This Phase 1 trial investigates the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7812653 following intrathecal administration in participants with early symptomatic Alzheimer's disease (eAD). The study is sponsored by Hoffmann-La Roche (also known as Roche) and represents an early-stage therapeutic approach targeting AD through direct CNS delivery.
RO7812653 is an investigational antibody-based therapeutic that targets a novel epitope in Alzheimer's disease pathology. The intrathecal delivery route represents an innovative approach to overcome the blood-brain barrier and achieve therapeutic concentrations in the CNS.
This Phase 1 trial investigates the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7812653 following intrathecal administration in participants with early symptomatic Alzheimer's disease (eAD). The study is sponsored by Hoffmann-La Roche (also known as Roche) and represents an early-stage therapeutic approach targeting AD through direct CNS delivery.
RO7812653 is an investigational antibody-based therapeutic that targets a novel epitope in Alzheimer's disease pathology. The intrathecal delivery route represents an innovative approach to overcome the blood-brain barrier and achieve therapeutic concentrations in the CNS.
| Field | Value |
|-------|-------|
| NCT ID | [NCT07234942](https://clinicaltrials.gov/study/NCT07234942) |
| Status | Recruiting |
| Phase | Phase 1 |
| Enrollment | 50 participants (estimated) |
| Sponsor | Hoffmann-La Roche |
| Design | Randomized, double-blind, placebo-controlled, parallel group |
| Masking | Quadruple (participant, care provider, investigator, outcomes assessor) |
| Start Date | January 27, 2026 |
| Primary Completion | April 19, 2028 (estimated) |
| Study Completion | March 5, 2030 (estimated) |
| Route | Intrathecal administration |
| Phase | Description | Duration |
|-------|-------------|----------|
| Screening | Assessment of eligibility | 4 weeks |
| Treatment | Single ascending dose (SAD) or multiple ascending dose (MAD) | Up to 12 weeks |
| Follow-up | Safety and pharmacokinetic assessment | Up to 40 weeks |
Current FDA-approved AD therapeutics face significant challenges:
The intrathecal (IT) delivery approach offers several potential advantages[@intrathecal]:
| Advantage | Description |
|-----------|-------------|
| Bypasses BBB | Direct delivery to cerebrospinal fluid (CSF) |
| Lower dose required | ~10-100x lower doses than IV administration |
| Reduced systemic exposure | Lower risk of peripheral side effects |
| Direct CNS targeting | Higher drug concentrations at target site |
| Reduced ARIA risk | Lower systemic antibody exposure |
The intrathecal delivery of therapeutics must account for CSF dynamics[@cgfriver]:
Therapeutics delivered intrathecally must navigate these dynamics to achieve adequate brain parenchymal penetration.
| Arm | Treatment | Route | Dose | Schedule |
|-----|-----------|-------|------|-----------|
| Active - Low Dose | RO7812653 | Intrathecal | Low | Single dose |
| Active - Mid Dose | RO7812653 | Intrathecal | Mid | Single dose |
| Active - High Dose | RO7812653 | Intrathecal | High | Single dose |
| Placebo | Saline solution | Intrathecal | N/A | Matching schedule |
The study uses a single ascending dose (SAD) design with sequential escalation:
| Endpoint | Description | Assessment Timepoint |
|----------|-------------|---------------------|
| Safety | Incidence and severity of adverse events (AEs) | Up to ~40 weeks |
| Tolerability | Discontinuations due to AEs | Up to ~40 weeks |
| Suicidality | C-SSRS score change from baseline | Up to ~40 weeks |
| Endpoint | Description | Timepoint |
|----------|-------------|-----------|
| PK - Plasma | Plasma concentration of RO7812653 | Up to 40 weeks |
| PK - CSF | CSF concentration of RO7812653 | Up to 40 weeks |
| Immunogenicity | Anti-drug antibody (ADA) presence | Up to 40 weeks |
| Location | Institution | Status |
|----------|-------------|--------|
| Amsterdam, Netherlands | Brain Research Center Amsterdam | Recruiting |
| London, UK | National Hospital For Neurology and Neurosurgery | Recruiting |
Additional sites may be added during the trial.
While specific details of RO7812653's molecular target are proprietary, the development of intrathecal antibody therapeutics for AD generally targets:
| Target Category | Description |
|-----------------|-------------|
| Amyloid-beta | Anti-Aβ antibodies to reduce plaque burden |
| Tau | Anti-tau antibodies to reduce neurofibrillary tangles |
| Novel targets | New therapeutic modalities (e.g., apoE, synaptic proteins) |
| Biomarker | Sample | Purpose |
|-----------|--------|---------|
| Aβ40/Aβ42 | CSF | Amyloid plaque dynamics |
| Total tau | CSF | Neurodegeneration marker |
| Phosphorylated tau (p-tau) | CSF | Tau pathology |
| Neurofilament light chain (NfL) | CSF/Plasma | Axonal injury[@neurofilament] |
| Biomarker | Sample | Purpose |
|-----------|--------|---------|
| Red blood cells in CSF | CSF | Meningeal hemorrhage |
| Protein in CSF | CSF | Infection/inflammation |
| Glucose in CSF | CSF | Infection/metabolism |
| Drug | Company | Target | Phase | Status |
|------|---------|--------|-------|--------|
| RO7812653 | Roche | TBD | Phase 1 | Recruiting |
| Lecanemab (LEQEMBI) | Eisai/Biogen | Aβ protofibrils | Approved (IV) | Launched |
| Donanemab | Eli Lilly | Aβ plaque | Phase 3 (IV) | Filing |
| Gantenerumab | Roche | Aβ plaque | Phase 3 (IV) | Discontinued |
| Crenezumab | Roche | Aβ oligomers | Phase 2 | Discontinued |
| Approach | Description | Development Stage |
|----------|-------------|------------------|
| Intrathecal antibodies | Direct CNS delivery | Phase 1-2 |
| Intranasal delivery | Nose-to-brain pathway | Preclinical-Phase 1 |
| Focused ultrasound | BBB opening for IV delivery | Phase 2 |
| AAV gene therapy | CNS expression of therapeutic proteins | Preclinical |
| Risk | Description | Mitigation |
|------|-------------|------------|
| Spinal headache | CSF leak causing positional headache | Bed rest post-procedure |
| Infection | Meningitis risk | Sterile technique |
| Bleeding | Spinal hematoma | Pre-procedure coagulation check |
| Nerve injury | Transient neurological symptoms | Expert administration |
| Brain herniation | Rare complication with mass effect | MRI screening |
| Event | Expected Frequency | Management |
|-------|-------------------|------------|
| Post-LP headache | 10-20% | Hydration, caffeine |
| Back pain | 5-10% | Analgesics |
| Nausea | 3-5% | Anti-emetics |
| CSF pleocytosis | Rare | Monitoring |
| Infection | Very rare | Sterile technique |
The trial is actively recruiting as of March 2026. The trial initiated in January 2026 and is expected to complete primary endpoints by April 2028, with full study completion in March 2030.
Milestones:
The following diagram shows the key molecular relationships involving RO7812653 for Early Symptomatic Alzheimer's Disease discovered through SciDEX knowledge graph analysis: