Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings

Current Medical Research and Opinion

Volumn 30, Issue 10, 2014, Pages 2021-2032

  Henley, David B ^a   Sundell, Karen L ^a   Sethuraman, Gopalan ^a   Dowsett, Sherie A ^a   May, Patrick C ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

Adverse events; Alzheimer's disease; Gamma secretase inhibitor; Notch; Safety; Semagacestat; Tolerability

Indexed keywords

PLACEBO; SEMAGACESTAT; ALANINE; AZEPINE DERIVATIVE; N2-((2S)-2-(3,5-DIFLUOROPHENYL)-2-HYDROXYETHANOYL)-N1-((7S)-5-METHYL-6-OXO-6,7-DIHYDRO-5H-DIBENZO(B,D)AZEPIN-7-YL)-L-ALANINAMIDE; NOOTROPIC AGENT; SECRETASE;

ACNE; ACTINIC KERATOSIS; ACUTE KIDNEY FAILURE; ADULT; AGED; ALLERGIC REACTION; ALOPECIA; ALZHEIMER DISEASE; ANAPHYLAXIS; ARTICLE; BASAL CELL CARCINOMA; BODY WEIGHT DISORDER; BREAST DISEASE; BRONCHITIS; COGNITIVE DEFECT; CONGESTIVE HEART FAILURE; CONNECTIVE TISSUE DISEASE; CONTROLLED STUDY; COUGHING; DECREASED APPETITE; DEHYDRATION; DEPRESSION; DERMATITIS; DIARRHEA; DOUBLE BLIND PROCEDURE; DRUG DOSE REDUCTION; DRUG SAFETY; DRUG WITHDRAWAL; EAR INFECTION; ELECTROCARDIOGRAM; EPISTAXIS; ERYTHEMA; EYE DISEASE; FAINTNESS; FEMALE; FLATULENCE; FOLLICULITIS; FUNCTIONAL DISEASE; GASTROESOPHAGEAL REFLUX; GASTROINTESTINAL DISEASE; GASTROINTESTINAL HEMORRHAGE; HAIR COLOR; HEAD INJURY; HEART VENTRICLE TACHYCARDIA; HEMORRHOID; HERPES SIMPLEX; HOT FLUSH; HUMAN; HYPERHIDROSIS; HYPERNATREMIA; HYPOPIGMENTATION; HYPOTENSION; IMMUNOPATHOLOGY; INFECTIOUS PNEUMONIA; INFESTATION; KERATOACANTHOMA; KIDNEY DISEASE; LABORATORY TEST; LIVER DISEASE; LUNG CANCER; LUNG TUMOR; MACULOPAPULAR RASH; MAJOR CLINICAL STUDY; MALE; MEDIASTINUM DISEASE; MELANOMA; METABOLIC DISORDER; MUSCULOSKELETAL DISEASE; MYCOSIS; NAUSEA AND VOMITING; NECK PAIN; NEUROLOGIC DISEASE; NUTRITIONAL DISORDER; OTALGIA; PAPULAR RASH; PNEUMONIA; PROSTATE HYPERTROPHY; PRURITUS; PSORIASIS; QT PROLONGATION; RANDOMIZED CONTROLLED TRIAL; RASH; RESPIRATORY TRACT DISEASE; RESPIRATORY TRACT INFECTION; SINUSITIS; SKIN CANCER; SKIN CARCINOMA; SKIN DEFECT; SKIN DISEASE; SKIN INFECTION; SKIN MANIFESTATION; SKIN PAPILLOMA; SQUAMOUS CELL CARCINOMA; SUNBURN; THORAX DISEASE; TORSADE DES POINTES; UROGENITAL TRACT DISEASE; VERTEBRAL CANAL STENOSIS; VITAL SIGN; WEIGHT REDUCTION; ANALOGS AND DERIVATIVES; ANTAGONISTS AND INHIBITORS; DOSE RESPONSE; DRUG MONITORING; DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS; EARLY TERMINATION OF CLINICAL TRIAL; METABOLISM; MIDDLE AGED; OUTCOME ASSESSMENT; PATHOPHYSIOLOGY; PHASE 3 CLINICAL TRIAL (TOPIC); RISK ASSESSMENT;

