New Data from Past BACE Inhibitor Trials Shed Light on Side Effects
BACE inhibitors succeeded in stemming the tide of Aβ production in the brain, but the drugs also slightly dulled cognition and shrank the brain, bringing the trials to a screeching halt. Rather than washing their hands of a failure and moving on, researchers continue to dig through the trial data to find out exactly what happened, and perhaps even to chart a way forward for the drugs. Three recent studies—all led by Michael Egan at Merck—add new insight.
- Verubecestat triggered a rapid atrophy that did not get worse.
- This happened in amyloid-rich regions, and did not track with neurodegeneration.
- Exploratory cognitive measures from verubecestat and lanabecestat trials indicate opposite effects on memory and verbal fluency.
One, published November 30 in Brain, described regional patterns of brain volume loss in Merck’s EPOCH trial of verubecestat. The shrinkage came on fast but did not progress. It happened mostly in areas burdened by amyloid, uncoupled from cognitive impairment or neurodegeneration. A study in the November 21 Journal of Alzheimer’s Disease reported that, in the same trial, retinal biomarkers and brain atrophy were not linked. Another, published October 13 in Alzheimer’s and Dementia, was a collaboration between Merck, Eli Lilly, AstraZeneca, and academic scientists. It reported exploratory cognitive outcome measures from two trials of the BACE inhibitors verubecestat and lanabecestat in prodromal and early AD, respectively. Both drugs took an early toll on episodic memory but, strangely perhaps, boosted verbal fluency.
The findings do not amount to a complete explanation. Rather, they add to a growing, if largely unspoken, sense that the cognitive impairment and brain volume loss caused by BACE inhibitors is mild, non-progressive, and potentially reversible. They also flag specific changes in cognition or brain volume that could be used to quickly find a safe dose in future trials.
“I congratulate both companies on sharing more detailed data from the terminated trials and on their collaborative effort to compare two trials and inhibitors,” wrote Stefan Lichtenthaler of the German Center for Neurodegenerative Diseases in Munich. “Although the molecular basis of the cognitive side effects is not yet clear, the three studies together provide very helpful guidance for possible future BACE inhibitor trials.”
Over a brutal two-year period, five Phase 3 trials of BACE inhibitors ran into the ground. In the end, the whole class of drug—including Merck’s verubecestat, Janssen’s atabecestat, Novartis’ umibecestat, Eli Lilly/AstraZeneca’s lanabecestat, and Eisai/Biogen’s elenbecestat—were tied to cognitive deficits, brain atrophy, or both (Dec 2017 conference news; Nov 2018 conference news; Jul 2019 news).
Since then, scientists have continued to pore over the data, hoping to understand how this class of drugs veered off course (Dec 2019 conference news). In the Generation trials of umibecestat, researchers continued to monitor cognition and brain volume in trial participants after treatment was stopped, and reported that cognitive deficits and, to some extent, brain volume loss, were reversible (Aug 2020 conference news). Similarly, David Henley at Janssen Research & Development, and colleagues, reported at the 2019 AAIC that cognitive deficits triggered by atabecestat largely abated three months after treatment stopped (scroll to abstract FTS3-01-04, Henley et al., 2019). Their paper is in press, see comment below.
Verubecestat was the first to fall. The Phase 3 EPOCH trial, which enrolled people with mild to moderate AD, stopped in 2017, and the APECS trial of people with prodromal AD stopped soon after (Feb 2017 conference news; Dec 2017 conference news; Nov 2018 news). The drug was associated with hippocampal volume loss in EPOCH, but not with cognitive worsening beyond what was caused by AD. In APECS, however, the drug appeared to make people’s cognition worse (May 2018 news; Apr 2019 news).
In their follow-up study, first author Cyrille Sur and colleagues dove deeper into the imaging data collected during EPOCH. The trial included more than 2,000 participants who took either 12 mg or 40 mg of verubecestat, or placebo, for 78 weeks. More than 450 in each dose group had MRI scans at baseline, while a smaller number did so again at 13, 52, and 78 weeks. Brain volume—as gauged by cortical thickness, whole brain volume, or hippocampal volume—slipped for all groups throughout the trial, but it slipped by more in the two groups on drug. This difference emerged at 13 weeks, and it held steady throughout the trial.
