21 November 2012. In a Phase 2 trial of Bristol-Myers Squibb’s oral γ-secretase inhibitor avagacestat, AD patients who took high doses suffered more adverse effects and appeared to fare worse cognitively than those on placebo. Christopher van Dyck of Yale University School of Medicine, New Haven, Connecticut, showed this at the 2011 Alzheimer’s Association International Conference in Paris (see ARF conference story). Now, the detailed findings appear in print in the November Archives of Neurology, with company scientists Vladimir Coric and Robert Berman of BMS in Wallingford, Connecticut, as lead and senior authors, respectively. Experts find little promise in the trial results, calling them a red flag for γ-secretase inhibitors in general. If a shred of hope remains, they say, it may come from the company’s ongoing Phase 2 study in prodromal AD.
Avagacestat—also known as BMS-708163—initially looked good because it seemed to overcome a key problem of γ-secretase inhibitors: gastrointestinal and immune system troubles linked to other substrates, most notably Notch (Milano et al., 2004; Wong et al., 2004). In-vitro work reported by company scientists suggested the BMS inhibitor is ~190-fold more selective for blocking processing of amyloid-β precursor protein (APP) than of Notch (see ARF conference story). Phase 1 data seemed supportive, as single doses up to 800 mg and multiple doses up to 150 mg a day caused no adverse effects.
The six-month Phase 2 study tested four doses of the γ-secretase inhibitor against placebo in 209 people with mild to moderate AD at 41 sites in the U.S., Denmark, Finland, and Sweden. The lower doses (25 and 50 mg) were relatively well tolerated. Participants receiving 100 and 125 mg of the compound daily had gastrointestinal, skin, and other side effects that prompted study withdrawal more than twice as frequently as in the lower-dose or placebo groups.
At the two lower doses, cerebrospinal fluid (CSF) biomarker data were mixed. CSF levels of Aβ1-34, Aβ1-14, Aβ1-15, and Aβ1-16 rose in a dose-dependent manner. Produced by α-secretase processing of APP, these short Aβ isoforms provide indirect evidence of γ-secretase inhibition, suggesting target engagement (Portelius et al., 2011). However, Aβ1-40 and Aβ1-42 levels did not budge in treated patients. The authors attributed this to small sample size (only 45 of 209 participants agreed to lumbar puncture) and/or methodologic challenges associated with CSF measurements.
Perhaps most concerning was that the clinical data showed trends toward cognitive decline at the highest two doses. This is “eerily similar” to the data on Eli Lilly’s γ-secretase inhibitor semagacestat, suggested Sascha Weggen of Heinrich-Heine University in Düsseldorf, Germany. In a Phase 3 trial, the Lilly compound made AD patients worse, forcing the company to halt the study in 2010 (see ARF related news story). All told, Weggen found the Phase 2 avagacestat data “highly worrisome for γ-secretase inhibitors as a class.”
Michael Wolfe of Brigham and Women’s Hospital, Boston, Massachusetts, said the results indicate “that, first and foremost, we need to have agents that are much more selective for inhibiting the cleavage of APP over that of the Notch receptor.” In an e-mail to Alzforum, Wolfe suggested that the avagacestat data call into question the compound’s preference for APP. “If [the inhibitor] is indeed as selective as BMS says, then it needs to be more selective still,” he wrote.
Other research challenges the claimed APP vis-à-vis Notch selectivity (Chávez-Gutiérrez et al., 2012; Crump et al., 2012). These studies “did not see any selectivity with the BMS compound, Weggen noted, adding that his lab has “similar unpublished data on avagacestat, suggesting at best a 10-fold difference between inhibition of APP and Notch processing.”
Aside from Notch, some researchers believe that problems linked to γ-secretase inhibitors could stem from their effects on APP processing. Cell culture studies suggest that endogenous Aβ may be beneficial, promoting synaptic plasticity by regulating glutamate release (ARF related news story on Abramov et al., 2009). If true, then reducing Aβ levels greatly by way of γ-secretase inhibition could potentially harm cognition, noted Hugo Geerts of In Silico Biosciences in Berwyn, Pennsylvania. In another study, avagacestat treatment did not improve learning and memory in APP mice, and actually worsened cognition in normal mice (ARF related news story on Mitani et al., 2012), whereas Notch-controlled gene expression remained unchanged. The authors attributed the cognitive decline instead to accumulation of APP C-terminal fragments, suggesting these peptides could be harmful to people as well.
Meanwhile, scientists await results from the ongoing Phase 2 trial of avagacestat in prodromal AD, in which people at risk for AD receive 50 mg of the inhibitor daily for two to four years. “Interim data from this study and data from the completed Phase 2 study in mild to moderate Alzheimer’s will inform our plans for further development of this compound,” Sonia Choi of Bristol-Myers Squibb Public Affairs told Alzforum via e-mail. “We plan to complete an interim analysis this quarter.” She said the company is “not in a position to facilitate discussion” about the Phase 2 trial results at this time, meaning its scientists are muzzled for the time being. The prodromal AD trial began in May 2009. Enrollment was challenging, but is complete; the company screened 1,350 candidates to find about 270 who met criteria for amnestic mild cognitive impairment (aMCI) and had CSF evidence of AD pathology (see ARF conference story).—Esther Landhuis.
Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M, Richter RW, Soininen H, Thein S, Shiovitz T, Pilcher G, Colby S, Rollin L, Dockens R, Pachai C, Portelius E, Andreasson U, Blennow K, Soares H, Albright C, Feldman HH, Berman RM. Safety and Tolerability of the γ-Secretase Inhibitor Avagacestat in a Phase 2 Study of Mild to Moderate Alzheimer Disease. Arch Neurol. Nov 2012;69(11):1430-1440. Abstract