Semagacestat C19H27N3O4 is a candidate drug for a causal therapy against Alzheimer's disease. As of 2008[update], it is undergoing a Phase III clinical trial, the IDENTITY study, including 1500 patients from 22 countries. It is produced by Eli Lilly and Elan (USA).[1][2]
Method of action
Beta-Amyloid is a peptide of 39 to 43 amino acids. The isoforms with 40 and 42 amino acids (Aβ40/42) are the main constituents of amyloid plaques in the brains of Alzheimer's disease patients. β-amyloid is formed by proteolysis of APP. Research on laboratory rats suggest that the soluble form of this peptide is a causative agent in the development of Alzheimer's.
Semagacestat blocks the enzyme gamma secretase, which (along with gamma-secretase) is responsible for APP proteolysis.[2]
Issues
- Phase I and II studies showed a decrease of Amyloid concentration in the blood plasma about three hours after application of semagacestat, but an increase of 300% 15 hours after application. No reduction was shown in the cerebrospinal fluid. As a consequence, the phase III study works with much higher doses.[3]
- Gamma-secretase has other targets, for example the notch receptor. It is not known whether this could cause long-term side effects.[3]
- In a recent study an experimental vaccine was found to have cleared patients of amyloid plaques but did not have any significant effect on their dementia, casting doubt on the utility of approaches lowering amyloid levels.[4]
References
- H. Spreitzer (July 21, 2008). "Neue Wirkstoffe - Semagacestat" (in German). Österreichische Apothekerzeitung (15/2008): 780.
- Prous Science: Molecule of the Month July 2008
- Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2008/2009
- Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JAR (July 2008). "Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial" (Subscription required). The Lancet 372 (9634): 216-233.