The anti-Aβ antibody crenezumab missed both its primary endpoints in two Phase 2 clinical trials, according to results presented at the Alzheimer’s Association International Conference 2014, held in Copenhagen July 12-17. The ABBY trial fell short on goals set for cognition and function. The smaller BLAZE study, which was designed to measure biomarker effects, showed no effect on cognition as a secondary endpoint. Results of both trials indicated that the drug was safe and well-tolerated. Post-hoc analysis of the data, presented by Jeffrey Cummings, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, hinted that the drug may yet slow decline in patients with mild AD, echoing the outcome of trials of solanezumab, an anti-Aβ antibody being developed by Eli Lilly (see Oct 2012 news story).
Perhaps because researchers in the field have grown used to negative clinical trial data, the news seemed anticlimactic, sparking little debate from the packed hall at the Bella Center in Orestad, just north of the Danish capital. In interviews with Alzforum, some researchers lamented the practice of slicing and dicing data to find significant effects in ever-smaller patient groups, while others noted that this was an opportunity to learn and to design a Phase 3 trial to test if the treatment works.
Crenezumab is a monoclonal antibody developed by AC Immune and licensed to Genentech. It binds all forms of Aβ, including monomers, oligomers, and fibrils. "Of all the immunotherapies currently in trials, I thought crenezumab might have the best chance of working," Dave Morgan, University of South Florida, Tampa, told Alzforum. "It not only binds and helps remove plaques, but also blocks Aβ aggregation at substoichiometric amounts." Crenezumab was designed to limit inflammatory responses while still promoting uptake of Aβ by microglia (see Jul 2012 research news).
In ABBY, 122 patients with mild to moderate Alzheimer’s were randomized to 300 mg of crenezumab injected subcutaneously every two weeks, while 62 volunteers got placebo. Another 163 patients received 15 mg/kg of the antibody intravenously every four weeks and 84 were given a placebo. The IV method delivered about twice as much antibody as the subcutaneous route over the 68-week course of treatment. No overall difference emerged between the placebo and treatment groups on cognitive co-primary outcomes measured by the ADAS-Cog12 and the CDR sum of boxes. Daily function, as determined by the ADCS Activities of Daily Living, declined as quickly in patients taking the drug as in those on placebo. In prespecified analysis of patients with an MMSE score of 20-26, i.e. the milder subgroup, the higher IV dose tended to slow cognitive decline, but the results missed statistical significance. A second, exploratory analysis of the 121 patients with even milder AD, an MMSE of 22-26, showed a trend toward efficacy at 49 weeks and a statistically significant effect at the end of the trial.
The smaller BLAZE trial enrolled 91 patients with mild to moderate AD who tested positive for brain amyloid on a Florbetapir PET scan. Here too, low and high doses of crenezumab were given via subcutaneous (25 treatment, 13 placebo) and intravenous routes (29 treatment, 15 placebo). The result on PET amyloid imaging—the primary outcome of BLAZE—will be presented at the Clinical Trials on Alzheimer's Disease conference in November, said Cummings. The higher dose of crenezumab trended toward preserving cognition in this trial.
"We believe that this was a very good outcome for a Phase 2 trial designed and powered as it was," Andrea Pfeifer, CEO of AC Immune, told Alzforum. "We believe showing a signal and target engagement is a positive outcome for a trial that was not designed to be a pivotal one," she said. Pfeifer stressed that it was important to estimate a treatment effect in Phase 2, because this provides a baseline from which to power a Phase 3 trial. Rachelle Doody, Baylor College of Medicine, Houston, told Alzforum she was concerned that many people, particularly in the media, were jumping to the conclusion that crenezumab was doomed, looking at the data as if it were a Phase 3 trial. "They are trying to emphasize a message that is at best a small piece of what was learned, and at worst a distortion," she said.
What was learned? "About all we can say for sure about these findings is the drug appears safe," said Todd Golde, University of Florida, Gainesville. Similar sentiments came from Eric Reiman, Banner Alzheimer's Institute, Phoenix. "The findings show [crenezumab] failed to meet its primary endpoints; beyond that, interpretation would be preliminary," he said. Doody called the parallels between the crenezumab and solanezumab data thought-provoking. In both, ADAS-Cog trends showed separation between placebo and treatment groups that grew over time. Both treatments target soluble Aβ. "While we have to wait for the biomarker data, if both [solanezumab and crenezumab] have similar signals, it makes you wonder if it is necessary to target fibrillar Aβ," she suggested (see Apr 2013 conference news). Doody has consulted for many pharmaceutical companies, including Roche, Genentech, and AC Immune, but not for Eli Lilly.
Reiman, who co-leads the Alzheimer's Prevention Initiative, also commented on the similarities to the solanezumab data. The results have bearing on the API’s ongoing trial of crenezumab in families carrying an autosomal-dominant presenilin mutation (see Mar 2011 research news). "We are encouraged by the continued safety and tolerability, which is very important in healthy volunteers, and that the pattern looked strikingly similar to what Lilly reported for solanezumab," Reiman told Alzforum. "API is predicated on the idea that introducing treatment early will have a more profound effect. If that turned out to be confirmed, it would be very encouraging."
The API trial uses the subcutaneous regimen, which showed no cognitive benefit in ABBY, even in the post-hoc analysis. “Based on these findings we will discuss with health authorities the possibility of increasing the subcutaneous dose leading to comparable concentrations as in the IV dose,” Reiman told Alzforum. Pfeifer noted that when treating a healthy population, it could be assumed that a lower dose may be needed than in a treatment trial. She said she had no doubt the API trial will continue.
On the separate question of whether Genentech will launch new clinical trials of crenezumab based on these results, a company spokesperson stuck to this formal statement, “We are continuing to further analyze the Phase 2 data and will be meeting with health authorities, including the FDA and the EMA, in 2014. It is premature for us to discuss the development plans for crenezumab.”—Tom Fagan
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