Semagacestat for Alzheimer's Disease

Termination of a Phase 3 Trial of Semagacestat for the Treatment of Alzheimer's Disease

Rod BugawanNovember 14, 2013

Lipscomb University College of Pharmacy

Learning Objectives

• Describe Alzheimer’s Disease (AD) and recognize the risk factors

• Describe the pathophysiology of AD• Recall the currently approved drug treatments• Describe semagacestat’s mechanism of action• Explain semagacestat’s role in therapy

What is Alzheimer’s Disease

• Alios Alzheimer – 1906• Not a normal part of aging• Irreversible, progressive brain disease:– Slowly destroys memory and thinking skills– Disorientation and ability to reason– Death

• Risk factors: old age, family history, genetics (APOE-e4)

http://www.nia.nih.gov/alzheimers/topics/alzheimers-basics

Epidemiology and Costs

• More than 5 million American are living with Alzheimer’s Disease (AD). 6th leading cause of death in the United States (US)

• 1 out of every 3 Seniors in the US die from AD or other dementia

• $203 Billion for 2013, $1.2 trillion by 2050• In 2012, 15.4 million caregivers provided more

than 17.5 billion hours of unpaid care valued at $216 billion

http://www.alz.org/alzheimers_disease_facts_and_figures.asp

http://www.alz.org/alzheimers_disease_facts_and_figures.asp

Change in number of deaths (2000-2010)

Learning Objectives

• Describe Alzheimer’s Disease (AD) and recognize the risk factors

• Describe the pathophysiology of AD• Recall the currently approved drug treatments• Describe semagacestat’s mechanism of action• Explain semagacestat’s role in therapy

Pathophysiology

https://neurowiki2012.wikispaces.com/Down+Syndrome

• Amyloid-beta plaques• Neurofibrillary tangles• Neuronal degradation

Pathophysiology

• Schematic depiction of the process of amyloid-beta (AB) protein plaque formation. (National Institute on Aging)

https://neurowiki2012.wikispaces.com/Down+Syndrome

Beta and Gamma Secretase

Aβ protein plaques in cortex and hippocampus

APPAmyloid Precursor Protein

Learning Objectives

• Describe Alzheimer’s Disease (AD) and recognize the risk factors

• Describe the pathophysiology of AD• Recall the currently approved drug

treatments• Describe semagacestat’s mechanism of action• Explain semagacestat’s role in therapy

Current FDA approved drugs• Cholinesterase inhibitors for mild to moderate AD– Work by stopping the breakdown of the acetylcholine, a

neurotansmitter needed for communication– Donepazil, galantamine, rivastigmine, tacrine

• N-methyl-D-aspartate (NMDA) receptor antagonists for moderate to severe AD– Brains most prominent excitatory neurotransmitter– Works by regulating excess glutamate caused by AD, slowing

down neuronal damage– Memantine

http://www.alz.org/alzheimers_disease_standard_prescriptions.asp

Learning Objectives

• Describe Alzheimer’s Disease (AD) and recognize the risk factors

• Describe the pathophysiology of AD• Recall the currently approved drug treatments• Describe semagacestat’s mechanism of

action• Explain semagacestat’s role in therapy

Semagacestat’s Mechanism of Acation

Schematic depiction of the process of amyloid-beta (Aβ) protein plaque formation (National Institute on Aging)

https://neurowiki2012.wikispaces.com/Down+Syndrome

Beta and Gamma Secretase

Aβ protein plaques in cortex and hippocampus

APPAmyloid Precursor Protein

Study Objective

• Will semagacestat slow the progression of AD compared to placebo?

Study Design

• Phase 3, multicenter, randomized, parallel, double-blind, placebo-controlled trial

• 1537 patients with mild to moderate AD• 100 mg or 140 mg of semgacestat, or placebo

in a 1:1:1 ratio• Outcome: changes in cognition and

functioning based on assessment scales

Doody RS et al: A Phase 3 Trial of Semagacestat for Treatment of Alzheimer’s Disease. N Engl J Med 2013 369(4)

Methods - Assignment

• Screened 2009 patients, 1537 went randomization• Randomized by site (clinic location) and mild to

moderate AD• Inclusion criteria

– 55 years or older with mild to moderate AD without depression

– Magnetic resonance imaging (MRI) or computerized tomography (CT) scan within the past year with no findings inconsistent with a diagnosis of AD

– Female must be without menstruation 12 consecutive months or have ovaries removed

Doody RS et al.

