A biologic drug for diabetes effective in early Parkinson's disease

A biologic drug for diabetes effective in early Parkinson’s disease

Lixisenatide, a popular biologic drug for type 2 diabetes, was found to delay the progression of Parkinson’s disease in a Phase II clinical trial.
Disease symptoms remained stable during the 12-month treatment with lixisenatide, while they worsened in placebo-treated patients. Benefit was sustained 2 months after discontinuation, indicating the neuroprotective activity of the drug. Unfortunately, lixisenatide caused many unpleasant gastrointestinal side effects.
Larger clinical trials will be required to confirm efficacy, establish benefit-risk ratio and obtain regulatory approval. These will take several years to complete.

Lixisenatide, a popular biologic drug used for treating type 2 diabetes, has shown benefit in patients with early Parkinson’s disease in the recently completed Phase II trial called LIXIPARK. After 12 months of treatment, motor disability measured with Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) remained stable in the drug-treated group, in stark contrast to the placebo control group, which experienced deterioration (-0.04 vs 3.04 points, respectively). Notably, the difference persisted even after 2 months of washout period, leading researchers to the conclusion that lixisenatide may exert neuroprotective effect and slow the disease progression. On the other hand, secondary endpoints such as levodopa equivalent doses failed to confirm the primary analysis, perhaps due to the limited power. Consequently, investigators recommended caution and note that “longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson’s disease”. This is particularly important considering the mixed results of previous studies with similar drugs.

The evaluated biologic, lixisenatide, belongs to the group of glucagon-like peptide-1 (GLP-1) receptor agonists, which mimic the action of a natural hormone responsible for stimulating insulin release from pancreatic beta-cells in response to elevated glucose levels. Thanks to this glucose-dependent activity, GLP-1 receptor agonists carry a minimal risk of severe hypoglycemia, which contributes to their widespread use in patients with insufficiently controlled diabetes. A peculiar idea to investigate a sugar-lowering agent in Parkinson’s disease came from encouraging results of pre-clinical studies performed in a mouse model of the disease. In these studies, administration of lixisenatide prevented the reduction in dopamine synthesis in substantia nigra and suppressed inflammation associated with chronic microglial activation. These findings were bolstered by the epidemiological evidence showing that Parkinson’s incidence is lower among diabetic patients treated with GLP-1 receptor agonists or similar medications.

In addition to the required confirmation in Phase III trials, several other issues must be addressed before pursuing the regulatory approval. Despite the benefit of lixisenatide being statistically significant, many specialists question the clinical significance of 3-point improvement observed in the study. If the drug’s effectiveness remains at the same small level in the long term, its use in the management of Parkinson’s disease will be of limited value. It is possible however that the efficacy of lixisenatide accrues over time, halting the disease progression for many years, during which most untreated patients would likely experience profound deterioration. The bar for success is set particularly high here, considering the unpleasant adverse reactions reported by a significant number of patients. In the LIXIPARK trial, nausea was reported to occur in 46% of participants receiving lixisenatide and vomiting in 13%. Patients treated with GLP-1 receptor agonists may also experience many other gastrointestinal side effects such as bloating, stomach pain or diarrhea, in many cases leading to treatment discontinuation or dose reduction. Considering the poor prognosis of Parkinson’s disease, with a sizeable proportion of patients eventually developing levodopa-resistant motor dysfunctions and/or other complications, there is still a pressing demand for new, more efficacious disease-modifying drugs. However, the ultimate verdict on whether lixisenatide or other GLP-1 receptor agonists live up to the expectations of the medical community, can be only reached once the results of confirmatory Phase III trials become available. And these will take several years to complete

Prepared by:

Adam Tuszyner

Sources and further reading

SMeissner, Wassilios G., et al. “Trial of Lixisenatide in Early Parkinson’s Disease.” New England Journal of Medicine 390.13 (2024): 1176-1185.
McGarry, Andrew, et al. “Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson’s disease: a randomised, double-blind, placebo-controlled trial.” The Lancet Neurology 23.1 (2024): 37-45.
Athauda, Dilan, et al. “Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial.” The Lancet 390.10103 (2017): 1664-1675.
McCarty, Delilah, Megan Coleman, and Cassie L. Boland. “Lixisenatide: a new daily GLP-1 agonist for type 2 diabetes management.” Annals of Pharmacotherapy 51.5 (2017): 401-409.
Hassan, Anhar, et al. “The profile of long-term Parkinson’s disease survivors with 20 years of disease duration and beyond.” Journal of Parkinson’s disease 5.2 (2015): 313-319.
Kim, Han‐Joon, et al. “Motor complications in Parkinson’s disease: 13‐year follow‐up of the CamPaIGN cohort.” Movement Disorders 35.1 (2020): 185-190.