In the age of COVID-19, this year’s CTAD was a virtual one. As an FDA advisory committee picked apart aducanumab’s case for approval elsewhere, presentations at CTAD hoisted another therapeutic—BAN2401—into the spotlight. The protofibril-trained antibody continued to beat back amyloid in extension studies, and forged ahead into Phase 3. Also at CTAD, scientists took stock of clinical studies affected by the pandemic, and presented rigorous validations of smartphone-based cognitive tests. As the pandemic rages on, the field is trying to adapt and move forward in evaluating new treatments for AD.
BANish Aβ? BAN2401 Antibody Makes Its Move in Phase 3 Program
Part 1 of 3
While much of the Alzheimer’s world was enthralled by the drama of the FDA advisory committee’s shellacking of aducanumab’s application for marketing approval (Nov 2020 news) the Clinical Trials in Alzheimer’s Disease (CTAD) conference, held November 4-7, featured encouraging data and ambitious plans for a different monoclonal anti-Aβ antibody—BAN2401.
As seen at the virtual meeting, participants in an open-label extension of BAN2401’s large Phase 2 trial, who had previously taken placebo, saw large drops in brain amyloid, while those who had previously received high doses maintained low amyloid levels. Meanwhile, Eisai has enrolled more than 1,200 people into CLARITY-AD, a Phase 3 trial evaluating the antibody’s efficacy in people with MCI or mild AD. For its part, the public-private Alzheimer’s Clinical Trial Consortium started two studies—a Phase 2 and a Phase 3—aimed to tease out effects of this biologic drug in two stages of preclinical AD, designated by amyloid load (see Part 2 of this story). And separately, after years of slow development, plus some interference from COVID-19, a trial-ready cohort is finally enrolling amyloid-positive participants for secondary prevention trials (see Part 3).
Trained against large, soluble aggregates of Aβ called protofibrils, BAN2401 was developed by BioArctic, subsequently licensed by Eisai for clinical development, and later partnered with Biogen. Eisai used an ambitious, adaptive design for its 856-participant Phase 2 study, which shifted new enrollees into more effective-looking dose arms as the trial progressed. In that trial, BAN2401 missed its primary cognitive endpoint at 12 months but, by 18 months, had dramatically reduced amyloid and also slowed cognitive decline in the highest dose group (Dec 2017 news and Jul 2018 news).
Complicating the interpretation was that this highest dose group had few ApoE4 carriers, because regulators had ordered the sponsor midway through the trial to stop randomizing them to that dose. The concern was their incidence of amyloid-related imaging abnormalities due to edema (ARIA-E). Subsequent analyses reaffirmed the treatment benefit despite this snafu (Nov 2018 news).
Spurred by this result, Eisai invited participants who had completed the placebo-controlled portion of the trial back to join a 24-month open-label extension. All participants in this OLE received the highest dose of BAN2401—10 mg/kg twice monthly. They had been off treatment for an average of two years, with the gap ranging from nine to 60 months. At last year’s CTAD, Eisai had reported that despite this interruption, amyloid plaques remained at bay for those who had received the two highest doses of BAN2401—10 mg/kg either monthly or twice-monthly (Dec 2019 conference news). Alas, while amyloid plaques stayed away, cognition once again slipped during the gap period, suggesting, perhaps, that the antibody’s continued activity against protofibrillar forms of Aβ was needed for a cognitive benefit.
At this year’s CTAD, Eisai’s Chad Swanson showed 12-month brain-imaging data from the OLE. Of the 180 people who are getting BAN2401 in the extension, 38 had previously been on placebo, 60 on 10 mg/kg biweekly, 45 on 10 mg/kg monthly, and 37 had received one of the lower doses of BAN2401. Swanson presented longitudinal amyloid-PET imaging data for a subset of 76 participants who had gotten either placebo or one of the two highest doses in the core trial.
For previous placebo recipients, their longitudinal scans indicated a steep drop in amyloid between baseline and the first three months of the OLE, with a continued lowering at 12 months. In these treatment-naïve participants, amyloid fell by 0.33 SUVR over 12 months, from 1.38 to 1.05 SUVR, dipping below the threshold for brain amyloid positivity of 1.1 SUVR.
People who had received monthly infusions of 10mg/kg BAN2401 during the core study started the OLE with an average SUVR of 1.22. Over the 12-month extension, it dropped by a further 0.12 SUVR to 1.1. Those who had received 10 mg/kg twice monthly in the core study started the OLE with 1.08 SUVR, and inched down further to 1.04 12 months later.
What about ARIA-E in the OLE? The incidence of this side effect mirrored data from the placebo-controlled portion of the study. ARIA-E cropped up in 14 people, or 7.8 percent of all participants. As expected, it was more frequent, at 8.9 percent, among people who had previously received placebo. Thirteen of the 14 cases occurred in ApoE4 carriers, most within the first three months of the OLE. Three of the 14 cases experienced symptoms of ARIA-E, and all resolved within four to 12 weeks.
While the core study had automatically stopped treatment for all ARIA-E cases, the researchers took a less conservative approach in the OLE. They continued to dose six participants who had mild to moderate ARIA-E, as gauged by radiographic intensity on MRI, and this caused no ill effects.
