The DIAN Treatment Trials: An Update

Sunday, May 6 4:00-5:00 PM CDT

Presented by Randall Bateman, MD

DIAN Therapeutic Trials Unit Director DIAN Clinical Core Leader

Agenda

I. Introductions

II. DIAN Update

III. DIAN Trials update

a. Expanded Registry

b. Therapeutic Trials Topics

IV. Q & A

The Dominantly Inherited Alzheimer’s Network DIAN

Admin – JC Morris

Clinical – RJ Bateman

Biomarkers – AM Fagan

Biostatistics – C Xiong

Genetics – AM Goate

Imaging – T Benzinger

Informatics – D Marcus

Neuropathology – NJ Cairns

• United States: Washington Univ (Bateman), MGH/BWH (Sperling), Butler Hosp/Brown

Univ (Salloway), Columbia Univ (Mayeux), Indiana Univ (Ghetti), UCLA (Ringman), U of Pittsburgh (Klunk), Mayo Clinic, Jacksonville (Graff-Radford)

• Europe: Institute of Neurology, Univ College London (Rossor), Ludwig-Maximilians-Universität München (Danek), University of Tübingen (Jucker)

• Australia: Prince of Wales Medical Research Institutes, Sydney (Schofield), Mental Health Health Research Institute, Melbourne (Masters), Edith Cowan Univ , Perth (Martins)

f Pittsburgh (Klunk), Mayo Clinic, Jacksonville (Graff-Radford)

Coordinating Center Cores

Performance Sites

Clinical Trials Committee DIAN family participant , Paul Aisen, Randy Bateman, Neil Buckholtz, Nick Fox,

Alison Goate, Bill Klunk, Ranjit Mani, John Ringman, Laurie Ryan, Stephen Salloway, Reisa Sperling, Chengjie Xiong

DIAN Clinical Core Enrollment Report

Initial Visits Actual

Follow-up Visits In-Person

Follow-up Visits Remote

Year One (9/2008-6/2009) 11 0 0

Year Two (7/2009-6/2010) 76 0 5

Year Three (7/2010-6/2011)

103 25 40

Year Four (7/2011 through 2/2012) 52 34 60

YTD Totals 242 59 105

DIAN Therapeutic Trials Unit (TTU) Update

• October, 2011: DIAN trials grant submitted to NIH.

• December, 2011: DIAN Pharma Consortium formed (10 leading pharmaceutical companies) and TTU funded

• 14 compounds nominated and reviewed:

– anti amyloid-beta, passive immunotherapies, secretase inhibitors, others

– 5 proposed for immediate consideration.

• April, 2012: Expanded Registry launched

Pharma Consortium Members

DIAN Expanded Registry www.dianexpandedregistry.org

Reaching out to

Participants,

Physicians

And families

DIAN Expanded Registry

• Provides an overview of Autosomal Dominant Alzheimer’s disease (ADAD), links to other web resources (alzforum.org).

• Operational as of Feb 2012, announced in April, ~65 interested participants have registered.

– Current DIAN observational study participants, family members and those interested in future trials are registering on the website

– Physicians and researchers interested in participating as an investigator or referring potential patients from their practice are also registering

DIAN Expanded Registry

DIAN Clinical Trials NIA Grant Overview

Title: Dominantly Inherited Alzheimer Network Trials: An Opportunity to Prevent Dementia .

Application submitted October 5, 2011, reviewed March 2, 2011

Summary: The application proposes to initiate DIAN clinical trials with a two-phase study to

delay, prevent, or restore cognitive loss in AD mutation carriers.

The first phase to determine the biological engagement of the drug target and impact on

biomarkers of neurodegeneration.

The second phase to determine if there is a cognitive benefit of treatment.

Grant Review Summary Statement

“There was much enthusiasm for this innovative application and its efficient linking with DIAN. The overall goal of prevention for those patients at very high risk of AD in this cohort is highly significant. The innovative design, strong investigative team and environment and the compelling pilot data from the parent DIAN participants are other big strengths of the proposed study.”

Concern: Ability to recruit sufficient numbers of participants (only counting numbers enrolled)

Trial Design Outline – Years 1 & 2 • 3 parallel, placebo controlled, double-blinded,

biomarker outcome trials

• Up to 80 participants enrolled in each trial – 40 mutation carriers (30 on active drug treatment, 10 on

placebo)

– 10 to 40 non-carriers on placebo to maintain genetic status blind

• Drug treatment duration = 2 years

• Placebo participants pooled from the trials to provide a common pool of 30 placebo for comparison of biomarker (phase IIb) outcomes.

Trial Design Outline Years 3-5 Outcomes:

• If one trial is successful, it will continue while enrolling a total of 240 participants

• If none of the three original trials is successful, and three new drugs are suitable and available, start 3 new biomarker trials.

A B

5 0 1 2 4 3

Years

A (80)

B (80)

C (80)

B (240)

Figure 1. Trial Design and Potential Outcomes. 240 participants are enrolled into a four arm study of drug A, drug B, drug C, and placebo. Mutation negative participants are assigned placebo, while mutation positive participants are randomized to drug or placebo in a 3:1 ratio (A). 80 participants will be enrolled in each of three two-year biomarker trials; 40 mutation carriers and up to 40 non-carriers will be enrolled in each trial. Biomarker outcomes through week 96 will be assessed before the start of Year 3. In B, one trial is successful and continues while enrolling a total of 240 participants in the three-year cognitive endpoint trial. In C, none of the three original trials is successful, and three new two-year biomarker trials are begun.

