amilomotide (CAD106) / Novartis - LARVOL DELTA

Immunotherapeutic approaches for Alzheimer's disease: Exploring active and passive vaccine progress. (PubMed, Brain Res) - "ACC001 or PF05236806 vaccine has the same Aβ fragment and QS21 as an adjuvant. CAD106 stimulates response against Aβ1-6...AN1792, the first-generation vaccine was formulated in proinflammatory QS21 adjuvant...Immunotherapies have been at the forefront of these initiatives in recent years. The review covers the recent updates on active and passive immunotherapy for AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dermatology • Infectious Disease

Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes. (PubMed, Alzheimers Dement) - "This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials."

Journal • Alzheimer's Disease • CNS Disorders • APOE

Outreach, Screening, and Randomization of APOE ε4 Carriers into an Alzheimer's Prevention Trial: A global Perspective from the API Generation Program. (PubMed, J Prev Alzheimers Dis) - "It is feasible to recruit, screen and randomize cognitively unimpaired APOE ε4 carriers, particularly APOE ε4 HMs for a global AD prevention trial. The Generation Program was on track to complete enrollment by end of 2019. Factors that were key to this success included: working with sites to develop customizable outreach, recruitment, and screening programs specific to their site needs, providing forums for sites to exchange best practices, and developing partnerships between the sponsor team and trial sites."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Dementia • APOE

[VIRTUAL] API Generation program: Active immunotherapy CAD106 slows amyloid deposition in cognitively unimpaired APOE4 homozygotes (AAIC 2021) - "CAD106 is the first active immunotherapy shown to slow amyloid deposition in humans. Treatment with CAD106 might have a positive risk/benefit profile for prevention of amyloid deposition in high-risk populations."

Alzheimer's Disease • CNS Disorders • Psychiatry • Amyloid PET

"(3/6) These are: Semagacestat, Avagacestat, Solanezumab, CAD106, Crenezumab, Gantenerumab, Avagacestat, Verubecestat, Atabecestat, Lanabecestat, Crenezumab, Elenbecestat, Umibecestat, Donanemab." (@AlbertoEspay)

[VIRTUAL] Past and current vaccine and immunotherapy development in Alzheimer’s disease (CTAD 2020) - "Vaccine candidates such as CAD106 and UB-311 use selective epitopes and were developed to avoid the undesirable inflammatory effects that were seen with AN1792...Positive ADAS-cog effect sizes were seen for AN1792, Solanezumab EXPEDITION 3, BAN2401 and Aducanumab ENGAGE...Active vaccination achieving a predictable and high antibody response in amyloid positive, early AD participants increases the likelihood of technical success. The longer duration of immune response with active immunization combined with safety advantages make the modality well suited to AD"

IO Biomarker • Allergy • Alzheimer's Disease • CNS Disorders

[VIRTUAL] The Generation Program: Baseline characteristics of cognitively unimpaired APOE4 carriers recruited for Generation Study 1 and Generation Study 2 (AAIC 2020) - P2/3 | "Background: The Alzheimer Prevention Initiative (API) Generation Program evaluated the effectiveness of the BACE1 inhibitor, umibecestat, and the active immunotherapy, CAD106, in delaying the onset of AD symptoms in APOE4 carriers. The Generation program collected a broad set of parameters for the worlds largest cohort of cognitively unimpaired APOE4 carriers. Baseline characteristics of participants enrolled in the Generation Program were consistent with the target population at risk for AD. Findings in relation to genotype, age, sex and amyloid status will be discussed."

Alzheimer's Disease • CNS Disorders

[VIRTUAL] The API Generation Program: Biomarker phenotyping of cognitively unimpaired participants screened in Generation Study 1 and Generation Study 2 (AAIC 2020) - "Background: API Generation Program evaluated the effectiveness of the BACE1 inhibitor umibecestat and the active immunotherapy CAD106 in delaying the onset of AD symptoms in APOE4 carriers. These data describe the biomarker signature of the worlds largest cohort of cognitively unimpaired APOE4 carriers with and without elevated amyloid. The anonymized study data, biomarker samples as well as images collected will be shared with the scientific community after study completion and reporting. ELECSYS is a registered trademark of Roche."

Biomarker • IO Biomarker • Amyloid PET • CSF Aβ42 • CSF P-tau • FDG PET • MRI • Tau PET

Generation S1: A Study of CAD106 and CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease (clinicaltrials.gov) - P2/3; N=480; Terminated; Sponsor: Novartis Pharmaceuticals; Trial completion date: Mar 2025 ➔ Apr 2020; Active, not recruiting ➔ Terminated; Trial primary completion date: Dec 2024 ➔ Apr 2020; Study was terminated by Novartis after a planned review by DMC of unblinded data identified worsening in some measures of cognitive function

Clinical • Trial completion date • Trial primary completion date • Trial termination • Alzheimer's Disease • CNS Disorders

To investigate the safety and tolerability of repeated subcutaneous injections of CAD106 in Alzheimer's patients (clinicaltrials.gov) - P2, N=24; Active, not recruiting -> Completed

Trial completion • Alzheimer's Disease

Q3 2012 Results (Novartis) - Anticipated filing for Alzheimer's disease in 2016 or later

Anticipated regulatory • Alzheimer's Disease

Role of Fluid Biomarkers and PET Imaging in Early Diagnosis and its Clinical Implication in the Management of Alzheimer's Disease. (PubMed, J Alzheimers Dis Rep) - "There is no cure for AD to date-the disease progression cannot be stopped or reversed; approved pharmacological agents (donepezil, galantamine, and rivastigmine; memantine) provide symptomatic treatment. However, the disease-modifying therapies are promising; aducanumab and CAD106 are in phase III trials for the early stages of AD. In conclusion, core CSF biomarkers reflect pathophysiology of AD in the early and late stages; the application of approved radiotracers have potential in amyloid-PET brain imaging to detect early AD."

Biomarker • Clinical • Journal • Review • Amyloid PET

Generation S1: A Study of CAD106 and CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease (clinicaltrials.gov) - P2/3; N=480; Active, not recruiting; Sponsor: Novartis Pharmaceuticals; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

The Generation Program: Preliminary data on baseline characteristics of participants randomized in Generation Study 1 and Generation Study 2 (CTAD 2019) - P2/3; "Background: The Alzheimer Prevention Initiative (API) Generation Program assessed the effectiveness of the BACE1 inhibitor umibecestat or an active immunotherapy (CAD106) in delaying the onset of AD symptoms in APOE4 carriers...Generation Study 2: 1143 participants were randomized (CNP520 15mg or 50mg or placebo), 226 were APOE4 HMs and 917 were HTs...Across both studies at Screening, 1111 LPs, 2934 amyloid PET scans with either florbetapir, flutemetamol or florbetaben, and 145 tau PET scans with flortaucipir, were performed... This is the largest cohort of APOE4 HMs (including about 35% below amyloid elevation threshold) and amyloid-positive APOE4 HTs recruited in a global clinical trial program. Baseline characteristics of participants enrolled in the Generation Program were consistent with the target early AD population without objective cognitive impairment. Striking similarities in most Baseline characteristics reflect the main eligibility criteria shared across both t

Clinical • IO Biomarker • Amyloid PET • APOE • FDG PET • MRI • Tau PET

ALZHEIMER’S PREVENTION INITIATIVE GENERATION PROGRAM: UPDATE AND NEXT STEPS (CTAD 2019) - "Following the disclosure of mild cognitive detrimental e ects with verubecestat and atabecestat at CTAD in October 2018, Novartis and its partners, Banner Alzheimer’s Institute and Amgen, implemented a series of measures to enhance oversight of the safety of study participants receiving umibecestat or placebo...GS1 Cohort 1 with CAD106 was not affected at the time of the CNP520 termination... The Generation Program has introduced programs and procedures to support enrollment in multi-study prevention trials, and it has demonstrated the ability to conduct them in an exceptionally large number of cognitively unimpaired participants willing to learn their AD risk estimate. Results from the Generation Program will be analyzed including follow-up visits o -treatment to evaluate the potential reversal of the observed early worsening of cognitive measures. Trial findings, data, biological samples, and motivated amyloid-positive and -negative participants will provide important..."

