Cytomegalovirus Retinitis

According to Global Info Research (GIR), the global antisense oligonucleotide (ASO) drug market reached approximately USD 2.8 billion in sales in 2023 and is projected to grow to around USD 10.6 billion by 2030, with a compound annual growth rate (CAGR) of 21.5%. Notably, the global oligonucleotide drug market grew from USD 10 million in 2016 to USD 3.25 billion in 2021, reflecting an impressive CAGR of 217.8%. As a cutting-edge therapeutic approach, ASOs precisely target the mRNA or pre-mRNA of disease-causing genes, modulating their expression to offer novel solutions for genetic and neurodegenerative diseases and other hard-to-treat conditions. With high specificity and a direct mechanism of action, ASOs not only correct abnormal gene expression but also inhibit harmful protein synthesis at the source, demonstrating significant potential for clinical applications. Advances in technology and ongoing clinical trials are driving ASO therapies towards maturity, heralding a new era of precision medicine focused on gene regulation. The transaction status of ASOs in Patsnap SynapseFactors driving ASO market growth include:·Increased Research and Development: A surge in R&D activities related to gene therapy and personalized medicine has fueled demand for ASO technology. With advancements in genomics, scientists are gaining a better understanding of gene expression regulation mechanisms and can utilize ASO technology to precisely target specific gene sequences. ·Rising Incidence of Genetic Disorders: The growing prevalence of genetic disorders has increased demand for effective treatments, and ASO technology offers promising options. For example, in the case of genetic conditions like Duchenne muscular dystrophy (DMD), ASOs can restore the production of functional proteins by altering mRNA splicing. ·Advances in Drug Delivery: Progress in ASO delivery methods, including peptide carriers and lipid nanoparticles, has simplified ASO therapy administration. These delivery technologies not only enhance ASO stability and bioavailability but also reduce side effects, improving therapeutic efficacy. ·Supportive Regulatory Environment: Regulatory agencies are increasingly supportive of innovative gene therapies, creating favorable conditions for ASO drug development. For instance, both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have established pathways to expedite the approval process for rare and orphan drugs. ·Strategic Collaborations: Collaborations between biotech firms, major pharmaceutical companies, and research institutions promote innovation and accelerate ASO therapy development. These partnerships facilitate resource sharing, expertise exchange, and technology advancements, speeding the transition of drugs from the lab to the market. How Does ASOs Work?ASOs play a vital role in gene expression regulation through several mechanisms: ·Gene Targeting: ASOs are designed to target specific genes or mRNA molecules. Each ASO molecule is complementary to a particular mRNA sequence, enabling it to bind and interact with the target mRNA. RNase H-Mediated mRNA Degradation: Once inside the cell, the ASO binds to the target mRNA. This binding recruits RNase H, which degrades the mRNA paired with the ASO, leading to mRNA breakdown. Complementary Base Pairing: The ASO’s guide strand binds to complementary mRNA through base pairing. This binding is highly specific and only occurs when there is a perfect or near-perfect match between the ASO and the target mRNA. ·mRNA Degradation: The ASO-mRNA binding triggers RNase H to cleave the mRNA at the interaction site. This cleavage prevents the mRNA from being translated into functional proteins. ·Gene Expression Silencing: As mRNA is degraded, the cell cannot produce the corresponding protein. This effectively silences the gene’s expression, reducing or entirely stopping the production of the protein encoded by the gene. ·Temporary Effect: ASO-mediated gene silencing is typically temporary. As the affected mRNA degrades and cellular machinery continues to function, gene expression can return to normal once the ASO is no longer present. RNase H Degradation Mechanism of ASOsIn addition, ASOs can modify pre-mRNA splicing through steric hindrance, thus regulating gene translation. These combined mechanisms make ASOs a powerful gene expression regulation tool suitable for treating various diseases, including but not limited to genetic disorders, cancer, infectious disease prevention, and neurological disease treatment. ASO Drug Segmentation TrendsDue to their high molecular weight and charged properties, ASOs have difficulty naturally crossing cell membranes in the body, thus requiring specialized delivery systems. Below are some main classifications of ASO delivery methods: Delivery of ASOs1.Naked Oligonucleotides: ·Direct Administration: Unmodified ASOs are directly administered via injection or other methods, typically at higher doses due to susceptibility to enzymatic degradation and challenges with cellular uptake. 