Larisa Reyderman of Eisai presented an ARIA-E interpretation from both the trial’s core and OLE portions. Based on pooled ARIA-E incidence statistics from Phase 1 and Phase 2 studies of BAN2401, Reyderman developed a pharmacokinetic/pharmacodynamic model that predicted ARIA-E incidence in the OLE. Essentially, Reyderman reported that exposure to BAN2401—as gauged by Cmax, its maximum serum concentration—was the primary predictor of ARIA-E. In addition, ApoE4 carriers had a 26 percent higher risk of ARIA-E than noncarriers. Overall, the Eisai researchers concluded that incidence of ARIA-E was low, and that milder cases could stay on the antibody rather than leave the trial.
Swanson told Alzforum that 22 of out of the 180 participants in the OLE, or 12.2 percent, had ARIA-H, another imaging abnormality caused by microhemorrhages. In the core study, ARIA-H did not appear to track with BAN2401 dose, as 5.3 percent of people in the placebo group and 6.8 percent of those in the 10mg/kg biweekly group had ARIA-H. For those in one of the lower BAN2401 dose groups, ARIA-H incidence ranged from 11 to 18 percent.
This data informed the design of subsequent Phase 3 studies of BAN2401, which will allow continued dosing of people with mild ARIA-E. For more on that, see Part 2 of this story. —Jessica Shugart
- FDA Advisory Committee Throws Cold Water on Aducanumab Filing
- BAN2401 Forges AHEAD into Phase 3, Preclinical AD
- TRC-PAD Funnel Finally Touches Down
- No Man’s Land: Neither Early Success nor Failure for BAN2401
- BAN2401 Removes Brain Amyloid, Possibly Slows Cognitive Decline
- Second Look at BAN2401 Data Still Positive, Despite Snafu
- Amyloid Clearance: Check. Cognitive Benefit: Um … Maybe.
No Available Further Reading
BAN2401 Forges AHEAD into Phase 3, Preclinical AD
Part 2 of 3
As data from Phase 2 open-label extension studies is trickling in (see Part 1 of this story), the true test of BAN2401’s efficacy in both the early and preclinical stages of Alzheimer’s disease begins. In presentations at the virtual CTAD conference, held November 4-7, researchers described the population recruited into CLARITY-AD, Eisai and Biogen’s Phase 3 trial of BAN2401 in people at the earliest symptomatic stages of AD. This trial started in March 2019 and is nearing full enrollment. Meanwhile, AHEAD 3-45—a paired Phase 2 and Phase 3 study testing the antibody in two preclinical stages of AD—has started recruiting. This secondary prevention trial is headed by the Alzheimer’s Clinical Trial Consortium, in collaboration with Eisai and Biogen.
At CTAD, Eisai’s Shau Yu Lynch updated viewers on the status of CLARITY-AD, including baseline characteristics of the participants enrolled so far. In contrast to its more complicated adaptive predecessor, this trial follows a straightforward parallel group design, randomizing half of participants to receive biweekly infusions of placebo, or 10 mg/kg BAN2401, over 18 months. Change in the CDR-SB between baseline and 18 months serves as the primary endpoint, with other cognitive measures included among secondary endpoints. In addition, the trial will track MRI, amyloid and tau-PET scans, and CSF and plasma biomarkers including Aβ42, neurogranin, NfL, total and p-tau, in a subset of participants throughout the trial. Those who complete the trial can join an open-label, two-year extension that will continue to monitor imaging and fluid biomarkers and cognition.
To date, the trial has enrolled 1,222 of its projected 1,500 participants. At baseline, the randomized cohort is quite similar to that of the Phase 2 study, Lynch reported. Participants average 72 years of age, just over half are women, and their baseline cognitive scores reflect their early symptomatic stage of AD. Seventy-six percent are white, 18 percent Asian, 3 percent black. Sixteen percent of the cohort is of Hispanic or Latino ethnicity.
Based on data from the Phase 2 trial and ongoing OLE, the researchers expect one in 10 participants in the treatment arm of this Phase 3 trial to develop ARIA-E. Rather than automatically discontinue dosing in those patients, they will monitor their ARIA-E and continue dosing in those whose ARIA-E is mild to moderate, based on the radiographic severity of the abnormality on MRI.
In the wings of this symptomatic trial, AHEAD 3-45, the ambitious pair of secondary prevention trials, is now ramping up. Reisa Sperling of Harvard Medical at CTAD presented the design and early imaging data on the first enrollees.
Essentially, AHEAD 3-45 comprises sister studies, each trying to treat a different stage of preclinical AD. Participants—all of whose cognition is still normal—are placed into A3 or A45 based on their amount of amyloid accumulation as measured with PET scans. Those whose brain amyloid levels fall between 20 and 40 centiloids—below the threshold of brain-wide positivity as per a visual read—enter A3, while those who post above 40 centiloids enter A45.
Researchers will track the same cognitive, biomarker, and imaging measures in both trials. However, the primary outcomes differ between the two. A3, a Phase 2 study, aims to enroll 400 participants and will use their change in amyloid-PET as its primary endpoint. A45, a Phase 3, will enroll 1,000 volunteers and use change in their performance on the preclinical Alzheimer’s cognitive composite version 5 (PACC5) as its primary. Both trials are slated to run for 216 weeks—aka, a whopping four years.
The AHEAD 3-45 selection process relies heavily on amyloid-PET imaging. The goal for A3 is to nip amyloid accumulation in the bud during its early phase of rapid acceleration, in hopes of forestalling subsequent tangle formation. For A45, by contrast, the aim is to aggressively remove amyloid and prevent an all-out “ca-tau-strophy,” Sperling said, whereby tau pathology spreads broadly into the neocortex and cognition starts to decline.
