Trial of Lixisenatide in Early Parkinson’s Disease

Summary
Lixisenatide, a GLP-1 receptor agonist (GLP-1RA), plus dopaminergic therapy appears to halt the progression of motor disability in patients with early-stage Parkinson’s disease but had gastrointestinal side-effects (i.e., nausea and vomiting). Lixisenatide seems to keep the motor symptoms from getting any worse if taken consistently. Dopaminergic therapy, which is standard of care currently, presents with a mild worsening of motor symptoms at 12 months in this trial. If tolerable, a GLP-1RA on top of standard of care could be a good strategy to perserve motor capacity in Parkinson’s disease patients. Patients with early-stage Parkinson’s less than 60 years old may experience greater benefit with GLP-1RA therapy.

Thoughts
Lixisenatide is a GLP-1 receptor agonist used for treating diabetes and off-label for obesity made by Sanofi. It was FDA approved in July 2016 and discontinued it as of January 1, 2023. They state it was “a business decision and was not due to safety of efficacy concerns”. I am guessing this decision was made because patent protection for lixisenatide expired in 2020 and prescription volume decreased as other GLP-1RA’s came into the market. We could look at claims data to understand prescribing trends of lixisenatide from 2020-2023, comparing it to semaglutide and other GLP-1RAs’ prescription trends.

Meissner et al 2024 conducted a phase 2 double-blind randomized placebo-controlled trial to assess the effect of lixisenatide on the progression of motor disability in persons with Parkinson’s disease.

Key inclusion criteria were: - people 40-75 years of age diagnosed with Parkinson’s disease in the past three years treated with an optimized stable dopaminergic medication regimen (MAO-B inhibitor or dopamine agonist) for at least 1 month before initiation of trial agents - less than 3 on the Hoehn-Yahr scale (those w/o mild to moderate bilateral mootor involvement, dyskinesia, atypical or secondary parkinsonism) - MoCA at least 26 indicating normal cognitive functioning - No Diabetes mellitus - No treatment with prior GL-1RA - BMI at least 18.5 - No hyperthyroidism, uncontrolled hypothyroidism, severe renal insufficiency, active liver disease, severe depression, substance use disorder, unexplained pancreatitis, chronic pancreatitis, or pancreatectomy

Participants were assigned in a 1:1 ratio to receive subcutaneous lixisenatide or placebo as an add-on to their current Parkinson’s disease medications for 12 months. Patients injected themselves, in both groups, 15 minutes before dinner each night. Lixisenatide was administered at 10 micrograms per day for 14 days and dose was increased to 20 micrograms per day for the remaining of the 12 months. 28 of the 78 participants in the lixisenatide group had unnaceptable side effects when receiving the target 20 mcg dose per day and switched to the reduce 10 mcg dose per day. 74 completed follow up at 14 months in lixisenatide and 75 completed follow up at 14 months in placebo.

The MDS-UPDRS part III score was used to measure motor symptoms. The scores range from 0 (no symptoms) to 132 (severe symptom rating on all 33 categories). Categories include speech, facial expressions, rigidity in major joints, finger tapping, hand movements, pronation-supination of hands, toe tapping, leg agility, arising from chair, gait, freezing of gait, postural stability, posture, body bradykinesia, postural tremor of hands, kinetic tremor of hands, rest tremor amplitude, and constancy of rest tremor. Many of these symptoms can be debilitating for people with Parkinson’s and can meaningfully affect their quality of life and doing daily acts of living independently.

In the lixisenatide group, mean score decreased by 0.04 points from 15.3 to 14.9 and increased 3.04 points from 15.8 to 18.8. After a two month washout period, mean score was 17.7 (+2.8 points) in the lixisenatide group and 20.6 (+1.8) in the placebo group. The mean MDS-UPDRS increased by 0.9/mo and 1.4/mo in treatment and placebo groups, respectively - rates that were higher for each group when compared to their on-medication state. This suggests that the effects of therapy (dopaminergic or GLP-1RA) wear off when patients are taken off them. We can see that progression of motor symptoms continue in the lixisenatide group once patients are taken off indicating that the medication’s effects do not make lasting changes and need to be taken regularly.

In other studes, a threhsold of 3.25 points on the MDS-UPDRS part III score was identified as clinically important to the participants (Horvath et al 2015). In this study, the difference between mean scores at 12 months between placebo and treatmentt was 3.08, slightly below this threshold but very close.

There have been other non-GLP-1RA drugs trialed in Parkinson’s recently. Prasinezumab, a monoclonal antibody designed to bind aggregated alpha-synuclein, was tested against placebo (participants in either group were not allowed dopamingeric therapy, but were allowed MAO-B inhibitors) in early-stage Parkinson’s disease patients (Hoehn and Yahr stage 1 and 2, just like the lixisenatide study) (Pagano et al 2024). Mean change from baseline to 52 weeks in MDS-UPDRS part III scores was 2.66 points lower and 0.87 points between prasinezumab vs placebo and prasinezumab + MAO-Bi vs. placebo + MAO-Bi. As compared to placebo, prasinezumab treated patients after 52 weeks showed a decrease in MDS-UPDRS part III scores by 2.55 points in stage 2 Hoehn and Yahr patients (n = 238) but an increase by 3.14 points in stage 1 patients (n = 78). The study was similarly powered to the lixisenatide trial and also only considered early stage patients (Hoehn and Yahr < 3). It did not allow baseline dopaminergic therapy unlike lixisenatide and compared to true placebo. Despite these favorable conditions, it showed a difference of 2.55 points between groups whereas the lixisenatide trial showed a difference of 3.04 points. This suggests that although prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease, the benefit is likely not as strong as lixisenatide treatment.

Results from phase 2 trial of NLY01, a GLP1RA by D&D pharmatech, showed that age (< 60 and over 60) may be a factor in response. Post-hoc analysis of the lixisenatide data showed that at 12 months, lixisenatide had a larger treatment effect in participants younger than 60 years of age than in those 60 years of age (difference in scores on MDS-UDPRS part II was 5.22 vs 1, respectively).

In the treatment group, GI side effects were noted include 46% reporting nausea, 13% with vomiting and 8% with GERD relative to placebo reporting 12%, 3%, and 1% respectively. These side effects are commonly reported across all GLP-1’s. One patient (1.3%) experienced pancreatitis, a known but serious adverse effect of GLP-1RA’s.

The mechanism by which GLP-1RA’s work in the treatment of Parkinson’s is currently unknown. One suggestion is that GLP-1RA may enhance synamptic dopamine levels that could lead to benefit with respect to symptoms in Parkinson’s disease based on clinical studies assessing the effect of a different GLP-1RA (e.g., exenatide) in addiction disorders.

GLP-1RA therapy offers a new strategy to treat patients with Parkinson’s disease. The lixisenatide results are encouraging and supported by studies with similar outcomes using other GLP-1RA’s like liraglutide. Recently, liraglutide was shown to MDS-UPDRS part III scores by 13.1 points and non-motor symptoms by 6.6 points relative to placebo after 52 weeks of therapy and 2 weeks of washout (Hogg et al 2024). These results support the lixisenatide results.