Assessing the Therapeutic Potential of AOC 1001 in Myotonic Dystrophy Type 1


Steve Hughes, MD, chief medical officer at Avidity, provided perspective on recently announced positive phase 1/2 and OLE data evaluating AOC 1001, an investigational antisense oligonucleotide, in patients with myotonic dystrophy type 1.

Steve Hughes, MD, chief medical officer at Avidity

Steve Hughes, MD

Myotonic dystrophy type 1 (DM1) is a progressive and often fatal disease caused by a triplet-repeat in the DMPK gene, resulting in a toxic gain of function mRNA. DM1 primarily impacts skeletal and cardiac muscle; however, patients can suffer from a constellation of manifestations including myotonia and muscle weakness, respiratory problems, fatigue, hypersomnia, cardiac abnormalities, and cognitive impairments, among others. AOC 1001, Avidity Biosciences’ lead product candidate utilizing its Antibody Oligonucleotide Conjugates (AOC) platform, is designed to address the root cause of myotonic dystrophy type 1 (DM1) by reducing levels of disease-related mRNA called DMPK.

At the 28th Annual Congress of the World Muscle Society, held October 3-7, in Charleston, South Carolina, new data from the open-label extension (OLE) of the phase 1/2 MARINA trial (NCT05027269) demonstrated the safety and efficacy of AOC 1001 in DM1. Throughout the OLE, the most common adverse events were procedural pain (22%) and pain in extremity and headache (16%). Functional and patient reported outcome measures such as the 10-Meter Walk Run test, Timed Up and Go, and the DM1-Activ Patient Reported Outcome, all showed directional improvements through treatment with AOC 1001. In addition, patients who dose-escalated from 2 mg/kg to 4 mg/kg as part of the easement of the partial clinical hold showed no neurological events and no MRI changes following dosing.

Following these data, NeurologyLive® reached out to Steve Hughes, MD, chief medical officer at Avidity, to gain greater insight about these data and the therapeutic potential of AOC 1001. Hughes provided comments on the safety profile of the agent, its mechanism of action as an antisense oligonucleotide, and the goals of treating DM1. Furthermore, he spoke on how the data will help guide a follow-up phase 3 study.

NeurologyLive®: What were the greatest take-home points the clinical community should be aware of from MARINA?

Steve Hughes, MD: The new positive data from the Phase 1/2 MARINA® trial and MARINA open-label extension (MARINA-OLE™) study, presented at the 28th Annual Congress of the World Muscle Society (WMS) in early October, provide further evidence of the potential of AOC 1001 as an effective treatment option for people living with myotonic dystrophy type 1 (DM1). New AOC 1001 data demonstrated improvement in multiple additional functional measures including hand grip, muscle strength and patient reported outcomes, augmenting positive data showing improvements in myotonia, muscle strength and mobility in people living with DM1 that were previously reported at the American Academy of Neurology (AAN) Annual Meeting earlier this year in April. With new long-term safety data from over 200 infusions totaling 46.2 patient-years of exposure, AOC 1001 continues to demonstrate favorable safety and tolerability, with most adverse events mild to moderate.

Why does AOC 1001 represent a promising therapeutic option for DM1? What about its mechanism of action makes us believe it can be successful?

Our proprietary AOCs™ (Antibody Oligonucleotide Conjugates) are unique in that they are designed to combine the specificity of monoclonal antibodies (mAbs) with the precision of oligonucleotide therapies to target a range of different cells and tissues beyond the liver, which up until now have been inaccessible with existing RNA-based therapeutics. Our AOCs are built leveraging decades of research on the power of oligonucleotides and years of in-house engineering that integrates oligonucleotides, modulation of RNA processes, antibody engineering and conjugation, and advanced drug delivery techniques.

In December 2022, Avidity led a major advancement in the field of RNA therapeutics, announcing positive data from a preliminary assessment of the Phase 1/2 MARINA trial of AOC 1001 in DM1 demonstrating the first-ever successful targeted delivery of RNA to muscle in humans. This revolutionary advancement for the field of RNA therapeutics provides evidence that we can overcome a challenge that has eluded scientists for decades – the opportunity to target tissues beyond the liver.

AOC 1001 is designed to address the root cause of DM1 by reducing levels of a disease-related mRNA called DMPK, which stands for myotonic dystrophy protein kinase. AOC 1001 consists of a mAb that binds to transferrin receptor 1 (TfR1) conjugated with a small interfering RNA (siRNA) specifically targeting 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.

Data presented to date from the AOC 1001 development program are very encouraging. We will continue to follow the data to achieve our ultimate goal of improving people’s lives by delivering a new class of RNA therapeutics designed to target the root cause of serious diseases previously untreatable with RNA therapeutics, including DM1.

In myotonic dystrophy type 1, what are some of the main goals of treatment? Have the goals of treating these patients shifted over time?

DM1 is a progressive, complex, multisystemic disease that primarily affects skeletal, cardiac, and smooth muscle and symptoms can vary from patient to patient. Symptoms may include muscle weakness and myotonia, respiratory and cardiac problems, fatigue, hypersomnia, severe gastrointestinal complications, and cognitive and behavioral impairment – resulting in a significant decline in quality of life. There are no approved treatments that target the underlying cause of DM1. Historically, the standard of care has been palliative care to treat the different symptoms that people living with DM1 experience. Palliative treatments may include medications, rehabilitative therapy, assistive devices (such as a cane or wheelchair), or even surgery in some cases. These treatment options are aimed to improve the quality of life of people living with DM1 as much as possible but they unfortunately, do not slow the progression of disease. Our goal in developing AOC 1001 is to reduce DMPK mRNA and address the underlying cause of disease, potentially alleviating the spectrum of symptoms that people with DM1 experience.

Can you discuss the safety profile of AOC 1001 and what it has shown thus far?

New long-term safety data of AOC 1001 continue to demonstrate favorable safety and tolerability with over 200 infusions totaling 46.2 patient-years of exposure. Most adverse events (AEs) have been mild to moderate. The most common AEs in the MARINA-OLE study were procedural pain (22%), pain in extremity (such as arm, leg or foot pain/soreness), and headache (both 16%).There was one resolved AE of mild increase in liver enzymes. There have been no reported AEs of anemia in the MARINA-OLE study. In the Phase 1/2 MARINA trial, anemia was asymptomatic except for one participant who did not require treatment. Also importantly, there have been no discontinuations in the ongoing MARINA-OLE study.

In May 2023, the U.S. Food and Drug Administration (FDA) eased the partial clinical hold on AOC 1001, allowing Avidity to double the number of participants in the MARINA-OLE study receiving 4 mg/kg of AOC 1001 from 12 to 24 participants. Data from the 12 participants dose-escalated from 2 mg/kg to 4 mg/kg of AOC 1001 as part of the easement of the partial clinical hold showed no neurological events and no MRI changes following dosing. The company continues to work as quickly as possible to resolve the partial clinical hold.

What are the future plans for this drug? Are there still aspects about its use that we still need to learn more about?

With these new data in hand, we believe that we have a robust data package to finalize the Phase 3 study design for AOC 1001 while we continue to define the global regulatory path. We also plan to share a first look at efficacy data from the MARINA-OLE study in the first half of 2024 and we continue to work as quickly as possible to resolve the partial clinical hold on the AOC 1001 program.

Data from the AOC 1001 program thus far, including the new functional data and long-term favorable tolerability and safety data, are very encouraging and incredibly exciting for the DM1 community. The data strengthen our belief that AOC 1001 has the potential to help people living with DM1 who are in desperate need of treatments.

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