The new year is now well underway and it’s time once again to scan the broad CNS landscape to identify the trends that will shape the research and commercial environments over the next 12 months. Our annual CNS market outlook has become a tradition here at Blue Matter, as we first began publishing it in early 2021.
As anyone in this space knows, the CNS landscape is quite broad, covering an exceptionally wide range of disease states and therapeutic modalities. It’s so broad and diverse that it can be very challenging to distill everything down to a handful of discrete trends. Furthermore, each individual trend could take barrels of “digital ink” to fully cover. Nevertheless, we’re going to forge ahead and give it a try.
Overall, we’ll consider a balance of “patient friendly” advances (such as less invasive routes of administration, continued investment in symptomatic therapies, and engineering of existing therapies to reduce side effects) and “science forward” advances (such as new modalities, novel targets leveraging advances in basic science, and more accurate biomarkers).
Here’s the list, distilled down to five core topics:
- Merger and acquisition (M&A) and dealmaking trends
- Alzheimer’s developments and emerging trends
- The emergence of blood-brain barrier (BBB) shuttle technology as the “next frontier”
- Notable failures that are changing how we think about targets and pathways
- Notable advances that may lead to therapeutic innovation
Now, let’s dive in and explore each one a bit more deeply.
M&A and Dealmaking Trends
M&A and dealmaking activity in CNS started 2025 on a strong footing, highlighted by Johnson & Johnson’s acquisition of Intra-Cellular Therapies. The transaction centered on Caplyta®, an antipsychotic approved for schizophrenia and bipolar disorder. In November, an additional FDA approval expanded its label into major depressive disorder (MDD). This additional indication significantly broadens Caplyta’s commercial potential and strategically complements J&J’s existing psychiatric franchise, including its ketamine-based nasal spray Spravato®. The deal underscores continued appetite among large pharma for late-stage or commercial CNS assets that can both diversify revenue streams and strengthen established therapeutic platforms.
Beyond this headline transaction, recent business development activity points to sustained strategic interest across neurological and psychiatric indications. Notable examples include Novartis’s acquisition of Avidity, driven by portfolio synergies in neuromuscular disease; Sanofi’s acquisition of Vigil Neuroscience; and Biogen’s ex-US licensing deal for Stoke Therapeutics’ Dravet syndrome program. These transactions illustrate a range of deal structures, reflecting a flexible approach to risk-sharing and pipeline replenishment in a high-uncertainty therapeutic area.
Looking ahead, structural pressures are likely to maintain dealmaking momentum, particularly as the industry approaches a major patent cliff, with nearly 70 blockbuster drugs expected to lose exclusivity between 2025 and 2030. While this challenge spans multiple therapeutic areas, it is especially relevant in CNS, where internal R&D productivity has historically been volatile and costly. As a result, innovation is increasingly concentrated in small and mid-sized biotechs running high-risk clinical programs, creating a robust pipeline of external opportunities for larger pharmaceutical companies seeking growth and risk diversification through M&A and business development.
Alzheimer’s Developments & Trends
2026 will represent the 3rd anniversary of the approval of Leqembi®, the first disease modifying therapy marketed for Alzheimer’s disease (AD). As clinical experience with amyloid antibodies has grown and companies continue to test various scientific hypotheses, the consensus among experts in the field is increasingly that success in Alzheimer’s will require multiple mechanisms of action (MOAs) and modalities, potentially used in combination, and deployed at the right times during the disease process. Let’s explore the good and the bad as we stand here in early 2026, then consider what the future could hold.
On the positive side, we have seen improvements in blood-based biomarkers for Alzheimer’s, which helps make it easier to diagnose and identify patients that may benefit from monoclonal antibodies (mAbs). In 2025, the FDA cleared, for the first time, a diagnostic blood test for Alzheimer’s disease: Fujirebio’s Lumipulse® G that detects pTau 217 and beta amyloid. Roche also secured a green light for its pTau-181 blood test later in the year.
The Alzheimer’s Association, in its first clinical guidelines on blood biomarker testing, said that tests like these—that are highly sensitive and specific—can potentially be used instead of current diagnostic methods like PET scans and cerebrospinal fluid tests. However, most other guidelines still recommend the use of blood tests alongside other diagnostic tools.
We’re also seeing more “patient friendly” routes of administration for existing therapies. For example, lecanemab was approved as a subcutaneous (SC) injection for maintenance doses. That’s more patient friendly than intravenous administration but the SC injection process can still be complicated for someone with cognitive impairment. Now, lecanemab SC is under review for initiation dosing as well.
On the negative side, the much-awaited study of semaglutide in Alzheimer’s failed in the phase 3 EVOKE trial. Additional research is needed to understand whether there are presymptomatic use cases for GLP1s, what the optimal dosing might be, and so on. This failure is very unfortunate. A success of this magnitude could have attracted more generalist investors that would have “lifted all boats” in the CNS space.