2.Chemical Modifications: ·Modified Oligonucleotides: Chemical modifications enhance ASO stability, such as 2'-O-methylation, phosphorothioate (PS) modification, and locked nucleic acid (LNA) modifications, which improve stability, reduce degradation, and increase cellular uptake efficiency. 3.Ligand Conjugation: ·GalNAc Conjugation: Conjugating ASOs with GalNAc (N-acetylgalactosamine) ligands enhances selective delivery to liver cells, a method used in Alnylam Pharmaceuticals' products. ·Other Ligands: Various ligands are used to target delivery to specific cells or tissues. 4.Nanoparticles: ·Lipid Nanoparticles (LNPs): Encapsulating ASOs within LNPs protects them from degradation and aids cellular entry. LNPs can circulate through the bloodstream to target organs or tissues and enter cells via endocytosis. ·Polymer Nanoparticles: Using polymer matrices to encapsulate ASOs also enhances stability and internalization efficiency. 5.Exosomes: ·Exosome Delivery: Using naturally secreted vesicles (exosomes) as carriers delivers ASOs to target cells, reducing immune responses and enhancing specificity. 6.Viral Vectors: ·Adeno-Associated Virus (AAV): Though primarily used in gene therapy, AAV may also be utilized to deliver ASOs in certain cases. 7.Localized Delivery: ·Direct Injection: Directly injecting ASOs into the affected area, such as muscle or the central nervous system, is suitable for treating diseases localized to specific organs or tissues. ·Inhalation Therapy: For respiratory diseases, ASOs can be delivered to the lungs via inhalation. Each delivery method has unique advantages and limitations, and selecting the appropriate system depends on the therapeutic target, disease type, and ASO's chemical properties. With technological advancements, new delivery platforms and methods are emerging, aiming to improve the efficacy and safety of ASO therapies. ASO Applications by IndicationTop 10 ASOs indications in Patsnap Synapse1.Genetic Disorders: ·DMD: Drugs like Exondys 51 and Vyondys 53 from Sarepta Therapeutics, and Roche's Ryonspurt (Golodirsen), facilitate exon skipping to restore functional dystrophin protein synthesis. ·Spinal Muscular Atrophy (SMA): Spinraza (Nusinersen) from Biogen modifies SMN2 gene splicing to increase SMN protein levels. 2.Neurological Diseases: ·Familial Amyloid Polyneuropathy (FAP): Drugs like AstraZeneca’s Onpattro (Patisiran) and Takhzyro (Lanadelumab), the former using RNAi to reduce TTR protein levels, while the latter, a monoclonal antibody, prevents hereditary angioedema attacks. ·Amyotrophic Lateral Sclerosis (ALS): Tofersen from Biogen targets mutant SOD1 protein reduction for treating SOD1 gene mutation-associated ALS. 3.Metabolic Disorders: ·Transthyretin Amyloidosis (ATTR): Tegsedi (Inotersen) by Akcea Therapeutics and Ionis Pharmaceuticals, and Vyndaqel (Tafamidis) by Pfizer, reduce circulating TTR levels or stabilize the TTR tetramer to prevent amyloid fiber formation. ·Familial Hypercholesterolemia (FH): Waylivra (Volanesorsen) from Akcea Therapeutics and Ionis Pharmaceuticals lowers lipoprotein(a) levels for treating homozygous familial hypercholesterolemia (HoFH). 4.Viral Infections: ·Chronic Hepatitis B (CHB): Viread (Tenofovir Disoproxil Fumarate) and Hepcludex (Bulevirtide) from Gilead Sciences, with the former suppressing viral replication and the latter as the first approved ASO for chronic hepatitis B treatment. ·Cytomegalovirus Infection (CMV): Vitravene (Fomivirsen) from Isis Pharmaceuticals, treats CMV retinitis in immunocompromised individuals. 5.Cancer: ·Hematologic Malignancies: Revlimid (Lenalidomide) from Celgene and Erwinaze (Erwinia L-asparaginase) from Jazz Pharmaceuticals, with the former treating multiple myeloma and the latter acute lymphoblastic leukemia (ALL). 6.Cardiovascular Diseases: ·Heart Failure (HF): Cardior Pharmaceuticals is developing RNA-based therapies to restore myocardial function by inhibiting non-coding RNAs (ncRNAs). 7.Other Rare Diseases: ·Homozygous Familial Hypercholesterolemia (HoFH): Waylivra (Volanesorsen) from Akcea Therapeutics and Ionis Pharmaceuticals lowers lipoprotein(a) levels to treat HoFH. Regional Analysis of ASO DevelopmentASOs are experiencing robust growth globally, with North America and Europe leading the way due to their advanced technologies and regulatory frameworks. Meanwhile, the Asian market, especially China, is rapidly emerging as a significant driver of global ASO drug development, fueled by its vast demand potential and increasing innovation capacity. Global Distribution of ASO Research and Development RegionsIn recent years, the ASO industry has been undergoing a global transformation with notable growth momentum, particularly in the North American market. For a time, market control was firmly held by the two major players, Sarepta and Ionis. However, 2023 marked a turning point. A wave of new oligonucleotide drugs gained approval, reshaping the competitive landscape. In May 2023, Tofersen, an ASOs co-developed by Biogen and Ionis, received regulatory approval. This was followed by the December approval of Eplontersen, an ASO therapy introduced by AstraZeneca in collaboration with Ionis. Concurrently, Novo Nordisk's RNAi therapy Nedosiran was successfully launched in September, and Astellas's nucleic acid aptamer drug Izervay for geographic atrophy received approval in August. This shift in approvals has gradually disrupted the Sarepta-Ionis market duopoly. Key Players in the ASO Development MarketCompetitive Landscape of ASOs in Patsnap Synapse1.Ionis Pharmaceuticals Ionis Pharmaceuticals is a pioneer in the field of ASO therapies and remains at the forefront of ASO development. Since its founding in 1989, Ionis has led the ASO sector with a core platform that includes ligand-conjugated antisense technology (LICA), allowing targeted delivery of drugs to specific cells and tissues by conjugating ligands with specific cell surface receptors. As of 2023, Ionis has developed seven ASO products, collaborating with various pharmaceutical companies for late-stage drug development. 2.Sarepta Therapeutics A leader in the DMD space, Sarepta Therapeutics actively participates in ASO discovery and development, focusing on muscle-related diseases. The company has achieved FDA approval for four DMD drugs, including Eteplirsen, Golodirsen, Casimersen, and Elevidys. The first three are ASOs, while Elevidys is a gene therapy. Sarepta’s core platform utilizes phosphorodiamidate morpholino oligomer (PMO) technology to enable exon skipping, allowing pre-mRNA to bypass mutated exons during translation to restore functional dystrophin protein, alleviating symptoms of DMD. 3.Biogen Biogen focuses on developing ASO therapies for neurological disorders. In collaboration with Ionis, Biogen developed Nusinersen (marketed as SPINRAZA), the world’s first ASO drug for treating spinal muscular atrophy (SMA). Since its launch in 2016, Nusinersen’s sales have approached $10 billion, demonstrating ASO’s vast market potential. Biogen and Ionis’s joint development of Qalsody (tofersen), approved by the FDA in April 2023, treats amyotrophic lateral sclerosis (ALS) in adults with SOD1 gene mutations, marking the fourth new drug approved for ALS globally. Recent Innovations in ASO DevelopmentThe ASO field has seen significant advancements recently, such as the approval of Tofersen by Biogen and Ionis for specific types of ALS and Eplontersen by AstraZeneca and Ionis for treating transthyretin amyloidosis (ATTR). These developments not only expand therapeutic options but also offer new hope for patients with rare and severe diseases. Moreover, companies like Ausper Biopharma and SicaGene are advancing their own ASO pipelines, further enriching the field and highlighting ASO technology's potential in precision medicine. ConclusionASOs have shown tremendous potential as an emerging treatment modality within precision medicine. By targeting disease-causing mRNA, ASOs can effectively inhibit harmful protein synthesis or correct faulty splicing, providing novel therapeutic avenues for genetic disorders, neurodegenerative diseases, and certain cancer types. In recent years, successful market entries of drugs like Tofersen and Eplontersen have not only demonstrated ASO therapies' efficacy and safety in clinical applications but also signal the arrival of more innovative drugs that will benefit a broader patient population. These advancements signify the maturation of ASO technology in biomedical research, injecting fresh momentum into the healthcare industry and ushering in a new era of gene-regulation-centered therapies. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery! Reference 1. O'Leary, K., Guiding the development of individualized ASO therapies. Nat Med, 2023.2. Schuele, R., et al., Advancing ASO therapies from development to implementation. Nat Med, 2024. 30(10): p. 2725-2726.3. Crooke, S.T., et al., Antisense technology: an overview and prospectus. Nat Rev Drug Discov, 2021. 20(6): p. 427-453.

