POLG

Scientists report that a progressive neurodegenerative disease can be triggered by a viral infection. The mechanism relates to mitochondrial roles in antiviral defense mechanisms. A multidisciplinary team of scientists led by University of Helsinki report that a progressive neurodegenerative disease can be triggered by a viral infection. The mechanism relates to mitochondrial roles in antiviral defense mechanisms. The scientists report that a specific gene variant affecting the mitochondria disturb cellular antiviral defense responses. The results implicate that viral infections can trigger and modify symptoms of neurological diseases in subjects carrying genetic sensitivity. The article is published in Nature. Viking-age gene mutation alters viral defense Why a disease manifests at a certain age, and what kind of triggers may be involved, are still open questions. Recent data indicate that mitochondria, the cellular centers of energy and nutrient metabolism, have new important roles in protecting cells from both internal and external stresses. Importantly, a novel role of mitochondria in strengthening the immune system has been recognized, but the relevance of these functions for human diseases has been unclear. The current study shows that deficient mitochondrial functions in immune defense is connected to manifestation of brain diseases and sometimes also liver dysfunction. A multidisciplinary team led by academy professor Anu Suomalainen discovered that a genetic variant affecting the function of mitochondrial POLG enzyme delays detection of viral infection, leading to delayed severe inflammatory reaction damaging the brain and liver. The POLG variant originates from a single individual dating back to Viking times and has spread to populations of European origin. Especially Northern European countries show high carrier frequencies: one in a hundred individuals in Finland and Norway. If a subject inherits the POLG-variant from both parents, a neurological disease, MIRAS (mitochondrial recessive ataxia syndrome), manifests. However, the ages of onset and manifestations of MIRAS are highly variable, raising the question whether the disease is triggered by additional factors. Using a variable set of model systems, the team shows that the POLG variant leads to a weakened initial immune activation in response to viral infection, followed by a delayed, overactivated inflammation damaging the brain and liver. The scientists suggest that this mechanism explains why some MIRAS patients manifest in teenage with severe epilepsy, while some other patients with the same genetic background show disease signs years or even decades later, as motor coordination defects or Parkinson's disease. "Our results indicate that external factors, such as viral infections, can modify manifestation and age-of-onset of neurological diseases," postdoctoral scientist Yilin Kang comments. "Identification of susceptibility factors and triggering mechanisms are valuable targets for new therapy developments. The current findings indicate the importance of new mitochondrial functions in maintaining brain health." The work has been made possible by Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, Research Council of Finland , European Molecular Biology Organization and PolG foundation.

NEW YORK and PARIS, Nov. 15, 2023 /PRNewswire/ --The PolG Foundation is a nascent foundation established in 2022 by a PolG family, with the mission to support and accelerate research to find effective treatments and a cure for PolG mitochondrial disorders. To view the Multimedia News Release, please click: Continue Reading THE PoLG FOUNDATION ©Mei Fa Tan , Montreux Media Ventures With both a dedicated and experienced Board of Directors and Scientific Advisory Board, including some of the top mitochondrial scientists in the world, the Foundation is quickly becoming a leading funder of basic, translational, and clinical PolG research. Working with the global scientific community, we are investing in developing critical tools and continue to make our findings available to mitochondrial scientists, clinicians, and patients worldwide. In addition to the development of IPS Cell Lines, RNA Sequencing and two transgenic mouse models for the use of PolG researchers, the Foundation is also actively working on the creation of a PolG global registry and prospective natural history study. Frederik de Nassau, a POLG warrior and son of founding parents, designs a MITO clothing line to raise awareness and funds for The PolG Foundation. View Shop - A central pillar of the Foundation is to raise funding and provide grants to world-class investigators of basic science, clinical trial research and development of novel therapies for PolG mitochondrial disorders in both paediatric and adult PolG populations. Today, The PolG Foundation is pleased to announce four awardees granted to our first Call for Research Initiatives proposals. We are excited to see these grants being implemented by the four research groups who will pursue outstanding R&D work in the field of POLG biology: Prof Vamsi K. Mootha Broad Institute of MIT and Harvard, Boston (USA) Title: A variant-to-function map of POLG via deep