Muscular Dystrophy Congenital, Merosin Negative

LAMA2-CMD is characterised by the absence of the LAMA2 protein, leading to severe, early-onset muscular dystrophy. Credit: Ines Nepo/Shutterstock. The US Food and Drug Administration (FDA) has granted orphan drug designation (ODD) to Modalis Therapeutics’ investigational therapy, MDL-101, aimed at treating congenital muscular dystrophy type 1A (LAMA2-CMD). An epigenetic editing therapy, MDL-101 includes a guide nucleotide targeting the LAMA1 gene — a close homolog of the disease-causing LAMA2 gene. It utilises an enzyme-null Cas9 (dCas9) fused with a trans-activating domain, driven by a muscle-specific promoter and delivered via a muscle-specific AAV [adeno-associated virus] vector. MDL-101 works by upregulating LAMA1 gene products in patients’ muscle tissue to compensate for loss of function resulting from LAMA2 mutations. This approach has the potential to offer a one-time, long-lasting treatment option for individuals with LAMA2-CMD. ODD status facilitates the development of treatments for conditions affecting fewer than 200,000 patients in the US. See Also: UAE’s clinical trials space matures with experience from Covid-19 FDA approves Iterum’s ORLYNVAH NDA for uUTI treatment Under the ODD status for MDL-101, Modalis will receive benefits including exemption from application fees on filing new drug applications, tax reductions for clinical development and preferential treatment for the development and promotion of the asset in the US. On receipt of regulatory approval, MDL-101 would also receive seven years of exclusive sales rights in the US market. The US regulator previously granted rare paediatric disease designation for gene therapy for patients with LAMA2-CMD. LAMA2-CMD is characterised by the absence of the LAMA2 protein, a critical component comprising more than 3,000 amino acids. This leads to severe, early-onset muscular dystrophy, and due to the protein’s size, conventional gene therapy approaches such as using an AAV vector are challenging. Modalis focuses on the development of precision genetic therapies leveraging its epigenome editing technology, CRISPR-GNDM. This technology enables modulation of gene expression without causing double-strand DNA breaks. Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva . Editorial content is independently produced and follows the highest standards of journalistic integrity. Topic sponsors are not involved in the creation of editorial content. Free Whitepaper Cell and gene therapies: Pipe dream to pipeline The cell and gene industry is gaining momentum, with a new wave of therapies promising to transform the way doctors treat, and even cure, disease. In this report, Cytiva and GlobalData have collaborated to explore the rise of the cell and gene therapy industries, the current state of the market, present and future opportunities for advancement, and the challenges that lie ahead. Thank you. You will receive an email shortly. Please check your inbox to download the Whitepaper. By Cytiva Thematic By downloading this Whitepaper, you acknowledge that GlobalData may share your information with Cytiva Thematic and that your personal data will be used as described in their Privacy Policy

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.

BOSTON, March 4, 2024 /PRNewswire/ -- Constant Therapeutics LLC, a biopharmaceutical company focused on the development of treatments impacting the Alternative Renin-Angiotensin System, today announced that the first patient was dosed March 3, 2024, in the Company's phase 2 clinical trial of TXA127, the Company's lead peptide product under development as a potential treatment for Duchenne Muscular Dystrophy-associated (DMD-associated) Cardiomyopathy. The phase 2 trial is an open-label, multi-center trial designed to evaluate the safety and efficacy in non-ambulatory patients with DMD-associated Cardiomyopathy who are 16 years and older and who are receiving systemic glucocorticoids. Patients will receive 6 months of treatment and have the option to enter a 12-month extension study. The study is being conducted in Israel at Sheba Medical Center and Hadassah Medical Center and is expected to enroll 10 patients. "This is a significant milestone for Constant and for the DMD community," said Rick Franklin, CEO of Constant Therapeutics. "There are few treatments for DMD patients with cardiomyopathy, and heart failure is a leading cause of death in this disease. We are excited to initiate this carefully designed trial, and we look forward to sharing the data with the DMD community upon completion of the trial." About Constant Therapeutics LLC Constant Therapeutics LLC is a private biopharmaceutical company focused on the development of treatments that effect the Alternative Renin-Angiotensin System. The lead compound, TXA127, is a pharmaceutical formulation of the naturally occurring peptide Angiotensin (1-7) and is being developed for the treatment of stroke recovery and DMD-associated Cardiomyopathy. For more information on Constant Therapeutics, please visit our website at . About TXA127 TXA127 is a pharmaceutical formulation of the naturally occurring human peptide angiotensin-(1‐7). In addition to its specific effects in cardiac dysfunction, TXA127 has shown therapeutic activity in animal models of chronic stroke, Duchenne Muscular Dystrophy (DMD), Limb‐Girdle Muscular Dystrophy (LGMD), Congenital Muscular Dystrophy (MDC1A), Marfan Syndrome and Epidermolysis Bullosa. Contact: [email protected] +1-617-245-0289 SOURCE Constant Therapeutics