The CG01 epilepsy project


CombiGene is developing a groundbreaking AAV-based gene therapy with the potential to dramatically improve the quality of life of a group of epilepsy patients for whom there is currently no effective treatment. CombiGene uses a gene therapy vector, an adeno-associated virus (AAV), to administer a combination of neuropeptide Y (NPY) and its receptor Y2 directly to the part of the brain where the epileptic attack starts.

The main preclinical efficacy studies are concluded with positive results. In autumn 2020 CombiGene established a large-scale production platform that will be able to produce CG01 for the final preclinical studies, the upcoming clinical program and future commercial use. The next step is to initiate the final preclinical studies, not least the mandatory safety studies. At the end of the preclinical program, CombiGene can apply to initiate the first studies in humans (so-called clinical studies).

CombiGene’s epilepsy project reaches milestones according to plan

CombiGene has conducted a wide range of preclinical studies that have taken the epilepsy project forward step by step. In 2021, the company will focus on the final preclinical studies in order to be able to start the first study in humans in 2022. Below is a summary of completed preclinical studies.


Successful preclinical dose response study

At the beginning of 2017, a successful preclinical dose response study was completed that provided CombiGene with new and valuable information. Gene therapy is unique compared to other drugs in that the patient only receives the treatment once or a few times – after which the body’s own cells continue to produce the substances for which the drug encodes. It was therefore important to gain an understanding in preclinical studies of the effect of different doses of the drug candidate and the dose required to provide a good therapeutic effect on epilepsy in the experimental model. Results from preclinical studies can rarely be directly translated into human treatment, but provide valuable knowledge of the dose-dependent properties of the drug candidate.


Successful proof of concept study in a model of chronic epilepsy

After completing the dose response study, CombiGene began a proof of concept study with CG01 in a model of chronic epilepsy led by Professor Merab Kokaia, one of CombiGene’s scientific founders. The model used mimics the course of the disease in human temporal lobe epilepsy and the study included the use of magnetic resonance (MRI) and electroencephalography (EEG) examinations, i.e., the same methods used when examining patients in clinics. The final results of the study presented in early 2018 show that CombiGene’s drug candidate CG01 has clear anti-epileptic effects. The study was published 2019 in Molecular Therapy.


Human expression study confirms that human brain cells take up CombiGene’s drug candidate

In the last quarter of 2017, CombiGene, in collaboration with Associate Professor David Woldbye at the University of Copenhagen, also of CombiGene’s scientific founders, and Professor Merab Kokaia at Lund University, conducted a “human expression study”. The study was conducted on human epileptic brain tissue donated after resective epilepsy surgery where the part of the brain causing the epileptic seizures is removed. Data from the study show that CG01 is expressed in human epileptic brain tissue, i.e. the cells take up and express NPY and Y2 after application of the drug candidate CG01. The study confirms that the technique of administering genes with the help of the drug candidate works in human tissue exactly as intended. The human tissue used in the study comes from epilepsy patients who are resistant to traditional treatment – the very group of patients that CombiGene initially intends to treat with CG01. The results are therefore very encouraging.


Pharmacokinetic study indicates long-term expression in humans

At the beginning of 2020, CombiGene completed the preclinical pharmacokinetic study, which was conducted to see how long-lasting the expression of NPY and Y2 can be expected to be. The study clearly shows that the expression (incidence) of neuropeptide Y (NPY) and its receptor Y2 increases markedly already one week after the injection of CG01 and then increases over the next two weeks to reach a plateau after three weeks and then remain stable for the entire duration of the study, i.e. six months. The study thus provides further information that an injection into human brain tissue should have an effect for many years.


Learning and memory study shows that CG01 has no significant impact on cognitive functions

The learning and memory study, which was completed shortly after the pharmacokinetics study, shows that NPY and Y2, the active substances encoded in CG01, do not have a significant negative impact on cognitive functions. NPY is associated with numerous physiological processes in the body, including memory and learning ability. It was therefore important to be able to demonstrate that an increased expression of NPY and Y2 does not show any negative impact on memory or learning in the experimental model used in the study.


Cell tropism study confirms that CG01 is only expressed by neurons

CG01 is intended to reach the nerve cells, that is, the cells that trigger the epileptic seizures. CombiGene’s tropism study, which ended in August 2020, shows that CG01 works exactly as intended: the drug candidate is absorbed into the nerve cells of the hippocampus, but not in the supporting cells, the so-called glial cells. The results of the study are very encouraging because they are further confirmation that CG01 reaches brain cells as intended. The knowledge from the tropism study also provides a detailed understanding of how CG01 works and answers questions about the drug candidate’s tropism that regulatory authorities have asked.


