into a lower dosage range than had been studied previously.

The study protocol and amendments were approved by an institutional review board at each study site. The study was conducted in accordance with the ethical principles communicated in the Declaration of Helsinki and in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice guidelines, applicable regulatory requirements and in compliance with the protocol. All patients provided written informed consent prior to study participation.

Study population

Men and women, aged between 50 to 89 years (inclusive), diagnosed with probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria [5], were enrolled. Other major inclusion criteria were: florbetapir (¹⁸F-AV-45) PET scan demonstrating significant amyloid burden, as determined by visual analysis of the PET image by qualified readers at a single imaging core laboratory; brain magnetic resonance imaging (MRI) scan consistent with the diagnosis of AD; a Mini-Mental State Examination (MMSE) score of 18 to 26 (inclusive) at screening; a Rosen Modified Hachinski Ischemic score of 4 or less; and the availability of a responsible caregiver.

Key exclusion criteria were: evidence of any clinically significant medical illness other than AD, a brain MRI scan indicative of any other significant abnormality, including 4 or more microhemorrhages or more than one lacunar infarct, a major psychiatric disorder or chronic illness, a history of stroke or seizure, autoimmune disease, or myocardial infarction within the last 2 years, and cancer. Participants were excluded if they smoked ≥20 cigarettes per day, had received prior treatment with experimental immunotherapeutics for AD, or could not undergo MRI. Women of child-bearing potential were also excluded from the study.

Concomitant medications

Stable dosages of cholinesterase inhibitors or memantine were permitted. Experimental medications for AD, systemic immunosuppressive medications, chemotherapeutic agents, anticonvulsants, anticoagulants, opioid pain relievers, and related synthetic derivatives were prohibited. Chronic use of anxiolytics, sedatives, hypnotics, antipsychotics, antidepressants, over-the-counter sleep aids, and vitamin B12 supplements by injection were discouraged, unless medically indicated. Topical and nasal corticosteroids for asthma, intra-articular corticosteroids, and Ginkgo biloba were permitted. Routine vaccinations were permitted but not within 1 week of the study product administration.

Study medication

Active doses were prepared from a single concentration of bapineuzumab (20 mg/mL), such that each injection was 1.0 mL in volume and contained the assigned dose of bapineuzumab. Placebo was supplied as a sterile liquid dosage containing identical ingredients without bapineuzumab. Study medication was packaged in blinded kits.

Study design and treatments

The study consisted of a 7-week screening period, a dosing period of 12 months, and a posttreatment follow-up period of 1 month. All patients were randomized (1 : 1:1 : 1) to receive either placebo or one of the three doses of bapineuzumab (2, 7, or 20 mg/month) as 1 mL SC injections once monthly, starting on day 1 of the dosing period for a total of 12 injections. Randomization was balanced by using randomly permuted blocks, and was stratified by APOE*E4 allele status (carrier versus noncarrier).

Study evaluations

Primary endpoint

The primary endpoint was the change from baseline to month 12 in cerebral amyloid signal as measured by florbetapir PET scan, in a global cortical average (GCA) of 5 regions of interest (ROI), consisting of the anterior cingulate, frontal cortex, lateral temporal cortex, parietal cortex, and posterior cingulate/precuneus.

Florbetapir PET scans were obtained for all patients at baseline, months 6 and 12 or early termination (ET). A PET scan time of 15 min duration was performed beginning 50 (±5) min after intravenous injection of 10±1 mCi (370 MBq) of ¹⁸F-florbetapir. To obtain standardized uptake value ratios (SUVRs), a quantitative PET image analysis was conducted at the core imaging laboratory. An SUVR for each ROI was calculated by dividing the standardized uptake value (SUV) of the target region by the SUV of cerebellar gray matter (reference region) per established methods [6]. The GCA SUVR was derived by averaging the SUVRs of the 5 componentROIs.

Secondary endpoints

Incidence of ARIA-E: A key secondary endpoint was the incidence of ARIA-E, as assessed by fluid attenuated inversion recovery (FLAIR) MRI [7] at baseline and months 3, 6, 9, and 12.

Safety: Safety and tolerability were monitored throughout the study. In addition to ARIA-E, safety assessments included treatment-emergent adverse events (TEAEs), deaths, events of special circumstance (intracranial hemorrhage, seizures/convulsions, deep vein thrombosis, and pulmonary embolism), adverse drug reactions (ADRs), clinical laboratory tests, electrocardiogram (ECG), vital signs, brain MRI, suicidality assessments, and physical and neurological examinations.

