Anti-amyloid antibodies are at long last showing promise for treating Alzheimer’s disease, but for long-term use, researchers are seeking cheaper and easier options than monthly infusions. They want that elusive once-a-day pill. BACE inhibitors have been the leading option, but with all trials of these drugs now halted due to cognitive worsening, isn’t the approach just plain dead? At the 12th Clinical Trials on Alzheimer Disease conference, held December 4–7 in San Diego, California, researchers debated this question at a roundtable. Most were not yet ready to write off BACE inhibitors. As an oral drug that directly suppresses Aβ production, these compounds still represent a practical way to slow plaque accumulation and maybe, just maybe, put the brakes on the disease at an earlier stage.
- Cognitive deficits on BACE inhibitors appear to be small, stable, and specific to memory.
- Scientists calculate that 25 percent inhibition would suffice to stop plaque growth.
- Still unknown: Would a low dose avoid the memory decline?
“It’s hard to look away from BACE as a target,” said Michael Irizarry of Eisai.
To be sure, many questions remain to be answered before researchers will know whether any dose with the current batch of compounds is safe enough for long-term use. Chief among them are: Is the cognitive deficit reversible? Does it relate to neurodegeneration? Does it occur at low doses?
Some of the answers can come from analyzing existing data from the halted trials. This process is currently ongoing at many companies. In San Diego, pharma representatives provided an additional glimpse at this. The data to date suggest that the cognitive side effect does not worsen over time and may perhaps reverse once dosing stops. From the current high-dose trial data, however, researchers cannot tell what might happen to cognition at very low doses. Eric Reiman of Banner Alzheimer’s Institute in Phoenix suggested that lower doses be tested in a new trial that would include extensive safety monitoring. “The benefits of BACE inhibition in amyloid-negative people at genetic risk for AD could outweigh the risks,” Reiman said. Others agreed. Concern about trial participants, particularly people who have found out their ApoE genotype in hopes of prevention trials, pervaded the meeting, and researchers agreed all should be done to keep those cohorts engaged.
Pharmaceutical companies have been sharing their data with each other in hopes of solving the BACE inhibitor puzzle and finding a way to move forward. This cooperative spirit continued in San Diego. “This degree of industry collaboration is unprecedented,” noted Maria Carrillo of the Alzheimer’s Association.
Researchers at Merck first reported finding a small cognitive deficit associated with BACE inhibition in their Phase 3 verubecestat trials, which had already been halted due to lack of efficacy (Dec 2017 conference news; Apr 2019 news). Similar news on the other BACE inhibitors followed in rapid succession, with Janssen’s atabecestat, Novartis’ umibecestat, and Biogen and Eisai’s elenbecestat all now linked to cognitive worsening (Nov 2018 conference news; Jul 2019 conference news; Sep 2019 news). To most researchers, the preponderance of the data imply a drug class effect, rather than something off-target.
In addition to the cognitive deficit, BACE inhibitor treatment also consistently comes with weight loss, skin rashes, and increased neuropsychiatric symptoms. Perhaps most concerning, data from some of the trials show greater brain atrophy on drug, as well, suggestive of accelerated degeneration. Lilly’s lanabecestat has not been tied to a statistically significant cognitive deficit, but does associate with greater volume loss (May 2019 conference news).
Cognitive Deficits Consistent Across the Drug Class
In San Diego, presenters focused most of their attention on the cognitive problems. Ana Graf of Novartis showed more data from the two terminated API Generation trials of umibecestat. The trials enrolled ApoE carriers who were cognitively healthy, with an average MMSE of 29. They took either 15 or 50 mg per day of umibecestat. These doses lowered their Aβ40 in cerebrospinal fluid by 70 and 87 percent, respectively.
On the RBANS cognitive composite, people on either dose of drug performed worse on tests of immediate and delayed memory than the placebo group did. Their deficit appeared at the earliest time point tested, three months, and stayed consistent at six months. The Cohen’s d effect size was 0.2-0.3, which is considered small. In addition, more people in the treatment group than on placebo declined by one standard deviation or more on the RBANS, or experienced any decline on the CDR-SB, Graf said, though she did not provide those numbers. Graf noted that one-third of the cohort was amyloid-negative, demonstrating that plaques are not required for this cognitive effect.
