27 August 2008. At the International Conference for Alzheimer’s Disease, held 26-31 July in Chicago, several investigators presented data on compounds in Phase 2. Below is a summary of an approach targeting a neurotransmitter receptor, two approaches targeting Aβ, and one testing a nutrient supplement. In addition to these, Phase 2 data of AL-108, a neuroprotective compound administered through the nose, presented data that Alzforum had summarized recently after a similar conference presentation in Boston (see ARF related news story).

Boosting Neurotransmission: SB-742457
SB-742457 by GlaxoSmithKline is one of a range of small-molecule drugs that aim to right neurochemical disturbances in AD. The cholinergic and also the serotonergic neurotransmitter systems, among others, are impaired as Alzheimer’s develops and progresses, and they present opportunities for renewed efforts at propping up neurotransmission. These drugs are not billed as targeting primarily what many consider to be causal AD pathways of Aβ amyloidosis and tauopathy. Instead they are more modestly presented as improving symptoms of memory loss and behavior in AD and other forms of dementia, perhaps as part of future combination drug regimens.

SB-742457 is a new antagonist of the 5-HT receptor 6, a largely CNS-specific type of serotonine receptor subfamily (Upton et al., 2008). At ICAD, GSK researchers presented clinical data on two Phase 2 trials, as well as preclinical data on cognition models. Gareth Maher-Edwards of GSK described a dose-finding trial in 371 people with mild to moderate AD who received one of three doses of this antagonist or placebo for 24 weeks, and then had its efficacy assessed by means of the CIBIC+ scale to look for global function and the ADAS-Cog to look for cognitive change. Dropout rates ranged from 13 to 20 percent depending on the dose. Maher-Edwards reported a statistically significant improvement over baseline in CIBIC+ at the highest dose, also a trend without statistical significance for a slight improvement in ADAS-Cog.

A second, smaller trial of 197 patients compared this highest dose of 35 mg/day dose of the serotonin receptor antagonist to 5 mg/day of donepezil, a widely prescribed cholinesterase inhibitor that is standard therapy in AD, and placebo. Using the same outcome measures, SB-742457 showed small treatment effects of roughly similar size to donepezil. The placebo groups did not decline by six months in either of these two trials, so the small reported drug effects are essentially improvements over baseline consistent with a symptomatic effect. People who started the trials with lower MMSE values, i.e., the more impaired patients, appeared to respond a little better, and the drug appeared to be safe and well tolerated, Maher-Edwards said. He added that four deaths in the study were due to traffic accidents, cancer, and a heart attack but unrelated to the study drug.

Rather than proceed to Phase 3, GSK is continuing to explore this drug in Phase 2 with two more six-month trials. An 89-center, 672-patient trial testing a single dose of SB-742457 in some 670 patients in addition to donepezil is recruiting at present, and a slightly smaller trial comparing SB-742457 to donepezil is set to get going later this year. Besides the usual cognitive, global, and safety measures, these trials will look for pharmacogenomic effects, but they have no fluid or imaging biomarker components.

Other neurochemical targets under active study include nicotinic and muscarinic acetylcholine receptors, as well as 5-HT4 receptors (for coverage of active clinical programs on the latter two, see ARF recent Keystone story) and the serotonine 1A receptors.—Gabrielle Strobel.

This is Part 1 of a three-part series. See also Part 2