Bump in the Road or Disaster? BACE Inhibitors Worsen Cognition
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Currently, hopes for an Alzheimer’s prevention therapy hang on BACE inhibitors that squelch generation of Aβ peptides. When these compounds failed to slow cognitive decline in symptomatic patients, researchers argued that they might work at earlier disease stages, before neurodegeneration has become entrenched. Alas, at the 11th Clinical Trials on Alzheimer’s Disease conference, held October 24–27 in Barcelona, Spain, researchers at Merck shook the field with the stunning announcement that in a Phase 3 trial, people with prodromal AD who took the inhibitor verubecestat scored worse on cognitive tests than those on placebo. Michael Egan of Merck reported that the effect was small, but significant. The cognitive deficit appeared at the earliest time point and did not grow over time, nor did it appear to correlate with increased neurodegeneration.
- In prodromal AD patients, verubecestat caused a small, stable cognitive deficit.
- Other BACE inhibitors do the same thing, suggesting on-target mechanism.
- Scientists said more research is needed to determine if this can be managed.
What’s worse, other data suggest this may be a general property of BACE inhibitors. In Barcelona, researchers from Janssen and Lilly presented similar data on their compounds. Participants on all three inhibitors also had more neuropsychiatric symptoms and lost more brain volume. The troubling findings did not hold across the board, however. Biogen and Eisai reported a cognitive benefit in a small trial of its inhibitor elenbecestat, and no sign of neuropsychiatric symptoms or increased atrophy.
At CTAD, at least, researchers appeared to take this latest gut punch in stride. The mood at the conference was one of resolve rather than discouragement. Academic scientists said they want to figure out the mechanism behind the adverse effects, if they are reversible, and whether they are specific to certain patient populations or stages of disease. Many thought the data implied a stable synaptic deficit rather a speeding up of pathology. Because the cognitive loss appeared to be dose-dependent, scientists suggested that lower doses, or an intermittent dosing schedule, might alleviate the problem. Notably, no one at CTAD said the new data threw the amyloid hypothesis in doubt.
“I think there is a safe dose for BACE inhibition. We just need to find it,” said Robert Vassar of Northwestern University in Chicago. Paul Aisen of the University of Southern California, San Diego, agreed. “I believe BACE inhibition may still be an important part of our armamentarium against AD. It remains our leading candidate for primary prevention.”
Class Effect? Three Different Inhibitors Knock Cognition
In 2017, Merck halted its Phase 3 EPOCH study of verubecestat in patients with mild to moderate AD, after an interim analysis forecast that it would fall short. Subsequent analysis confirmed that participants on drug declined cognitively and functionally at the same rate as controls (Feb 2017 news; Dec 2017 conference news; May 2018 news). In February 2018, Merck conceded that the prodromal AD trial, APECS, appeared futile, too, and halted dosing (Feb 2018 news).
In Barcelona, the field got its first detailed look at APECS data. This trial enrolled 1,454 people with subjective memory decline and a positive amyloid PET scan. They had an average MMSE of 26 and age of 72. In a planned two-year trial, 484 people took 40 mg of verubecestat, 485 took 12 mg, and 485 took placebo. Although the trial ended a year early, many participants had completed the full dosing schedule by February 2018.
On the primary outcome measure, the CDR-SB, the 40 mg group scored worse than controls at nearly every time point from 13 weeks to 104 weeks. The effect was small, with a Cohen’s d of 0.2 mean difference divided by standard deviation between the treatment and placebo groups. However, it was significant at the 5 percent level, i.e. p<0.5. How about the lower dose? The 12 mg group also performed below controls, although for them the difference only reached significance at the 52 and 78 week time points.
Treatment groups did worse on the ADAS-Cog13 as well, scoring about one to 1.5 points higher than controls from 13 weeks on. On this test battery, the difference between drug and control groups shrank over time, with the 12 mg group no longer significantly different from placebo starting at 78 weeks.
Did the cognitive decrement matter to people’s lives? Participants taking verubecestat scored worse on the ADCS-ADL measure. The functional deficit appeared a little later than the cognitive one, starting at week 39. Both treatment groups progressed to dementia faster than did controls, at a rate of 25 percent per year instead of 20. Participants on drug also had more anxiety, depression, and disturbed sleep than those on placebo.
