The CTAD Organising Committee members opened the 2021 congress, expressing their pleasure at being able to meet face-to-face again and noting that since the last CTAD conference, AD has now entered the treatment age.
“This is a landmark year in terms of progress in AD research. The first drug is available for clinical use to target the neurobiology of AD. We have fantastic blood-based biomarkers coming along, tau therapeutics are continuing to move forward and we have many other therapeutic approaches … Overall, I think it is a tremendously exciting time.”
Paul Aisen, San Diego, USA (CTAD Organising Committee member)
Therapeutic trials in AD: A new hope for 2022?
The opening keynote lecture of the congress was delivered by CTAD Lifetime Achievement Award winner Ronald Petersen, Rochester, USA, who asked: what are reasonable clinical expectations of interventions with AD therapies? Prof Petersen suggested that the ‘bluntness’ of existing clinical instruments may not be sensitively tuned to detect subtle therapy-induced changes. Overall, available clinical evidence and statistical analysis indicates that the effects of interventions targeting amyloid and tau are consistent, albeit modest. However, AD does not exist alone and must be considered in the context of multiple age-related pathologies.
AB, amyloid beta; CSF, cerebrospinal fluid; CN, cognitively normal; MCI, mild cognitive impairment; MRI, magnetic resonance imaging; Rx, prescription; TDP, TAR DNA binding protein.
Moving forward with therapeutic trials in the AD arena, it will be important to consider timing of intervention as this relates to disease stage (i.e. symptomatic versus pre-symptomatic), trial duration, sequential impact of therapies and stratification of patients. Combination therapies for AD will be a necessity, Prof Petersen concluded.
The FDA accelerated approval of aducanumab
This panel discussion session focused on FDA accelerated approval of aducanumab - described as a ‘controversial and polarising decision.’ Both pivotal phase III trials of aducanumab, EMERGE and ENGAGE, were stopped early after meeting prespecified futility criteria so datasets are incomplete. Results were also discordant, with EMERGE (NCT02484547) positive and ENGAGE (NCT02477800) negative on clinical outcomes. Specifically, in EMERGE, high-dose aducanumab significantly reduced clinical decline as measured by primary and secondary endpoints - Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale–Cognitive Subscale (13-item ADAS-Cog13) and Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL-MCI). Conversely, in ENGAGE, aducanumab showed no significant impact on clinical decline by any of these measures.
Maria Carrillo, Chicago, USA, explained how the Alzheimer’s Association has advocated hard for approval of aducanumab and described this as a ‘hopeful time’. She highlighted access, information and progress as key focus areas for the future and stressed the importance of removing barriers to prescribing of both approved and upcoming AD therapies which deepens health inequality. To better understand the impact on aducanumab on clinical outcomes and patient care, the Alzheimer’s Association has launched a new National Registry in collaboration with other key stakeholders which will gather real-world longitudinal data.
Jason Karlawish, Pennsylvania, USA, gave an ethical analysis of the FDA approval which he described as ‘one of the most controversial’ in the history of the agency. Dr Karlawish explained that trust in science relies on the open sharing of information and public debate and noted that the responsibility now falls on the Alzheimer’s community to discern whether the system it works in needs repair. Dr Karlawish called for the prompt convening of an FDA advisory board meeting to consider the questions the FDA previously deliberated in private - focusing specifically on the question of beta amyloid as a surrogate.
An academic perspective on the FDA approval was provided by Gil Rabinovici, San Francisco, USA, who sought to introduce nuance into the debate. Dr Rabinovici said that an important role for academics will be to pilot the introduction of this new class of drugs and model them for real-world use to ensure they are applied in the clinic in an informed and safe way. Many pharmacies have still not added aducanumab to their formularies due to a lack of trust in the FDA’s decision and a negative media narrative continues to surround the drug. Transparency and diversity in AD therapeutic trials remains an important priority for the future, Dr Rabinovici concluded.