The researchers also measured volume changes in 31 brain regions between baseline and 78 weeks. They found that in people on placebo, regions known to degenerate in AD, such as the entorhinal cortex, amygdala, fusiform cortex, and hippocampus, shrank the most throughout the trial. A similar atrophy pattern happened in the treatment groups, with additional verubecestat-related volume loss to boot. However, the drug did not appear to accelerate AD-related neurodegeneration.
How did the atrophy attributable to verubecestat relate to amyloid? The researchers addressed this question in several ways. Looking at the pattern of verubecestat-related brain volume loss, they found that it coincided with regions most prone to amyloid accumulation. This shrinkage was prominent in the cuneus, precuneus, lateral occipital, and supramarginal cortex, which are among regions burdened by amyloid early in disease. They found no significant treatment effect in white-matter regions, or in regions known to be largely free of amyloid deposition, such as the cerebellum. Alas, despite this apparent link to amyloid, there was no correlation between a person’s baseline amyloid load in a given region and his or her subsequent drug-related volume loss.
Is this volume loss due to plaque reduction? It’s not that simple. According to longitudinal amyloid-PET imaging data collected from a subset of 42 participants, a person’s amyloid reduction over 78 weeks had nothing to do with how much his or her hippocampus shrank. If anything, the relationship trended in the opposite direction: Patients with less amyloid reduction tended to lose more hippocampal volume triggered by verubecestat.
These regional MRI findings mesh with a more fine-grained analysis of the imaging data that David Scott of Bioclinica presented at the Clinical Trials in Alzheimer’s Disease (CTAD) meeting held virtually in November. Tracking change by way of voxel-based morphometry, Scott found similar patterns of verubecestat-related volume loss, which were aligned with amyloid-rich regions.
A more sinister explanation might be that verubecestat shrank the brain by killing neurons. That’s unlikely because the drug-induced atrophy stayed stable throughout the trial, as does CSF biomarker data collected from a subset of 118 participants. The researchers reported that this mysterious volume loss did not correlate with the neurodegeneration marker neurofilament light (NfL). The researchers also found no relationship between the degree of verubecestat-related brain volume loss at week 13 and scores on the ADAS-Cog11. Because participants in this trial, who had mild to moderate AD, already had significant cognitive deficits that worsened throughout the trial, it may have been difficult to detect any deficits triggered by the drug, the researchers noted. This is distinct from the situation in the APECS trial, in which participants were still in the earliest stages of the disease and the drug did worsen their cognition.
In a separate study led by Egan, first author Robert Sergott and colleagues checked whether the brain shrinkage in EPOCH tracked with biomarkers in the eye. They did this because mouse studies had raised the specter of retinal toxicity with BACE1 inhibition. Separately, changes in retinal structure have been proposed as potential AD biomarkers (Aug 2018 news; Apr 2019 conference news), and EPOCH included several retinal biomarkers as exploratory outcome measures. In short, the researchers found no evidence of any retinal changes relating to verubecestat treatment, and the thickness of the retina tracked at best weakly with AD-related neurodegeneration throughout the 78-week trial.
If it wasn’t neurodegeneration or amyloid reduction, then why did the brain get a little smaller on verubecestat? For all his searching, Egan still does not know, he told Alzforum. He speculated that it could relate to microglia around Aβ plaques. Perhaps with Aβ production being way down around plaques, immune cells weren’t being recruited and riled any more, dampening inflammation. Robert Vassar of Northwestern University in Chicago had a similar take, noting that BACE activity is highest in dystrophic neurites around plaques. Shutting down production of Aβ from these hubs of pathology may have doused inflammatory responses enough to ease local swelling, leading to a non-progressive volume loss. This would explain why the brain shrank in regions flush with plaques, he said.
