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DIAD Family WebinarSaturday, October 26, 20194:00-6:00 PM CDT / 22:00 – 00:00 BST

RANDALL BATEMAN, M.D. DIREC TOR, D IAN TRIALS UNIT

ERIC MCDADE. D.O. ASSOCIATE DIREC TOR, D IAN TRIALS UNIT

AGENDABreaking news on aducanumabOpen Label Extension (OLE)Cognitive Run-In (CRI) Next Steps: Future Drug ArmsPrimary Prevention UpdateDIAN Expanded Registry (EXR) and Family Conference

recap

If you have a question during the webinar, please use the chat function and type in your question or email it to: dianexr@wustl.edu

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EMERGE/ENGAGE OverviewTwo identically designed Phase 3 studies

Enrolled patients with mild cognitive impairment due to Alzheimer’s disease (AD) and mild AD dementia

All patients screened with PET for elevated brain amyloid beta levels

~ 2/3 of patients were ApoE4 carriers in each study, well balanced across arms

Primary endpoint: CDR-SB (Clinical Dementia Rating-Sum of Boxes) at 18 months

All treatment arms included titration

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Summary of Phase 3 aducanumab dataAcross multiple clinical endpoints, the larger aducanumab dataset demonstrated a statistically significant reduction of clinical decline in early AD patients in EMERGE, and Biogen believes data from a subset of ENGAGE support these findings

Exposure to high dose aducanumab was important for efficacy

Differences in exposure to high dose aducanumab largely explain the different results between the futility analysis and the new analysis of this larger dataset, as well as the different results between the two studies

Following consultation with the FDA, Biogen believes it is reasonable to submit a regulatory filing for aducanumab based on these data

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Open Label Extension (OLE) An Open Label Extension (OLE) study is a period in a study following the

double-blind period where all participants get active study drug and it is not blinded (everyone is aware of active treatment administration) This permits participants to receive active drug while regulatory agencies review

drug applications for approval; this bridges the timeframe to a marketing approval to get drug from your doctor.

This allows continued assessment of the efficacy, durability, and sustainability of the treatment.

Further, it enables additional data collection and information of the treatment by assessing participants who received placebo in the double-blind and then receive active in the OLE period (this is known as ‘cross-over’)

All participants: Must still be active in the study and cannot have met any discontinuation criteria

required by the protocol Will start OLE as though it’s their first dose, i.e. re-start titration however the MRI

schedules may be less than before due to availability of more safety data

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Open Label Extension (OLE) If the drug arm you are in is not positive but the other drug arm is, you will be

allowed to switch; however, a period of at least 6 months must have passed since your last dose of the other drug (6 month ‘washout’ period)

Timing: It is possible that OLE may start in March/April/May 2020

Participants WILL have to know their mutation status for OLE!

Will I learn whether I was on active or placebo in the double-blind period? To maintain the integrity of the data and assessment (including cross-over) in the OLE

period, participants will NOT be informed of whether they were on active or placebo. This will alleviate any unintentional bias by sites or participants for the clinical and

cognitive measures. It may be possible to find out whether you were on active or placebo once the OLE period

has ended. This information would not change your medical or trial management

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OLE Genetic Counseling & Testing - Discussion The OLE period does not include a placebo, so you must

know you are a mutation carrier in order to enroll into OLE.

Polling questionsPlease contact the DIAN EXR at dianexr@wustl.edu or call 844-DIAN-EXR (844-342-6397) to arrange genetic counseling and testing.

It may be possible to use results of genetic testing done through the trial (to clinical standards). The EXR will discuss options with you.

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OLE Procedures Annual Visits: Lumbar puncture PET Scan: PIB-PET and AV-1451 tau PET MRI Blood biomarkers

Additional Requirements - Solanezumab: no ECG, no safety labs, 1 titration safety MRI

Additional Requirements - Gantenerumab: Local Baseline ECG (if one not performed in the prior 6 months) Annual safety labs New formulation for OLE = G4 (more bioavailable / less volume) Decreased MRI frequency (but still included in titration ~ every 3 dose)

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Enrollment into CRI is active when a drug arm is not open for recruitment. Primary Prevention: ≤ -15 estimated years to onset or “EYO” (younger /

earlier than -15 years from age of onset) Secondary Prevention: -15 to +10 EYO

Purpose / Benefit of CRI: This is part of next drug arm! Provides statistical power for future drug arm(s): participant data will be

used in primary endpoint analysis of treatment arm once added Pre-identified group of participants (more rapid enrollment once drug arms

open) Reduce recruitment time once open allows for earlier readout (and rapid

drug availability to population, if positive) Decreased regulatory start-up (initial/new submission vs. amended

submission timeline)

