Semagacestat was a candidate drug for a causal therapy against Alzheimer's disease. It was developed by Eli Lilly and Élan, clinical trials were conducted by Eli Lilly. Phase III trials included over 3000 patients, but in August 2010, a disappointing interim analysis, in which semagacestat performed worse than the placebo, led to the trials being stopped. Β-Amyloid is a peptide of 39 to 43 amino acids. The isoforms with 40 and 42 amino acids are the main constituents of amyloid plaques in the brains of Alzheimer's disease patients. Β-Amyloid is formed by proteolysis of amyloid precursor protein. 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 γ-secretase, responsible for APP proteolysis. Phase III double-blind clinical trials started in March 2008 with the IDENTITY study, including 1500 patients from 22 countries; this study was intended to run until May 2011. The successor trial with further 1500 patients, IDENTITY-2, started in September 2008.
The open-label trial IDENTITY-XT, which included patients who have completed one of the two studies, started in December 2009. On 17 August 2010, it was announced. Preliminary findings show that not only did semagacestat fail to slow disease progression, but that it was associated with “worsening of clinical measures of cognition and the ability to perform activities of daily living”. Furthermore, the incidence of skin cancer was higher in the treatment group than the placebo group. A number of issues have been raised during clinical trials: Phase I and II studies showed a decrease of Aβ40/42 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 studies worked with much higher doses. Γ-Secretase has other targets, for example the notch receptor. It is not known. In a 2008, histological analysis of post-mortem brains from deceased subjects, enrolled in a phase 1 study of an experimental vaccine demonstrated that the drug appeared to have cleared patients of amyloid plaques but did not have any significant effect on their dementia, which in some people's mind cast doubt on the utility of approaches lowering β-amyloid levels.
A notable feature of the results of the semagacestat phase III interim analysis is that subjects on treatment did worse in cognitive assessment and activities of daily living than did subjects in the placebo group. This contrasts with the results from the phase III trial of Myriad's γ-secretase modulator tarenflurbil, which found that the subjects in the treatment group tracked the placebo control group closely; the implications of this finding on other companies undertaking development of molecules targeting γ-secretase is not clear
Nicholas Heath is an English footballer who plays for Midland Football Combination Premier Division side Bolehall Swifts, where he plays as a midfielder. Heath began his professional career with Football League Two side Kidderminster Harriers, Nick only went on to make one appearance for the club, which finished a 2–0 away defeat to Macclesfield Town. Bolehall Swifts Heath was made club captain. In his first season Swifts reached the final of the Coventry Charity cup which they lost 2-0 to Alvis Sporting. However, in season 13-14 Heath lifted the Birmingham Midweek Floodlit Cup after Swifts beat Southam Utd 9–2. At the end of the 13–14 season Heath has made 80 appearances scoring 2 goals. Nick Heath at Soccerbase Nick Heath profile at kidderminsterharriers.com Nick Heath profile at harriers-online.co.uk