Congenital muscular dystrophy

LAMA2-CMD is an early onset congenital muscular dystrophy caused by the absence of the LAMA2 protein. Image credit: Shutterstock/ Dan76. Modalis Therapeutics has been awarded a rare paediatric disease designation by the US Food and Drug Administration (FDA) for its congenital muscular dystrophy type 1a (LAMA2-CMD) gene therapy. As per the designation, the Japan-based company will be eligible to receive a priority review voucher if the drug candidate, MDL-101, is approved by the FDA. Recipients can redeem priority review vouchers themselves for any chosen drug or instead sell them to other pharma companies. Having the ability to slash four months off FDA review time, vouchers can sell for about $100m. The designation comes after a period of uncertainty for the vouchers’ future, with the programme facing a tight deadline on sunset provisions. The US House of Representatives ultimately passed a bill last week to reauthorise the rare paediatric priority review voucher program through September 2029. Modalis said it also pursuing orphan drug status for its candidate, with the FDA currently reviewing the company’s application. Orphan drug status provides benefits such as tax credits for US-based clinical trials and market exclusivity. See Also: FDA approves PureTech’s KarXT to treat schizophrenia in adults FDA greenlights Regeneron’s Dupixent for the treatment of COPD LAMA2-CMD is an early-onset congenital muscular dystrophy caused by the absence of the LAMA2 protein. Affected infants can have severe muscle weakness, hypotonia, and joint deformities, amongst others. As those with the disease grow, spinal curvature and speech issues can also develop. There are no approved therapies to treat LAMA2-CMD. Gene therapies for LAMA2-CMD using an adeno-associated virus (AAV) vector are difficult to develop as LAMA2 is made up of 3,000 amino acids, meaning it cannot be loaded onto a vector, according to Modalis. The company is therefore using its clustered regularly interspaced short palindromic repeats (CRISPR)-based epigenome editing technology to develop the therapy. MDL-101 works by inducing the expression of the sister gene LAMA1 in muscle tissues, which compensates for the deficient function of LAMA2. Modalis’s CEO Haru Morita said: “We have received many requests for our efforts from children and families around the world suffering from this disease for which there is currently no treatment, and we feel a mission to respond to the expectations of patients who are eagerly awaiting the start of clinical trials as soon as possible.” Modalis expects to file an investigational new drug (IND) application in 2025, according to a Q2 2024 financial results press release.

Pictured: Collage of Sarepta Therapeutics, DNA, and an IV bag/Taylor Tieden for BioSpace Sarepta Therapeutics is anticipating full FDA approval and a label expansion for its gene therapy, Elevidys, with the company indicating on its Q1 earnings call last week that a draft label is imminent. But the therapy has come under the microscope regarding its high cost and clinical effectiveness. Elevidys, which won accelerated approval for Duchenne muscular dystrophy (DMD) patients aged 4 to 5 in June 2023, has benefited Sarepta economically, pulling in over $200 million in 2023 and another $133.9 million in the first quarter this year. Whether it is of benefit to patients, however, depends on who you ask. High Demand for Elevidys DMD is one of the more severe forms of inherited muscular dystrophy, according to the National Institutes of Health. The disease is caused by mutations in the dystrophin gene, leading to muscle fiber degeneration and weakness. Debra Miller, CEO of CureDuchenne, told BioSpace that Elevidys, the first gene therapy for DMD, has been “tremendous” for families enrolled in trials and has demonstrated positive effects for patients. Michael Kelly, the organization’s chief scientific officer, added that the FDA was “super brave” and made the right decision in giving Elevidys accelerated approval. “There is an enormous appetite in parents whose children are 4 to 5 to get access to this drug, and there is an equally enormous appetite for younger children . . . to get access to this drug. We’ve seen many examples