LIVTENCITY Is the First and Only Post-Transplant Anti-CMV Treatment Approved in Japan That Targets/Inhibits UL97 Protein Kinase1 CMV Is One of the Most Common and Serious Post-transplant Infections and Can Lead to Secondary Infections and Serious Consequences, Including Loss of Transplanted Organ and Failure of Graft2,3 OSAKA, Japan & CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Takeda (TSE:4502/NYSE:TAK) today announced that LIVTENCITY® (maribavir) has been approved by the Japanese Ministry of Health, Labour and Welfare (MHLW) for post-transplant cytomegalovirus (CMV) infection/disease that is refractory to existing anti-CMV therapies.4 LIVTENCITY is the first and only post-transplant anti-CMV treatment approved in Japan that targets and inhibits pUL97 kinase and its natural substrates.1 “We are pleased by the approval of LIVTENCITY in Japan, which will provide the transplant community with a new option for treatment of post-transplant CMV infection in patients refractory to other therapies,” said Yasushi Kajii, Head, R&D Japan Region at Takeda. “A diagnosis of CMV infection can be particularly challenging for patients, and serious complications such as increased organ rejection and hospitalization rates can occur, when not successfully treated. We believe LIVTENCITY has the potential to help address the challenges faced by people with post-transplant CMV and transform the treatment landscape for patients in Japan.” The approval is primarily based on the results of the Phase 3 SOLSTICE trial (NCT02931539), which evaluated the safety and efficacy of LIVTENCITY versus alternative antiviral treatments for patients with CMV infection/disease refractory* to prior therapies who underwent hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT), and the Japanese Phase 3 open-label study in patients with CMV infection, including those with refractory* CMV infection who underwent HSCT or SOT (NCT05137717). In the SOLSTICE trial (maribavir n=235, alternative treatments n=117), maribavir showed statistically significant improvement when compared to alternative antiviral treatments at the end of Week 8 for the primary endpoint of confirmed CMV viremia clearancea in post-transplant (HSCT or SOT) adults with refractory* CMV infection.5 Of the 234 patients included in the safety evaluation, adverse reactions (related cases) were observed in 141 patients (60.3%).5 An open-label, multicenter, single-arm study was conducted to evaluate the efficacy and safety in Japanese patients in post-transplant (HSCT or SOT) adultsc (41 randomized, including 3 subjects with CMV infection refractory* to the most recently administered anti-CMV agent). The primary endpoint of CMV viremia clearanceb at the end of Study Week 8 was achieved in 33.3% of patients with refractory* CMV infection.4 Of 41 subjects included in the safety evaluation, adverse reactions (related events) were observed in 36.6% (15 subjects). 4 About LIVTENCITY LIVTENCITY (maribavir), an orally administered (tablet) anti-CMV compound, is the first and only antiviral agent that targets and inhibits the CMV-specific UL97 protein kinase and thus its natural substrates.1 As of June 2024, LIVTENCITY is approved in more than 30 countries for post-transplant CMV refractory* to prior therapies, including such major markets as Japan, the United States, Canada, Australia, the European Union and China. LIVTENCITY Product Overview in Japan Product Name LIVTENCITY 200 mg tablets. Generic Name Maribavir Indications The post-transplant cytomegalovirus (CMV) infection/disease that is refractory to existing anti-CMV therapies. Precautions concerning indications This drug should be administered to post-transplant patients with CMV infection/disease who have responded inadequately to other therapies. Efficacy and safety have not been studied in patients with CMV infection of the central nervous system and CMV retinitis. Based on nonclinical studies, this drug is expected to cross the blood-brain barrier but has low potential to enter the central nervous system. Dosage and Administration Usually, the recommended dosage for adultsc is 400 mg of maribavir to be administered orally twice daily. About Takeda’s SOLSTICE Trial The TAK-620-303 (SOLSTICE) trial (NCT02931539, EudraCT 2015-004725-13) was a Phase 3 global, multicenter, randomized, open-label, active-controlled trial to assess the efficacy and safety of maribavir treatment compared to investigator-assigned treatment (alternative antiviral therapies) in 352 HSCT and SOT recipients with CMV infections that were refractory* or resistant to one or a combination of the alternative antiviral therapies: ganciclovir, valganciclovir, foscarnet, or