Periodic Reporting for period 2 - GA-VAX (Advancing a vaccine targeting genetic amyotrophic lateral sclerosis (C9orf72 ALS) to the clinical stage)
Periodo di rendicontazione: 2023-10-01 al 2025-01-31
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 in their lifetime, 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. Remarkably, our vaccine reduces neuronal damage to a similar extent when administered in already symptomatic mice, underscoring the vaccine’s potential both for treatment and prevention.
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 United States, Germany, Italy, France, Spain, and the United Kingdom. The ~9000 mutation carriers at risk of developing the disease within 10 years could benefit even more from our approach. C9orf72 patients developing frontotemporal dementia (FTD), a related neurodegenerative disease, are an additional market. Our highly complementary industry/academia team has all the expertise and resources to advance this promising treatment approach towards clinical evaluation. Intravacc contributes world-class manufacturing capabilities and clinical development expertise for peptide/carrier conjugate vaccines, while DZNE provides extensive knowledge of disease pathology, alongside advanced preclinical models and assays. Together, we aim to optimize the antigen, establish scalable manufacturing processes, and conduct rigorous preclinical evaluations aligned with EMA and FDA regulatory frameworks.
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 the project or partner with a larger pharmaceutical company to bring GA-VAX to market. By advancing GA-VAX towards clinical application, we aim to create a meaningful impact on the lives of C9orf72 patients and provide a scalable model for addressing other neurodegenerative diseases through active immunization.
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 United States, Germany, Italy, France, Spain, and the United Kingdom. The ~9000 mutation carriers at risk of developing the disease within 10 years could benefit even more from our approach. C9orf72 patients developing frontotemporal dementia (FTD), a related neurodegenerative disease, are an additional market. Our highly complementary industry/academia team has all the expertise and resources to advance this promising treatment approach towards clinical evaluation. Intravacc contributes world-class manufacturing capabilities and clinical development expertise for peptide/carrier conjugate vaccines, while DZNE provides extensive knowledge of disease pathology, alongside advanced preclinical models and assays. Together, we aim to optimize the antigen, establish scalable manufacturing processes, and conduct rigorous preclinical evaluations aligned with EMA and FDA regulatory frameworks.
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 the project or partner with a larger pharmaceutical company to bring GA-VAX to market. By advancing GA-VAX towards clinical application, we aim to create a meaningful impact on the lives of C9orf72 patients and provide a scalable model for addressing other neurodegenerative diseases through active immunization.
The GA-VAX project has made significant progress in developing a novel vaccine for C9orf72 ALS, addressing critical challenges in manufacturability, immunogenicity, and preclinical validation. Key activities and achievements include: 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, ensuring compatibility with Good Manufacturing Practice (GMP) requirements. Immunization studies in mice show that the new antigen induces higher antibody titers than our prototype vaccine. Importantly, immunization studies in our C9orf72 mouse model demonstrated significant improvement of motor deficits and reduction of biomarkers of neuroaxonal damage without significant safety concerns. We have completed an additional screening study to further optimize the adjuvant for maximum efficacy, and have produced the toxicology batch that will be is used for the GLP toxicology study in rats and pivotal efficacy studies in C9orf72 mouse models.
We have proactively engaged with the Paul Ehrlich Institute (PEI) to obtain scientific advice on regulatory requirements, including safety, efficacy, and Chemistry, Manufacturing, and Controls (CMC) studies to ensure that the resulting data package will be suitable to support a clinical trial application.
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, ensuring compatibility with Good Manufacturing Practice (GMP) requirements. Immunization studies in mice show that the new antigen induces higher antibody titers than our prototype vaccine. Importantly, immunization studies in our C9orf72 mouse model demonstrated significant improvement of motor deficits and reduction of biomarkers of neuroaxonal damage without significant safety concerns. We have completed an additional screening study to further optimize the adjuvant for maximum efficacy, and have produced the toxicology batch that will be is used for the GLP toxicology study in rats and pivotal efficacy studies in C9orf72 mouse models.
We have proactively engaged with the Paul Ehrlich Institute (PEI) to obtain scientific advice on regulatory requirements, including safety, efficacy, and Chemistry, Manufacturing, and Controls (CMC) studies to ensure that the resulting data package will be suitable 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 (Schenk, Nat Rev Neuro 2002). 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.