“You can’t look at the clinical data from EMERGE and ENGAGE and say it’s ‘slam dunk’ evidence. But equally you can’t look at EMERGE as an anomaly when you have the context of other in-class drugs that are showing lowering amyloid is having an impact on clinical outcomes, albeit modest, and moving tau biomarkers in the right direction.”
Gil Rabinovici, San Francisco, USA
Amyloid-reducing antibodies in development for AD
Recent advances in plasma biomarkers to improve preclinical and prodromal AD trials
Jeffrey Dage, Indianapolis, USA, discussed the measurement of blood-based biomarkers of AD in therapeutic clinical trials. Plasma Aβ is an established marker for target engagement in AD and reduces the development of amyloid pathology by ~10–15%. Assuming assays are precise and robust, the plasma Aβ ratio may be useful for enriching trials for amyloid-positive patients. Plasma phospho (p)-tau is an Alzheimer’s pathology-related pharmacodynamic biomarker. Assays for plasma p-tau can achieve suitable performance to identify subjects with Alzheimer’s pathology (i.e. a high likelihood of being A+T+) and with an increased risk of cognitive decline over 2 years.
Use of biomarkers in AD clinical trials
Randall Bateman, St Louis, USA, expanded on the use of blood plasma measures of Aβ, tau and neurofilament light (NfL) species for screening and application in clinical trials. Using a blood test facilitates ‘more shots on goal’, he explained, making AD clinical trials faster and less expensive. Within the next few years more tests will become commercially available and combining blood-based biomarkers such as Aβ42/Aβ40 and p-tau isoforms will improve assay accuracy. The future will also see broader use of AD blood tests in routine dementia evaluations and as, new treatments are approved, they may be applied in the screening and confirmation of AD brain pathology before initiating therapy.
“When preventative treatments are approved, cognitively normal individuals will be routinely screened for AD brain pathology with AD blood tests.”
Randall Bateman, St Louis, USA
Diagnostic and prognostic algorithms based on blood biomarkers for use in clinical trials were explored by Oskar Hansson, Lund, Sweden. He described a simple model for predicting AD dementia within 4 years in non-demented individuals with cognitive complaints using easily accessible methods: the plasma biomarkers plasma -tau217 and apoliprotein E (ApoE), together with cognitive domains of memory and execution. When considering enrichment for clinical trials, plasma p-tau and tau positron emission tomography (PET) predict subsequent tau accumulation and can be used to reduce the required sample size. Longitudinal plasma p-tau217 may also have utility as an outcome measure in clinical trials, with steeper increases correlating with faster cognitive decline and brain atrophy.
Anti-tau drug development of AD and other tauopathies
In this keynote address, Adam Boxer, San Francisco, USA, explained that there are three potential tauopathy indications - AD, progressive supranuclear palsy (PSP) and microtubule-associated protein tau (MAPT) diseases - with AD currently holding ‘the inside track’. To date, there have been six negative phase II trials of anti-tau monoclonal antibodies (mAbs) targeting different epitopes; although second-generation antibodies appear more promising. Other anti-tau therapies with different mechanisms of action are also in or approaching the clinic. The Alzheimer’s Clinical Trial Consortium (ACTC) Alzheimer’s Tau Platform (ATP) is a new proof-of-concept trial which aims to block the deposition of insoluble tau - the so-called 'cataustrophe' - as measured by PET. This trial will randomise 900 patients with biologically defined AD (A+T+) to one of six arms comprising placebo, anti-Aβ or anti-tau alone or a combination of both. The primary endpoint is the MK6240 accumulation rate. Although tau gain-of-function is strongly implicated in disease and tau is central to neurodegeneration, it is still important to remain open to alternative tau hypotheses, Prof Boxer concluded.
Mode of action of anti-tau therapies
“Tau gain-of-function is strongly implicated in disease.”