cidofovir. Adult patients underwent a 2-week screening period, followed by randomization 2:1 to maribavir (n=235) (400 mg, twice daily) or alternative antiviral treatments (n=117) (as dosed by the investigator) for up to 8 weeks. After completion of the treatment period, subjects entered a 12-week follow-up phase.5 The trial’s primary efficacy endpoint was confirmed CMV viremia clearance a at the end of Week 8. The key secondary endpoint was confirmed CMV viremia clearance and CMV infection symptom control† at the end of Study Week 8 with maintenance of this treatment effect through Study Week 16.5 About Cytomegalovirus (CMV) CMV is a beta herpesvirus that commonly infects humans; serologic evidence of prior infection can be found in 40-100% of various adult populations.6 CMV typically resides latent and asymptomatic in the body but may reactivate during periods of immunosuppression. Serious disease may occur in individuals with compromised immune systems, which includes patients who receive immunosuppressants associated with various types of transplants including HSCT or SOT.5,7 Out of the estimated 200,000 adult transplants per year globally, CMV is one of the most common viral infections experienced by transplant recipients, with an estimated incidence rate between 16-56% in SOT recipients and 30-80% in HSCT recipients.7,8 In transplant recipients, reactivation of CMV infection can lead to secondary infections and serious consequences, including graft loss and, in extreme cases, can be fatal.2,3,5 About Takeda Takeda is focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline. As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. For more information, visit . LIVTENCITY Safety Information Contraindications Contraindications include Hypersensitivity to the active substance or to any of the excipients and co‑administration with ganciclovir or valganciclovir. Special warnings and precautions for use Some maribavir pUL97 resistance-associated substitutions confer cross-resistance to ganciclovir and valganciclovir. CMV DNA levels should be monitored, and resistance mutations should be investigated in patients who do not respond to treatment. Treatment should be discontinued if maribavir resistance mutations are detected. LIVTENCITY is not expected to be effective in treating CMV CNS infections (e.g. meningo‑encephalitis). LIVTENCITY has the potential to increase the concentrations of immunosuppressants that are cytochrome P450 (CYP)3A/P-gp substrates with narrow therapeutic margins (including tacrolimus, cyclosporine, sirolimus and everolimus). The plasma levels of these immunosuppressants must be frequently monitored throughout treatment with LIVTENCITY, especially following initiation and after discontinuation of LIVTENCITY, and doses should be adjusted, as needed. The concomitant use of LIVTENCITY and certain medicinal products may result in known or potentially significant medicinal product interactions, some of which may lead to: possible clinically significant adverse reactions from greater exposure of concomitant medicinal products. reduced therapeutic effect of LIVTENCITY. Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium‑free’. Pregnancy & Breast-feeding: LIVTENCITY is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast‑feeding should be discontinued during treatment with LIVTENCITY. Interactions Effect of other medicinal products on maribavir: Co-administration of maribavir with strong cytochrome P450 3A (CYP3A) inducers rifampicin, rifabutin or St. John’s wort is not recommended. If co-administration of maribavir with other strong or moderate CYP3A inducers (e.g., carbamazepine, efavirenz, phenobarbital and phenytoin) cannot be avoided, the maribavir dose should be increased to 1 200 mg twice daily. No dose adjustment is needed when maribavir is co‑administered with CYP3A inhibitors. Effect of maribavir on other medicinal products: If dose adjustments of concomitant medicinal products are made due to treatment with maribavir, doses should be readjusted after treatment with maribavir is completed. Co-administration of maribavir with valganciclovir and ganciclovir is contraindicated. Concomitant administration of maribavir and medicinal products that are sensitive substrates of CYP1A2 with a narrow therapeutic window (e.g., tizanidine and theophylline) should be avoided due to the risk for lack of efficacy of CYP1A2 substrates. When the immunosuppressants tacrolimus, cyclosporine, everolimus or sirolimus are co-administered with maribavir, immunosuppressant levels should be frequently monitored throughout treatment with maribavir, especially following initiation and after discontinuation