Postmortem neuropathological data presented at CTAD support the idea that verubecestat changes the plaque environment. Alberto Lleó of the Hospital de Sant Pau in Barcelona, Spain, used immunohistochemistry and immunoblotting to detect different forms of Aβ and synaptic markers in the brain of a 63-year-old man who had received 12 mg verubecestat for 38 months. Compared to samples from a group of untreated patients with early onset sporadic AD, the sample from the treated patient contained fewer non-fibrillar, soluble forms of Aβ, despite harboring similar levels of insoluble, fibrillar Aβ. Furthermore, the verubecestat-treated patient had fewer dystrophic neurites around plaques than did the untreated patients.
Jochen Herms of the German Center for Neurodegenerative Diseases, Munich, favors a different explanation. Animal studies have shown that BACE inhibitors affect the density of excitatory synapses, regardless of amyloid (Nov 2014 news; Zhu et al., 2018). “The acute and non-progressing loss in brain volume can easily be the consequence of a loss of a subset of synapses that are sensitive to BACE inhibition,” he wrote. “It is much less likely that this acute volume loss is an amyloid-related process.”
The distinction is important, according to Eric McDade of Washington University in St. Louis. McDade wrote that understanding the relationship between amyloid burden and the detrimental effects of BACE1 inhibition will be helpful for primary versus secondary prevention trials with lower doses of the inhibitors. For example, would amyloid-negative participants be at greater or lesser risk of faster atrophy than amyloid-positive people? Knowing this would be important in the design of any future BACE inhibitor trials in the Dominantly Inherited Alzheimer’s Network (DIAN).
Curious Cognitive Effects Line Up
Perhaps the BACE inhibitors’ most unsettling problem was that they worsened cognition. At conferences and in conversation, the size of this effect has been compared to drinking a glass of wine, or taking a Benadryl. What do the data say? To take a closer look at how the drugs alter cognition, the sponsors of two Phase 3 trials joined forces to report secondary and exploratory cognitive outcome measures. APECS tested verubecestat in prodromal AD and, after failing an interim futility analysis, was cut short by a year. Egan subsequently reported that participants on the 40 mg dose fared worse on the CDR-SB, its primary outcome, and slipped faster into dementia than did those on 12mg or placebo. ADCS-ADLMCI scores, a secondary outcome, also worsened more on treatment (Apr 2019 news). AMARANTH, a trial of lanabecestat in MCI due to AD or mild AD, halted 16 months early when it failed its futility analysis. Lanabecestat did not appear to influence scores on the ADAS-Cog13, that trial’s primary outcome measure (Wessels et al., 2019).
For the current study, investigators jointly analyzed secondary cognitive outcomes from APECS and exploratory cognitive outcomes from AMARANTH. Because they rely on many statistical tests and are therefore more likely to produce a spurious chance result, exploratory outcome results are rightly met with a hefty dose of skepticism. Egan told Alzforum that the joint analysis was meant to lend power and credibility to the findings.
APECS used the Alzheimer’s Disease Cooperative Study–Activities of Daily Living for Mild Cognitive Impairment scale (ADCS-ADLMCI) and the 3-domain Composite Cognition Score (CCS-3D) as secondary outcomes. The CCS-3D encompasses multiple tests to evaluate episodic memory, attention/processing speed, and executive function. Co-first authors Alette Wessels of Eli Lilly and Christopher Lines of Merck reported that CCS-3D scores in the treatment groups slipped relative to placebo starting at week 13. This worsening was driven by episodic memory and attention/processing speed. In particular, treatment-related deficits were largest and most consistent for digit symbol coding, a test of memory and processing speed. In contrast, participants on drug outperformed those on placebo in the third domain—executive function. That benefit was driven by scores on letter and category fluency tests.
Domains Dissociated. In the EPOCH trial, people on 12 mg (red) or 40 mg verubecestat (blue) scored worse than those on placebo (grey) in digit symbol coding (left), but better in letter fluency (right).
