The "graveyard" of innovative research and development, AD, still attracts countless adventurers.

Recently, Biogen announced the topline results of the Phase II CELIA study for its antisense oligonucleotide (ASO) therapy, Diranersen (BIIB080), in the treatment of early Alzheimer's disease.

The data revealed that the CELIA study did not meet its primary endpoint, which was to assess the relationship between changes in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) from baseline and dose response at week 76. However, despite this setback, Biogen decided to proceed with the Phase III registration and development of Diranersen.

Priya Singhal, Executive Vice President and Head of Research and Development at Biogen, pointed out: "This is the first time that a tau-targeting drug has demonstrated unprecedented and compelling efficacy and biomarker results in a randomized early Alzheimer's disease study."

This statement evidently failed to dispel market concerns, and the capital market chose to vote with its feet. On the day of the news release, Biogen's stock price rose before trading, then turned down, and closed down about 5%.
The decision to push forward against the trend has left the industry both puzzled and curious. Why did Biogen choose to take the risk and advance a drug that has not met its primary endpoint to Phase III amidst skepticism?
 

01、A confusing choice

The design of the CELIA study itself is not complicated.

This trial enrolled 416 subjects with mild cognitive impairment (caused by Alzheimer's disease) or mild Alzheimer's disease dementia, who received intrathecal injections of Diranersen at three different doses for a duration of 76 weeks. All study participants had not previously received anti-amyloid treatment. The primary endpoint of the study was to assess the change in CDR-SB from baseline at week 76, using a dose-response approach. CDR-SB is one of the most commonly used assessment tools in Alzheimer's disease clinical trials, primarily evaluating memory, orientation, household activities, community affairs, and self-care abilities. In recent years, key trials for newly approved Alzheimer's disease drugs have used it as the primary or secondary endpoint. 

The pre-specified cognitive endpoint analysis showed that the clinical decline rate was slowed down in all three dose groups, especially in subjects treated with the lowest dose (60 mg every 24 weeks) of Diranersen. However, the expected linear relationship between drug dose and CDR-SB change was not established, and the study did not meet the primary endpoint. Jeff Cummings, a professor of brain science at the University of Nevada, Las Vegas, stated that the CELIA study is the first to demonstrate that reducing tau protein may have a significant impact on disease progression, which is of great significance for advancing new mechanisms of action and shaping the next generation of Alzheimer's disease therapies. Biogen pointed out that Diranersen successfully reduced tau protein levels in patients' brains. Tau protein plays an important role in the normal function of brain cells, but in patients with Alzheimer's disease, tau protein accumulates abnormally and forms intracellular tangles, leading to neurodegeneration and cognitive decline. 

Diranersen is an antisense oligonucleotide (ASO) gene drug originally discovered by Ionis Pharmaceuticals, and Biogen obtained the global exclusive rights in 2019. The drug is designed to target microtubule-associated protein tau (MAPT) mRNA, reducing tau protein production from the source, and is administered via intrathecal injection. In 2025, the FDA granted Diranersen Fast Track designation. The complete results of the CELIA study are scheduled to be presented at the Alzheimer's Association International Conference (AAIC) in July this year. Stifel financial analyst Paul Matteis bluntly stated in a report to clients: "Frankly, we don't know why the dose-response here is not linear." He described this as "an open question that is crucial to understanding the strength and authenticity of this signal." 

However, he also admitted that overall, he felt "somewhat encouraged" and looked forward to more data. Brian Abrahams of RBC Capital Markets was more cautious, saying that any new mechanism that could successfully target Alzheimer's disease could be a "significant long-term victory," but it was "too early" to judge whether Diranersen could meet this standard. Biogen's enthusiasm for advancement "suggests that there may be something valuable in it," but due to the lack of details on the magnitude of efficacy, doubts about dose dependence, and the potential need for improvements in the dosing regimen, "we remain cautious." 

The current data are far from providing an answer to whether improvements in biomarkers can be translated into definite clinical benefits. Despite the failure of Phase II, Biogen did not suspend research and development or adjust its strategy. It skipped the conventional Phase IIb study for dose optimization and directly announced the advancement to Phase III registration development. This is unreasonable. Unless Biogen has no time to wait for "reasonableness.".  

02、Biogen's "heart-wrenching history" with Alzheimer's disease

To understand Diranersen's decision to move forward, one must look back at Biogen's long and costly history in the AD field. It is a history of repeated failures and perseverance. In 2007, Biogen licensed Aducanumab (marketed as Aduhelm) from Neurimmune. About 10 years ago, Biogen publicly estimated that the research and development cost of Aduhelm would be $2.5 billion, while analysts generally predicted that Aduhelm's peak sales would reach a record high of $14.5 billion.

