AOC-Pompe Disease / Eli Lilly, Avidity Biosci, Novartis - LARVOL DELTA

Neutral Backbone Modifications Enhance the Pharmacokinetics and Biodistribution of Antibody-Oligonucleotide Conjugates with High Drug-to-Antibody Ratios. (PubMed, J Med Chem) - "PG-modified DAR2 AOCs improved pharmacokinetics and tissue distribution in mice while maintaining activity. These findings lay the groundwork for optimizing high-DAR AOCs."

Journal • PK/PD data • TFRC

Long-Term Safety and Tolerability of Del-Desiran in Myotonic Dystrophy Type 1: Final Results from MARINA-OLE™ (EAN 2026) - "Delpacibart etedesiran (del-desiran; AOC 1001) is an investigational antibody oligonucleotide conjugate comprised of a monoclonal antibody targeting transferrin receptor 1 for muscle delivery and an siRNA that induces degradation of DMPK mRNA to treat the underlying cause of DM1. Del-desiran showed favorable long-term safety and tolerability in adults with DM1. These data represent the longest safety results for a DMPK-targeted therapy and highlight potential of del-desiran to drive a new treatment paradigm for DM1. NEJ has received grant funding from NINDS (R01NS104010, U01NS124974), NCATS (R21TR003184), CDC (U01DD001242), and the FDA (2R01FD006071); receives royalties from the CCMDHI and the CMTHI, and research funds from Avidity Biosciences, A Novartis Company, Takeda, Sanofi Genzyme, Dyne, Novartis, Vertex Pharmaceuticals, Fulcrum Therapeutics, ML Bio, and Sarepta; provided consultation for Arthex, Novartis, AMO Pharma, Takeda."

Clinical • Late-breaking abstract • Genetic Disorders • Hematological Disorders • Muscular Dystrophy • Myotonic Dystrophy

Accelerating drug discovery with mass spectrometry-driven bioanalytical innovations and beyond. (PubMed, Bioanalysis) - "The emergence of structurally complex therapeutic modalities, including bispecific antibodies, antibody-drug conjugates, fusion proteins, incretins, radioligand therapeutics, antibody-oligonucleotide conjugates, and small interfering RNAs, demands advanced mass spectrometry workflows across the ADME pipeline...We identify five convergent innovation priorities: (1) addressing modality complexity through integrated ADME workflows; (2) continued advancement of instrument sensitivity for low-dose therapeutics; (3) resolving biotransformation challenges through enhanced analytical resolution; (4) improving qMSI capabilities for therapeutic-level tissue detection; and (5) implementing AI/ML-driven automation for data complexity management. Rather than advocating for MS-only solutions, we recommend integration of mass spectrometric structural specificity with complementary high-throughput technologies; immunoassays, hybridization ELISA, qPCR, and element-specific detection, to..."

Journal

High-dose biologics and bioconjugates delivery: Integrating molecular optimization with device design and routes of administration. (PubMed, Adv Drug Deliv Rev) - "Monoclonal antibodies (mAbs) and emerging bioconjugates such as antibody-drug conjugates (ADCs) and antibody-oligonucleotide conjugate (AOCs) now span oncology and immunology areas...Emerging modalities will further continue to influence the development of devices, including considerations for dosing frequency. Achieving this integrated vision requires a deeper understanding of pharmacokinetic failure modes and regulatory frameworks governing biologic-device development combination products."

Journal • Review • Oncology • Pain

Development of a DUX4-targeting antibody oligonucleotide conjugate as a therapy for FSHD. (PubMed, Nucleic Acids Res) - "Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular disease in which genetic mutations activate DUX4 expression in skeletal muscle. These data demonstrate the potential of AOC 1020 to treat the underlying cause of FSHD by suppressing DUX4 expression in muscles of patients with FSHD. The safety and efficacy of AOC 1020 is currently being investigated in clinical trials."

Journal • Fibrosis • Immunology • Muscular Dystrophy • ACTA1 • DUX4 • TFRC

Delpacibart Etedesiran Improves the Molecular Pathology of Myotonic Dystrophy Type 1 in the Phase 1/2 MARINA® Study. (PubMed, Mol Ther) - "We designed an antibody-oligonucleotide conjugate (AOC™), delpacibart etedesiran (del-desiran), to deliver a DMPK-targeting small interfering RNA to muscle via transferrin receptor 1-mediated cell internalization. The extent of increase in functional MBNL was associated with consistent trends towards muscle function improvement, confirming del-desiran's mechanism of action and supporting its development as a treatment for DM1. The translation of its pharmacodynamic activity from preclinical models (patient-derived myotubes and Macaca fascicularis (Cynomolgus monkeys)) to patients with DM1 demonstrates del-desiran's consistency across species and reveals the potential broad utility of the AOC™ platform in further neuromuscular diseases."

