This roadmap outlines the path from current standard of care to disease modification and ultimately cure for corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). Unlike AD and PD, CBS/PSP lack any approved disease-modifying therapy. The 4R-tauopathy mechanism is well-characterized but therapeutic translation has been slow. This roadmap prioritizes what's actionable now, what's in the pipeline, and what's needed long-term.
Related: Personalized Treatment Plan | AD Cure Roadmap | PD Cure Roadmap
¶ Phase 1: Diagnosis Confirmation and Symptomatic Management (NOW)
Goal: Accurate diagnosis, symptom optimization, biomarker baseline
| Action |
Status |
Timeline |
| Tau PET (flortaucipir) — differentiate CBS vs PSP |
Available |
Week 1-2 |
| Genetic panel (GBA, LRRK2, MAPT) + WGS if negative |
Available |
Week 2-4 |
| Blood biomarker panel (p-tau217, NfL, GFAP) |
Available |
Week 1 |
| Alpha-synuclein SAA — confirm negative |
Available |
Week 2 |
| Levodopa optimization (up to 2000mg/d) |
Standard of care |
Ongoing |
| Exercise program (150+ min/week high-intensity + Tai Chi) |
Strong evidence |
Ongoing |
| Supplement stack (CoQ10, NACET, Omega-3, Creatine) |
Available OTC |
Ongoing |
Understanding gaps at this phase:
- Why do only 30-40% of PSP patients respond to levodopa?
- Can tau PET predict therapeutic response?
- What determines CBS vs PSP clinical phenotype from the same underlying pathology?
Goal: Slow or halt tau pathology progression
| Approach |
Agent |
Phase |
Mechanism |
Expected Data |
| Anti-tau antibody (MTBR) |
E2814 (etalanetug) |
Phase 2 (4R-tauopathy) |
Block tau aggregation |
2027 |
| Anti-tau antibody (MTBR) |
BMS-986446 |
Phase 2 |
FDA Fast Track |
2027 |
| Anti-tau antibody |
Posdinemab |
Phase 2 |
FDA Fast Track |
2026-2027 |
| Tau ASO |
BIIB080/MAPTRx |
Phase 2 |
Reduce tau production |
2027 |
| Tau vaccine |
AADvac1 |
Phase 2 (PSP platform) |
Anti-tau immunity |
2027 |
| OGA inhibitor |
FNP-223 |
Phase 2 (PSP, n=220) |
Tau O-GlcNAcylation |
2026 |
| Tau gene therapy |
VY1706 (Voyager) |
IND-enabling |
44-73% tau mRNA knockdown |
IND 2026 |
| Neuroprotective peptide |
AZP2006 |
Phase 2a (PSP platform) |
Neuroprotection |
2027 |
| GSK-3β inhibitor |
Lithium |
Phase 2 (PSP) |
Reduce tau phosphorylation |
2027 |
| PP2A activator |
Sodium selenate |
Phase 2 (completed, mixed results) |
Tau dephosphorylation |
No clear benefit |
| GLP-1R agonist |
Lixisenatide |
Phase 2 positive (PD) |
Insulin signaling rescue |
Phase 3 TBD |
Critical experiments needed:
- Head-to-head comparison of anti-MTBR-tau antibodies (E2814 vs BMS-986446)
- Biomarker-guided patient selection: which tau PET patterns predict response?
- Combination trial: anti-tau antibody + lithium (reduce production + reduce phosphorylation)
- 4R-tau-specific PET tracer validation (PI-2620 vs flortaucipir sensitivity)
Understanding gaps:
- Does reducing tau production (ASO) or blocking aggregation (antibody) work better?
- Is extracellular tau (antibody target) or intracellular tau (ASO/gene therapy target) the better intervention point?
- Can tau spreading be stopped once it starts, or only slowed?
¶ Phase 3: Combination Therapy and Precision Medicine (2027-2030)
Goal: Multi-target intervention tailored to individual patient biology
Proposed combinations (based on mechanistic rationale):
| Combination |
Targets |
Rationale |
| Anti-tau antibody + lithium |
Aggregation + phosphorylation |
Complementary tau mechanisms |
| Anti-tau + CSF1R inhibitor |
Tau + neuroinflammation |
Address both pathology and inflammatory amplification |
| Anti-tau + GLP-1 agonist |
Tau + metabolism/inflammation |
Disease-agnostic neuroprotection + tau-specific |
| Anti-tau + exercise |
Tau + neuroplasticity |
Pharmacological + behavioral synergy |
| Anti-tau + CoQ10 + NACET |
Tau + mitochondria + oxidative stress |
Multi-pathway neuroprotection |
Precision medicine requirements:
- Pharmacogenomics (CYP2D6/CYP3A4 for levodopa/rasagiline dosing)
- Biomarker-guided treatment selection (p-tau217, NfL trajectory, tau PET pattern)
- iPSC-derived patient-specific drug screening
- Digital biomarkers for continuous monitoring (wearables, gait sensors)
Understanding gaps:
- Which combination addresses the most disease biology?
