Two Phase 2 Multiple Ascending–Dose Studies of Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate Alzheimer’s Disease

Abstract

Vanutide cridificar (ACC-001), an immunotherapeutic vaccine, is a potentially disease-modifying therapy that aims to reduce brain amyloid-β (Aβ) plaques in patients with Alzheimer’s disease (AD). ACC-001 was evaluated in two phase 2a, multicenter, randomized, third party–unblinded, placebo-controlled, multiple ascending–dose studies of ACC-001 (3μg, 10μg, 30μg) with and without QS-21 adjuvant that enrolled patients with mild-to-moderate AD (n = 245). Patients were treated with up to five doses of study vaccine or placebo and followed for safety and tolerability (primary objective) and anti-Aβ IgG immunogenicity (secondary objective) up to 12 months after the last vaccination. Exploratory assessments included cognitive/functional measures, brain magnetic resonance imaging (MRI) volumetry, and pharmacodynamic markers in plasma and cerebrospinal fluid (CSF). The most frequent treatment-emergent adverse events (≥10%) were local injection reactions and headache. Amyloid-related imaging abnormalities with vasogenic edema occurred in two (0.8%) patients (ACC-001 30μg + QS-21; ACC-001 10μg). ACC-001 + QS-21 elicited consistently higher peak and sustained anti-Aβ IgG titers compared with ACC-001 alone. Plasma Aβ_x–40 was significantly higher in all ACC-001 + QS-21 groups versus placebo (weeks 16–56), with no evidence of dose response. Exploratory cognitive evaluations, volumetric brain MRI, and CSF biomarkers did not show differences or trends between treatment groups and placebo. ACC-001 with or without QS-21 adjuvant has an acceptable safety profile in patients with mild-to-moderate AD.

Keywords

Active immunization Alzheimer’s disease amyloid-β peptides amyloid-β protein amyloid plaques clinical trial immunotherapy

INTRODUCTION

The predominant component of senile plaques in Alzheimer’s disease (AD) is amyloid-β (Aβ) peptide, particularly a 42-amino acid isoform (Aβ_1–42) derived from a larger amyloid-β protein precursor [1, 2]. Genetic and pathologic evidence support a role for aberrant production or clearance of Aβ in the genesis of AD [1 , 4].

Immune-mediated interventions with vaccine immunotherapy directed against Aβ have induced a polyclonal response and only require periodic administration compared with monoclonal antibodies (passive immunotherapy), which require infusion and have to be given frequently [5, 6]. Clinical studies of vaccine immunotherapy with the full-length Aβ_1–42 peptide (AN1792) in patients with mild-to-moderate AD demonstrated some encouraging findings, including reduced Aβ plaque accumulation in several brain regions in immunized patients compared with nonimmunized patients on autopsy [7 –13], benefits on some cognitive and memory measures, and reductions in cerebrospinal fluid (CSF)-tau among antibody responders. These responses were seen in post-hoc analyses of the phase 2a study that was halted due to the occurrence of meningoencephalitis in approximately 6% of AN1792-treated patients, which was thought to be caused by an Aβ-directed cytotoxic T-cell response to a major T-cell antigenic epitope within the carboxyl portion of Aβ_1–42 [6 , 14–16].

Therefore, a novel peptide-carrier protein conjugate using an amino-terminal fragment of Aβ (Aβ_1–7) was developed to avoid potentially harmful T-cell responses while maintaining an antibody response similar to that of AN1792 [6]. Vanutide cridificar (ACC-001), a construct consisting of multiple Aβ_1–7 peptides conjugated to the CRM₁₉₇ carrier protein, produced measurable anti-Aβ antibody responses in nonhuman primates without evidence of anti-Aβ T-cell responses when injected alone or with QS-21 adjuvant [17]. Safety, tolerability, and immunogenicity of ACC-001 with or without QS-21 adjuvant were demonstrated in two phase 2 studies in Japanese patients with mild-to-moderate AD using slightly different administration schedules [18] and a phase 1 single ascending–dose study in the United States (unpublished).

This paper reports on the planned pooled analysis of two phase 2 studies of ACC-001 immunization in patients with mild-to-moderate AD, one conducted in the European Union and one in the United States. The primary objective was to assess safety and tolerability of ACC-001 with or without QS-21 over 1 year of treatment followed by 6–12 months of follow-up after the last injection of investigational product, for a maximum of 2 years. The secondary objective was to evaluate immunogenicity of ACC-001 with or without QS-21 adjuvant. Exploratory endpoints included cognitive and functional measures, brain magnetic resonance imaging (MRI) volumetry, CSF biomarkers, and plasma Aβ_x–40.

MATERIALS AND METHODS

Patients

Two phase 2a, multicenter, randomized, third-party–unblinded, adjuvant- and placebo-controlled, multiple ascending–dose, safety, tolerability, and immunogenicity studies of ACC-001 with and without QS-21 adjuvant enrolled patients with mild-to-moderate AD dementia at 17 sites in the European Union and 13 sites in the United States beginning in May 2007, with the last subject visit in February 2013. Inclusion and exclusion criteria were consistent with previous immunotherapy studies in AD (Supplementary Table 1) [14, 19]. Key inclusion criteria were age 50–85 years; probable AD per the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association [20]; Mini-Mental State Examination (MMSE) score [21] of 16–26 (21–26 in Germany only); and screening brain MRI consistent with AD diagnosis. Acetylcholinesterase inhibitors or memantine were permitted if the dose was stable for at least 120 days prior to baseline. Patients were stratified by MMSE score of moderate AD (16–20) or mild AD (21–26) at randomization.