Journal • P1/2 data • CNS Disorders • Genetic Disorders • Muscular Dystrophy • Myotonic Dystrophy • ACACA

An Antibody-Oligonucleotide Conjugate for Myotonic Dystrophy Type 1. (PubMed, N Engl J Med) - P1/2 | "Our results are consistent with delivery of del-desiran to muscle and amelioration of aberrant alternative splicing in some patients with myotonic dystrophy type 1; two serious adverse events occurred. These data support further clinical investigation. (Funded by Avidity Biosciences; ClinicalTrials.gov number, NCT05027269.)."

Clinical • Journal • CNS Disorders • Genetic Disorders • Muscular Dystrophy • Myotonic Dystrophy

Colloidal Stability Assessment of a Model Antibody Oligonucleotide Conjugate. (PubMed, Mol Pharm) - "The greater protein-protein intermolecular interactions of the AOC native state are believed to be caused by short-range attractive electrostatic interactions between the localized negative charge of the oligonucleotide and positive surface charge of the mAb. These interactions could be effectively minimized by raising solution pH and/or screening charge by increasing the ionic strength."

Journal • Genetic Disorders

AOC 1044 induces exon 44 skipping and restores dystrophin protein in preclinical models of Duchenne muscular dystrophy. (PubMed, Nucleic Acids Res) - "We developed AOC 1044, an antibody-oligonucleotide conjugate (AOC) that combines a PMO-targeting exon 44 with an antibody against the transferrin receptor (TfR1), enhancing delivery to muscle tissues for patients with DMD amenable to exon 44 skipping (DMD44)...In nonhuman primates, single or repeated AOC 1044 doses resulted in dose-dependent increases in PMO concentration and exon 44 skipping across a range of muscle tissues, including the heart. Collectively, these findings highlight AOC 1044 as a promising therapeutic candidate for patients with DMD44, offering improved muscle targeting and meaningful dystrophin restoration, with potential clinical benefits in reducing muscle degeneration."

Journal • Preclinical • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • TFRC

Novel Precision Cardiology Treatment for PRKAG2 Cardiomyopathy, a Subset of Patients with Wolff-Parkinson-White Syndrome (AHA 2024) - "Antibody oligonucleotide conjugates (AOCs) can be designed to target PRKAG2 mRNA to treat PRKAG2 syndrome.Aims...Our data suggests AOC technology can be used efficiently to deliver siRNA to the heart. This precision cardiology treatment can significantly reduce PRKAG2 mRNA expression, offering a promising therapeutic approach for PRKAG2 syndrome, a currently incurable genetic condition with very limited treatment options."

Clinical • Cardiomyopathy • Cardiovascular • CNS Disorders • Congestive Heart Failure • Genetic Disorders • Heart Failure • Movement Disorders • TFRC

Structure-Activity Relationship of Antibody-Oligonucleotide Conjugates: Evaluating Bioconjugation Strategies for Antibody-Phosphorodiamidate Morpholino Oligomer Conjugates for Drug Development. (PubMed, J Med Chem) - "We demonstrate that αmTfR1-PMO conjugates induce dystrophin protein restoration in the skeletal and heart muscles of mdx mice. Our results show that αmTfR1-PMO conjugates are a potentially effective approach for the treatment of DMD."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • MTFR1

Structure-Activity Relationship of Antibody-Oligonucleotide Conjugates: Evaluating Bioconjugation Strategies for Antibody-siRNA Conjugates for Drug Development. (PubMed, J Med Chem) - "By utilizing cleavable and noncleavable linkers, we demonstrated the impact of linkers on PK and mRNA KD. To achieve optimal properties of antibody-siRNA conjugates, a careful selection of siRNA chemistry, DAR, conjugation sites, linkers, and antibody isotype is necessary."

Journal

Therapeutic Promise of Antibody-Oligonucleotide Conjugates for Rare Neuromuscular Disease (New Directions 2024) - No abstract available

CNS Disorders

Bioanalytical Approaches to Support the Development of Antibody-Oligonucleotide Conjugate (AOC) Therapeutic Proteins. (PubMed, Xenobiotica) - "Although the approaches herein can be applied to in vitro characterization of AOCs, this paper will focus on in vivo applications. This workflow relies on high-resolution mass spectrometry as the principal means of detection and leverages chromatographic, affinity-based, and enzymatic sample preparation steps."

