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

Summary

Background

Immunotherapy targeting the amyloid β (Aβ) peptide is a potential strategy to slow the progression of Alzheimer's disease. We aimed to assess the safety and tolerability of CAD106, a novel active Aβ immunotherapy for patients with Alzheimer's disease, designed to induce N-terminal Aβ-specific antibodies without an Aβ-specific T-cell response.

Methods

We did a phase 1, double-blind, placebo-controlled, 52-week study in two centres in Sweden. Participants, aged 50–80 years, with mild-to-moderate Alzheimer's disease were entered into one of two cohorts according to time of study entry and then randomly allocated (by use of a computer-generated randomisation sequence) to receive either CAD106 or placebo (4:1; cohort one received CAD106 50 μg or placebo, cohort two received CAD106 150 μg or placebo). Each patient received three subcutaneous injections. All patients, caregivers, and investigators were masked to treatment allocation throughout the study. Primary objectives were to assess the safety and tolerability of CAD106 and to identify the Aβ-specific antibody response. Safety assessment was done by recording of all adverse events, assessment of MRI scans, physical and neurological examinations, vital signs, electrocardiography, electroencephalography, and laboratory analysis of blood and CSF. Patients with Aβ-IgG serum titres higher than 16 units at least once during the study were classified as responders. This study is registered with ClinicalTrials.gov, number NCT00411580.

Findings

Between August, 2005, and March, 2007, we randomly allocated 31 patients into cohort one (24 patients to CAD106 treatment and seven to placebo) and 27 patients into cohort two (22 patients to CAD106 treatment and five to placebo). 56 of 58 patients reported adverse events. In cohort one, nasopharyngitis was the most commonly reported adverse event (10 of 24 CAD106-treated patients). In cohort two, injection site erythema was the most commonly reported adverse event (14 of 22 CAD106-treated patients). Overall, nine patients reported serious adverse events—none was thought to be related to the study drug. We recorded no clinical or subclinical cases of meningoencephalitis. 16 of 24 (67%) CAD106-treated patients in cohort one and 18 of 22 (82%) in cohort two developed Aβ antibody response meeting pre-specified responder threshold. One of 12 placebo-treated patients (8%) had Aβ-IgG concentrations that qualified them as a responder.

Interpretation

Our findings suggest that CAD106 has a favourable safety profile and acceptable antibody response in patients with Alzheimer's disease. Larger trials with additional dose investigations are needed to confirm the safety and establish the efficacy of CAD106.

Funding

Novartis Pharma AG.

Introduction

Alzheimer's disease is a complex neurodegenerative disease that affects about 26 million people worldwide, with an increasing global prevalence and societal cost.¹ Many factors might cause the disease, but converging evidence indicates a central role of aggregated forms of amyloid β (Aβ) peptide.2, 3, 4, 5 Although the exact mechanism of Aβ toxicity is unknown, interventions that block Aβ aggregation and deposition are thought to be promising therapeutic options.⁶

Immunisation targeting the Aβ peptide is effective in halting progression of amyloid pathology in transgenic mice.7, 8, 9, 10, 11, 12 Compared with passive immunotherapy, active immunotherapy offers long-term advantages owing to the continuous production and affinity maturation of therapeutic antibodies over time and to the need for less frequent administration.¹³ However, the first phase 2 clinical trial in patients with Alzheimer's disease treated with active Aβ immunotherapy, AN1792, was suspended because meningoencephalitis was recorded in 6% of treated patients.¹⁴ An Aβ-specific T-cell response has been strongly suspected as the cause of this adverse event, because AN1792 consists of full-length Aβ_1-42 that carries many T-cell epitopes.15, 16

Neuropathological analysis of AN1792-treated patients showed a reduction in brain amyloid plaques.17, 18 Long-term follow-up studies confirmed AN1792-treated patients who had an antibody response had reduced functional decline and caregiver dependence compared with placebo-treated patients, as well as a reduction in CSF tau concentrations; effects on cognitive function were less apparent.19, 20 These results indicate the potential benefits of active immunisation in the slowing of disease progression, provided that an Aβ-specific T-cell response can be avoided.

CAD106 is a novel immunotherapy designed to stimulate the generation of antibodies against a small Aβ peptide fragment (Aβ_1–6) acting as a B-cell epitope and avoiding an Aβ-specific T-cell response.¹² To induce an immune response, the peptide is coupled to a carrier that contains 180 copies of the coat protein of bacteriophage Qβ. Immunisation with CAD106 reproducibly prevented brain amyloid plaque accumulation in two transgenic mouse models of Alzheimer's disease, with reductions of up to 80% in the plaque area compared with controls.¹²

This first-in-human clinical study was done primarily to investigate the safety, tolerability, and Aβ-specific antibody response of CAD106 in patients with mild-to-moderate Alzheimer's disease. We also assessed the effects of CAD106 on disease-related biomarkers, and on the progression of Alzheimer's disease.