Clinical Treatment Advances for Alzheimer’s Disease

Executive Summary

The 12-month period from January 2025 to January 2026 marked a pivotal phase in the evolution of Alzheimer’s disease (AD) therapeutics, characterized by the advances in the anti-amyloid antibody class, the transformative integration of blood-based biomarkers into clinical practice, and a complex landscape of mixed results for novel mechanisms. While the first generation of disease-modifying therapies (DMTs) gained broader regulatory acceptance and began to generate real-world evidence, significant hurdles in access, reimbursement, and safety management came into sharp focus.

Regulatory agencies in the US, EU, and China solidified the role of anti-amyloid treatments. In the US, Eisai/Biogen’s lecanemab received FDA approval for more convenient dosing regimens, including a less frequent intravenous (IV) maintenance schedule and a first-in-class subcutaneous (SC) autoinjector for at-home administration 25, 26. This life-cycle management strategy aims to alleviate the significant burden on healthcare systems. In Europe, both lecanemab and donanemab navigated the regulatory process, with lecanemab securing a conditional marketing authorisation from the European Commission in April 2025, albeit with restrictions for patients with one or zero APOE4 alleles and a mandate for a post-authorisation safety registry 27, 28. Eli Lilly’s donanemab overcame an initial negative opinion from the CHMP to gain a positive recommendation in July 2025, signaling growing regulatory comfort with this class 10, 11. China also advanced, accepting a BLA for subcutaneous lecanemab after its initial IV approval in early 2024 30, 31, 32.

However, regulatory approval did not translate to uniform global access. In the US, CMS continued its "Coverage-with-Evidence-Development" policy, with Medicare projecting a spend of approximately $3.5 billion on Leqembi in 2025 33, 34. In stark contrast, the UK's NICE issued draft guidance declining routine funding for lecanemab and donanemab, citing modest clinical benefit relative to their high cost 36, 37. This divergence highlights the significant health technology assessment (HTA) challenges that lie ahead.

The clinical trial landscape produced a mix of high-profile failures and targeted successes. Several non-amyloid small molecule programs, including Cassava’s simufilam, AbbVie’s ABBV-552, and Athira’s fosgonimeton, failed to meet their primary endpoints in late-stage trials, underscoring the difficulty of targeting alternative pathways 1 5, 6. Conversely, therapies targeting specific, biomarker-defined populations showed promise. Annovis Bio’s buntanetap demonstrated a statistically significant cognitive benefit on ADAS-Cog 11 in its Phase II/III study, particularly in a biomarker-positive subgroup 24. Alzheon’s valiltramiprosate (ALZ-801) showed a 52% slowing of cognitive decline in a prespecified MCI subgroup of APOE ε4/4 homozygotes 4. UCB’s anti-tau antibody bepranemab failed in its overall population but showed a 29% slowing on the CDR-SB in a subgroup of patients with low baseline tau and no APOE4 alleles 24.

Safety, particularly Amyloid-Related Imaging Abnormalities (ARIA), remained a central theme. The FDA issued a safety communication in August 2025 recommending more frequent MRI monitoring for lecanemab users to better manage ARIA risk 12. Real-world evidence from the ALZ-NET registry and other cohorts began to emerge, suggesting ARIA rates in clinical practice (around 13% for lecanemab) may be slightly lower than in pivotal trials, with low rates of serious events or discontinuations 43, 46.

Arguably the most significant advance was the regulatory clearance and initial adoption of plasma-based biomarkers. The FDA cleared Fujirebio’s Lumipulse G pTau217/Aβ42 ratio test and Roche’s Elecsys pTau181 assay for diagnostic and rule-out purposes, respectively 13, 14, 39. This marks a paradigm shift toward a "blood-first" diagnostic approach, poised to streamline patient identification, improve trial recruitment, and facilitate broader, earlier access to treatment.

Looking ahead, the pipeline remains robust. Key milestones expected in the next 12-24 months include Phase 3 readouts for Novo Nordisk’s semaglutide (EVOKE/EVOKE+) and Alzheon’s ALZ-801, alongside regulatory decisions for donanemab in the US and EU 17. The convergence of new formulations, validated blood tests, and growing real-world experience is setting the stage for the next chapter of AD care, one that will be defined by personalized treatment strategies, complex access negotiations, and a continued search for more effective and safer therapeutic options.