Is this just verubecestat, or a class effect? Ominously, other data at Barcelona pointed to the latter. Gary Romano of Janssen presented preliminary data from the Phase 2/3 EARLY trial of atabecestat, which was halted during its recruitment phase due to liver toxicity (May 2018 news). EARLY targeted a preclinical population, with participants having a CDR of zero and confirmed amyloid positivity by PET or cerebrospinal fluid. The 557 participants took atabecestat for no more than 18 months; more than half of them for only three. Equal numbers of participants received placebo, 5 mg, or 25 mg.
In this trial, only the high-dose group had a statistically significant cognitive decrement. They scored about 1 point worse than controls on the PACC cognitive composite at six and 12 months, and about four points worse on the RBANS at three months. This group started with 183 participants at baseline, but only 110 completed the three-month assessment, 66 the six-month, and 28 the 12-month. For later time points, the number of participants was even smaller, and findings not statistically significant. Breaking the data down by cognitive domain, the deficits appeared mainly memory, Romano said. The researchers saw no differences in ADCS-ADL in this study, but they did pick up more depression, anxiety, and sleep or dream-related problems.
Meanwhile, John Sims of Lilly said that findings for lanabecestat look similar to those for verubecestat, although he showed no data. Lilly recently pulled the plug on lanabecestat after futility analysis suggested no benefit in symptomatic disease (Jun 2018 news).
“I think we will find a BACE inhibitor class issue,” Sims said. Egan agreed that the weight of evidence now points toward an on-target, BACE-related mechanism. How dire this news is for BACE inhibitors, and whether all patient populations will be equally affected, are unanswered questions at this point.
Based on the evidence to date, it appears cognitive dampening mainly occurs early on in disease, at prodromal stages. While mild AD patients in the verubecestat EPOCH trial showed a trend toward cognitive worsening, it was not consistent. In Barcelona, Eli Lilly’s Albert Lo presented similar data on the company’s newest investigational BACE inhibitor, LY3202626. Its Phase 2 NAVIGATE trial was terminated after an interim futility analysis gave it little chance of success. NAVIGATE had enrolled 316 amyloid-positive people with mild AD whose average MMSE was 23; randomizing 133 to placebo, 55 to 3 mg, and 128 to 12 mg of drug. Researchers prioritized the higher dose as enrollment went along, so the 3 mg group consisted of those who had started earlier and had the longest exposure to drug. The researchers saw no clear effect on cognition, though there were hints of a deficit in the 3 mg group at 24 weeks on the ADAS-Cog13 and at 52 weeks on the MMSE.
Overall, researchers were unsure why BACE inhibitors would cause more harm early in disease than later. Bruce Albala of Eisai in Woodcliff Lake, New Jersey, noted that people at prodromal stages have a wider cognitive range, perhaps allowing researchers to detect subtle deficits.
What Do the Exceptions Mean?
Other data in Barcelona suggest that not all BACE inhibitors follow this pattern. In a panel discussion, Ana Graf of Novartis noted that the company's BACE inhibitor CNP520, which it develops in collaboration with Amgen, exhibited no ill effects in a small dose-finding study of elderly controls (Aug 2017 conference news). About 60 participants took varying doses of drug for three months, with no deficits apparent on monthly computerized cognitive tests. The participants had no increase in neuropsychiatric symptoms either, though they did report vivid dreams. Graf suggested that some BACE inhibitors may not cause cognitive effects because of differences in their mechanisms of action.
Take elenbecestat, for example. Shau Yu Lynch of Eisai reported sharply divergent data for this BACE inhibitor, which selectively inhibits BACE1 over BACE2, unlike most others in development. Yu Lynch claimed that elenbecestat slows cognitive decline. She reported a small, 18-month Phase 2 trial, in which 70 participants took either placebo or 5, 15, or 50 mg of drug. The groups started out evenly balanced, but people on the lower doses were switched to 50 mg as the trial proceeded. Half had mild, the rest prodromal AD. Treatment groups declined one-third less on the CDR-SB and ADCOMS than the placebo group did, with their separation beginning to show at about six months. No neuropsychiatric symptoms cropped up in this study, though people on drug had more nightmares (May 2017 conference news; Jun 2018 news).
Egan cautioned, however, that subtle cognitive deficits might not be detectable in trials with sample sizes as small as 60 or 70. Only a highly powered trial can detect the slight worsening seen with verubecestat, he said. The Merck trials represent the largest data sets for BACE inhibitors to date.
