This year’s International Conference on Alzheimer's Disease (ICAD) was held in Chicago from July 26 – 31. In addition to the much anticipated Phase II data on the amyloid beta (Aß) antibody bapineuzumab (WYE, ELN), it was interesting to see the breadth of different types of compounds in development. As a result of the rapidly changing research in the field, the Alzheimer’s association announced the conference would subsequently be held annually, instead of every other year.

Unfortunately, the bapineuzumab data was disappointing. Besides safety concerns, the variable efficacy and changes in the statistical analysis heightened questions whether the positive subgroup results were just due to chance, though some observers felt there was a respectable positive signal in the overall population.

The data did little to raise confidence in the Aß hypothesis (that Aß is the primary culprit in AD), and illustrated the pitfall that trying to show cognitive improvement in Phase II for a disease-modifying agents may require a large and long study, if the efficacy signal is not very strong or only subgroups of patients are impacted.

On the other hand, extension data from another Phase II study evaluating cognition found that Gammagard (BAX), a plasma-derived collection of antibodies used to treat immunodeficiencies, did show a statistically significant improvement at 9 months, though there were also mitigating factors that raised questions about the robustness of the data (for example, the comparator group were patients who started on placebo and then switched to Gammagard).

Some other development programs have decided to take an alternate route, looking primarily for positive biomarker results in shorter Phase II trials and then proceeding directly to Phase III. It is not yet known how well the biomarkers correlate with efficacy in humans, however, leaving a great deal of uncertainty for the Phase III trials.

Drugs in this category include Lilly’s Aß antibody LY2062430 and gamma-secretase inhibitor LY450139, which reduces the production of Aß. LY2062430 did show some circumstantial evidence that it may be able to impact Aß plaques despite its binding only to soluble forms, though this could not be verified on brain imaging. Since reducing plaques could be important for efficacy (in addition to clearing toxic soluble Aß), the data raised some glimmer of hope that LY2062430 could be efficacious while avoiding vasogenic edema associated with bapineuzumab, though some feel that vasogenic edema is a direct result of releasing Aß from plaques rather than inflammation.

LY450139 has not been shown to significantly reduce levels of Aß in the cerebrospinal fluid (CSF), raising concerns about its impact on Aß in the brain. Hence it was encouraging to see evidence that it reduced the synthesis of Aß found in the CSF.

Biomarker data from other gamma secretases, GSI-953 (WYE) and BMS-708163 (BMY) were also presented. BMS-708163 is the only one of the three that showed lowering of CSF Aß levels in humans, which could be because a relatively higher dose can be used, since it should be better at avoiding the metabolism of Notch protein and consequent side effects. Correlations between clinical and preclinical biomarker effects were presented for GSI-953, showing it still might be able to reduce brain Aß even though at the doses tested it did not reduce CSF Aß levels. However, its impact on Aß42 (in blood plasma) was lower than on the less toxic form, Aß40, raising additional uncertainty for the drug.

Inhibition of beta secretase may be safer than gamma secretase, but it has been technically difficult to make these compounds. Hence it was encouraging to see an abstract on beta secretase inhibitor CTS-21166 (Comentis and Astellas) indicating that oral dosing could lead to drug blood levels that should have an effect on plasma Aß.

Despite all the research into drugs impacting Aß, the recent failures of Alzhemed and Flurizan, along with patients with severe dementia despite clearance of Aß plaques by AN-1792, has raised questions about the Aß hypothesis and spurred interest in other mechanisms. Hence data from a drug that may interfere with tau protein aggregation, Rember (TauRx), generated significant interest, despite shortcomings in the trial and potential other mechanisms of action that may just improve symptoms rather than the course of the disease.

Another drug that generated considerable interest was Dimebon (MDVN). Data from its Phase II trial was published just prior to the start of the conference, improving confidence in the results (there were questions since the study was conducted in Russia). Dimebon has the strongest efficacy data among the Alzheimer drugs in development, and interest at the conference was heightened by a presentation showing that its mechanism of action likely involves mitochondria (which could mean disease modification), as well as some signals for stabilizing cognitive decline in an extension study. Still, there was animal data suggesting it could work through a cholinergic (and hence symptomatic) mechanism, the extension data was not pristine, and we have lingering concerns over side effects.

Other interesting data were presented on the Aß vaccine CAD106 (NVS and Cytos), the metal chelator PBT-2 (PRAN), the RAGE antagonist PF 04494700 (PFE and TransTech), the 5-HT6 antagonist GSK742457 (GSK), and the 5-HT4 partial agonist PRX-03140 (EPIX and GSK). Finally, following comments on these data, we list all the abstracts added to BioMedTracker from ICAD.

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