Critical Path for Alzheimer's Disease

The US Food and Drug Administration (FDA) issued a Letter of Support for cerebral spinal fluid (CSF) analytes Aβ1-42, total-tau, and phosphor-tau as exploratory prognostic biomarkers for enrichment in AD trials.

US FDA Letter of Support (February 26, 2015)

This letter, issued to CAMD, describes the FDA’s thoughts on early intervention in AD, and the importance of identifying patients with mild cognitive impairment (MCI) who are likely to develop further cognitive impairment within the time frame of a clinical trial, to potentially lead to therapies with greater impact. The FDA encourages the inclusion of these exploratory CSF biomarkers in clinical trials to evaluate their utility in clinical trial enrichment.

The US Food and Drug Administration (FDA) issued a Letter of Support for low baseline hippocampal volume (HV) measured by magnetic resonance imaging (MRI) as exploratory prognostic biomarkers for enrichment in AD trials.

US FDA Letter of Support (March 10, 2015)

This letter, issued to CAMD, describes the FDA’s thoughts on the value of measuring hippocampal atrophy over the course of a clinical trial. The FDA encourages the exploration of the possible use of low baseline HV (as measured by MRI) for the purpose of clinical trial enrichment.

The CPAD team has developed a non-linear mixed effects model for the longitudinal trajectory of Clinical Dementia Rating – Sum of Boxes (CDR-SB), based on patient-level data from the ADNI-1 and ADNI-2 trials. The Investigation Into Delay to Diagnosis of Alzheimer’s Disease With Exelon (InDDEx) trial was used as an external validation dataset. The model accounts for baseline intra-cranial volume-corrected hippocampal volume (ICV-HV), apolipoprotein E4 (APOE-ɛ4) carrier status, baseline MMSE scores, baseline age and CDR-SB, as well as sex as other relevant covariates. This model allows the user to perform simulations to inform sample size estimation and power calculations, as well as evaluating enrichment strategies, over a varied range of assumptions and trial design options.

Current approaches for sample size estimation, based on literature metadata of the estimated standard deviation for the clinical endpoint and the expected effect size, do not account for differences in clinical and demographic characteristics of the enrolled trial population, disease worsening profile over time, and the different levels of variability (e.g., between-study, between-subject, and residual variability). The current version of the model accounts for the contribution of the aforementioned aspects and is being used to develop a web-based aMCI clinical trial simulator with a user-friendly graphical interface. This tool will simulate clinical trials based on user-defined trial and subject characteristics at study entry.

The EMA supports the primary objectives of the applicant and has decided to issue a Letter of Support to the CPAD Consortium to encourage industry sponsors to share the patient-level data from completed phase II and III clinical trials in the intended target population as defined in the COU statement, including active and control arms, with CPAD. This will allow the CPAD team to complete the development and validation of the proposed quantitative novel methodology in drug development, while also encouraging the CPAD team to disseminate and provide access to the current version of the model for implementation by sponsors actively designing clinical trials in aMCI.

The goal of the proposed simulation tool is to serve as a public resource for sponsors designing trials of new therapies for Alzheimer’s disease (AD). CAMD intends that this simulation tool will provide quantitative support in the design and planning of clinical trials involving subjects with mild to moderate AD. The submission further suggests that the proposed tool could be used during all clinical stages of AD drug development, including proof-of-concept, dose-ranging, and confirmatory trial design and could encompass various types of treatment mechanisms (e.g. symptomatic and disease-modifying). The submission outlines several intended applications of the proposed tool:

• Sample size calculations
• Determination of optimal trial durations and treatment effect measurement times • Comparison of the sensitivity of competing trial designs to assumptions about the types of expected treatment effects (time to maximal effect, effects that increase or decrease over time)
• Determination of the most appropriate data analytic methods for novel trial designs

U.S. FDA Letter of Support June 12, 2013

On 20 March 2013 the Applicant Critical Path Global Ltd. requested qualification opinion for the proposed Disease Progression and Trial Evaluation Model.

The context of use: “The proposed Disease Progression and Trial Evaluation Model, as defined in this document, is suitable for qualification for use in Drug development as a longitudinal model for describing changes in cognition in patients with mild and moderate AD, and for use in trial designs in mild and moderate AD.”

Dr. David Brown was appointed as coordinator. The Qualification Team comprised of: Dr. Susan Morgan Mr. Rob Hemmings, Dr. Ferran Torres, Dr. Bertil Jonsson, Dr. Monique Wakelkamp, Dr. Valentina Mantua, Prof. Luca Pani. The Patient representative for the procedure was Mr. Jean Georges. The EMA Scientific Administrator for the procedure was Dr Maria Isaac.

The procedure started during the SAWP meeting held on 02 – 04 April 2013.

The Qualification Team meeting took place on 07 May 2013. The discussion meeting with the Applicant took place on 04 June 2013. During its meeting held on 03 – 06 June 2013, the SAWP agreed on the opinion to be given to the Applicant.

During its meeting held on 24 – 27 June 2013, the CHMP adopted the opinion to be given to the Applicant. Excluding commercially confidential information, the draft qualification opinion was released for public consultation on the 19 July 2013 to 27 August 2013.

During its meeting held on 2-4 September 2013, the SAWP agreed on the final opinion to be given to the Company. During its meeting held on16-19 September, the CHMP adopted the final opinion to be given to the Company.

