At 2nd Kloster Seeon Meeting, Renewed Optimism for Targeting BACE1
More than 100 BACE aficionados gathered September 25 near Munich for the 2nd Kloster Seeon Meeting on BACE Proteases in Health and Disease. Organized by Stefan Lichtenthaler, German Center for Neurodegenerative Diseases in Munich, and Robert Vassar from Northwestern University, Chicago, the meeting convened academic and industry leaders to take stock of the latest developments in BACE research and chart a path for further exploration. The meeting was a hit. It turns out trapping researchers in a converted monastery for two full days with access to only science, food, and a beer cellar leaves attendees begging for more. Highlights included reports of new conditional knockout mice that could lay bare the developmental and adult roles of BACE1, inhibitors selective for BACE1, updates on substrates both new and known, and some novel insights into the ramifications of BACE inhibition at the cellular level. Notably, there was more confidence than at the first Kloster Seeon meeting in 2013 that BACE inhibition just might end up working.
“This meeting is fantastic,” noted Pfizer’s Kelly Bales as she watched her fellow “monks for a day” struggle with one of the more vexing problems during after-dinner social time—how to knock down those bowling pins. “This is how all meetings should be organized,” was a refrain heard both above the din of the alley and in the meeting hall. Fun aside, a sense of camaraderie was palpable. “This is perhaps the only BACE meeting on the calendar where industry and academic researchers can share findings, discuss the challenges each group faces, and come to a mutual understanding,” noted Vassar. “We all have the same goal. We want to advance, and at end of the day, have [approved] drugs that treat or prevent AD in a safe and effective manner,” he told Alzforum.
Silence Is Golden?
A sense emerged from the meeting that the field was moving closer to that goal. A panel discussion between Ulf Neumann from Novartis, Basel, Switzerland, and Christian Haass, Ludwig Maximilians University, Munich, and moderated by Pierluigi Nicotera, who leads the German Center for Neurodegenerative Diseases, Bonn, was more tempered than the 2013 meeting, when academics voiced deep concern that pharma was heading down the same road with β-secretase inhibitors as they had with γ-secretase inhibitors. The latter not only hastened cognitive decline, but led to serious side effects, including skin cancer, that were attributed to interference with γ-secretase processing of Notch (see Nov 2012 news; Dec 2012 news).
Three years on, fears that neuregulin or some other β-secretase substrate might be the “Notch of the BACE programs” are fading. “There is now excitement in the BACE field that inhibitors may be safe enough for long-term treatment of AD,” said Lichtenthaler. This is partly because the retinal toxicity that plagued some early BACE inhibitors arose from off-target inhibition of cathepsin D, which newer BACE inhibitors avoid, and by the no-news-is-good-news silence from the ongoing clinical studies. AstraZeneca/Eli Lilly, Biogen/Eisai, Janssen/Shionogi, Merck, and Novartis have BACE inhibitors in Phase 2 or 3 trials, and so far there have been no reports of adverse events or intervention by the data safety review board to halt the trials, as there were with the γ-secretase inhibitors. Lynn Hyde from Merck, Kenilworth, New Jersey, said that as of June this year, 1,000 people had completed the 18-month Phase 3 EPOCH trial of their BACE inhibitor Verubecestat. Many at the meeting saw it as a hopeful sign that no serious safety issues have emerged from any of the ongoing trials.
Still, some concerns linger. Despite a long list of precautions and toxicity tests that Neumann listed as essential for any drug program, Haass wondered how γ-secretase inhibitors were ever allowed to move forward into the clinic. He worried that the same thing might happen again, to the detriment of the image and public support for Alzheimer’s research. Industry researchers agreed that with 20-20 hindsight, γ-secretase programs probably should not have moved forward. “Just as there are pressures in academia to publish, there can be pressure in industry to come up with something,” said Neumann, “and under that pressure the wrong decision can be made.” However, others noted that those decisions are not made in isolation—independent safety boards review data before and during trials. “We learned a lot from those trials,” said Samantha Budd from Biogen, Cambridge, Massachusetts. Others agreed, saying that the field is nowhere close to being in the same place with BACE inhibitors.
