Ana Graf

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

BACKGROUND Immunotherapy targeting the amyloid β (Aβ) peptide is a potential strategy to slow the progression of Alzheimers disease. We aimed to assess the safety and tolerability of CAD106, a novel active Aβ immunotherapy for patients with Alzheimers 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 Alzheimers 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 Alzheimers disease. Larger trials with additional dose investigations are needed to confirm the safety and establish the efficacy of CAD106. FUNDING Novartis Pharma AG.

AFQ056 in Parkinson Patients With Levodopa-Induced Dyskinesia: 13-Week, Randomized, Dose-Finding Study

AFQ056 is a novel, selective metabotropic glutamate receptor 5 antagonist. This was a 13‐week, double‐blind, placebo‐controlled study. Patients with Parkinsons disease and moderate‐to‐severe levodopa (l‐dopa)‐induced dyskinesia who were receiving stable l‐dopa/anti‐parkinsonian treatment and were not currently receiving amantadine were randomized to receive either AFQ056 (at doses of 20, 50, 100, 150, or 200 mg daily) or placebo (1:1:1:1:2:3 ratio) for 12 weeks. The primary outcome was the modified Abnormal Involuntary Movements Scale. Secondary outcomes included the 26‐item Parkinsons Disease Dyskinesia Scale, the Patients/Clinicians Global Impression of Change, and the Unified Parkinsons Disease Rating Scale parts III (motor evaluation) and IV (severity of motor complications). Safety was assessed. In total, 98 of 133 (73.7%) AFQ056‐treated patients and 47 of 64 (73.4%) patients in the placebo group completed the study. Baseline characteristics were comparable. Patients randomized to AFQ056 200 mg daily administered in 2 doses demonstrated significant improvements at Week 12 on the modified Abnormal Involuntary Movements Scale compared with placebo (difference, −2.8; 95% confidence interval [CI], −5.2, −0.4; P = 0.007). Based on final actual doses, there was a dose‐response relationship on the modified Abnormal Involuntary Movements Scale, with 200 mg daily demonstrating the most robust effect (difference, −3.6; 95% CI, −7.0, −0.3; P = 0.012). Improvements in dyskinesia were supported by change on Unified Parkinsons Disease Rating Scale part IV item 32 (50 mg daily: difference, −0.7; 95% CI, −1.1, −0.2; P = 0.003; 200 mg daily: difference, −0.5; 95% CI, −0.8, −0.1; P = 0.005). No significant changes were observed on the 26‐item Parkinsons Disease Dyskinesia Scale, the Unified Parkinsons Disease Rating Scale part IV item 33 or items 32 and 33, or the Patients/Clinicians Global Impression of Change. Unified Parkinsons Disease Rating Scale part III scores were not significantly changed, indicating no worsening of motor symptoms. The most common adverse events (with incidence greater with AFQ056 than with placebo) were dizziness, hallucination, fatigue, nasopharyngitis, diarrhea, and insomnia. AFQ056 demonstrated anti‐dyskinetic efficacy in this population without worsening underlying motor symptoms. These results will guide dose selection for future clinical trials.

Active immunotherapy options for Alzheimer's disease.

Alzheimer’s disease (AD) is the most common cause of dementia and a major contributor to disability and dependency among older people. AD pathogenesis is associated with the accumulation of amyloid-beta protein (Aβ) and/or hyperphosphorylated tau protein in the brain. At present, current therapies provide temporary symptomatic benefit, but do not treat the underlying disease. Recent research has thus focused on investigating the molecular and cellular pathways and processes involved in AD pathogenesis to support the development of effective disease-modifying agents. In accordance with the existing Aβ-cascade hypothesis for AD pathogenesis, immunotherapy has been the most extensively studied approach in Aβ-targeted therapy. Both passive and active immunotherapies have been shown to effectively reduce Aβ accumulation and prevent downstream pathology in preclinical models. Following AN1792, second-generation active immunotherapies have shown promising results in terms of antibody response and safety. Comparatively, tau immunotherapy is not as advanced, but preclinical data support its development into clinical trials. Results from active amyloid-based immunotherapy studies in preclinical models indicate that intervention appears to be more effective in early stages of amyloid accumulation, highlighting the importance of diagnosing AD as early as possible and undertaking clinical trials at this stage. This strategy, combined with improving our understanding of the complex AD pathogenesis, is imperative to the successful development of these disease-modifying agents. This paper will review the active immunotherapies currently in development, including the benefits and challenges associated with this approach.