To set the amyloid cutoffs for each trial, the researchers drew upon large longitudinal datasets including the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and the Australian Imaging, Biomarker, and Lifestyle (AIBL) study (Feb 2020 news).
Given the distinct goals of the two trials, they will use different dosing regimens. Based on data from BAN2401’s Phase 2 study, a monthly dose of 10 mg/kg BAN2401 may be sufficient to reduce amyloid below a critical threshold of 20 centiloids in people who start the trial with intermediate amyloid levels, i.e., those in A3. Those who start out with more amyloid, in A45, will receive this amount twice a month.
To reduce odds of ARIA-E, both trials will start with a titration period, ramping up to their respective target doses over eight weeks. Finally, volunteers in A45 will move onto a lower, monthly maintenance dose after 60 weeks. To mitigate danger posed by the COVID-19 pandemic, infusions will be given in participants’ homes, Sperling said. The trialists also plan to incorporate remote assessments whenever possible, though key cognitive tests, including the PACC5, need to be conducted in the clinic.
Sperling emphasized that the trial is using NAV4694 to measure amyloid for screening as well as monitoring throughout both trials. NAV4694 is a superior PET tracer that was stuck in development limbo for years and has only recently become available (May 2010 conference news; Oct 2014 news). The tracer rivals the sensitivity of PiB, yet uses the more stable fluorine 18 (F18) radioisotope instead of PiB’s ephemeral C11. Sperling believes the greater sensitivity of this tracer will prove essential to accurately gauge low levels of amyloid, and changes in those levels with treatment (Therriault et al., 2020).
What do these participants look like? Sperling showed amyloid imaging data from the first 33 who were scanned during screening. As predicted from past studies, the researchers found that about half, i.e. 16, were amyloid-negative. Among the other half, three fell into the intermediate range of 20-40 centiloids, while the remaining 14 had obvious accumulation above 40 centiloids. Sperling declined to say how many participants had already enrolled, but said that the first patient was randomized to A45 in September, and to A3 the first week of November.
At four years in duration, AHEAD 3-45 is a long haul. Its length is necessary to tease out a treatment benefit in people in the preclinical stage of the disease, where change comes slowly. With the pitfalls of aducanumab’s clinical path duly noted, no interim futility analyses are planned for AHEAD3-45, Sperling said. However, the scientists do plan to conduct an interim analysis at 96 weeks. At that point, they will take stock of cognitive and biomarker data from both trials. Only if the findings were to be “wildly positive” would the researchers consider halting the blinded portion of the trial and moving all participants into an open-label extension, Sperling said. Similarly convincing data from CLARITY-AD, which will finish before AHEAD3-45, could also influence this decision, she added.
Where do all these preclinical patients come from? For that, see Part 3 of this story.—Jessica Shugart
- BANish Aβ? BAN2401 Antibody Makes Its Move in Phase 3 Program
- How Much Amyloid Will Kick Off Tangles, and Decline?
- Geneva: The AstraZeneca Ligand—The Fairest of Them All?
- Lilly Teams Up With AstraZeneca for BACE Inhibitor Phase 2/3 Trial
- TRC-PAD Funnel Finally Touches Down
- Therriault J, Benedet AL, Pascoal TA, Savard M, Ashton NJ, Chamoun M, Tissot C, Lussier F, Kang MS, Bezgin G, Wang T, Fernandes-Arias J, Massarweh G, Vitali P, Zetterberg H, Blennow K, Saha-Chaudhuri P, Soucy JP, Gauthier S, Rosa-Neto P. Determining Amyloid-β Positivity Using 18F-AZD4694 PET Imaging. J Nucl Med. 2021 Feb;62(2):247-252. Epub 2020 Jul 31 PubMed.
No Available Further Reading
TRC-PAD Funnel Finally Touches Down
Part 3 of 3
Recruiting asymptomatic participants for secondary prevention trials such as AHEAD 3-45 is no small feat. How do you find people who are well on the road to Alzheimer’s disease but feel fine, thank you very much? Scientists cut their teeth on this quest with the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study, an ongoing secondary prevention trial that took 3.5 years, from 2014 to 2017, to enroll its 1,150 amyloid-positive but cognitively normal participants. At the time, the means were public outreach through a website, advertisements, public appearances by its leaders, etc. Other trialists hosted swabbing parties for ApoE genotyping (Dec 2017 conference news).
In an effort to queue a large group of eager trial participants with known cognitive and biomarker characteristics, scientists led by Paul Aisen at the University of Southern California Alzheimer’s Therapeutic Research Institute, La Jolla, created the trial-ready cohort for preclinical and prodromal Alzheimer’s Disease, aka TRC-PAD, platform in 2017.
Think of TRC-PAD as a funnel, whereby thousands of prospective study participants join an online registry at the top, and become progressively more characterized—for cognition, genetics, and biomarkers—as they filter their way to the bottom. The resulting amyloid-positive cohort is primed to enter secondary prevention trials.
