Semagacestat for Alzheimer's Disease

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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.

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Semagacestat for Alzheimer's Disease

  1. 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. 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. 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. 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. 5. Change in number of deaths (2000-2010) http://www.alz.org/alzheimers_disease_facts_and_figures.asp
  6. 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. 7. Pathophysiology • Amyloid-beta plaques • Neurofibrillary tangles • Neuronal degradation https://neurowiki2012.wikispaces.com/Down+Syndrome
  8. 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. 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. 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. 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. 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. 13. Study Objective • Will semagacestat slow the progression of AD compared to placebo?
  14. 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. 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. 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. 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. 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. 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. 20. Doody RS et al.
  21. 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. 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. 23. Results – Baseline Characteristics Doody RS et al.
  24. 24. Results - Mean Change From Baseline Cognition score Daily Living Score Doody RS et al.
  25. 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. 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. 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. 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. 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. 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. 31. Questions http://www.alz.org/braintour/plaques_tangles.asp

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