Diane Stephenson, PhD; Executive Director, CAMD Coalition Against Major Diseases (CAMD) – Advancing Regulatory Science for AD CSF Biomarkers Diane Stephenson, PhD; Executive Director, CAMD

CAMD AD CSF Biomarker Team Members AbbVie—Devan Devanarayan, Just Genius, Leslie Carter, Jeff Waring Alzheimer’s Association—Maria Carrillo, Jim Hendrix Biohaven– Rob Berman Biomarkable—Hugo Vanderstichele Boehringer Ingelheim—Mark Gordon Critical Path Institute—Diane Stephenson, Steve Arneric, Robin Shane, Volker Kern, Klaus Romero Eisai—June Kaplow, Johan Luthman Eli Lilly—Peng Yu, Brian Willis, Bob Dean, Janice Hitchcock FDA—Jim Kaiser Genentech/Roche—Susan Yule Janssen—Mahesh Samtani MSD—Bob Umek Novartis—Richard Meibach Pfizer—Kaori Ito Roche Diagnostics—Richard Batrla-Utermann, Tobias Bittner University of Antwerp—Sebastiaan Engelborghs University of California, UC Davis—Laurel Beckett University of Pennsylvania—Les Shaw University of Göteborg—Kaj Blennow AD CSF Team Co-chairs: Hugo Vanderstichele Bob Dean

Objective of CAMD CSF Biomarker Team FDA Biomarker Qualification of CSF analytes (Aβ1-42, tau, p-tau) for the purpose of enrichment in clinical trials at the Pre-dementia stage Out of Scope: Regulatory approval/clearance of CSF biomarkers as In Vitro Diagnostics Approval of CSF biomarkers as companion diagnostics (IVD) Use of CSF biomarkers as pharmacodynamic biomarkers Use of CSF biomarkers as clinical outcomes or surrogates of efficacy

Progress since last GBSC FDA issues letter of support to CAMD CSF biomarker team FDA qualifies first clinical biomarker for prognostic use in COPD FDA requests novel candidate biomarkers and posts results Overall increased Transparency Evidentiary standards for qualification is being highlighted in multiple workshops FDA posts Biomarker qualifications under review CAMD receives first ever case of biomarker data contributed from AD clinical trial Draft manuscript from CSF team nearly ready for submission

Pathways to integrate biomarkers in drug development Amur et al., Clin Pharm & Ther Vol 98(1) July 2015

CAMD Biomarkers aiming for FDA Qualification Prognostic Application, AD & PD Low Hippocampal volume at baseline for enrichment in pre-dementia trials Baseline measures of β-amyloid protein, tau, and phosphotau levels in CSF as biofluid biomarkers for enrichment in pre-dementia AD trials Dopamine transporter neuroimaging as a prognostic biomarker to exclude those subjects termed as SWEDDs (scans without evidence of dopamine deficiency) for clinical trials in early motor PD subjects SPECT imaging of DAT in healthy and PD

FDA issues letters of support to CAMD biomarkers teams March 26, 2015 http://www.alzforum.org/news/research-news/fda-gives-nod-alzheimers-and-parkinsons-biomarkers

FDA Letter of Support (LoS) What is a Letter of Support? A LoS describes CDER’s thoughts on the potential value of a biomarker and encourages further evaluation to enhance visibility of the biomarker, encourage data sharing, and stimulate additional studies. Why issue a Letter of Support? To encourage identification, development, and qualification of new drug development tools to overcome hurdles in drug development programs and to enhance drug safety and efficacy. What is it not: a fully qualified biomarker or approved IVD

CAMD AD CSF Biomarker FDA Letter of Support The need for data sharing & Consensus data standards

CSF Biomarker Letter of Support (contd) Biomarker Validation comments: Analytical performance expectations

Assay manufacturers highlight FDA and EMA LoS C-Path’s Predictive Safety Testing Consortia (PSTC) consortia achieves Letter of Support for kidney safety biomarkers, including NGAL