If academic scientists were concerned about industry’s rush to trial, then industry scientists were equally concerned about their academic colleagues’ rush to publish, sometimes with a penchant to exaggerate. Haass agreed. “Academics tend to overstate findings because they want to get papers in the best journals. This should stop immediately,” he said. Budd noted that if even one paper reports a potential side effect, then drug sponsors are obliged to test for it even if subsequent reports don’t bear out the original report. “This can increase the cost of trials, because unless you have proven [the side effect] is not in humans, you have to take that one publication into account. Toxicity tests do not stop with animal models, it continues all the way through the clinic,” she said.
That said, Lichtenthaler held that academic research not be dismissed too readily. Industry has criticized academia for publishing results that cannot be reproduced, and sometimes this is true, he acknowledged. “But the argument is also so fashionable these days, it is overdone.” While it is true that some phenotypes of BACE1 knockouts only emerge in certain animals, that does not mean we should just forget about them, said Lichtenthaler, who also holds a postion at the Technical University of Munich. “Background and strain difference come into play, and we don’t know which mouse best reflects the human population,” he said. Haass agreed that the current trend to simply view any preclinical study as being wrong is worrisome. “For example, Dale Schenk’s first AD vaccine study was completely right and highly reproducible,” he said.
Against this backdrop, how does the field today identify the side effects of BACE inhibition in mice that are likeliest to manifest in people? The researchers in Seeon appeared to rally around an initiative envisioned by Haass. “As we find new substrates, and new processing pathways for BACE, why don’t we set up a common platform to investigate them?” he asked, noting that any individual company would find it difficult to work on all of these areas by itself. “If we had a shared platform, we could finally come to concrete conclusions,” he said. Matthew Kennedy from Merck was all for this idea. He likened it to an initiative co-sponsored by the Michael J. Fox Foundation and industry to study inhibitors of the LRRK2 kinase. “Frankly, we’ve gained more from that in terms of data and knowledge than we have from the BACE field,” he said. Haass and Nicotera suggested that the EU would do well to fund this type of collaboration.—Tom Fagan
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No Available Further Reading
RIKEN Center for Brain Science
No adverse side effect of β-secretase inhibitors is indeed good news, but something has been bugging me since I read the news. We can attribute the absence of β-secretase inhibitors’ side effect to an alternative cleavage by α-secretase. The α-secretase cleaves APP at K 16 and L 17 of the Aβ sequence, resulting in generation of Aβ17-40/42, previously termed p3 fragment.
Biochemically, Aβ17-40/42 is more hydrophobic and oligomerization-prone than Aβ1-40/42 because the C-terminal portion of Aβ1-40/42 carries most of the initial β-sheet structure. In this respect, Aβ17-40/42 is more amyloidogenic and potentially more pathogenic than Aβ1-40/42.
On the contrary, pathologically, we do not observe much Aβ17-40/42 in AD brain when we use an Aβ17-40/42-specific antibody (Saido et al., 1996; Iwatsubo et al., 1996). We do not have a logical explanation for this this discrepancy, but one possibility is that Aβ17-40/42 is easier to catabolize in vivo than Aβ1-40/42.
In any case, it is important to confirm that β-secretase inhibition will not cause accumulation of Aβ17-40/42 in brain. If Aβ17-40/42 accumulates in brain, we will see adverse side effects in a decade or two.
Lastly, selectivity of β-secretase inhibitors against BACE2 is also important because the action of BACE2 on APP results in generation of Aβ11pE-40/42, which is more amyloidogenic both biochemically and pathologically (Saido et al., 1996; Iwatsubo et al., 1996).
Saido TC, Yamao-Harigaya W, Iwatsubo T, Kawashima S. Amino- and carboxyl-terminal heterogeneity of beta-amyloid peptides deposited in human brain. Neurosci Lett. 1996 Sep 13;215(3):173-6. PubMed.
Iwatsubo T, Saido TC, Mann DM, Lee VM, Trojanowski JQ. Full-length amyloid-beta (1-42(43)) and amino-terminally modified and truncated amyloid-beta 42(43) deposit in diffuse plaques. Am J Pathol. 1996 Dec;149(6):1823-30. PubMed.
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