Semagacestat was a candidate drug for a causal therapy against Alzheimer's disease

Alzheimer's disease

Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

. It was originally developed by Eli Lilly

Eli Lilly and Company

Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...

 and Élan

Élan

Élan Corporation plc is a major drugs firm based in Athlone, County Roscommon, Ireland which has major interests in the United States. In the late 1990s its value on the Irish Stock Exchange reached over €20bn. It has secondary listings on the London Stock Exchange and the New York Stock Exchange....

, and clinical trial

Clinical trial

Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

s were conducted by Eli Lilly. Phase III trials included over 3000 patients, but in August 2010, a disappointing interim analysis, in which semagacestat performed less well than the placebo, led to investigators being instructed to tell subjects to stop taking the drug.

Mechanism of action

β-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

Proteolysis

Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...

 of APP

Amyloid precursor protein

Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...

. 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

Gamma secretase

Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases...

, which (along with β-secretase) is responsible for APP proteolysis.

Clinical trials

Phase III double-blind clinical trials started in March 2008 with the IDENTITY study (Interrupting Alzheimer's dementia by evaluating treatment of amyloid pathology), 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

Open-label trial

An open-label trial or open trial is a type of clinical trial in which both the researchers and participants know which treatment is being administered....

 IDENTITY-XT, which included patients who have completed one of the two studies, started in December 2009. On 17 August 2010, it was announced that the phase III trials failed. Preliminary findings show that not only did semagacestat fail to slow disease progression, but that it was actually associated with “worsening of clinical measures of cognition and the ability to perform activities of daily living”. Furthermore, the incidence of skin cancer was significantly higher in the treatment group than the placebo group.

Issues

A number of issues have already been raised during clinical trials:

• Phase I and II studies showed a decrease of Aβ40/42 concentration in the blood plasma
  Blood plasma
  Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
  
   about three hours after application of semagacestat, but an increase of 300% 15 hours after application. No reduction was shown in the cerebrospinal fluid
  Cerebrospinal fluid
  Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
  
  . 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 whether this could cause long-term side effects.
• In a 2008, histological analysis of post-mortem brains from deceased subjects who had previously been enrolled in a phase 1 study of an experimental vaccine (Elan AN1792) 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 significantly 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 very closely. The implications of this finding on other companies undertaking development of molecules targeting γ-secretase is not yet clear.