アルツハイマー病におけるプレシジョンメディシンの実現　
～ AD/PD 2023 Conference ハイライト ～

May 9, 2023
Justyna Lisowska

Every year, neuroscience experts from all over the world unite at the AD/PD conference to present and discuss the latest R&D breakthroughs in Alzheimer’s, Parkinson’s, and other related pressing neurological disorders. The key theme of the conference this year was the current advancements and the future of Alzheimer’s Disease (AD) diagnosis and management. Many presentations and discussions highlighted:

• Recent findings from clinical trials, including follow-up studies evaluating the long-term effects of approved disease-modifying treatments (DMTs): Lecanemab and Aducanumab, and
• Progress in biomarker development with a focus on blood-based markers (BBBMs) and their potential applications, as well as
• Examples of new emerging therapeutic opportunities.

The Genedata Profiler team attended the conference to understand the opportunities and hurdles in the field to best serve this fast-evolving therapeutic landscape. It was clear that, with the rising trend toward precision medicine, companies will need to embrace digitalization to leverage a major asset: their data. By providing a comprehensive solution, Genedata Profiler^® is ready to address the challenges associated with exploring and sharing large amounts of multimodal neuroscience data, allowing companies to unlock their innovative potential and accelerate drug time-to-market.

The Precision Medicine Approach in AD Drug Development

According to key opinion leaders present at the panel discussion “Immunotherapies in AD - from basics to approval”, the success of approved DMTs exemplifies the value of the precision medicine approach in neuroscience clinical development.

Compounds targeting amyloid β (Aβ) have been investigated for years but the majority failed to reach clinical endpoints. According to experts, there are key determining factors that differentiated recent successful trials from those which failed in the past, leading to clinical approvals. These include data-informed decisions regarding:

• The right target: binding the appropriate amyloid species/epitope,  
• The right patients: targeting populations with confirmed AD neuropathology at an earlier stage of disease progression, and
• The right safety: increasing the dose or treatment exposure time, while mitigating the risks of adverse events such as amyloid-related imaging abnormalities (ARIA).

As highlighted during the panel discussion, this was made possible due to the development of biomarkers and more specifically the introduction of the ATN classification system[1]  (an unbiased descriptive system applicable to all patients) that marked the shift from the clinical to the biological concept of AD. CSF, PET, and MRI-based indicators of amyloid, tau, and neurodegeneration have been used as entry criteria and outcome measures in DMT trials. These markers also provide an opportunity for early diagnosis and preventive treatment. Unfortunately, due to their invasiveness, high cost, and low accessibility, they are not widely used in the clinic for such purposes.

How Can We Use Blood-Based Biomarkers (BBBMs)?

A lot of discussions and presentations at the conference focused on the progress in the development and future applications of more accessible BBBMs.

Recent technological advances have greatly contributed to the identification of sensitive and specific AD biomarkers (among which pTau217 and pTau181 seem to be the most reliable candidates). While such markers have become progressively incorporated in the research context to facilitate patient stratification and enrichment or serve as pharmacodynamic biomarkers or even surrogate endpoints, it appears we are still far from benefitting from them in clinical practice.  To date, BBBMs are used to confirm AD in symptomatic patients, and experts agree that they are not ready for use as stand-alone diagnostic tools. Bringing them into primary care could lead to misinterpretation, especially when analyzed out of the patient’s broader context. Also, although early diagnosis and intervention are believed to considerably improve the efficacy of current AD therapies, these biomarkers are not yet recommended for pre-clinical stage patients due to the:

• lack of a complete understanding of the variability in disease progression, and the
• lack of available preventive treatment that could be administered to such patients.

Instead, BBBMs are perceived as useful pre-screening tools to funnel more patients toward confirmatory CSF and PET tests to streamline the diagnosis and identification of eligible patients for DMTs.

