PLA2G6

CDMO will perform HQ plasmid production in support of Phase I/II clinical trials for Infantile Neuroaxonal Dystrophy ALDERLEY PARK, England--(BUSINESS WIRE)-- Charles River Laboratories International, Inc. (NYSE: CRL) and the INADcure Foundation, a nonprofit organization whose mission is to support the development of treatments for Infantile Neuroaxonal Dystrophy (INAD) and other forms of PLA2G6-related neurodegeneration (PLAN), today announced a plasmid DNA manufacturing alliance. The collaboration will leverage Charles River’s market leading contract development and manufacturing organization (CDMO) expertise in High Quality (HQ) plasmid DNA production, to manufacture its leading candidate for Phase I/II clinical trials. In INAD patients, a mutation or genetic alteration in the PLA2G6 gene causes mitochondrial and axonal membrane defects that lead to neuronal damage with axonal swellings and accumulation of pre-synaptic spheroids. Leena and Anil Panwala founded the INADcure Foundation in 2016, following the diagnosis of their two-year-old daughter, Ariya. Upon discovering there was no dedicated organization or centralized effort driving INAD research forward, they launched the Foundation with the mission to accelerate research and drive drug discovery. After seven years of unwavering dedication and with the tremendous support of INAD-afflicted families worldwide, the Foundation is furthering the development of a gene therapy treatment specifically designed for children affected by this rare neurodegenerative disease. What is INAD? INAD, otherwise known as phospholipase associated neurodegeneration (PLAN), is a rare disease with no known treatment or cure. Like other neurodegenerative diseases, INAD is progressive, and symptoms include poor motor function, involuntary eye movements, seizures, hearing loss, and difficulty swallowing and breathing. INAD affects over 150 children worldwide with a life expectancy of 10 or less years. Plasmid DNA Manufacturing Services Charles River’s plasmid DNA production, specifically HQ plasmid, combines key features of Good Manufacturing Practice (GMP) manufacture with rapid turnaround times to accelerate the timeline to clinic. Plasmid DNA is a critical starting material for many cell and gene therapy therapeutics and demand continues to outstrip supply. In response to this, Charles River recently announced the opening of a state-of-the-art HQ plasmid manufacturing center of excellence to address these supply shortages and support the growing needs of the cell and gene therapy field. Charles River, with the acquisitions of Cobra Biologics, Vigene Biosciences, and Cognate BioServices, in 2021, has extended its comprehensive cell and gene therapy portfolio to include CDMO capabilities spanning plasmid DNA, viral vector, and cellular therapy production for clinical through to commercial supply. To learn more about plasmid DNA production, watch Andrew Frazer, PhD, Associate Director, Scientific Solutions, Gene Therapy CDMO Services’ on-demand webinar: Advancements in Manufacturing for Rapid Delivery of pDNA Starting Materials. Approved Quotes “The opportunity to work with INADcure is exactly why we do the work we do. Their work is incredibly important to patients with this ultra-rare disorder. We are excited for the INADcure team to achieve this next stage of treatment development.” - Kerstin Dolph, Corporate Senior Vice President, Biologics Solutions, Charles River “Our collaboration with Charles River brings us closer to accomplishing our goal of delivering breakthrough treatments for INAD. We are excited to begin HQ plasmid DNA manufacturing to further develop our treatment with their experienced team. Their invaluable expertise will undoubtedly contribute to the advancement of our gene therapy program.” - Leena Panwala, Founder & Executive Director at INADcure. About INADcure The INADcure Foundation is a 501(c)(3) nonprofit charity whose mission is to support the development of treatments, including a cure, for Infantile Neuroaxonal Dystrophy (INAD) and other forms of PLA2G6-related neurodegeneration (PLAN). Its work includes advancing our understanding of this devastating disease, educating the public about INAD and other forms of PLA2G6-related neurodegeneration, advocating for better access to treatment, and supporting the families and caregivers of children diagnosed with INAD worldwide. For more information, visit . About Charles River Charles River provides essential products and services to help pharmaceutical and biotechnology companies, government agencies and leading academic institutions around the globe accelerate their research and drug development efforts. Our dedicated employees are focused on providing clients with exactly what they need to improve and expedite the discovery, early-stage development and safe manufacture of new therapies for the patients who need them. To learn more about our unique portfolio and breadth of services, visit . View source version on businesswire.com: Contacts Charles River Investor Contact: Todd Spencer Corporate Vice President, Investor Relations 781.222.6455 todd.spencer@crl.com Charles River Media Contact: Amy Cianciaruso Corporate Vice President, Chief Communications Officer 781.222.6168 amy.cianciaruso@crl.com Source: Charles River Laboratories International, Inc. View this news release online at:

