AOC 1044 for Duchenne Muscular Dystrophy

(EXPLORE44OLE Trial)

Recruiting in Palo Alto (17 mi)

+9 other locations

Age: < 65

Sex: Male

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Waitlist Available

Sponsor: Avidity Biosciences, Inc.

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

AOC 1044-CS2 (EXPLORE44-OLE) is an Open-label Study to Evaluate the Pharmacodynamics and Long-Term Safety and Tolerability of AOC 1044 Administered Intravenously to DMD Participants with Mutations Amenable to Exon 44 Skipping.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on corticosteroids, you must be on a stable dose for 30 days before screening and throughout the study.

What data supports the idea that AOC 1044 for Duchenne Muscular Dystrophy is an effective treatment?

The available research does not provide specific data on AOC 1044 for Duchenne Muscular Dystrophy. Instead, it discusses other treatments like drisapersen and golodirsen, which are used for similar purposes. These treatments work by helping the body produce a partially functional version of a protein called dystrophin, which is missing in people with Duchenne Muscular Dystrophy. While these studies show some promise in increasing dystrophin production, they do not provide direct evidence for the effectiveness of AOC 1044. ^{1 2 3 4 5}

What safety data exists for AOC 1044 (Delpacibart zotadirsen) for Duchenne Muscular Dystrophy?

The provided research does not contain any safety data for AOC 1044, Delpacibart zotadirsen, del-zota, or AOC-1044. The studies mentioned focus on the safety and efficacy of mometasone furoate and beclomethasone dipropionate for asthma treatment, which are unrelated to AOC 1044 or Duchenne Muscular Dystrophy. ^{6 7 8 9 10}

Is the drug AOC 1044 a promising treatment for Duchenne Muscular Dystrophy?

Yes, AOC 1044 is a promising treatment for Duchenne Muscular Dystrophy. It uses a method called exon skipping, which helps produce a shorter but functional version of the dystrophin protein. This approach has shown potential in improving muscle function and strength, making it one of the most promising treatments for this condition. ^{11 12 13 14 15}

Research Team

Carmen Castrillo, MD

Principal Investigator

Avidity Biosciences, Inc.

Eligibility Criteria

This trial is for individuals with Duchenne Muscular Dystrophy (DMD) who have specific genetic mutations that can be treated by skipping exon 44. Participants must have completed a prior study, EXPLORE44, without significant issues tolerating the treatment.

Inclusion Criteria

I have not had major side effects from AOC 1044.

I successfully finished the EXPLORE44 study as approved by my doctor and the study sponsor.

Exclusion Criteria

Presence of any new condition or worsening of existing condition that could affect a participant's safety or ability to comply with study procedures

Treatment Details

Interventions

• AOC 1044 (Exon Skipping Agent)

Trial Overview The trial is testing AOC 1044, an intravenous medication designed to skip exon 44 in DMD patients. It aims to assess the drug's long-term safety and its effect on the body over time in an open-label setting.

Participant Groups

Group I: AOC 1044 Multiple Dose Levels Experimental Treatment 1 Intervention

AOC 1044 will be IV infused every 6 weeks or 8 weeks for approximately 2 years.

Who Is Running the Clinical Trial?

Avidity Biosciences, Inc.

Lead Sponsor

Trials

8

Recruited

960+

Findings from Research

In a Phase 2 study involving 51 ambulant Duchenne muscular dystrophy (DMD) patients, drisapersen at a dose of 6 mg/kg/week showed a potential benefit in improving the 6-minute walking distance (6MWD) compared to placebo, with a mean difference of 27.1 meters at week 24.

Drisapersen was generally well-tolerated, with the most common side effects being injection site reactions and subclinical proteinuria, indicating a manageable safety profile for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo-controlled Phase 2 Trial of Drisapersen for Duchenne Muscular Dystrophy. McDonald, CM., Wong, B., Flanigan, KM., et al.[2022]

The study developed shorter 25-mer phosphorodiamidate morpholino oligonucleotides (PMOs) that can effectively induce dystrophin restoration in Duchenne muscular dystrophy (DMD), showing comparable efficacy to the longer 30-mer PMO eteplirsen.

Using shorter PMOs could allow for higher dosing, which enhances drug uptake into muscle fibers, potentially leading to greater dystrophin restoration and improved clinical outcomes for patients with DMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Shorter Phosphorodiamidate Morpholino Splice-Switching Oligonucleotides May Increase Exon-Skipping Efficacy in DMD. Akpulat, U., Wang, H., Becker, K., et al.[2021]

Exon skipping shows potential as a treatment for Duchenne muscular dystrophy, which is a serious genetic disorder affecting muscle function.

However, the path to getting these therapies approved is complicated and may need more early testing and clearer regulatory support to ensure safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exon-skipping therapy: a roadblock, detour, or bump in the road? Hoffman, EP., McNally, EM.[2021]

In a study involving 233 children aged 4-11 years with mild-to-moderate persistent asthma, both doses of mometasone furoate (MF-DPI) were found to be well tolerated over 52 weeks, showing a similar safety profile to beclomethasone dipropionate (BDP-MDI).

The most common adverse events were upper respiratory tract infections, with no significant safety concerns or clinically relevant changes in laboratory values, indicating that both treatments are safe options for managing asthma in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety of mometasone furoate administered via a dry powder inhaler in children: Results of an open-label study comparing mometasone furoate with beclomethasone dipropionate in children with persistent asthma. Noonan, M., Leflein, J., Corren, J., et al.[2021]

In a six-month trial involving asthmatics who required oral corticosteroids, a high dose of 2,000 micrograms per day of beclomethasone dipropionate (BDP) significantly reduced oral steroid requirements by 57%, compared to a 34% reduction in the standard 800 microgram dose group.

