Science & Innovation - Capsida Biotherapeutics

OUR PIPELINE IS MAKING THE IMPOSSIBLE POSSIBLE

CAPSIDA APPROACH

Capsid Engineering, Cargo Optimization, Translational Biology, Process Development and Manufacturing, and Clinical Development All Under One Roof

Capsida Biotherapeutics has designed one of the industry’s only fully integrated, end-to-end gene therapy solutions.

Built through a combination of in-house R&D and industry partnerships, our therapeutic approaches – including gene replacement and gene editing – are designed to bring therapies to patients with both monogenic and polygenic diseases.

CAPSID ENGINEERING

At Capsida, the scale at which we can engineer and screen capsids is unrivaled. Our scientists build large-scale libraries of diverse capsid variants and biologically screen them, identifying optimal capsids to target tissues and cells in diseased organs. Our process benefits from:

Precise targeting:

Our therapies are designed to target specific organs and cell types while limiting off-target tissue tropism and cell transduction, generating a significantly increased therapeutic index.

Positioning for superior safety and efficacy:

Our non-invasively IV-administered therapies have the potential to be administered at lower doses than wild-type AAV vectors, opening opportunities for indications previously inaccessible by gene therapy.

High-throughput screening and Automation:

By biologically screening billions of capsid variants in models relevant to humans, we’re able to select for organ and cell-type specificity through a desired route of administration. Our automation platform significantly increases throughput yielding larger data sets to improve accuracy and reproducibility to identify optimal capsids more efficiently.”.

Iterative processes:

Through iterative rounds of engineering and screening, we have generated an unrivaled depth of biological data which we mine for improved capsids for targets in our pipeline. Continued efforts allow for building of the capsid profile to meet the needs of a specific program.

Precise targeting:

Our therapies are designed to target specific organs and cell types while limiting off-target tissue tropism and cell transduction, generating a significantly increased therapeutic index.

Positioning for superior safety and efficacy:

High-throughput screening and Automation:

Iterative processes:

DISCOVERY AND PRECLINICAL

To quickly advance our mission of providing meaningful therapeutic opportunities for patients with unmet medical need, Capsida progresses preclinical disease proof-of-concept in parallel with capsid engineering. Our R&D efforts begin by assessing the expected therapeutic need for a specific disease indication, providing guidance for the capsid engineering efforts, and performing continuous disease discovery efforts to refine therapeutic expectations.

In each case, the novel engineered capsid is just half of the drug product. Our development process for the other half, the encapsulated gene cargo, begins by investigating the appropriate therapeutic strategy suited for the disease of interest – whether that is traditional gene replacement, targeted knock-down, vectorized antibodies or gene editing. Our scientists progress development and optimization of cargo in lockstep with that of the capsid, providing parallel and complimentary paths for improvement of efficacy and safety profiles for our novel drug products.

Optimized cargo is then paired with novel vectors into a therapeutic for validation of the disease model and selection of the development candidate.

MANUFACTURING OPERATIONS

At Capsida, we are singularly focused on rapidly getting our high quality, life-changing therapies to patients who are suffering from debilitating diseases. Our end-to-end internal process development, analytical development and manufacturing capabilities keeps the entire process in-house, eliminating the need for contract development and manufacturing organizations (CDMOs). With a robust quality management system overseeing our internal operations, we can reliably deliver high quality medicines to patients in need.

Our AAV suspension manufacturing process is currently scaled to 200L, with the ability to expand to 1000L scale.. Through close integration with our Capsid Engineering team, we conduct extensive manufacturability assessment to ensure the productivity and product quality of our selected capsid/cargo candidates to enable speed to clinic at the lowest possible cost.

In 2021 we commissioned our brand-new cGMP manufacturing facility in Thousand Oaks, California. The facility includes modular clean-room suites for drug substance and filling operations that have been designed and constructed with environmental and personnel controls to meet commercial cGMP requirements. Internal Analytical Development and Quality Control laboratories are in place to support rapid assay development and product release. As our product portfolio grows, we have the ability to expand our manufacturing footprint as needed.