The same trends emerged in AMARANTH, whose exploratory outcomes were the Repeatable Battery for the Assessment of Neuropsychological Status, Letter Fluency, Category Fluency, and WAIS-III Digit Symbol Coding. For the RBANS, which measures attention, language, visuospatial/constructional abilities, and immediate and delayed memory, participants in both the 20 mg and 50 mg lanabecestat groups slipped relative to placebo at multiple time points across the trial. They also underperformed on Digit Symbol Coding, with those in the 50 mg dose group scoring lower than placebo at all time points, and those in the 20 mg group underperforming at weeks 26 and 52. But here, too, participants in both drug groups scored higher on letter and category fluency than did those in the placebo groups.
Scopalamine, an anti-cholinergic drug used to model cognitive impairment, also blurs episodic memory while improving letter fluency. Researchers have hypothesized that its contrasting effects are caused by a disinhibition that dampens performance on some tasks while boosting it for others (Pompéia et al., 2002).
To Egan, the data imply that BACE inhibition might exert unique influences in different regions of the brain. For example, mouse studies suggest that BACE inhibition can cause synaptic dysfunction in the hippocampus, which would explain the episodic memory effect. In prefrontal and frontal regions needed for verbal fluency, perhaps BACE performs different functions that aren’t affected by the inhibitor. Perhaps the benefit of BACE inhibition—i.e., stemming the production of Aβ monomers and, from there, oligomers—can shine through in these centers, he hypothesized.
It is also plausible that exactly which among its many substrates BACE1 primarily cleaves—and therefore the effect of inhibition—differs between brain regions, Vassar noted. In the hippocampus, where synaptic plasticity is paramount, insufficient processing of substrates like close homolog of L1 (CHL1) or seizure-6, which function in plasticity, could be detrimental (Jun 2012 news; Oct 2016 conference news).
Colin Masters, University of Melbourne, Australia, believes that these effects likely result from on-target inhibition of APP processing. “If the normal cleavage of APP releases the extracellular and intracellular domains, and if the normal function of APP is for heterotypic interactions at the peri-synaptic zones that are used for synaptic plasticity (for learning and memory functions), why then should we not expect 80 percent inhibition to result in deficits in learning and memory?” Masters noted that only 5 percent of Aβ produced every hour accumulates. He believes that much smaller degrees of inhibition, i.e. much lower inhibitor doses, might be sufficient to keep Aβ accumulation in check—and be safer.
“The comparative paper demonstrates impressively that a detailed analysis of the diverse cognitive tests is important, as it shows previously unanticipated cognitive worsening of lanabecestat—not globally but on a subset of tests, whereas improvement in other tests can now also be appreciated,” wrote Lichtenthaler. To his mind, the findings imply that specific cognitive tests—such as digit symbol coding—may help trialists find the right dose of BACE inhibition within a short trial.
What do BACE inhibitor follow-up studies portend for the future of these drugs? To Paul Aisen of the University of Southern California in San Diego, a co-author on this latest batch of papers, now is not time to throw in the towel. “Secretase inhibition remains the most direct method of addressing the accumulation of amyloid in the AD brain, and may be ideal to treat amyloid dysregulation in individuals at high risk for amyloid accumulation (i.e., primary prevention of AD),” he wrote. “It is very important that we investigate the safety of lower doses to consider further early intervention studies; we know well how to monitor the toxicity, so we have a feasible path forward.”—Jessica Shugart
- Verubecestat Negative Trial Data: What Does it Mean for BACE Inhibition?
- Bump in the Road or Disaster? BACE Inhibitors Worsen Cognition
- Cognitive Decline Trips Up API Trials of BACE Inhibitor
- Picking Through the Rubble, Field Tries to Salvage BACE Inhibitors
- Umibecestat-Driven Cognitive Decline Is Reversible
- Merck Pulls Plug on Phase 2/3 BACE Inhibitor Trial
- Paper Alert: Verubecestat EPOCH Findings Published
- Results from Verubecestat APECS Trial Published
- Does Retinal Thinning Reflect Early Alzheimer’s?
