ADCOMS Demons nstrates Improved d Sensitivity to Disease e Progr - - PowerPoint PPT Presentation

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ADCOMS Demons nstrates Improved d Sensitivity to Disease e Progr - - PowerPoint PPT Presentation

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ADCOMS Demons nstrates Improved d Sensitivity to Disease e Progr ogres ession on and Treatmen ent Effec ects in n Ear arly y AD Veronika Logovinsky, MD, PhD CONFIDENTIAL 1 Pres esen entation on O Outline Veronika

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ADCOMS Demons nstrates Improved d Sensitivity to Disease e Progr

  • gres

ession

  • n and Treatmen

ent Effec ects in n Ear arly y AD

Veronika Logovinsky, MD, PhD

1

CONFIDENTIAL

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SLIDE 2

Pres esen entation

  • n O

Outline

  • Veronika Logovinsky is a full time employee of

Regeneron Pharmaceutical Inc., NY, USA

2

CONFIDENTIAL

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SLIDE 3

Pres esen entation

  • n O

Outline

  • Why do we need a new tool?
  • General approach to the task
  • Development of ADCOMS as a clinical assessment outcome
  • What can we learn from individual selected items?
  • Sensitivity to decline and to treatment effects: ADCOMS

versus existing clinical batteries

  • Results from prospective studies
  • Regulatory Support for New Sensitive Evidence-Based

Clinical Outcomes in Early AD

  • Conclusions

3

CONFIDENTIAL

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Why do do w we ne need a a new new clinical a asses sessm smen ent t tool?

  • Convergent effort within Alzheimer’s disease (AD) field to

target early stages of disease, such as mild cognitive impairment (MCI)

  • AD community recognizes that no standard clinical

endpoints exist that are sensitive to disease progression and treatment effect in MCI populations

  • Significant burden for conducting trials in MCI → long and

large trials, difficult to impossible to manage

  • Not all is lost: there are select items in existing clinical

scales that are relevant to an MCI population

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CONFIDENTIAL

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Method

  • dolog
  • gy

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  • True clinical progression in MCI is represented by items that show

– consistent decline across different MCI studies and – provide unique contributions

  • Partial Least Square (PLS) Regression Model

– Fits a statistical model to pooled placebo data from 4 MCI studies over 1 year – Maximizes covariance between individual items and progression over time – Results in a better predictive model when there are numerous correlated individual items

  • Use the model to select a linear combination of items from existing clinical

tools (ADAS-Cog, MMSE, CDR-SB, NTB, …)

– Combination most sensitive to decline → the new clinical tool – Items assigned weights by the PLS model to optimize sensitivity to decline

CONFIDENTIAL

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≤25% ≥62%

10 20 30 40 50 60 70 80 90 100 Percentage of times item was selected

Items C Clearly S Separated i into T Two D Distinct G Groups

Reliability assessed using split sample validation (100 random training samples and test samples)

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ADAS MMSE CDR

CONFIDENTIAL

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SLIDE 7

Item ems a and T nd Thei heir R Rel elative e Contributions

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Maximum Possible % of Composite Observed Maximum % of Composite Observed

ADAS

Delayed Word Recall 10 4% 10 6% Orientation 8 7% 7 9% Word Recognition 12 2% 12 3% Word Finding Difficulty 5 4% 4 4%

MMSE

Orientation to Time 5 11% 5 15% Constructional Praxis 1 2% 1 3%

CDR

Personal Care 3 8% 1 4% Community Affairs 3 17% 2 15% Home and Hobbies 3 14% 2 13% Judgment and Problem Solving 3 11% 2 10% Memory 3 9% 2 8% Orientation 3 12% 2 11%

  • ADAS-cog items

contribute ~22% (vs. ~17% if maximum values assigned)

  • MMSE items contribute

~18% (vs. ~13% if maximum values assigned)

  • CDR-sb items contribute

~61% (vs. ~71% if maximum values assigned)

CONFIDENTIAL

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SLIDE 8

ADCOMS Shows Hi High gh S Sen ensiti tivity ty and R Rel eliability ty i in MCI a and Mild D Dementi tia

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0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00