In June 2021, the FDA approved Aduhelm for marketing through accelerated approval. This was the first new drug for Alzheimer's disease approved by the FDA since 2003. Upon the announcement, Biogen's stock price soared, and the entire Alzheimer's disease (AD) field seemed to usher in a belated spring. However, this approval was highly controversial. In 2019, Biogen first suspended the phase III clinical trials of Aduhelm and then conducted a retrospective analysis, stating that although the results of one trial showed no significant effect of Aduhelm, another trial demonstrated that Aduhelm could improve patients' cognitive abilities. Based on this, Biogen resolutely decided to pursue the Biologics License Application (BLA) for Aduhelm. However, after its launch, Aduhelm's sales performance was disastrous. In the first nine months of 2023, Aduhelm's global sales were less than $11 million. In January 2024, Biogen was forced to announce the cessation of the development and commercialization of Aduhelm, returning all rights to Neurimmune. 

A gamble that had taken nearly 17 years ended in a fiasco. This was far from Biogen's only setback in the AD field. In 2019, Biogen and Eisai announced the termination of the phase III study of the oral BACE inhibitor elenbecestat. The Data Safety Monitoring Committee deemed it necessary to stop the trial due to an unfavorable risk-benefit ratio. Currently, the AD drug still in commercialization in Biogen's pipeline is Lecanemab (brand name Leqembi). 

In March 2014, Eisai and Biogen officially signed a joint development and commercialization agreement, with Eisai responsible for global research and regulatory submissions, and having the final decision-making authority; Biogen was responsible for market promotion and sales. Leqembi's mechanism of action has dual targeting characteristics, selectively binding to soluble Aβ fibrils and insoluble Aβ aggregates/plaques, and clearing brain amyloid through activating the phagocytic activity of microglia. In January 2023, the FDA approved Leqembi for marketing through accelerated approval, and it was subsequently granted full approval. In the Clarity AD phase III clinical trial, after 18 months of treatment, the rate of cognitive and functional decline (assessed by the CDR-SB scale) in the Leqembi group was 27% slower than that in the placebo group, providing crucial support for the subsequent full approval. 

Unfortunately, the commercial performance of Leqembi was also mediocre. In the first quarter of 2026, Leqembi's revenue reached $168 million, marking a year-on-year increase of 74%, with the US market contributing the core share. While this figure sounds impressive, it is far from being a "blockbuster" success when compared to the vast patient base of Alzheimer's disease. Over the past five years, Biogen's overall revenue has shown a downward trend. The multiple sclerosis product line, which once supported the company's performance, is facing competition from generic drugs, and the growth of Spinraza, a drug for spinal muscular atrophy, is also becoming increasingly flat.

 Biogen is currently in a critical period of adjusting its neuroscience direction and focusing resources on developing high-potential projects. Beyond targeting β-amyloid, Diranersen represents another path - genetic intervention targeting tau protein. For a company that has invested years in the Aβ track but has reaped little, the tau target is almost Biogen's "last bet" that cannot be given up. This is why, even though the Phase II data is shrouded in mystery, Biogen is determined to move forward into Phase III. 

03、Track Dogfight

Biogen is not the only player making a big bet in the AD field.

According to Business Research Insights, the global market size of Alzheimer's Disease (AD) drugs is projected to grow from $9.22 billion in 2026 to $15.87 billion in 2035, representing a compound annual growth rate (CAGR) of 6.23%. Given such a vast market, no pharmaceutical company would want to miss out. Statistics indicate that Aβ deposition and tau hyperphosphorylation continue to occupy a pivotal position in AD drug research and development, with 18% and 11% of currently in-development drugs targeting these two core pathological mechanisms, respectively. Emerging mechanisms such as neurotransmitter receptors (22%), neuroinflammation/immunity (17%), synaptic plasticity/neuroprotection (6%), energy metabolism (6%), growth factors, lipid metabolism, protein homeostasis, vascular function, and circadian rhythm are also gradually becoming hotspots in AD research and development.

 Anti-Aβ monoclonal antibodies remain the mainstream. Since 2021, the FDA has expedited the approval of three new drugs for the treatment of AD, all of which are anti-Aβ monoclonal antibodies, including Biogen's Aducanumab (now delisted) and Lecanemab, as well as Eli Lilly's Donanemab. The core mechanism of these drugs is to delay cognitive decline by clearing excessively deposited and neurotoxic Aβ from the brain. Although Lecanemab and Donanemab have demonstrated in Phase III studies that they can delay cognitive decline to some extent, the exact causal relationship between Aβ clearance and clinical benefit remains controversial. Adverse Reactions to Immunotherapy (ARIA) side effects (cerebral edema and microbleeds) also raise concerns among doctors and patients. Targeting tau protein is another core pathway. In AD, the abnormality of tau protein is mainly manifested as hyperphosphorylation, causing it to detach from microtubules, leading to microtubule disintegration, axonal transport disruption, and the aggregation of detached tau proteins into neurofibrillary tangles. More importantly, the distribution density of tau tangles is highly correlated with the degree of cognitive decline in patients. However, the development of tau-targeted drugs is also fraught with challenges.