Mechanism Is a Mystery
What do these drugs do to memory? Discussion in Barcelona quickly turned to synapses. BACE1 loiters in presynaptic terminals. In mice, high doses of BACE inhibitor interfere with synaptic plasticity and memory formation (Nov 2014 news). “An early separation of curves that does not widen is consistent with a synaptic effect,” Aisen noted.
Stefan Lichtenthaler of the German Center for Neurodegenerative Diseases in Munich nominated three of the more than 40 known BACE1 substrates as potential culprits in the synapse. Seizure protein 6 (SEZ6) helps maintain dendritic spine density and long-term potentiation, with BACE1 knockout mice impaired in both (Oct 2016 conference news). Perhaps SEZ6 effects manifest as cognitive deficits or neuropsychiatric symptoms in people, Lichtenthaler speculated. Another candidate, close homolog of L1 (CHL1), guides axons to their targets. Vassar and colleagues recently knocked out BACE1 in adult mice and saw stunted growth of mossy fiber axons in the hippocampi (Sep 2018 news). Finally, neuregulin helps maintain myelination and muscle spindles; its absence during development causes seizures (Jul 2013 news; Dec 2013 conference news). Lichtenthaler suggested probing these proteins first to find answers.
Alternatively, it could be that inhibiting cleavage of APP itself causes problems, Lichtenthaler added. Suppressing BACE1 has been reported to promote an alternate cleavage pathway, in which η-secretase snips APP to create a synaptotoxic Aη fragment (Aug 2015 news), hence buildup of this fragment after BACE1 inhibition could theoretically blunt synaptic transmission. Lastly, older work suggests that Aβ itself stimulates presynaptic release, and that too little of it causes harm (Nov 2009 news).
Could blocking of BACE2 be to blame? Most current inhibitors act on both BACE1 and BACE2. BACE2 is expressed in the brain and more so under conditions of inflammation. Even so, Lichtenthaler thought the enzyme’s normally low levels in brain make it an unlikely culprit (Mar 2018 news).
Some clues to what may be happening in the brain came from MRI data. In the APECS verubecestat trial, hippocampal volume shrank about half a percentage point more in the 40 mg treatment group than in the others. The difference appeared at 13 weeks, and held steady at 104. Likewise, people who took any dose of LY3202626 lost more volume over a year in the hippocampus, medial temporal lobe, and parietal regions than controls did. In contrast, in the elenbecestat study, hippocampal volume declined equally on drug and placebo.
This volume loss puzzled researchers. Some speculated it could represent a loss of dendritic spines or mossy fiber axons, in keeping with mouse data. Another recent study claims BACE inhibition can squelch hippocampal neurogenesis, which might also affect volume (Aug 2018 news).
As expected from previous mouse and human studies, amyloid load dipped slightly with BACE inhibitor treatment (Jan 2016 news). On the highest dose of verubecestat, the PET signal fell by 0.04 SUVR, a statistically significant difference. Lilly reported a similar drop in people taking LY3202626, although it did not reach significance in this smaller study. Janssen did not report amyloid PET findings, while Eisai and Biogen claimed a drop of about 25 centiloid in people taking elenbecestat, on a par with reductions seen after a year of anti-amyloid antibody treatment (Aug 2018 conference news).
The cognitive deficits seen with BACE inhibitors do not appear to come with increased neurodegeneration. None of these trials reported any change in tau PET or CSF tau or NfL relative to placebo. Although loss of gray matter increased on drug, this MRI finding did not correlate with cognitive scores, Egan said. “It looks like the effect is independent of AD progression,” Eric Reiman of Banner Alzheimer’s Institute in Phoenix told Alzforum.
What Now For BACE Inhibitors?
Researchers at CTAD emphasized that this is not the end of the road for BACE inhibitors. One crucial question is whether a person’s cognition rebounds after he or she stops taking the inhibitor. Egan said APECS was not designed to address this, but Merck is doing exploratory analyses now. Romano presented preliminary data implying the deficit might be reversible. In a single cognitive assessment done after atabecestat treatment stopped, scores rose slightly for people who had been on drug. However, Romano cautioned that the number of participants at this time point was small, about 36 per group. Lichtenthaler noted that in mice, spine density fully recovers after withdrawing BACE inhibitor.
