DMD exon 53

Designation highlights significant unmet needs in DMD; dystrophin data from potentially registrational FORWARD-53 trial of WVE-N531 are on track for 3Q 2024 In previous Part A trial, WVE-N531 achieved industry-leading exon skipping of 53% and muscle tissue concentrations that were approximately 20-30 times higher than those reported by exon skipping technologies leveraging muscle delivery conjugates CAMBRIDGE, Mass., Aug. 12, 2024 (GLOBE NEWSWIRE) -- Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health, today announced that the U.S. Food and Drug Administration (FDA) has granted Rare Pediatric Disease Designation to WVE-N531 for the treatment of boys with Duchenne muscular dystrophy (DMD) who are amenable to exon 53 skipping. WVE-N531 is currently being evaluated in the potentially registrational FORWARD-53 clinical trial and Wave expects to deliver data, including dystrophin protein expression from muscle biopsies after 24 weeks of treatment, in the third quarter of 2024. “This designation from FDA underscores that significant unmet needs remain in DMD, and it also supports Wave’s innovative and purposeful approach to drug development in the rare disease space,” said Anne-Marie Li-Kwai-Cheung, MChem, MTOPRA, RAPS, Chief Development Officer at Wave Life Sciences. “With our WVE-N531 program, we are aiming to restore clinically meaningful levels of near full length, functional dystrophin protein. Positive data from FORWARD-53 would also unlock additional programs for other exons in our pipeline, with the goal of developing best-in-class medicines that address the underlying cause of the disease for up to 40% of boys with DMD.” WVE-N531 is an exon skipping oligonucleotide designed to induce production of endogenous, functional dystrophin protein. In the previously completed Part A study (three 10 mg/kg doses every other week), WVE-N531 achieved industry-leading mean exon skipping levels of 53% and mean muscle tissue concentrations of ~42,000 ng/g (~6,100 nM), which is approximately 20-30 times higher than levels reported by exon-skipping technologies leveraging muscle delivery conjugates in DMD patients. The Part A data also demonstrated distribution to myogenic stem cells (also known as satellite cells) in all study participants. Myogenic stem cells are progenitor cells for new myoblasts, and Wave is not aware of any other clinical data for exon skipping therapies or gene therapies that have demonstrated myogenic stem cell uptake. Preclinical data in non-human primates also demonstrated concentrations of WVE-N531 in the heart and diaphragm that exceeded skeletal muscle, which indicates the potential for WVE-N531 to also offer cardiac and respiratory benefits. WVE-N531 is currently being investigated in FORWARD-53, a potentially registrational, open-label clinical trial in 11 boys with DMD. Endpoints include dystrophin expression after 24 and 48 weeks of treatment, as well as pharmacokinetic, safety and tolerability data. Rare Pediatric Disease Designation is granted by the FDA for serious or life-threatening diseases which primarily affect individuals less than 18 years of age and fewer than 200,000 people in the United States. If a New Drug Application for WVE-N531 is approved by the FDA, Wave would be eligible to receive a Priority Review Voucher. About Duchenne Muscular DystrophyDuchenne muscular dystrophy (DMD) is a fatal X-linked genetic neuromuscular disorder caused predominantly by out-of-frame deletions in the dystrophin gene, resulting in absent or defective dystrophin protein. Dystrophin protein is needed for normal muscle maintenance and operation. Because of the genetic mutations in DMD, the body cannot produce functional dystrophin, which results in progressive and irreversible loss of muscle function, including the heart and lungs. Worldwide, DMD affects approximately one in 5,000 newborn boys. Approximately 8%-10% of DMD patients have mutations amenable to treatment with an exon 53 skipping therapy. Exon skipping aims to address the underlying cause of DMD by promoting the production of dystrophin protein to stabilize or slow disease progression. About Wave Life SciencesWave Life Sciences (Nasdaq: WVE) is a biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health. Wave’s RNA medicines platform, PRISM®, combines multiple modalities, chemistry innovation and deep insights in human genetics to deliver scientific breakthroughs that treat both rare and prevalent disorders. Its toolkit of RNA-targeting modalities includes editing, splicing, RNA