PCCB

CAMBRIDGE, MA / ACCESSWIRE / April 3, 2024 / Moderna, Inc. (NASDAQ:MRNA) today announced that interim data for a first-in-human, phase 1/2, open-label, dose optimization study and extension study, evaluating the safety and efficacy of mRNA-3927, an investigational mRNA therapy for propionic acidemia (PA), has been published in Nature. "We are excited to share the first published clinical data utilizing an mRNA therapy for intracellular protein replacement," said Kyle Holen, M.D., Moderna's Senior Vice President and Head of Development, Therapeutics and Oncology. "PA is a rare, inherited metabolic disorder that results from the body's inability to process certain parts of proteins and lipids due to a specific enzyme deficiency. For people with PA, harmful amounts of toxic metabolites can build up in the body and lead to metabolic decompensation events (MDEs) and multisystemic complications. These interim data indicate early signs of potential clinical benefit with mRNA-3927, and importantly also demonstrate that mRNA-3927 has infrequent treatment-limiting side effects. I'm particularly proud of these results given that there are currently no therapeutic treatments approved for patients with this disease." The ongoing global Phase 1/2 clinical trial (ClinicalTrials.gov Identifier: NCT04159103) is a multicenter, open-label study designed to assess the safety, pharmacodynamics, and pharmacokinetics of mRNA-3927 in participants aged one year and older with genetically confirmed PA. Data from the study was previously presented at the 2023 American Society of Gene & Cell Therapy (ASGCT) Annual Meeting. As of the latest data cut (May 31, 2023), 16 participants received investigational therapy mRNA-3927 across five cohorts as part of the dose optimization and extension studies. Of these, 12 participants completed the study and enrolled in the open-label extension study. Over 340 intravenous doses were administered, accounting for over 15 person-years of treatment. To date, mRNA-3927 has been well tolerated in participants at the doses administered, with no dose-limiting toxicities observed. Fifteen participants reported treatment-emergent adverse events (TEAEs), while nine participants experienced drug-related TEAEs. Serious adverse events (SAEs) were reported in eight participants. Most SAEs were related to PA and unrelated to mRNA-3927. Five participants had mild infusion-related (IRR) TEAEs; however, most events occurred at the first doses. A reduction in the number of MDEs was observed. The relative risk for MDEs was reduced by 70% during the treatment period of the dose optimization study. No MDEs were observed with higher doses of mRNA-3927. Additional participants are now being enrolled into the study as part of a dose expansion phase to allow for further characterization of the efficacy, safety, and pharmacodynamic activity of mRNA-3927. About Propionic Acidemia Propionic acidemia is a rare, serious, inherited metabolic disorder with significant morbidity and mortality, affecting one in 100,000-150,000 individuals worldwide. PA is caused by pathogenic variants in the propionyl-coenzyme A carboxylase (PCC) α or β subunits (PCCA and PCCB genes, respectively), leading to PCC deficiency and subsequent accumulation of toxic metabolites. PA is characterized by recurrent life-threatening MDEs and multisystemic complications. Some of the most common multisystemic complications include neurological manifestations, cardiomyopathy, arrhythmia, growth retardation, recurrent pancreatitis, bone marrow suppression, and predisposition to infection. Long-term, insults by toxic metabolites cause multiorgan complications and are correlated with recurrent MDEs. Currently, there are no effective therapies for PA that target the underlying root cause of the disease. About mRNA-3927 mRNA-3927 is a novel, IV-administered, lipid nanoparticle (LNP)-encapsulated dual investigational mRNA therapy that encodes for PCCA and PCCB subunit proteins to restore functional PCC enzyme activity in the liver. By encoding for the PCC enzyme, mRNA-3927 has the potential to replace a missing or dysfunctional enzyme. About Moderna Moderna is a leader in the creation of the field of mRNA medicine. Through the advancement of mRNA technology, Moderna is reimagining how medicines are made and transforming how we treat and prevent disease for everyone. By working at the intersection of science, technology and health for more than a decade, the company has developed medicines at unprecedented speed and efficiency, including one of the earliest and most effective COVID-19 vaccines. Moderna's mRNA platform has enabled the development of therapeutics and vaccines for infectious diseases, immuno-oncology, rare diseases and autoimmune diseases. With a unique culture and a global team driven by the Moderna values and mindsets to responsibly change the future of human health, Moderna strives to deliver the greatest possible impact to people through mRNA medicines. For more information about Moderna, please visit modernatx.