Oyster $60M Degrader Bet Faces High Alzheimer's Bar Without Precedent

Neuroscience Startups Attract Significant Venture Capital

Venture capitalists are showing renewed interest in neuroscience drug research, with funding for central nervous system-focused startups gaining momentum. London-based Oyster Therapeutics recently secured $60 million in a Series A round led by 4BIO Capital, with participation from Eli Lilly and others. Oyster aims to degrade a notorious protein linked to Alzheimer's disease. This funding contributes to the $664 million raised by neuroscience biotechs by mid-November 2026, following significant investments in previous years, signaling a resurgence in this challenging therapeutic area.

• After a period of perceived high risk, venture capitalists are increasingly investing in neuroscience, with CNS-focused startups attracting $1.09 billion, $1.58 billion, and $1.9 billion between 2023 and 2025, respectively. This trend signals a resurgence of investor confidence in the challenging but potentially lucrative brain drug research sector.
• London-based Oyster Therapeutics successfully raised $60 million in a Series A round. This funding was led by 4BIO Capital and included participation from major pharmaceutical company Eli Lilly, alongside eight other investors. This substantial investment highlights strong belief in Oyster's approach to tackling neurological disorders.
• Oyster Therapeutics is focused on developing therapies to degrade a specific, notorious protein implicated in Alzheimer's disease. This strategic focus on a key pathological hallmark of Alzheimer's positions Oyster at the forefront of innovative research aimed at addressing this complex neurodegenerative condition.

Why New Approaches to Alzheimer's Remain Critical

Current Alzheimer's disease management remains constrained by therapies that offer only modest symptomatic relief without stopping progression, while newer disease-modifying options introduce significant safety and eligibility trade-offs. Persistent uncertainties around treatment duration, early off-label use, and patient selection further complicate interpretation of benefits in practice and in trials.

• Symptomatic therapies provide modest relief without disease modification: Three cholinesterase inhibitors (CIs) are currently available and have been approved for the treatment of mild to moderate AD, with memantine, an N-methyl-D-aspartate receptor noncompetitive antagonist, as a further therapeutic option available for moderate to severe AD. Current treatments for Alzheimer's disease (AD) provide modest symptomatic relief but do not slow the progression of the disease.

• No empiric basis for duration of antidementia therapy and only temporary effects on some measures: There are no empiric data to support guidelines for duration of therapy with antidementia drugs. The association of persistency index with ADAS-Cog followed a quadratic trend (P < 0.01), with analysis suggesting that persistency slowed ADAS-Cog decline temporarily.

• Earlier-than-labeled use associated with more impaired and rapidly declining patients: Academic physicians frequently prescribe ChEIs and memantine earlier than indicated in the US Food and Drug Administration-approved labeling to patients who are relatively more severely impaired or who are rapidly progressing toward cognitive impairment. The use of these medications in ADNI is associated with clinical decline and may affect the interpretation of clinical trial outcomes.

• Anti-amyloid antibodies carry substantial ARIA, infusion-reaction, and tolerability burden with ApoE4 gene-dose effect: The pooled ARIA incidence was 19% (95% CI: 16%-23%), which was significantly modulated by ApoE4 status (RR 1.45 for heterozygotes, 3.54 for homozygotes vs noncarriers) and the pooled symptomatic ARIA incidence was 3% (95% CI: 2%-4%). IRRs occurred in 26% (95% CI: 19%-34%), with heterogeneity reduced in patients receiving specific pre-infusion prophylaxis, while the pooled rate of discontinuation due to AEs was 8% (95% CI: 5%-11%), with discontinuation due to ARIA occurring in 5% (95% CI: 3%-7%) of patients in RWE studies.

• Narrow eligibility excludes most atypical phenotypes despite early symptomatic disease: Depending on the eligibility framework applied, 70%-85% of patients would not meet treatment criteria. Bedside cognitive thresholds were the primary drivers of ineligibility (50%-67% of exclusions), despite most patients having early symptomatic disease (global CDR 0.5-1; 82%), with imaging-based exclusions (22%-27%) and severity thresholds (moderate or severe dementia, 19%-23%) also frequent.