D (80)

E (80)

F (80)

3:1 active to

placebo

(pooled placebo)

Drug A, B, or C

monthly for 22 mo DIAN study

(run-in)

Biomarker, clinical, and cognitive measures and

samples

C

0 1 2 4 3 5

Years

A (80)

B (80)

C (80)

Clinical Trial Design

• Study visits:

– Monthly infusions or injections

– Safety MRI every 3 months

– Length of commitment is 2 years for first part of study, 3 additional years if a treatment is successful

Schedule of Events

PROCEDURE:

VISIT SITE DIAN DIAN Sat Sat Sat Sat Sat Sat Sat Sat Sat Sat Sat DIAN

Visit No V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14

Timing (wks.) -4 to 0 0 4 8 12 16 20 24 28 32 36 40 44 48

Informed consent X

Medical/Treatment History X X X X X X X X X X X X X X

Clinical Assessment X X

Physical/Neurological Exam X X

Vital signs X X X X X X X X X X X X X X

12- lead ECG X X X

Questionnaire(s) X X X X X

Hematology/Chemistry/LFTs/UA X X X X X X

Pregnancy testing (dipstick) X X X X X X X X X X X X X X

Study Therapy Administration X X X X X X X X X X X X X

Cognitive Testing X ? X

PET-PIB X X

F-18 PET X X

Safety MRI X X X

Volumetric MRI X X

Lumbar Puncture (CSF) X X

FDG-PET X X

DIAN = DIAN observational study site location Sat = Satellite site

Inclusion/Exclusion

• -15 before to +10 years after parental age of onset

• Possible symptomatic or mild dementia eligible

• Greater than 18 years of age

• Non-carriers who know their mutation status are not eligible

Genetic Testing

• DIAN can pay for discovery testing for appropriate families or DIAN participants.

• DIAN can pay for Genetic Counseling and Testing.

• DIAN Coordinators will assist in finding a genetic counselor in participant’s own area.

• DIAN Coordinator will arrange payment with the associated billing office.

Trial Design Key Points

• Run-in design using DIAN data – Need consistent DIAN follow-up visits

• DIAN participants will have the first opportunity to enroll in the trials. DIAN participants will be taken first as they have baseline data collected

– Others will be welcomed but may need to do DIAN baseline measurements

• 75% chance of receiving active drug (25% chance of placebo)

Patient Randomization Chart

Brief review and consenting to hear more details about the study and possible drug you may receive

Full, detailed review of the study procedures, office visits, drug therapies (sign consent)

Assigned to drug treatment or placebo (blinded to you and the physician).

Begin 22 months of drug therapy.

DIAN Trials Grant Resubmission

Reviewers’ concern: Ability to recruit sufficient numbers of participants

Actions to address concerns

• Show proof of participant numbers and interest in trials

– Expanded registry

– Site Expansion

– Input from participants (letters of support, survey)

DIAN Trials Participant Status

Numbers in parentheses are estimated based on percentage enrolled in DIAN

Total Participants Enrolled 242*

(N=estimated based on %)

% Mutation Carriers 63% (N=152)

% eligible for trials

Age-range: 15 years before - 10 years after

the Parental Age at Onset

69% (N=105)

Note: Goal is 120

CDR = 0 46% (N=48)

CDR = 0.5 (prodromal) 36% (N=38)

CDR => 1.0 (dementia) 18% (N=19)

DIAN Trials Next Steps

• DIAN Trials Start-Up: now through end of year

– Grant resubmission: July 5th , 2012

– Protocol design (currently underway): statistical analysis; participant procedure/assessments selection; final therapy selection

– FDA Meeting (late summer): meet with the FDA for their input and approval to proceed with the planned trial protocol

– Site identification (currently underway): identification of sites with capabilities, experience, and training in performing trials in this patient population (neurologists)

– Training of all sites (physicians and nurse coordinators) for the trial

DIAN Trials Next Steps

• DIAN Trials Start-Up: continued

– Ethics / IRB approval at each location (several months): review board to ensure trial is ethical and there are no patient safety issues; review informed consent document

– Participant enrollment into the trial: end of year through next year

– Participants undergo therapy administration and procedures to measure the effect of the therapy

Q & A Session

Questions from Participants

1. Will an individual’s stage of disease (mildly vs. greatly symptomatic) affect their eligibility or response to treatment.

2. Do you know what drugs will be used?

3. Do you know what the possible side effects are?

4. How will the study be administered?

Questions continued…

5. How frequent are the study visits?

6. Are we able to have weekend treatments?

7. How long would a person be in a trial?

8. If you know you have the mutation, would you be able to tell if the drug is working?

9. When will the trials begin?

Questions continued…

10.Will the participant continue taking their current medications (Namenda, Aricept, etc.) while on the trial drug?

11.If not, how long before the trial drug is administered should the participant stop taking their medication?

12.How is it decided which trial drug the participant is to receive?

Questions continued…

13.What side effects of the trial drug should we (caretakers) be aware of and expect?

14.Due to DIAN site locations vs. participant locations, have you been able to work out a system to have participant’s doctor administer the trial drug?