Forward-Looking Statements and Market Data
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We are pioneering a new class of oligonucleotide-based therapies called Antibody Oligonucleotide Conjugates, or AOCs, designed to overcome the current limitations of oligonucleotide therapies in order to treat a wide range of serious diseases. We utilize our proprietary AOC platform to design, engineer and develop therapeutics that combine the tissue selectivity of monoclonal antibodies, or mAbs, and the
precision of oligonucleotide therapies in order to access previously undruggable tissue and cell types and more effectively target underlying genetic drivers of diseases. We are initially focused on muscle diseases to demonstrate the capabilities of our AOCs, and our muscle franchise consists of five programs. Our lead product candidate, AOC 1001, is designed to treat myotonic dystrophy type 1, or DM1, a rare monogenic muscle disease. Following regulatory clearance, we plan to initiate a Phase 1/2 clinical trial of AOC 1001 in the second half of 2021. We also intend to advance AOC product candidates in our four other muscle programs focused on the treatment of facioscapulohumeral muscular dystrophy, or FSHD, Duchenne muscular dystrophy, or DMD, muscle atrophy and Pompe disease. In addition to our muscle franchise, we have development efforts focused on immune, cardiac and other cell types.
Oligonucleotide therapeutics are designed based on genomic information to specifically inhibit or modify the expression of disease-related proteins and RNAs. Considerable progress has been made toward harnessing the potential of oligonucleotides, and multiple oligonucleotide therapies have been approved for the treatment of several diseases. However, in light of their physical properties, effective systemic delivery of oligonucleotides to a broad range of cells and organs has been one of the most significant factors limiting their utility. Our deep experience with oligonucleotide therapeutics, modulation of RNA processes, antibody engineering and conjugation, and drug delivery techniques provide the foundation for our efforts to address some of the key limitations of oligonucleotide therapies. We collectively refer to the know-how and proprietary technology born out of this experience, and their systematic application in the design and development of our product candidates, as our AOC platform.
Using our AOC platform, we have established a framework for screening potential cell surface protein-mAb pairs to determine which pairs are well-suited to deliver oligonucleotides to specific cell types to induce pharmacologic changes. In addition to engineering optimized mAbs, we are able to engineer and deploy various types of oligonucleotides whose specific mechanisms of action are designed to modify RNA function in different ways. This flexibility allows us to use oligonucleotides tailored to have the potential to modulate a given disease process, and we further engineer our oligonucleotides to maximize their specificity, potency and stability. Beyond the specific mAb and oligonucleotide components of our engineered AOCs, we also optimize the antibody conjugate design, including the linker, for stability and durability.
We believe that the product candidates derived from our AOC platform will have the potential to offer the following distinct advantages:
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Expand scope of diseases addressable with oligonucleotides: (i) utilize identified cell surface protein-antibody pairs to design oligonucleotides in order to address various previously undruggable tissue and cell types to induce pharmacologic changes in those tissues and cells; (ii) flexibility to deploy an appropriate oligonucleotide type for different diseases; and (iii) optimize all structural components of our AOCs for effective delivery—the oligonucleotide, the mAb and the antibody conjugate design. |
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Potential to mitigate toxicity by limiting drug exposure: (i) selection of the most potent oligonucleotide type; (ii) targeted delivery to tissues and cells; and (iii) infrequent administration. |
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Less frequent dosing: (i) ability to deliver oligonucleotides to tissues and cells at concentrations that produce pronounced and prolonged pharmacodynamic effects as observed in our preclinical models; and (ii) ability to select appropriate oligonucleotide mechanisms to maximize durability. |
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Readily reproducible and scalable: (i) AOCs synthesized using well-established and scalable methods for manufacturing mAbs and oligonucleotides; and (ii) ability to use a single mAb across multiple programs provides significant leverage around development costs and timelines associated with each incremental muscle program. For example, we use the same mAb targeting TfR1 across all our muscle programs. |
We are initially focused on muscle diseases for which we believe our AOC approach can overcome the limitations of current oligonucleotide therapies. For example, a single dose of an AOC administered to
mice demonstrated a 95% reduction of target gene expression in mouse skeletal muscle, which in part led us to focus on developing a pipeline of AOCs in muscle diseases.
The first program in our muscle franchise is for the treatment of DM1 and we are developing our lead product candidate, AOC 1001, as a potentially disease-modifying therapeutic. DM1 is a monogenic, autosomal dominant, progressive disease that primarily affects skeletal and cardiac muscle and is caused by a mutation in the dystrophy myotonic protein kinase, or DMPK, gene product or DMPK RNA. DM1 is estimated to affect over 40,000 people in the United States and there are similar prevalence estimates for Europe. However, we believe that, consistent with other rare diseases, the patient population is currently underdiagnosed due to the lack of available therapies. AOC 1001 consists of a proprietary mAb that binds to a transporter protein, transferrin receptor 1, or TfR1, conjugated with a small interfering RNA, or siRNA, that is designed to address the underlying cause of DM1 by reducing the levels of DMPK RNA. In preclinical studies, we observed the ability of our AOC to deliver siRNAs to muscle cells, and reduce levels of messenger RNA, or mRNA, for the DMPK gene, the molecular driver of the disease, in a durable, dose-dependent manner, meaning a long-lasting effect that is proportional to the amount of the AOC administered. Following regulatory clearance, we plan to initiate a Phase 1/2 clinical trial of AOC 1001 in patients in the second half of 2021 to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and exploratory clinical measures associated with AOC 1001. Due to the lack of available therapies in this rare disease, should our trial be successful, we plan to explore the potential to advance AOC 1001 into registrational trials in order to expedite making AOC 1001 available for a patient population in severe need.
