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Exenatide-PD3

Exenatide once a week versus placebo as a potential disease-modifying treatment for people with Parkinson's disease in the UK: a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial

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Year of Publication: 2025

Authors: Vijiaratnam N, Girges C, Auld G, ..., Foltynie T

Journal: The Lancet

Citation: Lancet 2025;405:627-36

Link: https://doi.org/10.1016/S0140-6736(24)02808-3

Clinical Question

Does weekly extended-release exenatide 2 mg slow the rate of motor progression in people with moderate Parkinson's disease compared to placebo over 96 weeks?

Bottom Line

In this phase 3 trial of 194 participants with moderate Parkinson's disease, exenatide 2 mg weekly for 96 weeks was safe and well tolerated but showed no evidence of disease-modifying benefit on motor progression or any secondary outcomes compared to placebo, in contrast to earlier positive phase 2 trials.

        Major Points
        First large, long-duration phase 3 trial of exenatide in Parkinson's disease (96 weeks treatment)
No significant difference in primary outcome: MDS-UPDRS part III OFF-medication worsened by 5.7 points (exenatide) vs 4.5 points (placebo); adjusted coefficient 0.92 (95% CI -1.56 to 3.39, p=0.47)
No benefits in any secondary outcomes including motor ON scores, cognition, quality of life, or DaT-SPECT imaging
Subgroup analyses by age, sex, age at diagnosis, and H&Y stage showed no differential effects
95% of participants with CSF tested positive for α-synuclein SAA
Exenatide safe with similar serious adverse events (9% vs 11%)
More GI symptoms and weight loss in exenatide group (1.8 kg vs 1.3 kg loss)
CSF exenatide concentration ~1% of plasma levels, raising CNS penetration questions

      

Design

Study Type: Phase 3 randomized controlled trial

Randomization: 1

Blinding: Double-blind

Enrollment Period: January 23, 2020 to April 23, 2022

Follow-up Duration: 96 weeks

Centers: 6

Countries: United Kingdom

Sample Size: 194

Analysis: Intention-to-treat using linear mixed-effects model with random site and patient effects

Inclusion Criteria

Age 25-80 years
Diagnosis of Parkinson's disease meeting Queen Square Brain Bank criteria
Hoehn and Yahr stage ≤2.5 when on dopaminergic treatment
On dopaminergic treatment for at least 4 weeks
Able to self-administer investigational medicinal product

Exclusion Criteria

Suspicion of another cause for parkinsonism
BMI <18.5 kg/m²
MoCA score <21
PHQ-9 score ≥16
Previous exposure to exenatide
Impaired renal function (creatinine clearance <50 mL/min)
History of pancreatitis
Type 1 or type 2 diabetes
Severe gastrointestinal disease
Previous intracerebral neurosurgical intervention for PD

Arms

Field	Control	Exenatide
Intervention	Visually identical placebo by subcutaneous pen injection once per week	Extended-release exenatide 2 mg by subcutaneous pen injection once per week
Duration	96 weeks	96 weeks

Outcomes

Outcome	Type	Control	Intervention	P-value
MDS-UPDRS part III score OFF-medication at 96 weeks	Primary	Worsened by 4.5 points (SD 11.4)	Worsened by 5.7 points (SD 11.2)	0.47
MDS-UPDRS part III ON-medication at 96 weeks	Secondary	Worsened by 4.6 (8.9)	Worsened by 5.7 (11.3)	0.55
MoCA at 96 weeks	Secondary	Improved by 0.1 (1.9)	Worsened by 0.1 (2.0)	0.39
PDQ-39 summary index at 96 weeks	Secondary	Worsened by 1.3 (8.9)	Worsened by 1.5 (8.5)	0.49
DaT-SPECT striatal binding ratio change	Secondary	No difference	No difference between groups	Not significant
Serious adverse events	Adverse	11/97 (11%)	9/97 (9%)
Any adverse event	Adverse	92/97 (95%)	96/97 (99%)
Nausea	Adverse	20 events	51 events
Anorexia	Adverse	7 events	33 events
Serum amylase increased	Adverse	1/97 (1%)	9/97 (9%)

Subgroup Analysis

Preplanned subgroup analyses by age (<60 years), sex, age at diagnosis (<55 years), and H&Y stage showed no significant differences. Post-hoc analysis among α-synuclein SAA-positive participants showed no difference.