In a symposium at this year’s virtual Clinical Trials on Alzheimer's Disease (CTAD) conference, held November 4-7, Aisen and three other leaders of TRC-PAD talked about the platform’s evolution. After three years in the making, it is finally enrolling “trial-ready” participants, and AHEAD 3-45 is the first study to reap the benefits. In August, the investigators published four papers detailing TRC-PAD’s intricacies in the Journal of Prevention of Alzheimer’s Disease.
At CTAD, Aisen said that the first of TRC-PAD’s three major phases is an online web registry called the Alzheimer’s Prevention Trials (APT) Webstudy. It came online in January 2018. Participants answer questions about their family history and any known genotype or amyloid status. Importantly, they also rate their own cognition with the cognitive function index (CFI), and take the Cogstate brief battery test, every three months. An algorithm tracking their performance, and change over time, selects participants likely to have brain amyloid and invites them via a site referral system (SRS) to schedule their first in-clinic visit.
At that visit, participants take more extensive cognitive tests and are genotyped for ApoE. Those deemed at highest risk of having amyloid deposition are referred for amyloid screening. If they are positive, they can move into the trial-ready cohort and await placement into a treatment trial. Researchers used data from the A4 trial to hone the algorithms that move participants from the top to the bottom of the funnel.
So far, the APT Webstudy has 38,000 participants. Alas, roughly two-thirds of them come from established feeder registries, USC’s Sarah Walter reported at CTAD. These include the Alzheimer’s Prevention Registry (APR) at Banner Alzheimer’s Institute, which has supplied nearly 13,000 registrants from its own 352,000 members, the Alzheimer’s Association’s TrialMatch registry, from which nearly 9,000 have joined, UC Irvine’s Consent-2-Contact registry, and UC San Francisco’s Brain Health Registry. In addition to registries, TRC-PAD has been recruiting through social media, local television and newspaper ads, and through study sites. So far, TRC-PAD has been slow to bring in new people “from the wild” (Aug 2016 conference news), a stated goal of large efforts around the globe to find participants for preclinical Alzheimer’s treatment trials.
Unsurprisingly, then, the demographics of APT Webstudy registrants reflect those of its feeder registries: predominantly white and highly educated. Efforts are underway to boost the cohort’s diversity, for example by way of a recently launched Spanish-language version of the online registry, and by reaching out to African American communities, Walter said.
Retention in registries has proved to be another big problem in realizing the vision of large trial-ready cohorts. Partly that is due to people tiring of repeated cognitive assessment, but partly also to thousands of registrants being suspended for years in an online holding pattern while intervention trials are slow in coming. With the APT Webstudy, 96 percent of new registrants completed their initial cognitive screening, but participation dwindled thereafter, with only 38 and 30 percent returning for their next two follow-up assessments, respectively. Only 70 or so loyal APT Webstudy enthusiasts have completed 11 online assessments, Walter said.
TRC-PAD leaders also noted that so far, the Cogstate battery they use to track cognition does not work on smartphones. Getting a phone-friendly test up and running that is similarly sensitive to amyloid elevation is a top priority, Aisen said.
Why is the platform so slow in coming? It took considerable time and effort to gather data and develop algorithms to select and move participants from the web study to the site-referral system, which would involve in-clinic visits. “Just about the week we figured it out, in February 2020, COVID-19 hit,” Sperling told Alzforum. “The timing was disastrous.” The pandemic threw a wrench into TRC-PAD’s progression, as sites shut down observational studies. However, now that pandemic protocols are in place, in-person visits are resuming, albeit at a slower pace than planned.
At CTAD, Gustavo Jimenez-Maggiora, USC, presented current TRC-PAD stats. As of September 2020, 2,450 participants have been referred from the APT Webstudy to a study site; another 342 were referred to study sites from elsewhere. One hundred and fifty have completed an in-person visit, of which 117 have been authorized for amyloid screening. Of the 88 participants who were screened for amyloid so far, 51 were found to have elevated levels. Of those, 36 have enrolled in the trial-ready cohort.
This translates into one amyloid-positive participant for every 1.7 people scanned, Oliver Langford of USC reported in his presentation. This is better than A4, which needed to scan 2.5 people to yield one with amyloid. Still, the funneling process has to speed up considerably to support recruiting for the AHEAD 3-45 and other trials.
Another trial testing CT1812, aka Elayta, a small molecule that shields synapses from Aβ oligomers, plans to draw from TRC-PAD starting next year. While both these studies are run by the Alzheimer’s Clinical Trials Consortium (ACTC), Aisen told Alzforum that TRC-PAD enrollees will be eligible to join any trial being conducted at their site.
TRC-PAD is working to incorporate plasma biomarkers to improve the screening process. In particular, the researchers plan to incorporate plasma Aβ42/40 ratios in their screening pipeline. TRC-PAD investigators are currently comparing different Aβ42/40 plasma assays for their ability to predict amyloid status in the first few hundred participants to undergo amyloid-PET scans or CSF draws. Once an assay is selected, the researchers expect plasma tests will further cut down the number of scans needed to find amyloid-positive participants.
Besides readying a cohort for trials, figuring out how to employ plasma biomarkers for trial screening could prove to be one of TRC-PAD’s most valuable contributions to AD clinical research, Sperling said. The scientists will evaluate plasma and PET side-by-side for now. They are hoping that a blood test deployed early on will further cut down the number of needed, and more expensive, scans, per enrollee.
While TRC-PAD is gearing up, another massive effort to recruit participants for AD clinical trials is shutting down. The European Prevention of Alzheimer’s Dementia study has run out of money (see clinicaltrials.gov). EPAD had been supported for five years by the Innovative Medicines Initiative (IMI), which is funded jointly by the European Union and the European pharmaceutical industry (Aug 2016 conference news).
EPAD aimed to recruit, and deeply phenotype, thousands of potential clinical trial participants across Europe, and then to run side-by-side Phase 2 trials with a shared placebo group and a Bayesian adaptive design. By the time the five-year funding period ended, the cohort had more than 2,000 participants, each phenotyped for multiple cognitive measures, genetics, and CSF biomarkers, but, alas, no drug sponsors to run trials. “We had everything but a drug,” said Craig Ritchie of the University of Edinburgh, who headed EPAD.
Why did no would-be trial sponsor take the plunge? Failed Phase 1 trials were one reason, lack of internal funding another, plus companies hesitated to be the first to take a risk on this innovative platform design, Ritchie said. That there was no funding to maintain the trial-ready cohort as trials took off may have also given sponsors cold feet.
After the loss of IMI funding at the end of 2019, EPAD secured some funds from philanthropic sources to wrap up final study visits and to maintain the massive dataset for the cohort. Then COVID-19 hit, and follow-up visits were halted, too.
But all is not lost. The more than 2,000 participants enrolled in EPAD are “desperately keen” to join a clinical trial, Ritchie said. Around 300 of them are cognitively normal but have amyloid, making them perfect subjects for secondary prevention trials. To help them join trials, Ritchie said EPAD is partnering with organizations such as the Global Alzheimer’s Platform Network (GAP-Net), a U.S.-centered network of study sites that aims to boost the efficiency and quality of AD clinical trials (Mar 2019 conference news). GAP-Net coordinates with TRC-PAD. And of course, participants will be eligible to join trials conducted within their own countries.
While EPAD will not realize its dream of running head-to-head proof-of-concept trials with multiple drugs, Richie hopes that the cohort will nevertheless find its way into clinical trials. Last but not least, the rich EPAD dataset is available to the neurodegenerative disease research community for analysis. (See Parts 1 and 2 of this story.)—Jessica Shugart
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- Coming to a Center Near You: GAP and EPAD to Revamp Alzheimer’s Trials
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- BANish Aβ? BAN2401 Antibody Makes Its Move in Phase 3 Program
- BAN2401 Forges AHEAD into Phase 3, Preclinical AD
No Available Further Reading
Learning Troubles Spied by Smartphone Track with Biomarkers
When it comes to teasing out the earliest whiffs of cognitive impairment, nothing beats a comprehensive in-person exam at the memory clinic … right? Well, that may be changing. New findings presented at the Clinical Trials in Alzheimer’s Disease conference, held November 4-7, suggest that performance on smartphone tests tracks closely with more traditional paper-and-pencil tests taken in the clinic, and aligns with AD biomarkers. In fact, repeated mobile tests may be particularly sensitive detectors of deficits in learning—one of the earliest harbingers of cognitive decline in the long preclinical phase.
COVID-19 has thrust the need for remote assessments into sharp relief. But remote tests of cognition and health will prove essential for clinical research long after the pandemic has passed, Jeffrey Kaye of Oregon Health Sciences University in Portland said in his keynote address. For one thing, older people have many other reasons to stay home—toxic air from wildfire smoke among them, Kaye noted.
Going remote offers a plethora of advantages, such as including larger and more diverse participants in clinical studies, conducting more frequent longitudinal assessments, and making measurements more sensitive. The latter could boost the signal-to-noise ratio of cognitive outcomes in treatment studies, Kaye believes, allowing for smaller, shorter trials.
At CTAD, researchers showed results of their work to validate smartphone tests of memory in established observational cohorts, compare them head-to-head with tests in the clinic, and exploit opportunities inherent in frequent smartphone testing.
Emrah Düzel of the German Center for Neurodegenerative Diseases in Magdeburg compared widely used in-clinic neuropsychological tests to a smartphone memory test. Created by neotiv, a German company co-founded by Düzel, the smartphone test was designed to detect subtle deficits in episodic long-term recall. This type of memory relies on circuitry in the entorhinal cortex and hippocampus, and begins to falter in the preclinical stages of AD. In the clinic, the Free and Cued Selective Reminding Test (FCSRT) and parts of the Preclinical Alzheimer’s Cognitive Composite (PACC) put this form of memory to the test. In neotiv’s objects-in-room recall (ORR) smartphone test, participants see a series of 25 three-dimensional rooms, each containing two unique objects. Immediately after viewing each room, participants are asked to select, from a group of three objects, which one belongs in a designated spot in the room. Thirty minutes later, they are asked to do this again for each room. The result is a total recall score, comprising both immediate and long-term recall.
Düzel and colleagues tried ORR on a subset of participants in the DZNE Longitudinal Cognitive Impairment and Dementia Study, aka DELCODE. This observational project tracks cognition in 200 healthy controls, 100 first-degree relatives of AD patients, 400 people with subjective memory problems, 200 with mild cognitive impairment, and 200 with AD dementia. DELCODE participants undergo an extensive battery of cognitive tests in the clinic, hence are suitable to validate the mobile test.
