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 are designed to bring disease modifying therapies to patients with rare and common diseases across all ages.

PIPELINE

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 three 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 three 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 have demonstrated in non-human primates (NHPs) that we can transduce more brain cells while reducing transduction of liver and other organs, following intravenous (IV) administration. In addition, our engineered capsids are well tolerated with no clinical pathology or immunogenicity findings, including the liver and DRGs. 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 even when delivered via invasive brain surgery methods transduce a very small percentage of brain cells, restricting their use to diseases where limited transduction is sufficient – mostly a subset of ultra-rare, infant diseases.

Capsida’s proprietary technology enables the creation of engineered capsids that can achieve expression in 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 expression in non-targeted organs – especially the liver, enabling 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 (across the spine into the cerebrospinal fluid bathing the spinal cord), or direct administration into the brain tissue. Capsida has developed IV-delivered capsids with ~4000-fold difference in CNS expression versus liver targeting relative to naturally occurring AAV9.

We have three wholly owned programs. Our programs for Genetic Epilepsy Due to STXBP1 Mutations and Parkinson’s disease associated with GBA mutations (PD-GBA) are 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 estimated to affect one in 30,000 children globally. It is associated with severe developmental delay and intellectual disability, 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 throughout the 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. Our STXBP1 development candidate is designed to stably supplement 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 and significantly improves the quality of life for patients with genetic epilepsy due to STXBP1 mutations. The STXBP1 program is in IND enabling studies to support initiation of clinical trials in the first half of 2025. Capsida has a license agreement and research collaboration with Baylor College of Medicine and Associate Professor of Neuroscience Mingshan Xue, who has developed STXBP1 mouse models and AAV gene therapy approaches, to support development of this program.

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

Parkinson’s Disease Associated with GBA Mutations

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, with an estimated prevalence of more than 10 million adults worldwide and nearly 1 million in the United States. Current evidence suggests up to 15% of PD patients have GBA1 mutations, making this the most common genetic risk factor for PD. A key hallmark of PD is the loss of specific cells in the brain called nigrostriatal dopaminergic neurons, and development and spread of Lewy bodies, which are aggregated protein inclusions. PD-GBA is associated with motor and non-motor symptoms, including tremor, rigidity, slowness of movement, cognitive decline, psychiatric symptoms, and sleep disturbances. Currently, there are no approved disease modifying treatments for any form of PD, including PD-GBA. Though standard of care is available for treatment of motor symptoms, motor fluctuations and dyskinesias (abnormal involuntary movements) develop in many patients, and non-motor symptoms will frequently persist, all of which can be debilitating in and of themselves.

Capsida is developing a novel gene therapy, CAP-003, for the treatment of PD-GBA. Capsida’s gene therapy offers the potential to supplement GBA1 protein with a single intravenous infusion, enabling long-term disease modification and substantially slowing disease progression with limited treatment burden. Capsida aims to target critical cortical and sub-cortical areas of the brain associated with PD-GBA, such as the substantia nigra, caudate nucleus, putamen, cortex, and thalamus. The PD-GBA program is in IND enabling studies to support initiation of clinical trials in the first half of 2025.

Sidransky E et al., 2009; Braak et al., 2003, Parkinson’s Foundation

Capsida’s Fully Integrated Capabilities

Our pipeline is enabled by our fully integrated cross functional capabilities in Capsid Engineering, Discovery and Preclinical, Manufacturing Operations, and Clinical Development.

PIPELINE

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Central Nervous System Disorders

We have three wholly owned programs. Our programs for Genetic Epilepsy Due to STXBP1 Mutations and Parkinson’s disease associated with GBA mutations (PD-GBA) are described below:

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

Parkinson’s Disease Associated with GBA Mutations

Sidransky E et al., 2009; Braak et al., 2003, Parkinson’s Foundation

Capsida’s Fully Integrated Capabilities

Our pipeline is enabled by our fully integrated cross functional capabilities in Capsid Engineering, Discovery and Preclinical, Manufacturing Operations, and Clinical Development.

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-invasive, IV-delivered 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 IV administration for CNS diseases, or optimal route of intra-ocular administration for ophthalmic diseases. 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 effectively address a specific disease.

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:

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:

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 therapeutic efficacy needed to treat a given disease indication, which guides capsid engineering efforts, and then assessing candidate capsid performance in preclinical disease models, NHPs and human disease-relevant in vitro models.

In each case, the novel engineered capsid is just half of the drug product. Our development process for the other half, the encapsidated gene cargo, begins by investigating the appropriate therapeutic strategy suited for the disease of interest – whether that is gene supplementation, 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 complementary paths for improvement of efficacy and safety profiles for our novel drug products.

Optimized cargo is then paired with the novel capsid and the complete drug substance is characterized for its ability to safely achieve efficacy thresholds expected to treat the disease. Once a development candidate has been selected, IND-enabling translational efforts begin to define the safe and efficacious therapeutic index of the drug product and establish clinical dosing rationale.

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 assessments 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 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.

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.