Periodic Reporting for period 1 - GA-VAX (Advancing a vaccine targeting genetic amyotrophic lateral sclerosis (C9orf72 ALS) to the clinical stage)
Periodo di rendicontazione: 2022-06-01 al 2023-09-30
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by protein aggregation in the motor neurons of the brain and spinal cord that leads to respiratory failure within 2-5 years. The best available drugs extend life by ~3 months. ALS affects about 1 in 500 people, mostly for unknown reasons, but 5-10% of cases in Caucasians are caused by a mutation in the C9orf72 gene. We have shown that this mutation leads to the expression of large aggregating poly-glycine-alanine (poly-GA), which triggers downstream pathology. We have developed a poly-GA peptide vaccine that reduces aggregates and largely prevents motor deficits in a mouse model. Our vaccine reduces neuronal damage to a similar extent when administered in already symptomatic mice. Since regular lifelong vaccination is required to maintain sufficient antibody levels, GA-VAX represents an attractive business case in the orphan disease space with ~2500 prevalent C9orf72 ALS cases in the US, DE, IT, FR, ES, UK. The ~9000 mutation carriers at risk of developing the disease within 10 years could benefit even more from our approach. Our highly complementary industry/academia team has all the expertise and resources to advance this promising treatment approach towards clinical evaluation. Intravacc provides the manufacturing and clinical development expertise for peptide/carrier conjugate vaccines, while DZNE provides in-depth knowledge of disease pathology and all necessary model systems and assays. The project includes antigen optimization, manufacturing and preclinical evaluation according to EMA and FDA regulatory requirements. This will allow us to prepare a clinical trial application in C9orf72 ALS patients. In addition, we will use this data package to raise capital for the Phase 1 trial from a patient organization or investor to further de-risk or partner with a larger pharmaceutical company to bring GA-VAX to market.
The prototype vaccine ((GA)10 conjugated to keyhole limpet hemocyanin, KLH) is highly aggregation-prone, which is incompatible with drug manufacturing and quality requirements for use in patients. Prior to the GA-VAX project, DZNE had tested solubility and antigenicity of ~20 different formulations, resulting in a greatly improved antigen. In the GA-VAX project, we tested 10 derivatives of this candidate for manufacturability and optimized antigenicity. This resulted in a peptide/carrier conjugate with high solubility even at high concentrations and excellent manufacturing properties. In addition, we started to compare the stimulatory effect of different adjuvants. Immunization in mice and in vitro assays show that the new antigen induces higher antibody titers than our prototype vaccine. A dose-response immunogenicity study in wild-type mice and a pilot efficacy study in our C9orf72 ALS mouse model are currently ongoing. Based on the results, we will produce the toxicology batch that will be is used for the pivotal safety and efficacy studies designed to support a clinical trial application.
Active vaccination is an attractive approach for neurodegenerative diseases, because it is potentially cheaper and easier to administer than antibody therapy. Active vaccination for Alzheimer’s disease has been disappointing due to low immunogenicity in the aged target population and serious adverse events in 6% of patients. An additional problem is that targeting aggregating proteins is difficult, because the antigens themselves often aggregate, making GMP-compliant production and clinical use impossible. We have succeeded in developing highly soluble variants of poly-GA that are still immunogenic. Our approach may serve as a guide for targeting other neurodegenerative diseases with active vaccination.