Düzel reported data from the first 58 DELCODE participants to try out the ORR test, of whom 44 had taken it twice, spaced two weeks apart. The test-retest scores on the two time points were highly correlated for each participant, suggesting this unsupervised smartphone assessment was consistent and reliable. Importantly, Düzel said, a person’s total recall scores on the smartphone ORR were highly correlated with their scores on the in-clinic FCSRT and PACC. Düzel hopes to enlist 200 DELCODE participants in the smartphone substudy, and measure total recall biweekly for 48 weeks.
Another neotiv co-founder, David Berron from the BioFINDER team at Lund University in Sweden, described at CTAD how a smartphone test matched up with in-clinic tests as well as AD biomarkers. Berron had previously designed computerized cognitive tests that target specific brain regions known to be affected by aging and AD pathology. In an object-discrimination task, participants are presented with an object, for example, a sofa. Then, they are shown more sofas, and asked whether each is the same, or different, from the original. Previously, Berron had reported that this task employs circuitry in the anterior medial temporal lobe; it falters with age and even more so when tau accumulates in the region (Berron et al., 2018; Maass et al., 2019).
Berron and colleagues designed a smartphone-based version of the object-discrimination task, and tried it on 59 participants from BIOFINDER, a Swedish longitudinal study tracking changes in CSF and imaging biomarkers and cognition. Fifty-one were cognitively normal, including 39 without and 12 with biomarker-confirmed amyloid accumulation. The remaining eight had brain amyloid and mild cognitive impairment.
After installing the app on their phones in the clinic, the participants took the tests at home once a month. At CTAD, Berron reported data from the first two unsupervised sessions. Firstly, Berron saw a strong correlation between a person’s performance on the in-clinic, supervised version of the test and their scores on the unsupervised, smartphone version. Secondly, performance on the smartphone test correlated with that of the delayed-word-recall portion of the ADAS-Cog.
Intriguingly, Berron reported that while no one scored more than 80 percent correct on the mobile test, several reached maximum scores on the ADAS-Cog delayed word recall. This “ceiling effect” suggests that the ADAS-Cog was too easy for this mostly cognitively normal cohort. The mobile test had neither ceiling nor floor effects, suggesting it was well-suited to test cognition in this cohort.
Berron previously found that transentorhinal cortex activity is essential for this object-discrimination task and, at CTAD, he reported that scores on the test’s mobile version correlated with tau accumulation, as gauged by tau-PET, in the transentorhinal region. The thickness of this region also correlated with better performance on the task. Finally, Berron found that higher CSF p-tau217 concentration came with lower scores on the smartphone test.
Curiously, these associations were absent for another smartphone test that asks participants to detect changes in scenes, rather than objects. Berron’s previous work suggested that scene discrimination involves more posterior regions of the medial temporal lobe, where tau accumulates later. Berron hypothesized that this task might pick up deficits at later stages of AD.
Smartphone Sees Your Learning Curve
While memory loss is the hallmark symptom of Alzheimer’s, new studies increasingly point to problems with learning as emerging even earlier during the long preclinical phase of the disease. Differences in learning have long muddled cognitive outcomes in clinical studies, because some participants benefit more than others from practicing the same tests at each sitting. Some studies have indicated that this practice effect is smaller in people with brain amyloid than in their amyloid-negative peers (Baker et al., 2019; Hassenstab et al., 2015). This prompted the idea that, rather than being a thorn in trialists’ sides, perhaps a practice effect could serve as a canary in the coal mine. In other words, is the loss of this effect in fact a sensitive cognitive discriminator of people with preclinical AD?
At CTAD, Kate Papp of Brigham and Women’s Hospital, Boston, described the development of a smartphone app that can rapidly detect these learning deficits through repeated assessments.
Previously, Papp and colleagues noticed weaker practice effects among amyloid-positive than -negative participants in the Harvard Aging Brain Study (HABS). For an in-clinic memory test, this difference played out over years on annual tests, but more recently, she noticed diverging learning curves between amyloid-positive and -negative participants within months, on memory tests taken monthly at home. The researchers gave 94 cognitively normal HABS participants iPads, and tracked their performance on a monthly Cogstate face-name-matching test over a year. Participants started off with similar scores regardless of amyloid status, but those with low amyloid improved more with practice than those with high amyloid. Their learning curves started to diverge by the second test session.
Could even more frequent tests—on a smartphone—tease out learning differences within days, instead of months? To address this, Papp and colleagues developed the Boston Remote Assessment for Neurocognitive Health (BRANCH). The assessment can be taken on any device with internet access. It consists of a battery of cognitive tasks aimed at picking up deficits in associative memory and pattern separation. The tests are relevant to daily life, and include tasks related to groceries, traffic signs, face/name matching. The scientists developed BRANCH over the course of a year, with input from HABS volunteers.
At CTAD, Papp showed first data validating BRANCH in a subset of 168 cognitively normal HABS participants who had undergone extensive cognitive testing in the clinic. They ranged from 50 to 90 years old; 78 had amyloid and tau PET scans. Their scores on a single session of BRANCH correlated well with scores on the PACC5, the paper-and-pencil battery designed for preclinical AD. Notably, BRANCH performance also tracked with levels of both amyloid and tau. The data cast BRANCH as a measure of cognition that could be sensitive to preclinical AD, Papp believes.
Papp also showed early work aimed at using BRANCH to measure learning curves. A subset of 32 HABS participants completed BRANCH on their phones for five consecutive days. The slope of their learning curves over the five-day stint correlated with their previous performance on PACC5, albeit not to a statistically significant degree in this small sample. Papp called this result initial validation of using BRANCH to detect learning curves. She is currently testing whether these curves are consistent on test-retest, developing more versions of the tests so they can be repeated at different times, and linking learning curves to AD biomarkers.
