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# Practical Feasibility Assessment: CSF p-tau217 as Surrogate Endpoint for Donanemab Cessation

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## Executive Summary

Of the seven hypotheses, three demonstrate sufficient plausibility to warrant development investment (H1, H2, H6). The remaining four (H3, H4, H5, H7) have critical feasibility barriers that make near-term clinical implementation unlikely. The composite biomarker approach—using p-tau217 as the primary endpoint while incorporating vascular imaging to stratify patients—is the most practical near-term solution.

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## Viable Hypotheses: Detailed Assessment

### Hypothesis 1: Kinase Activity Reduction (Revised: 0.52)

**Druggability Assessment:**
GSK3β and CDK5 are established drug targets, but this hypothesis proposes p-tau217 *measurement* as a proxy for kinase activity reduction—not kinase inhibition as a therapeutic strategy. This is critical: the practical question is whether we can *use* p-tau217 as a surrogate for an unmeasured biological process.

| Dimension | Assessment |
|-----------|------------|
| Target validation | GSK3β/CDK5 are validated enzyme targets with known crystal structures; however, pathway from amyloid clearance to kinase activity reduction is inferred |
| Assay feasibility | Current CSF p-tau217 assays (Janssen, ALZpath, Roche) are commercially available and CLIA-validated; no direct kinase activity assay in CSF exists |
|Mechanism-to-marker gap | Significant: p-tau217 reflects multiple processes (phosphorylation rate + release + clearance), not specifically kinase activity |

**Existing Compounds:**
- GSK3β inhibitors: Tideglusib (Phase II completed, no efficacy), BIIB080 (IONSTRIKKER, currently in trials) — none show p-tau217 modulation independent of amyloid effects
- CDK5 inhibitors: No clinical-stage compounds due to safety concerns (CDK5 is essential for neuronal development); research compounds only

**Development Cost/Timeline:**
- To validate the proxy relationship: Requires longitudinal study measuring p-tau217 alongside novel kinase activity biomarkers in donanemab-treated patients
- Estimated cost: $15-25M (requires bespoke assay development)
- Timeline: 4-6 years to establish whether p-tau217 reliably reflects kinase activity status
- Regulatory pathway: Would require qualification through FDA's Biomarker Qualification Program

**Safety Concerns:**
- Not applicable to measurement use; the concern is that relying on a proxy whose mechanistic basis is weak creates risk of false cessation decisions
- If p-tau217 normalizes but kinase activity remains elevated (due to non-amyloid drivers), treatment cessation would be premature

**Practical Verdict:** **Marginal viability.** The mechanistic chain is too weak to justify cessation decisions based on this hypothesis alone. However, p-tau217 remains valid as an endpoint given its empirical correlation with treatment response—regardless of whether the GSK3β/CDK5 explanation is correct.

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### Hypothesis 2: Temporal Dissociation (Revised: 0.51)

**Druggability Assessment:**
This hypothesis concerns biomarker kinetics, not a therapeutic target. The "druggability" question is whether the temporal differential can be exploited for earlier cessation.

| Dimension | Assessment |
|-----------|------------|
| Clinical utility | High: Earlier cessation reducesARIA risk, treatment burden, and cost |
| Mechanistic basis | Weak: Kinetic differential may be assay-driven rather than biology-driven |
| Regulatory precedent | Strong: FDA has accepted biomarker-based endpoints for drug approval (Aduhelm accelerated approval based on amyloid PET) |

**Existing Evidence:**
- TRAILBLAZER-ALZ 2: Plasma p-tau217 declined significantly faster than amyloid PET SUVR
- TRAILBLAZER-ALZ (first trial): CSF p-tau217 showed treatment effects at 24 weeks before amyloid PET effects plateaued
- Phase 3 READOUT-PRO (Janssen): Plasma p-tau217 trajectory used for interim analysis

**Development Cost/Timeline:**
- No new assay development required; existing LUMIPULSE and Simoa p-tau217 assays are validated
- Statistical validation: Requires formal non-inferiority analysis comparing clinical outcomes in patients stopped at p-tau217 threshold vs. amyloid PET threshold
- Estimated cost: $20-30M (primarily trial extension/follow-up)
- Timeline: 3-4 years if leveraging existing TRAILBLAZER-ALZ 2 long-term extension data
- FDA engagement: Pre-submission meeting recommended; FDA may require 2-year post-cessation follow-up data

**Safety Concerns:**
- ARIA-E incidence peaks at 12-24 weeks; earlier cessation reduces risk but must be weighed against potential for undertreatment
- If p-tau217 normalization occurs before meaningful downstream effect, some patients may stop while still benefiting
- Missing long-term data: What happens to patients who stop at p-tau217 normalization but have persistent low-level amyloid?

