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DUBLIN--( BUSINESS WIRE )--The "AAV vectors in gene therapy - Pipeline Insight, 2022" drug pipelines has been added to ResearchAndMarkets.com's offering. AAV vectors in gene therapy: Overview Out of the several viral vectors that have been used to date for delivering the genes of interest, the Adeno-associated viral (AAV) vector appears to be the safest and effective vehicle and can maintain long-term gene and protein expression following a single injection of the vector. AAV vectors are the leading viral vectors for gene delivery to treat a variety of human diseases. Recent advances in developing clinically desirable AAV capsids, optimizing genome designs, and harnessing revolutionary biotechnologies have contributed extensively to the growth of the gene therapy field. AAV Vectors in Gene Therapy Emerging Drugs GS010: Gensight Biologics LUMEVOQ (GS010; lenadogene nolparvovec) targets Leber Hereditary Optic Neuropathy (LHON) by leveraging a mitochondrial targeting sequence (MTS) proprietary technology platform, arising from research conducted at the Institut de la Vision in Paris, which, when associated with the gene of interest, allows the platform to specifically address defects inside the mitochondria using an AAV vector (Adeno-Associated Virus). The gene of interest is transferred into the cell to be expressed and produces the functional protein, which will then be shuttled to the mitochondria through specific nucleotidic sequences in order to restore the missing or deficient mitochondrial function. "LUMEVOQ" was accepted as the invented name for GS010 (lenadogene nolparvovec) by the European Medicines Agency (EMA) in October 2018. Valoctocogene roxaparvovec: BioMarin Pharmaceutical Valoctocogene roxaparvovec is an investigational AAV5 gene therapy under regulatory review for the treatment of severe hemophilia A. It is currently in preregistration stage of development. In June 2021, BioMarin resubmitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA). In the United States, BioMarin intends to submit two-year follow-up safety and efficacy data on all study participants from the Phase III GENEr8-1 study to support the benefit/risk assessment of valoctocogene roxaparvovec, as previously requested by the Food and Drug Administration (FDA). BioMarin is targeting a Biologics License Application (BLA) resubmission in the second quarter of 2022, assuming favorable study results, followed by an expected six-month review by the FDA. DTX401: Ultragenyx Pharmaceutical DTX401 is an investigational AAV8 gene therapy designed to deliver stable expression and activity of G6Pase-? under control of the native promoter. DTX401 is administered as a single intravenous infusion and has been shown in preclinical studies to improve G6Pase-? activity and reduce hepatic glycogen levels, a well-described biomarker of disease progression. In a Phase I/II clinical study, all nine patients showed a clinical response, with significant reductions in the need for cornstarch and improvements in glucose control and other metabolic parameters compared to baseline. The drug is currently being evaluated in Phase III clinical trial to treat patients with Glycogen storage disease type I. AAV5-RPGR: MeiraGTx AAV-RPGR is an investigational gene therapy for the treatment of patients with X-linked retinitis pigmentosa (XLRP) caused by disease-causing variants in the eye specific form of the RPGR gene (RPGR ORF15). AAV-RPGR is designed to deliver functional copies of the RPGR gene to the subretinal space in order to improve and preserve visual function. MeiraGTx and development partner Janssen are currently conducting a Phase III clinical trial of AAV-RPGR in patients with XLRP with disease-causing variants in RPGR ORF15. Timrepigene emparvovec: Biogen Timrepigene emparvovec is an AAV2 vector administered by subretinal injection, which aims to provide a functioning CHM gene and expression of the REP-1 protein to restore membrane trafficking and thereby slow, stop or potentially reverse decline in vision. Data from the Phase 1/2 studies demonstrated a slower rate of decline in visual acuity in patients treated with timrepigene emparvovec compared to untreated patients in the natural history study. In addition, some patients treated with timrepigene emparvovec showed improvements in visual acuity. The studies also demonstrated that timrepigene emparvovec was generally well tolerated with an acceptable safety profile. The safety and efficacy of a single subretinal injection of timrepigene emparvovec is currently being evaluated in the ongoing Phase III STAR study. AMT 061: UniQure