Key Targets and Modalities: Looking Ahead
The table below provides a brief flyover of key targets and modalities, along with comments about what we can expect in the coming months.
| Amyloid Beta | Recent advances in amyloid-beta targeting focus on improving brain delivery while reducing safety risks seen with first-generation antibodies. A key example is Roche/Genentech’s trontinemab, a blood–brain barrier (BBB) shuttle–conjugated anti-amyloid mAb designed to enhance penetration into the brain. Its potential value lies not only in its ability to clear amyloid plaques, but also in its improved side-effect profile, particularly with respect to ARIA (amyloid-related imaging abnormalities), which are a changes in the brain that can be detected via MRI and are common side effects of anti-amyloid therapies. Phase 1/2 data reported in August 2025 showed that 91% of patients receiving the highest dose became amyloid-negative within six months, while the rate of ARIA-E (brain swelling) was just 1%—substantially lower than rates observed with earlier agents such as Leqembi® and Kisunla™. Based on these results, Roche has initiated two identical Phase 3 trials (TRONTIER-1 and TRONTIER-2) in patients with early symptomatic Alzheimer’s disease to confirm clinical benefit and safety at scale. |
| Tau | Tau has proven to be a challenging therapeutic target in AD; a recent failure that exemplifies this challenge (though certainly not the only failure in this space) is J&J's novel therapy, posdinemab, which failed to slow disease progression in a highly anticipated trial. Nonetheless, the evaluation of new tau-targeting modalities is ongoing. Biogen’s tau program (BIIB080) is widely considered the "ultimate test" for the tau hypothesis, as it effectively bypasses the intracellular targeting issues that have plagued previous antibody-based therapies. It showed encouraging phase 1 data. The phase 2 CELIA trial is expected to release results in the first half of 2026 and should demonstrate if tau is a relevant target. Investor enthusiasm around tau is currently limited, but this could change quickly if and when positive results start rolling in. |
| PROTACS (Proteolysis Targeting Chimeras) & Molecular Glues | Approaches from oncology, specifically PROTACs and molecular glues, are now being utilized in Alzheimer's research. In principle, molecular glues or PROTACs can promote lysosomal degradation of toxic protein precursors or aggregates characteristic of AD. One challenge is the ability of these molecules to penetrate the BBB. It remains to be seen whether this will be a relevant therapeutic approach in Alzheimer’s. However, these molecules would likely not have AIRA issues, which is an attractive feature. |
Intervening Earlier in the Disease
A key strategic direction is to treat patients earlier in the disease continuum, before irreversible damage has occurred. Lilly’s TRAILBLAZER-ALZ 3 study of donanemab in preclinical AD exemplifies this shift. The trial is enrolling cognitively normal but biomarker-positive individuals and is designed as an event-driven study, with readout expected in late 2026 or early 2027. If successful, this program could support treatment initiation at a much earlier stage, significantly expanding the addressable patient population and reinforcing the concept that amyloid-directed therapies may have their greatest impact prior to overt cognitive decline.
Continued Focus on Symptomatic Approaches
In parallel with disease-modifying therapies (DMTs), there remains strong interest in symptomatic strategies aimed at preserving cognitive function. Notably, CobenfyTM , BMS’ muscarinic agonist approved in schizophrenia, is currently being studied for its effects on Alzheimer’s disease-related psychosis (ADRP) as part of the 3-trial ADEPT program. ADRP is a difficult-to-treat symptom that has profound impacts on patients and caregivers.
An earlier-stage and more novel area of focus for symptomatics is synaptic health-related targets, based on the hypothesis that synaptic protection may help alleviate both cognitive and behavioral symptoms of Alzheimer’s. An example of this strategy is Cognition Therapeutics’ zervimesine, an oral small molecule designed to act as a neuroprotective agent by shielding neurons and synapses from toxic oligomer binding.
While symptomatic therapies have historically been viewed as less transformative than DMTs, their clinical importance may be underestimated—particularly in elderly patients, where tolerability and quality-of-life improvements are paramount. In this population, symptomatic approaches may be as impactful as disease-modifying agents, especially when used in combination regimens where DMTs are available, supporting a more holistic treatment paradigm.
BBB Shuttle Technology as the “Next Frontier”
Improving BBB penetration remains a critical hurdle in CNS drug development. Currently, many potentially effective drugs fail because they can’t reach sufficient concentrations in the brain to engage their targets. To compensate, manufacturers often resort to very high doses, which can lead to systemic toxicities, or utilize highly invasive routes of administration (ROAs) like intrathecal administration that are burdensome for both patients and providers. BBB shuttle technology offers a “next frontier” solution by making complex therapies like monoclonal antibodies (mAbs) potentially more viable, while enabling lower, safer dosing.