Adam Boxer, San Francisco, USA
New hope in translational research for development of drugs for AD
Dennis Selkoe, Boston, USA, began this roundtable session by setting out the key principles involved in moving multiple molecular targets in AD pathobiology from the laboratory to the clinic. Targets beyond Aβ are important to advance, including tau antibodies and antisense oligonucleotides (ASOs), lipid/ApoE modulators and neuroprotective agents. Dr Selkoe reflected that amyloid antibodies show promise and may provide the earliest route to clinically meaningful treatment, despite their shortcomings to date. Aβ therapeutic strategies are also scientifically well-grounded and worthy of further translation, he noted. However, combination therapies remain crucial and could begin with an amyloid-clearing antibody coupled with a tau ASO.
Panel discussants then considered the clinical practice implementation of aducanumab, describing its approval as a ‘turning point’ in the treatment of AD. Kirk Daffner, Boston, USA, reviewed the framework developed for implementing aducanumab in clinical practice and stressed the importance of creating therapeutic guidelines through compromise and consensus building. Ultimately, the decision to treat a patient needs to be a clinical one, he stressed. Stephen Salloway, Providence, USA, commented that while demand for aducanumab is high, rollout remains slow, and clinicians are currently working through waiting lists to ensure patients are appropriate for treatment. MRI monitoring is very important as patient safety needs to be front and centre, stressed Dr Salloway, particularly as it looks likely similar agents will receive accelerated approval in the future.
“We only treat patients with early AD with aducanumab and the main reason for exclusion is advanced stage of disease. We’re trying to be very careful about this and follow the evidence that we have.”
Stephen Salloway, Providence, USA
Digital therapies for mild cognitive impairment: new pathway to treatment
Digital therapies and digital biomarkers were discussed in this roundtable session. Murali Doraiswamy, Durham, USA, explained how the pandemic has helped to embed digital medicine and artificial intelligence as part of the basic infrastructure of AD care, ranging from telemedicine to platform trials, digital phenotyping and therapeutics. At least a dozen digital therapeutics are making their way through late-stage clinical trials and preliminary results appear promising, with improvements in cognition and function and slowing of brain atrophy seen in phase II trials.
“Digital therapeutics are not just apps for enhancing brain health. They are evidence-based treatment solutions that are driven by high quality software which have been proven through good quality randomised clinical trials and have been scrutinised by regulators.”
Murali Doraiswamy, Durham, USA
Jeffrey Shuren, Silver Springs, USA, explained that the greatest value for digital therapeutics and diagnostics lies in the opportunity to provide interventions in real-time if needed and to empower AD patients and caregivers to take actions to better handle their own care and activities of daily living. On the subject of digital biomarkers, Rhoda Au, Boston, USA, said these should be thought of in a more expansive way: not just one device or app, but multisensory with different combinations of inputs. Digital biomarkers may help overcome one of the key challenges in AD which is to accurately measure cognitive function, particularly in the earliest stages of disease. Work is ongoing to evaluate and define digital patterns that correlate with PET positivity. Dr Au also highlighted the potential of smartphone cognitive assessment apps to increase the frequency of detection of the digital signal. James Williams, Cambridge, USA, echoed the fact that this is exciting time in the digital therapeutics field, which has the potential to remove logistic barriers to comprehensive dementia care. However, it is important to ensure the technology used is available, accessible and affordable, he cautioned, and tech support for patient populations with mild cognitive impairment will be key.
Phase II trial of semorinemab in mild-to-moderate AD: topline results
This late-breaking readout roundtable session showcased top-line results from the phase II LAURIET clinical study (NCT03828747) of semorinemab, an anti-tau antibody that targets all known isoforms of full-length tau, in 272 patients with mild-to-moderate AD. Cecilia Monteiro, San Francisco, USA, presented results for the study’s co-primary endpoint at Week 49 which showed that semorinemab significantly reduced the rate of cognitive decline as measured by Alzheimer’s Disease Assessment Scale Cognitive Subscale 11 (ADAS-Cog11), but had no significant effect on functional decline assessed by AD Cooperative Study Activities of Daily Living (ADCS-ADL). The treatment effect in ADAS-Cog11 was driven primarily by the memory domain. Semorinemab showed no significant effect on global or functional decline by other secondary outcome measures and had no impact on tau accumulation as measured by [18F]GTP1 Tau PET. The antibody showed an acceptable and well-tolerated safety profile consistent with previous studies. Further analysis of the LAURIET trial data is currently in progress.