In 2020, Roche and AC Immune announced the failure of their tau antibody, semorinemab, in the Phase II TAURIEL study, as it failed to meet the primary endpoint of CDR-SB and missed all efficacy endpoints. Since then, tau protein drugs from multiple companies have also stalled in early clinical stages. Currently, Diranersen stands out as the first ASO drug to simultaneously report a reduction in tau protein signals and potential cognitive benefits in a randomized, controlled Phase II study. Targeting the APOE gene and neuroinflammation/immune modulation have emerged as new directions in recent years. APOE4 is the most significant genetic risk factor for late-onset Alzheimer's Disease (AD), with one copy of APOE4 increasing the risk of disease by threefold and two copies by 8-12 fold. Voyager Therapeutics' APOE gene therapy garnered significant attention, but the company announced a temporary halt to the project in March 2026. In terms of neuroinflammation, INmune Bio's selective sTNF inhibitor, XPro1595, showed positive trends in specific subgroups of its Phase II trial and did not exhibit Atypical Inflammation Relapse (ARIA) side effects, yet it also failed to meet the primary clinical endpoint.

Beyond failure, there is also new dawn. For instance, Fosun Pharma has introduced AR1001 from AriBio in South Korea. This is an oral small molecule PDE-5 inhibitor that can clear amyloid plaques, inhibit abnormal phosphorylation of tau protein, suppress inflammatory reactions, and provide neuroprotective effects. Its global multicenter Phase III POLARIS-AD study has enrolled over 1,500 patients and is expected to announce top-line results in 2026. Fosun Pharma will pay an option fee of US$60 million, and upon exercise, will also pay a down payment of up to US$180 million and regulatory milestone payments.

— Written at the end —

Returning to the initial question: Why did Biogen insist on pushing through Phase III despite the failure to meet the primary endpoint? From a scientific perspective, the CELIA study did leave some signals worth further exploration, but Biogen's high-risk decision was also clearly driven by commercial considerations. However, Biogen's options are limited. After years of setbacks in the Alzheimer's disease (AD) battlefield, Diranersen has emerged as the most promising drug in Biogen's remaining AD pipeline. The history of Alzheimer's disease drug development is essentially a history of learning from failures. 

From early cholinesterase inhibitors to later BACE inhibitors, γ-secretase modulators, and then the ups and downs of Aβ antibodies, as well as the tau-targeted therapies, APOE gene therapies, and neuroinflammatory modulators currently being explored - each path carried hope and also experienced disillusionment. For Biogen, Diranersen is a high-risk bet, but in the field of AD, no bet is low-risk. Giant companies such as Eli Lilly, Roche, and Eisai are continuously testing the waters with billions of dollars of investment, and every success or failure accumulates experience for the entire field. Currently, there are still too many uncertainties in the research related to Diranersen, but at least in one thing, Biogen's attitude is clear: it will not actively withdraw from this game. The story of AD drug development is just an epitome of the wave of CNS drug innovation. Currently, the research and development of new drugs for CNS diseases is ushering in a critical window for mechanism breakthroughs and clinical translation.

 The first China Pharma Innovation Conference (CPIC 2026), hosted by Tongxieyi, will be held at the National Exhibition and Convention Center (Shanghai) from July 22 to 24, 2026. The conference will feature a "CNS Innovative Drug Development Session", bringing together top experts from home and abroad to deeply discuss frontier topics such as new target discovery, clinical development strategies, and global registration pathways, and is committed to building a high-energy exchange platform for R&D innovation and industrial collaboration in the CNS field. We sincerely invite industry colleagues to join this intellectual feast and witness the rise and globalization of China's CNS new drugs.

Reference article: 

1. Biogen Pushes Forward with Tau Drug Despite Alzheimer's Study Failure; biopharmadive
2. Why did Biogen choose to rush ahead after the failure of Phase II clinical trials?; Pharmaceutical Times
3. The first "Alzheimer's disease" drug in nearly 20 years has been approved, but the controversy remains huge
4. Panorama of Alzheimer's disease drug development pipeline in 2025; official from ACRO Biosystems