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AOC 1001 for Myotonic
Dystrophy Type 1 (DM1)

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DM1 is a monogenic, autosomal dominant, progressive disease that primarily affects skeletal and cardiac muscle. The disease is highly variable with respect to disease severity, presentation and age of onset. All forms of DM1, except the late-onset form, are associated with high levels of disease burden and premature mortality. DM1 patients can suffer from various manifestations of the disease including myotonia and muscle weakness, respiratory problems, fatigue, hypersomnia, cardiac abnormalities, severe gastrointestinal (GI) complications, and cognitive and behavioral impairment.

DM1 is caused by an increase in the number of CUG triplet repeats found in the 3’ non-coding region of the DMPK gene product. The number of repeats ranges from up to approximately 35 in healthy individuals to many thousands in DM1 patients. The higher than normal number of CUG repeats form large hairpin loops that entrap the DMPK pre-mRNA in the nucleus and impart toxic activity, referred to as a toxic-gain-of function. Specifically, mutant DMPK pre-mRNA sequesters a critical CUG binding protein, muscle blind-like protein (MBNL), forming nuclear foci and inhibiting its ability to perform its normal function of guiding pre-mRNA processing of gene transcripts from many other genes. As a result, multiple pre-mRNAs that encode key proteins are mis-processed. The resulting atypical proteins that are translated ultimately cause DM1. When DMPK and CUG levels are reduced as result of DPMK mRNA level reductions, nuclear foci are diminished and MBNL can perform its normal function.

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DM1 Disease Process

AOC 1001 consists of a proprietary mAb that binds to a transporter protein, transferrin receptor 1 (TfR1), conjugated with an 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 mRNA for the DMPK gene, the molecular driver of the disease, in a durable, dose-dependent manner.

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We plan to submit an investigational new drug application (IND) for AOC 1001 in 2021 and expect to initiate a Phase 1/2 clinical trial by the end of the same year.

Treatment of mice with a single dose of AOCs carrying a DMPK siRNA produce marked, long lasting reductions in the expression of DMPK.

mRNA Knockdown (Gastrocnemius)

• >75% knockdown with most active sequences at ED50 <1 mg/kg (single dose)
• Duration of effect was >5 weeks after a single dose

DM1 cells show a distinct pattern of splicing that differs from healthy myotubes because of sequestration of MBNL1. Reduction in expression of DMPK mRNA and CUG repeats results in a normalization of the splice patterns. siRNA-induced knockdown produces the predicted splice normalization. Moving a therapeutic forward for DM1 requires a monoclonal antibody to the human transferrin receptor. Humanization of an anti-human transferrin receptor antibody for development has been completed, and bioconjugation CMC activities to enable clinical applications have been initiated. This human antibody is effective at delivering siRNA payloads to the skeletal muscles of non-human primates.

Muscle Atrophy

Muscle atrophy is the loss of skeletal muscle mass that leads to muscle weakness and physical disability. Muscle atrophy can be caused by immobility, aging, malnutrition, medications, or a wide range of injuries or diseases that impact the musculoskeletal or nervous system. Examples of diseases that cause muscle atrophy include those characterized by large patient populations such as sarcopenia and cachexia, as well as many rare genetic muscle diseases.

Muscle atrophy is caused by a change in the balance between catabolic (protein breakdown) and anabolic (protein synthesis) signals that activate pro-inflammatory cytokine pathways that induce protein degradation or inhibit growth factor pathways that promote protein synthesis, respectively. Genetic profiling of atrophic muscles has identified a group of ubiquitin ligases (E3 ligases) that are upregulated upon induction of muscle atrophy. Of these, the muscle-specific E3 ligase muscle ring finger protein 1 (MuRF1) has been shown to be upregulated in most in vivo models, as well as in clinical trials. Furthermore, genetic ablation of MuRF1 in mice has been shown by third parties to render muscles partially resistant to various conditions of muscle atrophy.

Our AOC consists of our proprietary mAb targeting TfR1 conjugated with an siRNA designed to downregulate the levels of MuRF1 mRNA, a muscle-specific ubiquitin ligase (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.

We are currently in the process of selecting a product candidate to advance into clinical development.

DMD is a monogenic, X-linked recessive disease caused by mutations in the gene that encodes for dystrophin, a protein critical for the normal function of muscle cells. DMD almost exclusively occurs in boys and is progressive, irreversible and ultimately fatal. The dystrophin protein maintains the integrity of muscle fibers and acts as a shock absorber through its role as the foundation of the dystrophin associated glycoprotein complex, a group of proteins that connects the inner and outer elements of muscle cells. The absence of functional dystrophin leads to stresses and tears of muscle cell membranes, resulting in muscle cell death and the progressive loss of muscle function.