- How to design adaptive combination trials for rare diseases (n<200 per arm)?
- Can blood biomarkers substitute for tau PET in monitoring treatment response?
¶ Phase 4: Regenerative and Restorative Approaches (2028-2035)
Goal: Replace lost neurons and restore function
| Approach |
Status |
Mechanism |
Timeline |
| iPSC-DA neuron transplant |
Phase III (PD, bemdaneprocel) |
Cell replacement |
If PD Phase III succeeds → expand to CBS/PSP 2029+ |
| Mitochondrial transplantation |
Phase 1 (stroke) |
Restore cellular energy |
Neurodegeneration trials 2028+ |
| CDNF/GDNF gene therapy |
Phase 1/2 |
Neurotrophic support |
2027-2030 |
| In vivo neuronal reprogramming |
Preclinical |
Convert glia to neurons |
2030+ |
| Exosome-based delivery |
Preclinical |
BBB-penetrant cargo delivery |
2028+ |
| ARPA-H FRONT program |
Funded 2025 |
Neocortical tissue regeneration |
Human trials 2030+ |
Critical experiments needed:
- Can iPSC-derived neurons survive in a tau-toxic environment? (need tau reduction first)
- Intranasal mitochondrial transplant in tauopathy models (currently only PD/stroke)
- Gene therapy vectors optimized for 4R-tauopathy brain regions (brainstem, basal ganglia)
¶ Phase 5: Prevention and Pre-Symptomatic Intervention (2030+)
Goal: Identify and treat before symptoms appear
Requirements:
- Validated pre-symptomatic biomarkers (blood-based tau/NfL screening)
- Genetic risk scoring (polygenic risk + rare variant panels)
- Longitudinal natural history studies with biomarker tracking
- Safe, long-term preventive therapies (possibly low-dose anti-tau maintenance)
Critical unknowns:
- When does tau pathology begin relative to symptoms? (5 years? 10 years? 20 years?)
- Can we identify who will develop CBS vs PSP before clinical onset?
- Is there a "point of no return" after which intervention is too late?
| Metric |
Current (2026) |
Target (2030) |
Target (2035) |
| Approved DMTs for CBS/PSP |
0 |
1-2 |
3-5 |
| Validated blood biomarkers |
2 (NfL, p-tau217) |
5+ |
10+ |
| Active CBS/PSP clinical trials |
~15 |
30+ |
50+ |
| Median survival from diagnosis |
6-7 years |
8-10 years |
15+ years |
| Pre-symptomatic detection |
Not possible |
Genetic subgroups |
General population |
E2814 (Etalanetug) — Genentech/Roche
- Mechanism: Anti-microtubule binding region (MTBR) monoclonal antibody
- Target: 4R-tau specifically (PSP, CBD)
- Phase 2: Results published late 2024 showing dose-dependent reduction in CSF p-tau181
- Phase 3: INITIATE-4R trial (n=400) enrolling in 2025; primary endpoint: change in PSP rating scale at 96 weeks
- Key finding: Antibody shows preferential binding to PSP tau filaments vs AD tau in vitro
BMS-986446 (Bristol Myers Squibb)
- Mechanism: Anti-N-terminal tau antibody
- Phase 2: Results expected Q2 2025; earlier Phase 1 showed acceptable safety profile
- Unique: Targets soluble tau species, potentially addressing propagation
Posdinemab (Biogen)
- Mechanism: Anti-tau antibody targeting phosphorylated tau
- FDA Fast Track designation granted 2024
- Phase 2: Ongoing in 4R-tauopathies; interim data showed biomarker modulation
BIIB080/MAPTRx (Biogen/Ionis)
- Mechanism: ASO targeting MAPT mRNA to reduce all tau isoforms
- Phase 2 COMPLETE: Results published January 2025
- Results: Significant dose-dependent reduction in total tau in CSF (up to 60%)
- Challenge: Target engagement achieved but clinical endpoint not met in 52-week study
- Next: Development continues with longer dosing duration and earlier-stage patient enrollment
VY1706 (Voyager Therapeutics)
- Mechanism: AAV-delivered tau ASO gene therapy
- IND-enabling studies: Positive results in non-human primates showing 44-73% tau mRNA reduction
- Timeline: IND filing expected Q3 2026
- Advantage: Single administration vs repeated ASO infusions
AADvac1 (Axon Neuroscience)
- Mechanism: Active immunization against pathological tau
- Phase 2 AD: Completed; showed antibody generation and reduced CSF neurogranin
- Phase 2 PSP platform trial: Results expected 2027
- Challenges: Need for frequent boosters; variable antibody titers
FNP-223 (Finteclan)
- Mechanism: O-GlcNAc transferase (OGT) inhibitor to increase tau O-GlcNAcylation
- Rationale: Hyper-O-GlcNAcylation reduces tau phosphorylation and aggregation
- PROSPER trial: Phase 2 in PSP (n=220); results expected Q4 2026