A BRANCH a Day. Learning curves took shape as participants logged BRANCH sessions for five consecutive days. [Courtesy of Kate Papp, Brigham and Women’s Hospital.]
Besides tapping HABS, Papp and colleagues are evaluating BRANCH in remote cohorts from online registries. Papp believes tests like it might help in prescreening for secondary prevention trials, which are increasingly relying on such registries to recruit (Nov 16 conference news).
Papp’s BWH colleague, Reisa Sperling, told Alzforum that she aims to try BRANCH in a subset of participants in the AHEAD 3-45 study, which is testing the BAN2401 anti-Aβ antibody in amyloid-positive people who are cognitively normal (Nov 2020 conference news). Sperling believes that learning curves could prove far more sensitive than other cognitive measures in preclinical AD, and may even be useful in screening for primary prevention trials.
BRANCH reflects a growing appreciation in the field for the promise of using learning curves in preclinical AD, especially with smartphones. At CTAD, Jason Hassenstab of Washington University, St. Louis, showed a smidgen of early data on a newly developed mobile phone version of his groups’ Online Repeated Cognitive Assessment. Originally designed for home computers, ORCA measures people’s progress in learning Chinese characters over six days. A recent study had showed that people without plaques learned the characters quicker than those with (Sep 2020 news). At CTAD, Hassenstab reported that the smartphone version of this test—called Mobile ORCA—can pick up learning curves within two days, with a total testing time of just 24 minutes.
Hassenstab also presented findings on practice effects from the DIAN-TU study, which missed its primary endpoint (Apr 2020 conference news). In a nutshell, asymptomatic carriers of autosomal-dominant AD mutations showed substantial practice effects on several cognitive tests, compared to mutation carriers who were already symptomatic at the beginning of the trial, or who became symptomatic during the trial; the latter two groups did not benefit from practice. Noncarriers had the strongest practice effects.
Hassenstab said that the DIAN investigators were surprised by the extent of these practice effects in their first treatment trial. He believes that tests such as Mobile ORCA could potentially turn these learning differences into an asset—as sensitive measures in future clinical trials.—Jessica Shugart
- BAN2401 Forges AHEAD into Phase 3, Preclinical AD
- In Preclinical Alzheimer’s, Learning Falters Before Memory
- Berron D, Neumann K, Maass A, Schütze H, Fliessbach K, Kiven V, Jessen F, Sauvage M, Kumaran D, Düzel E. Age-related functional changes in domain-specific medial temporal lobe pathways. Neurobiol Aging. 2018 May;65:86-97. Epub 2018 Jan 31 PubMed.
- Maass A, Berron D, Harrison TM, Adams JN, La Joie R, Baker S, Mellinger T, Bell RK, Swinnerton K, Inglis B, Rabinovici GD, Düzel E, Jagust WJ. Alzheimer's pathology targets distinct memory networks in the ageing brain. Brain. 2019 Aug 1;142(8):2492-2509. PubMed.
- Baker JE, Pietrzak RH, Laws SM, Ames D, Villemagne VL, Rowe CC, Masters CL, Maruff P, Lim YY. Visual paired associate learning deficits associated with elevated beta-amyloid in cognitively normal older adults. Neuropsychology. 2019 Oct;33(7):964-974. Epub 2019 Aug 1 PubMed.
- Hassenstab J, Ruvolo D, Jasielec M, Xiong C, Grant E, Morris JC. Absence of practice effects in preclinical Alzheimer's disease. Neuropsychology. 2015 Nov;29(6):940-8. Epub 2015 May 25 PubMed.
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In Phase 2 Trial, Neflamapimod Aids Cognition in Lewy Body Dementia
If at first you don’t succeed, try, try again. This adage seemed to pay off for the clinical development of the drug neflamapimod. After failing to curb cognitive decline in people with AD, the drug appears to have done just that in people with dementia with Lewy bodies (DLB), according to results from a small Phase 2 trial presented at this year’s virtual Clinical Trials on Alzheimer’s Disease (CTAD) meeting, held November 4-7. John Alam of EIP Pharma, Boston, reported that participants who took three 40 mg capsules of the drug per day posted improvements in a neuropsychological test battery focused on executive function and attention—two cognitive domains most affected in people with the disease.
Neflamapimod inhibits the alpha isoform of p38 MAP kinase. In preclinical studies, the drug stemmed damaging pro-inflammatory responses in the brain and protected synapses. More recently, researchers have tied its beneficial effects to inhibition of Rab5, a small endosomal GTPase that causes endosomal dysfunction when overactive, as observed in AD (Germann and Alam, 2020). A forthcoming paper in Cell Reports, led by Ralph Nixon at New York University, found that overactivation of Rab5 leads to an AD-like neurodegenerative phenotype in mice, in the absence of Aβ.
In 2016, Alam and Philip Scheltens from VU Amsterdam reported findings from two small Phase 2a trials of neflamapimod, without placebo groups, in people with MCI or mild AD (Dec 2016 conference news). Participants in the first trial received twice-daily doses of either 40 or 125 mg of the drug, and only those on the lower dose had a reduction in amyloid. The findings suggested that higher doses of the drug may have squelched neuroinflammatory processes needed to mop up Aβ.