Retrotope, based in Los Altos, California, cited data from its Phase II/III trial of RT001 in patients with infantile neuroaxonal dystrophy (INAD). They also reported on a concurrent natural history study of INAD patients’ disease onset and progression. INAD is an ultra-rare, progressive, fatal, infant genetic neurological disorder. It is on a spectrum of diseases called PLA2G6-associated neurodegeneration. A congenital disability in the PLA2G6 enzyme causes an inability to effectively clear the byproducts of lipid peroxidation (LPO), which are toxic. This results in a “death signal” that leads to rapid neuronal cell death in the brains of developing infants. Alex Fay, Assistant Professor of Neurology, University of California, San Francisco and one of the study’s principal investigators, noted, “INAD is an ultra-rare, relentlessly progressive and fatal disease that currently has no approved treatments. This trial compared a group of children with INAD treated with RT001 with a natural history cohort, and the results indicate that RT001 slows progression and prolongs survival compared to no treatment. The findings are striking and suggest that RT001 has the potential to deliver a meaningful impact on neurological function and survival of children with INAD.” RT001 is an isotopically stabilized, synthetic linoleic acid (LA) that Retrotope discovered and developed using its technology platform, which combats the oxidative stress and cellular degeneration that comes from lipid peroxidation (LPO). Polyunsaturated fatty acids (PUFAs) make up the cell and mitochondrial membranes. The LPO process targets PUFAs. Retrotope’s technology generates stabilized PUFAs, such as RT001, incorporating into all membranes and down-regulating LOP to protect membranes from degeneration. The clinical trial included 19 INAD patients and the concurrent natural history of 36 INAD patients as the control group. There were no significant differences between the baseline characteristics in the two cohorts. Patients in the treatment cohort were dosed with RT001 for a minimum of one year with a 30-day treatment-free follow-up. The patients receiving RT001 demonstrated an improvement of 6.42 rank points on the Modified Ashworth Spasticity Scale compared to the control cohort. Similar treatment benefits were observed for the RT001 cohort compared to controls across all five of the efficacy outcomes scales. Progression free survival (absence of pneumonia or death event) was a pre-specified secondary endpoint. The RT001 group demonstrated a statistically significant 82.5% decrease in morbidity risk compared to the controls. A pre-specified exploratory endpoint of survival showed a statistically significant mortality risk decrease of 88.8%. Confirmed deaths were “dramatically lower” in patients receiving RT001 compared to the control group, 11% versus 31%, respectively. “We are very pleased by these topline results and excited to meet with the FDA to discuss the next steps in our ongoing effort to bring RT001 to the INAD patient community,” said Peter G. Milner, Chief Medical Officer of Retrotope. “With clear evidence of benefit on patient survival, as well as consistent improvements observed in all analyzed efficacy endpoints including those which measured vital function and activities of daily living, we believe these study results support the potential of RT001 to address a critical unmet need in hits orphan disease patient population.” Retrotope has ongoing trials for RT001 in amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP) and Friedreich’s ataxia (FA), three of the four most common orphan neurodegenerative diseases. According to Clinical Trials Arena, the company is targeting a funding round in the first quarter of 2022 to raise $100 million. On August 11, the company indicated that it had completed enrollment for its Phase II study of RT001 for progressive supranuclear palsy (PSP). PSP is a progressive, neurodegenerative disease resulting in impaired balance, problems with eye movement, speech, and swallowing, rigid muscle tone, and ultimately, cognitive impairment. It usually affects people between the ages of 60 and 70. It is often misdiagnosed as Parkinson’s disease and Alzheimer’s disease. On April 21, Retrotope completed enrollment of its Phase II trial of RT001 in ALS (Lou Gehrig’s disease). They exceeded the enrollment target of 40 patients in less than six weeks. They expect data from the trial by the end of the year.