mutational scanning Synopsis of the work: POLG-deficiency is associated with tremendous allelic heterogeneity, and at present it is very challenging to know which observed variants are benign versus pathogenic. The goal is to create a comprehensive dashboard for POLG that connects all possible variants to biological and biochemical functions. Next generation DNA synthesis to create a saturation mutagenesis library for POLG will be combined with functional genetic screens that quantitatively score POLG variants. It will be a durable toolbox that will be valuable for both basic research and clinical communities. Prof Anu Suomalainen Wartiovaara University of Helsinki, Research Programs Unit, Faculty of Medicine (Finland) Title: TargetPOLG: Mechanisms of POLG-disease and approaches to therapy Synopsis of the work: The Finnish POLG patient's cohort we support has the same homozygous mutation, however, manifest with a variability of symptoms, indicating that strong environmental and/or genetic factors affect the variable outcomes of POLG disease, from childhood to middle-age. Understanding and targeting such mechanisms have the potential to control the progression of POLG disease. Specifically, mechanisms will be explored and identified that might contribute and promote POLG-disease manifestations. Selected molecular targets will be tested and challenged to generate preclinical evidence for human trials. Dr Kristina Xiao Liang, Department of Clinical Medicine, University of Bergen (Norway) Title: Stem Cell-Based Study for Drug Discovery for POLG disease Synopsis of the work: The overarching goal of the project is to establish a human stem cell-based 2D neural system and 3D brain organoid platform for drug discovery and to identify mitochondria-targeting therapies that are repurposing-ready and can quickly trigger clinical trials in POLG patients. Dr Yi Shiau Ng, Wellcome Centre for Mitochondrial Research (WCMR), Newcastle University (UK) Title: Coalition for trial readiness in POLG (C4TR-POLG): Clinical trial readiness for POLG-related mitochondrial disease and ataxia: a prospective, longitudinal study identifying sensitive and ecologically valid biomarkers Synopsis of the work: Studying treatments for ultra-rare forms of mitochondrial disease is challenging. Participant pools are small and restricted by rigid inclusion and exclusion criteria. There is often incomplete understanding of genotype–phenotype relationships and natural history to inform trial endpoint development. Tackling these disparities is recognised as a long-standing, complex conundrum. Leveraging value in multi- stakeholder innovative networks is urgently needed. Fully aligned with the strategy of the Foundation, these research grants cover different building blocks that characterise the disease: from understanding how the disease develops and progresses, to monitoring phenotypes with outcome measures. Herewith, we are committed to discovering and developing potential new medicines and therapies. As a standard bearer for the global PolG community, we are deeply moved by all the interest and support received from individuals, foundations, scientific, biotech, pharma, patient advocacy and medical ecosystems. With your help and financial backing we can further our ambitious mission by discovering new therapies and a potential cure for PolG. Thank you! Donate: ©2023 | The POLG Foundation is a 501(c)(3) non-profit organization. EIN 87-1876876. Donations are tax-deductible in the USA as allowable by law. Donations may be sent to: THE POLG FOUNDATION, 99 Park Ave., 24th Floor, New York, NY 10016 Contact: Paula Casanova [email protected] Photo - Logo - SOURCE The PolG Foundation

CORAL GABLES, Fla., March 08, 2023 (GLOBE NEWSWIRE) -- Catalyst Pharmaceuticals, Inc. ("Catalyst") (Nasdaq: CPRX), a commercial-stage, patient-centric biopharmaceutical company focused on in-licensing, developing and commercializing novel high-quality medicines for patients living with rare diseases, today announced that an article was recently published in Epilepsia showed that perampanel reduces seizures with high effectivity in patients with rare genetic epileptic disease. The article is available online at . The case review from a group of European neurologists treating rare epilepsies working under the framework of NETRE (Network for Therapy in Rare Epilepsies) reports how perampanel (FYCOMPA®) is capable of significantly reducing seizures in patients with epilepsies that result from specific genetic mutations. Out of 137 patients treated with perampanel, 60 patients (43.5%) sustained over 75% reduction in seizure frequency, including 38 (27.5%) with greater than 90% reduction in seizure frequency. High efficacy was consistently observed in certain rare genetic variants, including SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, and NEU1. "The findings reported in the article appear to validate that the unique mechanism of action for FYCOMPA® may allow it to be efficacious in treating patients with rare genetic seizure disorders that can be difficult to manage,” said Gary Ingenito, M.D., Ph.D., Chief Medical and Regulatory Officer of Catalyst. “We look forward to continuing to bring FYCOMPA® to all