The high dose BDP not only maintained good asthma control but also improved pulmonary function and baseline serum cortisol levels, indicating its safety and efficacy in managing long-term steroid-dependent asthma without increasing the risk of side effects like dysphonia or oropharyngeal candidiasis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Six-month double-blind, controlled trial of high dose, concentrated beclomethasone dipropionate in the treatment of severe chronic asthma. Tarlo, SM., Broder, I., Davies, GM., et al.[2019]

Antisense oligonucleotide (AO)-mediated exon skipping therapy for Duchenne muscular dystrophy (DMD) has shown promising results, with significant contributions from Japanese patients leading to its development and proof of concept.

The therapy has been validated in multiple cases, including a patient with a nonsense mutation and another with an exon deletion, paving the way for over 300 published studies on its efficacy and potential for marketing authorization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contributions of Japanese patients to development of antisense therapy for DMD. Matsuo, M., Takeshima, Y., Nishio, H.[2016]

Antisense oligonucleotides (AOs) targeting dystrophin through a method called exon skipping show promise as a treatment for Duchenne muscular dystrophy (DMD), with an AO for skipping exon 51 already receiving accelerated approval in the USA.

The study emphasizes the need for combined therapies, especially in older DMD patients, and outlines a methodology for delivering AOs in a mouse model to enhance muscle size and strength by targeting both dystrophin and myostatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic Intravenous Administration of Antisense Therapeutics for Combinatorial Dystrophin and Myostatin Exon Splice Modulation. Lu-Nguyen, N., Dickson, G., Malerba, A.[2019]

Patients with Duchenne muscular dystrophy (DMD) who have deletions skippable for exon 44 or 45 show some dystrophin expression, but at lower levels compared to those with exon 51 deletions, suggesting exon 51 skipping may be more effective in producing functional dystrophin.

The study indicates that dystrophin transcript stability is a key factor in predicting dystrophin expression levels, with unstable transcripts in DMD patients potentially serving as a biomarker for response to antisense oligonucleotide treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical characterization of patients with in-frame or out-of-frame DMD deletions pertinent to exon 44 or 45 skipping. Anthony, K., Arechavala-Gomeza, V., Ricotti, V., et al.[2022]

A new cellular model using MYOD1-transduced urine-derived cells (MYOD1-UDCs) from DMD patients shows significantly better efficiency for exon skipping compared to traditional rhabdomyosarcoma cells, making it a more relevant system for drug screening.

The study highlights that the effectiveness of exon skipping varies based on the specific DMD mutation, and that the sequence of the antisense oligonucleotide eteplirsen is less effective than other tested sequences, emphasizing the need for optimization in drug design.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Highly sensitive screening of antisense sequences for different types of DMD mutations in patients' urine-derived cells. Takizawa, H., Takeshita, E., Sato, M., et al.[2021]

Antisense oligonucleotides (AOs) can effectively induce exon skipping in the DMD gene, potentially allowing for the production of a functional dystrophin protein in patients with Duchenne muscular dystrophy (DMD).

The development of personalized AOs tailored to specific mutations in the DMD gene is crucial, as different mutations require different exons to be skipped for effective treatment, indicating a need for extensive optimization and clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing antisense oligonucleotides using phosphorodiamidate morpholino oligomers. Popplewell, LJ., Malerba, A., Dickson, G.[2012]

References

1. United States pubmed.ncbi.nlm.nih.gov

Placebo-controlled Phase 2 Trial of Drisapersen for Duchenne Muscular Dystrophy. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Shorter Phosphorodiamidate Morpholino Splice-Switching Oligonucleotides May Increase Exon-Skipping Efficacy in DMD. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Exon-skipping therapy: a roadblock, detour, or bump in the road? [2021]

6. England pubmed.ncbi.nlm.nih.gov

Long-term safety of mometasone furoate administered via a dry powder inhaler in children: Results of an open-label study comparing mometasone furoate with beclomethasone dipropionate in children with persistent asthma. [2021]

7. India pubmed.ncbi.nlm.nih.gov

Comparison of mometasone furoate administered by metered dose inhaler with beclomethasone dipropionate. [2015]

8. England pubmed.ncbi.nlm.nih.gov

Systemic exposure to inhaled beclometasone/formoterol DPI is age and body size dependent. [2015]

9. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of inhaled extrafine beclomethasone dipropionate in adults with asthma: a randomized, parallel-group, dose-ranging study (BEAM). [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Six-month double-blind, controlled trial of high dose, concentrated beclomethasone dipropionate in the treatment of severe chronic asthma. [2019]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Contributions of Japanese patients to development of antisense therapy for DMD. [2016]

12. United States pubmed.ncbi.nlm.nih.gov

Systemic Intravenous Administration of Antisense Therapeutics for Combinatorial Dystrophin and Myostatin Exon Splice Modulation. [2019]

13. United States pubmed.ncbi.nlm.nih.gov

Biochemical characterization of patients with in-frame or out-of-frame DMD deletions pertinent to exon 44 or 45 skipping. [2022]

14. Netherlands pubmed.ncbi.nlm.nih.gov

Highly sensitive screening of antisense sequences for different types of DMD mutations in patients' urine-derived cells. [2021]

15. United States pubmed.ncbi.nlm.nih.gov

Optimizing antisense oligonucleotides using phosphorodiamidate morpholino oligomers. [2012]