Criticisms

Recruitment 6 participants short of target (194 vs 200) due to COVID-19 and drug expiry
Only 66/194 had CSF collected for α-synuclein SAA
93% White population limits generalizability
Excluded patients with type 2 diabetes who may benefit more
CSF exenatide ~1% of plasma levels - inadequate CNS penetration?
Differential weight loss may have compromised blinding
Results contradict prior positive phase 2 trials without clear explanation

Funding

NIHR (EME scheme 16/167/19), Cure Parkinson's, AstraZeneca (provided drug)

Based on: Exenatide-PD3 (The Lancet, 2025)

Authors: Vijiaratnam N, Girges C, Auld G, ..., Foltynie T

Citation: Lancet 2025;405:627-36

Content summarized and formatted by NeuroTrials.ai.

Exenatide-PD3

(2025)

Objective

To establish whether exenatide could slow the rate of progression of Parkinson's disease over 96 weeks compared to placebo

Study Summary

• No benefit on MDS-UPDRS III OFF-medication score at 96 weeks (exenatide +5.7 vs placebo +4.5, P=0.47)
• No evidence to support exenatide as disease-modifying treatment; CSF penetration only ~1% of plasma levels

Intervention

Extended-release exenatide 2 mg subcutaneous injection weekly for 96 weeks vs placebo

Inclusion Criteria

Age 25-80 years; PD diagnosis (Queen Square Brain Bank criteria); Hoehn & Yahr ≤2.5 on treatment; MoCA ≥21; on dopaminergic therapy ≥4 weeks

Study Design

Arms: Exenatide 2 mg weekly, Placebo

Patients per Arm: Exenatide: 97 (92 ITT), Placebo: 97 (96 ITT)

Outcome

• Primary: MDS-UPDRS III OFF at 96 weeks: no difference (adjusted coefficient 0.92, 95% CI -1.56 to 3.39, P=0.47) - NEGATIVE
• Secondary: No differences in any MDS-UPDRS parts, MoCA, DaT-SPECT, or quality of life measures

Bottom Line

Major Points

First large, long-duration phase 3 trial of exenatide in Parkinson's disease (96 weeks treatment)
No significant difference in primary outcome: MDS-UPDRS part III OFF-medication worsened by 5.7 points (exenatide) vs 4.5 points (placebo); adjusted coefficient 0.92 (95% CI -1.56 to 3.39, p=0.47)
No benefits in any secondary outcomes including motor ON scores, cognition, quality of life, or DaT-SPECT imaging
Subgroup analyses by age, sex, age at diagnosis, and H&Y stage showed no differential effects
95% of participants with CSF tested positive for α-synuclein SAA
Exenatide safe with similar serious adverse events (9% vs 11%)
More GI symptoms and weight loss in exenatide group (1.8 kg vs 1.3 kg loss)
CSF exenatide concentration ~1% of plasma levels, raising CNS penetration questions

Study Design

Study Type: Phase 3 randomized controlled trial
Randomization: Yes
Blinding: Double-blind
Sample Size: 194
Follow-up: 96 weeks
Centers: 6
Countries: United Kingdom

Primary Outcome

Definition: MDS-UPDRS part III score OFF-medication at 96 weeks

Control	Intervention	HR/OR	P-value
Worsened by 4.5 points (SD 11.4)	Worsened by 5.7 points (SD 11.2)	- (-1.56 to 3.39)	0.47

Limitations & Criticisms

Recruitment 6 participants short of target (194 vs 200) due to COVID-19 and drug expiry
Only 66/194 had CSF collected for α-synuclein SAA
93% White population limits generalizability
Excluded patients with type 2 diabetes who may benefit more
CSF exenatide ~1% of plasma levels - inadequate CNS penetration?
Differential weight loss may have compromised blinding
Results contradict prior positive phase 2 trials without clear explanation

Citation

Lancet 2025;405:627-36

View Original Publication →

Exenatide-PD3

Exenatide once a week versus placebo as a potential disease-modifying treatment for people with Parkinson's disease in the UK: a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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