- ARIAS: Zooming in On Eye-based Biomarkers for Alzheimer’s
- At High Doses, BACE1 Inhibitors Hinder Synaptic Plasticity in Mice
- BACE Secrets: Newly Identified Substrates May Regulate Plasticity
- BACE Inhibition and the Synapse—Insights from Seeon
- Zhu K, Peters F, Filser S, Herms J. Consequences of Pharmacological BACE Inhibition on Synaptic Structure and Function. Biol Psychiatry. 2018 Oct 1;84(7):478-487. Epub 2018 Jun 23 PubMed.
- Wessels AM, Tariot PN, Zimmer JA, Selzler KJ, Bragg SM, Andersen SW, Landry J, Krull JH, Downing AM, Willis BA, Shcherbinin S, Mullen J, Barker P, Schumi J, Shering C, Matthews BR, Stern RA, Vellas B, Cohen S, MacSweeney E, Boada M, Sims JR. Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials. JAMA Neurol. 2019 Nov 25; PubMed.
- Pompéia S, Rusted JM, Curran HV. Verbal fluency facilitated by the cholinergic blocker, scopolamine. Hum Psychopharmacol. 2002 Jan;17(1):51-9. PubMed.
- Blume T, Filser S, Jaworska A, Blain JF, Koenig G, Moschke K, Lichtenthaler SF, Herms J. BACE1 Inhibitor MK-8931 Alters Formation but Not Stability of Dendritic Spines. Front Aging Neurosci. 2018;10:229. Epub 2018 Jul 26 PubMed.
- Sur C, Kost J, Scott D, Adamczuk K, Fox NC, Cummings JL, Tariot PN, Aisen PS, Vellas B, Voss T, Mahoney E, Mukai Y, Kennedy ME, Lines C, Michelson D, Egan MF. BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer's disease brain. Brain. 2020 Dec 1;143(12):3816-3826. PubMed.
- Sergott RC, Raji A, Kost J, Sur C, Jackson S, Locco A, Patel A, Furtek C, Mattson B, Egan MF. Retinal Optical Coherence Tomography Metrics Are Unchanged in Verubecestat Alzheimer's Disease Clinical Trial but Correlate with Baseline Regional Brain Atrophy. J Alzheimers Dis. 2021;79(1):275-287. PubMed.
- Wessels AM, Lines C, Stern RA, Kost J, Voss T, Mozley LH, Furtek C, Mukai Y, Aisen PS, Cummings JL, Tariot PN, Vellas B, Dupre N, Randolph C, Michelson D, Andersen SW, Shering C, Sims JR, Egan MF. Cognitive outcomes in trials of two BACE inhibitors in Alzheimer's disease. Alzheimers Dement. 2020 Nov;16(11):1483-1492. Epub 2020 Oct 13 PubMed.
- Sperling R, Henley D, Aisen PS, Raman R, Donohue MC, Ernstrom K, Rafii MS, Streffer J, Shi Y, Karcher K, Raghavan N, Tymofyeyev Y, Bogert J, Brashear HR, Novak G, Thipphawong J, Saad ZS, Kolb H, Rofael H, Sanga P, Romano G. Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial. JAMA Neurol. 2021 Mar 1;78(3):293-301. PubMed.
To make an annotation you must Login or Register.
University of Melbourne
The BACE 1 inhibitors are a powerful and specific class of drugs. They were used at very high doses, aiming for 70-90 percent inhibition of APP processing (as were the γ-secretase inhibitors). With the benefit of hindsight, we should not be surprised that they ran into major side effects. It would be reasonable to assume that these side effects are the result of on-target inhibition of APP processing. After all, this was what they were designed to do. If the normal cleavage of APP is to release the extracellular and intracellular domains, and if the normal function of APP is for heterotypic interactions at the peri-synaptic zones which are used for synaptic plasticity (for learning and memory functions), why, then, should we not expect 80 percent inhibition to result in deficits in learning and memory?