We are developing AOCs to treat the underlying cause of DMD. The oligonucleotides in our AOCs are designed to promote the skipping of specific exons to allow the production of the dystrophin gene product. In preclinical studies, we observed that treatment of an mdx mouse with an AOC caused a greater than 50-fold increase in exon skipping compared to an equimolar dose of the unconjugated oligonucleotide.

We are focusing our initial efforts on the development of AOCs for mutations amenable to skipping Exon 44, Exon 45 and Exon 51 and we intend to conjugate these individual oligonucleotides to our proprietary mAb targeting TfR1.

Facioscapulohumeral Muscular Dystrophy (FSHD) and Pompe Disease

We are also pursuing programs in FSHD and Pompe disease, both rare muscle diseases. FSHD is one of the most common forms of muscular dystrophy with onset typically in teens and young adults. FSHD is caused by aberrant expression of a gene, double homeobox 4 (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.

Pompe disease is a rare, autosomal recessive lysosomal storage disease caused by a mutation in the gene that encodes for acid alpha-glucosidase (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 (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 (GYS1) mRNA to diminish the toxic accumulation of glycogen in muscle. We are in the process of developing lead candidates for both FSHD and Pompe disease.

We also intend to pursue the development of AOCs in cell types in addition to muscle. For example, we are collaborating with Eli Lilly and Company for the discovery, development and commercialization of AOCs directed to up to six mRNA targets initially in immunology and other select indications outside of muscle.

In preclinical models, we observed the ability of AOCs not only to deliver to the liver, skeletal and cardiac muscle, but also to other tissue and cell types, including immune cells. For example, we have identified multiple receptor-antibody pairs that could be used in our AOCs in order to deliver siRNAs into different immune cells, including those related to immuno-oncology. In preclinical studies, we observed significant AOC-mediated mRNA knockdown in CD8+ and CD4+ tumor infiltrating lymphocytes and Tregs in vivo, while also observing no effect on mRNA levels in T or B cells in the spleen. These observations around the specificity and selectivity of our AOCs are the basis for our interest in exploring the utility of our AOCs in immunology.

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Information from the National Library of Medicine

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Layout table for eligibility information

Ages Eligible for Study:	18 Years to 70 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No
Sampling Method:	Probability Sample

DM1 has a prevalence rate of approximately 1 per 2,300. There are no expected gender differences. Both men and women will be selected for this study.

Children with DM1 are not included in this project because the pathophysiological basis of congenital and childhood DM1 appears to be mechanistically distinct.

Inclusion criteria:

• Age 18 to 70 (inclusive)
• Competent to provide informed consent
• Clinical diagnosis of DM1 based on research criteria1 or positive genetic test
• Comment: The clinical research criteria require myotonia, muscle weakness in a characteristic distribution, and history of similar findings in a first degree relative. Genetic testing confirmed the diagnosis of DM1 in > 99% of individuals who satisfied these criteria.2

Exclusion criteria:

• Symptomatic renal or liver disease, uncontrolled diabetes or thyroid disorder, or active malignancy other than skin cancer.
• Current alcohol or substance abuse
• Concurrent enrollment in clinical trial for DM1, or participation in trial within 6 months of entry.
• Concurrent pregnancy or planned pregnancy during the course of the study.
• Concurrent medical condition that would, in the opinion of the investigator or clinical evaluator, compromise performance on study measures.
• Note: non-ambulatory participants are not excluded, but are limited to <15% of enrollment.

Dm1000

Inclusion criteria for participants in the muscle biopsy sub-study:

• Of the 95 patients undergoing the tibialis anterior muscle biopsy, at least half will have at least moderate weakness of ankle dorsiflexion, defined as MRC score ≤ 4+. This is in order to obtain a muscle tissue sample in a person more severely affected with myotonic dystrophy. Approximately 10 patients at each site will undergo the muscle biopsy.

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Exclusion criteria for 95 participants in the muscle biopsy sub-study:

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• Known CTG repeat expansion size less than 100 repeats, unless there are clear cut signs of limb weakness and muscle wasting. This is in order to obtain a muscle tissue sample in a person more severely affected with myotonic dystrophy.
• Use of anticoagulant such as warfarin or a direct oral anticoagulant (e.g. dabigatran) due to the increased risk of bleeding.
• Use of aspirin or non-steroidal anti-inflammatory agents should be discontinued 3 days prior to the biopsy procedure, if possible.
• Platelet count <50,000 (if known) due to the increased risk of bleeding.
• History of a bleeding disorder due to the increased risk of bleeding.
• Advanced wasting of tibialis anterior (TA) muscle that precludes needle muscle biopsy in order to ensure that a sample taken would be of muscle and not just fat and fascia.
• Previous muscle biopsy of either TA in order to provide muscle tissue samples of non-biopsied muscles.