interference and antisense silencing, providing Wave with unmatched capabilities for designing and sustainably delivering candidates that optimally address disease biology. Wave’s diversified pipeline includes clinical programs in Duchenne muscular dystrophy, Alpha-1 antitrypsin deficiency and Huntington’s disease, as well as a preclinical program in obesity. Driven by the calling to “Reimagine Possible”, Wave is leading the charge toward a world in which human potential is no longer hindered by the burden of disease. Wave is headquartered in Cambridge, MA. For more information on Wave’s science, pipeline and people, please visit www.wavelifesciences.com and follow Wave on X (formerly Twitter) and LinkedIn. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, the potential significance and implications of receiving the Rare Pediatric Disease Designation from the FDA; the potentially registrational nature of our FORWARD-53 trial for WVE-N531; our expectations that WVE-N531’s industry-leading exon skipping and muscle tissue concentrations has the potential to become the leading exon-skipping therapeutic in DMD; our expectations that high tissue concentrations and high exon skipping may result in high dystrophin restoration following a sufficient follow up period; our understanding of the importance of satellite cells for muscle regeneration; our expectation that WVE-N531 muscle concentrations in the clinic may be higher in heart and diaphragm than in skeletal muscle; and our expectations of the anticipated therapeutic benefits of WVE-N531 for DMD over existing therapies. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release and actual results may differ materially from those indicated by these forward-looking statements as a result of these risks, uncertainties and important factors, including, without limitation, the risks and uncertainties described in the section entitled “Risk Factors” in Wave’s most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as amended, and in other filings Wave makes with the SEC from time to time. Wave undertakes no obligation to update the information contained in this press release to reflect subsequently occurring events or circumstances. Investor Contact:Kate Rausch+1 617-949-4827krausch@wavelifesci.com Media Contact:Alicia Suter+1 617-949-4817asuter@wavelifesci.com

FORWARD-53 is fully enrolled with potentially registrational dystrophin expression data expected in 2024 Previous clinical proof-of-concept data demonstrated highest level of exon skipping ever observed in the clinic and that WVE-N531 was present in myogenic stem cells, which are important for potential muscle regeneration Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage RNA medicines company committed to delivering life-changing treatments for people battling devastating diseases, today announced the initiation of dosing in the Phase 2 FORWARD-53 clinical trial, which is evaluating WVE-N531 as a treatment for boys with Duchenne muscular dystrophy (DMD) who are amenable to exon 53 skipping. FORWARD-53 is designed to assess functional dystrophin protein at 24 and 48 weeks with every other week dosing of WVE-N531. “Following encouraging data from the WVE-N531 proof-of-concept trial, we believe we are on the right path toward addressing a significant unmet need in DMD – the generation of endogenous dystrophin protein to levels that meaningfully impact the trajectory of the disease,” said Anne-Marie Li-Kwai-Cheung, MChem, MTOPRA, RAPS, Chief Development Officer at Wave Life Sciences. “Our clinical data in boys with DMD amenable to exon 53 skipping demonstrated the highest level of exon skipping ever observed in the clinic, and high muscle concentrations of WVE-N531 in skeletal muscle of 6.1 micromolar. Importantly, in our non-human primate studies, muscle concentrations were higher in the diaphragm and heart than in skeletal muscle. Additionally, while FORWARD-53 is dosing every other week, we have the potential for monthly dosing in the future. For these reasons, we are excited about the potential of WVE-N531. We are grateful to the DMD community for their continued support and look forward to announcing dystrophin expression data in 2024, as well as advancing exon skipping candidates for other mutations if FORWARD-53 is successful.” FORWARD-53 is a potentially registrational, open-label, Phase 2 clinical trial that has enrolled 10 boys with DMD who are amenable to exon 53 skipping. The trial is powered to evaluate functional, endogenous dystrophin expression following 24 and 48 weeks of every other week, intravenous dosing at 10 mg/kg. The primary endpoint is dystrophin protein levels, and the trial is also evaluating pharmacokinetics, digital and functional endpoints, and safety and tolerability. FORWARD-53 is fully enrolled, and Wave expects to deliver data, including dystrophin expression from muscle biopsies, in 2024. Wave’s Phase 1b/2a Part A proof-of-concept trial in boys with DMD amenable to exon 53 skipping demonstrated high muscle concentrations of WVE-N531 (mean of 6.1 micromolar or 42 micrograms/gram) and mean exon skipping of 53% (range: 48-62%) at six weeks, after boys received three doses of 10 mg/kg every other week. WVE-N531 appeared safe and well-tolerated, with all treatment-related adverse events being mild. Additionally, at Wave’s R&D Day in September 2023, the company shared an analysis of muscle biopsy data from the Part A proof-of-concept trial indicating that WVE-N531 was present in myogenic stem cells, which are important for potential muscle regeneration. These are the first clinical data in DMD to demonstrate uptake in myogenic stem cells at the early, six-week timepoint and further support the potential differentiation of WVE-N531 from other therapeutics, including gene therapies. Duchenne muscular dystrophy (DMD) is a fatal X-linked genetic neuromuscular disorder caused predominantly by out-of-frame deletions in the dystrophin gene, resulting in absent or defective dystrophin protein. Dystrophin protein is needed for normal muscle maintenance and operation. Because of the genetic mutations in DMD, the body cannot produce functional dystrophin, which results in progressive and irreversible loss of muscle function, including the heart and lungs. Worldwide, DMD affects approximately one in 5,000 newborn boys. Approximately 8%-10% of DMD patients have mutations amenable to treatment with an exon 53 skipping therapy. Exon skipping aims to address the underlying cause of DMD by promoting the production of dystrophin protein to stabilize or slow disease progression. Wave Life Sciences (Nasdaq: WVE) is a clinical-stage RNA medicines company committed to delivering life-changing treatments for people battling devastating diseases. Wave aspires to develop best-in-class medicines across multiple therapeutic modalities using PRISM, the company’s proprietary discovery and drug development platform that enables the precise design, optimization, and production of stereopure oligonucleotides. Driven by a resolute sense of urgency, the Wave team is targeting a broad range of genetically defined diseases so that patients and families may realize a brighter future. To find out more, please visit www.wavelifesciences.com and follow Wave on X (formerly Twitter) @WaveLifeSci. The content above comes from the network. if any infringement, please contact us to modify.

Locanabio expects to submit IND application in mid-2024 for first program, LBIO-115, designed to promote skipping of exon 51 in the dystrophin RNA transcript SAN DIEGO, CA, USA I October 06, 2023 I Locanabio, Inc., a genetic medicines company developing RNA-targeted therapeutics for patients with rare genetic neuromuscular and neurodegenerative diseases, today announced the presentation of data demonstrating the packaging and delivery of its proprietary small nuclear RNA (snRNA) platform using adeno-associated virus (AAV). The poster describes specific applications of this vectorized platform showing robust dose-dependent exon skipping at multiple exons enabling restoration of nearly full-length dystrophin protein for the potential treatment of DMD in a single administration therapy. “As these data demonstrate, our vectorized snRNA platform combines the therapeutic potential of exon skipping with the delivery advantages of an AAV gene therapy,” said John Leonard, Ph.D., Locanabio’s chief scientific officer. “Gene therapy approaches to DMD are limited by the large size of the dystrophin protein necessitating the use of a replacement gene encoding a microdystrophin that lacks important functional domains of the full-length protein. In contrast, exon skipping enables the production of a near full-length dystrophin from the native transcript expressed in affected tissues. However, prior exon skipping approaches with first generation antisense oligonucleotides (ASOs) have been limited by poor biodistribution and tolerability resulting in negligible restoration of dystrophin protein. We have developed a packaging and manufacturing solution that enables us to efficiently package multiple snRNAs into a single AAV vector to enhance exon skipping potency and enable relevant tissue distribution and potentially durable effect following a single administration.” In human DMD cells harboring relevant mutations, dose-dependent exon skipping and dystrophin restoration was demonstrated with snRNA constructs specific for exons 51, 53, 44, or 45. Locanabio’s lead candidate, LBIO-115, an AAV expressing multiple snRNAs that specifically promote skipping of exon 51, was evaluated in a humanized mouse model of DMD (del52hDMD.mdx mice) amenable to exon 51 skipping. Intravenous administration resulted in dose-dependent exon skipping that correlated with tissue expression of the snRNA and that was sustained throughout the 12-week study. Importantly, dystrophin protein expression increased between weeks 4 and 12 and resulted in relocalization of nNOS expression to the sarcolemma, indicating restoration of a functional dystrophin protein following exon skipping. A similar therapeutic profile was observed for LBIO-135, an AAV expressing multiple snRNAs designed to promote skipping of exon 53, in the del52hDMD/mdx mouse model which is also amenable to exon 53 skipping. Locanabio’s presentation at WMS2023 is available on the Scientific Posters and Publications page of the company’s website. “These proof-of-concept data demonstrate the potential of our proprietary vectorized snRNA platform to overcome previous challenges with packaging multiple snRNA constructs into the AAV genome and open up this field for therapeutic application,” said Jim Burns, Ph.D. Locanabio’s chief executive officer. “The ability to package multiple snRNA cassettes amplifies potency relative to delivery of single ASOs for exon skipping. Our first product candidate, LBIO-115, is advancing through preclinical studies and we expect to submit an investigational new drug (IND) application in mid-2024. Eighty percent of DMD mutations are amenable to exon skipping and therapies that target skipping of exons 51, 53, 44, and 45 could potentially address 35% of the total DMD patient population.” Locanabio’s Vectorized snRNA Platform Locanabio is using engineered small nuclear RNAs, or snRNAs, delivered using AAV gene therapy to target disease-causing RNA with a one-time administration. snRNAs target RNA exclusively and precisely and are non-immunogenic. They can effect a wide variety of mechanisms including exon-skipping to either restore a reading frame or regulate mRNA and protein expression, target disease causing toxic RNA repeat sequences and recruit endogenous adenosine deaminases acting on RNA (ADARs) for therapeutic RNA editing. Their small size allows the delivery of multiple snRNAs in a single AAV vector which can be used to increase potency or allow targeting of multiple RNAs. About Duchenne Muscular Dystrophy (DMD) DMD is a rare fatal X-linked recessive degenerative neuromuscular disorder caused by mutations in the dystrophin gene. The disease affects approximately 1 in every 3,500 to 5,000 males born worldwide. The dystrophin gene is the largest human gene. DMD causing mutations can occur at various places in the gene and most result in large exon deletions or duplications and dysfunctional dystrophin protein. Dystrophin plays a key structural role in muscle. It is one of a group of proteins whose function is to strengthen muscle fibers and protect them from injury as muscles contract and relax. Without it, muscle cells become damaged which leads to muscle wasting. Patients with DMD experience progressive muscle wasting, difficulty controlling movement, respiratory failure and heart failure leading to full time wheelchair use in teens and early 20’s and reduced life expectancy. About Locanabio, Inc. Locanabio is a leader in developing a new class of genetic medicines that has the potential to significantly improve the lives of patients with devastating genetic diseases by correcting the message of disease-causing RNA. Our proprietary platform uses gene therapy to deliver RNA-binding systems, including snRNA, Cas13d and PUF, that can be engineered to selectively manipulate disease-causing RNA by multiple mechanisms. Our systems are designed to provide a durable therapy with a single administration without altering a cell’s DNA. Locanabio’s platform has applications across a range of tissues and diseases, and we are currently advancing programs in rare genetic neuromuscular and neurodegenerative diseases. For more information, visit www.locanabio.com . SOURCE: Locanabio