Pharmacokinetics: Plasma bapineuzumab concentrations were obtained at predose, month 5, month 12, and on two random days occurring 2–14 and 15–27 days postdose. In addition, CSF concentrations of bapineuzumab were assessed at screening and at 12 months.

Pharmacodynamics: The PD evaluation was the change from baseline in plasma amyloid-beta (Aβ_x-40), estimated from serum anti-Aβ titers and plasma Aβ concentration collected at predose, month 5, month 11, and month 12/ET.

Immunogenicity: Anti-bapineuzumab antibody screening confirmation and titer in serum and CSF samples were measured by a validated, semiquantitative enzyme-linked immunosorbent assay (ELISA) method. Peripheral venous blood samples (4 mL each) were collected at randomization and months 5, 11, and ET. The CSF samples were to be assayed for anti-bapineuzumab antibodies only if the corresponding serum anti-bapineuzumab antibody assay was positive.

Exploratory endpoints

Change in brain volumes: Volumetric analysis was performed on brain MRIs obtained at screening and 6 and 12 months or ET. Methods and results are presented in the supplementary section.

Clinical efficacy: Change from baseline was assessed for several clinical measures: the AD Assessment Scale – Cognitive subscale/11 items (ADAS-Cog/11); the Disability Assessment for Dementia (DAD) scale; and the Clinical Dementia Rating Sum of Boxes (CDRSB). Assessments were performed at baseline, 3 months, 6 months, and ET. Results are presented in the summary section.

Statistical evaluations

Sample size justification

The sample size proposed in the original protocol (N = 120 patients) was based on the original study duration of 24 months. When the study was truncated at 12 months, power was recalculated by taking into account the shorter observational period, which was expected to correspond to a smaller treatment effect but with less missing data.

Based on the power recalculation, the 146 already enrolled patients were considered to be sufficient to provide 94% power to detect a treatment difference (between the pooled 2 highest bapineuzumab doses and placebo) of 0.129 for the baseline to month 12 change in florbetapir GCA SUVR, based on a 2 sample t-test using month 12 completers and assuming a dropout rate of 20% and a standard deviation of 0.16 [2]. The power was 86% when comparing individual bapineuzumab doses and placebo.

Analysis populations

The primary endpoint was analyzed using the florbetapir PET analysis population which included patients who received at least one dose of the study medication and who had both the baseline and at least one post-baseline value of their respective measurement (GCA SUVR and serum bapineuzumab concentration, respectively). The safety analysis population included all randomized patients who received at least one dose of the study medication. Immunogenicity analysis was based on the safety population.

Statistical analyses

Demographic and baseline characteristics and all assessments including safety were summarized descriptively by treatment group.

Changes from baseline in florbetapir PET GCA SUVR were analyzed using a restricted maximum likelihood-based mixed-model for repeated measures (MMRM). This model included fixed effects for treatment (bapineuzumab 2, 7, and 20 mg/month, placebo), APOE* E4 status stratum (carrier and noncarrier), baseline GCA SUVR, visit (categorical), age at baseline, and treatment-by-visit interaction. An unstructured variance-covariance matrix was used to model the within-patient variability. Least-squares (LS) means and the corresponding 95% confidence intervals (CI) were calculated for change from baseline over time within individual treatment groups and the between-group treatment difference. The same analyses were also performed separately for the mild and moderate disease severity subgroups and for APOE*E4 carriers and noncarriers.

Incidence proportions of ARIA-E were calculated by dividing the number of patients who had the event by the number of patients in each dosage arm. Exact binomial 95% CIs for the incidence proportions were calculated for each individual treatment group. Summary statistics were reported for the trough concentrations of bapineuzumab in serum and CSF by treatment groups.

TEAEs and serious TEAEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA Version 15.1) and summarized by system-organ class (SOC) and preferred terms. Safety evaluation also included assessment of laboratory tests, vital signs, ECGs, and physical and neurological examinations.

RESULTS

Patient disposition and demographics

A total of 146 patients (2 mg/month: n = 37; 7 mg/month: n = 36; 20 mg/month: n = 37; placebo: n = 36) were randomized and received at least 1 dose of the study medication (Fig. 1). No patient completed the planned study duration of 24 months as the treatment phase was truncated to 12 months. A total of 114 (78.1%) patients received study treatment through at least month 11 and finished either the scheduled 12-month clinical and biomarker assessments, or an ET visit. Other than termination of the study by the sponsor, the most common reasons for early discontinuation from the study in all treatment groups were “withdrawal by the patient” (n = 25, 17.1%) and “other” (n = 31, 21.2%).