Journal • Review

Phase 1/2 Trial Evaluating AOC 1044 in Healthy Volunteers and Participants with DMD Mutations Amenable to Exon 44 Skipping (DMD44): EXPLORE44 Trial Design (AAN 2024) - P1/2 | "AOC 1044 is an antibody-oligonucleotide conjugate (AOCTM) comprised of a humanized anti-transferrin receptor 1 (TfR1) antibody conjugated to multiple copies of a phosphorodiamidate morpholino oligomer (PMO) targeting DMD44 mRNA to produce truncated but functional dystrophin protein.Design/EXPLORE44TM (NCT05670730) is a randomized, placebo-controlled, double-blind phase 1/2 trial conducted in two parts...N/A"

Clinical • P1/2 data • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • TFRC

Antibody oligonucleotide conjugates: Development of AOC 1001 for the treatment of myotonic dystrophy (ACS-Fall 2023) - "Introduction to oligonucleotides and AOC 1001AOC 1001 preclinical and Phase-1 clinical data"

Genetic Disorders • Muscular Dystrophy • Myotonic Dystrophy

Targeted tissue delivery of RNA therapeutics using antibody-oligonucleotide conjugates (AOCs). (PubMed, Nucleic Acids Res) - "In mice, we show that AOC-mediated delivery is operable across various oligonucleotide modalities. AOC PKPD properties translated to higher species, providing promise for a new class of oligonucleotide therapeutics."

Journal • TFRC

Preliminary Assessment of the Phase 1/2 Clinical Trial Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AOC 1001 Administered Intravenously to Adult Patients with Myotonic Dystrophy Type 1 (DM1) (MARINA) (AAN 2023) - P1/2 | "AOC 1001 is an antibody oligonucleotide conjugate (AOC) comprised of a DMPK siRNA conjugated to a humanized antibody targeting human transferrin receptor 1 (TfR1), designed for functional delivery to muscle cells, where it can reduce the toxic DMPK-specific mRNA that is responsible for DM1 pathogenesis. These results will be presented. Conclusions AOC 1001 represents a novel potential therapy addressing the underlying cause of DM1."

Clinical • P1/2 data • PK/PD data • CNS Disorders • Genetic Disorders • Muscular Dystrophy • Myotonic Dystrophy • TFRC

Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of AOC 1020 Administered Intravenously to Adult Patients with Facioscapulohumeral Muscular Dystrophy (FORTITUDE) Trial Design (AAN 2023) - "Strategies targeting DUX4 expression in skeletal muscle of individuals with FSHD via oligonucleotides are promising therapeutic approaches.AOC 1020 is an antibody-oligonucleotide conjugate (AOCTM) comprised of a DUX4-targeting siRNA conjugated to a humanized antibody targeting transferrin receptor 1 (TfR1) to facilitate delivery to muscle. Exploratory measures of efficacy include pharmacodynamics, PROs, and measures of muscle function, strength, and composition by MRI. Results N/A Conclusions N/A"

Clinical • P1/2 data • PK/PD data • Muscular Dystrophy • DUX4 • TFRC

AOC 1020: An Antibody Oligonucleotide Conjugate (AOC) in Development for the Treatment of FSHD (WMS 2022) - "Single treatment also prevented FSHD-related muscle phenotype in this mouse model. Data presented provide support for AOC 1020 to enter the clinic for the treatment of FSHD by end of 2022."

Late-breaking abstract • ACTA1 • TFRC

Exploring Antibody-Oligonucleotide Conjugates (ADC-USA 2022) - "Discussing what are oligonucleotides Exploring how antibodyoligonucleotides can help solve oligo delivery challenges Overviewing Avidity Biosciences’ ADC technology"

DUX4 siRNA Optimization for the Development of an Antibody-Oligonucleotide Conjugate (AOC) for the Treatment of FSHD (AAN 2022) - "Data presented herein provide rationale and support for entering the clinic with the DUX4 AOC for the treatment of FSHD in 2022."

ACTA1

Antibody-Oligonucleotide Conjugates (AOCs) Demonstrate Potent and Durable Exon Skipping and Dystrophin Restoration in a Mouse Model of Duchenne Muscular Dystrophy (AAN 2022) - "Data presented herein demonstrate the potent and durable activity of the AOC platform for the treatment of Duchenne Muscular Dystrophy in an animal model of the disease and provides further support and rationale to investigate its utility for clinical application."

Preclinical • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Engineering Antibody Oligonucleotide Conjugates (AOCs): Taking Receptor-Mediated Uptake One Step Further (New Directions 2021) - No abstract available

[VIRTUAL] DUX4 siRNA optimization for the development of an Antibody-Oligonucleotide Conjugate for the treatment of FSHD (MDA 2021) - "To this aim, we have performed a series of in vitro DUX4 siRNA screening studies in a variety of FSHD patient-derived myotubes, that have allowed us to select the most potent siRNA sequences with minimal off-target profile. Ultimately, the best DUX4 siRNA will be conjugated to the TFRC antibody to generate the therapeutic AOC™ for FSHD that will be further characterized in vivo."

Muscular Dystrophy