Key Bullet Findings

Lecanemab Life-Cycle Advances: The FDA approved a less frequent (once every four weeks) IV maintenance dose and a weekly subcutaneous autoinjector for lecanemab, aiming to reduce treatment burden 25, 26.
EU Regulatory Approvals: The European Commission granted conditional marketing authorisation for lecanemab in April 2025, followed by a positive CHMP opinion for donanemab in July 2025 after an initial rejection, solidifying the standing of anti-amyloid therapies in Europe 11, 27.
Divergent Global Reimbursement: While the US CMS provides coverage for DMTs through a registry, the UK's NICE rejected routine funding for lecanemab and donanemab due to cost-effectiveness concerns, highlighting major access hurdles in Europe 33, 36.
Blood-Based Biomarkers Approved: The FDA cleared two plasma p-tau assays (Fujirebio pTau217/Aβ42 and Roche pTau181) for clinical use, enabling a "blood-first" approach to AD diagnosis and simplifying patient screening 13, 39.
Mixed Late-Stage Trial Readouts: Major failures were reported for simufilam, fosgonimeton, and ABBV-552 1, 5, 6. In contrast, positive results were seen in specific subgroups for buntanetap (biomarker-positive), valiltramiprosate (APOE4/4 MCI), and bepranemab (low-tau/APOE4-negative) 4, 24.
ARIA Management in Focus: The FDA issued a safety communication recommending increased MRI monitoring for lecanemab to detect ARIA 12. Real-world data showed ARIA-E rates of ~13% for lecanemab, with low discontinuation rates (2.8%) 43.
Robust Near-Term Pipeline: Major Phase 3 readouts are expected in 2026 for semaglutide (EVOKE/EVOKE+), ALZ-801 (APOLLOE4), and remternetug, with regulatory decisions pending for donanemab 17.

Timeline of Key Events (January 2025 – January 2026)

Jan 26, 2025: FDA approves lecanemab IV once every four weeks maintenance dosing 25.
Mar 28, 2025: EMA CHMP issues an initial negative opinion on donanemab 10.
Apr 15, 2025: European Commission grants conditional marketing authorisation for lecanemab (Leqembi) in the EU 27.
May 16, 2025: FDA grants De Novo clearance to Fujirebio’s Lumipulse G pTau217/Aβ42 plasma test, the first of its kind 13.
Jun 2025: NICE (UK) issues final guidance declining routine funding for lecanemab/donanemab 36, 37.
Jul 1, 2025: Leqembi launches in first EU markets (Germany, Austria) 29.
Jul 25, 2025: EMA CHMP reverses its decision, issuing a positive opinion for donanemab 11.
Aug 2025: FDA issues a safety communication recommending earlier and additional MRI monitoring for lecanemab users 12.
Aug 31, 2025: FDA approves the lecanemab (IQLIK™) subcutaneous autoinjector for weekly maintenance dosing 26.
Oct 2025: China’s NMPA accepts the BLA for subcutaneous lecanemab 31, 32.
Oct 13, 2025: FDA clears Roche’s Elecsys pTau181 plasma assay for primary care use 14, 39.
Nov 2025: The US ALZ-NET registry surpasses 2,500 enrolled patients on DMTs 46.
Dec 17, 2025: China’s NMPA approves Roche’s multi-analyte CSF diagnostic kit 41.

1. Regulatory Decisions and Guidance

The regulatory environment in 2025 was dynamic, with major agencies in the US, EU, and China making key decisions that expanded the availability of DMTs while also tightening safety oversight.

United States (FDA):

Lecanemab Formulations: Eisai and Biogen successfully executed a life-cycle management strategy for lecanemab. On January 26, 2025, the FDA approved a supplemental BLA for once every four weeks IV maintenance dosing regimen following an 18-month induction period, reducing the infusion burden25. This was followed by the landmark approval on August 31, 2025, of the IQLIK™ weekly subcutaneous autoinjector for at-home maintenance dosing, a first for the anti-amyloid class 26.
Safety Guidance: Reflecting ongoing concerns about ARIA, the FDA issued a Drug Safety Communication in August 2025 recommending "earlier & additional MRIs" for patients on lecanemab to ensure prompt detection and management of this key side effect 12.

