20 August 2008. At the International Conference for Alzheimer’s Disease, 26-31 July in Chicago, investigators reported results on a range of different clinical trials. There were no breakthroughs but the field is shifting. While some new drug candidates are entering the pipeline, others have dropped out and saw their postmortem discussion at ICAD. Here is a closing summary on one of them:
On July 2, the sponsors of Flurizan/tarenflurbil had announced in four terse sentences that this γ-secretase-modulating agent had fallen flat in its definitive Phase 3 trial and was finished as a development product (see ARF related news story). At ICAD, Robert Green of Boston University gave a detailed presentation about the disappointing trial. The Phase 2 trial had seemed to give some hint of clinical efficacy for the highest dose in patients with mild AD (see ARF related news story on trial design), and formal publication of the trial in Lancet recently had fanned hopes further that Flurizan might do some good at this disease stage (Wilcock et al., 2008).
According to the Phase 3 results, it did not. On both primary efficacy endpoints, the ADAS-Cog and the ACDS activities of daily living scales, the treatment and placebo curve overlapped almost completely. There was no effect whatsoever in the group as a whole. And while the overall side effect profile was similar between placebo and treatment groups, anemia, infections, and gastrointestinal ulcers did appear more often in people on Flurizan, Green reported.
According to Green, some 20 percent of patients stayed stable or improved. However, neither pre-specified nor post-hoc analyses, of ApoE genotype or other factors, brought up any correlations as to why that might be.
If the trial failed and the drug is dead, then why write about it at all? This 18-month trial had redeeming features that inspire confidence that the field as a whole will be able to show efficacy and safety once better disease-modifying drugs roll around, Green said. “This is the largest Phase 3 trial in AD ever completed. It was a model case of a public-private partnership to test drugs as we are entering the era of disease-modifying drugs,” Green said.
The trial was designed and conducted well, and it proceeded smoothly as 133 U.S. centers followed the protocol without a troubling degree of site variation, Green said. The 1,649 participants were randomized into well-matched groups, the placebo group declined as expected, and the trial was powered sufficiently. Dropout rates were 33 percent for placebo and 39 percent for Flurizan, and the investigators followed the pre-specified analysis plan. “It’s important to acknowledge that this was an extremely successful trial in terms of its conduct. It showed that patients decline enough over 18 months to see a signal. That had been questioned before. This is very important—we can see the effect of a disease-modifying compound,” Green said.
It seems that the field assigns blame for this failure to Flurizan itself. This compound had shown effects in vitro and in vivo in mice (e.g., Eriksen et al., 2003; Kukar et al., 2007). However, not enough of it reached its intended target in the human brain. Other scientists noted that the human exposure of Flurizan never reached concentrations close to the observed IC50 in vitro. Therefore, it is reasonable to speculate that γ-secretase in the brain of the patients was never effectively modulated. Neither the Phase 2 nor the Phase 3 trial presented CSF data to show clearly how much of the drug enters the brain and that it alters Aβ levels there. In fact, a Phase 1 trial conducted by Douglas Galasko and colleagues at the University of California, San Diego, observed no significant reductions in plasma and CSF Aβ42 levels of healthy volunteers treated with the highest dose of Flurizan that was then used in the Phase 3 trial (Galasko et al., 2007). “In hindsight, it is fair to assume that Flurizan, given its poor potency and brain permeability, failed because of insufficient pharmacodynamics,” said Sascha Weggen from the Heinrich-Heine-University in Düsseldorf, Germany.
For this reason, scientists questioned whether this trial tested the amyloid hypothesis and the therapeutic concept of γ-secretase modulation at all. A number of other companies large and small are continuing research on their own, hopefully more potent, γ-secretase modulators. “It is important to point out that Flurizan was just a first-generation γ-secretase modulator. One could argue that its poor pharmacological properties and marginal efficacy in preclinical studies made it an ill-advised first try, but its good safety profile also made it an opportunity that needed to be explored. Now we need to develop improved compounds that efficiently modulate γ-secretase activity in brain of preclinical animal models and humans,” Weggen added. For his part, Green was philosophical. To reporters, he cited a quote by Woody Allen: “If you are not failing every now and then, it’s a sign you are not doing anything very innovative.”—Gabrielle Strobel.