AMT-061 (etranacogene dezaparvovec) is an experimental gene therapy that uniQure is developing to treat hemophilia B. AMT-061 uses a modified and harmless adeno-associated virus 5 (AAV5) to deliver a highly functional copy of the F9 gene, called FIX-Padua, to patients' cells. The FIX-Padua gene version was shown to result in FIX clotting activity eight times greater than that associated with the standard F9 gene. As such, the one-time therapy - administrated directly into the bloodstream - is expected to increase FIX levels, helping to prevent and control bleeds. If approved, the therapy will be marketed globally by CSL Behring, which closed a commercialization and licensing agreement with uniQure in May 2021. UniQure and CSL Behring expect to file a regulatory application to the U.S. Food and Drug Administration (FDA) in early 2022 seeking AMT-061's approval for hemophilia B. Research and Development. RGX-314: REGENXBIO RGX-314 is being investigated as a potential one-time treatment for wet AMD, diabetic retinopathy, and other chronic retinal conditions. RGX-314 consists of the NAV AAV8 vector, which encodes an antibody fragment designed to inhibit vascular endothelial growth factor (VEGF). RGX-314 is believed to inhibit the VEGF pathway by which new, leaky blood vessels grow and contribute to the accumulation of fluid in the retina. REGENXBIO is advancing research in two separate routes of administration of RGX-314 to the eye, through a standardized subretinal delivery procedure as well as delivery to the suprachoroidal space. REGENXBIO has licensed certain exclusive rights to the SCS Microinjector from Clearside Biomedical, Inc. to deliver gene therapy treatments to the suprachoroidal space of the eye. According to the company's pipeline, the drug is currently in the Phase III stage of development. SPK-8011: Spark Therapeutics Investigational SPK-8011, a novel bio-engineered adeno-associated viral (AAV) vector utilizing the AAV-LK03 capsid, also referred to as Spark200, contains a codon-optimized human factor VIII gene under the control of a liver-specific promoter. The Food and Drug Administration (FDA) granted orphan-disease designation and breakthrough therapy designation in the US, while the European Commission has granted orphan designation to SPK-8011. NFS-01: Neurophth Investigational NR082, a novel recombinant adeno-associated viral serotype 2 vector (rAAV2) containing a codon-optimized of NADH-dehydrogenase subunit 4 (ND4) gene under the control of the cytomegalovirus promoter and enhancer, is a novel ophthalmic injection that is being developed for the treatment of Leber hereditary optic neuropathy (LHON) associated with ND4 mutations. It is currently being evaluated in Phase II/III clinical trial. GT 005: Gyroscope Therapeutics GT005 is designed as an AAV2-based one-time investigational gene therapy for GA secondary to AMD that is delivered under the retina. GT005 aims to restore balance to an overactive complement system, a part of the immune system, by increasing production of the CFI protein. Complement overactivation has been strongly correlated with the development and progression of AMD. The CFI protein regulates the activity of the complement system. It is believed that increasing CFI production could dampen the system's overactivity and reduce inflammation, with the goal of preserving a person's eyesight. Gyroscope is also evaluating GT005 in two Phase II clinical trials. Further product details are provided in the report AAV vectors in gene therapy: Therapeutic Assessment This segment of the report provides insights about the different AAV vectors in gene therapy drugs segregated based on following parameters that define the scope of the report, such as: Major Players in AAV vectors in gene therapy There are approx. 70+ key companies which are developing the therapies for AAV vectors in gene therapy. The companies which have their AAV vectors in gene therapy drug candidates in the most advanced stage, i.e. Preregistration include, BioMarin Pharmaceutical. Phases The publisher's report covers around 235+ products under different phases of clinical development like Late stage products (Phase III) Mid-stage products (Phase II) Early-stage product (Phase I) along with the details of Pre-clinical and Discovery stage candidates Discontinued & Inactive candidates Route of Administration Key Players BioMarin Pharmaceutical Gensight Biologics PTC therapeutics Ultragenyx Pharmaceutical MeiraGTx Pfizer Biogen uniQure Pfizer Ultragenyx Pharmaceutical REGENXBIO Biogen Spark therapeuics (Roche) Sarepta therapeutics Neurophth Therapeutics LYSOGENE Gyroscope Therapeutics Nanoscope