Final choice of production method and complete production platform

At the beginning of autumn 2020, CombiGene completed the extensive work to establish a production platform for CG01. The platform consists of three parts: production of quality assured starting material (plasmids), analytical methods that are integrated as quality control in the production process and the production process itself.

Starting material. The production of the starting material, i.e. plasmids, is done from so-called master cell banks. Since the starting material, thanks to the master cell banks, is always one and the same a constant quality is guaranteed. The master cell banks and production of plasmids are managed by CombiGene’s partner Cobra Biologics.

Analytical methods. Ensuring that pharmaceuticals are of the same quality at each individual production time is a key regulatory requirement. To meet this, CombiGene, in collaboration with CGT Catapult, has developed a tailor-made analysis package to ensure that the production of CG01 meets these regulatory requirements.

Production. CombiGene has through the preclinical program used an adherent production method, which is well suited for the production of limited volumes. However, scaling up the adherent production sufficiently to meet future production needs for CG01 is too costly and time-consuming. CombiGene has therefore chosen a so-called suspension method, which can be easily scaled to large volumes and thus drive the further development of CG01 faster and at lower cost than would otherwise be the case.

After completing a successful pilot production of CG01 in July 2020 at the Spanish gene therapy manufacturer Viralgen, CombiGene and Viralgen signed an agreement on the production of CG01 in September 2020. By working with Viralgen and their suspension method, based on AskBio’s Pro10™ production method, CombiGene can use a single process to produce materials for the CG01 project’s final preclinical studies, the clinical studies and future commercial use. Pro10™ production method is well proven, as underlined by the fact that in the autumn of 2020 AskBio was acquired by Bayer for USD 2 billion with the possibility of an additional USD 2 billion in milestone payments.


Preparing for biodistribution and security studies

Since the second half of 2020, CombiGene is producing and quality assuring the material to be used in the mandatory biodistribution and safety studies. In parallel with the production of CG01, CombiGene will conduct studies together with the UK based company Neurochase to optimize how CG01 is to be administered to the human brain tissue and the technology to be used for this purpose. The biodistribution and safety studies will be conducted by CombiGene’s CRO partner Northern Biomedical Research(NBR) and all bioanalytical analysis will be done at Accelero.


Collaborating partners

Cobra Biologics is a leading international contract development and manufacturing organization, (CDMO) that develops and manufactures biological and pharmaceutical products for preclinical and clinical trials as well as for the production of commercial products and pharmaceuticals. Cobra has extensive expertise in the production of DNA, viral vectors, microbiota and technical proteins.

Cell and Gene Therapy Catapult was established as an independent centre of excellence to promote the growth of the UK cell and gene therapy industry by bridging the gap between scientific research and full-scale commercialisation. The organization offers leading knowledge, technology and innovation to enable companies to take products to clinical trials as well as to contribute expertise in clinical process development, manufacturing, regulatory issues, health economics and marketing.

Viralgen is a joint venture between AskBio and Columbus Venture Partners that together have decades of experience in technology and drug development from a variety of platforms and can offer best-in-class production to the gene therapy market.

Northern Biomedical Research is a contract research company and has collaborated with clients in research, pharmaceutical industry and biomedicine for more than 25 years. The company specializes in pharmacology, toxicology, biodistribution and pharmacokinetics (the doctrine of drug metabolism in the body). The company is based in Spring Lake, Michigan, USA.

Neurochase, founded by Professor Steven Gill, aims to make groundbreaking targeted therapies available to patients with neurological disorders using cutting-edge technology. Neurochase’s team specializes in creating tailored therapeutic strategies for direct administration of drugs using so-called “Convection Enhanced Delivery” (CED). The company provides accurate, targeted and safe direct administration of pharmaceuticals to the central nervous system and develops globally scalable treatment strategies and solutions for the pharmaceutical and biotech industry.

Accelerō® Bioanalytics GmbH is a GLP (Good Laboratory Practice) certified test facility located in Berlin, Germany. The company offers services in many areas such as pharmacokinetic characterization, biodistribution and immunogenicity. All analytical methods are developed and validated according to the respective EMA, FDA, and/or ICH guidelines.

CombiGene’s lead project CG01 has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 823282

About CombiGene

CombiGene’s vision is to provide patients affected by severe life-altering diseases with the prospect of a better life through novel gene therapies. CombiGene’s business concept is to develop effective gene therapies for severe life-altering diseases where adequate treatment is currently lacking. Development assets are sourced from an external research network and developed to achieve clinical proof of concept. Drug candidates for common diseases will be co-developed and commercialized through strategic partnerships, while the company may manage this process on its own for drugs targeting niched patient populations. The company is public and listed on the Swedish marketplace Nasdaq First North Growth Market and the company’s Certified Advisor is FNCA Sweden AB, +46 (0)852 80 03 99



CombiGene AB, Medicon Village, SE-223-81 Lund


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