European Union (EMA):

Lecanemab: On April 15, 2025, the European Commission granted a conditional marketing authorisation for Leqembi (lecanemab). The approval was restricted to patients with mild cognitive impairment (MCI) or mild dementia who have one or zero APOE4 alleles and included a mandate for a post-authorisation safety registry to monitor ARIA 27, 28.
Donanemab: Eli Lilly’s donanemab had a more turbulent path. The CHMP initially issued a negative opinion on March 28, 2025. However, following a re-examination request by Lilly, the committee reversed its stance and delivered a positive opinion on July 25, 2025, recommending marketing authorisation for early AD 10, 11.

China (NMPA):

Following its initial approval of IV lecanemab in early 2024, the NMPA continued to prioritize AD treatments. In March 2025, it was reported that the IV maintenance posology was under priority review 30. In October 2025, the NMPA accepted the BLA for the subcutaneous formulation of lecanemab, putting it on a fast track for potential approval in 2026 31, 32.

2. Pivotal Phase 2/3 Clinical Trial Readouts

The past year saw critical data readouts that refined the understanding of existing drug classes and tested novel mechanisms, with mixed outcomes.

Table 1: Key Phase 2/3 Clinical Trial Readouts (Jan 2025–Jan 2026)

Candidate (Sponsor)	Mechanism	Phase	Population	Key Efficacy Finding	p-value
Buntanetap (Annovis Bio)	α-syn/Aβ/tau inhibitor	II/III	Mild-to-moderate AD (N=325)	+3.32 point improvement on ADAS-Cog 11 (30mg dose vs. baseline)	0.015 (vs. placebo)
Valiltramiprosate (ALZ-801) (Alzheon)	Aβ oligomer inhibitor	III	APOE ε4/ε4 Early AD (N=320)	52% slowing on ADAS-Cog13 in prespecified MCI subgroup	0.041 (nominal)
Bepranemab (UCB)	Anti-tau mAb	II	Prodromal-mild AD (N=466)	29% slowing on CDR-SB in low tau/APOE4 non-carrier subgroup	Not Reported
Simufilam (Cassava)	Altered filamin A	III	Mild-to-moderate AD (N≈1,400)	No significant difference vs. placebo on ADAS-Cog12 & ADCS-ADL	>0.05
Fosgonimeton (Athira)	HGF/MET agonist	II/III	Mild-to-moderate AD (N=287)	No significant effect (Global Statistical Test Δ = -0.08)	0.70
ABBV-552 (AbbVie)	SV2A modulator	IIb	Mild AD (N=263)	No efficacy (ΔADAS-Cog14 vs. placebo: -0.02 to +0.25)	>0.65

Detailed Findings & Safety Signals:

Success in Subgroups: The positive signals from buntanetap, valiltramiprosate, and bepranemab highlight a critical trend: efficacy is increasingly found in biomarker-defined subgroups 4, 24. Buntanetap's effect was strongest in patients with a high baseline pTau217/tTau ratio. Valiltramiprosate's effect was confined to its target population of APOE4/4 homozygotes with MCI. Bepranemab failed in the overall population but showed a clear signal in the ~50% of patients with low baseline tau and no APOE4 alleles, along with a 63-67% reduction in tau accumulation on PET scans in this group 24.
High-Profile Failures: The termination of Cassava’s simufilam Phase 3 trials (RETHINK & REFOCUS) for futility was a significant setback for the program, although the drug was reported to be safe and well-tolerated 1. The negative readouts of fosgonimeton also tempered enthusiasm for non-amyloid/tau synaptic-focused mechanisms 5, 6.
Safety Profiles:
- ARIA: This remains the most-watched safety signal for anti-amyloid antibodies. Model-based cross-trial comparisons presented at CTAD 2025 estimated ARIA-E incidence at ~13% for lecanemab, ~24% for donanemab, and ~35% for aducanumab 45. Real-world data for lecanemab showed an ARIA-E rate of 12.9%, with only 2.8% of patients discontinuing due to the side effect 43. Tau-targeting therapies like bepranemab and LMTX showed minimal to no ARIA risk 24.
- Discontinuations: Discontinuation rates varied by mechanism. For fosgonimeton, 14.2% of patients stopped treatment due to adverse events (mostly injection-site reactions), compared to 4.6% on placebo 6. In contrast, buntanetap and bepranemab were reported to be well-tolerated with low discontinuation rates 24.

3. Biomarker and Diagnostic Advances

2025 was a landmark year for AD diagnostics, with blood tests moving from research to clinical reality.