For the dosed patients, the demographic and baseline characteristics were generally balanced across the treatment groups, except for the 7 mg/month group, which had nominally higher ratings of disease severity on MMSE and ADAS-Cog (Table 1). The majority of patients were women (57.5%), and white (97.3%). More than half of the patients (60.3%) were APOE*E4 carriers, most with 1 copy of the allele. In total, 40.4% of patients had first degree relatives with AD, and 84.2% of patients had received symptomatic AD treatment previously.

The distribution of patients by total number of monthly SC injections and the total person-weeks of exposure to study drug were similar across all treatment groups, as summarized in Table 2. The majority of the patients (74%, 108/146) received at least 12 injections of bapineuzumab or placebo.

Biomarkers

The florbetapir PET analysis population included 138 patients (2 mg/month: n = 35; 7 mg/month: n = 34; 20 mg/month: n = 36; placebo: n = 33) (Table 3). In this analysis, a positive change from baseline indicated increasing fibrillar amyloid signal. A negative treatment difference (change from baseline for bapineuzumab minus change from baseline for placebo) indicated less accumulation of fibrillar amyloid with bapineuzumab. At month 12, the LS mean change from baseline was in a negative direction in each bapineuzumab group (an indication of a reduction in fibrillar amyloid burden), compared with no change in the placebo group.

A significant reduction from baseline to month 12 in SUVR was reported only for the 7 mg/month group (p = 0.038), but there were no significant between-group differences for this measure (Fig. 2) and no evidence of dose-related trends. The MMRM analyses of SUVRs for individual ROIs (frontal cortex, anterior cingulate, lateral temporal cortex, parietal cortex, and posterior cingulate/precuneus) did not show significant changes from baseline at month 12 except for the 7 mg/month group for anterior cingulate (p = 0.033), parietal cortex (p = 0.048), and posterior cingulate/precuneus (p = 0.024) ROIs. No between group differences were noted.

In subgroup analyses based on disease severity, change in SUVR from baseline to month 12 was significant only in the 7 mg/month group in patients with mild AD (p = 0.016). Similarly, in the subgroup analysis based on APOE*E4 status, the baseline to month 12 change was significant only for noncarriers (p = 0.049) in the 7 mg/month group. The only between-group difference that was statistically significant was for 7 mg/month versus placebo in patients with mild AD (p = 0.046).

There were no significant differences between bapineuzumab and placebo for the other biomarker endpoints except for left hippocampal boundary shift integral. There were statistically significant reductions in left hippocampal volume at month 12 as compared to mean volumes at baseline for all bapineuzumab and placebo treatment groups. The difference from placebo was statistically significant only for the 20 mg group (p = 0.050) indicating that the extent of reduction in hippocampal volume from baseline for the 20 mg group was more as compared to the reduction from baseline for the placebo group (Supplementary Table 1).

Safety

Overall, two patients had ARIA-E, one APOE*E4 carrier receiving 2 mg/month and one noncarrier receiving 20 mg/month, resulting in an incidence proportion for ARIA-E of 2.7% in each group. The events were asymptomatic and mild in severity, and were identified on a scheduled MRI as both sulcal and parenchymal involvement at 6 months (20 mg/month) and 9 months (2 mg/month). The radiologic abnormalities resolved by 62 and 73 days for these 2 patients, respectively. The patient receiving 2 mg/month also had an adverse event of ARIA-H based on an increase from 1 small microhemorrhage (<10 mm in size) at screening to 8 at 9 months (the time of ARIA-E detection). Only one microhemorrhage was in the same region as the ARIA-E. Both patients continued in the study after resolution of ARIA-E until the study was terminated.

Overall, subcutaneous bapineuzumab 2, 7, and 20 mg/month given for 12 months were well tolerated. The percentages of patients with any TEAEs were similar in the bapineuzumab 2 mg/month group (78.4%) and placebo (77.8%) groups, while higher in the 7 mg/month (94.4%) and 20 mg/month (89.2%) groups (Table 4). The placebo group had a lower percentage of patients with TEAEs considered related to the study drug by the investigator, but a higher percentage of patients with TEAEs leading to discontinuation.

Serious TEAEs occurred in a smaller percentage of patients in the placebo group than in the bapineuzumab groups (Table 4). Only two serious TEAEs were considered related to the study drug by the investigator: increase in hepatic enzyme in one patient receiving 7 mg/month, and chronic obstructive pulmonary disease in another patient receiving 20 mg/month. Two deaths were reported; one in the placebo group (delirium) and one in the bapineuzumab 7 mg/month group (acute respiratory failure), and these were not considered to be related to the study drug by the investigator.