FDA Speaks Out: What is Needed Enhanced data sharing and collaborative efforts among consortia Qualification packages that don’t try to “boil the ocean” Limited versus expanded context of use Data/specimen repositories which can support expanded contexts of use for biomarkers once additional data is aggregated Upfront conversations around context of use—which drives the level of evidence needed More communication about the value and progress made by consortia efforts Greater clarity around levels of evidence for qualification. This takes the entire scientific community – not just FDA Patience…we are learning as we go….. Dr ShaAvrhee Buckman, Director, Office of Translational Sciences , FDA

Evidentiary Considerations for Integration of Biomarkers in Drug Development Symposium Aug 21st, 2015 Univ Maryland The objective of the symposium is to begin to define and ultimately codify the scientific and regulatory expectations for the qualification of biomarkers  Two biomarker classes will be discussed Safety biomarkers Biomarkers used for trial enrichment  The symposium format is designed to elicit participant feedback on defining evidentiary standards based on hypothetical biomarker qualification projects with varying complexities of COUs. Website: http://www.pharmacy.umaryland.edu/centers/cersievents/biomarkers

Paving the way for the future - promising biomarkers CAMD biomarker teams submitted two candidate biomarkers: CSF Neurogranin (Kaj Blennow, Erik Portelius, Hugo Vanderstichele) Tau PET imaging (Mike Weiner, Pat Cole, Susan DeSanti, Dawn Matthews, Jeff Sevigny) CONFIDENTIAL

CSF Team…….What is needed for success? Context of Use Level of Evidence Qualification CSF analytes as Prognostic biomarkers for Enrichment in AD Pre-dementia trials Assay analytical performance Reliability & Reproducibility Clinical validation: Possible Supportive Studies - ADNI DESCRIPA Wash Univ ADRC BMS Avagacestat MORE

ADNI and CAMD Synergies ADNI goals align with CAMD goals ADNI Scientific Questions Validate Biomarkers for Clinical Trials Standardize Biomarkers for use in Clinical Trials Optimize Biomarkers for Clinical trials Provide a platform for simulated clinical trial platform All CAMD regulatory Achievements were enabled by ADNI AD CDISC consensus Clinical Data Standards AD EMA qualification opinion - hippocampal volume AD FDA and EMA regulatory endorsement of AD disease model FDA letters of support, AD biomarkers

How can you help? Sharing of analytical performance data similar to what was shared with ADNI3 biofluid core group Patience with the process and awareness of challenges in data and sample sharing Employ CDISC AD standards (CSF biomarkers) in ongoing and future studies. Patient informed consent to enable data sharing of clinical data and samples Contribute to CAMD CSF biomarker team to achieve goal that will improve efficiency and cost of CSF biomarker implementation in trials

Acknowledgements Critical Path Institute Staff FDA colleagues: John-Michael Sauer, PSTC Executive Director FDA colleagues: James Kaiser, ShaAvhree Buckman, Billy Dunn, Nick Kozauer, Shashi Amur, Chris Leptak CAMD Members CSF Team Co-chairs Bob Dean, Hugo Vanderstichele Johan Luthman CAMD Co-Director, Mark Gordon Alzheimer’s Association C-Path acknowledges the generous support of FDA and our CAMD members

BACK UPS

Progress in ADNI could help us now Johan Luthman, biofluid BM WG ADNI PPSB, April 2015

F FDA Qualifies the First Clinical Biomarker for Prognostic Use, July 2nd

Lessons Learned, plasma fibrinogen qualification Consortia driven 5 clinical data sets (each with >1000 patients)….all observational, no RCTs Only one of the datasets fits COU and was analyzed to support qualification Assay specific cutpoints was OK Bridging between assays was considered but it looks like not required in advance OK to qualify biomarker based on multiple assays and platforms All encouraging news for our team

CSF Biomarkers predict MCI progression to AD