Therapeutics Homology medicines Ultragenyx Pharmaceutical Passage Bio Freeline therapeutics Astellas Pharma Aspa therapeutics Adrenas Therapeutics ESTEVE Sio Gene Therapies Amicus therapeutics 4D Molecular therapeutics Taysha Gene Therapies Atsena Therapeutics BioMarin Pharmaceutical Abeona Therapeutics REGENXBIO uniQure Taysha Gene Therapies Asklepios BioPharmaceutical Sarepta Therapeutics Abeona Therapeutics Forge Biologics Sangamo therapeuics Bayer LogicBio therapeutics Solid Biosciences Applied Genetic Technologies Spark therapeuics (Roche) Eli lilly and company Lexeo Therapeutics Spark therapeutics Gensight Biologics Alcyone Lifesciences MeiraGTx Audentes therapeutics Vivet Therapeutics Takeda Astellas Gene Therapies Homology Medicines Adverum Biotechnologies Libella Gene Therapeutics Rocket Pharmaceuticals Brain Neurotherapy Bio, Inc. Ocugen Asklepios BioPharmaceutical Neurogene Jaguar Gene Therapy, LLC Axovia Therapeutics Coave therapeutics Novartis/ Arctos medical Novartis/Vedere Bio REGENXBIO Inc. StrideBio Abeona therapeutics Sanofi/ Sirion therapeutics Capsida Biotherapeutics Kriya therapeutics Neurophth Poseida Therapeutics, BridgeBio Pharma DiNAQOR/ Biomarin ViGeneron AskBio/Selecta Biosciences Prevail therapeutics Intas Pharmaceuticals Tenaya Therapeutics Scout Bio therapeutics Ocugen Oyster Point pharmaceuticals Cyprium Therapeutics Solid Biosciences Amicus Therapeutics Coave therapeutics AvantiBio Voyager Therapeutics/ Pfizer Aruvant Sciences Alcyone Lifesciences Gene Therapy Research Institution Co., Ltd. For more information about this drug pipelines report visit https://www.researchandmarkets.com/r/ylu69s .

Interim data from Phase 1/2 propionic acidemia (PA) multi-dose Paramount trial shows mRNA-3927 was well-tolerated to date, with encouraging early signs of potential for clinical benefit Interim data from Phase 1/2 glycogen storage disease 1a (GSD1a) single-dose Ba1ance trial shows mRNA-3745 was well tolerated to date, with encouraging early signs of potential for clinical benefit Moderna announces a new development candidate, mRNA-3139, for ornithine transcarbamylase (OTC) deficiency, a rare genetic disorder Phase 3 clinical trial of RSV vaccine, mRNA-1345, has enrolled more than 24,000 of the 34,000-participant target Phase 3 immunogenicity and safety study of flu vaccine, mRNA-1010, is fully enrolled; Company to pursue accelerated approval pathway in 2023 Company is on track to report data from its Phase 2 personalized cancer vaccine (PCV) study in 4Q 2022 CAMBRIDGE, MA / ACCESSWIRE / September 8, 2022 / Moderna, Inc. (NASDAQ:MRNA), a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines, today announced advances across its portfolio of mRNA programs presented at the Company's annual R&D Day. "We continue to make significant progress in accelerating our pipeline. Our Phase 3 flu and RSV clinical trials are rapidly advancing toward completion. We are seeing early clinical benefits in two rare disease programs and we expect to report on data from our personalized cancer vaccine trial later this year," said Stéphane Bancel, Chief Executive Officer of Moderna. "As a reflection of the Company's growth and progress, we are preparing for multiple product launches globally." Updates and recent progress include: mRNA Therapeutics Rare Diseases: Proof-of-Concept Studies Propionic Acidemia: Propionic acidemia (PA) is a rare and severe metabolic disorder. PA is characterized by a deficiency of propionyl-CoA carboxylase, an enzyme involved in the breakdown of proteins, certain fatty acids, and other substances. This deficiency leads to the build-up of toxic compounds that can cause serious health problems like repeating episodes of life-threatening metabolic crises and damage to the brain, nervous system, and heart. There is no approved pharmacologic therapy for PA. Moderna's mRNA therapy for PA, mRNA-3927, encodes for two proteins that can help the body make the missing enzyme that is absent in PA patients. The Phase 1/2 Paramount clinical trial, evaluating the safety and pharmacology of mRNA-3927, is actively enrolling PA patients. Several critical milestones have been reached in the trial. Over 120 repeated intravenous doses have been administered to 10 patients. So far, mRNA-3927 is well-tolerated at the doses tested. To date, there has been no dose-limiting toxicity, discontinuations due to safety, or drug-related serious adverse safety events. Three of the ten study participants have been dosed with over one year of continuous treatment. All eligible participants have decided to continue with treatment by participating in the Open Label Extension Study. PA is characterized by recurrent life-threatening metabolic decompensation events (MDEs) which are clinical crises that occur when there is a build-up of toxic metabolites. Due to the objective and disease-defining nature of MDEs, regulators have provided initial support for MDE as a clinically meaningful, preferred primary clinical endpoint for development. Based on preliminary data, there was a decrease in the number of MDEs post-mRNA-3927 treatment. The trial will continue with testing the next dose level (0.6 mg/kg IV every two weeks). Glycogen Storage Disease 1a: Glycogen Storage Disease 1a (GSD1a) is a rare, inherited metabolic disorder. GSD1a is caused by a deficiency of an enzyme called glucose 6-phosphatase (G6Pase-α). G6Pase-α is critical for the release of glucose in the blood, and is needed to maintain normal blood sugar levels. Patients with GSD1a may have life-threatening events when their blood sugar levels are too low. They may also experience long-term liver complications, possibly including cancer. There are no approved pharmacologic therapies for GSD1a. Young children with GSD1a require tube feeding at night and life-long regular blood glucose monitoring with strict adherence to a special diet of frequent feedings (every 4-6 hours) and uncooked or modified cornstarch. Taking care of GSD1a patients places a significant burden on family members. Participants have been dosed in Moderna's Phase 1/2 Ba1ance trial that is evaluating a GSD1a therapeutic candidate, mRNA-3745. This study is the first to evaluate the safety, tolerability, and pharmacology of a single intravenous dose of mRNA-3745 in adult participants with GSD1a. Early data on safety and pharmacodynamics are consistent and encouraging. In two patients, intravenous infusion of mRNA-3745 was well tolerated to date, and showed extension of fast duration and normalization of glucose during fast. Enrollment and safety evaluations are continuing, with initial data expected in 2023. Methylmalonic acidemia: PA and methylmalonic acidemia (MMA) share similar biology and disease pathology (deficiency of an enzyme in the propionate pathway) with subsequent accumulation of toxic metabolites. MMA is a rare genetic disease with significant morbidity and mortality caused by a deficiency in an enzyme called methylmalonyl-CoA mutase (MUT). MMA mostly affects children, and there is no approved pharmacologic therapy. Long-term complications of MMA can include problems with neurocognitive function, slower growth, and heart, kidney, and blood problems. The first two groups of patients are fully enrolled in Moderna's Landmark Study, a Phase 1/2 clinical trial to evaluate the safety and pharmacology of mRNA-3705 for MMA. mRNA-3705 is designed to instruct the body to restore the missing or dysfunctional proteins that cause MMA. Moderna is recruiting participants in the United Kingdom, Canada, and the U.S. Initial data from the trial are expected by 2023. Rare Disease: New Development Candidate Leveraging data and learnings from the rare disease program, Moderna announces a new development candidate, mRNA-3139, for ornithine transcarbamylase (OTC) deficiency. mRNA-3139 uses the same lipid nanoparticles (LNP) as in Moderna's GSD1a program and is the Company's sixth rare disease candidate. OTC deficiency is a rare genetic condition characterized by complete or partial lack of the OTC enzyme, resulting in ammonia build-up in the blood. The clinical presentation of OTC deficiency is very heterogeneous, with more severe symptoms including seizures, enlarged liver, and respiratory difficulty. For more severe or non-responsive cases that progress towards liver failure, treatment may include liver transplantation. Late-Stage Respiratory Vaccines COVID-19 Boosters Moderna has launched two vaccine boosters to meet different needs across the largest markets: mRNA-1273.214 and mRNA-1273.222. mRNA-1273.214 is a COVID-19 bivalent booster vaccine that targets both the original strain of SARS-CoV-2 and the Omicron variant of concern (BA.1). Clinical trials demonstrated that this booster vaccine increased the immune response against the more recent Omicron strains (BA.4 and BA.5). They found the results to be similar regardless of prior infection status or age. Moderna developed mRNA-1273.222 in accordance with guidance from the U.S. FDA to develop a booster vaccine targeting the Omicron BA.4 and BA.5 variants, combined with mRNA-1273. A Phase 2/3 clinical trial for mRNA-1273.222 is currently underway and fully enrolled. Moderna has rapidly scaled manufacturing of COVID-19 boosters and began delivery of doses in August. Seasonal Influenza Vaccine Program: Influenza, which occurs seasonally, causes respiratory illnesses and places a substantial burden on healthcare systems. Worldwide, the influenza virus leads to 3-5 million cases of severe illness and 290,000-650,000 influenza-related respiratory deaths annually. About 8% of the US population experiences symptoms from influenza each year, with 140,000-710,000 hospitalizations and 12,000-52,000 deaths per year. mRNA-1010 is a vaccine candidate that encodes for hemagglutinin (HA) glycoproteins of the four influenza strains recommended by the World Health Organization (WHO) for the prevention of influenza. HA is a major influenza surface glycoprotein that is considered an important target to generate broad protection against influenza and is the primary target of currently available influenza vaccines. A Phase 3 immunogenicity and safety study of mRNA-1010 in the Southern Hemisphere is fully enrolled (~6,000 participants). Initial regulatory feedback supports an accelerated pathway for approval. Moderna is also preparing to launch a Phase 3 efficacy trial in the Northern Hemisphere to demonstrate superior effectiveness of mRNA-1010 against a currently licensed seasonal influenza vaccine. Respiratory Syncytial Virus Vaccine Program: Respiratory syncytial virus (RSV) causes a substantial disease burden in older adults aged 65 years and older. There are approximately 177,000 RSV-related hospitalizations in adults 65 and older in the U.S. each year and approximately 14,000 RSV-related deaths. Globally, there are more than 1.5 million episodes of acute respiratory tract infection related to RSV each year. Moderna's pivotal Phase 3 placebo-controlled clinical trial of mRNA-1345, an RSV vaccine, will evaluate its effectiveness in older adults (adults 60 years of age and older); so far, the trial has enrolled more than 24,000 of the anticipated 34,000 participants. The study has been designed to provide an efficacy readout in the 2022-2023 winter season. Since RSV also causes a significant disease burden in children, mRNA-1345 is being tested in an ongoing Phase 1 trial in pediatric populations. Combination Respiratory Vaccines In addition to single-agent vaccines, the Company is progressing several combination respiratory vaccines, including a fully enrolled Phase 1/2 trial testing mRNA-1073 targeting SARS-CoV-2 and influenza. Clinical trials for mRNA-1230, targeting SARS-CoV-2, influenza, and RSV are expected to be initiated this year. Late-Stage Latent Vaccine: CMV Trials Cytomegalovirus Vaccine Program: Cytomegalovirus (CMV), a type of latent herpes virus, is the most common cause of infection that occurs before birth worldwide and is responsible for more than $1 billion in annual healthcare costs. CMV can cause long-term health problems in infected infants, such as hearing loss, vision impairment, cerebral palsy, learning disabilities, and decreased muscle strength and coordination. Moderna's CMV vaccine candidate, mRNA-1647, comprises six mRNAs encoding two antigens in one vaccine and is designed to protect against CMV infection. mRNA-1647 is being evaluated in the Phase 3 CMVictory trial to prevent congenital CMV. To date, more than 40% of anticipated participants are enrolled. The study will determine the efficacy, safety, and immunogenicity of mRNA-1647 against CMV infection in women ages 16-40 years. Enrollment is ongoing in the U.S. and internationally. In addition to congenital infection, CMV has a major impact on morbidity and mortality in transplant patients. CMV is a frequent complication after transplantation since the ability to fight infection after transplant is decreased. Moderna is planning to test mRNA-1647 in a randomized, placebo-controlled, study to evaluate the efficacy, safety, and immunogenicity of mRNA-1647 in patients who have undergone a high-risk stem cell transplant. Personalized Cancer Vaccine Personalized cancer vaccines (PCV) target an individual patient's unique tumor mutations to selectively treat their cancer. Moderna's PCV program is being developed in collaboration with Merck. mRNA-4157 is a PCV candidate designed to stimulate an immune response by boosting T cells, which are believed to be necessary for a curative cancer therapy. Moderna's Phase 2 clinical trial will determine if mRNA-4157 in combination with KEYTRUDA®, an approved cancer therapy, can improve recurrence-free survival (at 12 months) in patients with resected melanoma at high risk of recurrence, compared to KEYTRUDA alone. KEYTRUDA was selected as the comparator in the trial because it is considered the standard of care for high-risk melanoma patients. The Phase 2 trial is fully enrolled and primary data are expected in 4Q 2022. Commercial Preparation As Moderna's pipeline advances, preparations are underway for multiple vaccine launches globally between 2023-2026. Commercial priorities include planning for the 2023 endemic COVID-19 market, expanding into respiratory vaccine markets with single-agent and combination vaccines for RSV, influenza, and COVID-19, preparing for a possible CMV vaccine launch, and entering the therapeutics market. Moderna to pursue accelerated pathway for potential approval of the flu vaccine (mRNA-1010) in 2023. Moderna continues to invest in building global manufacturing capabilities to support multiple product launches, including seasonal updates and different product formulations. 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 in areas including mRNA and lipid nanoparticle formulation, and an integrated manufacturing plant that allows 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-19 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 named a top biopharmaceutical employer by Science for the past seven years. To learn more, visit . 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: clinical trends in Moderna's Phase 1/2 PA trial; Moderna's pursuit of an accelerated approval pathway for mRNA-1010 and the timing of potential approval; the timing of data from Moderna's trials of its product candidates targeting PCV, MMA,GSD1a and RSV; the initiation of clinical trials for mRNA-1230, targeting SARS-CoV-2, influenza and RSV; Moderna's commercial priorities; the timing of future product launches; Moderna's manufacturing capabilities; and the timing of delivery of COVID-19 boosters. 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, 2021 and Quarterly Report on Form 10-Q for the quarterly period ended March 31, 2022, each 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: Mary Beth Woodin Senior Director, R&D Communications 617-899-3991 MaryBeth.Woodin@modernatx.com Investors: Lavina Talukdar Senior Vice President& Head of Investor Relations 617-209-5834 Lavina.Talukdar@modernatx.com SOURCE: Moderna,Inc. View source version on accesswire.com:

In the late 1990s and early 2000s, healthcare providers and researchers noticed that some patients with HIV (approximately 5%) experienced a severe hypersensitivity reaction to the drug abacavir, in some cases causing multiple organ failure, anaphylactic shock and even death. They were eager to determine why only certain patients were affected so they could continue to prescribe this highly effective therapy while minimizing the risk of potential harm. Early research urged providers to closely monitor patients taking abacavir and discontinue the therapy if signs of a reaction occurred. Researchers set out to see if a genetic variant or polymorphism was associated with hypersensitivity to abacavir. By early 2002, the first studies associating a variant with abacavir hypersensitivity were published. Today, all patients must undergo genetic testing for the high-risk genetic variant before starting abacavir therapy. These discoveries were major milestones in an emerging and rapidly growing area of precision medicine that has since identified numerous other associations between genetic variation and optimal drug response or adverse reaction profile. More specifically, the field of pharmacogenetics, which uses a patient’s genetic test results to identify the most effective, lowest-risk drug therapies for their individual conditions, has become an increasingly recognized optimization strategy for prescribing decisions. An emerging field Each year, more findings emerge about how our DNA influences how we respond to drugs. This data has been accumulating at such a rapid rate that the FDA now offers two informational resources for prescribers: Table of Pharmacogenomic Biomarkers in Drug Labeling and a Table of Pharmacogenetic (Pharmacogenetics) Associations, which lists gene-drug interactions that the agency has determined to have sufficient scientific evidence to suggest that there are gene-based differences in drug response. The lists, however, cover different aspects of pharmacogenetic information. While there is some overlap between the resources, the scope of information is different, and neither is comprehensive. The desire for a more complete and organized view of pharmacogenetic information is the main reason why my pharmacist colleagues and I decided to review, analyze and break down the information in the FDA resources. We grouped the pharmacogenetic information referenced in the tables into seven categories that described the nature of the drug-gene interaction. Additionally, we determined whether the gene was known to impact drug safety (adverse reaction risk), drug efficacy (risk of reduced effectiveness), neither or both. The study, “Characterization of Pharmacogenetic Information in Food and Drug Administration Drug Labeling and the Table of Pharmacogenetic Associations,” was published in the peer-reviewed journal Annals of Pharmacotherapy. We wanted to have a structured and systematic approach to reviewing pharmacogenetic information in order to appreciate the full breadth of the nature and potential clinical impact of the information. This can lay the foundation for structuring meaningful pharmacogenetic information into the prescriber’s clinical decision-making process. After all, only 9% of primary care physicians report ordering a pharmacogenetics (PGX) test according to the results of a 2020 survey, and less than 4% report that they feel confident in their ability to interpret the results. At the same time, however, 80% of respondents reported they would be likely or very likely to consult a pharmacogenetics-trained pharmacist for help interpreting a report. Educating all stakeholders about pharmacogenetics information and including such information in clinical decision support guidance could help protect more patients and improve outcomes. Driving safe and effective decisions Clinicians’ time is limited, and pharmacogenetics (PGX) test result reports are often lengthy and complex, so it is not surprising that few of the survey respondents were eager to include such information in their decision making. The FDA supplies pharmacogenetics information, but again, few providers have the time to carefully review it for relevancy to their individual patients. Our study attempts to provide an organized view of the types and outcomes of clinically relevant FDA-reviewed pharmacogenetics information. We analyzed individual FDA-approved prescribing information listed in the Table of Biomarkers in Drug Labeling (first released in 2008) as well as the Table of Pharmacogenetic Associations (first released in 2020). The FDA created the latter table in response to claims from some pharmacogenetics testing firms that were “not adequately supported by sound science,” according to a statement from the agency. Our review began with more than 400 drug-gene pairs, but our list was narrowed to 308 pairs once we eliminated drug-gene pairs with information that did not describe an effect of genetic variation on drug disposition or response. Although most drugs studied were used in oncology, the drugs spanned a variety of other therapeutic areas including psychiatry, neurology, infectious disease and cardiology. Our categories of pharmacogenetic information were: polymorphism-affecting drug metabolism polymorphism-affecting drug transport polymorphism affecting a drug’s direct protein target variant associated with increased adverse drug reaction susceptibility variant associated with poor therapeutic effect biomarker-defined drug indication biomarker-defined adverse drug reaction Nearly all (97%) of the drug-gene pairs were associated with either a biomarker-defined drug indication (36%), polymorphic drug metabolism (33%) or increased adverse reaction susceptibility (28%). Examples of the latter category include increased risk for abacavir hypersensitivity in individuals who carry the HLA-B *57:01 gene or increased risk for hemolytic anemia in individuals with deficiency in a certain enzyme (glucose-6-phosphate dehydrogenase). Our characterization showed that 87% of the drug-gene pairs were associated with a safety or efficacy-related outcome, and most drugs were affected by variation in just a single gene. Just the beginning We expect pharmacogenetics data will become commonplace in select prescribing decisions in the near future. Increasingly, research is demonstrating the “clinical utility” of including gene-based recommendations in prescribing decisions, thus making genetic testing more accessible, and health care payers more willing to support test coverage and reimbursement. Certainly, genetic information is used today to drive some decisions, but the relevancy and quality of the data are only part of the reason for its limited adoption thus far. Prescribers need a pharmacogenetics knowledge base to determine a safe and effective medication and dosage for their patients, but they also need pharmacogenetics test information to be easily accessible, interpretable and meaningful. Our study is just one of many steps toward meeting the challenge of delivering pharmacogenetics information at or near the point of ordering so prescribers can easily and efficiently make optimal therapeutic decisions for their patients.