Randomization and masking

Patients were randomized to receive either placebo or one of three dose levels of ACC-001 (3, 10, or 30μg) with or without QS-21 adjuvant (50μg) in an escalating cohort design. Phosphate-buffered saline (PBS) served as control for the ACC-001– alone groups; QS-21 alone was control for ACC-001 + QS-21 groups. The following randomization ratios were used: Dosage Level 1, 36:12 ACC-001 (3μg) + QS-21 (50μg):QS-21 (50μg); Dosage Level 2, 60:20:12:36 ACC-001 (10μg) + QS-21 (50μg):QS-21 (50μg):ACC-001 (10μg):PBS; Dosage Level 3, 36:12:4:12 ACC-001 (30μg) + QS-21 (50μg):QS-21 (50μg):ACC-001 (30μg):PBS. A “pioneer” strategy allowed safety evaluation by an external data monitoring committee (eDMC) of the first third of patients in each dosage level before dosing all patients and proceeding to the next higher dosage level. Interim analyses indicated that QS-21 may be required for optimal immune responses; hence, ACC-001– alone dosages were removed. All parties were blinded to treatment allocation except for the dispensing pharmacists, who were not involved in patient evaluation.

Both studies were approved by the central or local institutional review board and/or independent ethics committee; written informed consent was obtained from patients or legally authorized representatives and caregivers.

Procedures

Investigational product was administered by intramuscular injection on day 1 and at months 1, 3, 6, and 12. According to a PBS substitution rule, if levels of anti-Aβ IgG reached 4000 U/mL 2 weeks prior to each immunization at month 3, 6, or 12, PBS was substituted for the active immunization to limit anti-Aβ antibody titers raised in response to active immunization with ACC-001, in order to avoid potentially boosting the titer to a level that might be associated with an increased risk of adverse events (AEs). Interim analyses of safety and immunogenicity results indicated that this approach was unnecessary; therefore, PBS substitution discontinued in cohort 4. Patients were followed for safety, immunogenicity, and all other exploratory outcomes for up to 12 months after the last immunization. Patients who completed 6-month (12-month for cohort 1) follow-up after the last immunization and met eligibility criteria could be entered into a long-term extension study (European Union: NCT00955409; United States: NCT00960531).

Outcomes

Safety assessments included brain MRIs conducted at baseline, before each injection, and at the end of study. Except in France, central readings were performed only on baseline MRIs to assess eligibility or when a local reader observed a brain MRI abnormality; all brain MRIs in France had a central safety reading at each subsequent visit. Treatment-emergent AEs of special circumstance (AESCs) were to be reported as a serious AE within 24 hours of investigator awareness, whether they were considered serious or not, including amyloid-related imaging abnormalities of edema/effusion (ARIA-E), intracranial and cerebral hemorrhage, vasculitis, and immune-mediated events following investigational product injection (anaphylaxis, angioedema, urticaria, and clinical syndrome diagnostic of serum sickness). Blood samples were analyzed for T-cell reactivity using enzyme-linked immunosorbent spot (ELISPOT) assays at baseline, week 26, and week 56 (US study only) [6].

Anti-Aβ IgG titers were measured at multiple time points, including at baseline, 2 weeks before and after each immunization, and 12 months after the last immunization, by qualified enzyme-linked immunosorbent assay (ELISA).

Exploratory assessments of cognitive and functional endpoints, changes in brain MRI volume, and plasma and CSF biomarkers are summarized in Supplementary Table 2.

Statistical analyses

As the study design and data collection of the two studies were the same, data from both studies were analyzed together as planned. Descriptive summary statistics are provided for safety and immunogenicity results. Safety analyses were conducted on the safety population, which included all randomized patients who received at least one injection of investigational product. Immunogenicity analysis was conducted on the immunogenicity population, defined as all randomized patients who received at least one injection of investigational product and had at least one immunogenicity data point. Statistical analyses of the exploratory cognitive, functional, and biomarker endpoints are summarized in the respective data tables and described in Supplementary Table 2.

RESULTS

Patients

Of the 245 patients randomized, 184 patients were to receive ACC-001 alone or with QS-21, 44 were to receive QS-21 alone, and 17 were to receive PBS only (Fig. 1). More than 60% of patients overall completed 12 months of treatment and 6 months of follow-up (Fig. 1). The primary reasons for discontinuation were treatment-emergent AEs (TEAEs) (6.5%), patient request (4.5%), caregiver request (3.7%), and “other” (3.7%). Treatment groups were generally balanced with respect to age, race, duration of AD, and MMSE score (Table 1). Overall, 65% of subjects were from the United States and 35% from the European Union.

Safety and tolerability

TEAEs due to any cause occurred in 92.6% of patients and had comparable incidence across treatment groups. The most frequently reported TEAEs (Table 2) were local injection reactions and headache. Injection site pain was reported by a higher percentage of patients in the ACC-001 + QS-21 group (24.3%) than in the ACC-001– alone and control (QS-21 alone and PBS) groups (10.6% and 9.8%, respectively).

Injection site reactions were experienced by 27.9% of patients. The most frequent injection site reactions were injection site pain (16.8%), injection site erythema (9.4%), injection site swelling (6.6%), and headache (5.3%). Most injection reactions (82.4%) were mild in severity, transient (1–7 days), and did not appear to be dose dependent.