Table 2: Key Diagnostic Approvals and Advances (Jan 2025–Jan 2026)

Date	Agency	Technology	Intended Use	Key Performance Metric
May 16, 2025	FDA	Fujirebio Lumipulse G pTau217/Aβ42 Plasma Ratio	Aid in diagnosis of AD in symptomatic adults ≥55	PPA: 91.7%, NPA: 97.3% vs. PET/CSF 13
Oct 13, 2025	FDA	Roche Elecsys pTau181 Plasma Assay	Primary-care "rule-out" test for cognitive decline	NPV: 97.9% 14, 39
Jun 23, 2025	FDA	Expanded Indications for Amyloid-PET Tracers	Broader clinical use for differential diagnosis of dementia	Supports earlier detection and therapy eligibility 40
Dec 17, 2025	NMPA (China)	Roche CSF Panel (Aβ42/Aβ40 + pTau)	First CSF multi-analyte AD kit cleared in China	41

These approvals are expected to fundamentally alter the diagnostic pathway for AD. The availability of highly accurate plasma tests like the Lumipulse pTau217/Aβ42 ratio and the Elecsys pTau181 assay will allow primary care physicians to more effectively triage patients with cognitive complaints, identifying those who need confirmatory PET or CSF testing and are potential candidates for DMTs. This shift is projected to significantly widen the diagnostic funnel and support broader treatment access.

4. Real-World Access, Reimbursement, and Evidence

The transition from clinical trials to real-world practice has exposed significant friction in access and reimbursement.

United States: The Centers for Medicare & Medicaid Services (CMS) maintained its "Coverage-with-Evidence-Development" policy, requiring patients receiving DMTs to be enrolled in a registry 33. The ALZ-NET registry, a key platform for this, enrolled over 2,500 patients by November 2025, providing early safety data consistent with clinical trials 46. Medicare's projected Part B spending on Leqembi was estimated at $3.5 billion for 2025, with beneficiaries facing a 20% coinsurance, highlighting the substantial economic impact 34, 35.
Europe: The reimbursement landscape is fragmented and challenging. In a major decision, the National Institute for Health and Care Excellence (NICE) in England and Wales issued guidance in June 2025 declining routine NHS funding for lecanemab and donanemab, deeming their benefits too modest to justify the cost 36, 37. In contrast, Germany and Austria began national reimbursement negotiations following the EU approval, with first launches in July 2025 29.
China: Access is being driven by provincial-level initiatives. In mid-2025, commercial insurance pilots in cities like Shenzhen and Hainan added Leqembi to "innovative drug" lists, offering partial subsidies ahead of anticipated national reimbursement (NRDL) negotiations in late 2026 38.
Real-World Evidence (RWE): Initial RWE is encouraging. An interim analysis of 178 patients on lecanemab from 15 US centers, presented at AAIC 2025, found that 83.6% remained stable or improved on clinical scales (CDR, FAQ). The real-world ARIA-E rate was 12.9%, with a serious ARIA rate leading to discontinuation of only 2.8% and no fatal intracranial hemorrhages reported 43.

5. Near-Term Clinical Pipeline Milestones (2026-2027)

The AD pipeline remains active, with several critical data readouts and regulatory decisions expected in the next 12-24 months.

Table 3: Selected Upcoming Pipeline Milestones

Candidate (Sponsor)	Modality / Target	Event	Expected Timing
Semaglutide (Novo Nordisk)	GLP-1 agonist / Neuroinflammation	Phase 3 EVOKE / EVOKE+ Top-line Data	H2 2026 17
Donanemab (Eli Lilly)	Anti-Aβ plaque mAb	FDA Traditional Approval Decision (PDUFA)	H2 2026
Remternetug (Eli Lilly)	Next-gen anti-Aβ mAb (SC)	Phase 3 Top-line Data	Q4 2026
ALZ-801 (Valiltramiprosate) (Alzheon)	Oral Aβ oligomer inhibitor	Phase 3 APOLLOE4 Top-line Data	Mid-2026
GV-971 (Green Valley)	Oligosaccharide / Neuroinflammation	Global Phase 3 Interim Futility Analysis	Late 2026
AC Immune-Takeda Oral Tau Vaccine	Oral Tau Vaccine	Phase 2 ABATE Readout	2025 19
Obicetrapib (NewAmsterdam)	CETP inhibitor / Cholesterol	BROADWAY CV/AD Biomarker Substudy Data	H1 2026 21

Disclosure: All analysis is conducted by Noah. This content is for informational purposes only and does not constitute investment or medical advice.