AGED; ALANINE; ALZHEIMER DISEASE; AMYLOID PRECURSOR PROTEIN SECRETASES; AZEPINES; CLINICAL TRIALS, PHASE III AS TOPIC; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; DRUG MONITORING; DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS; EARLY TERMINATION OF CLINICAL TRIALS; FEMALE; HUMANS; MALE; MIDDLE AGED; NOOTROPIC AGENTS; OUTCOME ASSESSMENT (HEALTH CARE); RISK ASSESSMENT;

EID: 84909980892     PISSN: 03007995     EISSN: 14734877     Source Type: Journal    
DOI: 10.1185/03007995.2014.939167     Document Type: Article

References (46)

1. Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 2013;80:1778-83
2. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002;297:353-6. Erratum in: Science 2002;297:2209
3. Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 2007;8:101-12
4. Gitter BD, Czilli DL, Li W, et al. Stereoselective inhibition of amyloid beta peptide secretion by LY450139, a novel functional gamma secretase inhibitor. Neurobiol Aging 2004;25(Suppl 2):S571
5. Siemers ER, Quinn JF, Kaye J, et al. Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer's disease. Neurology 2006;66:602-4
6. Boggs LN, Fuson KS, Gitter BD, et al. In vivo characterization of LY450139, a novel, stereoselective, functional gamma-secretase inhibitor. Neurobiol Aging 2004;25(Suppl 2):S218
7. Hyslop PA, May PC, Audia JE, et al. Reduction in a-beta(1-40) and A-beta(1-42) in CSF and plasma in the beagle dog following acute oral dosing of the gamma secretase inhibitor, LY450139. Neurobiol Aging 2004;25(Suppl 2):S147
8. Lanz TA, Karmilowicz MJ, Wood KM, et al. Concentration-dependent modulation of amyloid-beta in vivo and in vitro using the gamma-secretase inhibitor, LY-450139. J Pharmacol Exp Ther 2006;319:924-33
9. Borghys H, Tuefferd M, Van Broeck B, et al. A canine model to evaluate efficacy and safety of γ-secretase inhibitors and modulators. J Alzheimers Dis 2012;28:809-22
10. Ness DK, Boggs LN, Hepburn DL, et al. Reduced β-amyloid burden, increased C99 concentration and evaluation of neuropathology in the brains of PDAPP mice given LY450139 dihydrate daily by gavage for 5 months. Neurobiol Aging 2004;25(Suppl 2):S238-9
11. Siemers E, Skinner M, Dean RA, et al. Safety, tolerability and changes in amyloid beta concentrations after administrations of a gamma-secretase inhibitor in volunteers. Clin Neuropharmacol 2005;28:126-32
12. Fleisher AS, Raman R, Siemers ER, et al. Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer's disease. Arch Neurol 2008;65:1031-8
13. Bateman RJ, Siemers ER, Mawuenyega KG, et al. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol 2009;66:48-54
14. Doody RS, Raman R, Farlow M, et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med 2013;369:341-50
15. Pollack SJ, Lewis H. Secretase inhibitors for Alzheimer's disease: challenges of a promiscuous protease. Curr Opin Investig Drugs 2005;6:35-47
16. De Strooper B, Annaert W, Cupers P, et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 1999;398:518-22
17. Wong GT, Manfra D, Poulet FM, et al. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 2004;279:12876-82
18. Milner LA, Bigas A. Notch as a mediator of cell fate determination in hematopoiesis: evidence and speculation. Blood 1999;93:2431-48
19. Searfoss GH, Jordan WH, Calligaro DO, et al. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem 2003;278:46107-16
20. Siemers ER, Dean RA, Friedrich S, et al. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmacol 2007;30:317-25
21. Fleisher AS, Sowell BB, Taylor C, et al.; Alzheimer's Disease Cooperative Study. Clinical predictors of progression to Alzheimer disease in amnestic mild cognitive impairment. Neurology 2007;68:1588-95