Lastly, as these markers have mainly been examined on Caucasian patients, scientists do not know how BBBMs could perform in a more diverse, general population. During the plenary lecture, data shown by Michelle Mielke, chair of the Department of Epidemiology and Prevention and Professor of Epidemiology, Gerontology, and Geriatric Medicine at the Wake Forest University School of Medicine, suggests that there are multiple factors associated with patient disease history (e.g., chronic kidney disease, vascular diseases, dyslipidemia, diabetes), previous/concurrent pharmacotherapy, sex, race, and ethnicity that may considerably affect BBBM measurements compared to CSF-derived biomarkers. This may require further exploration.

The Need for Combination Therapies

The impact of patient-specific characteristics on disease development and progression as well as the efficacy and safety of currently available treatments remains an important focus for future investigations. As discussed at the forum “Phase I-III in AD: Drug development and relevance for heterogeneity of the disease”, it is highly advised to enlarge inclusion criteria (medications, co-pathologies), diversify (genotypes, ethnicities), and further stratify trial cohorts accordingly, while mitigating the risk of adverse events[2], to better capture the heterogeneity of the general population.

In addition, experts advocate for embracing disease molecular complexity. As approved anti-Aβ drugs demonstrate modest clinical benefit, it is advisable to target other molecules from the amyloid cascade such as tau in parallel. The Tau NextGen trial, testing anti-tau Ab in combination with Lecanemab, is currently the only study of this type but more are underway.  Moreover, although thesuccess of approved immunotherapies validates the amyloid hypothesis of AD pathogenesis, it does not contradict the existence of other concomitant mechanisms. Reducing the amyloid load may not be enough to prevent clinical impairment. Thus, other molecular targets (e.g., neuroinflammation, synaptic dysfunction), including those linked to co-pathologies, should be further investigated, and considered for combination therapies to improve disease management.

Next-Generation Therapeutic Modalities

Michael Irizarry, Senior Vice-President of Clinical Research and Deputy Chief Clinical Officer at Eisai, believes that, in the context of AD, where multiple processes occur, combination therapies may require multiple therapeutic modalities. The choice between small molecules, antibodies, or nucleotide-based therapeutics very much depends on the druggable target and its accessibility. For instance, while antibodies seem to perform better for initiating amyloid clearance, they cannot be used for intracellular targets. Instead, as shown by Jessica Collins, Principal Scientist at Biogen, at one of the sessions, anti-sense oligonucleotides, which can penetrate cells, might be a great alternative to reduce intracellular tau tangles.

While extension studies of approved immunotherapies evaluating their long-term efficacy and safety profile are still ongoing, companies are looking into other cost-effective and more accessible therapeutic strategies. For instance, they are renewing their interest in small molecule oral agents that could fine-tune amyloid production and/or its aggregation into neurotoxic oligomers for instance by modulating γ-secretase activity (e.g., Alzstatin from AlzeCure Pharma) or targeting Aβ monomers (ALZ-801 from Alzheon, Inc.). Such treatments can be used to maintain the low load of amyloid in the brain after its clearance or as preventive treatments in asymptomatic patients. When it comes to disease prevention, companies like AC Immune or Vaxxinity have shown that active vaccination against tau or amyloid may be also an effective strategy. Finally, gene therapies offer a new avenue of treatment for carriers of AD deterministic gene mutations. All these different therapeutic approaches will likely be prescribed to different AD patients depending on their disease stage. Yet, to make this possible, we need better tools to effectively stratify patients. 

Digital Enablement of Precision Medicine Strategy

As the field progresses toward precision medicine, the ability to leverage research, clinical trial, and real-world data for actionable insight generation becomes more and more important to better guide clinical trial design and disease management. At Genedata, we are committed to supporting biopharmaceutical companies and research organizations in their digital transformation efforts to enhance the development of next-generation treatments and biomarker-driven diagnostic tools. By providing an off-the-shelf secure infrastructure for data integration, analytics, and cross-functional collaboration, the Genedata Profiler® platform empowers companies to maximize the value of data, boosting their innovative potential and bringing efficiency into clinical development.

Discover how our solution enables leading organizations to translate data into insights for identifying predictive and prognostic biomarkers to improve disease management and make data-driven decisions for smarter clinical trials.