• Non-pharmacological and investigational symptomatic strategies show limited or adjunctive benefit: Non-pharmacological interventions demonstrated short-term cognitive benefits primarily in mild Alzheimer's disease populations and should be interpreted as adjunctive symptomatic strategies rather than direct substitutes for pharmacological therapy. Despite associated risks such as adverse events and amyloid-related imaging abnormalities linked to disease-modifying therapies, lecanemab provides moderate benefits, while donanemab appears less effective.

Oyster's Protein Target and Emerging Alzheimer's Strategies

Recent research focuses on non-classical pathogenic pathways including neuroinflammation, mitochondrial dysfunction, impaired autophagy and proteostasis, and synaptic degeneration. Therapeutic strategies are shifting toward multi-target approaches that integrate amyloid modulation, tau protein-directed interventions, and attenuation of maladaptive neuroinflammatory responses.

• TREM2 signaling and innate immune regulation: TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, and HLA-DRB5-HLA-DRB1 are linked to neuroinflammation, with TREM2 signaling, NLRP3 inflammasome activation, and complement cascade dysregulation described as the most clinically actionable targets. Candidate agents include AL002 (anti-TREM2 antibody), AL003 (anti-CD33 antibody), BAN2401 (anti-Aβ protofibrils), and novel NSAIDs.

• NLRP3 inflammasome and P2X7 receptor axis: Activation of the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome by Aβ clusters triggers microglial activation, while purinergic receptor P2X7 (P2X7R) activation in microglia initiates neuroinflammation. Microglial autophagic degradation inhibits activation of the NLRP3 inflammasome, and thonningianin A promotes autophagic degradation of the NLRP3 inflammasome via AMPK/ULK1 and Raf/MEK/ERK signaling pathways.

• Autophagy-lysosomal and mTOR-TFEB regulation: Mammalian target of rapamycin kinase (mTOR), transcription factor EB (TFEB), and mTOR-TFEB axis regulate lysosomal biogenesis and autophagic flux. Cu(II) activates mTOR, inhibits TFEB expression and lysosomal biogenesis, and reduces microglial clearance of oligomeric β-amyloid (Aβo), an effect prevented by pharmacological antagonism of mTOR with PP242.

• Mitochondrial and mitophagy targets PINK1 and SIRT3: Impaired mitophagy results in accumulation of defective mitochondria in Alzheimer's disease. Aloe-emodin activates mitophagy through AMPK/PGC-1α/SIRT3 pathway, with changes in expression of Beclin1, LC3, P62, Parkin, and PINK1-related proteins and recovery of mitochondrial membrane potential, GSH, ROS and Ca2+ levels.

• ABCA1-mediated lipidation and nuclear receptor agonists: ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE) and impacts Aβ deposition and clearance via control of apoE lipidation. ABCA1 is transcriptionally regulated by Liver X Receptors (LXR) and Retinoic X Receptors (RXR), providing a starting point for synthetic LXR and RXR agonists.

• Synaptic plasticity targets: Synaptic scaffold protein PSD-95, CaMKII, brain-derived neurotrophic factor (BDNF) expression and TrkB signaling pathways, and GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) are explored as targets. Inhibiting over-activation of GluN2B-containing NMDARs upregulates CaMKIIα/BDNF/TrkB signaling and improves levels of synaptic proteins SYP and PSD-95, while sulforaphane enhances neuronal BDNF expression via HDAC inhibition.