Mavoglurant (AFQ056) in combination with increased levodopa dosages in Parkinson's disease patients

Long-term use of levodopa (L-dopa) in patients with Parkinsons disease is associated with development of dyskinesia. This study explored whether Parkinsons disease patients with L-dopa-induced dyskinesia experience improved OFF-time from higher L-dopa doses without worsening of dyskinesias when receiving adjunctive mavoglurant. Patients with moderate-to-severe L-dopa-induced dyskinesia were randomized to receive mavoglurant or placebo. Mavoglurant (AFQ056) was up-titrated over two weeks from 25 mg twice daily (bid) to 100 mg bid (L-dopa kept stable), followed by three weeks during which the daily L-dopa dosage was increased by up to 300 mg/day. A sample size of 30 was initially planned; however, the study was terminated prematurely due to enrollment challenges. OFF-time showed greater improvements in the mavoglurant group (n = 7) compared with the placebo group (n = 7); difference at week 5 was –2.77 h (90% confidence interval –5.44, –0.09 h; p = 0.09). ON-time without troublesome dyskinesia increased more from baseline to week 5 in the mavoglurant group (4.38 h) versus the placebo group (0.63 h). Clinician-rated measures were conflicting. The Modified Abnormal Involuntary Movement Scale scores showed a slight improvement with mavoglurant compared with placebo, while the Unified Dyskinesia Rating Scale parts III and IV worsened slightly with mavoglurant compared with placebo. Due to the low patient numbers and conflicting clinician-rated outcomes data, our findings are not conclusive. However, our results suggest that mavoglurant combined with higher doses of L-dopa may be effective in treating patients with Parkinsons disease experiencing L-dopa-related motor fluctuations and dyskinesias.

A 24-Week, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety and Tolerability of the Rivastigmine Patch in Japanese Patients with Alzheimer's Disease

Background: As of 2010, the rivastigmine patch was licensed for the treatment of Alzheimer’s disease (AD) in 64 countries. Methods: This 24-week, multicenter, randomized, double-blind, placebo-controlled study evaluated the efficacy, safety and tolerability of the 5-cm2 (9-mg loading dose; 4.6 mg/24 h delivery rate) and 10-cm2 (18-mg loading dose; 9.5 mg/24 h delivery rate) rivastigmine patch in Japanese patients with AD. Results: In the primary analysis population (intent-to-treat last observation carried forward) at week 24, delayed deterioration was seen with the 10-cm2 patch versus placebo on the Japanese version of the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-J cog; p = 0.005) and the Japanese version of the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC plus-J; p = 0.067). Participants receiving the rivastigmine patch showed numerically less decline versus placebo at week 24 on the CIBIC plus-J, although this did not reach statistical significance. Statistical significance for the CIBIC plus-J was met following adjustment for body weight and baseline Mini-Mental State Examination score as dynamic allocation factors (p = 0.042) and on the Disability Assessment for Dementia (DAD; p = 0.024) and Mental Function Impairment (MENFIS; p = 0.016) subscales. Serious adverse events were rare and were consistent with the known safety profile of the rivastigmine patch. Conclusion: The rivastigmine patch has a favorable efficacy and tolerability profile in Japanese patients with AD.

Mavoglurant in Parkinson's patients with l-Dopa-induced dyskinesias: Two randomized phase 2 studies.

Two phase 2 randomized, double‐blind studies were designed to evaluate efficacy and safety of immediate‐release (study 1) and modified‐release (study 2) mavoglurant formulations in PD l‐dopa‐induced dyskinesia.