Co-primary endpoint at Week 49 in the LAURIET study
Discussants described the results as ‘puzzling’ and said it would be important to demonstrate that the effect on ADAS-Cog11 seen in the LAURIET study was reliable and reproducible, especially given the lack of impact on functional outcomes and in the context of failure of the previous TAURIEL trial (NCT03289143) in prodromal/mild AD. In response, Dr Monteiro noted that ‘no matter how we sliced the data in terms of subgroup analyses we always saw the same effect on ADAS-Cog11’ which speaks to the robustness of the overall result. Asked for a potential biological explanation, the panel suggested that semorinemab’s selective effects on memory may reflect more than one underlying mechanism of tau-dependent toxicity in the brain.
“After 12 months of treatment, participants with mild-to-moderate AD receiving semorinemab 4500 mg Q4W (every 4 weeks) showed evidence for slowing of cognitive decline on ADAS-Cog11, primarily on the memory domain.”
Cecilia Monteiro, San Francisco, USA
Bringing repurposed drugs to market: challenges and opportunities from research to commercialisation
Repurposing represents an important part of the AD research pipeline, offering an accelerated pathway for developing new treatments and an opportunity to reduce costs and shorten drug development timeframes. However, repurposing also poses significant challenges.
Challenges of repurposing drugs for the treatment of AD
Ana Pereira, New York, USA, presented work on the repurposing of the glutamate modulator riluzole for mild AD - built on promising preclinical data and the hypothesis that modulating dysregulated glutamatergic neural circuits could reduce toxicity associated with AD. A pilot phase IIa randomised controlled trial enrolled 42 AD patients treated with riluzole 50 mg twice daily or placebo for 6 months. Participants had a baseline MMSE score of 19–27 and were stable on acetylcholinesterase (ACH) inhibitor. The primary outcome measure was FDG PET to assess glucose metabolism in the brain. Patients in the riluzole treatment group showed less decline in glucose metabolism, with a particularly robust effect observed in the posterior cingulate cortex, which is a key hub network in AD. FDG PET measures also correlated with cognitive performance.
“This pilot study showed more preservation in glucose metabolism with riluzole versus placebo that correlated with cognitive performance and provides the rationale for a larger and longer study in AD.”
Ana Pereira, New York, USA
There is a marked reduction in dopamine receptors in the AD brain and cumulative evidence suggests that impaired dopaminergic transmission contributes to cognitive dysfunction in patients with AD. Giacomo Koch, Rome, Italy, discussed findings from a phase II, monocentric randomised clinical trial (NCT03250741) of the dopaminergic agonist rotigotine delivered via transdermal patch in 94 patients with mild-to-moderate AD. After 24 weeks, rotigotine-treated patients showed improved performance on cognitive tests related to frontal lobe function and in activities of daily living. Discussions are underway with the FDA on the design of a complex 4-arm phase III trial, incorporating rotigotine in combination with the ACH inhibitor rivastigmine, which is due to start soon. A patent has also been awarded for the combination of these two drugs delivered via transdermal patch.
Proportion of today’s AD clinical trials studying repurposed/repositioned drugs
The potential of low-dose levetiracetam (AGB101), at ~10-fold lower dosages than used in epilepsy, for the treatment of age-related cognitive impairment and to delay progression of AD was reviewed by Michela Gallagher, Baltimore, USA. Neuronal circuits become hyperactive in prodromal AD and hyperactivity in the medial temporal lobe/hippocampus appears to be a critical driver of AD neuropathology. Low dose levetiracetam has shown promising results in amyloid and tau preclinical mouse models and appears to normalise inflammation biomarkers in the brain. HOPE4MCI (NCT03486938) is a fully enrolled randomised clinical trial (n=164) investigating AGB101 in patients with mild cognitive impairment due to AD, using CDR-SB scores as the primary outcome. Dr Gallagher explained that, although a little underpowered, the FDA have accepted HOPE4MCI as a pivotal trial. Data at Week 78 on the key endpoints from the study are due to be released in the very near future.