IO Biomarker • MRI

Generation S1: A Study of CAD106 and CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease (clinicaltrials.gov) - P2/3; N=481; Recruiting; Sponsor: Novartis Pharmaceuticals; Active, not recruiting ➔ Recruiting

Clinical • Enrollment open • APOE

Generation S1: A Study of CAD106 and CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease (clinicaltrials.gov) - P2/3; N=481; Active, not recruiting; Sponsor: Novartis Pharmaceuticals; Recruiting ➔ Active, not recruiting

Enrollment closed

Generation S1: A Study of CAD106 and CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease (clinicaltrials.gov) - P2/3; N=1340; Recruiting; Sponsor: Novartis Pharmaceuticals; Active, not recruiting ➔ Recruiting; N=481 ➔ 1340; Trial primary completion date: Aug 2024 ➔ Dec 2024

Clinical • Enrollment change • Enrollment open • Trial primary completion date

Generation S1: A Study of CAD106 and CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease (clinicaltrials.gov) - P2/3; N=481; Active, not recruiting; Sponsor: Novartis Pharmaceuticals; Recruiting ➔ Active, not recruiting; N=1340 ➔ 481

Clinical • Enrollment change • Enrollment closed

The Alzheimer's Prevention Initiative Generation Program: Study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer's disease. (PubMed, Alzheimers Dement (N Y)) - "Under the umbrella of the Alzheimer's Prevention Initiative Generation Program, therapies targeting Aβ, including CNP520 (umibecestat), a β-site-amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitor, and CAD106, an active Aβ immunotherapy, are in clinical development in preclinical AD. The Generation Program is designed to assess the efficacy, safety, and biomarker effects of the two treatments in individuals at high risk for AD. It may also provide a plausible test of the amyloid hypothesis and further accelerate the evaluation of AD prevention therapies."

Biomarker • Clinical • IO Biomarker • Journal • Review

The Alzheimer Prevention Initiative Generation Program: Evaluation of CNP520 in Preclinical Alzheimer's Disease (AAN 2019) - "Generation Study 1 evaluates CNP520 and CAD106 (an active amyloid immunotherapy), in separate cohorts, in participants who are homozygous (HM) for APOE4. The Generation Program is designed to provide efficacy, safety and tolerability data for CNP520 compared to placebo in people at risk for the onset of clinical symptoms of AD. Generation Study 1 and Generation Study 2 are currently enrolling."

IO Biomarker • Preclinical

CAD-106 + CNP520: Completion of P2b/3 GENERATION S1 trial (NCT02565511) in Alzheimer’s disease in 2025 (Novartis) - Q1 2019 Results

Trial completion date

Preventive Alzheimer’s trials keep amyloid hope alive - '''When somebody has dementia they’re really in that late stage of disease - the brain has seen significant injury by plaques and tangles,' says Michael Rafii...With the prevention trials, 'the idea is to go as early as possible'....While these prevention trials are focusing on patients with elevated risk of developing Alzheimer’s dementia because of their genetic profile or family history, the findings can be translated into patients with sporadic disease, Professor Bateman says: 'These are two forms of the same disease.'''

Media quote

CAD-106: Regulatory filing for Alzheimer’s disease in 2023 or later (Novartis) - Q4 & FY 2018 Results

Regulatory

IMMUNOLOGICAL AGENTS FOR NEUROCOGNITIVE DISORDERS- A REVIEW OF THE CURRENT EVIDENCE (EPA 2019) - "Finished trials with published Results were investigating a tau vaccine (AADvac 1- positive Results , phase 1 trial) and several vaccines directed against beta-amyloid plaques (ACC-001- negative Results , two phase 2A trials, gantenerumab- it may be efficient, but more trials are needed, bapineuzumab failed, phase 3 trial, BAN2401- it was efficient in a single phase 2A trial, AN1792- phase 2A trial produced positive effects and a follow-up after 4.6 years detected low anti-AN1792 antibody titers, and CAD106- only a phase 1 trial). The level of evidence for current immunological therapies targeting AD is not very encouraging, but many trials are currently ongoing or will start in near future."