1 / 39

EXPRESS Results

EXPRESS Results. Sibel Tekin, MD Clinical Program Leader Neuroscience Clinical Development and Medical Affairs Novartis Pharmaceuticals Corporation. Overview. Patient disposition and baseline characteristics Efficacy results for the double-blind core study

fruma
Download Presentation

EXPRESS Results

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. EXPRESS Results Sibel Tekin, MD Clinical Program LeaderNeuroscience Clinical Development and Medical AffairsNovartis Pharmaceuticals Corporation

  2. Overview • Patient disposition and baseline characteristics • Efficacy results for the double-blind core study • Safety findings for the core and extension studies

  3. Patient DispositionCore and Extension Studies 650 screened Core study 541 randomized to core study CSR Core T 7-1; Extension 362 Exelon 179 placebo 32 (17.9%)discontinued 99 (27.3%)discontinued 147 (82.1%) completed 263 (72.7%) completed Extension study 334 out of 410 entered O-L study 211 to Exe-Exelon 123 to Plc-Exelon 96 (78.0%) completed 177 (83.9%) completed

  4. Reasons for DiscontinuationCore Study SCE T3-5.

  5. Baseline CharacteristicsCore Study CSR Core Table 7-4, PTT7.4-1

  6. 40-6 Timing of Imaging (MRI or CT Scans)Core Study—All Randomized Patients Source data verification is ongoing.

  7. Baseline CharacteristicsCore Study CSR Core T 7-5, PTT7.4-2

  8. 15-12 DV Baseline Cognitive and Functional Assessment of EXPRESS Study PopulationCore Study—ITT-RDO Population CSR 2311 PTTs 9.1-1, 9.2-1, 9.2-7, 9.2-30, 9.2-34, 9.2-9, 9.2-13 † Total correct responses/min.

  9. Baseline Neuropsychiatric Symptoms Core Study—ITT+RDO Population Post-text table 9.2-24

  10. Dopaminergic Agents Before Start of Study Drug Core Study CSR Core T 8-3, PTT8.2-2, 8.2-4 † Includes Levodopa, Levodopa with benserazide, and Carbidopa

  11. Efficacy Double-Blind Core Study

  12. Primary Outcomes • Two primary outcome measures • Cognition: ADAS-cog • Global dementia assessment: ADCS-CGIC • Primary endpoint • Wk 24 • ITT+RDO population

  13. 15-14 DV ADAS-cog Least Squares (LS) Mean Change from Baseline Core Study—ITT+RDO Analysis p = 0.002 p < 0.001 Improvement 16 † Least squares means ± SE (adjusted for baseline and country). P-value based on ANCOVA using treatment and country as factors and baseline ADAS-cog as a covariate.

  14. ADCS-CGIC—Categorical Analysis at Wk 24Core Study—ITT+RDO Analysis CSR 2311 T 9-3, PTT9.1-8, 9.1-9, 9.1-10 p = 0.007† † p-value based on van Elteren test blocking for country.

  15. ADAS-cog—Change from Baseline at Wk 24Core Study CSR Core T 9-1 Results were also statistically significant at Wk 16 in favor of Exelon

  16. ADCS-CGIC—Categorical Analysis at Wk 24 Core Study Source: [Report 2311-Table 9-3 ] Results were also statistically significant at Wk 16 in favor of Exelon.

  17. Secondary Outcomes • Functioning • Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) • Behavior • Neuropsychiatric Inventory (NPI-10 and NPI-D for caregiver distress) • Attention • Cognitive Drug Research (CDR) computerized attention battery • Executive function • Delis-Kaplan Executive Function System (D-KEFS), letter fluency test

  18. 15-16 DV ADCS-ADL—LS Mean Change from Baseline at Wk 24 Core Study—ITT+RDO Analysis CSR 2311 T9-5 PTT 9.2-4 p = 0.023 Deterioration 16 24 Time, wk

  19. 15-17 DV NPI-10—LS Mean Change from Baseline at Wk 24Core Study—ITT+RDO Analysis Improvement CSR 2311 T9-6PTT 9.2-22, STDERR_ANCOVA from Jay Hsu p = 0.015 16 24 Time, wk

  20. 15-18 DV CDR Power of Attention—LS Mean Change from Baseline at Wk 24Core Study—ITT+RDO Analysis CSR 2311 T9-7 PTT9.2-10 Improvement p = 0.009 16 24 Time, wk Power of attention score = Simple reaction time + digit vigilance + choice reaction time.

  21. 15-21 DV Exelon (N= 335) Placebo (N = 166) D-KEFS Letter Fluency—Mean Change from Baseline at Wk 24Core Study—ITT+RDO Analysis CSR 2311 T9-8 PTT 9.2-30 Improvement p < 0.001 P-value based on van Elteren test blocking for country.

