This is Part 5 of a seven-part series. See also Part 1, Part 2, Part 3, Part 4, Part 6, and Part 7. Read a PDF of the entire series.

14 November 2012. The 5th Clinical Trials in Alzheimer’s Disease conference, held 29-31 October in Monaco, featured a new Phase 2 program that uses genetics to enrich an MCI population for an early-stage therapeutic trial. The drug at hand is called CHF5074. This erstwhile γ-secretase modulator has been recently recast as a microglial modulator that may hold promise for people who carry the ApoE4 allele. CHF5074 is about to enter the first of two long-term pharmacogenetic biomarker studies.

At CTAD, Bruno Imbimbo of Chiesi Pharmaceuticals in Rockville, Maryland, reminded the audience of the finding that long-term use of NSAIDs confers a degree of protection against Alzheimer’s, particularly in ApoE4 carriers (e.g., Szekely et al., 2008; Breitner et al., 2011). NSAIDs drew intense interest in AD research for some years after a widely noted finding by Sascha Weggen and colleagues that certain NSAIDs lower Aβ42 production independent of their action on the Cox enzymes (Weggen et al., 2001). Much of the subsequent research was driven by the goal of lowering Aβ by tweaking the γ-secretase complex with new NSAID derivatives.

This is how CHF5074 began in 2007, and PubMed papers on it up to January 2012 call it a γ-secretase modulator. Early studies measured its ability to affect Aβ- and other amyloid-related outcomes (e.g., Imbimbo et al., 2009). As the researchers tried to pin down exactly what the compound does, subsequent papers proposed other mechanisms of action, such as restoring neurogenesis (Imbimbo et al., 2010), reorganizing the astrocytic cytoskeleton (Lichtenstein et al., 2010), or reducing tau (Lanzillotta et al., 2011) and rescuing synaptic plasticity (Balducci et al., 2011).

At CTAD, Imbimbo built an argument for treating neuroinflammation in the years leading up to Alzheimer’s disease. He said that certain NSAIDs lead microglia to adopt either the M1 phenotype associated with cytokine and nitric oxide synthase production, or the M2 phenotype associated with amyloid phagocytosis. “It is very important in which way microglia get activated,” Imbimbo told the audience. In mixed glial cultures, CHF5074 blunts the M1 and stimulates the M2 response, Imbimbo said, and the cells’ subsequent phagocytic appetite decreases plaques and reverses cognitive deficits in several different lines of transgenic AD mice.

Chiesi Pharmaceuticals, an Italian drug company based in Parma, ran Phase 1 studies in healthy volunteers, as well as one Phase 2 study in people with MCI that currently continues in open-label extension (see ClinicalTrials.gov). That work has shown that the compound enters the brain and lowers CSF concentrations of sCD40L and TNF-α, biomarkers of neuroinflammation, in a dose-dependent fashion, Imbimbo told the CTAD audience. The MCI trial showed signals of benefit on executive function as measured by the Trail Making B Test, and in verbal memory as measured by word recall after 52 weeks of treatment. This was particularly true in ApoE4 carriers, Imbimbo said. The main side effect was mild diarrhea (Imbimbo et al., 2012).

With this, Chiesi decided to go ahead with a Phase 2 program called Genetically Enriched Population At Risk of Developing Alzheimer’s Disease (GEPARD-AD). Twenty-five U.S. sites led by Joel Ross of the Memory Enhancement Center in Eatontown, New Jersey, will participate. The protocol received input from Rachelle Doody of Baylor College of Medicine in Houston, Texas; Pierre Tariot of the Banner Alzheimer’s Institute in Phoenix, Arizona; Lon Schneider of the University of Southern California; and Paul Thompson of UCLA School of Medicine in Los Angeles.

One trial will enroll 87 MCI patients each for placebo, 200 mg, or 400 mg of drug per day; a potential second trial currently in planning is designed to enroll 141 cognitively normal people per group into the same regimen. Treatment will last for two years. As the name suggests, the trials enrich their predementia population not by measuring CSF or amyloid PET, but by seeking people who carry at least one ApoE4 allele. The second trial, of asymptomatic ApoE4 carriers, would attempt to enrich by requiring that a parent had Alzheimer’s. The program enrolls fairly young participants, aged 45 to 65, because both the influence of ApoE and the inflammatory component of AD on progression change with age, Imbimbo said. Outcome measures to be used in this trial include MRI volumetry, synaptic function by way of FDG-PET, CSF markers of AD, as well as CSF sCD40L and TNF-a, verbal and visuospatial memory, and the CDR-SB. At the time of writing, the first trial was set to start enrolling in December 2012. Since then, Chiesi has made a decision to hold off until the company has found a pharmaceutical partner. This was a business decision, not linked to safety or efficacy data, Imbimbo stated by e-mail to Alzforum.—Gabrielle Strobel.

This is Part 5 of a seven-part series. See also Part 1, Part 2, Part 3, Part 4, Part 6, and Part 7. Read a PDF of the entire series.