of families that have undergone treatment and [are] seeing real, measurable benefits,” Kelly told BioSpace. Uy Ear, vice president of U.S. healthcare—biotechnology at Mizuho Securities, told BioSpace that Elevidys’ uptake had been “pretty incredible.” However, Ear said that DMD patients are usually diagnosed at close to five years of age—close to the cutoff for Elevidys. Patients are aging out of the therapy, and Sarepta is essentially running out of patients, Ear said, so a label expansion is needed to get more patients on the treatment and continue the forward momentum. Sarepta is looking to expand access to Elevidys to DMD patients without an age restriction or ambulatory status. According to Ear, if the FDA does grant full approval and a label expansion, the impact will be significant for DMD patients. “Many parents and physicians, in general, believe that you need to treat these patients as early as possible and as quickly as possible, primarily because as each day goes by . . . they lose muscle, and you want to preserve this,” he said. Kelly added that full approval would allow for an easier pathway for other drugs in the pipeline for DMD to get approved. Benefit and Cost of Elevidys Questioned But while some experts are bullish on approval, others have cited potential drawbacks and concerns about the gene therapy. David Rind, the chief medical officer of the Institute for Clinical and Economic Review (ICER), penned an article in JAMA last week in which he noted that Elevidys missed its primary efficacy endpoint in two studies but still netted approval. In briefing documents released prior to the May 2023 advisory committee meeting for Elevidys, the FDA stated that the measurement of levels of micro-dystrophin in the muscle tissue only provided information about the “expression of the transgene product in cells transduced by [the therapy], rather than insight into a pharmacologic effect on a biomarker in the pathway of the disease.” While acknowledging its potential, Rind told BioSpace it is too early to determine if micro-dystrophin is an effective biomarker. “You’d like to know that micro-dystrophin has some effect on Duchenne muscular dystrophy before you call it a surrogate,” he said. “Normally, when we imagine a surrogate, there has been some connection between the thing you’re measuring and an outcome you care about. . . . Here, it’s a brand-new protein with no evidence that it affects the course of Duchenne muscular dystrophy, so it’s not a reasonable surrogate endpoint.” Rind recommended the FDA insist on a carefully controlled, longer term or larger trial in order to determine if Elevidys is beneficial, “rather than accepting a therapy that failed in its clinical endpoints.” In the JAMA article, Rind also called out the $3.2 million per dose price tag for the gene therapy as a significant point of contention. He said there is no scheme in the U.S. to deal with pricing issues. It would be “unfortunate” if the FDA does move forward with an expanded indication, but it seems like a distinct possibility, Rind said. Kelly said that while he understands the regulatory issues surrounding the therapy, there has been benefit reported by patients and parents. Ear noted that it is still too early to know what major issues or downsides exist with Elevidys, but that no major safety concerns have arisen to date. “If you believe the videos and the parent reports and the doctor reports of how incredibly effective this gene therapy is, it’s hard to explain why it failed in this clinical trial,” Rind countered. “If it’s that good, why weren’t the primary outcome measures able to show that?” Sarepta did not immediately respond to a request for comment from BioSpace. Overall, experts are anticipating that the gene therapy will get across the final finish line, and Kelly said it would be “difficult to swallow” for the DMD community if a full approval and eventual label extension is not granted. “Give the patient the choice in making the decisions and the treatment options,” Kelly said. “The families and individuals here are particularly well versed of the limitations [of the therapy].” Tyler Patchen is a staff writer at BioSpace. You can reach him at tyler.patchen@biospace.com. Follow him on LinkedIn.