patients that may benefit from it.” About Catalyst Pharmaceuticals With exceptional patient focus, Catalyst is committed to developing and commercializing innovative first-in-class medicines that address rare neurological and epileptic diseases. Catalyst’s flagship U.S. commercial product is FIRDAPSE® (amifampridine) Tablets 10 mg, approved for the treatment of Lambert-Eaton myasthenic syndrome ("LEMS") for adults and for children ages six to seventeen. In January 2023, Catalyst acquired the U.S. commercial rights to FYCOMPA® (perampanel) CIII, a prescription medicine approved in people with epilepsy aged four and older alone or with other medicines to treat partial-onset seizures with or without secondarily generalized seizures and with other medicines to treat primary generalized tonic-clonic seizures for people with epilepsy aged 12 and older. Further, Canada’s national healthcare regulatory agency, Health Canada, has approved the use of FIRDAPSE for the treatment of adult patients in Canada with LEMS. For Full Prescribing and Safety Information for FIRDAPSE®, please visit . For Full Prescribing Information, including Boxed WARNING for FYCOMPA®, please visit . For more information about Catalyst Pharmaceuticals, Inc., visit the Company's website at . About FYCOMPA FYCOMPA® (perampanel) CIII is a prescription medicine used in people with epilepsy aged 4 and older alone or with other medicines to treat partial-onset seizures with or without secondarily generalized seizures, and with other medicines to treat primary generalized tonic-clonic seizures for people with epilepsy aged 12 and older. FYCOMPA, an oral medication, is a selective non-competitive AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist. The precise mechanism by which FYCOMPA exerts its antiepileptic effects in humans is unknown. FYCOMPA is supplied as 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg film-coated tablets, and as a 0.5 mg/mL oral suspension formulation. FYCOMPA has been designated by the U.S. Drug Enforcement Administration as a federally-controlled substance (CIII). To date, FYCOMPA has been prescribed to over 500,000 patients globally. Forward-Looking Statements This press release contains forward-looking statements. Forward-looking statements involve known and unknown risks and uncertainties, which may cause Catalyst's actual results in future periods to differ materially from forecasted results. A number of factors, including those factors described in Catalyst's Annual Report on Form 10-K for the fiscal year 2021 and its other filings with the U.S. Securities and Exchange Commission ("SEC"), could adversely affect Catalyst. Copies of Catalyst's filings with the SEC are available from the SEC, may be found on Catalyst's website, or may be obtained upon request from Catalyst. Catalyst does not undertake any obligation to update the information contained herein, which speaks only as of this date. Important Safety Information: INDICATION FOR FYCOMPA FYCOMPA® (perampanel) is indicated in patients with epilepsy aged 4 years and older for partial-onset seizures (POS) with or without secondarily generalized seizures and adjunctive therapy for patients aged 12 years and older for primary generalized tonic-clonic (PGTC) seizures. IMPORTANT SAFETY INFORMATION FOR FYCOMPA WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS Serious or life-threatening psychiatric and behavioral adverse reactions including aggression, hostility, irritability, anger, and homicidal ideation and threats have been reported in patients taking FYCOMPA These reactions occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression Advise patients and caregivers to contact a healthcare provider immediately if any of these reactions or changes in mood, behavior, or personality that are not typical for the patient are observed while taking FYCOMPA or after discontinuing FYCOMPA Closely monitor patients particularly during the titration period and at higher doses FYCOMPA should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS In the partial-onset seizures clinical trials, hostility- and aggression-related adverse reactions occurred in 12% and 20% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 6% of patients in the placebo group. These effects were dose-related and generally appeared within the first 6 weeks of treatment, although new events continued to be observed through more than 37 weeks. These effects in FYCOMPA-treated patients led to dose reduction, interruption, and discontinuation more frequently than placebo-treated patients. Homicidal ideation and/or threat have also been reported postmarketing in patients treated with FYCOMPA. The combination of alcohol and FYCOMPA significantly worsened mood and increased anger. Patients taking FYCOMPA should avoid the use of alcohol. Patients, their caregivers, and families should be informed that FYCOMPA may increase the risk of psychiatric events. Patients should be monitored during treatment and for at least one month after the last dose of FYCOMPA, and especially when taking higher doses and during the initial few weeks of drug therapy (titration period) or at other times of dose increases. Similar serious psychiatric