AEs resulted in discontinuation of investigational product or withdrawal from study in 7.4% of patients. The most frequent AE leading to discontinuation/withdrawal was myocardial infarction in two (0.8%) patients (one patient each in the 3-μg and 10-μg ACC-001 + QS-21 groups); these events were not considered treatment related.

Two deaths occurred during the study, one following cardiac arrest in the ACC-001 10μg + QS-21 group and one due to metastatic lung cancer in the QS-21– alone group. Neither event was considered related to investigational product. Serious TEAEs were experienced by 17.2% of patients, and serious treatment-related TEAEs occurred in 3.3% of patients. Two (0.8%) patients from ACC-001 groups had asymptomatic (one patient) and symptomatic (one patient) ARIA-E; all other TEAEs were similar between ACC-001 treatment and placebo groups.

Treatment-related ARIA-E occurred in two (1.1%) of the 183 patients who received ACC-001 with or without QS-21 adjuvant (see Table 3 for patient characteristics). Asymptomatic ARIA-E was first detected on a routine MRI at week 78, 6 months after the fifth injection of ACC-001 30μg + QS-21. The patient was treated with methylprednisolone 500 mg/day for 3 days with resolution of ARIA-E on an MRI conducted less than 3 weeks later. The second patient developed symptomatic ARIA-E, which was first observed 65 days after the third injection of ACC-001 10μg alone on an unscheduled MRI conducted because of increased frequency and intensity of intermittent headaches. ARIA-E was not treated; symptoms resolved within 19 days and ARIA-E was considered resolved on MRI 404 days later.

Vasculitis was reported in one patient who received a total of three injections of ACC-001 3μg + QS-21 (Table 3). As preinjection anti-Aβ IgG titer was high (45,264 U/mL), the fourth injection was substituted with PBS. One hundred forty-eight days after the third injection of ACC-001 3μg + QS-21, the patient was hospitalized with ulcerative skin lesions, primarily of the feet, which the investigator reported as a serious AE of moderate vasculitis. However, biopsy of the lesion did not reveal histopathologic evidence of vasculitis consistent with review by the sponsor and an eDMC. The lesions resolved in less than 3 months and the patient was followed for safety and immunogenicity assessments for approximately 35 months after the event.

The IFN-γ ELISPOT assays conducted at week 26 with peripheral blood mononuclear cells did not show evidence of T-cell activation when stimulated with Aβ_1–7, Aβ_1–10, Aβ_1–15, Aβ_1–42, or CRM₁₉₇. None of the patients evaluated for cytotoxic T-cell responses because of a suspected or confirmed AESC showed evidence of T-cell responses.

Immunogenicity

Clear geometric mean anti-Aβ IgG titer increases from baseline compared with placebo after the first immunization was seen only in the ACC-001 + QS-21 10μg and 30μg treatment groups, and after the second immunization in the ACC-001 3μg + QS-21 and ACC-001– alone 10μg and 30μg groups (Fig. 2). Anti-Aβ IgG levels were consistently higher in the ACC-001 + QS-21 treatment groups compared with the ACC-001 alone treatment groups, and there was evidence of an ACC-001 dose response; however, there was substantial within-group variability in anti-Aβ IgG titer. The longevity of the responses could not be evaluated, as patients were eligible to enter the extension studies at week 78 to continue treatment, which greatly reduced sample size at week 104.

Exploratory efficacy assessments

Cognitive and functional endpoints

There were no statistically significant differences in change from baseline to week 78 in any of the cognitive or functional assessments (Alzheimer’s Disease Assessment Scale–Cognitive Total Score, Clinical Dementia Rating Sum of Boxes, Disability Assessment for Dementia, MMSE, Neuropsychiatric Inventory, and Neuropsychological Test Battery) between the ACC-001 + QS-21 or ACC-001– alone and control groups (Supplementary Fig. 1). No significant differences were observed in subgroup analyses based on disease severity (MMSE strata) or apolipoprotein E (APOE) ɛ4 carrier status (data not shown).

Pharmacodynamic markers

There were no statistically significant differences between active treatment groups and control in brain volume changes from baseline to week 78 (Table 4). There were no statistically significant differences between active treatment groups and control in CSF Aβ_x–40, Aβ_x–42, p-tau, or total tau changes from baseline to week 50 (Table 5). The least squares mean percentage change from baseline in plasma Aβ_x–40 in the ACC-001 + QS-21 group was significantly higher than controls from week 16 (35.1%, p < 0.001) through week 56 (86.8%, p < 0.001). No dose relation was apparent. No significant differences between ACC-001 alone and control were observed in plasma Aβ_x–40 change from baseline at any time point.

No exposure-response relations were demonstrated between IgG titer levels and cognitive or functional efficacy results, or between IgG titer levels and biomarker results (data not shown).