MSDR

Composite Score MSDR ADAS-Cog MSDR MMSE MSDR CDR-SB MSDR

Mild MCI

  • Across multiple studies and populations ACOMS is consistently better than established scales
  • If combination tool is based only on enriched (Aβ42 positive) MCI patients, it has similar sensitivity to

ADCOMS in enriched MCI population, but lacks reliability (data not shown)

CONFIDENTIAL

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ADC ADCOMS Improves Res esponsiv iveness/Sample le S Size Req equired C Com

  • mpared t

to

  • Origin

inal l Scales

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CONFIDENTIAL

1000 2000 3000 4000 5000 6000 7000

ADAS-cog Composite Score

1000 2000

CDR Composite Score

Sample Size per arm

1000 2000 3000 4000 5000

MMSE Composite Score

Pooled MCI APOε4 Carrier MCI CSF Aβ(1-42) Pooled Mild AD

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Respo pons nsivene ness t to Treatment E Effect: : Di Differenc nce o

  • f Do

Done nepe pezil Versus us P Placebo bo i in C Chang nge f from B Baseline ne

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CONFIDENTIAL

Study Population Study duration Treatment† ADAS- Cog CDR-SB MMSE Composite Eisai donepezil Study 1 MCI 12 mo 10 mg

  • Eisai donepezil

Study 3 Mild AD 6 mo 5 mg +

  • +

+ 10 mg +

  • +

ADCS MCI 12 mo 10 mg

  • +

+ 2000 IU Vitamin E

  • + indicates statistical significance at alpha=0.05; - indicated statistical significance was not reached

† Treatment was donepezil unless otherwise indicated

  • Responsiveness to treatment effect is driven by combination of all three scales
  • CDR-sb alone is not responsive to treatment effect
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Da Data f from P Phase 3 3 Scarl rlet Ro RoAD Study dy with G h Gantene nerum rumab: b: First I Inde depe pende ndent S Study t to Conf nfirm rm S Sensitivity o

  • f ADC

ADCOMS

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From “Comparative traditional psychometrics of cognitive and functional endpoints in a prodromal Alzheimer’s disease population” by Chris Edgar et al., 2015 presented by Roche Clinical Trials on Alzheimer's Disease, (Volume: Volume 2, Number 4)

Sensitivity to change evaluated as standardized response mean (SRM) from baseline to Week 104 in placebo arm (N ~260)

CONFIDENTIAL

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EISAI P Presentation o

  • f BAN

AN2401 Da Data: ADC : ADCOMS Shows Highe her S r Sens nsitivity t to De Decline C Compa pared t d to AD ADAS-Cog a and C d CDR DR-SB a at 1 12 months

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CONFIDENTIAL

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Regulatory Qualification: CAMD pCOA Project

Project Concept Proposal Letter of Intent to FDA Letter of Intent to EMA Aug 2, 2013 Mar 26, 2013 Aug 5, 2013 Project Concept Proposal Mar 26, 2013

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Response from FDA Response from EMA Oct 23, 2013 Oct 28, 2013 CAMD Launch meeting ADNI PPSB data mining session April, 2012 April 16-17, 2013

FDA and EMA collaborated on Clinical Outcome Assessment project to qualify ADCOMS with aim to harmonize all stages

Submission of Initial Briefing Package to EMA Submission of Initial Briefing Package to FDA July 22, 2014 July 22, 2014 Stage 1 Stage 2

  • Project stopped during Stage 2 after meetings with regulators
  • Concerns (particularly by FDA) about evidence-based approach to increase sensitivity of clinical outcome

CONFIDENTIAL

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Concl clusions

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CONFIDENTIAL

  • ADCOMS is novel tool made up of a combination of key sensitive items

from existing scales

  • Uses evidence-based approach (not traditional psychometric

development)

  • Optimized for decline over 12 months in prodromal AD as a weighted

linear combination of these items

  • Shows improved sensitivity to decline compared to current scales
  • Enables dramatic reductions in required sample sizes/arm for 12+ month

treatment trials in MCI

  • Captures response to treatment effects
  • Has been validated in prospective studies
  • Regulatory support for ADCOMS is unclear