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Cognitive Run-In (CRI)

Cognitive Run-In (CRI)Participation includesHome screening visit Initial, baseline visit to study site (to increase probability of

meeting inclusion when drug arm is added) Clinical and cognitive testing batteryMRI scan Possible tau PET scan (secondary prevention only, i.e. -15 to +10 EYO)

In-home, abbreviated cognitive testing visits approximately every 3 months, with a longer home version at 6 monthsAnnual visits to study site

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Next Steps: Future Drug ArmsFor Primary Prevention

1) Several classes of compounds are being considered for the next drug arm2) BACEi with reported cognitive worsening, pending updates for ongoing

programs

For Secondary Prevention1) Tau based drugs including antibodies are high priority for secondary

prevention Tau PET scans needed to help power future studies

2) Combination therapy with anti-amyloid-beta antibodies with tau targeted drug high priority and possible with OLE success of first amyloid drugs

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CRI – Tau NexGen NIH grant was submitted October 7th for 2 of the 3 tau

NexGen drugs (1st tau drug has already been funded)

If site is approved for CRI and enrolls, those participants will most likely be randomized to drug first (from a logistical standpoint).

The randomization for DIAN-TU Tau NexGen is planned for late 2020, with one or two tau based drugs (depending on NIH funding for second drug, and contracting/roll-out).

Each drug arm enrollment may be 100.

We expect to have ~100 CRI enrolled by later 2020.

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DIAN-TU Tau NexGen trials: Planned enrollment by arms

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Three classes of tau agents1. Anti-tau monoclonal antibodies

2. Genetic treatments designed to inhibit or modulate tau protein translation (e.g. antisense oligonucleotides [ASOs], small interfering RNA [siRNA], and adeno-associated viral [AAV] vectors)

3. Small molecule aggregation inhibitors. We propose to test each of these different mechanistic classes in the DIAN-TU

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Primary Prevention Plan: Update Officially funded in Sept 2018 (initial five years)

EYO -15 or earlier (younger)

Amyloid-specific therapies for a PiB outcome

4 years treatment (until last participant completes 4 years)

Therapy evaluation assessments: Plan for Q4 2019-Q1 2020 for drug selection Possible drug classes: Abeta Vaccines, Passive immunotherapy (Abeta) Results of 001 could impact the decisions for 002 (timelines)

For those of you that might qualify, please consider enrolling in the CRI.

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DIAN Expanded Registry (DIAN EXR) Provides information on current and future research opportunities focused on

dominantly inherited AD (DIAD)

Primary referral source for the DIAN-TU Trial

Two-way communication mechanism: Rapid outreach to families; vehicle for families to contact with questions

Additional benefits:◦ Source of information on dominantly inherited AD◦ Quarterly DIAN EXR newsletter◦ DIAD Family Conferences◦ Archived webinars◦ EXR ARC◦ Surveys to formally collect information from registrants on topics important to DIAN and to

DIAN-TU trial design◦ Exploratory Genetic Counseling and Testing (GCT) Program◦ Genetic counseling and testing for qualified family members interested in DIAN research but

who have not yet enrolled in DIAN-TU trial or DIAN Observational study

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DIAN Expanded Registry (DIAN EXR)

Serves as a key information and referral source for the DIAN Observational and DIAN-TU trials

Register: www.dianexr.orgCall: 1-844-DIAN-EXR (342-6397)

Email: dianexr@wustl.edu

Participant Interaction and Partnership

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2019 DIAD Family Conference: Mutation, Participation, Innovation

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Total attendees: 245• 131 family members and 114 researchers/professionals from

14 countries (United States and Puerto Rico, Argentina, Australia, Brazil, Canada, Colombia, Germany, Greece, Japan, Mexico, The Netherlands, Spain and the UK)

• Video recording of presentations now available on the DIAN website at: https://dian.wustl.edu/for-families/family-conferences/2019

Saturday, July 13thJ.W. Marriott LIVE • Los Angeles, CA USA

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Coming Soon: DIAN Participant Portal Presenting the Linkt app! A single

location for DIAN-related activity

Receive study opportunities, reminders, news, and announcements

Colorful, game-like setting with goals and rewards

Interaction with the ARC smartphone app

Also available via desktop/laptop

Invites to go out to Expanded Registry via email within the next month! Aiming for Obs involvement to follow

Through public/private support and partnership, the DIAN-TU has launched trials to provide advancement of treatments, scientific understanding and improvements in the approach to Alzheimer’s disease drug developments.

U01 AG042791, R01 AG046179,R01/R56 AG053267, R13 AG055232,U01 AG059798

*Financial support has also been provided by anonymous sources.

