---
type: entity
entity_type: research_program
name: Exenatide-PD3 Trial
domain: health
status: completed
supports:
- GLP-1 Parkinson's efficacy divergence between lixisenatide Phase 2 success and exenatide Phase 3 failure suggests disease stage and regional CNS penetrance are confounding variables not captured by class-level analysis
related:
- Lixisenatide halts motor symptom progression in early Parkinson's disease at 12 months in Phase 2 trial but faces >50% GI side effect rate limiting real-world viability
reweave_edges:
- GLP-1 Parkinson's efficacy divergence between lixisenatide Phase 2 success and exenatide Phase 3 failure suggests disease stage and regional CNS penetrance are confounding variables not captured by class-level analysis|supports|2026-05-09
- Lixisenatide halts motor symptom progression in early Parkinson's disease at 12 months in Phase 2 trial but faces >50% GI side effect rate limiting real-world viability|related|2026-05-09
---

# Exenatide-PD3 Trial

**Type:** Phase 3 randomized controlled trial  
**Drug:** Exenatide (GLP-1 receptor agonist)  
**Indication:** Parkinson's disease (disease-modifying therapy)  
**Design:** Multicenter, double-blind, placebo-controlled, n=194, 96 weeks  
**Sites:** 6 UK research hospitals  
**Funding:** National Institute for Health and Care Research (NIHR)  
**Primary Endpoint:** Movement symptom progression (motor function)  
**Status:** Failed (February 2025)

## Overview

Exenatide-PD3 was the largest and longest GLP-1 receptor agonist trial in Parkinson's disease to date. It tested whether exenatide once-weekly could slow disease progression by providing neuroprotection to dopaminergic neurons in the substantia nigra.

## Results

**Primary endpoint:** FAILED — exenatide did not stop movement symptoms from worsening over 96 weeks versus placebo.

**Secondary endpoints:** FAILED — no benefit in non-motor symptoms (quality of life, cognition, mood) compared to placebo.

**DaT-SPECT imaging:** No significant change versus placebo. This biomarker tracks dopaminergic neuron degeneration; zero signal indicates no neuroprotection at the structural level.

**CSF analysis (mechanistic finding):** Only small amounts of exenatide reached the substantia nigra, the brain region affected by Parkinson's. This suggests insufficient CNS penetration to the target region, despite exenatide crossing the blood-brain barrier in other areas.

## Context

This trial directly contradicts earlier Phase 2 work (Foltynie group, n=59) which showed significant motor benefit at 9 months (P=0.001). The Phase 3 failure raises questions about:
- Phase 2 selection bias or underpowering
- Regional brain penetrance as the limiting factor (not BBB crossing per se)
- Whether the Phase 2 signal was spurious

## Implications

The failure complicates the GLP-1 neuroprotection hypothesis. Two other GLP-1 agonists (semaglutide, liraglutide) remain in ongoing Phase 3 trials for Parkinson's. The CSF finding suggests that different GLP-1 agonists with distinct CNS penetration mechanisms (e.g., semaglutide via albumin binding → tanycytes) may achieve different substantia nigra concentrations and potentially different outcomes.

## Expert Response

Dr. Katherine Fletcher (Parkinson's UK): "Really disappointing news" and "a setback." Concerns raised that the failure may impact funding for other GLP-1 trials in Parkinson's.

## Timeline

- **2025-02-04** — Phase 3 results published in The Lancet: all endpoints failed, CSF analysis reveals insufficient substantia nigra penetration

## References

- The Lancet, February 4, 2025: [Exenatide-PD3 Phase 3 Results](https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)02808-3/fulltext)
- Parkinson's UK press response, February 2025