Company Currently Conducting Late-Stage Clinical Trials in Both Infantile Neuroaxonal Dystrophy (INAD) and Friedreich’s Ataxia (FA) RT001 also Granted Fast Track Designation by FDA in FA; Orphan Drug Designation by European Medicines Agency in INAD LOS ALTOS, Calif., Feb. 25, 2021 (GLOBE NEWSWIRE) -- Retrotope, a clinical-stage biopharmaceutical company focused on the development of novel, first-in-class therapies for degenerative diseases, today announced that the U.S. Food and Drug Administration (FDA) has granted two rare pediatric disease designations to RT001, the company’s lead development candidate. The first rare pediatric disease designation is for the treatment of infantile neuroaxonal dystrophy (INAD), with the second covering the treatment of Friedreich’s ataxia (FA). In addition, RT001 has been granted Fast Track designation by the FDA for the treatment of FA and orphan drug designation by the European Medicines Agency (EMA) for the treatment of INAD.   RT001 has previously been granted orphan drug designation in the U.S. for the treatment of multiple diseases, including FA, progressive supranuclear palsy (PSP) and PLA2G6-associated neurodegeneration, which includes INAD. Rare pediatric disease designation is granted by the FDA to drug candidates being developed to address serious and life-threatening diseases that primarily affect children, with onset of severe symptoms occurring prior to 18 years of age. To qualify for rare pediatric disease designation, these diseases must affect fewer than 200,000 people in the United States.   Under the FDA's rare pediatric disease priority review voucher program, a sponsor that receives an approval for a drug that has been granted rare pediatric disease designation may qualify for a voucher that can be redeemed to receive a priority review of a subsequent marketing application for a different product or sold to other companies. Retrotope is eligible to receive a priority review voucher should the company secure approval for RT001 in either one of these indications. The FDA’s Fast Track program is designed to facilitate the development, and expedite the review of, medicines to treat serious or life-threatening conditions and fill an unmet medical need. Recipients of Fast Track designation are eligible for greater access to the FDA during the clinical development process and may also qualify for priority review. Orphan drug designation may be granted by the EMA to therapeutic candidates that are intended to treat a serious condition that affects fewer than five in 10,000 people in the EU, and which demonstrate sufficient data to suggest the candidate may produce clinically relevant outcomes. The designation provides companies with certain benefits and incentives for clinical development and a period of market exclusivity, if approved. “We are proud to receive these key regulatory designations for RT001 in INAD and FA, as they validate and support the important work that we are undertaking to address rare, life-threatening diseases that are impacting young people around the world,” said Vidhya Gopalakrishnan, Ph.D., Retrotope’s chief development officer. “INAD and FA are both devastating diseases, not only for the patients affected but also for their loved ones. At Retrotope, we are working diligently to advance RT001 through late-stage clinical trials in both INAD and FA and remain committed to the goal of delivering a treatment to these patients that can make a meaningful difference in their lives.” RT001 is a clinical-stage isotopically stabilized, synthetic linoleic acid (LA) discovered and developed with Retrotope’s novel platform technology. This platform is designed to combat the oxidative stress and cellular degeneration that arises from lipid peroxidation (LPO). While all healthy human tissues undergo this physiological process of cell degeneration and repair, it is well-established that a wide range of serious degenerative diseases are precipitated when the LPO process gets out of balance. Polyunsaturated fatty acids (PUFAs), which make up cell and mitochondrial membranes throughout the body and are vital to healthy cellular function, are the target of the LPO process due