RESULTS FROM A FIRST-IN-HUMAN STUDY WITH THE BACE INHIBITOR CNP520

Luc Tritsmans, Luc Van Nueten, Niels Andreassen, Sebastiaan Engelborghs, Janssen Research & Development, Beerse, Belgium; 2 Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, M€ olndal, Sweden; Ortho-McNeil Pharmaceutical, Raritan, NJ, USA; Janssen Research & Development, Titusville, NJ, USA; 5 Hospital Mutua de Terrasa, Servicio de Neurologia, Terrassa, Spain; Hospital Universitario La Paz, Madrid, Spain; Hospital Clinico San Carlos, Servicio de Neurologia, Madrid, Spain; Fundaci o ACE, Barcelona, Alzheimer Treatment & Research Center, Barcelona, Spain; 9 Hospital Universitari La Fe Avinguda Abril Martorell, Valencia, Spain; Karolinska Institutet, Stockholm, Sweden; Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium. Contact e-mail: jstreffe@its.jnj.com

Aβ-specific antibodies induced by active immunotherapy CAD106 engage Aβ in plasma in AD patients

contact with the interstitial fluid of the brain, allowing for the analysis of biochemical changes that may be related to the disease. The levels of soluble amyloid precursor protein (sAPP) alpha and beta in the CSF have both been investigated as potential biomarkers for AD. Some studies have suggested the levels of sAPPb are lower in subjects with AD, other reports have shown that both sAPPa and sAPPb are increased in AD subjects. Potentially the lack of consistency in these results could be due to fluctuations in the levels of sAPP in the CSF. Intrasubject CSF levels of Ab have been shown to significantly increase when sampling occurred frequently over 24 hours. To address this, we have examined CSF samples taken multiple times over a 24 hour period from subjects with AD or from age-matched controls.Methods: CSF samples were collected by lumbar drain with an indwelling catheter at 0h,1h,4h,8h,12h,18h and 24h during a 24-hour period from 15mild-to-moderate AD patients and 7 non-demented age matched control subjects (CT). sAPPa and sAPPb were measured usingMSD duplex electro chemiluminescence assays.Results:Both sAPPa and sAPPb were detectable in CSF from mild-to-moderate AD and CT subjects. sAPPa and sAPPb levels in AD CSF did not show significant diurnal fluctuations across the time points during a 24-hour period, however, far more variability was observed in CSF from age-matched controls. The CV across the time points was approximately 10% for AD subjects, and 40% for age-matched controls. On average, the levels of both sAPPa and sAPPb were lower in AD subjects relative to age-matched controls at all time points measured. Conclusions:Our results show levels of sAPPa and sAPPbwere consistent across multiple time points in subjects with AD, however they were variable in CSF of age-matched controls. The source of the variability in sAPP CSF levels in control subjects is not known, however, the results suggest caution should be used for employing these analytes as diagnostic biomarkers for determining the presence of Alzheimer’s disease.

The Bace-1 inhibitor CNP520 for prevention trials in Alzheimer's disease

The beta‐site amyloid precursor protein cleaving enzyme‐1 (BACE‐1) initiates the generation of amyloid‐β (Aβ), and the amyloid cascade leading to amyloid plaque deposition, neurodegeneration, and dementia in Alzheimers disease (AD). Clinical failures of anti‐Aβ therapies in dementia stages suggest that treatment has to start in the early, asymptomatic disease states. The BACE‐1 inhibitor CNP520 has a selectivity, pharmacodynamics, and distribution profile suitable for AD prevention studies. CNP520 reduced brain and cerebrospinal fluid (CSF) Aβ in rats and dogs, and Aβ plaque deposition in APP‐transgenic mice. Animal toxicology studies of CNP520 demonstrated sufficient safety margins, with no signs of hair depigmentation, retina degeneration, liver toxicity, or cardiovascular effects. In healthy adults ≥ 60 years old, treatment with CNP520 was safe and well tolerated and resulted in robust and dose‐dependent Aβ reduction in the cerebrospinal fluid. Thus, long‐term, pivotal studies with CNP520 have been initiated in the Generation Program.

Measuring cognition and function in the preclinical stage of Alzheimer's disease

The Alzheimers Associations Research Roundtable met in November 2016 to explore how best to measure changes in cognition and function in the preclinical stage of Alzheimers disease. This review will cover the tools and instruments currently available to identify populations for prevention trials, and measure subtle disease progression in the earliest stages of Alzheimers disease, and will include discussions of suitable cognitive, behavioral, functional, composite, and biological endpoints for prevention trials. Current prevention trials are reviewed including TOMMOROW, Alzheimers Prevention Initiative Autosomal Dominant Alzheimers Disease Trial, the Alzheimers Prevention Initiative Generation Study, and the Anti‐Amyloid Treatment in Asymptomatic Alzheimers to compare current approaches and tools that are being developed.