TfR1 x DMPK

Avidity initiating global Phase 3 HARBOR™ study for delpacibart etedesiran this quarter Delpacibart etedesiran data from MARINA-OLE™ showed reversal of disease progression in multiple functional measures in DM1 compared to END-DM1 natural history data SAN DIEGO, May 8, 2024 /PRNewswire/ -- Avidity Biosciences, Inc. (Nasdaq: RNA), a biopharmaceutical company committed to delivering a new class of RNA therapeutics called Antibody Oligonucleotide Conjugates (AOCs™), today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to delpacibart etedesiran (AOC 1001), the company's lead clinical development program, for the treatment of myotonic dystrophy type 1 (DM1). Delpacibart etedesiran, abbreviated as del-desiran, is an investigational treatment designed to address the root cause of DM1, an underrecognized, progressive and often fatal neuromuscular disease with no approved therapies. "We are pleased that the FDA has granted Breakthrough Therapy designation to del-desiran for myotonic dystrophy type 1, underscoring the potential of del-desiran to be an effective treatment and the urgency of bringing this treatment to people living with DM1," said Sarah Boyce, president and chief executive officer at Avidity. "Initiation is underway for our global Phase 3 HARBOR™ study as we focus on rapidly advancing del-desiran for people living with DM1, who currently have no treatment options to address the underlying cause of this devastating rare muscle disease." Avidity is initiating the global pivotal HARBOR™ study of del-desiran this quarter. The primary endpoint in the Phase 3 HARBOR trial is video hand opening time (vHOT) and key secondary endpoints include muscle strength as measured by hand grip strength and quantitative muscle testing (QMT) total score, and activities of daily living as measured by DM1-Activ. Avidity recently reported positive long-term MARINA-OLE™ data demonstrating reversal of disease progression in adults living with DM1 across multiple endpoints including vHOT, muscle strength and DM1-Activ when compared to natural history data. In addition to receiving FDA Breakthrough Therapy designation, del-desiran has previously been granted Orphan Drug and Fast Track designations by the FDA and Orphan designation by the European Medicines Agency (EMA) for the treatment of DM1. About the Phase 2 MARINA-OLE™ Study MARINA-OLE™ is an open-label, multi-center trial designed to evaluate the long-term safety and tolerability of del-desiran (AOC 1001) in participants with DM1 who were previously enrolled in the MARINA® Phase 1/2 trial. This trial will continue to evaluate the safety, tolerability, PK, PD, and efficacy of del-desiran in participants enrolled in the randomized, placebo-controlled, Phase 1/2 MARINA clinical trial. Participants enrolled in the MARINA-OLE study receive quarterly doses of del-desiran regardless of whether they received active treatment or placebo in the MARINA study. The total duration of active treatment with del-desiran in the MARINA-OLE study is approximately 24 months. Once patients have completed active treatment, there will be a nine-month safety follow-up period. Avidity may extend active treatment beyond 24 months at a future timepoint. For more information on this study click here or visit and search for NCT05479981. About Del-desiran (AOC 1001) Del-desiran (AOC 1001), Avidity's lead product candidate utilizing its AOC platform, is designed to address the root cause of DM1 by reducing levels of a disease-related mRNA called DMPK. Del-desiran consists of a proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with a siRNA targeting DMPK mRNA. In preclinical studies, del-desiran successfully delivered siRNAs to muscle cells, resulting in durable, dose-dependent reductions of DMPK RNA across a broad range of muscles including skeletal, cardiac, and smooth muscles. Del-desiran is currently in Phase 1/2 development with the completed MARINA® trial and the ongoing MARINA-OLE™ trial in adults with DM1. The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have granted Orphan Designation for del-desiran and the FDA has granted del-desiran Fast Track Designation. About Myotonic Dystrophy Type 1 Myotonic dystrophy type 1 (DM1) is an underrecognized, progressive and often fatal disease caused by a triplet-repeat in the DMPK gene, resulting in a toxic gain of function mRNA. The disease is highly variable with respect to severity, presentation and age of onset, however all forms of DM1 are associated with high levels of disease burden and may cause premature mortality. DM1 primarily affects skeletal and cardiac muscle, however patients can suffer from a constellation of manifestations including myotonia and muscle weakness, respiratory