On-going phase II study of PT320, a long-acting Exenatide, the First-In-Class Drug for Parkinson's Disease Therapy

Exenatide is a glucagon-like peptide-1 receptor agonist (GLP-1 receptor agonist) belonging to the group of incretin mimetics. Also, Exenatide is a synthetic version of exendin-4, a hormone found in the saliva of the Gila monster, and it is a 39-amino-acid peptide, inducing insulin secretion. Exenatide binds to the intact human GLP-1 receptor in a similar way to the human GLP-1. Additionally, Exenatide has approximately 50% homology of amino acid with GLP-1.

(39-amino-acid peptide, synthetic version of exendin-4)

We previously demonstrated that treatment with Exendin-4, a GLP-1 receptor agonist, reduces MPTP-mediated dopaminergic neurodegeneration1 and 6-OHDA-induced Parkinson's disease model. We and others confirmed actions across animal models of Parkinson's dis-ease (PD)3 and recently demonstrated the efficacy of Exendin-4 in a double-blind placebo-controlled PD clinical trial.Due to its short half-life of 2.4 hours in the plasma of Exenatide, Peptron has developed and produced a sustained-release 2-week formulation of SR-Exenatide (PT320), resulting in sustained elevations of Exenatide for 20 days. With the result of preclinical and Phase I study of PT320, Peptron is testing the efficacy of PT320 of Parkinson's disease in the on-going Phase II trial. The PT320 for Phase II clinical studies is manufactured in the newly approved GMP facility using the SmartDepot Platform Technology.

SR-Exenatide PT320 for Parkinson's and other neurodegenerative disease

During exenatide developed as a diabetes medication, researchers at NIH have discovered the novel use of exenatide for the treatment of neurodegenerative diseases. Extensive in vitro and in vivo studies have demonstrated significant neurotropic and neuroprotective actions of exenatide in models of several disorders such as Parkinson's disease, Alzheimer's disease, peripheral neuropathy and traumatic brain injury (TBI).

PT320 s.c. administration provided sustained levels of Exendin-4 that can be maintained with biweekly serial dosing over an extended duration. The administration of Exendin-4 as a sustained release formulation results in greater brain penetration than does BID administration of immediate release Exendin-4 (CSF Exendin-4: 18.3 to 30 pg/ml for PT302 vs. < 6.9 pg/ml for immediate release Exendin-4 BID). Clinically relevant PT302 doses, evaluated by Exendin-4 levels in plasma and CSF, reduced the severity of a 6-OHDA unilateral medial forebrain bundle lesion as assessed by meth-induced rotational behavior, loss of TH+ cells in the substantia nigra, and TH+ immunoreactivity in the striatum. It indicated that PT302 was initially administered prior to or 6 days following the lesion. Hence PT302 has neuroprotective actions in a well-characterized toxin model of PD and may, therefore, be clinically useful for treating PD patients.

Additionally, Dr. Thomas Foltynie of UCL in London, UK have recently reported that exenatide showed promising clinical efficacy in Parkinson's disease patients. (PMID: 28781108). Extenatide improves symptoms of early and moderate Parkinson's disease, evaluated in phase I and phase II clinical trials (NCT01174810 and NCT01971242)

The treatment of exenatide was recently showed the beneficial effects on motor function in a randomized, placebo-controlled trial in Parkinson disease, and accumulating evidence suggests that impaired brain insulin and protein kinase B (Akt) signaling plays a pivotal role in PD pathogenesis. The result of this study is consistent with the target engagement of brain insulin, Akt and mTOR signaling pathways by exenatide and provide a mechanistic context for the clinical findings of the Exenatide-PD trial. This study suggests the potential of using exosome-based biomarkers as objective measures of target engagement in clinical trials using drugs that target neuronal pathways (PMID: 30640362).

Peptron has recently received an IND approval for PT320-Phase 2 clinical trial in Parkinson's disease and is preparing global clinical trials in the neurodegenerative disease. On going Peptron's PT320 phase II clinical trials (placebo-controlled RCT in three sites) will prove the efficacy of PT320 with potential biomarkers (e.g. mTOR) associated with treatment outcome for Parkinson's disease.


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