of maribavir and dose adjusted, when needed. Caution should be exercised when maribavir and sensitive P-gp substrates (e.g., digoxin, dabigatran) are co‑administered. Serum digoxin concentrations should be monitored, and dose of digoxin may need to be reduced, as needed (see Table 1). Co‑administration of maribavir with sensitive BCRP substrates such as rosuvastatin, is expected to increase their exposure and lead to undesirable effects. Adverse Reactions Very common (≥1/10) Taste disturbance, Diarrhoea, Nausea, Vomiting, Fatigue Common (≥1/100 to <1/10) Headache, Abdominal pain upper, Decreased appetite, Immunosuppressant drug level increased, Weight decreased The most commonly reported serious adverse reactions were diarrhoea (2%) and nausea, weight decreased, fatigue, immunosuppressant drug level increased, and vomiting (all occurring at < 1%). Please consult the LIVTENCITY (maribavir) approved label before prescribing, particularly in relation to dosing and treatment monitoring. For Japan, please consult the LIVTENCITY Japan Package Insert. For the European Union, please consult the Summary of Products Characteristics (SmPC). For China, please consult the LIVTENCITY China Package Leaflet. For full U.S. Prescribing Information, including the approved indication and important safety information, please visit: Important Notice For the purposes of this notice, “press release” means this document, any oral presentation, any question and answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited (“Takeda”) regarding this release. This press release (including any oral briefing and any question-and-answer in connection with it) is not intended to, and does not constitute, represent or form part of any offer, invitation or solicitation of any offer to purchase, otherwise acquire, subscribe for, exchange, sell or otherwise dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or other securities are being offered to the public by means of this press release. 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Nothing contained herein should be considered a solicitation, promotion or advertisement for any prescription drugs including the ones under development. * Including a subgroup with genotypic resistance to alternative antiviral treatments. a Defined as confirmed CMV DNA concentration below the lower limit of quantification (<LLOQ; i.e., <137 IU/mL) in two consecutive samples separated by at least five days. b Defined as confirmed CMV DNA concentration below the lower limit of quantification (<LLOQ; i.e., <34.5 IU/mL) in two consecutive samples separated by at least five days. c Defined as > 15 years old † CMV infection symptom control was defined as resolution or improvement of tissue-invasive disease or CMV syndrome for symptomatic patients at baseline, or no new symptoms for patients who were asymptomatic at baseline. References Avram S, et al. Novel drug targets in 2021. Nature Reviews Drug Discovery. 2022;21(5):328-328. Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infection & Chemotherapy. 2013;45(3):260 Camargo JF, Komanduri KV. Emerging concepts in cytomegalovirus infection following hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther. 2017;10(4):233-238. doi:10.1016/j.hemonc.2017.05.001 LIVTENCITY Package Insert in Japan. Avery R, Alain S, Alexander BD, et al. SOLSTICE Trial Investigators. Maribavir for refractory cytomegalovirus infections with or without resistance post-transplant: results from a phase 3 randomized clinical trial. Clin Infect Dis. 2022;75(4):690–701. doi:10.1093/cid/ciab988 de la Hoz RE, Stephanie G, Sherlock C. Diagnosis and treatment approaches to CMV infections in adult patients. J Clin Virol. 2002;25(Suppl 1):S1-S12. doi:10.1016/s1386-6532(02)00091-4 Azevedo LS, Pierrotti LC, Abdala E, et al. Cytomegalovirus infection in transplant recipients. Clinics (Sao Paolo). 2015;70(7):515-523. doi:10.6061/clinics/2015(07)09 Styczynski J. Who is the patient at risk of CMV recurrence: a review of the current scientific evidence with a focus on hematopoietic cell transplantation. Infect Dis Ther. 2018;(7):1-16. doi:10.1007/s40121-017-0180-z View source version on businesswire.com: Contacts International Media Rand Walton rand.walton@takeda.com Japan Media Shigeyuki Matsui shigeyuki.matsui@takeda.com Source: Takeda Pharmaceutical Company Limited View this news release online at:

Pictured: RNA/iStock, Artur Plawgo Based on the significant progress made over the last few decades with RNA therapeutics, RNA editing is widely considered the next generation of promising medicines in this field. RNA therapies have made significant progress over the last few years, with an increasing number of FDA approvals beginning in 1998 with Vitravene for CMV retinitis, followed by Macugen for macular degeneration in 2004 and Spinraza for spinal muscular atrophy in 2016. There have also been multiple siRNA-based drugs, including Onpattro for polyneuropathy of hereditary transthyretin-mediated amyloidosis in 2018. And finally, in 2020, perhaps the most well-known products in the RNA space were introduced: the mRNA-based COVID-19 vaccines. All of these demonstrate the strength of RNA therapies and their potential impact on diseases with high unmet need. RNA therapeutics are indeed elegant approaches to altering RNA and thus protein expression, opening the potential to target a broad array of diseases. The field has seen a renewed and increased interest as reversible changes offer flexibility and RNA approaches introduce therapeutic opportunities that were not accessible before. RNA editing technology was first known and recognized as an interesting approach to treating genetic conditions and reversing disease-causing mutations at the RNA level. RNA editing is a naturally occurring and highly active process that uses the body’s existing capabilities to perform nucleotide changes. Since 2014, when ProQR Therapeutics invented the technique of using oligonucleotides recruiting endogenous adenosine deaminase action on RNA, known as ADAR-mediated editing, the field has rapidly progressed. This growth can be attributed to the rapid progression of knowledge about the technology. Alpha-1 antitrypsin deficiency (AATD) is the first indication that many RNA editing companies have decided to pursue, as it provides the opportunity to address liver and lung symptoms of the disease. Clinical trials for AATD run by both Wave Life Sciences and Korro Bio are planned to begin this year and next. Genetic and Common Disorders There is great excitement in the field about using learnings from decades of oligonucleotide-based drug development, natural RNA editing, and knowledge of biological pathways to make RNA editing technology a compelling approach to target various pathophysiological processes. This offers, for example, the possibility not only of reducing or restoring protein expression but also of modulating protein activity involved in diseases. This application of RNA editing offers the potential to impact both genetic disorders and common conditions, such as metabolic and cardiovascular diseases. ProQR’s approach differentiates RNA editing, as it provides the opportunity to target conditions that have thus far not been treatable with other technologies. Indeed, RNA editing offers the possibility of introducing protective variants, informed by human genetics, that could address or prevent diseases including certain cholestatic or cardiovascular conditions. For example, it has been reported in the literature that an Old Order Amish-enriched variant in a functional B4GALT1 was associated with lower serum LDL-C and lower plasma fibrinogen. This protective variant can be introduced via ADAR RNA editing technology, which has the potential to simultaneously address the two cardiovascular risk factors. Delivery is an important aspect of oligonucleotide base therapeutics. RNA therapies, including RNA editing, have again made great progress and generally use conjugation or lipid nanoparticle approaches. As an example, Alnylam made tremendous progress in its siRNA-based treatments for amyloidosis, with Onpattro in 2018 offering an intravenous treatment once every three weeks. Only four years later, Amvuttra arrived on the market for the same condition but with a subcutaneous 3-month dosing approach. For now, the majority of RNA editing programs are focused on targeting the liver where delivery is relatively de-risked, although progress is also being made in exploring new frontiers such as the central nervous system, as evidenced by the partnerships between Roche and Shape Therapeutics and ProQR and Eli Lilly. In summary, the RNA editing space is making impressive progress. The recent approvals and clinical results demonstrating the potential of RNA therapy to target a broad array of organs are extremely encouraging for RNA editing. Near term, we expect to see further development of the technology, more programs advancing to clinical development, expansion of therapeutic areas addressed, and ultimately, we are hopeful that the next few years will bring considerable progress for patients in need. Gerard Platenburg is a cofounder of ProQR and has served as the company’s chief scientific officer since 2022. Gerard has an extensive background in RNA modulation and orphan drug discovery and development and currently leads ProQR's Innovation unit.