Urinary tract infection and upper respiratory tract infection were the most common TEAEs (≥10% of patients) in the placebo group. The TEAEs that occurred in≥10% of patients in any bapineuzumab dosage group were urinary tract infection, headache, cerebral microhemorrhage, diarrhea, vomiting,nausea, behavioral and psychiatric symptoms of dementia, cough, fall, back pain, and fatigue (Table 5).

Of the pre-identified events of special circumstance (ESCs), no patient had cerebral hemorrhage, intracranial hemorrhage, seizures/convulsions, deep vein thrombosis, or pulmonary embolism. Hypersensitivity reactions occurred in two patients in the 2 mg/month group (both with rash), one patient in the 7 mg/month group (rash), and one patient in the 20 mg/month group (swelling of face). There were no clinically notable differences in laboratory values, vital signs, ECGs, or physical/neurological examinations between the placebo and bapineuzumab groups.

Pharmacokinetics and pharmacodynamics

Trough serum bapineuzumab concentrations increased with increasing bapineuzumab dose in an approximately dose-proportional manner, mean trough concentration at month 11 : 2 mg/month: 409.3 ng/mL, 7 mg/month: 943.0 ng/mL, and 20 mg/month: 2436.3 ng/mL. Mean CSF bapineuzumab concentrations at month 12 or ET were 0.75, 1.92, and 5.37 ng/mL for the 2, 7, and 20 mg/month dose groups, respectively.

A dose-dependent increase in plasma Aβ concentrations was observed in bapineuzumab groups at month 12 (data not shown). Plasma Aβ concentrations in the placebo group were consistent at baseline and month 12.

Imunogenicity

No patient had serum anti-bapineuzumab antibodies detected at any timepoint. CSF samples were not analyzed for anti-bapineuzumab antibodies as no serum antibody assay was positive.

DISCUSSION

This study was conducted to determine the long-term effects of monthly SC injections of bapineuzumab (2, 7, and 20 mg/month), as compared with placebo, on cerebral amyloid PET signal and the incidence of ARIA-E in patients with mild to moderate AD. The planned 24-month duration of bapineuzumab treatment in this study was to be longer than that evaluated in other Phase II and III bapineuzumab studies (18 months). However, due to the truncation of treatment at 12 months, this objective could not be achieved.

Three doses (2, 7, and 20 mg/month) of SC bapineuzumab tested in this study were selected on the basis of previous clinical trials of bapineuzumab [3 , 9]. The 2 mg/month dose was selected to explore whether a lower dose might have a lower incidence and severity of ARIA-E and yet reduce fibrillar Aβ load. The 7 mg/month and 20 mg/month doses were selected to match the exposure of the two IV dose levels (0.15 and 0.5 mg/kg, respectively) that exhibited significant biological activities in previous Phase II studies [2, 9]. When it was observed that the dosages of 0.5 and 1.0 mg/kg in the Phase III studies failed to show efficacy, the SC doses evaluated in this study were judged unlikely to be efficacious and the study was truncated [3].

Cerebral amyloid is a key neuropathological feature of AD. In this study, no statistically significant difference was observed between any dose of bapineuzumab and placebo with respect to the reduction in florbetapir PET GCA SUVR at month 12 from baseline in the planned analyses. The florbetapir PET GCA SUVR at month 12 showed a statistically significant reduction from baseline for only the 7 mg/month dose, with no evidence of a dose-related trend. This may be due to the duration of SC bapineuzumab treatment (reduced from 24 months to 12 months), which is less than the duration (78 weeks) that was found to be effective in reducing PET SUVR in previous studies of IV bapineuzumab [3]. Other possible reasons include the low dosage range that was evaluated [3] and an underestimation of the required sample size, which was calculated based on data from only one study [2].

The bapineuzumab clinical development program was comprised of a number of Phase I, II, and III studies using an IV route of administration. In Phase III clinical trials, APOE *E4 carriers (bapineuzumab 0.5 mg/kg or placebo) and non-carriers (bapineuzumab 0.5, 1.0, and 2.0 mg/kg or placebo) were treated with 6 infusions at 13-week intervals for 18 months. Treatment emergent ARIA-E occurred in 15.8% and 0.8% of bapineuzumab and placebo treated patients. The majority of ARIA-E cases were mild and asymptomatic. ARIA-E was associated more frequently at higher doses and in APOE *E4 carriers and the 2 mg/kg dose was terminated early due to ARIA-E [3]. The monthly administration of 20 mg of bapineuzumab SC expected to yield a total exposure (AUC) was comparable to the infusion of 0.5 mg/kg of bapineuzumab IV at 3 month intervals, but with lower peak and higher trough levels as compared to bapineuzumab IV. Hence SC doses may have a better safety profile as compared to IV administration at the same systemic exposure due to a slower rate of drug absorption from the dermis layer with lower peak levels.