  22. Additional AnalysesCore Study Age, Gender, and Baseline Characteristics

  23. ADAS-cog—Treatment Difference (95% CI) at Wk 24 by Baseline SubgroupsCore Study—ITT+RDO Population –5 0 5 10 Favor placebo Favor Exelon *Mild dementia: MMSE 18 - 24 **Moderate dementia: MMSE 10 - 17

  24. 4-11 Exelon Placebo Patients With and Without Visual Hallucinations at Baseline—ADAS-cog at Wk 24Core Study—ITT+RDO Population Improvement 2.1† PTT 9.1-1c 2311 PTT 9.1-4c p = 0.015 4.3† p = 0.002 n = 107 60 220 101 With Without Visual hallucinations † Least squares means adjusted for baseline and country.

  25. 4-11 Exelon Placebo Patients With and Without Visual Hallucinations at Baseline—NPI-10 at Wk 24Core Study—ITT+RDO Population Improvement 4.2† PTT 9.1-1c 2311 PTT 9.1-4c p = 0.013 0.4† p = 0.713 n = 110 64 223 102 With Without Visual hallucinations † Least squares means adjusted for baseline and country.

  26. 9-25 DV Antipsychotic Use Core Study Final appeal dossier Nov 30 2005 Table 2-14 Discontinuation of use of antipsychotic medication is included in decreased dose group.

  27. Efficacy Summary • Both primary outcome measures assessing cognition and overall dementia • Statistically significant results in favor of Exelon • Across analysis populations • At both Wk 16 and 24 • Secondary outcome measures assessing activities of daily living, executive function, attention, and behavior • Statistically significant at Wk 24

  28. Safety Double-Blind Core and Open-Label Extension Studies

  29. Last Dose of Study Medication Core Study—Safety Population PHAT 2-105

  30. Percentage of Patients With Adverse Events (AEs) ≥ 5% in Any GroupCore and Extension Studies CSC T 4-2, Core PTT10.1-4; Extension PTT 10.1-4

  31. Percentage of Patients With Serious Adverse Events (SAEs) ≥ 1% in Any Group Core and Extension Studies CSC T 4-10

  32. Most Frequent Discontinuations Due to AEs (≥ 1% in Any Group)Core and Extension Studies CSC T 4-11, PTT10-2-1 (Core), 10.2-1 (Extension) 3 Exelon-treated and 2 placebo-treated patients in the core study and 2 patients in thePlc-Exelon group had multiple above-mentioned AEs leading to discontinuation.

  33. AEs Potentially Associated With Nonmotor Symptoms of PDCore and Extension Studies CSR 2311 T10-1, PTT10-1.1; 2311e1 T10-1, PTT 10.1-1

  34. Akinesia Balance disorder Bradykinesia Drooling Dysarthria Dyskinesia Dsytonia Fall Freezing phenomenon Gait abnormality Hypertonia Hypokinesia Motor dysfunction Movement disorder Muscle rigidity Musculoskeletal stiffness On and off phenomenon Parkinson’s disease worsening Parkinsonism worsening Rigors Salivary hypersecretion Tremor Predefined Group of Motor Symptom AEs— ‘Potentially Associated With PD’

  35. Editor: keep apostrophe around ‘potentially . . . 3-23DV Cardinal Extrapyramidal Motor Symptom AEs Core and Extension Studies SCS T8-2, PTT10.2-3, 10.1-1 (Core), PTT10.2-3, (Extension) PTT10.2-3 (SCS); Post hoc 2-26 (Extension PTL App. 7.1 1-18)

  36. 9 9-9 DV Consequences of AEs of Tremor and ‘Potentially Associated With PD’ Core Study Final appeal dossier Nov 30 2005 T 2-7 † For patients with more than 1 event, the most severe event was used. ‡ Percentages based on number of patients with events.

  37. 9-13 DV UPDRS Part III Change From Baseline at Wk 24 (Core) and Wk 48 (Extension) Final appeal dossier Nov 30 2005 T 2-9 † Calculated only for patients who had Wk 24 and Wk 48 evaluations from baseline at Wk 0. Negative change from baseline indicates improvement.

  38. Safety ConclusionCore and Extension Studies • Most frequent AEs in Exelon group were nausea, vomiting, and tremor • Majority were mild to moderate events with infrequent discontinuation • SAEs and deaths were consistent with events expected in the elderly population • Fewer events in the Exelon group • No increased cardiovascular or psychiatric events in the Exelon group

  39. Safety ConclusionCore and Extension Studies • Tremor was slightly higher in the Exelon group and was the main driver of AEs ‘potentially associated with PD’ • Majority were mild to moderate events with infrequent discontinuation • Underlying PD did not worsen based on UPDRS part III total scores • Long-term (1 yr) treatment in PDD was not associated with any new safety concerns

More Related