DISCUSSION

This study demonstrated an acceptable tolerability and safety profile for active treatment. Tolerability is comparable to licensed prophylactic vaccines in elderly subjects, with injection site pain more commonly observed in ACC-001 + QS-21 groups. The observed incidence of ARIA-E in patients who received ACC-001 in this study (1.1%) is lower than rates reported in the prospective safety read of phase 3 studies of bapineuzumab (4.2–15.3%) [19], which was even higher in the central retrospective MRI read (5.6–21.2%). The centrally read ARIA-E rate reported for solanezumab was also low (0.9%) [22], although the rate in this study may have been underestimated without central reading of all scans and the possibility that not all patients had evidence of amyloid pathology, as neither positron emission tomography (PET) or CSF assessments were used as screening criteria. Approximately 10–20% of patients with a clinical diagnosis of AD do not have significant amyloid pathology at postmortem [23, 24]; in other immunotherapy trial reports, up to 36% of APOE ɛ4 noncarriers and 6.5% of APOE ɛ4 carriers were amyloid-negative at baseline on PiB PET [19]. Baseline CSF biomarker concentrations (Aβ_x–40, Aβ_x–42, p-tau, and total tau) were within the range of the overall study population and may not be predictive of risk for developing ARIA-E. In addition, one of the two patients with ARIA-E had no measurable anti-Aβ IgG response.

ACC-001 appears to generate an Aβ-directed B-cell response without putatively deleterious T-cell responses observed with AN1792 [15], which is consistent with the design of ACC-001 to include a peptide (Aβ_1–7) too small to elicit specific Aβ T-cell responses. Such results extend findings from preclinical studies of ACC-001, which demonstrated that nonhuman primates immunized with ACC-001 did not show evidence of anti-Aβ T-cell activity [17] and are consistent with clinical findings from studies of CAD106, an anti-amyloid vaccine that includes the peptide Aβ_1–6 [25].

ACC-001 + QS-21 elicited a robust immune response at the low (3μg), medium (10μg), and high (30μg) dose levels as expressed by anti-Aβ IgG titers, with some evidence for a dose response. The long-term extension studies will evaluate the duration of antibody titers and response to boosting.

Exploratory clinical efficacy in this study revealed no differences or trends between treatment groups for changes from baseline in cognitive and functional assessments, but the study was not powered to detect any meaningful differences in the clinical endpoints. Brain atrophy was similar to that observed in other AD studies (19–21 mL/year) [19, 26]. Previous studies have shown greater brain loss in patients with AD treated with anti-amyloid immunotherapy [26]; in this study, although not significantly different, the brain volume loss in the ACC-001 + QS-21 group was 10% higher than in the placebo group. Aβ_x–40 binding was demonstrated to antibody generated by ACC-001 + QS-21, as was also demonstrated following immunization with CAD106, but was lower than for monoclonal antibodies [22 , 27–29]. While it is known that monoclonal antibodies cross the blood-brain barrier [30, 31], central nervous system (CNS) titers elicited by ACC-001 were not measured in this study. No exposure-response relations were demonstrated between anti-Aβ IgG levels and cognitive or functional efficacy results, or between anti-Aβ IgG levels and biomarker results (data not shown). Although the IgG titers in response to ACC-001 + QS-21 were high in the current studies, the threshold, affinity, and duration of antibody exposure required for a clinical response is unknown.

Because the current study did not use biomarkers to confirm AD diagnosis, a potential 25% error rate in AD diagnosis [32] and nonresponse in the amyloid-negative patients to an amyloid-targeting agent is possible. Alternatively, patients with mild-to-moderate AD may have disease too advanced to benefit from the ACC-001 elicited immune response, as Aβ overproduction and plaque deposition is thought to be an early event in AD development [1]. Subgroup analyses of bapineuzumab and solanezumab phase 3 trials showed clinical benefits only in subsets of patients with mild AD [19, 22]. Phase 2 studies of CAD106 in mild AD did not show benefits on cognitive endpoints despite most patients achieving an anti-Aβ antibody response; however, sample sizes were small [25]. Recently completed ACC-001 amyloid PET imaging studies in early and mild-to-moderate AD may have the appropriate patient population to assess if CNS target engagement can occur by ACC-001 + QS-21– elicited anti-Aβ antibodies.

