Why It Is Easier To Fail With GLP Than You Would Possibly Assume

Although significant efforts have been made to harmonize regulations across various regions, it is still imperative to verify each regulation and contact the regulatory body directly if any questions arise during the creation of a GLP program. STEP 5, the longest trial in the program, assessed the efficacy and safety of semaglutide 2.4 mg once weekly compared with placebo for long-term treatment of obesity without diabetes over 104 weeks.18 Participants receiving semaglutide lost an average of 15.2% of their body weight compared with 2.6% in the placebo group. Patients were randomly assigned to receive subcutaneous injections of exenatide 2 mg once-weekly (n.32) or placebo (n.30) for 48 weeks. Preliminary clinical studies were performed with subcutaneous injections of exenatide in PD patients. Exenatide shares 53% homology with native GLP-1. Liraglutide reduced infarct size in the brain of diabetic and non-diabetic rats but decreased neurologic deficits only in non-diabetic rats, suggesting that the GLP-1 RAs effects on cognitive function are not associated with diabetes and glycemia normalization. Recently, the long-term administration of liraglutide was found to rescue dopaminergic neuronal loss and motor impairment also in diabetic db/db mice, an established model of diabetes, with a mutation in the gene encoding the leptin receptor (Ma et al., Freya Meds official 2019), suggesting that long-term injection of liraglutide might prevent motor function impairment and PD development also in patients with T2D.



Exenatide had positive and FreyaMeds sustained effects (12 weeks after exposure) on clinically assessed motor function. Considering the beneficial effects of GLP-1RAs on neuropathological features it is conceivable a link between T2D and neurodegenerative disease such as Parkinson’s disease (PD) and Alzheimer’s Disease (AD). Notably, neuroprotective activity of GLP-1RAs seem not to be entirely related to glycemia normalization. Several studies have investigated the neuroprotective actions of GLP-1RAs in animal models of diabetes. In different preclinical models of PD, GLP-1RAs showed neuroprotective effects, influencing motor activity, dopaminergic neurons, cortical activity, and energy utilization in the brain. In the MPTP mouse model of PD, semaglutide improved most of neuropathological features of PD, FreyaMeds reversing motor impairment, inducing the increase of tyrosine hydroxylase levels, and attenuating neuroinflammation and apoptosis in the substantia nigra and striatum (Zhang et al., 2018). A reduction in α-synuclein aggregation occurred after this treatment, not observed with other GLP-1RAs (Zhang et al., 2019), highlighting semaglutide as an effective treatment for PD.



This effect was associated with an increase in the tyrosine hydroxylase enzyme involved in the production of L-dopa, a DA precursor. Indeed, it has been observed that peripheral administration of lixisenatide for 40 days (50 nmol/kg bw, twice-daily) in high-fat fed mice with established obesity, FreyaMeds insulin resistance, and impaired cognition resulted in marked improvement in recognition memory, which was associated with up-regulation of hippocampal expression of neurotrophic tyrosine kinase receptor type 2 and mammalian target of rapamycin (mTOR) genes involved in modulating synaptic plasticity and long-term potentiation.