Our mission is to serve patients and our fully integrated manufacturing capabilities differentiate us from others in our ability to fulfill that mission.

CLINICAL DEVELOPMENT

At Capsida, we are focused on improving the lives of patients with severe and debilitating diseases. First and foremost, we approach patients holistically, working closely with advocacy groups, patients, and caregivers to ensure we are meeting patient needs.

Our highly skilled clinical development leadership has extensive experience across a wide range of adult and pediatric diseases, treatment modalities, and innovative trial design with a proven track record of bringing novel medicines to market. We collaborate closely with regulatory science and clinical operations experts to ensure a holistic and comprehensive approach to drug development.

We are excited to partner with patients, caregivers, physicians, and health authorities to bring Capsida’s differentiated gene therapies to patients.

PIPELINE

Central Nervous System Disorders

Capsida’s innovation and intellectual property can be broadly applied to all therapeutic areas. We started in the central nervous system (CNS) because of the expertise and passion of our founders, and the significant prevalence and unmet need in CNS disorders. Capsida is currently progressing two wholly owned programs in CNS disorders in addition to our partnered programs, where we have the potential to co-develop and co-commercialize up to four CNS programs. Partnered programs target CNS and ophthalmology disease indications.

Central Nervous System Disorders

Crossing the blood-brain barrier to target the brain, while limiting exposure to non-targeted organs — such as the liver – has been a significant challenge in the gene therapy field. With our next-generation capsids, we can transduce brain cells with lower doses, which limits accumulation in the liver and other organs. As our capsids further evolve, we are achieving even higher on-target tropism while simultaneously de-targeting the liver.

Almost all gene therapies in CNS have been aimed at treating ultra-rare disorders, most often in infants. Typically, AAV9-delivered treatments penetrate a very small percentage of brain cells, restricting their use to diseases where limited penetration is sufficient – mostly a subset of ultra-rare, infant diseases.

Capsida’s proprietary technology enables the creation of engineered capsids that can penetrate a larger proportion of brain cells, enabling our pipeline of rare and more common CNS diseases with high unmet medical needs across all age groups.

These CNS therapies are engineered to target specific organs and to simultaneously limit the penetration of non-targeted organs – especially the liver, enabling intravenous (IV) administration. IV delivery is important, because this allows the greatest potential for efficacy by using the body’s natural blood flow to deliver our gene therapy to the CNS. Additionally, IV delivery limits the risks associated with more invasive delivery methods such as intra-cisterna magna (through the base of the skull into the cerebrospinal fluid surrounding the brain), intrathecal (through the spinal cord into cerebrospinal fluid), or direct administration into the brain tissue.

We have two wholly-owned programs. One remains undisclosed, but the other is described below:

Genetic Epilepsy Due to STXBP1 Mutations

Genetic epilepsy caused by mutations in the syntaxin-binding protein 1 (STXBP1) gene is a devastating developmental epileptic encephalopathy affecting one in 30,000 children globally. It is associated with severe developmental delay, treatment-resistant seizures, and sudden unexpected death in epilepsy (SUDEP). STXBP1 genetic epilepsy is caused by mutations in the STXBP1 gene encoding a protein involved in the release of neurotransmitters and neuropeptides, which are responsible for communication across neurons in the brain and central nervous system. There are no disease-modifying therapies for STXBP1 genetic epilepsy. Current treatments are supportive only, and include anti-seizure medication, and physical, occupational, and speech therapy.

Capsida is developing a novel gene therapy, CAP-002, for the treatment of this severe disorder with high unmet need. CAP-002 is designed to stably replace STXBP1 protein throughout the brain after a single intravenous infusion, with the goal of providing a disease modifying therapy that corrects the underlying disease pathology, halts disease progression and significantly improves the quality of life for patients with genetic epilepsy due to STXBP1 mutations.

López-Rivera et al, 2020, Abramov et al, 2020, Stamberger et al, 2016, Saitsu et al., 2008; Stamberger et al., 2016

EPILEPTIC ENCEPHALOPATHIES (STXBP1)

Syntaxin-binding protein 1 (STXBP1) encephalopathy is a devastating neurodevelopmental disorder affecting nearly one in 30,000 children. It is associated with severe developmental delay, treatment-resistant seizures, and early death.