STUDY INVESTIGATORS

Prof. Anne-Sophie Rigaud, Dr. Catherine Bayle, Dr. Olivier Hanon, Florence Latour, Dr. Hermine Lenoir, Dr. Jean-Bernard Mabire, Dr. Marie-Laure Seux, Groupe Hospitalier Broca-La Rochefoucauld, Centre de Gérontologie, Paris, France; Dr. Bruno Dubois, Dr. Jean-Christophe Corvol, Dr. Leonardo Cruz De Souza, Dr. Stephane Epelbaum, Dr. Michel Kalafat, Dr. Sara Leder, Dr. Stephane Lehericy, Dr. Marie Sarazin, Dr. Marc Teichmann, Claude Zacharias, Hôpital Pitié-Salpétrière, Bâtiment IM2A, Paris, France; Prof. Bruno Vellas, Dr. Amir Ait-Ameur, Philippe Bartoli, Catherine Faisant, Dr. Francoise Lala, Genevieve Lau, Pierre-Jean Ousset, Dr. Nathalie Sastre, CHRU PURPAN - Medecine Interne et Gerontologie Clinique Pavillon J.P. Junod –170, Toulouse, France; Dr. Sophie Auriacombe, Prof. Jean-Francois Dartigues (previous PI), Dr. Véronique Cressot, Dr. Maritchu Doireau, Alexandra Foubertsamier, Dr. Tsouria Gaida-Rostane, Dr. Isabelle Marcet, Dr. Isabelle Marcet, CHU Pellegrin, Bâtiment USN Tastet-Girard, Centre Mémoire de Recherche et de Ressources, Bordeaux Cedex, France; Dr. Bernard Francois Michel, Dr. Marie Noelle Lefebvre, Dr. Frank Rouby, Hopital Sainte Marguerite - Service de Neurologie Unite de Neurogeriatrie, Marseille, France; Dr. Jacques Touchon, Karim Bennys, Dr. Audrey Gabelle, Dr. Sandrine Lerouge, CHU Hopital Gui de Chaulliac Unite de Neurologie Comportementale, Montpellier, France; Prof. Florence Pasquier, Dr. Stephanie Bombois, Vincent Deramecourt, Dr. Marie Anne Mackowiak, Dr. Marion Paulin, Dr. Adeline Rollin-Sillaire, CHRU de Lille, Hopital Roger Salengro Secteur Neurologie et Centre de la Memoire, Lille Cedex, France; Dr. Oliver Peters, Dr. Agota Barabassy, Prof. Isabella Heuser, Dr. Britta Jaenen, Dr. Klaus-Peter Kuhl, Dr. Alexander Luborzewski, Dr. Christian Tobias Moeller, Catherine Oliver, Christiane Schwintzer, Klinik für Psychiatrie und Psychotherapie, Charite Universitätsmedizin Berlin Campus Benjamin Franklin, Berlin, Germany; Prof. Dr. Michael Huell, Sonja Gerber, Dr. Bernhard Heimbach, Dr. Iris Kaupp, Dr. Stefan Kloeppel, Dr. Brigitta Metternich, Dr. med. Berit Prinz, Dr. Johannes Schlachetzki, Dr. Klaus Schmidtke, Christina Stienissen, Dr. med Meike Terhorst, Zentrum für Geriatrie u. Gerontologie Freiburg Neurogeriatrie und Memory-Ambulanz Universitätsklinikum Freiburg, Freiburg, Germany; Prof. Dr. Lutz Froelich, Christine Bergmann, Kathrin Herold, Daniel Hüger, Carolin Knorr, Dr. Daniel Kopf, Gudrun Schulte-Brochterbeck, Roger Seitz, Jochen Stien, Dr. Magda Syren, Shama Thorvaldsen, Dr. Robert Waltereit, Abteilung für Gerontopsychiatrie Zentralinstitut für Seelische Gesundheit Mannheim Universität Heidelberg J5, Mannheim, Germany; Prof. Dr. Alexander, Friedrich Kurz, Dr. Timo Grimmer, Dr. Marion Ortner, Robert Georg Perneczky, Dr. Christian Sorg, Technische Universität München, Klinikum rechts der Isar Klinik für Psychiatrie und Psychotherapie, München, Germany; Prof. Dr. Peter Young, Dorothea Bracht, Dr. Michael Heneka, Prof. Stefan Knecht, Dr. Hubertus Lohmann, Marcus Müller, Dr. Julia Reinholz, Dr. Heike Wersching, Universitätsklinikum Muenster Klinik und Poliklinik für Neurologie, Muenster, Germany; Dr. Anja Schneider, Sabine Anton, Dr. Mirko Bibl, Susanne Döhlinger, Dr. med. Katrin Gade, Dr. Sibylle Haefner, Dr. Uta Heinemann, Dr. Imke Hoell, Dr. Karen Maertens, Klaus Magdeburg, Kiriaki Mavridou, Ulrike Muehlhaeuser, Dr. med. Hannah Luise Pellkofer, Dr. med. Berit Prinz, Dr. Katrin Elisabeth Radenbach, Dr. Arno Reich, Susanne Gabriele Siribuor, Dr. Gerthild Stiens, Klinik fär Psychiatrie und Psychotherapie Universitätsklinikum Georg-August-Universität, Goettingen, Germany; Dr. Jose Luis Molinuevo Guix, Magda Castellvi Sampol, Dr. Juan Fortea, Dr. Albert Llado Plarrumani, Dr. Jaume Olives Cladera, Lorena Rami Gonzalez, Dr. Raquel Sanchez del Valle Diaz, Cristina Sole Padulles, Hospital Clinico y Provincial Servicio de Neurologia, ICN. Planta 4 Escalera 8, Barcelona, Spain; Dr. Pedro Gil Gregorio, Dr. Jose M. Ribera-casado (previous PI), Dr. Alan Albarracin Delgado, Dr. Ariadna Besga Basterra, Dr. Monica Chung Jaen, Dr. Marisa Covarrubias Esquer, Jesus Criado Rios, Isabel Cruz Orduña, Antonio Rodriguez Calvo, Dr. Francisco Soria, Dr. Claudia Teran Benzaquen, Jara Velasco Garcia-Cuevas, Dr. Aurora Viloria Jimenez, Raquel Yubero Pancorvo, Hospital Universitario Clinico San Carlos, Servicio De Geriatria, Planta Baja, Ala Norte, Madrid, Spain; Dr. Rafael Blesa Gonzalez, Sofia Anton Aguirre, Maria Carmona Iragui, Teresa Gomez-Isla, Dr. Alberto Lleo, Laura Molina, Dr. Anna Pujol, Dr. Anna Maria Pujol Nuez, Dr. Maria del Pilar Sainz