28 August 2007. Last Sunday, Neurochem, Inc., the Montreal drug company developing Alzhemed as a new amyloid-reducing therapy for Alzheimer disease, announced that the results of its recently completed North American phase 3 trial to test tolerability, efficacy, and safety of Alzhemed in 1,052 AD patients were inconclusive. The Food and Drug Administration (FDA) ruled that the statistical models used to analyze both the cognitive efficacy data as well as the brain volume data were problematic, and that the results obtained could not support a claim for clinical efficacy. The decision comes after Neurochem announced problems with the trial at a conference this June (see ARF related news story).
Multiple factors contributed to the inconclusive results. Overall, variability among the 67 clinical sites in the trial overwhelmed the observed treatment effects, said Paul Aisen of Georgetown University in Washington, DC. Aisen served as scientific advisor to Neurochem and was the principal investigator of the trial of Alzhemed (aka tramiprosate). In particular, changes in people’s concomitant treatment with cognitive-enhancing drugs such as cholinesterase inhibitors, memantine, and antidepressants affected the results for the primary cognitive endpoints based on neuropsychological testing. Unexpected problems also arose in the control group and confounded the interpretation of Alzhemed efficacy. These, too, were most likely due to changes in concomitant medications, Aisen said. Thirty percent of the control group did not decline in cognition over the 18-month trial period; indeed, a portion of the control group unexpectedly demonstrated a significant improvement in cognition.
The company did note a trend in hippocampal volume change as measured by MRI. Patients treated with Alzhemed tended to show an increased atrophy rate as compared to the control group, suggesting a drug effect perhaps similar to what was seen in the halted AN-1792 trial (see ARF related news story). The data on hippocampal volume change was to be compared to secondary measures of whole-brain and entorhinal cortex volume change, also measured by MRI.
The next steps for Neurochem and the FDA are complicated, Aisen said. They depend on the recommendations of a newly appointed scientific advisory board led by Rachelle Doody of Baylor College of Medicine in Houston, Texas. The board’s report is expected by December 2007. The FDA is encouraging Neurochem to continue working on the U.S trial data set post-hoc. Aisen added that the company has committed to work with the FDA toward obtaining more conclusive results from the ongoing phase 3 trial of Alzhemed in European Union countries. The FDA has told Neurochem that the agency is open to considering modifications of study design, such as enrolling more people and changing treatment duration, as well as changes to the statistical analysis measures used in the EU trial.
One positive aspect of the European Alzhemed trial is that memantine treatment, a confounding factor in the U.S. trial, will not be allowed in that trial. A special challenge of the European trial is that it introduces another set of variables in that multiple sites in the member countries conduct cognitive testing in multiple languages.
Alzhemed’s fast-track status has not changed, although any approval date now will depend on the completion of the EU trial, which currently is an 18-month trial that enrolled the last patients earlier this summer. This would mean that data collection would be complete by end of 2008, with results expected by mid-2009.
On a general note, Aisen said that the problems that arose from this trial are not easily avoided. Indeed, he believes that this troubled trial will provide valuable lessons for the field of clinical AD research at large. The trial highlights the need to better manage the confounding variables and to minimize their effects on the results, and the new board is charged with providing advice on that. Patients who participated in the U.S. trial will have access to Alzhemed in an open-label extension for 1 year following conclusion of the 18-month treatment period. Neurochem expects that all data analysis of the North American trial will be ready to report by next summer’s ICAD meeting in July 2008 in Chicago.—Gwendolyn T. Wong.