Curiously, however, people taking umibecestat performed better than the placebo group on the RBANS language domain. In the discussion afterward, John Sims of Lilly noted that this is a consistent pattern with BACE inhibitors, seen with lanabecestat and verubecestat as well. It seems people on drug score worse than placebo on memory tests but better on language tests. “This is a huge mystery,” Sims said. Michael Egan of Merck said that these similar effects across many BACE inhibitor trials suggest unknown class effects of these drugs. “We need to understand the biology of BACE better. Are other substrates involved?” Egan asked.
Blinded follow-up visits with Generation participants will continue for the next six months, Graf said. Researchers are currently analyzing cognitive data collected three months after dosing stopped, which will reveal whether the cognitive deficits reversed.
Data from other inhibitors look similar. Irizarry provided a brief update on the elenbecestat Phase 3 trials, which were halted in September after a safety review found an unfavorable risk-benefit ratio. Called MISSION AD1 and 2, these trials tested 50 mg of elenbecestat, which lowers CSF Aβ40 by 70 percent. The last patient visits are finishing now, and the database will be locked early next year, Irizarry said.
Because these trials were halted early, only a few patients completed the full two-year course of treatment. Eisai has six-month data for about 1,700 patients, 12-month data for 900, 18-month data for 300, and two-year data for only 40. A cognitive deficit did not appear at the early time points, unlike with the other inhibitors. At the two-year mark, however, participants on elenbecestat scored worse than those on placebo on the CDR-SB. The difference was not statistically significant, but that may be because of limited power, with only about 20 people in each arm at this time point, Irizarry said.
Participants on elenbecestat also lost more weight and had more skin rashes and neuropsychiatric effects than controls, continuing a common theme with BACE inhibitors. Overall, the negative effects and lack of cognitive benefit tipped the scales against this drug, Irizarry said.
The findings overall echo data from the verubecestat Phase 3 APECS and EPOCH studies, which enrolled people with prodromal or mild AD, respectively. These trials tested doses of 12 or 40 mg verubecestat, suppressing Aβ40 in CSF by 67 to 84 percent, respectively. As with umibecestat and atabecestat, the cognitive deficit on verubecestat appeared at three months, the earliest time point studied, and did not worsen over time, Julie Stone of Merck said in San Diego.
What about lanabecestat? It did not report statistically significant cognitive worsening. Hints of a negative cognitive effect came through here, too, Sims told Alzforum. Researchers saw poorer performance on drug when they looked at subpopulations such as the MCI group, and they also saw memory deficits on highly sensitive exploratory cognitive measures. “My feeling is that the patterns across the inhibitors are pretty similar, although magnitudes may be slightly different,” Sims told Alzforum.
On the important question of whether cognition recovers, researchers thus far have little data to share. David Henley of Janssen presented the only findings on this in San Diego. He reported that participants who had taken five months of atabecestat and developed a cognitive deficit rebounded after three months off drug.
It is also unclear if the cognitive harm varies with disease stage. Eric McDade of Washington University in St. Louis noted that the deficit appears more obvious in preclinical than prodromal cohorts, but this may be because it is easier to measure a subtle cognitive effect in a less-impaired population. Furthermore, researchers do not know whether the memory problems are perceptible to patients. Reiman wondered how the deficit compared with other factors that blunt mental acuity, such as drinking wine.
The mechanism remains a mystery. The idea that has been bandied about the most—that the inhibitors block both isoforms of their target enzyme—seems not to be the reason for the problems with these recent trials. “We don’t think it is a BACE1 versus BACE2 issue,” Sims said. Elenbecestat and umibecestat are about threefold as selective for BACE1, but still triggered this symptom. Henley suggested that BACE1 substrates other than APP are likely involved.
Researchers agreed that animal studies will provide insight here. In San Diego, Riqiang Yan of University of Connecticut Health, Farmington, reminded the audience that BACE-null mice have a learning deficit, suggesting that BACE is required for synapses to function optimally. Knocking out BACE in the 5xFAD model reverses plaque deposition but does not completely restore synaptic function, again hinting that neuronal transmission requires BACE, Yan said (Hu et al., 2018). Other scientists, including Jochen Herms of DZNE in Munich, have been calling attention to this, as well.
Curiously, agonists of the metabotropic glutamate receptor 1 rescue synaptic plasticity in BACE knockouts, Yan said at CTAD. He showed unpublished data that agonists boosted excitatory presynaptic potentials back to wild-type levels and restored memory in the Morris water maze and open-field tests. “BACE inhibitors could be used in combination with a synaptic enhancer for better efficacy,” he suggested. Unlike antagonists, mGluR1 agonists are little studied, and none have been approved by the Food and Drug Administration.
Would a Low Dose Dodge the Bullet?
Many researchers hope that a much lower dose of inhibitor could avoid the cognitive harm, but so far there is little evidence to support this. All trials to date have tested doses that inhibit Aβ production by 50 percent or more. Stone cautioned that the cognitive deficit on verubecestat was not dose-dependent across the range of 70-85 percent inhibition. “We cannot predict from our data what the cognitive response would be at lower doses,” Stone said.
How low a dose would still effectively suppress amyloid accumulation? On this question, Merck researchers have more information. Pharmacokinetic data from their dosing studies allowed them to model the effect of dose on plaque. At the high doses tested, BACE inhibitor treatment nudges down plaque load. Stone and colleagues calculated that a dose of 2 mg verubecestat, corresponding to 27 percent inhibition of Aβ40 production, would stabilize plaque load, preventing further growth. For a person without amyloid accumulation, this dose might be sufficient to halt disease progression.
Sims agreed, noting that Lilly’s internal modeling suggests the same thing. “We should shoot for 25 percent lowering,” he said in San Diego. However, Sims also emphasized there is no guarantee this would prevent cognitive harm. “At a lower dose, would it just take longer for the cognitive deficit to appear?” he wondered. Some animal data do suggest that dose is a key factor for synaptic health. In mouse studies, high doses of BACE inhibitors inhibit dendritic spine growth and synaptic plasticity, while low doses do not (Nov 2014 news). These mouse studies image synapses through a cranial window to get a sense for how these dynamic structures change over time.
What Does Brain Volume Loss Mean?
Researchers at CTAD expressed concern about the cortical shrinkage measured by MRI. This old problem has bedeviled Alzheimer’s trialists since the earliest anti-amyloid drug trials, indeed since the long-defunct AN-1792 vaccine (Jul 2004 conference news). Fifteen years later, scientists are still unsure how to interpret it and, lo and behold, it happens with BACE inhibition too. MRI scans have picked up greater brain volume loss in drug than placebo groups on at least three BACE inhibitors: verubecestat, lanabecestat, and umibecestat. In San Diego, Graf reported that umibecestat shrank whole-brain and hippocampal volume after six months, the earliest time point measured, although she showed no numbers. Eisai researchers have not reported volume loss with elenbecestat, but analysis of this trial is still ongoing. Janssen has not presented MRI data for atabecestat.
It is unclear whether atrophy is linked to the cognitive deficit. It may seem obvious, but some data suggest not. Stone reported that, unlike the cognitive deficit, volume loss was worse on a higher dose of verubecestat. “MRI changes don’t seem to correlate with cognitive effects,” Henley said, as well. Reiman agreed. Others are less certain. McDade noted that some data do suggest a relationship. Intriguingly, volume loss does appear to be linked to amyloid load. In San Diego, Adam Schwarz, who is now at Takeda after 12 years working on brain imaging at Lilly, reported that most of the shrinkage seen on verubecestat occurred in regions with a high plaque burden. Showing data provided by Cyrille Sur at Merck, Schwarz reported that people taking 12 mg verubecestat lost around 0.4 percent more from their baseline volume, compared with the placebo group, in amyloid-positive than in amyloid-negative regions. For people taking 40 mg, this difference was 0.6 percent.
Fluid shifts associated with lessening inflammation are often mentioned as a hopeful potential explanation for the measured volume loss in treatment groups. At CTAD, too, researchers overall sounded cautiously optimistic that the loss may not reflect increased degeneration. Stone noted that the shrinkage appeared early during verubecestat treatment and did not worsen further, with atrophy thereafter tracking at the same rate as in controls. In San Diego, Egan and Matthew Kennedy of Merck reported that there were no differences in several CSF markers of neuronal injury or inflammation in verubecestat Phase 3 substudies. NfL, total tau, GFAP, and UCH-L1 tracked the same in people on verubecestat or placebo for 18 months. Over this time frame, NfL, GFAP, and UCH-L1 bumped up consistently by about 12 percent in all treatment groups. Total tau was noisy, with a high variability from person to person that averaged out to a 20 percent increase. Likewise, Graf reported no worsening of CSF markers of degeneration in the Phase 2a umibecestat trial.
Where Do BACE Inhibitors Go From Here?
At CTAD, academic and company researchers agreed that finishing thorough analyses of the data from the terminated trials is a critically important first step to answer several of the questions they posed. Assuming these data confirm that BACE inhibitors at high doses cause a cognitive deficit that is small, stable, and reversible, without accelerating degeneration, then what would be next? Researchers threw out several ideas. Sims mentioned conducting additional safety studies in a nonhuman primate model, perhaps using volume loss as a proxy for the cognitive deficit, if the two are shown to be linked. Henley suggested testing a lower dose range of BACE inhibitors in healthy volunteers to see if they affect memory. “The dose and target population will be critically important for future trials,” Irizarry agreed.
For his part, Reiman would prefer to start a Phase 3 trial of lower doses, with increased safety monitoring. The Alzheimer’s Prevention Initiative has invested tremendous effort and resources into recruiting the two large Generation cohorts. In San Diego, Jessica Langbaum of Banner announced that in addition to halting umibecestat, researchers have now stopped dosing with the active vaccine CAD106 as well. This decision was made to allow the researchers to conduct unblinded interim analyses to better assess CAD106's efficacy and potential for future trials, Graf said. With all dosing now stopped in these API trials, participants are left at loose ends.
These participants deserve particular respect and thoughtful, ongoing engagement that includes new trial options before too long, because they agreed to find out their ApoE genotype for research and are aware of their high risk of impending Alzheimer’s dementia. “We want to enroll amyloid-negative Generation homozygotes in a new trial before they are lost,” Reiman said. Langbaum noted that Banner researchers are waiting to see whether the memory problems on umibecestat are reversible before deciding whether that new trial will include BACE inhibitors again.
Even in the absence of a new drug to test, Banner researchers, including Pierre Tariot, plan to offer continuing support, follow-ups, and information on future research opportunities to participants to keep them engaged. Novartis is clearly aware of a responsibility toward this cohort. “Banner and partners are committed to finding ways to maintain the cohort,” Graf said.
McDade also thinks future BACE inhibitor trials make sense, particularly for people who are at high genetic risk of AD. “BACE is still a rational target in autosomal-dominant AD. There is a strong mechanistic justification, particularly for prevention at an early time point,” McDade said.—Madolyn Bowman Rogers
- Verubecestat Negative Trial Data: What Does it Mean for BACE Inhibition?
- Results from Verubecestat APECS Trial Published
- Bump in the Road or Disaster? BACE Inhibitors Worsen Cognition
- Cognitive Decline Trips Up API Trials of BACE Inhibitor
- End of the BACE Inhibitors? Elenbecestat Trials Halted Amid Safety Concerns
- BACE Inhibitors: Postmortem on One, Live Updates on Two
- At High Doses, BACE1 Inhibitors Hinder Synaptic Plasticity in Mice
- Philadelphia: Can a Shrinking Brain Be Good for You?
- Hu X, Das B, Hou H, He W, Yan R. BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions. J Exp Med. 2018 Mar 5;215(3):927-940. Epub 2018 Feb 14 PubMed.
- Do BACE Inhibitors Activate Microglia?
- Merck Pulls Plug on Phase 2/3 BACE Inhibitor Trial
- In Conditional BACE1 Knockouts, Hippocampal Axons Compromised
- BACE Block Nips New Plaques in the Bud, Old Ones Keep Growing
- Merck Axes Verubecestat for Prodromal AD, Researchers Say ‘Go Earlier’
- Paper Alert: Verubecestat EPOCH Findings Published
- Liver Tox Ends Janssen BACE Program
- Hanging in There: Another BACE Inhibitor Still Safe in Phase 2