STXBP1 encephalopathy is caused by mutations in the STXBP1 gene encoding a protein involved in the release of neurotransmitters and neuropeptides, which are responsible for communication across neurons in the brain and central nervous system.

There are no specific therapies for STXBP1 encephalopathy today. Treatment is supportive and includes anti-seizure medication and physical, occupational, and speech therapy to somewhat lessen the impact on daily life for patients and their families.

Capsida is developing a novel gene therapy, , for the treatment of this severe diseaseOur program is designed to stably replace STXBP1 protein throughout the brain after a single intravenous infusion, with the hope of correcting underlying pathology and significantly improving symptoms and quality of life for children with STXBP1 encephalopathy. [link to advocacy site (URL NEEDED)]

López-Rivera et al, 2020, Abramov et al, 2020, Stamberger et al, 2016, Saitsu et al., 2008; Stamberger et al., 2016

GBA-1 PARKINSON’S DISEASE

Parkinson’s disease is a brain disorder that causes unintended or uncontrollable movements, such as shaking, stiffness, and difficulty with balance and coordination. Symptoms usually begin gradually and worsen over time. As the disease progresses, people may have difficulty walking and talking. They may also have mental and behavioral changes, sleep problems, depression, memory difficulties, and fatigue.Mutations in GBA1, which encodes lysosomal enzyme glucocerebrosidase (GCase), are a relatively prevalent risk factor associated with Parkinson’s disease and aggravating disease progression. GBA1 mutations increase risk for developing PD (and related neurodegenerative disorders). PD-GBA similar to idiopathic PD, earlier onset and more rapid progression.

AMYOTROPHIC LATERAL SCLEROSIS (ALS)

Amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) is a devastating, late-onset, neurodegenerative disease characterized by loss of both upper and lower motor neuron function. ALS affects approximately 6 in 100,000 individuals. While most cases are sporadic, familial ALS is observed in 5 to 10% of individuals who are diagnosed with ALS.

Clinically, ALS presents with focal muscle weakness, twitching or slurred speech, over time the symptoms intensify and spread to the whole body. Eventually, affected individuals lose the ability to move, chew, swallow, speak and breathe. On average, death occurs within 3 to 5 years of symptom onset.

There is no cure for ALS. Current treatments options have been shown to slow the progression of symptoms and improve quality of life but they can’t reverse the damage or stop the motor neuron demise occurring throughout the brain and spinal cord.

Capsida is developing novel gene therapy for the treatment of ALS. Delivered in a single intravenous infusion and designed to target both upper and lower motor neuron degeneration, our hope is to address the progressive loss of function and ultimately the loss of life in patients with ALS.

Mehta et al., 2018; Ajroud-Driss and Siddique 2014; ALS Association website: als.org

FRIEDREICH’S ATAXIA (FA)

Friedreich’s ataxia (FA) is a debilitating, life-shortening degenerative neuromuscular disorder affecting approximately 1 in 50,000 people. Typically, onset begins in childhood and adolescence and is characterized by progressive loss of balance and coordination and muscle weakness, leading to confinement to a wheelchair. Disease advancement is also associated speech, vision, and hearing impairment as well as heart conditions and diabetes.

Friedreich’s ataxia is caused by a defect in the frataxin gene (FXN) that leads to decreased levels of the protein frataxin. This deficiency leads to decrease cell energy production that results in the degeneration of nerve cells in the brain and spinal cord. There are no currently approved therapies to slow or reverse the disease and treatment is focused on symptom management including physical, occupational and speech therapy.

Capsida is developing a novel gene therapy for the treatment of FA. Delivered as a single intravenous infusion and targeting the underlying pathology, our aim is to alter the progression of disease and improve the quality and length of life of those affected by FA.

Zesiewicz et al; Burk et al 2017; Cook et al 2017; Zhang et al; Corben et al.