**Practical Verdict:** **High viability.** This is the most immediately actionable hypothesis. The empirical data support faster p-tau217 decline kinetics, and the practical benefit (earlier cessation) is substantial. The mechanism doesn't need to be proven—only that cessation at p-tau217 threshold produces non-inferior outcomes compared to PET-based cessation.

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### Hypothesis 6: Vascular Amyloid Reservoir (Revised: 0.55)

**Druggability Assessment:**
This hypothesis is not about drug development but about *patient stratification*. CAA is not proposed as a therapeutic target, but as a confounder that must be measured.

| Dimension | Assessment |
|-----------|------------|
| Clinical utility | High: Identifies patients who may not achieve complete p-tau217 normalization |
| Diagnostic infrastructure | MRI (SWI for microbleeds), PET (CAA-R) exist but add cost and complexity |
| Mechanistic basis | Moderate: APOE ε4 correlation with delayed p-tau217 normalization is consistent across studies |

**Existing Tools:**
- MRI: SWI for lobar microbleeds (MRC-L/MRI protocol), 7T vessel wall imaging for leptomeningeal CAA
- PET: 11C-Pittsburgh B binding to vascular amyloid; ^18F-flutemetamol shows some CAA signal
- Fluid biomarkers: CSF sTREM2 (microglial activation), plasma GFAP (correlates with CAA in some studies)

**Development Cost/Timeline:**
- CAA stratification can be incorporated into existing trial designs with minimal additional cost
- Proposed composite cessation criteria:
  - p-tau217 < threshold (e.g., 80% reduction from baseline)
  - Amyloid PET < 24 CL (centiloids) — optional
  - No high-risk CAA features (≥3 lobar microbleeds, superficial siderosis)
- Estimated cost: $5-10M (for analysis of existing cohorts stratified by baseline CAA)
- Timeline: 2-3 years if analyzed within ongoing donanemab extension studies

**Safety Concerns:**
- Patients with CAA may have higher ARIA-E risk; earlier cessation may increase this risk if vascular amyloid is still present
- APOE ε4 carriers have higher CAA burden and higher ARIA risk—cessation criteria may need to be more conservative in this subgroup
- If cessation occurs with residual vascular amyloid, downstream tau pathology may continue

**Practical Verdict:** **High viability with caveats.** This hypothesis provides a practical framework for identifying patients who need extended treatment or alternative monitoring. The mechanistic uncertainty (does vascular amyloid actually drive ongoing tau pathology?) is less important than the empirical observation (APOE ε4 carriers have delayed p-tau217 normalization). Adopt as exclusionary/conditional criterion rather than absolute cessation requirement.

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## Non-Viable Hypotheses: Brief Assessment

### Hypothesis 3: Axonal Integrity (0.40) — **Reject**

| Issue | Impact |
|-------|--------|
| Temporal mismatch | NfL normalization lags p-tau217 by 6-12 months; mechanism doesn't fit data |
| Source confusion | CSF tau derives from extracellular release, not axonal transport |
| No intervention target | Nothing to "drug" here; biomarker only |

**Verdict:** Conceptually appealing but mechanistically incoherent. Do not pursue.

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### Hypothesis 4: Personalized Thresholds (0.35) — **Reject**

| Issue | Impact |
|-------|--------|
| Half-life unmeasurable | No validated method to quantify individual p-tau217 turnover rates |
| Assay floor effect | Below ~10 pg/mL, measurement variance exceeds biological signal |
| Non-linear trajectories | Individual trajectories don't follow predictable decline curves |

**Verdict:** Operationally infeasible with current technology. The concept is scientifically sound but cannot be implemented. Revisit if SILK-based kinetic studies demonstrate reliable half-life quantification.

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### Hypothesis 5: Neurogranin Co-Normalization (0.44) — **Reject for Individual Requirement**

| Issue | Impact |
|-------|--------|
| Non-concordant kinetics | Neurogranin normalizes slower; would extend treatment unnecessarily |
| No established threshold | No consensus on what constitutes "normalized" neurogranin |
| Mechanistic independence | Synaptic and tau pathology have independent drivers |

**Revised approach:** Use neurogranin as a *secondary confirmation* biomarker rather than a co-equal requirement. A composite synaptic-health score could replace binary co-normalization requirement. This is more feasible and reflects current thinking in the field (e.g., ATN framework).