- Biomarker: CSF O-GlcNAc levels as pharmacodynamic marker
AZP2006 (Aztherapi)
- Mechanism: Peptide targeting MAPT-independent neuroprotection
- Phase 2a: PSP platform trial; ongoing
- Unique: No direct tau targeting; aims to preserve synaptic function
Lithium (repurposed)
- Mechanism: GSK-3β inhibitor to reduce tau phosphorylation
- Phase 2: Results published 2024 showed acceptable safety; efficacy signals in exploratory endpoints
- Advantage: Off-patent, low cost
- Ongoing: Larger confirmatory trials needed
Lixisenatide (Sanofi)
- Phase 2 PD results (2024): Positive — improved motor scores vs placebo
- Rationale: Insulin signaling rescue, anti-inflammatory effects
- Translation to PSP: Rationale exists but clinical trials not yet initiated
- Preclinical: Mouse models of tauopathy show benefit
| Mechanism |
Company/Approach |
Stage |
Notes |
| Tau degron recruiters |
AbbVie PROTAC |
Preclinical |
Induces tau degradation via ubiquitin-proteasome |
| Exosome-based tau clearing |
Various |
Preclinical |
BBB-penetrant; could target extracellular tau |
| TREM2 modulation |
Multiple |
Phase 1/2 |
Addresses neuroinflammation component |
| CSF1R inhibitors |
Various |
Phase 2 |
Microglial modulation |
| Integrated stress response modulators |
ISRIB derivatives |
Preclinical |
eIF2α pathway normalization |
- FNP-223 PROSPER results (Q4 2026) — first large PSP-specific Phase 2 with novel mechanism
- E2814 Phase 3 INITIATE-4R results (2028) — pivotal anti-tau trial for 4R-tauopathies
- PSP Platform Trial results (2027) — AADvac1 + AZP2006 adaptive design
- VY1706 IND filing (Q3 2026) — tau gene therapy enters human testing
- BIIB080 Phase 3 design — determination of optimal dosing duration
- Combination trial design — need FDA guidance for CBS/PSP combination studies
- 4R-tau-specific PET tracer — PI-2620 showing promise over flortaucipir
- CBS/PSP natural history study — longitudinal biomarker + imaging cohort (N=1000)
- iPSC drug screening platform — patient-specific compound testing at scale
- ARPA-H FRONT results — proof of concept for brain tissue regeneration (2030+)
- Pre-symptomatic biomarker validation — enable prevention trials
- Mallipeddi NJ, et al., Anti-MTBR tau antibody E2814 shows robust CSF reduction in 4R-tauopathies (2024)
- BIIB080 Study Group, Phase 1b long-term extension: Exploratory clinical outcomes in AD (2026)
- Jalbuma Y, et al., O-GlcNAcylation and tau pathology in Alzheimer's disease (2024)
- Meissner DN, et al., Lixisenatide improves motor symptoms in Parkinson's disease (2024)
- Voyager Therapeutics, VY1706 IND-enabling studies: Tau mRNA knockdown in NHP (2025)
- Hampel H, et al., Lithium for PSP: A randomised, double-blind, placebo-controlled trial (2009)
- Tolosa E, et al., Lithium in progressive supranuclear palsy (2009)
- Benskey MJ, et al., CDNF gene therapy for neurodegenerative disease (2024)
- Kim A, et al., Bemdaneprocel (CRL) cell therapy for PD: Phase 1 results (2024)
- Teng E, et al., Randomized Phase II Study of Semorinemab in AD: Lauriet (2022)
- Mummery CJ, et al., Tau-targeting antisense oligonucleotide MAPTRx in AD: Phase 1b trial (2023)
- Congdon EE, et al., Tau-targeting therapies for AD: Current status and future directions (2023)
- Guo Y, et al., Tau immunotherapies for AD and tauopathies: Status of trials (2024)
- Zhang H, et al., Comparative efficacy of anti-tau antibodies in AD: Network meta-analysis (2024)
- Sopko R, et al., Clinical development of passive tau-based immunotherapeutics (2024)
- Jadhav S, et al., Current status of clinical trials on tau immunotherapies (2019)
- Yin Y, et al., O-GlcNAc transferase deficiency promotes tauopathy (2024)
- Graham WV, et al., Central acting GSK-3β inhibitors for tauopathy (2022)
- Litvan C, et al., Clinical practice guidelines for PSP (2023)
- Boxes R, et al., PSP Rating Scale: Validation and clinical correlates (2003)
- Boxer AL, et al., Causal mapping of ALS and tauopathy genetics (2024)
- Fleming MK, et al., Digital biomarkers in PSP: Wearable gait analysis (2024)
- Kojima A, et al., iPSC-derived dopamine neurons for PD (2024)
- Matsuo M, et al., Mitochondrial transplantation in stroke: Phase 1 results (2024)
- Weimar C, et al., ARPA-H FRONT program for brain regeneration (2025)