We also are developing AOCs to treat the underlying causes of FSHD, DMD, muscle atrophy and Pompe disease. FSHD is one of the most common forms of muscular dystrophy, with onset typically in teens and young adults. FSHD occurs in approximately one in every 20,000 individuals in the United States and we estimate that FSHD affects 16,000 to 38,000 people in the United States. However, we believe that, consistent with other rare diseases, the patient population is currently underdiagnosed due to the lack of available therapies. FSHD is caused by aberrant expression of a gene, double homeobox 4, or DUX4, in adult skeletal muscle and is characterized by progressive skeletal muscle loss. Our therapeutic strategy in FSHD is to use an AOC based on our proprietary mAb targeting TfR1, to deliver an siRNA targeted to the DUX4 mRNA. We are currently in the process of advancing our AOC FSHD program into investigational new drug application, or IND, enabling studies. Following additional preparatory preclinical studies and regulatory clearance, we plan to initiate clinical studies in 2022 to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and exploratory clinical measures associated with the AOC FSHD program. Due to the lack of available therapies in this rare disease, should our trial be successful, we plan to explore the potential to advance our AOC FSHD program into registrational trials in order to expedite making it available for a patient population in severe need.
Another program in our muscle franchise is for the treatment of DMD, which is the most common and severe form of muscular dystrophy and is progressive, irreversible and ultimately fatal. DMD occurs in approximately one in every 3,500 to 5,000 live male births and is estimated to affect 10,000 to 15,000 people in the United States. DMD is caused by mutations in the DMD gene that encodes for the gene product dystrophin, a protein critical for the normal function of muscle cells. These mutations lead to certain exons being misread resulting in the loss of function of the dystrophin protein. Our oligonucleotides are designed to promote the skipping of those exons to restore a functional version of the dystrophin protein. We are focusing our initial efforts on the development of AOCs for mutations amenable to skipping Exon 44, Exon 51 and Exon 45. We intend to conjugate the oligonucleotides to our proprietary mAb targeting TfR1. In a preclinical model of DMD, the mdx mouse model, we observed that treatment of mdx mice with an AOC caused a greater than 50-fold increase in exon skipping compared to an equimolar dose of the unconjugated oligonucleotide. We have three programs in development for DMD targeting Exon 44, Exon 51 and Exon 45. We are currently in the process of advancing our first program targeting Exon 44 into IND-enabling studies. Following additional preparatory preclinical studies and regulatory clearance, we plan to commence a clinical trial for our program targeting Exon 44 in 2022.
An additional program in our muscle franchise is for muscle atrophy. Muscle atrophy is the loss of skeletal muscle mass that leads to muscle weakness and physical disability and can be caused by malnutrition, medications, injury or diseases such as cachexia and many rare genetic muscle disorders.
Our product candidate will consist of our proprietary mAb targeting TfR1 conjugated with an siRNA designed to downregulate the levels of muscle RING-finger protein-1, or MuRF1, mRNA, a muscle-specific ubiquitin ligase, or E3 ligase, that has been shown to be upregulated upon induction of muscle atrophy. By targeting MuRF1, we have focused on an approach employing common effectors of both the catabolic and anabolic pathways associated with the degradation of protein in muscle cells, unlike prior attempts to find therapeutics that primarily addressed either catabolic or anabolic pathways. In preclinical studies, we observed that a single 3 mg/kg dose of the siRNA in our AOC resulted in a greater than 50% reduction in MuRF1 mRNA for over 20 weeks. We are in the process of evaluating multiple disease models of muscle atrophy to identify an optimal development path in rare disease indications and/or in diseases that impact large patient populations. Our continued research activities will inform our view on the indications and development path to pursue.
We are also pursuing a program in Pompe disease, a rare muscle disease. Pompe disease is a autosomal recessive lysosomal storage disease caused by a mutation in the gene that encodes for acid alpha-glucosidase, or GAA, that results in the buildup of glycogen in the body’s cells, causing impairment of normal tissue and organ function. Pompe disease is currently treated with enzyme replacement therapy, or ERT, which does not adequately address the breakdown of muscle tissue associated with the disease. Our program in Pompe disease also utilizes an AOC based on our proprietary mAb targeting TfR1 to deliver an siRNA targeting the glycogen synthetase 1, or GYS1, mRNA to diminish the toxic accumulation of glycogen in muscle. We are in the process of developing a lead candidate for Pompe disease.