22. Mizutari K, Fujioka M, Hosoya M, et al. Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. Neuron 2013;77:58-69
23. Shih IEM, Wang TL. Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res 2007;67:1879-82
24. Siemers E, Henley D, Sundell K, et al. Evaluating semagacestat, a gamma secretase inhibitor, in a Phase III Trial. Alz Dem 2011;7(Suppl):S484-5
25. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939-44
26. Lleo A, Saura CA. γ-secretase substrates and their implications for drug development in Alzheimer's disease. Curr Top Med Chem 2011;11:1513-27
27. Radtke F, Wilson A, Mancini SJC, MacDonald HR. Notch regulation of lymphocyte development and function. Nature Immunology 2004;5:247-53
28. Moriyama M, Osawa M, Mak SS, et al. Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells. J Cell Biol 2006;173:333-9
29. Hoshino N, Katayama N, Shibasaki T, et al. A novel role for Notch ligand Delta-1 as a regulator of human Langerhans cell development from blood monocytes. J Leukoc Biol 2005;78:921-9
30. Brittan M, Wright NA. Gastrointestinal stem cells. J Pathol 2002;197:492-509
31. Xia X, Qian S, Soriano S, et al. Loss of presenilin 1 is associated with enhanced β-catenin signaling and skin tumorigenesis. PNAS 2001;98:10863-8
32. Proweller A, Tu L, Lepore JJ, et al. Impaired notch signaling promotes de novo squamous cell carcinoma formation. Cancer Res 2006;66:7438-44
33. Li T, Wen H, Brayton C, et al. Epidermal growth factor receptor and Notch pathways participate in the tumor suppressor function of γ-secretase. J Biol Chem 2007;282:32264-73
34. Okuyama R, Tagami H, Aiba S. Notch signaling: its role in epidermal homeostasis and in the pathogenesis of skin diseases. J Derm Science 2008;49:187-94
35. Pinnix CC, Herlyn M. The many faces of Notch signaling in skin-derived cells. Pigment Cell Res 2007;20:458-65
36. Radtke F, Raj K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 2003;3:756-67
37. Izzedine H, Launay-Vacher V, Isnard-Bagnis C, Deray G. Drug-induced Fanconi's syndrome. Am J Kidney Dis 2003;41:292-309
38. Yi P, Hadden C, Kulanthaivel P, et al. Disposition and metabolism of semagacestat, a γ-secretase inhibitor, in humans. Drug Metab Dispos 2010;38:554-65
39. Müller T, Meyer HE, Egensperger R, Marcus K. The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics - relevance for Alzheimer's disease. Prog Neurobiol 2008;85:393-406
40. Bittner T, Fuhrmann M, Burgold S, et al. Gamma-secretase inhibition reduces spine density in vivo via an amyloid precursor protein-dependent pathway. J Neurosci 2009;2:10405-9
41. Mitani Y, Yarimizu J, Saita L, et al. Differential effects between γ-secretase inhibitors and modulators on cognitive function in amyloid precursor protein - transgenic and nontransgenic mice. J Neurosci 2012;32:2037-50
42. Inoue E, Deguchi-Tawarada M, Togawa A, et al. Synaptic activity prompts gamma-secretase-mediated cleavage of EphA4 and dendritic spine formation. J Cell Biol 2009;185:551-64
43. Ables JL, Breunig JJ, Eisch AJ, Rakic P. Not(ch) just development: Notch signaling in the adult brain. Nat Rev Neurosci 2011;12:269-83
44. Alberi L, Liu S, Wang Y, et al. Activity-induced notch signaling in neurons requires Arc/Arg3.1 and is essential for synaptic plasticity in hippocampal networks. Neuron 2011;69:437-44
45. Albright CF, Dockens RC, Meredith Jr JE, et al. Pharmacodynamics of selective inhibition of γ-secretase by avagacestat. J Pharmacol Exp Ther 2013;344:686-95
46. Coric V, van Dyck C, Salloway S, et al. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol 2012;6:1430-40