and behavioral events were observed in the primary generalized tonic-clonic (PGTC) seizure clinical trial. SUICIDAL BEHAVIOR AND IDEATION Antiepileptic drugs (AEDs), including FYCOMPA, increase the risk of suicidal thoughts or behavior in patients. Anyone considering prescribing FYCOMPA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Patients, their caregivers, and families should be informed of the risk and advised to monitor and immediately report the emergence or worsening of depression, suicidal thoughts or behavior, thoughts about self-harm and/or any unusual changes in mood or behavior. Should suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. DIZZINESS AND GAIT DISTURBANCE FYCOMPA caused dose-related increases in events related to dizziness and disturbance in gait or coordination. Dizziness and vertigo were reported in 35% and 47% of patients in the partial-onset seizure trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 10% of placebo-treated patients. Gait disturbance related events were reported in 12% and 16% of patients in the partial-onset seizure clinical trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 2% of placebo-treated patients. These adverse reactions occurred mostly during the titration phase. These adverse reactions were also observed in the PGTC seizure clinical trial. SOMNOLENCE AND FATIGUE FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events. Somnolence was reported in 16% and 18% of patients in the partial-onset seizure trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 7% of placebo-treated patients. Fatigue-related events were reported in 12% and 15% of patients in the partial-onset seizure trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 5% of placebo-treated patients. These adverse reactions occurred mostly during the titration phase. These adverse reactions were also observed in the PGTC seizure clinical trial. Patients should be advised against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of FYCOMPA is known. Patients should be carefully observed for signs of central nervous system (CNS) depression when FYCOMPA is used with other drugs with sedative properties because of potential additive effects. FALLS Falls were reported in 5% and 10% of patients in the partial-onset seizure clinical trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 3% of placebo-treated patients. DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS) DRESS, also known as multiorgan hypersensitivity, has been reported in patients taking AEDs, including FYCOMPA. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement. If signs or symptoms are present, immediately evaluate the patient and discontinue FYCOMPA if an alternative etiology for signs or symptoms cannot be established. WITHDRAWAL OF AEDs A gradual withdrawal is generally recommended with AEDs to minimize the potential of increased seizure frequency, but if withdrawal is a response to adverse events, prompt withdrawal can be considered. MOST COMMON ADVERSE REACTIONS The most common adverse reactions in patients aged 12 years and older receiving FYCOMPA (≥5% and ≥1% higher than placebo) include dizziness, somnolence, fatigue, irritability, falls, nausea, weight gain, vertigo, ataxia, headache, vomiting, contusion, abdominal pain, and anxiety. Adverse reactions in patients aged 4 to <12 years were generally similar to patients aged 12 years and older. DRUG INTERACTIONS FYCOMPA may decrease the efficacy of contraceptives containing levonorgestrel. Plasma levels of perampanel were decreased when administered with known moderate and strong CYP3A4 inducers, including, carbamazepine, phenytoin, or oxcarbazepine. Multiple dosing of FYCOMPA 12 mg per day enhanced the effects of alcohol on vigilance and alertness, and increased levels of anger, confusion, and depression. These effects may also be seen when FYCOMPA is used in combination with other CNS depressants. PREGNANCY AND LACTATION Physicians are advised to recommend that pregnant patients taking FYCOMPA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. Caution should be exercised when FYCOMPA is administered to pregnant or nursing women as there are no adequate data on the developmental risk associated with use in pregnant women, and no data on the presence of perampanel in human milk, the effects on the breastfed child, or the effects of the drug on milk production. HEPATIC AND RENAL IMPAIRMENT Use in patients with severe hepatic or severe renal impairment is not recommended. Dosage adjustments are recommended in patients with mild or moderate hepatic impairment. Use with caution in patients with moderate renal impairment. DRUG ABUSE AND DEPENDENCE FYCOMPA is a Schedule III controlled substance and has the potential to be abused and lead to drug dependence and withdrawal symptoms including anxiety, nervousness, irritability, fatigue, asthenia, mood swings, and insomnia. Please see full Prescribing Information, including Boxed WARNING. Source: Catalyst Pharmaceuticals, Inc. Investor Contact Mary Coleman Catalyst Pharmaceuticals, Inc. (305) 420-3200 mcoleman@catalystpharma.com Media Contact David Schull Russo Partners (858) 717-2310 david.schull@russopartnersllc.com