Potential Safety Concerns With Lixisenatide Despite Showing Slowed Motor Disability Progression in Phase 2 Trial for Early Parkinson Disease

Newly published in The New England Journal of Medicine, findings from the phase 2 LixiPark trial (NCT03439943) showed that treatment with lixisenatide (Adlyxin, Sanofi), a glucagon-like peptide-1 receptor agonist used as a therapy for diabetes, resulted in less progression of motor disability compared with placebo at 12 months in patients with early Parkinson disease (PD) but was associated with gastrointestinal adverse effects.¹ Thus, these finding suggest that longer and larger trials are needed to determine the effects and safety of lixisenatide in patients with PD.

Among 156 patients (lixisenatide, n = 78; placebo, n = 78), the mean score on the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III in the ON-medication state was 14.9 (95% CI, 13.3-16.6) in the lixisenatide group and 18.8 (95% CI, 16.6-21.0) in placebo at 12 months. Notably, the scores in the lixisenatide group improved from baseline by −0.04 points (95% CI, −1.62 to 1.54) and in the placebo group worsened by 3.04 points (95% CI, 1.46-4.62), equating to a difference of 3.08 (95% CI, 0.86-5.30; P = .007).

“There is a number called the 'clinically meaningful threshold' and we should appreciate that the results 'fell short' of this important metric so it is not ready for prime time in patients. In my view we should not rush to prescribe this drug or to try to creatively acquire it for our patients. We have been down this road many times including leukemia drugs, cough syrups and lithium for Parkinson. The data is not yet there to proceed to prescribing,” Michael S. Okun, MD, national medical advisor for the Parkinson's Foundation, told NeurologyLive®. “More importantly, the weight loss associated with GLP-1’s is not desirable in the majority of cases of Parkinson disease and the nausea and vomiting will not be a welcome symptom. The drug and trial is a step in the right direction, though there is much work to do.”

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This study was led by Wassilios Meissner, MD, PhD, head of the department of neurology for Neurodegenerative Diseases at University Hospital Bordeaux, and Olivier Rascol, MD, PhD, professor of clinical pharmacology at Toulouse University Hospital, both members of NS-PARK (F- CRIN), the French clinical research network on PD behind the project. In this phase 2, double-blind, randomized, placebo-controlled trial, investigators mainly assessed the impact of lixisenatide on the progression of motor disability in patients with PD. Participants diagnosed with PD less than 3 years earlier who received a stable dose of medications to treat symptoms and did not have motor complications, were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point of the study was change from baseline in scores on the MDS-UPDRS part III in patients in the ON-medication state at 12 months. The secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months, and doses of levodopa equivalent.

Following the 2-month washout period, the mean score on the MDS-UPDRS part III was 17.7 (95% CI, 15.7-19.7) in the lixisenatide group and 20.6 (95% CI, 18.5-22.8) in the placebo group at 14 months. Other secondary and exploratory efficacy measures showed similar results in the 2 groups at 6 months and 12 months. Investigators noted that the mean changes from baseline in the levodopa equivalent daily dosage were 35.8 mg per day (95% CI, 8.3 -63.2) with lixisenatide and 31.3 mg per day (95% CI, 9.2-53.5) with placebo.

Authors also noted no associations between baseline fasting blood glucose and insulin concentrations and scores on the MDS-UPDRS part III at month 12. In a post hoc subgroup analysis, results showed that lixisenatide had a numerically larger treatment effect in participants younger than 60 years of age than in those 60 years of age or older at 12 months (difference in scores on the MDS-UPDRS part III, 5.22 [95% CI, 1.95-8.48] vs. 1.00 [95% CI, −2.01 to 4.03]).

“For 30 years, we have been trying to understand how to slow the decline associated with PD over time. In this context, the positive results of the LixiPark phase 2 trial showing less progression of motor symptoms of PD over a year constitute a significant step forward in the future management of the disease. We look forward to confirming these encouraging results in the future, in order to translate such findings into clinical practice,” principal investigators Meissner and Rascol jointly said in a statement.²

Most participants reported at least 1 adverse event (AE)(lixisenatide, 86%; placebo, 71%), with gastrointestinal AEs noticeably more common with lixisenatide than placebo (nausea, 46% vs. 12%; vomiting, 13% vs. 3%; gastroesophageal reflux, 8% vs. 1%, respectively). In the 2 groups, the incidence of serious AEs was similar with 5 patients in each group. Only 1 serious AE in each group, pancreatitis in the lixisenatide group and syncope in the placebo group, was considered by the investigators to be treatment-related.

Only 6 participants reported weight loss as an AE in the lixisenatide group and no such AEs were reported in the placebo group. Authors did not observe between-group difference in the mean weight at any visit. Investigators noted 1 case of hypoglycemia in the placebo group which was not reported from any of the participants treated with lixisenatide. In a post hoc analysis, results revealed that the presence of nausea did not affect the magnitude of effect with respect to the primary end point in the lixisenatide group.

All told that it remains to be confirmed whether the apparent effect of the treatment on motor scores persists with longer exposure and at other stages of PD. Authors noted that the secondary end points provide no definite support for the primary end point findings, and longer washout periods may be required to know whether lixisenatide therapy has a long-lasting effect. Additionally, researchers did not use any imaging biomarkers in the study to monitor disease progression and changes with drug administration. Since the trial was conducted in France, the collection of data regarding race or ethnic group is prohibited by law. Authors only tested 1 dose of lixisenatide, and thus other doses might have better or worse effects in patients with PD.

“This is a very encouraging result for us here at Cure Parkinson’s. Along with our funding partners at Van Andel institute, we have been championing the repurposing of GLP-1 receptor agonists for Parkinson since 2010,” Simon Stott, director of research at Cure Parkinson’s, said in a statement.² “This is the second phase 2 clinical trial indicating that this class of diabetes drugs is doing something interesting in Parkinson. We congratulate the investigators who conducted this study, and we are truly grateful to the participants and their families for helping to advance the research into disease modifying therapies for Parkinson.”

REFERENCES
1. Meissner Wassilios G., Remy Philippe, Giordana Caroline, et al. Trial of lixisenatide in early Parkinson’s disease. NEJM. 2024;390(13):1176-1185. doi: 10.1056/NEJMoa2312323
2. Phase 2 clinical trial of Type 2 diabetes drug for treatment of Parkinson’s shows positive and promising results. News Release. Van Andel Institute. Published April 3, 2024. Accessed April 4, 2024. https://www.vai.org/article/phase-2-clinical-trial-of-type-2-diabetes-drug-for-treatment-of-parkinsons-shows-positive-and-promising-results/