Methods - Assignment

• Exclusion criteria– Not capable of swallowing whole oral medication– Has serious or unstable illness– Does not have reliable caregiver– Chronic alcohol or drug abuse in past 5 years

• 148 study locations globally

Doody RS et al.

Methods - Protocol

• Study drug, Semagacestat 100 mg or 140 mg, or placebo is dosed once a day for 76 weeks– No more than once daily because of inhibtion of

Notch• Titrate from 60 mg starting dose to assigned

dose to minimize adverse events (AEs)• 20 scheduled clinic visits

Doody RS et al.

Methods - Assessment

• Coprimary outcomes in 76 weeks– Alzheimer’s Disease Assessment Scale for

Cognition (ADAS-cog)– Alzheimer’s Disease Cooperative Study-Activities

of Daily Living scale (ADCS-ADL)• Compare changes of scores from baseline to

endpoint

Doody RS et al.

Methods - Assessment

• Secondary outcomes in 76 weeks– Clinical Dementia Rating –Sum of Boxes (CDR-SB)– Mini-mental State Examination (MMSE)– Neuropsychiatric Inventory (NPI)– Resource Utilization Dementia (RUD-Lite)….

• Subset of patients– Cerebral Spinal Fluid levels (CSF) of Aβ– CSF for tau – Imaging studies

Doody RS et al.

Assesse

ment

Scales

Doody RS et al.

Statistical Analysis

• Interim safety analysis after 50% patients completed 12 months or dropped out– Treatment worse than control (P < 0.05) – Conduct futility analysis, recommend to stop trial

• Mixed model repeated-measures analysis to compare model-adjusted least-squares means at 76 weeks

• All analysis Intent-to-treat (ITT)

Doody RS et al.

Statistical Analysis

• Baseline Characteristics– Categorical variables: Fisher’s Exact or Chi-square

test– Continuous variables: Analysis of Variance (ANOVA)

• Safety analysis based on ITT– Summary listing of adverse events– Fisher’s exact test used for pairwise comparisons

Doody RS et al.

Results – Baseline Characteristics

Doody RS et al.

Results - Mean Change From Baseline

Coprimary

2ndary

Cognition score Daily Living Score

Doody RS et al.

Results – Safety and Adverse Events

• Lost weight in drug group, placebo gained weight (P < 0.001)-1.5 +/- 4.4 kg in 100mg Semagacestat-1.6 +/- 4.7 kg in 140 mg Semagacestat0.4 +/- 3.9 kg in placebo

• Small increase from basline in QT interval for the treatment groups vs placebo (p < 0.001)

• AEs more common with semagacestat groupsMore cancers, skin and subcutaneous tissue disorders (P < 0.001)

Doody RS et al.

Results – Safety and Adverse Events

• Indirect evidence of Fancioni’s syndrome• Hepatocellulary injury, increase in cholesterol

levels, decrease in direct bilirubin, reduction in IgG• Rate of serious AEs higher in treatment group

(P < 0.001)– 24% in 100 mg semagacestat group– 25% in 140 mg semagacestat group– 14% in placebo

• More deaths (9, 14, 6), P = 0.25

Doody RS et al.

Learning Objectives

• Describe Alzheimer’s Disease (AD) and recognize the risk factors

• Describe the pathophysiology of AD• Recall the currently approved drug treatments• Describe semagacestat’s mechanism of action• Explain semagacestat’s role in therapy

Authors’ Conclusion on Semagacestat

• No benefit for treatment of mild-to-moderate AD• Associated with dose related clinical worsening• Study stopped after futility analysis• More adverse events and serious adverse events

Doody RS et al.

Theories on Clinical worsening

• Notch receptors impacted, is semagacestat more selective for Notch that APP?

• Lack of significant reduction in Aβ in CSF?• Other inhibitory substrates?

Doody RS et al.

Application

• No current trials with semagacestat• 40 open trials for AD that are recruiting http://www.clinicaltrials.gov/ct2/results?term=alzheimer%27s+disease&recr=Open&no_unk=Y

• Disease treatment pipeline– Amyloid Beta (Aβ), plaques– Tau protein, neurofibrillary tangles– Improving synaptic transmission– Oxidative stress and inflammatory pathways– Prevent AD– Looking upstream, Aβ plaques can be detected 20 years

before symptomshttp://www.pmlive.com/pharma_news/alzheimers_disease_pipeline_takes_multiple_hits_493398

---- semagacestat target

Questions

http://www.alz.org/braintour/plaques_tangles.asp