RESUMEN
In 2023, the U.S. Food and Drug Administration has approved 29 small molecule drugs. These newly approved small molecule drugs possess the distinct scaffolds, thereby exhibiting diverse mechanisms of action and binding modalities. Moreover, the marketed drugs have always been an important source of new drug development and creative inspiration, thereby fostering analogous endeavors in drug discovery that potentially extend to the diverse clinical indications. Therefore, conducting a comprehensive evaluation of drug approval experience and associated information will facilitate the expedited identification of highly potent drug molecules. In this review, we comprehensively summarized the relevant information regarding the clinical applications, mechanisms of action and chemical synthesis of 29 small molecule drugs, with the aim of providing a promising structural basis and design inspiration for pharmaceutical chemists.
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Aprobación de Drogas , United States Food and Drug Administration , Estados Unidos , Humanos , Preparaciones Farmacéuticas/síntesis química , Preparaciones Farmacéuticas/química , Descubrimiento de Drogas , Bibliotecas de Moléculas Pequeñas/síntesis químicaRESUMEN
The approval of pharmaceuticals in response to the COVID-19 pandemic is a global concern, and during emergencies, emergency approval or authorization systems that enable the rapid use of unapproved drugs to maintain national health are essential. However, there is limited research comparing these systems across countries and their effects. This cross-sectional study examined such systems in Japan (JP), Europe (EU), the United Kingdom (UK), and China (CN) for pharmaceuticals (n = 23) authorized under Emergency Use Authorization (EUA) in the United States (US) between December 2019 to July 2023. As of the end of July 2023, JP had granted approval or permission for 14 drugs (60.9%), EU for 14 (60.9%), UK for 12 (52.2%), and CN for three (13.0%). An examination of the developmental status of the 23 drugs revealed that JP had 6 drugs (26.1%), the EU had 3 drugs (8.7%), the UK had 5 drugs (21.7%), and CN had 16 drugs (69.6%) yet to be developed. The US had significantly more granted permissions and developed drugs, while CN the least. The UK had a significantly shorter period for approval than the US and the shortest overall. The EU had the shortest period from the issuance of EUA to approval dates. Although not statistically significant, JP had the longest duration until unapproved drugs could be used. Pharmaceuticals granted usage permission under the EUA in JP, the EU, and the UK were developed or on the market in over 70% of cases, whereas in CN, more than two-thirds were yet to be developed. This suggests that CN may not actively utilize pharmaceuticals from other countries for COVID-19 treatment and may rely on its own. When comparing the emergency approval and permission systems of each country, the most significant difference was in the type of system granting approval.
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COVID-19 , Aprobación de Drogas , China , Aprobación de Drogas/legislación & jurisprudencia , Estados Unidos , Japón , Reino Unido , Humanos , Europa (Continente) , Estudios Transversales , COVID-19/epidemiología , SARS-CoV-2/efectos de los fármacos , Tratamiento Farmacológico de COVID-19 , Urgencias Médicas , PandemiasAsunto(s)
Aprobación de Drogas , Glioma , Isocitrato Deshidrogenasa , United States Food and Drug Administration , Estados Unidos , Humanos , Glioma/tratamiento farmacológico , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológicoAsunto(s)
Aprobación de Drogas , Oncología Médica , United States Food and Drug Administration , Humanos , Estados Unidos , United States Food and Drug Administration/normas , Oncología Médica/normas , Oncología Médica/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversosRESUMEN
Glycan profile comparisons are one of the most tedious analytical exercises for establishing compliance with recombinant therapeutic protein batches. Based on its intensive research, the FDA has confirmed that lectin array binding with fluorescent monitoring is the fastest and most reliable method for profile comparisons. Using a database of over 150 biological products expressed in nine diverse mammalian cell systems, the FDA immobilized 74 lectins to study their binding using fluorescently labeled glycoproteins. The FDA identified nine distinct lectins from a custom-designed lectin microarray: rPhoSL, rOTH3, RCA120, rMan2, MAL_I, rPSL1a, PHAE, rMOA, and PHALs, which detect core fucose, terminal GlcNAc, terminal ß-galactose, high mannose, α-2,3-linked sialic acids, α-2,6-linked sialic acids, bisecting GlcNAc, terminal α-galactose, and triantennary structures, respectively. This method can be used for screening and routine testing and to monitor batch-to-batch variability of therapeutic proteins, including establishing analytical similarity as a crucial part of biosimilar development.
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Biosimilares Farmacéuticos , Lectinas , Polisacáridos , Lectinas/metabolismo , Lectinas/química , Polisacáridos/química , Polisacáridos/análisis , Biosimilares Farmacéuticos/análisis , Biosimilares Farmacéuticos/química , Humanos , Estados Unidos , United States Food and Drug Administration , Glicoproteínas/química , Glicoproteínas/análisis , Aprobación de Drogas , Fluorescencia , AnimalesRESUMEN
In 2023, the European Medicines Agency (EMA) granted approval to 77 new molecular entities (NMEs), consisting of 45 new chemical entities (NCEs) and 32 new biological entities (NBEs). These pharmacological agents encompass a broad spectrum of therapeutic domains, including oncology, cardiology, dermatology, diagnostic medicine, endocrinology, gastroenterology and hepatology, metabolic disorders, and neurology. Among the 77 approved pharmaceuticals, three received accelerated review status, and 17 (22 %) were granted orphan drug designation for the treatment of rare diseases. This review provides an overview of the clinical applications and synthetic routes of 42 newly approved NCEs by the EMA in 2023. The objective is to offer a comprehensive understanding of the synthetic approaches used in the development of these drug molecules, thereby inspiring the creation of novel, efficient, and applicable synthetic methodologies.