The results of this study demonstrated that all the three doses (2, 7, and 20 mg/month) of SC bapineuzumab once monthly were generally safe and well tolerated over 12 months. Overall, the incidence of ARIA-E was numerically lower than had been expected based on comparable exposures from IV dosing at 13-week intervals. ARIA-E occurred in 1 patient (2.7%) in the 2 mg group who received drug throughout ARIA-E, and in 1 patient (2.7%) in the 20 mg group who had interruption of bapineuzumab administration. ARIA-E was asymptomatic and mild in severity in both cases. Monthly administered SC bapineuzumab 7 mg did not produce any cases of ARIA-E, while the comparable 0.15 mg/kg IV dosage administered at 13-week intervals in two previous Phase II studies [10] produced ARIA-E in 7% of patients. Similarly, the incidence of ARIA-E was numerically lower with SC bapineuzumab 20 mg once monthly (carriers: 0%; noncarriers: 2.7%) than with the comparable 0.5 mg/kg IV dosage administered at 13-week intervals (9.8% in pooled APOE*E4 carriers and noncarriers in Phase II [10], and 21.2% in APOE*E4 carriers and 5.6% in noncarriers in the Phase III studies [11].

It is unlikely that truncation of the SC study had a significant effect on the incidence proportion of ARIA-E, since the majority of cases have been shown to occur early in immunotherapy studies. The lower incidence of ARIA-E in this study, in part, appears to be related to the different PK profiles of SC and IV bapineuzumab. While the AUC were comparable between corresponding SC and IV doses of bapineuzumab, the SC administration resulted in 4-fold lower steady state peak concentrations. We are not aware of published studies comparing the safety profiles of SC route to IV administration of a monoclonal antibody in AD. Winblad et al. [12] evaluated safety and tolerability of CAD106, an anti-amyloid vaccine designed to induce Aβ-specific antibodies by subcutaneous injection; however, there was no comparison to an alternative route of administration.

There were no anti-bapineuzumab antibodies detected in any of the serum samples tested in this study, suggesting a low immunogenic potential for bapineuzumab [9]. While the overall proportions of patients with any TEAE, with TEAEs considered related to study drug, and with serious AEs were less common for placebo, tolerability appeared equivalent, as the proportion of patients with TEAEs leading to discontinuation was higher in the placebo group than in the bapineuzumab groups. A majority of the TEAEs were mild or moderate in severity, and neither of the 2 deaths (one of which occurred in a patient who was receiving placebo) was considered related to the study drug by the investigator.

No evidence was found to support an effect of SC bapineuzumab on reducing fibrillar amyloid burden. However the truncation of the bapineuzumab treatment to 12 months, with the resultant reduction in cumulative exposure, would have reduced the ability to detect treatment differences.

Conclusion

The results of this truncated study did not demonstrate any clinically significant differences between placebo and once-monthly SC bapineuzumab 2, 7, or 20 mg for 12 months on change in cerebral amyloid signal from baseline. The study was originally powered to detect treatment differences at 24 months; however, study truncation reduced the exposure to the study drug, which potentially reduced the ability to detect treatment differences. Despite the requirement for all patients to have PET evidence of cerebral amyloid pathology at baseline, the incidence proportion of ARIA-E was numerically lower in this study than in prior studies of IV bapineuzumab. Bapineuzumab exhibited dose-proportional pharmacokinetics. Overall, 2, 7, and 20 mg/month doses of SC bapineuzumab were generally well tolerated and no new safety concerns were detected.

Footnotes

ACKNOWLEDGMENTS

The study presented in this report was sponsored by Janssen Alzheimer Immunotherapy Research & Development, LLC and Pfizer Inc. We acknowledge Dr. Vaibhav R. Deshpande (SIRO Clinpharm Pvt. Ltd.) for providing writing assistance and Dr. Bradford Challis (Janssen Research & Development, LLC) for additional editorial support for the development of this manuscript. The writing assistance was funded by Janssen Research & Development, LLC. The authors also thank the study participants, without whom the studies would never have been accomplished.

Authors’ disclosures available online ().

Appendix

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