The opinion given by CHMP is based on the claims and supporting documentation submitted by the Company, considered in the current state-of-the-art in the relevant scientific fields.

EMA Letter of Support September 19, 2013

The European Medicines Agency’s (EMA) qualification process is a new, voluntary, scientific pathway leading to either a CHMP opinion or a Scientific Advice of novel methodologies on innovative methods or drug development tools. It includes qualification of biomarkers developed by consortia, networks, public/private partnerships, learned societies or pharmaceutical industry for a specific intended use in pharmaceutical research and development.

The Qualification team was: Prof. Fernando de Andrés Trelles (coordinator), Prof. Luca Pani (CHMP member), Dr Bertil Jonsson, Christine Gispen de Wied. The EMA Scientific Administrator for the procedure was Dr Maria Isaac.

On 23 March 2011 the Applicant C-Path CAMD Biomarker Working Group requested qualification advice for the Candidate Biomarkers of Alzheimer’s Disease (AD).

The procedure started during the SAWP meeting held on 26 – 28 April 2011. The discussion meeting with the Applicant took place on 29 June 2011.

During its meeting held on 30 August – 01 September 2011, the SAWP agreed on the advice to be given to the Applicant. During its meeting held on 19 – 22 September 2011, the CHMP adopted the advice to be given to the Applicant.

The response given by CHMP is based on the questions and supporting documentation submitted by the Applicant, considered in the light of the current state-of-the-art in the relevant scientific fields.

EMA Letter of Support November 17, 2011

Due to differences in tracer properties, instrumentation, and methods of analysis, tau-PET outcome data cannot currently be meaningfully compared or combined. CPAD is leading a pre-competitive “Tau-PET Harmonization Working Group”, in partnership with leaders from industry and academia, to test and validate a harmonized scale for quantification of tau deposition that will allow comparison and generalizability across studies, cohorts and different tau radiotracers.

A harmonized tau-PET scale will improve the utility of tau-PET in various research and drug development efforts, including for trial enrichment, monitoring tau deposition over time, spatio-temporal characterization, and its use in disease-specific anti-amyloid and/or anti-tau therapeutic research and clinical trials.

Tau-PET Surrogacy Working Group

Efficacy in a clinical trial can be a measure of how a patient functions, feels or survives (reflecting clinical benefit), or a validated surrogate endpoint shown to predict a specific clinical benefit (both of which can result in a Traditional Approval), or a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit (resulting in an Accelerated Approval). When using biomarkers as surrogate endpoints, it’s important to note they are not a direct measure of how a patient functions, feels, or survives. They are intended to predict and reflect a clinical benefit.

Surrogate endpoints can help improve trial efficiency and regulatory decision making. Amyloid PET was used as a surrogate endpoint that is reasonably likely to predict clinical benefit, resulting in accelerated drug approvals for AD in recent years. Yet, considering the heterogeneity of disease pathology and progression in AD, it is necessary to identify and evaluate additional biological markers which can help track disease progression and treatment effects. CPAD is leading a global, pre-competitive collaborative “Tau-PET Surrogacy Working Group” of leading experts among CPAD members, academics and consultants to explore and evaluate the readiness of tau-PET as a surrogate endpoint.

By integrating patient-level data from high quality AD clinical trials, models will be developed to model natural AD progression for multiple cognitive and functional endpoints, as well as biomarkers. The fitted statistical models will be applied to address unmet needs at multiple points in the clinical trial design process, reducing unnecessary PET scans by screening with accessible blood-based biomarkers, optimized patient selection, and reduced trial size (and/or increased statistical power) with the help of enrichment models that predict cognitive decline using combinations of AD biomarkers. Longitudinal biomarker data will also be modeled against longitudinal cognitive trajectories to better understand the selection of biomarker-based endpoints to measure reduction in AD pathology in response to treatment.

The disease progression models will serve as the basis for clinical trial simulation tools to facilitate informed decision making in the drug development process and optimize patient and endpoint selection, as well as design of efficacy studies. The trial design models will serve to influence core clinical trial design decisions and thereby usher in the next generation of biomarker-driven clinical trials characterized by greatly improved efficiency and reduced costs.

• European Medicines Agency (EMA)
• Foundation for National Institutes of Health (FNIH)
• National Institute on Aging (NIA)
• National Institutes of Health
• National Institute of Neurological Disorders and Stroke (NINDS)
• U.S. Food and Drug Administration (FDA)

• Antoine Leuzy, PhD (Enigma Biomedical Group)
• Ioannis Pappas, PhD (LONI/GAAIN, USC)
• Brian Gordon, PhD (Washington U in St. Louis)
• Chengjie Xiong, PhD (Washington U in St. Louis)
• Duygu Tosun-Turgut, PhD (UCSF)
• Guoqiao Wang, PhD (Washington U in St. Louis)
• Nusrat Rabbee, PhD (Alladapt)
• Rhoda Au, PhD (Boston University)
• Robert Alexander, MD (Banner Health)
• Sheng Luo, PhD (Duke University)
• Vijaya Kolachalama, PhD (Boston University)
• Yan Li, PhD (Washington U in St. Louis)
• Hartmuth Kolb, PhD (Enigma Biomedical Group)