Pelayo, Isabel Sala Matavera, Maria Belen Sanchez Saudinos, Amparo Villar Canovas, Hospital de la Santa Creu i Sant Pau, Servicio de Neurología, Pta. 4, Barcelona, Spain; Dr. Jordi Pena-Casanova, Marta Casals Coll, Susana De Sola Llopis, Dr. Carmen Pascual, Sonia Quinones Ubeda, Gonzalo Sanchez Benavides, Hospital del Mar, Unidad de Demencia, Servicio de Neurologia, Barcelona, Spain; Dr. John Carl Morris, Molly Aeschleman, Mary A. Coats, Denise Dreyfus, Dr. James Edward Galvin Jr., Nupur Ghoshal, Joseph Gier, Pamela Jackson, Pamela F. Millsap, Dr. John Albert Morris Jr., Julie Nobbe, Dr. Barbara Joy Snider, Rawan Tarawneh, Christy Tomlinson, Alzheimer’s Disease Research Center Memory and Aging Project, Washington University School of Medicine, St. Louis, Missouri; Dr. Stephen P. Salloway, Betty Blackham, Wendy Fennelly, Michelle L. Gardner, Denise Jerue, Cheryl Kechichian, Patrick Kelley, Paul Malloy, Richard T. Marsland, Christopher J. Maxwell, Nicole C. Robbins Mclaughlin, Diane Medeiros, Kerry L. Mello, Ann E. Mikos, Diane Monast, Irene Piryatinsky, Amy Rangel, Patricia S. Read, Kenneth C. Rickler, Virginia J. Sofios, Dr. Reisa A. Sperling, Butler Hospital, Providence, Rhode Island; Dr. Christopher H. Van Dyck, Babak P. Azar, Nicole M. Barcelos, Carlos R. Beltran, Amanda L. Benincasa, Garrett S. Bowen, Teide Brisibe, Ravi Shankar V. Chivukula, Dr. Juan Carlos Cleves-Bayon, Sarah Jane C. De Asis, Susan P. Good, Samantha K. Henry, Jian Hu, Pilar Laborde-Lahoz, Dr. Martha G. MacAvoy, Marc P. Nespoli, Haakon Nygaard, Shriti Patel, Katherine L. Paturzo, Diana L. Ricitelli, Sarah C. Taylor, Satish Vallabhanei, Michelle D. Vinci, Allison F. Wagner, Norman S. Werdiger, Ilse Wiechers, Sigrid D. Wiemers, Lauren E. Wiznia, Yale University, Alzhemer’s Disease Research Unit, New Haven, Connecticut; Dr. Pierre N. Tariot, Helle Brand, Anna Danuta Burke, Dr. Adam S. Fleisher, Jessica Z. Langbaum, Carolyn Langlois, Dr. James B. Seward, Dr. Sheila Z. Vadovicky, Dr. Roy Yaari, Banner Alzheimer’s Institute, Phoenix, Arizona; Dr. Carl Howard Sadowsky, Dr. Cora P. Kessel, Rosalynn M. Martinez, Dr. Walter C. Martinez, John J. McManus, Dr. Ernesto A. Triana, Dr. Paul K. Winner, Dr. Jose Antonio Zuniga, Premiere Research Institute, West Palm Beach, Florida; Dr. Karen Lynette Bell, Dr. Sarah Janicki (previous PI), Dr. Evelyn Dominguez-Rivera, Dr. Lawrence Sterling Honig, Dr. Sarah Janicki, Lynda Mules, Arelys M. Rocha, Dr. Ruth B. Tejeda, Columbia University College of Physicians and Surgeons/Taub Institute for Research on Alzheimer’s Disease, New York, New York; Dr. Adam Louis Boxer, Katie S. Adams, Cindy F. Barton, Dr. Eric Fine, Kristen Fox, Dr. Darvis Frazier, Jessica Hall, Dr. Mary Koestler, Erwin Kong, Amanda LaMarre, Dr. Suzee E. Lee, Dr. Zachary Adam Miller, Robert Nicholson, Dr. David C. Perry, Dr. Gil Rabinovici, Dr. Howard J. Rosen, Dr. Sharon Sha, Kathryn Sullivan, Dr. Carmela Tartaglia, Dr. Victor George Valcour, Dr. Keith Vossel, Christine Walsh, University of California, San Francisco - Memory and Aging Center Department of Neurology, San Francisco, California; Dr. Kerri Louise Wilks, Damaris Alonso Beatriz Cymbermpf, Dr. Beth Emmie Safirstein, Dr. Alex Nestor Torres, MD Clinical, Hallandale Beach, Florida; Dr. Raymond Scott Turner, Dr. Paul Stephen Aisen, Alice Brown, Kathleen B. Johnson, Brigid A. Reynolds, Georgetown University Medical Center Department of Neurology, Washington, DC; Dr. Marwan Noel Sabbagh, Christine Belden, Dr. Joanne Mary Ceimo, Kathryn J. Davis, Dr. Sandra Ann Jacobson, Elizabeth A. Karoll, Karen Kohl, Jean E. Lopez, Michael Hassan Malek-Ahmadi, Bianca Montalvo, Patricia Narwocki, Zoran Obradov, Amy Rangel, Elliott Schwartz, Dr. Holly Shill, Sun Health Research Institute, Sun City, Arizona; Dr. Scott M. McGinnis, Rebecca E. Amariglio, Brendon Phillip Boot, Nancy J. Donovan, Meghan Frey, Roy Kamolika, Susie Kim, Dr. Gad A. Marshall, Lauren Olson, Dorene M. Rentz, Dr. Reisa A. Sperling, Dr. Martha B. Vander Vliet, Center for Alzheimer Research & Treatment, Brigham & Women’s Hospital, Boston, Massachusetts; Dr. Paul Robert Solomon, Lisa Barlow, Dr. Andrew Ethan Budson, Rita L. Burgher, Megan Casey, Dr. Lisa Karen Catapano-Friedman, Paula D. Levin, David Little, Madeline Machera-Robinson, Mary Pat Mazzola, Diana Michalczuk, Cynthia A. Murphy, Roger Paro, Aaron M. Ramirez, Dr. Martha Stitelman, The Memory Clinic, Bennington, Vermont; Dr. Joel Steven Ross, Dr. Gautam J. Desai, Victoria Dioguardi, Kaycee C. Doyle, Dr. Jose F. Gomez, Dr. Mark Ornstein, Debra Ross, Kelly Wilder-Willis, Memory Enhancement Center of America, Inc., Eatontown, New Jersey, Edison, New Jersey.