Vascular risk factors and AD: Implications for therapeutic trials
In this keynote address, Cynthia Carlsson, Madison, USA, explored the substantial evidence that supports the copathology of cerebral vessel disease and AD and the unequivocal link between vascular risk factors and dementia. Candidate drugs for repurposing in this field include antihypertensive, diabetes therapies and agents for treating dyslipidaemia. Several studies, including the large-scale SPRINT-MIND trial (NCT01206062), support an association between blood pressure lowering and reduced risk of incident dementia or cognitive impairment. Although cholesterol lowering in patients with AD does not appear to impact progression risk, an exploratory analysis in 73 cognitively healthy adults showed a positive effect of simvastatin on white matter integrity. A recent systematic review also concluded that antidiabetes drugs could be useful in the treatment of AD. For future therapeutic AD trials, it will be important to include patients with diverse vascular risk profiles, incorporate standardised reporting of vascular risk in trial participants, employ improved biomarkers to monitor cerebrovascular changes and recognise the impact of AD-related dementias (ADRD) risk reduction as a backdrop to disease-modifying therapy, summarised Dr Carlsson.
Vascular contributions to dementia
Top-line results from the GAIN trial: a phase II/III study of atuzaginstat in mild-to-moderate AD
Preliminary data from the GAIN study of atuzaginstat were presented by Michael Detke, San Francisco, USA, and Marwan Sabbagh, Phoenix, USA, in this late-breaking readout roundtable session.
Porphyromonas ginvigalis (Pg) infection upstream explains many features of Alzheimer’s risk and pathology which has led to investigation of Pg as a novel disease driver and potential new target for treating AD. Dr Detke explained that Pg secretes gingipains that cleave proteins to use a food source. Gingipains are key mediators of pathology and levels in AD brain tissue analysis correlate with symptoms. Atuzaginstat is a small molecule, orally bioavailable, brain penetrant inhibitor of lysine gingipain that was evaluated at two doses (40 mg and 80 mg twice a day) in the phase II/III GAIN trial in 643 patients with mild-to-moderate AD. The GAIN trial (NCT03823404) failed to reach statistical significance for the primary endpoint in the overall intent-to-treat population. However, prespecified analysis of three subgroups with biomarkers for Pg infection at baseline showed a significant 30–50% benefit on ADAS-Cog and CDR-SB across Pg-infected cohorts treated with the 40 mg dose. The efficacy magnitudes were consistent across sensitivity analyses and significant correlations were shown between change in Pg load and multiple clinical outcomes. In terms of safety, there was a numerical imbalance of deaths with atuzaginstat but all were deemed unrelated by blinded investigators. The most common treatment-related adverse event (AE) was diarrhoea, likely due to atuzaginstat’s effect on the gut microbiome. Planning is underway for a confirmatory trial of atuzaginstat 40 mg bid in mild-to-moderate patients with AD with Pg diagnosed by best empirical method.
Impact of P. gingivalis infection
Dose- and time-dependent changes in plasma p-tau181 in patients treated with aducanumab in the ENGAGE and EMERGE trials
This late-breaking readout roundtable session explored changes in levels of plasma p-tau, a key blood-based AD biomarker, in patients who received aducanumab in the ENGAGE and EMERGE phase III trials.
Oskar Hansson, Lund, Sweden, presented evidence from this large dataset consisting of approximately 7000 plasma samples gathered from 1815 patients with early AD. Results showed that aducanumab produced a significant dose- and time-dependent reduction in plasma p-tau181 consistently in both the ENGAGE and EMERGE studies. Importantly, the treatment effect of aducanumab on plasma p-tau181 was associated with lowering of amyloid PET standardised uptake value ratio (SUVR) and reduced cognitive and functional decline. This is consistent with the hypothesised relationship among the underlying pathologies of AD, Dr Hansson pointed out. Overall these findings demonstrated that modification of biomarkers fundamental to the underlying disease pathology of AD was associated with significant slowing of clinical decline as measured by CDR-SB, MMSE, ADAS-Cog13 and ADCS-ADL-MCI.
