With regard to function, Stephen Salloway of Brown University, Providence, Rhode Island, showed data indicating that the treatment group and the placebo group did not differ significantly on the neuropsychological test battery (NTB) or AD Cooperative Study-Activities of Daily Living Scale (ADCS-ADL). This means the study missed its co-primary endpoints. The scientists then moved on to subgroup analyses pre-specified in the protocol, and saw that patients with mild AD receiving 250 mg of ELND005 had significantly higher NTB scores at week 78 compared to placebo.
With regard to biomarkers, at week 78, the 84 patients receiving 250 mg of the drug had an increase in their brain ventricular volume compared to the 82 patients on placebo. Ventricular volume expansion indicates atrophy of brain matter. This difference was seen in the subset of patients with moderate AD, not in those with mild AD. Both mild and moderate patients treated with 250 mg of ELND005 also had a 27 percent decrease in CSF amyloid-β 42 (Aβ42) levels after 78 weeks of treatment. CSF total-tau (t-tau) and phosphorylated tau (p-tau) did not change with ELND005 treatment. In toto, then, patients with mild AD showed a positive trend on the study’s primary cognitive outcome and CSF Aβ42 reduction, but no significant change in ventricular volume or CSF t-tau or p-tau, whereas more advanced patients had no cognitive benefit or brain shrinkage.
One of the new kids on the block is PF-04447943, a selective phosphodiesterase-9A (PDE9A) inhibitor that elevates the amount of cyclic GMP in brain and CSF. Pfizer is testing the drug in AD, but as reported in Paris, results of a multicenter, randomized, double-blind, placebo-controlled Phase 2 trial were not particularly encouraging. Although the drug was generally safe, Elias Schwam of Pfizer in Groton, Connecticut, explained that after 12 weeks of treatment, there was no significant difference in ADAS-cog scores or in the global clinical scores between 91 patients with mild to moderate AD who received 25 mg of the drug and 100 patients who received placebo. “This suggests that, within mild to moderate, a target like cyclic GMC does not show efficacy in a short trial,” said Schwam. “Maybe the treatment is effective in earlier stages of disease.”
Too Little Too Late
A growing number of researchers are seeing recent failures in AD clinical trials as a sign that treatment is being given too late in the disease process. “We have had some spectacular Phase 3 failures in mild to moderate disease. It is precisely for these failures that we need to move earlier,” said Reisa Sperling of Harvard Medical School. She will be lead investigator for a therapeutic trial of preclinical AD planned by ADCS (see ARF related Webinar).
A proposal for another trial in preclinical AD has also been submitted for funding by the Alzheimer’s Prevention Initiative (API) of Banner Alzheimer’s Institute in Phoenix (see ARF conference series), according to a presentation by API’s co-director Pierre Tariot. If approved and funded, that trial should begin by the end of 2012, or, more likely, the beginning of 2013, Tariot told ARF.
In his presentation at AAIC, Tariot reviewed several alternative approaches for designing clinical trials for preclinical AD. He suggested that, in the future, when sufficient data become available to conduct the necessary modeling, Bayesian designs may be well suited to such studies. These permit use of accumulating data analyzed at frequent intervals to decide how to modify aspects of the study as it is being conducted (see ARF related news story). In the meantime, the first trial proposed by API incorporates a so-called adaptive frequentist design with a nested cohort study. The primary outcome of the study would be a change in cognition, but it would also measure different biomarkers. Changes in the biomarkers would be used to make decisions during the trial without prespecifying a hierarchy in response pattern. This information would then serve to design future trials in a different way, as well as to establish the predictive, prognostic, and correlateive value of biomarkers. “Multiple hypotheses can be addressed in this type of trial,” said Tariot.
The trial would be carried out in cognitively normal carriers and non-carriers of mutations causing early onset AD, including a large kindred from Colombia, in which AD is caused by the E280A presenilin-1 (PS1) mutation. Tariot and colleagues have calculated that the trial will probably need to enroll 300 participants without clinical symptoms of AD, including both mutation carriers and non-carriers; carriers would be randomized to treatment. API has proposed a prototype treatment in the grant proposal, although all involved agree that the best available agent will need to be used when such a trial is launched, and the choice could change. Tariot could not, however, disclose the drug the investigators have incorporated in the grant proposal. (see ARF related news story).
“I am really impressed with people wanting to go earlier, as it might be easier to go on to conduct another Phase 3 trial,” said Nick Fox of University College London, U.K., who chaired the session at which Tariot spoke. However, in discussions following the presentation, some conference attendees questioned the rationale of going full-steam with a large trial of preclinical AD before there are officially validated biomarkers or cognitive tests for the condition. Both API and a sister effort for preclinal-stage trials, the Dominantly Inherited Alzheimer's Network (DIAN), are doing extensive work on biomarkers and cognition in preparation for clinical trials in their respective populations.
Others question the conclusion that the current failure of AD drugs to succeed in trials of mild to moderate AD means researchers should focus on treating preclinical stages of disease. “People make the argument that, by the time you have AD, you have too much neuronal loss and it is too late. I do not think there are enough data to say that,” said Eric Siemers of Eli Lilly and Company. “The other drugs to date never got into the brain in sufficient quantities to really test the hypothesis. But if you can make the rate of cognitive decline faster [as it happened with semagacestat], you might also make it slower.”—Laura Bonetta.
This is Part 2 of a series on clinical trial news. See also Part 1.