SAFETY MONITORING COMMITTEE

Ron Petersen, MD (DMC Chair), Françoise Forette, MD, Sam Gandy, MD, PhD, Cornelia Dekker, MD, Peter A. Lachenbruch, PhD, Stephen C. Dreskin, MD, PhD, Kejal Kantarci, MD, MS.

Footnotes

ACKNOWLEDGMENTS

These studies were sponsored by Pfizer Inc and Janssen Alzheimer Immunotherapy, R&D, LLC. Editorial writing support was provided by Marsha Scott, PhD, at Phase Five Communications, and was funded by Pfizer Inc. The authors would like to extend their appreciation to Ronald Black, MD, for his extensive expertise in Alzheimer’s disease and seminal scientific contribution to the strategy and development of the ACC Program, and Dennis Bahm for his key role in getting the program launched. The authors would also like to extend their thanks to all of the patients and caregivers for their contributions throughout the course of these studies. ClinicalTrials.gov Identifiers: NCT00479557 (EU), NCT00498602 (US); EudraCT #: 2006-002061-39.

Authors’ disclosures available online ().

Appendix

References

Hardy

, Selkoe

(2002) The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science 297, 353–356.

Selkoe

(2011) Alzheimer’s disease. Cold Spring Harb Perspect Biol 3, pii–a004457.

Bateman

, Xiong

, Benzinger

, Fagan

, Goate

, Fox

, Marcus

, Cairns

, Xie

, Blazey

, Holtzman

, Santacruz

, Buckles

, Oliver

, Moulder

, Aisen

, Ghetti

, Klunk

, McDade

, Martins

, Masters

, Mayeux

, Ringman

, Rossor

, Schofield

, Sperling

, Salloway

, Morris

; Dominantly Inherited Alzheimer Network (2012) Clinical and biomarker changes in dominantly inherited Alzheimer’s disease [Erratum, N Engl J Med 2012; 780]. N Engl J Med 367, 795–804.

Karran

, Mercken

, De Strooper

(2011) The amyloid cascade hypothesis for Alzheimer’s disease: An appraisal for the development of therapeutics. Nat Rev Drug Discov 10, 698–712.

Schenk

(2002) Amyloid-beta immunotherapy for Alzheimer’s disease: The end of the beginning. Nat Rev Neurosci 3, 824–828.

Pride

, Seubert

, Grundman

, Hagen

, Eldridge

, Black

(2008) Progress in the active immunotherapeutic approach to Alzheimer’s disease: Clinical investigations into AN1792-associated meningoencephalitis. Neurodegener Dis 5, 194–196.

Nicoll

, Wilkinson

, Holmes

, Steart

, Markham

, Weller

(2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: A case report. Nat Med 9, 448–452.

Ferrer

, Boada Rovira

, Sánchez Guerra

, Rey

, Costa-Jussá

(2004) Neuropathology and pathogenesis of encephalitis following amyloid-β immunization in Alzheimer’s disease. Brain Pathol 14, 11–20.

Masliah

, Hansen

, Adame

, Crews

, Bard

, Lee

, Seubert

, Games

, Kirby

, Schenk

(2005) Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 64, 129–131.

10.

Bombois

, Maurage

, Gompel

, Deramecourt

, Mackowiak-Cordoliani

, Black

, Lavielle

, Delacourte

, Pasquier

(2007) Absence of beta-amyloid deposits after immunization in Alzheimer disease with Lewy body dementia. Arch Neurol 64, 583–587.

11.

Holmes

, Boche

, Wilkinson

, Yadegarfar

, Hopkins

, Bayer

, Jones

, Bullock

, Love

, Neal

, Zotova

, Nicoll

(2008) Long-term effects of Aβ₄₂ immunisation in Alzheimer’s disease: Follow-up of a randomised, placebo-controlled phase I trial. Lancet 372, 216–223.

12.

Boche

, Denham

, Holmes

, Nicoll

JAR

(2010) Neuropathology after active Aβ42 immunotherapy: Implications for Alzheimer’s disease pathogenesis. Acta Neuropathol 120, 369–384.

13.

Serrano-Pozo

, William

, Ferrer

, Uro-Coste

, Delisle

, Maurage

, Hock

, Nitsch

, Masliah

, Growdon

, Frosch

, Hyman

(2010) Beneficial effect of human anti-amyloid-β active immunization on neurite morphology and tau pathology. Brain 133, 1312–1327.

14.

Gilman

, Koller

, Black

, Jenkins

, Griffith

, Fox

, Eisner

, Kirby

, Rovira

, Forette

, Orgogozo

; AN1792(QS-21)-201 Study Team (2005) Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64, 1553–1562.

15.

Orgogozo

, Gilman

, Dartigues

, Laurent

, Puel

, Kirby

, Jouanny

, Dubois

, Eisner

, Flitman

, Michel

, Boada

, Frank

, Hock

(2003) Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61, 46–54.

16.

Cribbs

, Ghochikyan

, Vasilevko

, Tran

, Petrushina

, Sadzikava

, Babikyan

, Kesslak

, Kieber-Emmons

, Cotman

, Agadjanyan

(2003) Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with beta-amyloid. Int Immunol 15, 505–514.

17.

Hagen

, Seubert

, Jacobsen

, Schenk

, Pride

, Arumugham

, Warner

, Kinney

(2011) The Aβ peptide conjugate vaccine, acc-001, generates n-terminal anti-Aβ antibodies in the absence of Aβ directed t-cell responses. Alzheimers Dement 7, S460–S461.

18.

Arai

, Suzuki

, Yoshiyama

, Lobello

, Peng

, Liu

, Ketter

, Margolin

, Jackson

, Fujimoto

(2013) Safety, tolerability and immunogenicity of an immunotherapeutic vaccine (vanutide cridificar [ACC-001]) and the QS-21 adjuvant in Japanese individuals with mild-to-moderate Alzheimer’s disease: A phase IIa, multicenter, randomized, adjuvant and placebo clinical trial. Alzheimers Dement 9, 282.

19.

Salloway

, Sperling

, Fox

, Blennow

, Klunk

, Raskind

, Sabbagh

, Honig

, Porsteinsson

, Ferris

, Reichert

, Ketter

, Nejadnik

, Guenzler

, Miloslavsky

, Wang

, Lu

, Lull

, Tudor

, Liu

, Grundman

, Yuen

, Black

, Brashear

; Bapineuzumab 301 and 302 Clinical Trial Investigators (2014) Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 370, 322–333.

20.

McKhann

, Drachman

, Folstein

, Katzman

, Price

, Stadlan

(1984) Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34, 939–944.

21.

Folstein

, Folstein

, McHugh

(1975) “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12, 189–198.

22.

Doody

, Thomas

, Farlow

, Iwatsubo

, Vellas

, Joffe

, Kieburtz

, Raman

, Sun

, Aisen

, Siemers

, Liu-Seifert

, Mohs

; Alzheimer’s Disease Cooperative Study Steering Committee, Solanezumab Study Group (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370, 311–321.

23.

Rasmusson

, Brandt

, Steele

, Hedreen

, Troncoso

, Folstein

(1996) Accuracy of clinical diagnosis of Alzheimer disease and clinical features of patients with non-Alzheimer disease neuropathology. Alzheimer Dis Assoc Disord 10, 180–188.

24.

Lim

, Tsuang

, Kukull

, Nochlin

, Leverenz

, McCormick

, Bowen

, Teri

, Thompson

, Peskind

, Raskind

, Larson

(1999) Clinico-neuropathological correlation of Alzheimer’s disease in a community-based case series. J Am Geriatr Soc 47, 564–569.

25.

Farlow

, Andreasen

, Riviere

, Vostiar

, Vitaliti

, Sovago

, Caputo

, Winblad

, Graf

(2015) Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease. Alzheimers Res Ther 7, 23.

26.

Fox

, Black

, Gilman

, Rossor

, Griffith

, Jenkins

, Koller

; AN1792(QS-21)-201 Study (2005) Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology 64, 1563–1572.

27.

Black

, Sperling

, Safirstein

, Motter

, Pallay

, Nichols

, Grundman

(2010) A single ascending dose study of bapineuzumab in patients with Alzheimer disease. Alzheimer Dis Assoc Disord 24, 198–203.

28.

Winblad

, Andreasen

, Minthon

, Floesser

, Imbert

, Dumortier

, Maguire

, Blennow

, Lundmark

, Staufenbiel

, Orgogozo

, Graf

(2012) Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer’s disease: Randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol 11, 597–604.

29.

Adolfsson

, Philgren

, Toni

, Varisco

, Buccarello

, Antoniello

, Lohmann

, Piorkowska

, Gafner

, Atwal

, Maloney

, Chen

, Gogineni

, Weimer

, Mortensen

, Friesenhahn

, Ho

, Paul

, Pfeifer

, Muhs

, Watts

(2012) An effector-reduced anti-β-amyloid (Aβ) antibody with unique Aβ binding properties promotes neuroprotection and glial engulfment of Aβ . J Neurosci 32, 9677–9689.

30.

Bard

, Cannon

, Barbour

, Burke

, Games

, Grajeda

, Guido

, Hu

, Huang

, Johnson-Wood

, Khan

, Kholodenko

, Lee

, Lieberburg

, Motter

, Nguyen

, Soriano

, Vasquez

, Weiss

, Welch

, Seubert

, Schenk

, Yednock

(2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6, 916–919.

31.

Blennow

, Zetterberg

, Rinne

, Salloway

, Wei

, Black

, Grundman

, Liu

; AAB-001 201/202 Investigators (2012) Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch Neurol 69, 1002–1010.

32.

Karran

, Hardy

(2014) Antiamyloid therapy for Alzheimer’s disease— are we on the right road?. N Engl J Med 370, 377–378.