DIAN-TU Pharma Consortium

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DIAN-TU Administrative and Clinical Operations TeamRandall Bateman – Director and PI, Eric McDade – Associate Director

Sarah Adams, Stephanie Belyew, Erin Cattoor, David Clifford, Garland Edmonds, Molly Fitzgerald, Erica Fowler, Amanda Fulbright, Angela Fuqua, Kurtis Hanks, Ron Hawley, Dottie Heller, Latoya Jones, Michelle Jorke, Nicole Kelley,

Paulette MacDougall, Jacki Mallmann, Tayona Mayhew, Karen McCann, Susan Mills, Julie Murphy, Jennifer Petranek, Anna Santacruz, Jeanette Schillizzi, Jessi Smith, Annette Stiebel, Shannon Sweeney, Linda Watkins-Imhof, Ellen Ziegemeier

DIAN-TU CoresProject Arm Leaders: Steve Salloway, Martin Farlow, Lon SchneiderConsultants : Berry Consultants, Cornelia Kamp, Cardinal Health Regulatory Sciences, Granzer Regulatory Consulting, IQVIADIAN-TU Therapy Evaluation Committee: Paul Aisen, Randall Bateman, Jasmeer Chhatwal, Dave Clifford, David Cribbs, Kelly Dineen, Joel Eissenberg, Heidi Gibbar, David Holtzman, Mathias Jucker, Jeffrey Kelly, Virginia Lee, Cynthia Lemere, Eric McDade, Erik Musiek, Erik Roberson, Matthias Staufenbiel, Robert VassarDSMB Members: Gary Cutter, Steve Greenberg, Scott Kim, David Knopman, Kristine YaffeADCS: Ron Thomas ATRI: Paul AisenUniversity of Michigan: Robert KoeppeMayo Clinic: Clifford Jack

Administrative: Randall Bateman, Eric McDade and teamBiomarkers: Anne Fagan and teamBiostatistics: Chengjie Xiong, Guoqiao Wang and teamCognition: Jason Hassenstab and teamGenetics: Alison Goate, Carlos Cruchaga and teamImaging: Tammie Benzinger and teamNeuropathology: Rick Perrin and team

We gratefully acknowledge the DIAN and DIAN-TU participants and family members, DIAN Team, DIAN Steering Committee, Knight ADRC, Alzheimer’s Association, ADAD Forum, NIH U01AG042791, R01AG046179, R01/R56AG053267, U01AG059798, R13AG055232, DIAN-TU Pharma Consortium, GHR, Anonymous Foundation, Industry Partners (Eli Lilly & Co., Hoffman-LaRoche, Janssen, Avid Radiopharmaceuticals, Bracket, Cogstate), and Regulatory Representatives.

DIAN-TU Collaborators

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DIAN-TU Sites

United StatesUniversity of Alabama, Birmingham, Erik RobersonUSC Keck School of Medicine, Sonia Pawluczyk*University of California, San Diego, Doug GalaskoYale University, Christopher van DyckAdvocate Lutheran General Hospital, Darren GitelmanIndiana University, Jared BroschEmory University, James LahWashington University, Joy SniderColumbia University, Lawrence HonigUniversity of Pittsburgh, Sarah BermanUniversity of Puerto Rico, Ivonne Jimenez-VelazquezButler Hospital/Brown University, Ghulam SurtiUniversity of Texas Southwestern Medical Center, Diana KerwinUniversity of Washington, Seattle, Suman Jayadev

FranceHôpital Roger Salengro, Florence PasquierHôpital Neurologique Pierre Wertheimer, Maité FormaglioGroupe Hospitalier Pitie-Salpetriere, Bruno DuboisHôpital Charles Nicolle, David WallonHôpital Purpan, Jérémie Pariente

ItalyIRCCS Centro San Giovanni di Dio Fatebenefratelli, Giovanni FrisoniAzienda Ospedaliera Universitaria Careggi, Sandro Sorbi

CanadaUniversity of British Columbia, Robin HsiungSunnybrook Health Sci Centre, Mario MasellisMcGill University, Serge GauthierCHU de Quebec - Hôpital de l' Enfant Jésus, Robert Laforce*

United KingdomThe National Hospital for Neurology & Neurosurgery, Catherine Mummery

AustraliaMental Health Research Institute, Colin MastersMcCusker Foundation for AD Research, Roger ClarnetteNeuroscience Research Australia, William Brooks Spain

Hospital Clinic i Provincial de Barcelona, Raquel Sanchez-Valle

*New sites pending approval

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IrelandSt. Vincent’s University Hospital, Justin Kinsella

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THANK YOU!!