We have previously published data to suggest that the amount of hourly accumulation of Aβ is only 5 percent of total hourly production (Roberts et al., 2017). Similar data has been published by others, e.g. the Bateman lab. This suggests to us that a BACE 1 inhibitor used at a dose aimed to inhibit Aβ production by 5 to 10 percent would have been appropriate, at least in the mildest AD cases. It’s worth noting that the high-dose BACE 1 inhibitors did have an Aβ-lowering effect based on PET data.
The atrophy seen with verubecestat in amyloid-rich regions (Sur et al., Brain) could be interpreted as an on-target effect on APP processing, as these amyloid-rich regions are possibly related to the amount of normal processing of APP in these topographic regions. Similarly, the cognitive deficits described by Wessels et al. (Alz Dem) could also be the effect of the drug on normal APP processing. Both of these statements are speculative, but could be tested experimentally.
Hopefully we will see the rehabilitation of these drug classes (both β- and γ-secretase inhibitors) at some stage in the future. One scenario is a monoclonal antibody immunotherapy lowering the amyloid burden to baseline over one to two years, followed by maintenance therapy with an amyloid production inhibitor dosed at 5 to 10 percent inhibition, to keep the amyloid burden at baseline levels.
Roberts BR, Lind M, Wagen AZ, Rembach A, Frugier T, Li QX, Ryan TM, McLean CA, Doecke JD, Rowe CC, Villemagne VL, Masters CL. Biochemically-defined pools of amyloid-β in sporadic Alzheimer's disease: correlation with amyloid PET. Brain. 2017 May 1;140(5):1486-1498. PubMed.
This is a detailed analysis of the effect of the BACE inhibitor verubecestat on brain volume. I don’t understand why the authors did not consider with a single word that several preclinical studies have previously shown that certain BACE inhibitors acutely affect the density of excitatory synapses to explain the acute brain volume loss.
The acute and non-progressing loss in brain volume in this trial can easily be the consequence of a loss of a subset of synapses that are sensitive to BACE inhibition (Filser, et al. 2015; Zou et al., 2018; Blume et al., 2018). It is less likely that this acute volume loss is an amyloid-related process.
Zhu K, Peters F, Filser S, Herms J. Consequences of Pharmacological BACE Inhibition on Synaptic Structure and Function. Biol Psychiatry. 2018 Oct 1;84(7):478-487. Epub 2018 Jun 23 PubMed.
Blume T, Filser S, Jaworska A, Blain JF, Koenig G, Moschke K, Lichtenthaler SF, Herms J. BACE1 Inhibitor MK-8931 Alters Formation but Not Stability of Dendritic Spines. Front Aging Neurosci. 2018;10:229. Epub 2018 Jul 26 PubMed.
Filser S, Ovsepian SV, Masana M, Blazquez-Llorca L, Brandt Elvang A, Volbracht C, Müller MB, Jung CK, Herms J. Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions. Biol Psychiatry. 2015 Apr 15;77(8):729-39. Epub 2014 Oct 29 PubMed.View all comments by Jochen Herms
German Center for Neurodegenerative Diseases (DZNE)
I congratulate both companies on sharing more detailed data from the terminated trials and on their collaborative effort to compare two trials and inhibitors. This is very important to better understand the effects, but also the side effects, of BACE inhibitors. I am confident that the other companies will similarly report more data on their trials.
The comparative paper demonstrates impressively that a detailed analysis of the diverse cognitive tests is important, as it shows previously unanticipated cognitive worsening of lanabecestat—not globally, but on a subset of tests, whereas improvement in other tests (verbal fluency) can now also be appreciated.
Regarding the retina analysis, it is reassuring to see that the retina is not affected by BACE inhibition with verubecestat. This was initially a concern based on retina degeneration observed in one BACE1-deficient mouse line (Cai et al., 2012), but this phenotype was not seen in an independently generated BACE1-deficient mouse line (Rudan Njavro et al., 2020).
