A review of a drug, Semagacestat, for the treatment of Alzheimer's Disease, that did not get approved by the FDA due increased side effects.

1. Termination of a Phase 3 Trial of
Semagacestat for the Treatment of
Alzheimer's Disease
Rod Bugawan
November 14, 2013
Lipscomb University College of Pharmacy

2. 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

3. 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

4. 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

5. Change in number of deaths (2000-2010)
http://www.alz.org/alzheimers_disease_facts_and_figures.asp

6. 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

7. Pathophysiology
• Amyloid-beta plaques
• Neurofibrillary tangles
• Neuronal degradation
https://neurowiki2012.wikispaces.com/Down+Syndrome

8. Pathophysiology
• Schematic depiction of the process of amyloid-beta (AB) protein plaque
formation. (National Institute on Aging)
APP
Amyloid
Precursor
Protein
Beta and Gamma
Secretase
Aβ protein plaques in
cortex and hippocampus
https://neurowiki2012.wikispaces.com/Down+Syndrome

9. 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

10. 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

11. 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

12. Semagacestat’s Mechanism of Acation
Schematic depiction of the process of amyloid-beta (Aβ) protein plaque
formation (National Institute on Aging)
APP
Amyloid
Precursor
Protein
Beta and Gamma
Secretase
Aβ protein plaques in
cortex and hippocampus
https://neurowiki2012.wikispaces.com/Down+Syndrome

13. Study Objective
• Will semagacestat slow the progression of AD
compared to placebo?

14. 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)

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. Doody RS et al.

21. 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.

22. 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.

23. Results – Baseline Characteristics
Doody RS et al.

24. Results - Mean Change From Baseline
Cognition score
Daily Living Score
Doody RS et al.

25. 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 Semagacestat
0.4 +/- 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 groups
More cancers, skin and subcutaneous tissue disorders
(P < 0.001)
Doody RS et al.

26. 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.

27. 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

28. 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.

29. 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.

30. 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 ---- semagacestat target
Tau protein, neurofibrillary tangles
Improving synaptic transmission
Oxidative stress and inflammatory pathways
Prevent AD
Looking upstream, Aβ plaques can be detected 20
years before symptoms
http://www.pmlive.com/pharma_news/alzheimers_disease_pipeline_takes_multiple_hits_493398

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