These results ‘help to fill the gap’ between amyloid and tau, noted the panel, confirming both target engagement and modification of downstream tau biology with aducanumab. The reduction in amyloid PET correlated and corresponded with changes in plasma p-tau which fits well with the underlying biological conceptual model of AD. Dr Rabinovici said it was ‘encouraging’ to see the plasma p-tau181 results aligned between the EMERGE and ENGAGE studies even though the clinical outcomes from the two trials were discordant.
Metabolomics: a biochemical roadmap for drug discovery in AD
This symposium focused on the role of metabolomics and big data in AD. Rima Kaddurah Daouk, Durham, USA, outlined how AD metabolic trajectories have the potential to inform stage-specific drug development and yield new biomarkers. Of particular importance are the metabolome, which captures external influences on the gut microbiome, and the link between peripheral markers and central changes in AD. Metabolites and proteins also form the building blocks of biochemical pathways, making them prime targets for drug discovery. Most of the major classes of therapies currently used were developed based on metabolic knowledge, Dr Daouk pointed out.
In a specific illustration of metabolomics research, Priyanka Baloni, Seattle, USA, described how multi-omics analyses have identified sphingolipid pathways as a potential therapeutic target in AD. Notably fingolimod was shown to modulate S1P levels and alleviate cognitive deficits in APP/PS1 mice. Repurposing drugs that target sphingomyelin metabolic enzymes and modulate the S1P receptor could correct the dysregulation and potentially improve memory and synaptic function, Dr Baloni suggested.
Kamil Borkowski, Davis, USA, explained how metabolomics was used to identify two novel pathways involved in AD - soluble epoxide hydrolase (sEH) and ethonolamide - both of which are potentially targetable with available drugs. sEH metabolites were shown to be associated with cognition in both mild cognitive impairment patients and in the AD phenotype, plus evidence was uncovered for sHE involvement in genetic, transcriptional and protein levels in AD. Ethanolamides are a class of endocannabinoids which show reduced plasma and central levels in AD.
Diversity in AD clinical trials
“It is not enough to want or hope that enrolled participants represent the disease. We must plan for enrollment from the beginning if we are to conduct good science.”
Holly Massett, Bethesda, USA
Nancy Lynn, Los Angeles, USA, introduced ‘Brain Info LIVE’, a free community-based brain health educational campaign conceived by the Bright Focus Foundation which aims to reach underrepresented US populations. Based on the premise of ‘edu-tainment’ this multi-sector collaboration consists of free 30–45 minute virtual episodes streamed live and available on demand.
Likelihood of AD in underrepresented US populations
The National Alzheimer’s Disease Index developed by UsAgainstAlzheimer’s in partnership with the National Minority Quality Forum (NMQF) is harnessing community data to drive brain health. Jason Resendez, Washington, USA, explained that this new public health tool allows users to analyse Medicare data on ADRD by demographics and geographies, create maps to visualise Alzheimer’s related dementia (ARD) hotspots and understand infrastructure in highly impacted regions. We are learning more about the role of the ‘exposome’ in shaping AD risk, intervention success and heath outcomes particularly in underserved and marginalised communities but we need to do more to incorporate this into our work, Dr Resendez concluded.
The NEWIDEAS study from the Alzheimer’s Association Consortia aims to build an inclusive science that facilitates diverse clinical trials, explained Peggye Dilworth-Anderson, Chapel Hill, USA. Adopting a diverse and inclusive approach to research requires personal reflection and scientific research concerning race, culture, ethnicity and context. If applied successfully it can improve the quality and diverse representation of the collected data and help prepare the field for the future.
Key principles of diverse and inclusive research
“An inclusive approach in AD clinical trials ensures that those affected by disease will accrue the benefits of research.”
Peggye Dilworth-Anderson, Chapel Hill, USA
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