December 8, 2021

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Gene therapy and GLP-1 become hopes for Parkinson’s disease

Gene therapy and GLP-1 become hopes for Parkinson’s disease

 

Gene therapy and GLP-1 become hopes for Parkinson’s disease.  Over the years, despite the tremendous efforts made by the biopharmaceutical industry, the research on Parkinson’s disease seems to have reached a dead end. With several large pharmaceutical companies abandoning Parkinson’s disease research projects, the industry’s attention has turned to research on gene therapy and new uses for changing diabetes drugs.

Gene therapy and GLP-1 become hopes for Parkinson's disease

 

Both frustrated

Recently, due to lack of efficacy, Biogen and Sanofi abandoned their Parkinson’s disease drug candidates cipanemab and venglustat, respectively.

On February 3, Biogen announced in its 2020 annual performance and earnings report that the highly-regarded Parkinson’s disease drug candidate cinemaneab (BIIB054) did not reach the primary and secondary endpoints in the Phase II clinical study of SPARK.

The SPARK study analyzed the efficacy of anti-α-synuclein (syn) monoclonal antibody cinemanemab compared with placebo in reducing injury and disability in patients with Parkinson’s disease. Its primary endpoint is the Society for Movement Disorders Parkinson’s Disease Comprehensive Scale (MDS). -UPDRS) improvement of the total score. However, because the therapy “has not reached the proof-of-concept” and failed to provide benefits to patients in the study, the development of cinemamab has been discontinued.

Biogen initially hoped that cinemanemab could successfully compete with the syn therapy prasinezumab developed by Roche/Prothena. As early as last October, in the Phase II Pasadena study of early Parkinson’s disease, prasinezumab also failed to beat placebo in the total score of MDS-UPDRS. However, the two companies are committed to promoting prasinezumab for a phase IIb confirmatory study due to signs of effectiveness for motor symptoms.

On February 5, Sanofi stated that the phase II clinical trial MOVES-PD developed by the company for the treatment of Parkinson’s disease missed the primary endpoint and the development of this indication has been terminated. Venglustat is an oral glucosylceramide synthase (GCS) inhibitor that can cross the blood-brain barrier and is an innovative treatment for Parkinson’s disease. There is evidence that Venglustat can help a subgroup of patients with GBA gene mutations. This mutation is present in 10% of patients and is related to the early onset of the disease and poor prognosis (such as cognitive impairment and rapid disease progression).

In this study of 270 subjects, the aim is to evaluate whether daily venglustat can improve the unified Parkinson’s disease MDS-UPDRS. Despite the failure, the company said it will continue to study the potential efficacy of venglustat in a few rare diseases, including Multiple kidney disease, Tay-Sachs disease and Gaucher disease.

However, efforts to find drugs that can help relieve the symptoms of Parkinson’s disease are still continuing, and many new drugs have entered the stage of advanced clinical trials. This year will be critical to this field, and there will be 10 studies that are expected to obtain data or complete related studies in 2021.

Among them, the two most popular research directions for new drugs for Parkinson’s disease are: glucagon-like peptide 1 (GLP-1). GLP-1, which is traditionally used for type 2 diabetes, is also being used in Parkinson’s disease and Alzheimer’s disease. Diseases and other central nervous system diseases. In addition, gene therapy is the most promising therapy to provide a one-time treatment solution for Parkinson’s disease.

Reuse of GLP-1

Studies have shown that GLP-1 agonists have neuroprotective effects. At present, a variety of this mechanism of action has been marketed (diabetes indication) and new drugs are being tested for Parkinson’s disease.

AstraZeneca’s Bydureon (exenatide, exenatide) is conducting a phase III clinical trial called Exenatide-PD3 under the auspices of University College London. However, the final result is still early, and the preliminary completion date of the clinical trial of Existatide-PD3 is 2023. In an earlier trial conducted by the research team, at 60 weeks, the MDS-UPDRS score of the exenatide group after discontinuation of the drug increased by 1.0 point, while the placebo group decreased by 2.1 points.

At the same time, it is expected that the data of several GLP-1 agonist phase II studies will also be announced during the year, including Novo Nordisk’s Novo/Victoza (liraglutude, liraglutide), which is jointly funded by the company and Cidasai Chennai Medical Center and Cure Parkinson’s Trust have collaborated on the trial, which is scheduled to be completed in September this year.

Peptron will also complete the mid-term trial of the sustained-release exenatide preparation PT320 in September this year. Previously, Peptron said that the current treatment of Parkinson’s disease and other brain diseases can only improve symptoms such as improving motor and cognitive functions, but cannot improve the essential neurodegenerative process. PT302 has the potential to improve the essential neurodegenerative process, and PT302 can Cross the blood-brain barrier and provide long-term neuroprotection.

The start-up biotechnology company Neuraly is also evaluating a new formulation of exenatide, namely pegylated exenatide; it is reported that pegylation can increase the permeability of exenatide through the blood-brain barrier. The project lags behind Peptron, and its phase II trial will be completed next year.

Gene therapy is coming

Although gene therapy can provide long-term solutions for the treatment of a variety of neurological diseases, this approach has recently suffered considerable setbacks, and Parkinson’s disease is no exception: American gene therapy company Voyager’s gene therapy VY- for Parkinson’s disease AADC was put on hold after an abnormality was found in the patient’s MRI scan in December. Voyager’s partner Neurocrine then abandoned the project.

However, there are some projects that may achieve very promising results. Sio Gene Therapies’ AXO-Lenti-PD is a lentiviral vector-based gene therapy designed to restore local and continuous dopamine production in patients with advanced Parkinson’s disease by delivering three genes required for dopamine synthesis. However, this project is an upgraded version of the Oxford Biomedical Company’s Prosavin project. Prosavin was eventually abandoned due to its poor efficacy.

In the first two cohorts of the Phase II Sunrise-PD study, although there were very few patients, AXO-Lenti-PD brought a promising improvement in the UPDRS Part Ⅲ score after drug withdrawal. However, the project has been hit by manufacturing delays, and the process of providing clinical trial drugs for large-scale research has not yet been finalized.

Large pharmaceutical groups are also participating in Parkinson’s disease gene therapy. For example, Eli Lilly acquired Prevail in December last year for $880 million, thereby obtaining the latter’s Parkinson’s disease drug candidate PR001. PR001 is designed to express glucocerebrosidase through AAV9 vector to treat Parkinson’s disease and neuron Gaucher disease with GBA1 mutation. It is estimated that as many as 7-10% of Parkinson’s disease patients worldwide carry at least one GBA1 mutation.

The Phase I/II phase Propel trial of PR001 is underway. Before Prevail was acquired, the company said it would provide biomarkers and safety analysis for some patients by mid-2021.

Other early-stage transactions, such as AbbVie’s acquisition of Mitokinin, a preclinical project researcher, completed on March 2. Mitokinin’s main new PINK1 compound can selectively increase the activity of PINK1, which is the main regulator of mitochondrial quality control genetically related to Parkinson’s disease. By increasing the activity of PINK1, Mitokinin aims to solve the mitochondrial dysfunction that leads to the pathogenesis and progression of Parkinson’s disease.

With the advancement of late-stage trials of Parkinson’s disease drug research and development, and the announcement of the results, it is expected that a greater step will be taken in this disease in the next few years.

 

(source:internet, reference only)


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