Although the molecular basis of the cognitive side effects is not yet clear, the three studies together provide very helpful guidance for possible future BACE inhibitor trials. First, a detailed ophthalmological analysis of trial participants is not needed anymore. Second, specific cognitive tests, such as digit symbol coding, may help to evaluate in a short trial (e.g., three months) the right dose of BACE inhibition, ideally less than 50 percent, which precludes cognitive side effects. Third, the lack of an effect of BACE inhibition on NFL levels in individuals with diagnosed AD demonstrates that the future of BACE inhibition is for prevention and not treatment of AD.
Cai J, Qi X, Kociok N, Skosyrski S, Emilio A, Ruan Q, Han S, Liu L, Chen Z, Bowes Rickman C, Golde T, Grant MB, Saftig P, Serneels L, De Strooper B, Joussen AM, Boulton ME. β-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment. EMBO Mol Med. 2012 Sep;4(9):980-91. PubMed.
Rudan Njavro J, Klotz J, Dislich B, Wanngren J, Shmueli MD, Herber J, Kuhn PH, Kumar R, Koeglsperger T, Conrad M, Wurst W, Feederle R, Vlachos A, Michalakis S, Jedlicka P, Müller SA, Lichtenthaler SF. Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1. FASEB J. 2020 Feb;34(2):2465-2482. Epub 2019 Dec 27 PubMed.
The authors provide important findings that may help to answer some current uncertainties, as well as guide future consideration of this or a similar class of compounds:
Unfortunately, we do not know whether these cognitive effects would be identified at lower levels of BACE inhibition.
An important implication of the publication in the journal Alzheimer’s and Dementia is collaboration between two companies in combining data for further analyses and release to the public. This should serve as a model for future publications, particularly when there are compelling reasons (patient safety) and an obvious logic (significant overlap in the mechanism of the drug and the study outcomes).
In the neuroimaging study performed by Merck, their academic colleagues have taken a closer look at the regional atrophy patterns, regional associations with amyloid plaque load, as well as the longitudinal CSF measures of “neurodegenerative” markers to better evaluate the adverse effects of BACE inhibition by verubecestat. They demonstrate that although the regional volumetric changes, which were worse in the verubecestat groups and similar for both doses, were not strongly associated with the adverse cognitive effects, they were similarly detected at the earliest time point of measurement and were non-progressive, just like the cognition effect. Although there was not a strong association between any imaging measure of cognitive performance, these updated analyses clearly indicate 1) a strong temporal relationship between greater brain atrophy and the initial cognitive worsening and 2) that an acceleration of the AD process or neurodegeneration are unlikely the mechanistic cause. Again, as is the case with cognition, whatever the mechanistic link is appears to occur at BACE inhibition greater than 50-60 percent.
Previous studies of other amyloid-specific therapies have also identified worsening atrophy in the treated groups compared to placebo, hence the authors explored the modest decline in amyloid PET SUVR levels with the change in volumetric measures. They found no clear relationship, suggesting a clearing of amyloid plaques was unlikely to explain the change in brain atrophy. They did find a specific effect of worsening atrophy with BACE inhibition in brain regions with significant amyloid plaques and suggested that this was a potential link between brain atrophy from BACE inhibition. However, the areas of comparison (e.g., low-amyloid areas) were limited and unlikely to explain the differential volumetric losses compared to the placebo in the first place. Thus, it is remains uncertain whether BACE inhibition in areas with or without substantial amyloid plaque pathology might help to understand the detrimental effects of BACE inhibition. This last point is important, as it would be helpful in considering the potential future use of BACE inhibitors at lower doses in at-risk populations and whether amyloid-negative or -positive participants would be at greater risk of accelerated atrophy. The detailed analyses of the Novartis BACE inhibitor may provide some answers to this question.
Similar to the adverse cognitive effects, it remains unknown whether the volumetric differences between verubecestat and placebo normalize once BACE inhibition stops. Nonetheless, these two studies complement each other in demonstrating that BACE inhibitors at APP inhibition of greater than 50 percent clearly result in an early, consistent worsening of cognition (with the exception of verbal fluency) and atrophy in multiple brain regions, but that in both cases a continued acceleration of the neurodegenerative process is unlikely to be the cause. Likewise, they both provide important safety guidance on measures that could be used in future trials for therapies targeting the secretase pathway as a prevention or symptom therapy in AD.
Fundamental questions around local and temporary cognitive side effects of BACE inhibitors, and also γ-secretase inhibitors, become resolved as soon as we allocate a physiological role to Aβ monomer homeostasis in synaptic neuronal function in normal individuals and spontaneous AD cases. BACE elevation in early amyloid pathology is then regarded not as a cause of the pathology, but rather, a compensatory response to lack of physiological β-amyloid concentration at the level of the synapse. This β-amyloid dysregulation is supposed to start as soon as folding control by chaperones is impaired in the physiological β-amyloid regulation cycle.
Thus, damping the compensatory Aβ production via BACE inhibitors is the wrong approach to tackle Aβ pathophysiology in spontaneous AD. The right approach will need to be removal of early misfolded Aβ species to restore normal Aβ homeostasis at the synapse. BACE elevation is expected to normalize and take a role as biomarker upon successful Aβ oligomer treatment.
A clinical role for BACE inhibitors at low concentrations might be reserved for co-therapy in certain cases of familial AD.
Hillen H. The Beta Amyloid Dysfunction (BAD) Hypothesis for Alzheimer's Disease. Front Neurosci. 2019;13:1154. Epub 2019 Nov 7 PubMed.
Janssen Research & Development
Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School
USC Alzheimer’s Therapeutic Research Institute
Janssen Research & Development
Janssen Research & Development
University of Southern California
Alzheimer’s Therapeutic Research Institute, University of Southern California
Our primary manuscript from the EARLY trial of the BACE inhibitor atabecestat is in press. In the paper, we’ve addressed the interesting findings noted in the papers by Merck and Lilly. The EARLY trial was truncated due to hepatic safety concerns but in the preclinical AD population for which we obtained data, we did not observe improvement in the semantic fluency subtest on RBANS, although this subtest did not decline as clearly as episodic memory measures. Whole brain volume on MRI decreased at six months and 12 months in a dose-dependent manner. Unfortunately, MRI data were very limited beyond 12 months.
The reasons for the disparity between our results and those of Merck and Lilly are unclear and should be interpreted with caution as our results come from an incomplete trial. However, an obvious difference between the programs is the population studied. In EARLY, we enrolled preclinical AD participants with elevated brain amyloid and either no symptoms or subjective cognitive decline but considered cognitively unimpaired on the Clinical Dementia Rating (CDR global score 0). These participants likely started with more intact synaptic structure and function. How this would lead to the differences observed is a question requiring further study.
Our trial design permitted us to follow participants in the study without treatment. After up to six months of follow-up off treatment, the cognitive worsening observed on treatment appeared to recover, with cognition returning to baseline levels. Consistent with the findings from other sponsors, we did not observe greater increases in neurofilament light chain (NfL) with atabecestat compared to placebo.
Taken together, the EARLY trial data seem to corroborate the hypothesis that BACE inhibition does not cause irreversible neurodegeneration. It may be that with 18- or 24-month volumetric MRI data in the EARLY trial, the decrease in whole brain volume would have plateaued. However, the field should also consider the possibility that a preclinical AD population with more intact synapses may be more susceptible to effects of BACE inhibition.
Sperling R, Henley D, Aisen PS, Raman R, Donohue MC, Ernstrom K, Rafii MS, Streffer J, Shi Y, Karcher K, Raghavan N, Tymofyeyev Y, Bogert J, Brashear HR, Novak G, Thipphawong J, Saad ZS, Kolb H, Rofael H, Sanga P, Romano G. Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial. JAMA Neurol. 2021 Mar 1;78(3):293-301. PubMed.
Make a Comment
To make a comment you must login or register.