problems, fatigue, hypersomnia, cardiac abnormalities, severe gastrointestinal complications, and cognitive and behavioral impairment. Currently, there are no approved treatments for people living with DM1. About Avidity Avidity Biosciences, Inc.'s mission is to profoundly improve people's lives by delivering a new class of RNA therapeutics - Antibody Oligonucleotide Conjugates (AOCs™). Avidity is revolutionizing the field of RNA with its proprietary AOCs, which are designed to combine the specificity of monoclonal antibodies with the precision of oligonucleotide therapies to address targets and diseases previously unreachable with existing RNA therapies. Utilizing its proprietary AOC platform, Avidity demonstrated the first-ever successful targeted delivery of RNA into muscle and is leading the field with clinical development programs for three rare muscle diseases: myotonic dystrophy type 1 (DM1), Duchenne muscular dystrophy (DMD) and facioscapulohumeral muscular dystrophy (FSHD). Avidity is broadening the reach of AOCs with its advancing and expanding pipeline including programs in cardiology and immunology through internal discovery efforts and key partnerships. Avidity is headquartered in San Diego, CA. For more information about our AOC platform, clinical development pipeline and people, please visit and engage with us on LinkedIn and X. Forward-Looking Statements Avidity cautions readers that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. These statements are based on the company's current beliefs and expectations. Such forward-looking statements include, but are not limited to, statements regarding: the implications of Breakthrough Therapy designation for the advancement of del-desiran; the global pivotal Phase 3 HARBOR™ trial for del-desiran, the timing of its initiation and key endpoints to be used therein; the MARINA-OLE™ study, its design, goals, dosage amounts and timelines; the potential of Avidity's product candidates, including del-desiran, to treat rare diseases and Avidity's efforts to bring them to people suffering from applicable diseases; the potential of AOCs to target a range of different cells and tissues beyond the liver, and to treat cardiac and immunological diseases; and Avidity's plans to expand its AOC platform and to invest in its pipeline programs. This press release also contains estimates and other statistical data made by independent parties and by us. This data involves a number of assumptions and limitations, and the reader is cautioned not to give undue weight to such estimates. The inclusion of forward-looking statements should not be regarded as a representation by Avidity that any of these plans will be achieved. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in Avidity's business, including, without limitation: Avidity may not be able to resolve the partial clinical hold related to the serious adverse event which occurred in the Phase 1/2 MARINA trial; additional participant data related to del-desiran that continues to become available may be inconsistent with the data produced as of the date hereof, and further analysis of existing data and analysis of new data may lead to conclusions different from those established as of the date hereof; unexpected adverse side effects to, or inadequate efficacy of, Avidity's product candidates that may delay or limit their development, regulatory approval and/or commercialization, or may result in additional clinical holds which may not be timely lifted, recalls or product liability claims; Avidity is early in its development efforts; Avidity's approach to the discovery and development of product candidates based on its AOC platform is unproven, and the company does not know whether it will be able to develop any products of commercial value; potential delays in the commencement, enrollment, data readouts and completion of preclinical studies or clinical trials; Avidity's dependence on third parties in connection with preclinical and clinical testing and product manufacturing; regulatory developments in the United States and foreign countries; and other risks described in Avidity's Annual Report on Form 10-K for the fiscal year ended December 31, 2023, filed with the Securities and Exchange Commission (SEC) on February 28, 2024, and in subsequent filings with the SEC. Avidity cautions readers not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and the company undertakes no obligation to update such statements to reflect events that occur or circumstances that arise after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Investor Contact: Geoffrey Grande, CFA (619) 837-5014 [email protected] Media Contact: Navjot Rai (619) 837-5016 [email protected] SOURCE Avidity Biosciences, Inc.

Avidity plans to double the number of participants receiving 4 mg/kg of AOC 1001 in MARINA Open-Label Extension (MARINA-OLE™) study by dose escalating participants currently on 2 mg/kg of AOC 1001 FDA allows new participant enrollment for 2 mg/kg of AOC 1001 First look at data from the MARINA-OLE study planned for the end of 2023 SAN DIEGO, May 17, 2023 /PRNewswire/ -- Avidity Biosciences, Inc. (Nasdaq: RNA), a biopharmaceutical company committed to delivering a new class of RNA therapeutics called Antibody Oligonucleotide Conjugates (AOCs™), today announced that the U.S. Food and Drug Administration (FDA) has eased the partial clinical hold on AOC 1001, allowing Avidity to double the number of participants in the MARINA Open-Label Extension (MARINA-OLE™) study receiving 4 mg/kg of AOC 1001. The FDA is also allowing new participant enrollment for AOC 1001 at 2 mg/kg. Data from the MARINA-OLE study will be used to finalize the AOC 1001 pivotal dose and Phase 3 study design for adults with myotonic dystrophy type 1 (DM1), an underrecognized, progressive and often fatal neuromuscular disease with no approved treatment options. "This positive step forward in our discussions with FDA provides the opportunity to gather additional data on the 2-4 mg/kg dose range of AOC 1001 while, in parallel, finalizing our Phase 3 study design and aligning with health authorities on a global regulatory path for AOC 1001," said Sarah Boyce, president and chief executive officer at Avidity. "We recently announced positive topline data for AOC 1001 demonstrating functional improvement across multiple clinical outcome measures and look forward to sharing a first look at data from the MARINA-OLE study at the end of this year. We are focused on advancing AOC 1001 into a pivotal trial as quickly as possible as we know that the patient community is desperate for a treatment. We are extremely grateful to the DM1 community for their trust, support and ongoing partnership." The easing of the partial clinical hold allows a number of current participants to be dose escalated to 4 mg/kg of AOC 1001 in the MARINA-OLE study and allows new participant enrollment at 2 mg/kg of AOC 1001. In September 2022, FDA placed a partial clinical hold on all new participant enrollment of AOC 1001 due to a rare serious adverse event reported in a single participant in the 4 mg/kg cohort of the Phase 1/2 MARINA™ trial. Avidity announced positive topline AOC 1001 data from the Phase 1/2 MARINA trial demonstrating functional improvement in multiple clinical outcome measures, disease modification and a favorable safety and tolerability profile in adults with DM1 at the 75th American Academy of Neurology (AAN) Annual Meeting in April 2023. Avidity concluded the MARINA trial with 38 participants enrolled and continues to dose 36 of those participants at both 2 mg/kg and 4 mg/kg of AOC 1001 in the MARINA-OLE study to evaluate the long-term safety and tolerability of AOC 1001 in adults with DM1. Avidity plans to double the number of participants receiving 4 mg/kg of AOC 1001 by dose escalating approximately 12 participants currently receiving AOC 1001 2 mg/kg in the MARINA-OLE study. All other participants will remain on their current dose of either 2 mg/kg or 4 mg/kg of AOC 1001. Avidity remains on track to share a first look at the data from the MARINA-OLE study at the end of 2023. About the Phase 1/2 MARINA™ Trial The MARINA™ trial is a randomized, double-blind, placebo-controlled, Phase 1/2 clinical trial that enrolled 38 adults with DM1. The primary objective of this study was to evaluate the safety and tolerability of single and multiple ascending doses of AOC 1001 administered intravenously. The MARINA trial assessed the activity of AOC 1001 across key biomarkers, including spliceopathy, an important biomarker for DM1, and knockdown of DMPK mRNA. Though the Phase 1/2 trial was not powered to assess functional benefit, it explored the clinical activity of AOC 1001 in multiple measures of muscle function including myotonia, muscle strength, measures of mobility as well as patient reported outcomes and quality of life measures. Patients had the option to enroll in MARINA-OLE, an open-label extension study, at the end of the post-treatment period. For more information on this study click here or visit and search for NCT05027269. About the Phase 2 MARINA-OLE™ Study MARINA-OLE™ is an open-label, multi-center trial designed to evaluate the long-term