Alas, a subsequent, placebo-controlled Phase 2b trial testing the twice-daily 40 mg dose in people with MCI or mild AD missed its primary cognitive endpoint in 2019 (Dec 2019 conference news). Tantalizingly, Scheltens reported that participants with the highest plasma levels of the drug outperformed those with lower exposure on cognitive tests, hinting that slightly higher doses may have benefitted patients.
Might people with DLB respond better to the drug than those with AD? At CTAD, Alam reported positive results from a Phase 2 trial, called AscenD-LB, addressing this question (see clinicaltrials.gov). Conducted at 22 centers in the United States and two in the Netherlands, the placebo-controlled trial tested the efficacy of neflamapimod in people who had a clinical diagnosis of mild to moderate probable dementia with Lewy bodies, as well as reduced dopamine transporter protein as measured by a DAT scan. Participants were split 1:1 to receive either 40 mg neflamapimod or placebo. Participants who weighed less than 80 kg took two capsules per day, while those who weighed 80 kg or more took three.
At baseline, the study enrolled 91 participants, including 45 in the placebo group (including 18 who took two capsules and 27 who took three per day), 26 in the twice-daily (BID) neflamapimod group, and 20 who took neflamapimod three times per day (TID). Alam noted that participants in the twice-daily groups started the study with lower scores on several cognitive tests, suggesting they had slightly more advanced disease. These lower-weight participants were represented in both the treatment and placebo groups.
The primary outcome of the 16-week trial was a combined score on six measures within a neuropsychological test battery. The researchers had customized it to probe executive function and attention, the cognitive domains most impaired in DLB. Participants took the tests every four weeks, and the final outcome used a statistical model for repeated measures, using participants’ scores at every visit to determine efficacy.
The trial met its primary endpoint in participants who took three 40 mg capsules of neflamapimod per day. Their scores improved above baseline starting at four weeks, and held steady throughout the 16-week trial, Alam reported. For those in the placebo or neflamapimod BID groups, scores did not improve during the trial.
The eight-week visit was affected by the COVID-19 pandemic, which prevented 40 percent of participants from coming to the clinic. Therefore, this timepoint had less data. Even so, with a p value of 0.015 and an effect size of 0.52, the treatment benefit observed in the 40 mg TID group compared to the 40 mg BID or placebo groups was significant, Alam said. The significance and effect size improved slightly when the researchers imputed missing data at the eight-week timepoint, by carrying forward data from the previous visit. The researchers also conducted a series of sensitivity analyses to assess whether bodyweight, as opposed to dosage, dictated the treatment effects. These analyses suggested that the dosage of the drug, not the participants’ weight, was responsible for the treatment effect.
The trial included many secondary endpoints, some of which showed favorable trends for the neflamapimod TID group. One, the “timed up and go” test, showed a statistically significant benefit. It measures the time it takes a person to stand up from a chair, walk to a line three meters away, return to the chair, and sit down again. While the test clearly measures mobility, it also requires cognitive sharpness to complete quickly, Alam said. At the trial’s start, participants clocked in at an average of 13 seconds, indicating mild impairment. While people in the neflamapimod BID and placebo groups slowed down by an average of 1.5 seconds throughout the 16-week trial, those in the neflamapimod TID group sped up by 1.5 seconds.
The neflamapimod TID group trended toward improvement on the 10-item neuropsychiatric inventory throughout the trial, with benefit in less-severe depressive symptoms and hallucinations. People taking the drug three times a day trended toward improvement on the CDR-SB.
The international shopping list test, a measure of episodic memory, showed no significant differences between groups, though the neflamapimod TID group trended better than the others. Episodic memory deficits are less pronounced in people with DLB.
Alam presented no findings from the trial’s two additional secondary outcomes—the MMSE, and change in quantitative electroencephalogram (EEG) patterns associated with DLB. Alam said that while the neflamapimod TID group trended toward improvement on the MMSE, the findings were complicated by differences in scores between participants who took the test remotely and in-clinic. The EEG data are still being analyzed.
Neflamapimod was safe and well-tolerated. Ten participants dropped out of the trial early on, but no discontinuations were due to adverse events associated with the drug, Alam said. He believes these findings support evaluation in late-stage trials for people with DLB. Alam told Alzforum that EIP Pharma will soon meet with the FDA to discuss next steps. If all goes well, he expects a Phase 3 trial in DLB to begin in a year.
What about AD? That participants in the DLB study who took three, but not two, daily capsules of the drug saw a benefit is in agreement with pharmacokinetic data from the REVERSE-SD trial, Alam said. It suggested that a ~40 percent higher dose might be effective in people with AD. The findings therefore support the idea of giving the drug another try in people with that disease.
Alam called neflamapimod’s dose-finding saga a reality of developing drugs for the brain, where the inability to directly measure drug levels poses a major hurdle. “With the data we have gathered over last few years, in four different trials, I believe we now have a good handle on the dose response, and the reason why we were able to succeed in the DLB Phase 2 study,” Alam said.—Jessica Shugart
- Emerging Alzheimer’s Therapies Test the Waters at CTAD
- At CTAD, Early Failures and Hints of Success, from Small Trials
- Germann UA, Alam JJ. P38α MAPK Signaling-A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease. Int J Mol Sci. 2020 Jul 31;21(15) PubMed.
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