A breakthrough approach and supporting data using epigenome editing technology for the treatment of a type of muscular dystrophy, LAMA2-congenital muscular dystrophy (LAMA2-CMD), a genetic disorder, is presented. A single dose of MDL-101, using an AAV vector, demonstrated sustained upregulation of LAMA1 (Gene of Interest) in skeletal muscle tissues for up to 12 months, corrected muscle pathophysiology, significantly extended the lifespan, and increased the body weight of dyW mouse, a disease model of LAMA2-CMD. MYOAAV, an engineered AAV9 vector, significantly increased muscle tropism and consequently lowered the dose of the viral vectors at ten-times compared to conventional naturally occurring vectors. Systemic administration of MYOAAV version MDL-101 in adult and juvenile NHPs successfully demonstrated widespread muscle-specific vector distribution and induced LAMA1 to levels that restore function across skeletal muscle tissues without adverse effect, suggesting the potential for clinical efficacy as a therapeutic approach for serious genetic disorders. TOKYO & WALTHAM, Mass.--(BUSINESS WIRE)-- Modalis Therapeutics Corporation (Tokyo Stock Exchange: 4883), a pioneering company developing innovative drugs for the treatment of rare genetic diseases, utilizing its proprietary CRISPR-based epigenome editing technology CRISPR-GNDM®, posted the preprint paper titled “Efficient and durable gene activation by Cas9-mediated epigenome editing in vivo” on bioRxiv. The company reported data demonstrating exceptional durability, robust efficacy and safety in dyW mouse disease model of LAMA2-CMD and in adult and juvenile NHPs. LAMA2-CMD is a severe, early onset congenital muscular dystrophy caused by the absence of the LAMA2 protein. Despite significant advances in gene therapy and the approval of about a dozen therapies, the size of the disease-causing gene of LAMA2-CMD, which exceeds 3,000 amino acids, hinders the conventional gene therapy approach using AAV vectors to deliver the healthy version of the mutated gene. No approved therapies to address the root cause of this condition exist or are in clinical trials. Modalis’ proprietary CRISPR-GNDM®, is capable of specific modulation of the expression of disease-relevant genes, without introducing double-strand DNA breaks, and our MDL-101 is potentially the first-in-class therapeutics to solve the challenge and provide life-changing therapeutics for the patients of LAMA2-CMD. "We are thrilled to post our comprehensive preclinical data supporting the development of MDL-101 on bioRxiv. This study represents one of the first demonstrations of successful systemic epigenome editing in NHPs in a viable therapeutic format, as evidenced by significant target engagement and induction of LAMA1 gene expression across muscle tissues,” said Haru Morita, CEO of Modalis. “Additionally, our study is among the first to show that systemic Cas9 expression can be safe and well-tolerated in NHPs. These findings underscore the potential of CRISPR-GNDM® technology as a next-generation gene therapy platform for a variety of neuromuscular and other genetic disorders”. About bioRxiv (bioRxiv - the preprint server for Biology) bioRxiv is a preprint server for life science, medical, and biological journals. It allows for early publication without waiting for long peer review periods. Most of the leading journals in life science, medical, and biology area are partnered with bioRxiv, so manuscript files and metadata submitted to bioRxiv can be directly transmitted to partnered journals when we submit. In addition, papers submitted to bioRxiv are assigned a DOI and are eligible for citation. About MDL-101 MDL-101 is an experimental, epigenetic editing therapy under investigation for the treatment of LAMA2-Congenital Muscular Dystrophy (LAMA2-CMD). MDL-101 is comprised of a guide nucleotide targeting LAMA1 gene, a highly homologous sister gene of the disease-causing gene LAMA2, enzyme-null Cas9 (dCas9) fused with trans-activating domain driven by a muscle-specific promoter and coded in a muscle-specific AAV vector. MDL-101 upregulates LAMA1 gene products in patients’ muscle tissue to compensate for loss-of-function caused by mutation of LAMA2, and therefore has the potential to provide a one-time, durable treatment to benefit people living with LAMA2-CMD. About Modalis: Modalis Therapeutics develops precision genetic medicines using epigenome editing technology. Modalis is pursuing therapies for orphan genetic diseases using its proprietary CRISPR-GNDM® technology which enables the gene/locus-specific modulation of gene expression or epigenome editing without the need for DNA cleavage or altering DNA sequence. Headquartered in Tokyo with all research and development operations in Waltham Massachusetts, the company is listed on the Tokyo Stock Exchange’s Growth market. For additional information, visit . View source version on businesswire.com: Contacts Modalis Therapeutics Sawako Nakamura media@modalistx.com Source: Modalis Therapeutics Corporation View this news release online at: