PLATFORM TECHNOLOGY - Antibody Oligonucleotide Conjugates (AOCs™) - Revolutionizing a New Class of Targeted RNA Therapeutics

INTRODUCTION

Therapeutic agents designed to modify the function of spe­cific disease-related RNAs have been a promising approach in drug development for many years. Several recent advances in clinical research involving use of antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) indicate that messen­ger RNA (mRNA) is a proven target for treating genetic diseases, including many rare diseases. These first-generation RNA-based therapeutics designed to target mRNA are often limited to dis­eases in which treatments must be delivered by local injection or by targeting the liver. With recent advances in RNA technology, including development of Antibody Oligonucleotide Conjugates (AOCs™), we now have the potential for RNA therapeutics to tar­get new cells and tissues beyond the liver, a major challenge in the field in recent years. Broadening the range of tissues amenable to an AOC-based approach potentially enables the treatment of many more diseases than is possible with existing RNA therapeutics, including some conditions that affect larger patient populations. Avidity Biosciences recently demonstrated the first-ever successful targeted delivery of RNA to muscle in humans, a revolutionary advancement for the field of RNA therapeutics that may help transform the opportunities to advance research targeting many previously untreatable diseases in the years ahead.

AOCS™: BUILDING ON THE POWER OF OLIGONUCLEOTIDES

Researchers at Avidity Biosciences are building on learnings from ASOs and siRNAs that have represented major advances in the field of RNA therapeutics. Our team is creating a new class of RNA therapeutics called AOCs that have the potential to pre­cisely target and modify the underlying genetic drivers of dis­eases. Our proprietary AOC platform is designed to combine the specificity of monoclonal antibodies (mAbs) with the precision of oligonucleotide therapies to target the genetic defects associated with a wide range of diseases.

The AOC platform is built from years of in-house engineer­ing that integrates oligonucleotide therapeutics, modulation of RNA processes, antibody engineering and conjugation, and ad­vanced drug delivery techniques. The broad flexibility of the AOC platform enables us to deploy various types of oligonucleotides, including siRNAs and phosphorodiamidate morpholino oligomers (PMOs), that can be engineered to modify RNA func­tion in different ways to address specific disease processes. Ex­amples include siRNAs that can reduce the expression of disease-related RNA, and splice-modifying oligonucleotides that can correct aberrant RNA processing. By marrying two validated technologies – mAbs and oligonucleotides – there is the potential to treat many more diseases than is possible with ASOs and siRNAs alone.

There are three key building blocks that comprise AOCs – mAbs, oligonucleotides, and linkers. mAbs are advantageous because they have well-established safety profiles and high speci­ficity and affinity that has supported their widespread use for more than 30 years. Our team engineers mAbs to be effector-function null and selects epitopes that are poised to achieve optimal activity levels. We are employing a mAb to the transferrin receptor in some of our lead clinical pro­grams. Antibodies employed for future therapeutic programs by Avidity may use mAbs to different cell surface proteins as dictated by a disease we are targeting and specifically the target cell population.

When choosing the oligonucleotide component of AOCs, we consider several factors, including the underlying disease pathophysiology. siRNAs have shown ben­efits including favorable safety profiles (with no known thrombocytopenia, liver or renal toxicity), potency in the sub-nanomo­lar range, and sustained activity in both the cytoplasm and the nucleus. We select and modify siRNAs to diminish the risk of potential off-target effects post-administra­tion, and we engineer them to enhance their efficacy, durability, and safety profiles. PMOs present similar advantages com­pared to siRNAs, including favorable safety profiles, potency in the nanomolar range, and sustained activity to promote exon skipping.

Known linkers are used to conjugate mAbs and oligonucleotides and are engi­neered to enhance their stability and dura­bility. We also optimize several other key aspects of AOCs, including sites of conju­gation and the ratio of oligonucleotides to antibodies. Together, these AOC building blocks offer distinct advantages including:

• Ability to target tissue and cell types be­yond the liver
• Flexibility to select and deploy the most potent oligonucleotides
• Maximum therapeutic durability, en­abling infrequent dosing
• Readily reproducible and scalable pro­duction

Among all the advantages in this new class of drugs, the most important is the ability to target tissue and cell types be­yond the liver, which have been generally inaccessible to RNA therapeutics. We are pursuing development of AOCs that may target tissue and cell types, including skeletal muscle, cardiac tissue, and im­mune cells. Our first AOC programs are from our muscle disease franchise and in­clude clinical-stage programs in myotonic dystrophy type 1 (DM1), Duchenne mus­cular dystrophy (DMD), and facioscapulo­humeral muscular dystrophy (FSHD). The results with AOC technology thus far show strong potential to target a broader range of rare and common diseases in the future.

TARGETED DELIVERY OF RNA INTO SKELETAL MUSCLE

There are a range of muscle diseases, including many rare diseases, in which op­timal therapeutic activity can only be achieved by directly targeting muscle tis­sues where the underlying dysfunctional mRNA resides. Historically, this has been a significant challenge in the RNA thera­peutics field. But a growing body of clinical and preclinical data show the potential of AOCs to overcome the limitations of other RNA therapeutics and successfully reach muscle tissue. In December 2022, data from a preliminary assessment of the Phase 1/2 MARINA® clinical trial in DM1 showed that Avidity’s lead product candi­date, delpacibart etedesiran or del-desiran (AOC 1001), achieved a historical first-ever event in the RNA field – successful tar­geted delivery of RNA to muscle in humans.

This revolutionary advancement pro­vides evidence we can overcome a chal­lenge that has eluded scientists for decades – the opportunity to target tissues beyond the liver with RNA therapeutics. This breakthrough milestone was only the beginning. Avidity recently announced two significant data readouts from the DM1 program. In March 2024, we reported new positive long-term data from the Phase 2 MARINA open-label extension (MARINA-OLE™) trial of del-desiran show­ing reversal of disease progression in peo­ple living with DM1 across multiple endpoints, including video hand opening time (vHOT), muscle strength and activities of daily living, when compared to a matched END-DM1 natural history popu­lation over one year. The data also con­tinue to demonstrate favorable safety and tolerability, based on more than 265 infu­sions totaling 61.1 patient-years of expo­sure. Also, in October 2023, we announced positive data of del-desiran demonstrating improvement in multiple additional functional measures including hand grip, muscle strength and patient re­ported outcomes in people living with DM1. These data were presented at the 28th Annual Congress of the World Mus­cle Society (WMS). These data augment previously reported positive data showing improvements in myotonia, muscle strength, and mobility reported at the American Academy of Neurology (AAN) Annual Meeting in April 2023.

Del-desiran continues to be assessed in the ongoing MARINA-OLE study in adults living with DM1. We are initiating the global pivotal Phase 3 HARBOR™ trial, a randomized, placebo-controlled, dou­ble-blind study to evaluate del-desiran in adults living with DM1, by the end of June 2024.

A FOCUS ON DM1

DM1 is an underrecognized, progres­sive, and often fatal neuromuscular dis­ease that affects more than 40,000 people in the US and has no approved treatments that address the root cause of the disease. It is a complex, multisystemic disease that primarily affects skeletal, cardiac, and smooth muscle. Symptoms can vary from patient to patient but may include muscle weakness and myotonia (the impaired re­laxation and prolonged contraction of skeletal muscle), respiratory and cardiac problems, fatigue, hypersomnia, severe gastrointestinal complications, and cogni­tive and behavioral impairment – resulting in a significant decline in quality of life.

DM1 is caused by an increase in the number of CTG triplet repeats found in the myotonic dystrophy protein kinase (DMPK) gene, which are toxic. In healthy individu­als the number of repeats is approximately 35, but in people with DM1 there can be thousands. Del-desiran consists of a mAb that binds to transferrin receptor 1 (TfR1) conjugated with an siRNA that is engineered to reduce levels of DMPK mRNA in skeletal, cardiac and smooth muscle. The therapeutic hypothesis is that by reducing or inhibiting the formation of toxic DMPK mRNA, we can change the course of the disease in patients. This therapeutic ap­proach may potentially address the spec­trum of symptoms that people with DM1 experience. Del-desiran recently received FDA Breakthrough Therapy designation for the treatment of DM1. Del-desiran has previously been granted Orphan Drug and Fast Track designations by the FDA and Orphan designation by the EMA for the treatment of DM1.

ADDRESSING RARE MUSCLE DISEASES

Another advantage of the AOC plat­form is its flexibility. It has the potential to be used to develop multiple RNA-targeting therapies using similar principal compo­nents. Following successful targeted deliv­ery of RNA into skeletal muscle, AOCs have further demonstrated their potential to treat muscle diseases in addition to DM1. Avidity is also advancing AOCs in the clinic that are designed to address the root cause of the rare muscle diseases DMD and FSHD.

DMD is an X-linked, irreversible, pro­gressive disease caused by a genetic mu­tation that prevents the production of dystrophin, a protein that protects muscle cells from injury during contraction. The lack of functional dystrophin leads to stress and tears of muscle cell membranes, re­sulting in muscle cell death and progres­sive loss of muscle function.

Our AOCs are designed to promote the skipping of specific exons to allow the production of a functional dystrophin pro­tein. There are many different exon muta­tions that can cause DMD, but our initial development efforts are focused on AOCs that can induce skipping for exon 44. There are currently no approved treat­ments for people with DMD amenable to exon 44 skipping (DMD44). DMD44 is ex­tremely rare and affects approximately 900 people in the US (primarily boys).

AOC 1044 is an investigational ther­apy designed to deliver PMOs to skeletal muscle and heart tissue in order to skip exon 44 of DMD and enable dystrophin production. AOC 1044 is currently ad­vancing in the Phase 1/2 EXPLORE44™ trial, a randomized, placebo-controlled, double-blind study in healthy volunteers and participants with DMD44. In Decem­ber 2023, positive data from the EX­PLORE44 study showed AOC 1044 delivered unprecedented concentrations of PMO in skeletal muscle with up to 50-times greater concentrations of PMO in skeletal muscle following a single dose compared to peptide conjugated PMOs in healthy volunteers. AOC 1044 was well tolerated, demonstrated statistically signif­icant exon 44 skipping compared to placebo of up to 1.5% in healthy volun­teers after a single dose of 10 mg/kg AOC 1044, and increased exon skipping in all participants. Avidity plans to provide a first look at AOC 1044 data in people living with DMD44 in the second half of 2024.

FSHD is another type of muscular dys­trophy (one of the most common) for which AOCs have indicated their potential as an innovative treatment approach. FSHD is a rare, progressive, and variable hereditary muscle-weakening condition marked by significant pain, fatigue, and disability. The disease is caused by the ab­normal expression of a gene called double homeobox 4 (DUX4) and affects approxi­mately 16,000-38,000 people in the US. Symptoms often begin in adolescence and early adulthood. Patients typically first present skeletal muscle loss in the face, shoulders, arms, and trunk, eventually progressing to the lower body. Many pa­tients must eventually use a wheelchair for mobility. There are currently no approved treatments for FSHD.

AOC 1020 is an investigational siRNA AOC designed to reduce the ex­pression of the DUX4 mRNA and DUX4 protein. Prior research suggests that even small reductions in DUX4 expression may lead to significant clinical benefit for pa­tients. Taking advantage of the AOC plat­form, AOC 1020 utilizes the same mAb to deliver the therapeutic siRNA to muscle.

AOC 1020 is advancing in the Phase 1/2 FORTITUDE™ trial, a randomized, placebo-controlled, double-blind study in approximately 68 adults with FSHD. FOR­TITUDE will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynam­ics of AOC 1020 administered intra­venously. Avidity plans to share data from a preliminary assessment of AOC 1020 in approximately half of study participants in the second quarter of 2024.

EXPANDING INTO OTHER CELL TYPES

Avidity continues to explore the full potential of the AOC platform through in­ternal discovery efforts and research col­laborations and partnerships. For example, we recently expanded our inter­nal discovery pipeline to include new re­search and development candidates to treat conditions in skeletal muscle and car­diology. In November 2023, Avidity an­nounced a global licensing and research collaboration with Bristol Myers Squibb, potentially worth up to $2.3 billion total, focused on the discovery, development, and commercialization of multiple cardio­vascular targets leveraging the AOC plat­form. This new collaboration expands upon Avidity’s existing collaboration with MyoKardia, a wholly owned subsidiary of Bristol Myers Squibb, that is intended to help expand our therapeutic activities to include cardiac-specific indications.

Beyond cardiology, we are exploring the use of AOCs in the treatment of im­munologic diseases. We believe oligonu­cleotide therapies have the potential to address the challenges of immune re­sponses at the RNA level. However, the ability to modulate immune responses has been hampered by the inability to deliver these agents to immune cells. By identify­ing and optimizing antibodies for specific immune cell types, our goal is to leverage the AOC platform to develop product can­didates that can deliver siRNAs to disease-driving subsets of immune cells. Avidity is collaborating with Eli Lilly and Company initially on six mRNA targets in immunol­ogy and other select indications outside of muscle for the delivery, development, and commercialization of AOCs.

THE FUTURE OF RNA THERAPEUTICS

A rapidly growing body of evidence reinforces the significant promise of AOCs to address many areas of unmet need in health in entirely new ways, starting with skeletal muscle diseases. RNA therapeutics are a powerful approach when re­searchers are precise with targeting, which is only possible with expertise in molecular engineering and a comprehensive under­standing of different disease pathophysi­ologies. By focusing on continued innovation in the RNA field, we are on the way to expanding the possibilities of RNA therapeutics and opening the door to new potential treatments for a wider range of patients in the years ahead.

Dr. Arthur A. Levin serves as Distinguished Scientist and Strategic Leader at Avidity Biosciences and is a member of the Board of Directors. He previously held the position of Chief Scientific Officer at Avidity. He is a key opinion leader in the RNA therapeutics field who led teams responsible for the development of many oligonucleotides. Previously, he held the position of Executive Vice President of Research and Development at miRagen Therapeutics. Prior to that, he held senior drug development roles at Ionis (formerly Isis) Pharmaceuticals and Santaris Pharma. He has played key roles in the development of numerous oligonucleotides, including the first approved antisense drugs and the first microRNA-targeted therapeutic in clinical trials. He has a combined four decades of experience in all aspects of drug development from discovery through drug registration, both in large pharma and biotech companies. He has published more than 100 scientific articles and several of the most cited reviews in the field. He is on the scientific advisory boards of multiple institutions. He earned his PhD in toxicology from the University of Rochester and his bachelor’s degree in biology from Muhlenberg College.