Key Clinical and Strategic Milestones in 2026
The coming year features several pivotal milestones that will signal the maturity of these platforms:
- Denali Therapeutics’ ETV (Enzyme TransportVehicle™) Platform – The FDA has set a PDUFA date of April 5, 2026, for tividenofusp alfa (DNL310) for the treatment of Hunter Syndrome. If approved, this would mark the first-ever regulatory green light for a drug utilizing a BBB shuttle.
- Novartis and Sironax – Following an agreement in July 2025, Novartis is currently in a “validation window” to evaluate Sironax’s Brain Delivery Module (BDM) platform across its siRNA and protein degrader portfolios. An option exercise is expected in mid-2026, which would serve as a major signal of confidence in the platform’s ability to deliver complex biologics to the CNS.
- Roche’s Trontinemab – As a sector benchmark (mentioned in the section above), Roche continues to advance trontinemab, leveraging its proprietary shuttle technology to improve the delivery of anti-amyloid therapies for Alzheimer’s disease.
These advancements collectively aim to reduce clinical risk in the CNS space by ensuring that innovative therapies can finally bypass the brain’s natural defenses without compromising patient safety or comfort.
Notable Failures Changing How We Think About Targets & Pathways
Recent late-stage setbacks have reshaped thinking around several CNS targets and development strategies. Alector’s failure with latozinemab in progranulin (PGRN)-related frontotemporal dementia (FTD) is particularly instructive. Despite robustly increasing plasma PGRN levels, latozinemab did not translate those biomarker gains into clinical benefit. This outcome raises concerns that blood PGRN levels may be an insufficient surrogate for restoring functional activity within vulnerable populations. As multiple companies continue to pursue PGRN restoration approaches—including gene therapies from AviadoBio and Passage Bio—the bar has now been raised to demonstrate that this type of therapy can meaningfully slow disease progression rather than simply normalize protein levels.
While other FTD programs targeting alternative pathways are less directly impacted, the latozinemab failure underscores the growing regulatory and investor expectation that trials show effects on both biological and functional endpoints.
In psychiatry, Bristol Myers Squibb’s muscarinic agonist Cobenfy failed as an adjunctive treatment for schizophrenia, dampening near-term blockbuster expectations but not invalidating the underlying muscarinic hypothesis. The result is widely viewed as a limitation of adjunctive trial designs rather than a mechanistic refutation. This is because it’s inherently difficult to demonstrate incremental benefit on top of effective antipsychotics without very large effect sizes or large, tightly run trials.
Some subgroups (for example, patients with more pronounced negative symptoms or those on specific background antipsychotics other than risperidone) may show clearer benefit. This has fueled interest in more targeted development strategies.
Competitors such as Neurocrine and Maplight are continuing to develop muscarinics in this space and may be able to leverage the learnings from the Cobenfy trial failure to inform trial design (i.e., enriching for negative symptom patients). In addition, it is clear that there is still room for a “best in class” muscarinic option to emerge and surpass Cobenfy’s somewhat modest efficacy.
Notable Advances That May Lead to Therapeutic Innovation
Huntington’s Disease
Huntington’s disease has historically been marked by repeated late-stage failures and limited therapeutic progress. Recent advances—particularly the emerging hypothesis that somatic expansion of the mutant huntingtin gene may be a key driver of cell death—are reviving confidence that truly disease-modifying strategies may be achievable.
This renewed optimism was amplified by uniQure’s AMT-130 gene therapy program, which reported data suggesting a 75% slowing of clinical progression versus a natural-history control—results that some have described as potentially “game-changing.” uniQure initially planned an accelerated BLA submission in early 2026, positioning AMT-130 as a potential first-in-class DMT. However, late-2025 regulatory pushback from the FDA, which deemed the external control dataset insufficient to support a BLA, has thrown some added uncertainty into the program’s timeline and development path. While the regulatory strategy forward remains unclear, patients are anxiously awaiting a therapeutic option that can meaningfully slow disease progression.
Psychedelics
A major bottleneck for psychedelic therapies has been the need for—and burden of—closely supervised dosing due to acute psychoactive side effects, making at-home administration impossible. Delix Therapeutics may be the first psychedelic developer to crack that code. The FDA has approved (for clinical trial purposes only) at-home administration of its psychedelic, zalsupindole, in an upcoming trial. The approval is based on promising data from a recent trial in which patients experienced improvements in treatment-resistant depression symptoms without any trip-like effects.
If replicated, this could significantly expand scalability and payer acceptability, positioning non-hallucinogenic neuroplastogens as a more commercially viable evolution of the psychedelic paradigm.
Let’s Keep in Touch
As 2026 moves on, our team will monitor the trends and issues highlighted above. We’ll also publish additional resources on various topics within this diverse and rapidly evolving market. Follow Blue Matter on LinkedIn or check our Insights page regularly to get the latest. In addition, please contact us via our website if you have any questions or if you would like to discuss development and commercial strategy for your company’s CNS product(s) or portfolio.