safety and tolerability of AOC 1001 in participants with DM1 who were previously enrolled in the MARINA Phase 1/2 trial. This trial will continue to evaluate the safety, tolerability, PK, PD, and efficacy of AOC 1001 in participants enrolled in the randomized, placebo-controlled, Phase 1/2 MARINA clinical trial. Participants who enroll in the MARINA-OLE study currently receive quarterly doses of AOC 1001 regardless of whether they received active treatment or placebo in the MARINA study. The total duration of active treatment with AOC 1001 in the MARINA-OLE study is approximately 24 months. Once patients have completed active treatment, there will be a nine-month safety follow-up period. Avidity may extend active treatment beyond 24 months at a future timepoint. For more information on this study click here or visit and search for NCT05479981. About AOC 1001 AOC 1001, Avidity's lead product candidate utilizing its AOC platform, is designed to address the root cause of DM1 by reducing levels of a disease-related mRNA called DMPK. AOC 1001 consists of a proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with a siRNA targeting DMPK mRNA. In preclinical studies, AOC 1001 successfully delivered siRNAs to muscle cells, resulting in durable, dose-dependent reductions of DMPK RNA across a broad range of muscles including skeletal, cardiac, and smooth muscles. AOC 1001 is currently in Phase 1/2 development with the completed MARINA™ trial and the ongoing MARINA-OLE™ trial in adults with DM1. The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have granted Orphan Designation for AOC 1001 and the FDA has granted AOC 1001 Fast Track Designation. About Myotonic Dystrophy Type 1 Myotonic dystrophy type 1 (DM1) is an underrecognized, progressive and often fatal disease caused by a triplet-repeat in the DMPK gene, resulting in a toxic gain of function mRNA. The disease is highly variable with respect to severity, presentation and age of onset, however all forms of DM1 are associated with high levels of disease burden and may cause premature mortality. DM1 primarily affects skeletal and cardiac muscle, however patients can suffer from a constellation of manifestations including myotonia and muscle weakness, respiratory problems, fatigue, hypersomnia, cardiac abnormalities, severe gastrointestinal complications, and cognitive and behavioral impairment. Currently, there are no approved treatments for people living with DM1. About Avidity Avidity Biosciences, Inc.'s mission is to profoundly improve people's lives by delivering a new class of RNA therapeutics - Antibody Oligonucleotide Conjugates (AOCs™). Avidity is revolutionizing the field of RNA with its proprietary AOCs, which are designed to combine the specificity of monoclonal antibodies with the precision of oligonucleotide therapies to address targets and diseases previously unreachable with existing RNA therapies. Utilizing its proprietary AOC platform, Avidity demonstrated the first-ever successful targeted delivery of RNA into muscle and is leading the field with clinical development programs for three rare muscle diseases: myotonic dystrophy type 1 (DM1), Duchenne muscular dystrophy (DMD) and facioscapulohumeral muscular dystrophy (FSHD). Avidity is broadening the reach of AOCs with its advancing and expanding pipeline including programs in cardiology and immunology through internal discovery efforts and key partnerships. Avidity is headquartered in San Diego, CA. For more information about our AOC platform, clinical development pipeline and people, please visit and engage with us on LinkedIn and Twitter. Forward-Looking Statements Avidity cautions readers that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. These statements are based on the company's current beliefs and expectations. Such forward-looking statements include, but are not limited to, statements regarding: Avidity's plans to escalate dosages of AOC 1001 administered to participants in the MARINA-OLE™ study, the levels of such dosages and the number of participants to be involved; Avidity's ability to advance AOC 1001 into a pivotal dose and trial, and the timing thereof; a Phase 3 study design related to AOC 1001 and adults with DM1; the characterization of the Phase 1/2 MARINA™ topline data; regulatory matters and Avidity's related plans; expectations related to enrollment of participants into the MARINA-OLE study at certain dosage levels; the timing and progression