In 2025, the global field of Alzheimer's disease drug development advances amid anticipation and reflection. China, as a country with over 10 million patients and a rapidly increasing disease burden due to population aging, has an unprecedentedly urgent demand for such breakthrough therapies. This year, several domestically developed new drugs have entered the application or key clinical data release phase, and the industry and regulatory agencies are closely monitoring these achievements based on different targets such as Aβ, Tau, and neuroinflammation. However, the lessons of history are still fresh in our ears—just a few years ago, the BACE inhibitor Verubecestat, which was also highly anticipated, failed in two large-scale Phase III clinical trials, showing no cognitive benefits. This is not an isolated case but one of a series of "falling short at the finish line" examples, which clearly warn that the war strategy against this most complex brain disease must undergo fundamental changes. The past paradigm of pursuing a single "miracle bullet" is no longer sustainable, and the future lies in building a comprehensive ecosystem that integrates precision medicine, combination therapies, and digital management.
I. Why Do We Fail Time and Time Again? Redefining the Battlefield
The crux of the issue may lie in our long-term use of a "single disease" model to address a "cluster of diseases." Advances in biomarker research clearly indicate that patients diagnosed with "Alzheimer's disease" may exhibit fundamentally different underlying pathological mechanisms (such as neuroinflammation, vascular pathology, synaptic dysfunction, specific tau subtypes, etc.).
This directly led to the "catastrophic dilution" in clinical trials—drugs effective against subtype A were ineffective or even harmful in patients with subtypes B, C, and D, ultimately resulting in the failure of the overall data. Consequently, "patient stratification" is no longer an exploratory study that adds value but has become a critical factor determining success or failure. Any asset advancing to late-stage clinical trials will face a sharp increase in investment risk if it lacks a clear patient enrichment strategy based on blood, imaging, or digital biomarkers. Decision-makers must scrutinize the pipeline: Are our molecules targeting "Alzheimer's disease" or "a specific class of Alzheimer's disease patients with particular biological characteristics"?
II. The Way to Break the Block: Four Strategic Directions to Be Grasped
Future success will hinge on forward-looking strategic planning and execution across these four key areas.
First, the advancement of diagnostic thresholds and the redefinition of the battlefield: The maturation of blood biomarker (e.g., p-tau217) testing has been the most significant game-changer over the past five years. It enables the identification of high-risk individuals years before clinical symptoms manifest, with controllable costs. This directly defines a new R&D battlefield: prevention and ultra-early intervention. This necessitates a shift in R&D strategy: longer trial cycles but earlier intervention windows, theoretically offering greater therapeutic potential. Deep collaboration with diagnostic companies is required to develop companion diagnostics. Simultaneously, the target population must expand from "confirmed patients" to "high-risk populations," fundamentally altering market definitions. Innovative payment models based on long-term health benefits must be explored in collaboration with payers (health insurance, commercial insurers).
Second, the therapeutic approach has shifted from "individual treatment" to "cluster therapy": In the face of multiple pathological mechanisms, combination therapy is an inevitable scientific and commercial necessity. This includes "drug cocktails": for example, Aβ clearers + Tau inhibitors + neuroinflammation modulators. The key lies in exploring synergistic effects and addressing the complexity of toxicity management and registration pathways for combination therapies. The integration of "pharmacotherapy + digital": pharmacotherapy combined with digital cognitive therapy/remote monitoring. Digital therapies not only provide adjunctive treatment but also generate continuous, real-time data that can serve as dynamic efficacy indicators and provide robust support for post-marketing evidence generation.
Third, diversification of targets and construction of a risk-hedging portfolio: The R&D pipeline must be diversified to hedge against risks from a single mechanism. Key areas of current focus include: Neuroimmunology: TREM2 agonists, complement inhibitors, etc., aimed at "reprogramming" the brain's immune environment; Synaptic plasticity and protection: Therapies directly targeting the loss of neural connections, such as neurotrophic factor pathway enhancers; Cellular clearance and metabolism: Compounds that enhance autophagy (e.g., mitochondrial autophagy) and improve neuronal energy metabolism; Non-traditional targets: Regulation of the brain-gut axis, vascular protection, etc. A prudent strategy is to construct a balanced R&D portfolio encompassing different mechanisms of action and various development stages.
Fourth, innovation in research endpoints and evidence systems: The era of relying solely on traditional cognitive scales (e.g., ADAS-Cog) to define success is coming to an end. Early communication with regulatory authorities is crucial to jointly establish: composite endpoints that integrate cognitive, functional, and activities of daily living (ADL) assessments, as well as biomarker surrogate endpoints. In early-stage trials, a significant reduction in key pathological proteins should be utilized as a pathway for accelerated approval. Concurrently, proactive efforts should be made to leverage digital biomarkers and real-world data to build long-term efficacy evidence.
III. Action List
Re-evaluation and Precision of Pipelines: Immediately review existing pipelines with the latest biomarker research findings. Design "precision" sub-studies or exploratory biomarker analyses for promising molecules, and identify their target populations.
Building an Open Collaborative Ecosystem: Going it alone is unlikely to succeed. It is imperative to proactively establish strategic partnerships with AI-powered imaging analytics companies, hematological diagnostics enterprises, digital therapeutics platforms, and even lifestyle management companies, to jointly create a closed-loop solution encompassing 'screening-diagnosis-treatment-management'.
Portfolio thinking: Diversify investments across projects with different mechanisms of action and technological platforms (e.g., small molecules, antibodies, gene therapies). Balance internal R&D risks through license-in/out strategies, while focusing on early-stage scientific discoveries with disruptive potential.
Advance evidence and access planning: Starting from Phase II clinical trials, introduce health economics and outcome research teams to accumulate evidence for future negotiations with payers. Actively explore innovative payment agreements based on efficacy, such as risk-sharing and tiered payment, especially in the face of China's huge unmet demand and payment pressure.
IV. CONCLUSION: FROM THE SEARCHING OF "MIRACLES" TO THE CONSTRUCTION OF "SYSTEMS"
The setback in 2025 marked a painful yet necessary turning point in the history of Alzheimer's disease research and development. It heralded the end of the old paradigm of seeking a single' miracle drug. 'The future winners will not be lone heroes with' blockbuster drugs,' but rather ecosystem builders who can integrate precision diagnostics, multi-target combination therapies, digital health tools, and value-based payment solutions to provide a complete value chain for specific patient subtypes.
For China's researchers, this is both a challenge and an opportunity. While understanding the global R&D patterns, delving into precise insights into China's patient population, and leveraging local advantages in digital healthcare, artificial intelligence, and large-scale clinical resources, it is entirely possible to forge their own innovative path in this paradigm shift from "miracle" to "system." The battle is far from over, but the rules of the game have already been rewritten. What is needed now is not only scientific perseverance but also strategic clarity and decisiveness.
reference material
1. Confronting a 99.6% R&D Failure Rate: How Global Pharmaceutical Companies Can 'Mine Gold' in the Alzheimer's Disease Market?
https://www.163.com/dy/article/JQF66QDN05199NPP.html
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