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including statements regarding: the potential clinical benefits of mRNA-3927 for the treatment of propionic acidemia; the safety and tolerability of mRNA-3927; and plans for future clinical studies of mRNA-3927. In some cases, forward-looking statements can be identified by terminology such as "will," "may," "should," "could," "expects," "intends," "plans," "aims," "anticipates," "believes," "estimates," "predicts," "potential," "continue," or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. The forward-looking statements in this press release are neither promises nor guarantees, and you should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties, and other factors, many of which are beyond Moderna's control and which could cause actual results to differ materially from those expressed or implied by these forward-looking statements. These risks, uncertainties, and other factors include, among others, those risks and uncertainties described under the heading "Risk Factors" in Moderna's Annual Report on Form 10-K for the fiscal year ended December 31, 2023, filed with the U.S. Securities and Exchange Commission (SEC), and in subsequent filings made by Moderna with the SEC, which are available on the SEC's website at . Except as required by law, Moderna disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release in the event of new information, future developments or otherwise. These forward-looking statements are based on Moderna's current expectations and speak only as of the date of this press release. Moderna Contacts Media: Elise Meyer Senior Director, Corporate Communications +1 617-852-7041 Elise.Meyer@modernatx.com Investors: Lavina Talukdar Senior Vice President & Head of Investor Relations +1 617-209-5834 Lavina.Talukdar@modernatx.com SOURCE: Moderna, Inc. View the original press release on accesswire.com

First clinical trial reporting results of an mRNA therapeutic for intracellular protein replacement To date, mRNA-3927 has been generally well-tolerated at the doses administered, with encouraging early signs of dose-dependent pharmacology and potential clinical benefits No occurrence of dose-limiting toxicities or study discontinuations due to drug-related treatment-emergent adverse events (TEAEs) More than 280 doses of mRNA-3927 were administered. Five patients have more than a year of dosing Phase 1/2 trial advances to the dose-expansion phase CAMBRIDGE, MA, USA I May 19, 2023 I Moderna,Inc. (NASDAQ:MRNA), a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines, reported on interim data from the Phase 1/2 trial of mRNA-3927, an investigational mRNA therapy for propionic acidemia (PA), presented at the 2023 American Society of Gene + Cell Therapy (ASGCT) Annual Meeting. The ongoing global Phase 1/2 clinical trial ( ClinicalTrials.gov Identifier: NCT04159103 ) is a multicenter, open-label study designed to assess the safety, pharmacodynamics, and pharmacokinetics of mRNA-3927 in participants aged 1 year and older with genetically confirmed PA. The trial utilized a dose-escalation approach to evaluate the intravenous administration of mRNA-3927.The initial dosing regimen was 0.3 mg/kg administered intravenously every three weeks; subsequent doses were administered every two weeks. Participants who complete the dose optimization trial (10 doses) are eligible to continue treatment in an open-label extension study ( NCT05130437 ). The primary outcomes of the trial are safety and tolerability, while secondary and exploratory outcomes include pharmacology, evaluation of potential plasma biomarkers, and the frequency and duration of metabolic decompensation events (MDEs). mRNA-3927 has been well-tolerated at the doses administered, with encouraging early signs of dose-dependent pharmacology and potential clinical benefit. To date, a total of 16 participants have received doses of mRNA-3927 across five dose cohorts. Of these, 11 participants completed the study and enrolled in the open-label extension study, and five participants were treated with mRNA-3927 for over one year. Following treatment initiation with mRNA-3927, most participants who had reported MDEs in the 12 months prior to dosing had either a lower incidence or no MDEs post-treatment. In total, more than 280 doses of mRNA-3927 were administered across both studies, which is more than 13 patient-years' treatment experience. No dose-limiting toxicities or study discontinuations due to drug-related TEAEs have occurred. Fifteen participants reported TEAEs, while nine participants experienced drug-related TEAEs. Serious adverse events (SAEs) were reported in eight participants. Most SAEs were related to PA and unrelated to mRNA-3927. Six participants had mild infusion-related (IRR) TEAEs; however, most events occurred at the first doses. "We continue to observe encouraging results with mRNA-3927 as we enter the dose-expansion phase, where we will further assess safety, efficacy, and determine the recommended dose for future clinical studies. This is the first clinical trial reporting results of an mRNA therapeutic for intracellular protein replacement, and we currently have more than 13 patient-years of experience to date," said Kyle Holen, M.D., Moderna's Senior Vice President and Head of Development, Therapeutics and Oncology. "We express our immense gratitude to the patients, families, and