of the MARINA-OLE study and the dosage levels to be administered therein; any further changes to the status of the existing partial clinical hold; the safety, tolerability and benefits of AOC 1001; the timing of release of data from the MARINA-OLE study; the potential of Avidity's product candidates to treat rare diseases; the potential of the AOC platform and the potential of AOCs to target a range of different cells and tissues beyond muscle tissues, and to address diseases beyond those targeted by Avidity's current product candidates. The inclusion of forward-looking statements should not be regarded as a representation by Avidity that any of these items will be achieved. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in our business, including, without limitation: Avidity may not be able to fully resolve the partial clinical hold and the analysis related to the underlying cause of the serious adverse event, which may result in delays in the clinical development of AOC 1001; additional participant data related to AOC 1001 that continues to become available, through dose escalation or otherwise, may be inconsistent with the data produced as of the date hereof and the conclusions drawn therefrom; unexpected adverse side effects or inadequate efficacy of Avidity's product candidates that may delay or limit their development, regulatory approval and/or commercialization, or may result in additional clinical holds, recalls or product liability claims; Avidity is early in its development efforts; Avidity's approach to the discovery and development of product candidates based on its AOC platform is unproven, and the company does not know whether it will be able to develop any products of commercial value; potential delays in the MARINA-OLE study; the success of the MARINA-OLE study for AOC 1001; the results of the Phase 1/2 MARINA trial may not be predictive of results of the MARINA-OLE study; Avidity's dependence on third parties in connection with clinical testing and product manufacturing; regulatory developments in the United States and foreign countries, including acceptance of INDs and similar foreign regulatory filings and the proposed design of future clinical trials; Avidity could exhaust its available capital resources sooner than it currently expects and fail to raise additional needed capital; and other risks described in our Annual Report on Form 10-K for the year ended December 31, 2022, filed with the Securities and Exchange Commission (SEC) on February 28, 2023, and in subsequent filings with the SEC. Avidity cautions readers not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and the company undertakes no obligation to update such statements to reflect events that occur or circumstances that arise after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Investor Contact: Kathleen Gallagher (858) 401-7900 x550 [email protected] Media Contact: Navjot Rai (858) 401-7900 x550 [email protected] SOURCE Avidity Biosciences, Inc.

- Broad Distribution in CNS Demonstrated in Non-Human Primates - - Achieved Reduction of Toxic Nuclear DMPK RNA and Foci in the Brain in a DM1 Disease Model - WALTHAM, Mass., May 17, 2023 (GLOBE NEWSWIRE) -- Dyne Therapeutics, Inc. (Nasdaq: DYN), a clinical-stage muscle disease company focused on advancing innovative life-transforming therapeutics for people living with genetically driven diseases, is delivering an oral presentation today at the American Society of Gene & Cell Therapy (ASGCT) 26th Annual Meeting in Los Angeles highlighting new preclinical data demonstrating the FORCE™ platform achieved delivery to the central nervous system (CNS) in non-human primates and robust pharmacological effects in the brain in a model of myotonic dystrophy type 1 (DM1). Oral Presentation: FORCE™ Platform Delivers Oligonucleotides to the Brain in a DM1 Mouse Model and in NHPs (abstract #82) Session: Nucleic Acid Therapeutics Date/Time: Wednesday, May 17, 2023, at 4:00 p.m. PT Presenter: Stefano Zanotti, Ph.D., Executive Director, Head of Neuromuscular Research, Dyne The presentation will be available in the Scientific Publications & Presentations section of Dyne’s website following the session. The FORCE platform was designed to overcome the limitations of delivering oligonucleotide therapeutics to muscle tissue by leveraging transferrin receptor 1 (TfR1). TfR1-mediated delivery also has been shown by the field to facilitate uptake of therapeutics by the CNS. Many people living with rare muscle diseases experience CNS symptoms that contribute to the burden of disease, including cognitive deficits and dysregulated sleep, which affect individuals with DM1. Data being presented at ASGCT show that intravenous (IV) administration of FORCE conjugate, a TfR1-binding Fab antibody conjugated to an antisense oligonucleotide (ASO), achieved delivery to the CNS via TfR1 in both non-human primates (NHPs) and the innovative hTfR1/DMSXL mouse model. The hTfR1/DMSXL model, developed by Dyne, expresses the human TfR1 and carries a human DMPK gene with more than 1,000 CTG repeats that represents a severe DM1 phenotype. In these studies, FORCE conjugate was well tolerated. Highlights from the ASGCT data include: In NHPs, FORCE conjugate achieved superior delivery compared to unconjugated ASO when both were administered via IV. In addition, IV administration of FORCE showed broader distribution throughout the brain compared to intrathecal (IT) administration of unconjugated ASO. FORCE conjugate also delivered to the brain of hTfR1/DMSXL mice and demonstrated robust knockdown of toxic human nuclear DMPK RNA and foci reduction. “We have previously demonstrated that the FORCE platform enables delivery of oligonucleotides to skeletal, smooth and cardiac muscle in multiple, well-validated preclinical models, and we are excited to now highlight TfR1-mediated delivery to the CNS in these data at ASGCT. The CNS manifestations of neuromuscular disorders contribute significantly to the disease burden, and we look forward to further evaluating the potential of the FORCE platform in this area and advancing our commitment to delivering life-transforming therapies to patients,” said Oxana Beskrovnaya, Ph.D., chief scientific officer of Dyne. About Dyne Therapeutics Dyne Therapeutics is a clinical-stage muscle disease company focused on advancing innovative life-transforming therapeutics for people living with genetically driven diseases. With its proprietary FORCE™ platform, Dyne is developing modern oligonucleotide therapeutics that are designed to overcome limitations in delivery to muscle tissue. Dyne has a broad pipeline for serious muscle diseases, including clinical programs for myotonic dystrophy type 1 (DM1) and Duchenne muscular dystrophy (DMD), and a preclinical program for facioscapulohumeral muscular dystrophy (FSHD). For more information, please visit , and follow us on Twitter, LinkedIn and Facebook. Forward-Looking Statements This press release contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this press release, including statements regarding Dyne’s strategy, future operations, prospects and plans, objectives of management, and the potential of the FORCE platform, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “objective,” “ongoing,” “plan,” “predict,” “project,” “potential,” “should,” or “would,” or the negative of these terms, or other comparable terminology are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Dyne may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various important factors, including: uncertainties inherent in the identification and development of product candidates, including the initiation and completion of preclinical studies and clinical trials; uncertainties as to the availability and timing of results from preclinical studies and clinical trials; the timing of and Dyne’s ability to initiate and enroll patients in clinical trials; whether results from preclinical studies will be predictive of the results of later preclinical studies and clinical trials; whether Dyne’s cash resources will be sufficient to fund the Company’s foreseeable and unforeseeable operating expenses and capital expenditure requirements; as well as the risks and uncertainties identified in Dyne’s filings with the Securities and Exchange Commission (SEC), including the Company’s most recent Form 10-Q and in subsequent filings Dyne may make with the SEC. In addition, the forward-looking statements included in this press release represent Dyne’s views as of the date of this press release. Dyne anticipates that subsequent events and developments will cause its views to change. However, while Dyne may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing Dyne’s views as of any date subsequent to the date of this press release. Contacts: Investors Amy Reilly areilly@dyne-tx.com 857-341-1203 Media Stacy Nartker snartker@dyne-tx.com 781-317-1938