to their inherent instability. Free radicals in the body exploit the instability of PUFAs to trigger chain reactions that drive LPO and the resulting degradation of these vital PUFAs. Retrotope’s novel platform technology creates stabilized PUFAs, such as RT001, that become an integral part of all membranes and are capable of down-regulating LPO in order to protect membranes from degeneration. RT001 has been safely administered orally on a daily basis to more than 100 patients, spanning more than 1,000 patient months. Retrotope is currently conducting a potentially pivotal Phase 2/3 trial of RT001 in patients with INAD. The company has completed dosing and expects data to read out from the study in the first half of 2021. Additionally, the company is currently conducting a pivotal Phase 2/3 trial of RT001 in patients with FA. Enrollment in this study was completed in late 2020 and data is expected to read out by the end of 2021. “These designations awarded to Retrotope are aligned with the high unmet need and call for urgency in the FA community. FA most commonly has onset of symptoms during childhood, ages 10-15 years, with significant progression and functional loss taking place during this time. We believe it is important to conduct clinical trials in both children and adults with FA as intervening early will likely have the biggest therapeutic benefit in the long term,” said Jennifer Farmer, chief executive officer, Friedreich’s Ataxia Research Alliance (FARA). “The entire team at FARA is grateful for the dedication that Retrotope has demonstrated in its effort to develop a novel treatment for FA. We are excited that the company has completely enrolled its ongoing pivotal study of RT001 in patients with FA and look forward to the read out of data from the trial.” About Infantile Neuroaxonal Dystrophy (INAD) Infantile Neuroaxonal Dystrophy is an ultra-rare, infantile genetic neurological disorder and part of a spectrum of diseases called PLA2G6-associated neurodegeneration. Symptoms usually present between six and 18 months of age and there is often rapid onset of motor and intellectual regression. Later on, diminished muscle tone (hypotonia) and spasticity develop. The disease also leads to problems with vision and the eyes, the autonomic nervous system, and, in a minority of individuals, seizures. Usually, disease progression is rapid, and the disorder is invariably fatal in childhood.   There are currently no approved treatments for INAD. About Friedreich’s Ataxia (FA) Friedreich’s Ataxia is a debilitating and life-shortening neurodegenerative disease that affects approximately 5,000 people in the United States and over 20,000 people worldwide. FA results in the progressive loss of coordination and muscle strength which then leads to motor incapacitation, wheelchair dependence, and ultimately early death most commonly due to cardiomyopathy. There are currently no approved treatments for FA. About Retrotope Retrotope is a clinical-stage biopharmaceutical company focused on the development of first-in-class therapies for degenerative diseases ranging from orphan neurodegenerative indications to large market degenerative conditions. The company leverages its proprietary drug discovery platform to create novel, disease-modifying drugs designed to combat the oxidative stress and cellular degeneration that arises from lipid peroxidation (LPO). It does so through the creation of isotopically stabilized synthetic versions of polyunsaturated fatty acids (PUFAs) that trigger the downregulation of the LPO process. The company’s lead development candidate, RT001, is a clinical-stage isotopically stabilized, synthetic linoleic acid (LA) that is in development for a range of orphan neurodegenerative diseases including infantile neuroaxonal dystrophy (INAD), Friedreich’s ataxia (FA), amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) and progressive supranuclear palsy (PSP). In addition, the company is advancing its second development candidate, RT011, an isotopically stabilized, synthetic docosahexaenoic acid (DHA), toward the clinic for the treatment of dry age-related macular degeneration (AMD). For more information, please visit .