researchers who have contributed to our research efforts, and we look forward to continuing our efforts to explore the therapeutic potential of our mRNA platform for propionic acidemia and other rare diseases." About Propionic Acidemia (PA) and mRNA-3927 Propionic acidemia is a rare, serious, inherited metabolic disorder with significant morbidity and mortality, affecting one in 100,000-150,000 individuals worldwide. PA is caused by pathogenic variants in the propionyl-coenzyme A carboxylase (PCC) α or β subunits (PCCA and PCCB genes, respectively), leading to PCC deficiency and subsequent accumulation of toxic metabolites. PA is characterized by recurrent life-threatening MDEs and multisystemic complications. Multisystemic complications include neurological manifestations, cardiomyopathy, arrythmias, growth retardation, recurrent pancreatitis, bone marrow suppression, and predisposition to infection. Long-term, insults by toxic metabolites cause complications in various organs, and cognitive outcome is negatively correlated with the number of MDEs. Currently, there are no effective therapies for PA that target the underlying root cause of the disease. mRNA-3927 is a novel, IV-administered, lipid nanoparticle (LNP)-encapsulated dual mRNA therapy that encodes for PCCA and PCCB subunit proteins to restore functional PCC enzyme activity in the liver. By encoding for intracellular proteins, mRNA therapy has a potential role in preventing and treating acute metabolic decompensations. About Moderna In over 10 years since its inception, Moderna has transformed from a research-stage company advancing programs in the field of messenger RNA (mRNA), to an enterprise with a diverse clinical portfolio of vaccines and therapeutics across seven modalities, a broad intellectual property portfolio and integrated manufacturing facilities that allow for rapid clinical and commercial production at scale. Moderna maintains alliances with a broad range of domestic and overseas government and commercial collaborators, which has allowed for the pursuit of both groundbreaking science and rapid scaling of manufacturing. Most recently, Moderna's capabilities have come together to allow the authorized use and approval of one of the earliest and most effective vaccines against the COVID pandemic. Moderna's mRNA platform builds on continuous advances in basic and applied mRNA science, delivery technology and manufacturing, and has allowed the development of therapeutics and vaccines for infectious diseases, immuno-oncology, rare diseases, cardiovascular diseases and auto-immune diseases. Moderna has been officially recognized as a Great Place to Work in the U.S. by Great Place to Work ® . To learn more, visit www.modernatx.com . SOURCE: Moderna Therapeutics

Moderna has now given more than 280 doses of mRNA-3927. Moderna has early clinical evidence that its mRNA technology can treat a rare disease by replacing intracellular proteins. Participants in the phase 1/2 trial experienced a 66% overall relative risk reduction in the frequency of life-threatening events, encouraging the biotech to keep studying the candidate.  Massachusetts-based Moderna became a household name because of vaccines but, from its early days, has harbored the goal of turning human cells into drug production factories. By hijacking cellular machinery and getting the body to produce therapeutic molecules, Moderna wants to get proteins to intracellular targets and unlock new ways to treat disease.  The phase 1/2 trial marks the first time a biotech has reported clinical data on an mRNA therapeutic for intracellular protein replacement. In the study, children with propionic acidemia (PA), a rare inherited metabolic disorder, received multiple doses of a lipid nanoparticle-encapsulated dual mRNA therapy. Moderna’s therapy, mRNA-3927, encodes two subunit proteins, PCCA and PCCB, that form the enzyme that is deficient in patients with PA. By triggering production of the subunit proteins, Moderna could fix the root cause of the disease and prevent the buildup of harmful compounds that cause PA symptoms. Across the five dose cohorts covered by the data drop (PDF), Moderna saw no dose-limiting toxicities and three drug-related serious adverse events (SAEs). The most severe SAE was grade 3 pancreatitis in one patient. Moderna has now given more than 280 doses of mRNA-3927, with five patients taking the therapy for more than one year, and is forging ahead with the program. “We continue to observe encouraging results with mRNA-3927 as we enter the dose-expansion phase, where we will further assess safety, efficacy, and determine the recommended dose for future clinical studies. We currently have more than 13 patient-years of experience to date," Kyle Holen, M.D., head of development, therapeutics and oncology at Moderna, said in a statement. The phase 1/2 has generated early signs of efficacy. Many participants had metabolic decompensation events, which can be life threatening, before starting on mRNA-3927. Participants suffered fewer events after starting on the therapy, with Moderna tracking a 66% overall relative risk reduction across the trial and a 78% reduction in the four cohorts that received mRNA-3927 every two weeks.