GA-VAX

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease and the available medications extend life by only a few months.

With a lifetime risk of about 1 in 500, ALS is the third most common neurodegenerative disease, affecting motor neurons in the brain and spinal cord, resulting in progressive paralysis. Most patients die within 2 to 5 years of diagnosis. Current therapies can only alleviate symptoms, but cannot stop the loss of nerve cells and the underlying disease pathways.

ALS typically affects people between 40-70 years of age. Its etiology is multifactorial and the precise pathogenic mechanism is still unknown. In most of patients (85-90%) the cause of ALS is unknown (“sporadic ALS”) and hundreds of clinical trials have failed due to a lack of understanding of the pathomechanisms. In 10-15% of ALS patients the disease follows an autosomal dominant inheritance pattern, which means that half of the children of an affected patients are at high risk to develop disease. Genetic variants of ALS triggered by known mutations offer a unique chance for targeted therapy and potentially prevention.

Gene mutations have been identified as triggers for some forms of ALS. About 5-10% of all ALS cases in people of European descent are caused by a mutation in the C9orf72 gene, making it the most common genetic ALS variant. These patients carry a massively expanded (G₄C₂)_n repeat in a part of the C9orf72 gene that is normally not translated. Unexpectedly, the research group of Prof. Dr. Dieter Edbauer at DZNE discovered that the repeat sequence in the genome is translated into long aggregating repeat proteins, most abundantly poly-Glycine-Alanine (poly-GA). In cell and mouse models, poly-GA triggers ALS-related downstream pathology, ultimately causing neurons to die.

Prof. Edbauer’s team at DZNE developed an experimental vaccine that instructs the immune system to produce antibodies against these harmful poly-GA molecules. In a mouse model, vaccination reduces poly-GA aggregates and inflammation and largely prevents motor deficits. When starting vaccination in already symptomatic mice, the developed vaccine reduces neuronal damage to a similar extent. Regular lifelong vaccination will be required to maintain sufficient antibody levels.

GA-VAX represents an attractive business case in the orphan disease space with approximately 2500 prevalent C9orf72 ALS cases in the major markets (US, DE, IT, FR, ES, UK). Around 9000 mutation carriers at risk of developing the disease within 10 years could benefit even more from this approach. The GA-VAX vaccine concept could likely also help patients with the C9orf72 mutation who develop a related disease, called frontotemporal dementia (FTD).

The GA-VAX project aims to develop the previously identified ALS vaccine candidate to the point where it can be clinically tested in C9orf72 ALS and FTD patients. For this purpose, DZNE has joined forces with Intravacc B.V., a world-leading contract development and manufacturing organisation (CDMO) specializing in innovative vaccines for infectious diseases and therapeutic vaccines. The consortium has been awarded a grant of € 2.5 million from the European Union (EIC) to further develop a prototype ALS vaccine, including process development, scale-up and toxicology studies.

Together, Intravacc and DZNE have all the necessary expertise to advance this promising treatment approach for C9orf72 ALS and FTD towards clinical evaluation. While Intravacc contributes the know-how for the production and clinical development of peptide/carrier conjugate vaccines, DZNE provides in-depth knowledge of the disease pathology as well as all necessary model systems and access to patient cohorts for future clinical trials. Together, the partners have established a GMP-ready production process for the antigen and are conducting pivotal toxicology and efficacy studies in animals in accordance with ICH guidelines. This will allow the consortium to compile a draft clinical trial application for a Phase 1b/2a study in C9orf72 ALS and FTD patients. In addition, this data package will be used to raise capital for the Phase 1b/2a trial to bring the GA-VAX vaccine to the market. DZNE has established trial-ready ALS patient cohorts.