Many researchers suggested lowering the dose of BACE inhibitors and starting treatment earlier. Vassar said that in mice, BACE1 activity has to be curtailed by 90 percent to cut Aβ levels in half. All BACE inhibitor trials to date suppress Aβ production from 50 to 90 percent, suggesting they shut off BACE1 almost completely. This may be far more stringent than needed, Vassar suggested. Eric McDade of Washington University in St. Louis agreed, noting that the protective APP mutation lowers plasma Aβ40 only 28 percent (Martiskainen et al., 2017). Vassar and Lichtenthaler both recommended slashing Aβ production by no more than half; others suggested trying an intermittent dosing schedule to give other BACE1 substrates a chance to recover.
Lichtenthaler proposed measuring levels of the BACE1 substrates SEZ6, CHL1, and neuregulin, as well as Aη, in stored CSF samples from inhibitor trials to find out if changes in any of these proteins correlate with cognitive effects. If so, the proteins could be used as biomarkers to monitor dosing and find safe levels of inhibition, he said. Aisen concurred that these ideas have merit. “We have the tools to move forward,” he said.
In the meantime, some inhibitor trials will continue. Johan Luthman of Eisai said they have confidence in their program and will carry on. Novartis and Amgen’s CNP520 program will also remain active, although Pierre Tariot of Banner noted that they will need to see more data before deciding whether to alter their plans for CNP520 dosing in the ongoing API Generation trial of ApoE4 homozygotes. Egan said Merck is not yet taking a public position on verubecestat’s future, noting they will take findings from other inhibitors into account before making a decision.
McDade and colleagues at WashU have been planning to use BACE inhibitors in the first primary prevention trial for AD in the DIAN cohort (Aug 2017 conference news). McDade believes this strategy is still viable. Because the cognitive deficits appear quickly, it will be possible to adjust dosing to achieve a safe level, he said. He plans to use an adaptive design, start with a low dose of inhibitor, and titrate up. Since all BACE inhibitors so far produce vivid dreams and sleep disturbances, researchers can monitor sleep quality as a readout for side effects, he added. McDade compared the challenge to that of balancing safety and efficacy during chemotherapy.
What do AD patients think? Offering some perspective, Tariot noted that families in the verubecestat trial are begging the scientists not to throw in the towel on BACE inhibitor research. The magnitude of the cognitive deficit pales in comparison to cognitive side effects from chemotherapy, and to the terror of AD, trial participants tell him. Maria Carrillo of the Alzheimer’s Association observed that the first vaccine trials also had frightening side effects, but ARIA has now proven to be manageable. “Patients are counting on us to be bold,” she said.—Madolyn Bowman Rogers
References
Therapeutics Citations
News Citations
- Merck Pulls Plug on Phase 2/3 BACE Inhibitor Trial
- Verubecestat Negative Trial Data: What Does it Mean for BACE Inhibition?
- Paper Alert: Verubecestat EPOCH Findings Published
- Merck Axes Verubecestat for Prodromal AD, Researchers Say ‘Go Earlier’
- Liver Tox Ends Janssen BACE Program
- Scratch Lanabecestat: This BACE Inhibitor Doesn’t Work in Symptomatic AD, Either
- At AAIC, Encouraging Safety Data on a Variety of Small-Molecule Candidates
- Anti-Amyloid Drug Pipeline Shows No Sign of Drying Up
- Hanging in There: Another BACE Inhibitor Still Safe in Phase 2
- At High Doses, BACE1 Inhibitors Hinder Synaptic Plasticity in Mice
- BACE Inhibition and the Synapse—Insights from Seeon
- In Conditional BACE1 Knockouts, Hippocampal Axons Compromised
- Paper Alert: BACE1 Required for Muscle Spindle, Motor Control
- Blocking BACE—Do Adult Mouse Phenotypes Predict Side Effects?
- Enter Aη: Alternative APP Cleavage Creates Synaptotoxic Peptide
- What’s My Line?—Fishing for the True Role of Aβ
- Remember: BACE2 Is in the Brain, Too
- Alzheimer’s Disease-Related Proteins Needed for Neurogenesis
- BACE Block Nips New Plaques in the Bud, Old Ones Keep Growing
- Four Immunotherapies Now Banish Amyloid From the Brain
- Planning the First Primary Prevention Trial for Alzheimer’s Disease
Paper Citations
- Martiskainen H, Herukka SK, Stančáková A, Paananen J, Soininen H, Kuusisto J, Laakso M, Hiltunen M. Decreased plasma β-amyloid in the Alzheimer's disease APP A673T variant carriers. Ann Neurol. 2017 Jul;82(1):128-132. PubMed.
Other Citations
External Citations
Further Reading
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Comments
Northwestern University Feinberg School of Medicine
We are at a critical juncture for BACE1 inhibition research. The disappointing results of the recent BACE1 inhibitor clinical trials is giving way to the sentiment that BACE1 is too risky a therapeutic target to pursue for AD. This feeling is understandable, given the enormous cost and effort that each AD clinical trial entails. Some companies have terminated their BACE1 clinical trials and even discontinued their BACE1 programs entirely.
However, it is important to remember that the AD field has learned tremendously from these and other AD trials. The more we understand about the natural history of AD and the drug targets pursued, the closer we get to treatments. As Dr. Tariot so aptly noted at CTAD, the patients and their families are desperate and begging that we not throw out the baby with the bathwater on BACE1 inhibitor research.
We must remember that the cholesterol-lowering statin drugs for the prevention of heart disease would kill a person at high dose. Yet statins are the most prescribed drug class in the developed world and save millions of lives each year.
The same may be true someday for BACE1 inhibitors, with the exception that they likely would not cause fatalities, given that BACE1 knockout mice are quite viable despite some negative phenotypes. As we learn more about the pathophysiology of AD and the normal functions of BACE1 and its substrates, emerging from the fog of ignorance will appear an efficacious BACE1 inhibitor regimen to advance forward for the prevention of AD.
Indiana University School of Medicine
To alleviate BACE1 trials disappointment, I suggest not missing the APPointment. BACE1 inhibition should remain a viable strategy even though recently tested BACE1 inhibitors worsened cognition. We must be brave to tackle the “bumps” along the way of BACE inhibitors (Nov 2018 conference news). /news/conference-coverage/bump-road-or-disaster-bace-inhibitors-worsen-cognition
Multiple BACE1 inhibitors had this worsening effect, not just verubecestat but also atabecestat and lanabecestat. The "good boy" (elenbecestat) is unusual in that it is a BACE1-selective inhibitor. As already reported, Biogen and Eisai found a cognitive benefit in a small trial of its inhibitor elenbecestat, and no sign of neuropsychiatric symptoms or increased atrophy. The other inhibitors also inhibit BACE2. We discussed previously the problem of atabecestat and liver toxicity.
Bob Vassar rightly pointed out that current inhibitor doses are simply too high, and mentioned that the protective APP mutation only reduces circulating Aβ-40 peptide by 28 percent, which is far less than BACE1 inhibitors do at current doses (i.e., curtailing 90 percent BACE1 activity cuts only 50 percent Aβ levels). It is still reasonable to consider some form of BACE1 inhibition to treat AD, given recent work by Hu et al., who showed that conditional adult BACE1 knockout reversed amyloid deposition and improved cognitive function (Hu et al., 2018). A simple response to the above factors would be to retitrate the dose. This would, after all, salvage current approaches, considering the great sunk cost already devoted to them.
Putting this together, if the problem is an intersection of needing BACE1 vs. BACE2 specificity and having "positive inefficient" inhibition, this is another case for looking into microRNA (miRNA), which can certainly be made specific to sites on BACE1 mRNA but absent in BACE2, and it is inherently incomplete in activity. If a cocktail were to be used, that would allow even lower doses for each and confer specificity squared, cubed, etc.
Another bold step is to investigate protein level regulation, not of BACE1, but of the AD-associated BACE1 substrate: Aβ precursor protein (APP). Of course, APP has functions in addition to “have Aβ clipped from it.” Many of these functions are not adequately compensated for by the APLP family proteins. Complete inhibition of APP expression would be at least as unhealthy as complete inhibition of BACE1 expression. However, modulating the two target molecules could prove effective in reducing the overall threat without reaching a dangerous threshold, since, theoretically, BACE1 inhibition plus APP downregulation could produce clinical results at lower levels of each than would be required for a single-target approach. In any case, APP regulation as an alternate or supplement to BACE1 inhibition is worth exploring.
One method to specifically regulate APP protein levels could be specific miRNA to downregulate APP translation (Long et al., 2012). Unlike siRNA, which often completely inhibits translation, miRNA-mediated inhibition of APP translation is partial and could be less likely to overshoot the target. Combining lower-level BACE1 inhibition with mild APP downregulation could provide a one-two punch to knock out AD.
References:
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.
Long JM, Ray B, Lahiri DK. MicroRNA-153 physiologically inhibits expression of amyloid-beta precursor protein in cultured human fetal brain cells and is dysregulated in a subset of Alzheimer disease patients. J Biol Chem. 2012;287(37):31298-310.
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