바이오스펙테이터

바이오스펙테이터 Sungmin Kim 기자

Research on Biomarker intended for an objective analysis was added to the Protocol of Phase 2a Clinical Trial of ‘PT320’, the sustaining ‘Exenatide’ for Parkinson’s Disease, to identify Neuroprotectiv

Peptron is going to launch the clinical trial of therapeutic agent for Parkinson’s disease. Peptron acquired an approval of changing protocol of domestic Phase 2a Clinical Trial of ‘PT320’, the SR-Exenatide (sustained release Exenatide) on 21st (of this month). Together with this, the clinical trial in the United States of America, for patients of Parkinson’s disease suffering the dyskinesia induced by administration of levodopa (LID), is being prepared.

Jung Jin-gyeong, the head of business development team, introduced the significance and detailed development plans accompanying the approval of changed protocol of Phase 2a Clinical Trial in a recent meeting with reporters from Biospectator, “… in the Phase 2a Clinical Trial, we are going to assess neuroprotective, therapeutic, and ‘disease-modifying’ effects for patients with Parkinson’s disease at its initial stage when neurodegeneration has just started ….”, “… we reestablished the protocol for the clinical trial last year. In particular, it is of significance in that scientific analysis of biomarkers and exosome etc. is included in the clinical trial to appraise the efficacy of drug objectively…”.

Along with publications on results of studies that reported GLP-1R agonists such as ‘Exenatide’ etc. could reduce neuritis and protect nerve cells, the degree of attraction of attentions on drugs of GLP-1 series is growing in the field of developing therapeutics for degenerative brain diseases. Peptron also has neuroprotective effect. With the use of ‘Exenatide’, ‘PT320’, a GLP-1R agonist, was tested against disease models such as Parkinson’s disease, traumatic brain injury (TBI), LID, multiple system atrophy (MSA), and Alzheimer’s disease in nonclinical trials.

Peptron selected Parkinson’s disease in the clinical trial strategically as a disease for which medicine was efficacious among several degenerative brain diseases. Jung Jin-gyeong, the head of business development team, explained, “… among a variety of degenerative brain diseases, standards to assess clinical symptoms of Parkinson’s disease have been established clearly …”, “… besides, in the case of Parkinson’s disease, we have concluded it would be appropriate for the analysis of biomarkers based on studies wherein pathological signaling of Parkinson’s disease has been well explored…”.

In fact, ‘Exenatide’, a drug for diabetes mellitus, manifested its potential, showing possible therapeutic effect in patients suffering Parkinson’s disease. In 2017, the clinical report containing such results was published in the global academic journal of clinics, the ‘Lancet’. In the journal, the report on clinical results of the study led by authors revealed that behavioral symptoms (MDS-UPDRS part 3) of 60 patients suffering Parkinson’s diseases were reduced even at 12 weeks after terminating the administration of 2 mg of ‘Bydureon’ (AstraZeneca; the 1-week formulation of ‘Exenatide’) for 48 weeks (doi: 10.1016/S0140-6736(17)31585-4). This result of therapeutic efficacy for degenerative brain diseases, identified for the first time, surprised the business industry.

Thomas Foltynie of the ‘University of College London (UCL)’ who led the clinical trial at that time, participated as a member of the science advisory board (SAB) in the change of protocol of clinical trial of Peptron. Peptron reflected the protocol of clinical trial of the authors published their paper in ‘Lance’ in the design of its protocol of clinical trial. The company explained that Greig Nigel of National Institute of Health and Professor Choi Doo-seop of Mayo Clinic would work together in the elaboration of protocol of clinical trial.

By incorporating several opinions on the change of protocol of clinical trial, Peptron went through the preparatory procedure comprising development of criteria for selection/exclusion of patients, determination of the number of patients securing statistical significance, determination of dosage of drug, development of a strategy capable of differentiating the drug of GLP-1 series from others, and establishment of production facilities of GMP in the Osong Bio-Park Complex last year.

The Phase 2a Clinical Trial will be conducted on 99 patients with Parkinson’s disease at its initial stage. These 99 patients will be assigned into three groups [33 patients taking placebos, 33 patients to be prescribed with 1-week formulation of PT320 (2 mg), and 33 patients to be prescribed with 2-week formulation of PT320 (2.5 mg)] for 48 weeks. Approximately 4 weeks of time will be required for the screening of patients to be participating in the clinical trial. Upon completion of administration of drugs, patients will take the period of ‘washout’ for 12 weeks. Thereafter, at the 60th week after completing the clinical trial, the degree of fulfillment of clinical trial will be appraised. Upon completion of screening of patients in clinics, specimens of blood and cerebrospinal fluid (CFS) of patients will be collected before and after administration of drug and during the progress of clinical trial.

Indicators, such as UPDRS Part 3 for the appraisal of kinesis as the primary one, and UPDRS Part1, 2, and 4 as the secondary ones of the clinical trial, will be appraised together with biomarker and degree of dyskinesia. Seoul National University Hospital, Samsung Medical center, and Asan Medical Center will be institutes to conduct the clinical trial. Depending on the situation, the site for clinical trial can be expanded. Peptron expects the termination of clinical trial in 2021 by taking account of time required for inviting patients to be participating in the clinical trial.

In particular, the key point of clinical trial is the study on biomarker. The Dimitrios Research Team of NIH, who carried out the analysis of biomarker in the clinical trial conducted by Thomas Foltynie, will be in charge of analysis of biomarker. A panel analysis of 14 biomarkers including JAK2, AMPK, ERK1/2, TOR, and so on as important signaling factors in existing studies on Parkinson’s disease will be carried out. Analyses on exosome count in blood and cerebrospinal fluid will also be carried out to appraise the correlation with degrees of treatment.

Jung Jin-gyeong, the head of business development team, added, “… it would be difficult to attain accurate analysis with a sole factor. Thus, signatures observed to be specific to patients suffering Parkinson’s disease will be analyzed…”, “… besides, the concentration of Exenatide in cerebrospinal fluid will be analyzed to secure the therapeutic window of efficacy of drug for patients to find dosages of drugs pertinent to corresponding diseases based on the scientific ground”.

The distinguishing point of PT320, as a sustaining Exenatide targeting Parkinson’s disease, can be classified into three aspects.

First, it is a 2-week formulation of the drug. Jung Jin-gyeong, the head of business development team, stated, “… Peptron intends to develop a 2-week formulation of the drug strategically. Such development will differentiate the company in terms of commercialization…”, “… the safety and tolerance of the 2-week formulation of drug have been identified in the domestic Phase 1 Clinical Trial conducted previously.”

Second, it is the higher transmissivity of blood brain barrier.

Peptron appraised the transmissivity of blood brain barrier of PT320 compared to Exenatide from models of Parkinson’s disease and traumatic brain injury (TBI). The transmissivity of blood brain barrier (CSF/Concentration of Drug in Blood) of approximately 2% was found, which was regarded as being very high in a non-clinical trial. On the contrary, Exenatide in cerebrospinal fluid of the model of Parkinson’s disease was detected rarely. The higher level of blood brain barrier transmissivity resulted in excellent therapeutic efficacy for models of actual Parkinson’s disease and traumatic brain injury (TBI).

Third, it is predicted to have less adverse effect. PT320 is a sustaining formulation that can keep the concentration of a drug in the blood stably compared to oral administration of Exenatide daily. Oral administration of drug is known to have fluctuating concentration of the drug in blood. Higher and lower concentrations of drug in blood can cause adverse effects. Besides, in the aspect of platform of sustainable drugs, the ‘Smart Depot’ platform of Peptron is advantageous in that it can control the speed of in vivo exposure to drugs.

In short, Peptron anticipates that a comparatively less dosage of 2.5 mg of Exenatide of PT320 in a 2-week formulation would have better efficacy for patients suffering Parkinson’s disease with less adverse effects.

Peptron currently prepares for the clinical trial in USA that will be initiated next year. Targeted subjects will be patients suffering Parkinson’s disease and dyskinesia induced by the administration of levodopa (LID). Jung added, “… strategically, we have selected the ‘LID’ designated as a disease requiring orphan drug (ODD). The choice will be advantageous in respect of development of new drug.” The clinical trial in USA, whether to start from Phase 1 or Phase 2, will be determined according to the discussion with FDA, USA. Finally, Jung stated, “… the clinical development of PT320 for Parkinson’s disease is open to future partners.”