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### Hypothesis 7: Isoform Shift (0.48) — **Reject**

| Issue | Impact |
|-------|--------|
| Detection technology doesn't exist | No validated assay distinguishing disease-specific from physiological p-tau217 |
| Conformational assumption unproven | No evidence that amyloid-driven tau has distinct conformations detectable in CSF |
| Development timeline | 10+ years to develop, validate, and clinical-test such an assay |

**Verdict:** Interesting mechanistic hypothesis but not actionable within any reasonable development timeline. Defer to academic investigation.

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## Recommended Development Pathway

### Phase 1 (Years 1-2): Validation Using Existing Data

**Primary activity:** Analyze TRAILBLAZER-ALZ 2 and TRAILBLAZER-ALZ extension data to validate:
- p-tau217 threshold for cessation (receiver-operating characteristic analysis for predicting amyloid PET <24 CL)
- CAA stratification criteria (APOE ε4 status, MRI microbleed burden)
- Long-term outcomes in patients who met proposed cessation criteria

**Cost:** $3-5M (data analysis, regulatory consultation)

### Phase 2 (Years 2-4): Prospective Validation

**Primary activity:** Design Phase 4 study or pragmatic trial:
- Randomized withdrawal design: Stop treatment at p-tau217 threshold vs. amyloid PET threshold
- Primary outcome: 2-year cognitive trajectory
- Secondary outcomes: ARIA incidence, biomarker trajectories post-cessation

**Cost:** $40-60M (assuming 500-800 patients, 2-year follow-up)

**Regulatory engagement:** Pre-IND meeting with FDA to discuss surrogate endpoint qualification pathway

### Phase 3 (Years 4-6): Regulatory Submission

**Goal:** Develop p-tau217-based cessation criteria for inclusion in product label

**Required evidence:**
- Non-inferior clinical outcomes compared to PET-based cessation
- Consistent effect across APOE ε4 subgroups (with appropriate caveats)
- Safety data from patients who stopped at p-tau217 threshold with varying CAA burden

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## Composite Cessation Algorithm (Proposed)

```
CESSATION ELIGIBILITY CHECKLIST:
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
□ MRI: No high-risk CAA features
  (≤2 lobar microbleeds, no cortical superficial siderosis)
  
□ CSF/Plasma p-tau217: ≥75% reduction from baseline
  AND absolute value below assay-specific threshold
  
□ (Optional) Amyloid PET: <30 CL
  [Not required if p-tau217 criteria met,
   but recommended in ambiguous cases]

□ Clinical stability: No significant decline on
  co-primary cognitive measures over 6 months
  
□ APOE ε4 carriers: Consider more conservative
  p-tau217 threshold (e.g., ≥80% reduction)
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
STOPPING CRITERIA: All conditions met
CONTINUING CRITERIA: p-tau217 not normalized but amyloid PET <30 CL
CESSATION INADVISABLE: High-risk CAA features present
```

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## Final Practical Assessment Matrix

| Hypothesis | Practical Viability | Development Cost | Timeline | Recommendation |
|------------|---------------------|------------------|----------|----------------|
| H1: Kinase activity | Low | $15-25M | 4-6 yr | Monitor research; not actionable |
| H2: Temporal dissociation | **High** | $20-30M | 3-4 yr | **Priority investment** |
| H3: Axonal integrity | Rejected | N/A | N/A | Abandon |
| H4: Personalized thresholds | Rejected | N/A | N/A | Abandon (await technical advances) |
| H5: Neurogranin co-validation | Low (revise approach) | $10-15M | 3-4 yr | Use as composite score, not binary requirement |
| H6: Vascular amyloid | **High** | $5-10M | 2-3 yr | **Priority investment** (stratification criterion) |
| H7: Isoform shift | Rejected | N/A | N/A | Abandon (technology gap) |

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## Bottom Line

The practical path forward is **H2 + H6**: Use p-tau217 as the primary cessation criterion (leveraging its empirically faster decline kinetics) while incorporating CAA stratification (via MRI and APOE genotyping) to identify patients who may need extended treatment or alternative monitoring. This composite approach addresses the mechanistic uncertainties through pragmatic stratification rather than requiring proof of every mechanistic claim.

Estimated total development investment: **$35-50M over 4-6 years** to generate data sufficient for regulatory discussion and potential label update.