Navigating the Evolving Alzheimer's Treatment Landscape

The past five years have marked a shift from symptom management to amyloid-targeting disease modification in early Alzheimer's disease. Lecanemab (BAN2401), a humanized IgG1 monoclonal antibody that binds with high affinity to Amyloid-β protofibrils, is the first monoclonal antibody for Alzheimer's disease to receive full FDA approval, while regulatory approvals for both lecanemab and donanemab in the United States have followed. Aducanumab, a human monoclonal antibody that selectively targets aggregated soluble amyloid beta oligomers and insoluble amyloid beta fibrils, was approved by the US Food and Drug Administration in June 2021 under the accelerated approval pathway. Across phase II and III randomized controlled trials, lecanemab reduced amyloid burden with 81% of patients achieving amyloid-negative PET scans (Clarity AD trial) and showed a 27% reduction in cognitive decline on the ADCOMS scale, donanemab demonstrated 76% plaque clearance and a 35% slowing in cognitive decline in early AD patients, and aducanumab showed dose-dependent effects on plaque clearance but had inconsistent cognitive outcomes. When pooled, data from high-clearance anti-amyloid immunotherapies trials confirm a statistically significant clinical effect on cognitive decline after 18 months (difference in cognitive decline measured with CDR-SB after 18 months between the high dose immunotherapy groups vs. placebo = -0.24 points; P=0.04, frequentist random-effect model).

This efficacy has been accompanied by amyloid-related imaging abnormalities (ARIA), including vasogenic edema (ARIA-E) and microhemorrhages/siderosis (ARIA-H). Pooled ARIA-E prevalence was 6.8% and ARIA-H was 15.8%, with anti-amyloid-β therapy significantly increasing odds of ARIA-E (OR 7.93; 95% CI 4.50-13.98) and ARIA-H (OR 1.87; 95% CI 1.28-2.72) versus placebo. The highest ARIA-E risk was seen with donanemab and aducanumab, followed by gantenerumab and lecanemab. APOE ε4 carriage significantly elevated ARIA-E (OR 2.28) and ARIA-H (OR 2.07) risk, with a clear gene-dose effect in homozygotes, and APOE4 homozygotes carriers were associated with a 5.53-fold (2.48 to 13.07) increased odds of developing ARIA-E compared to non-carriers. MRI, especially FLAIR and susceptibility-sensitive imaging, is essential for baseline risk stratification and monitoring, with key imaging biomarkers including microbleeds and superficial siderosis. Real-world cohorts reinforce this profile: in a single center in Eastern China including 76 early-stage AD participants treated with lecanemab, amyloid-related imaging abnormalities (ARIA) were observed in 11 participants, with solitary ARIA-H in 7 participants and ARIA-E with or without cerebral micro-hemorrhage in 4, while at Asan Medical Center among 105 at-risk patients who received at least four infusions and had at least one monitoring MRI, ARIA developed in 20 (19%): ARIA-E/H in 6 (5.7%) and isolated ARIA-H in 14 (13.3%).

The landscape is now extending toward preclinical intervention, biomarker-driven selection, and system-level implementation. TRAILBLAZER-ALZ 3 is investigating donanemab in preclinical Alzheimer's disease using a plasma phosphorylated tau-217 (p-tau217) assay to detect AD pathology for eligibility, screening participants 55-80 years of age (N = 63,124) and enrolling plasma p-tau217-eligible participants (N = 2196) with Clinical Dementia Rating scale-Global scores of 0 (n = 1202) and 0.5 (n = 664). Plasma P-tau217 and ADCS-PACC, individually and in combination, improved prediction of cognitive/functional decline in asymptomatic older adults, with the full model combining all predictor variables yielding the highest AUCs across A4 Solanezumab (0.80 ± 0.06), A4 Placebo (0.80 ± 0.06), and LEARN (0.78 ± 0.08). At the same time, non-amyloid approaches have not altered the course at scale: simufilam did not meet co-primary or secondary endpoints in two Phase 3 trials in mild-to-moderate AD, and Alzheimer's disease drug development has produced a 99.6 percent failure rate for disease-modifying compounds (244 compounds tested 2002-2012, one regulatory approval). In Korea, the rapid increase in treatment demand exceeded outpatient infusion capacity, resulting in progressively longer waiting times — up to 20 weeks 9 months after program initiation — highlighting the need for referral networks and risk-adapted MRI protocols before and during therapy.