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Aprobación de Drogas , Humanos , Europa (Continente) , Estructura MolecularRESUMEN
INTRODUCTION: Advancements in oncology have revolutionized cancer treatment, with new drugs being approved at different rates worldwide. Our objective was to evaluate the approval of new oncological drugs for solid tumors by the Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Brazilian Health Regulatory Agency (ANVISA) since 2008. METHODS: Data were collected from public and online databases by searching for the date of submission, the date of the procedure, the date of approval, clinical indication, and drug characteristics. The distribution was tested using the Shapiro-Wilk, test and comparisons were made using the Mann-Whitney U test; the data are reported using median days and interquartile range (IQR1-IQR3). RESULTS: In total, 104 new oncologic drugs for the treatment of solid tumors were approved by the three agencies: 98 by the FDA, 90 by the EMA, and 68 by ANVISA. The cancer types with the highest number of first indications were lung cancer (n = 24), breast cancer (n = 15), and melanoma (n = 15). Most approvals were for oral medications (n = 63) and tyrosine-kinase inhibitors or other small-molecule inhibitors (n = 54). Time to approval after submission was as follows: the FDA-224 days (167-285); the EMA-364 days (330-418); and ANVISA-403 days (276-636) (p < 0.00001 for the FDA to the EMA and the FDA to ANVISA). The difference between submission dates among the agencies was as follows: EMA-FDA: 24 days (0-85); ANVISA-FDA: 255 (114-632); and ANVISA-EMA: 260 (109-645). The difference in approval dates between the agencies was as follows: EMA-FDA: 185 days (59-319); ANVISA-FDA: 558 (278-957); and ANVISA-EMA: 435 days (158-918). CONCLUSIONS: New oncologic drugs are submitted to the FDA and EMA for approval on similar dates; however, the longer appraisal period by the EMA pushes the approval date for Europe to approximately 6 months later. The same steps at ANVISA delay the approval by 1.5 years. Such procedures cause a significant difference in available medications between these regions.
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Antineoplásicos , Aprobación de Drogas , Neoplasias , United States Food and Drug Administration , Humanos , Brasil , Estados Unidos , Europa (Continente) , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológicoRESUMEN
Targeting Meis1 and Hoxb13 transcriptional activity could be a viable therapeutic strategy for heart regeneration. In this study, we performd an in silico screening to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the resolved crystal structure of Meis1 and Hoxb13 bound to DNA. Paromomycin (Paro) and neomycin (Neo) induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay and disruption of DNA binding by electromobility shift assay. X-ray crystal structure revealed that both Paro and Neo bind to Meis1 near the Hoxb13-interacting domain. Administration of Paro-Neo combination in adult mice and in pigs after cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved left ventricular systolic function and decreased scar formation. Collectively, we identified FDA-approved drugs with therapeutic potential for induction of heart regeneration in mammals.
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Proliferación Celular , Proteínas de Homeodominio , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide , Miocitos Cardíacos , Regeneración , Animales , Regeneración/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Proliferación Celular/efectos de los fármacos , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide/metabolismo , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide/genética , Neomicina/farmacología , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Modelos Animales de Enfermedad , Aprobación de Drogas , Ratones , Función Ventricular Izquierda/efectos de los fármacos , United States Food and Drug Administration , Ratas , Estados Unidos , Cristalografía por Rayos X , Masculino , Ratones Endogámicos C57BL , Porcinos , Células Cultivadas , Transcripción Genética/efectos de los fármacosRESUMEN
Approval of drug products for market registration warrants, among other data, evidence to support their safety and effectiveness in the target populations. The extent of investigations to provide the supporting evidence varies between the new innovator products and their follow-on versions generally referred to as Generic Drugs Products in the United States and Hybrids in the Europe. The new drug applications entail large data sets encompassing both nonclinical and clinical product developments. Safety and effectiveness in man is studied in sequentially phased clinical trials, including post marketing evaluations (Where applicable). However, for the generic/hybrid products the safety and effectiveness are established through determination of bioequivalence in head-to-head comparison between the originator and the follow-ons. Methods for documentation of bioequivalence for drug products that reach target site(s) through systemic circulation are aligned worldwide. However, establishing bioequivalence of orally inhaled drug products is complex as drug delivery to the local site(s) of action is independent of the systemic circulation. Documentation of bioequivalence gets further complicated due to the Drug-Device combination nature of these products. The guidelines for establishment of BE of locally acting orally inhaled drugs products vary among certain geographies. This article examines the scientific underpinning of distinctions and similarities between the US and EU guidelines.
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Unión Europea , Equivalencia Terapéutica , Humanos , Administración por Inhalación , Aprobación de Drogas , Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/administración & dosificación , Europa (Continente) , Guías como Asunto , Preparaciones Farmacéuticas/administración & dosificación , Estados UnidosRESUMEN
This article addresses the research and development (R&D) productivity challenge of the pharmaceutical industry, focusing on United States Food and Drug Administration (FDA)-related new drug approvals of the top 20 pharmaceutical companies (2014-2023). We evaluated the degree of innovation in new drugs to determine the innovativeness of these leading companies. A key finding of our analysis is the decline in the number of new drugs approved by the FDA for these leading companies over the investigated time period. This trend suggests that some of the leading companies are losing ground in R&D innovation, raising concerns about their ability to sustain competitive advantage, ensure long-term market success, and maintain viable business models.
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Aprobación de Drogas , Industria Farmacéutica , Humanos , Estados Unidos , United States Food and Drug AdministrationAsunto(s)
N-Metil-3,4-metilenodioxianfetamina , Trastornos por Estrés Postraumático , United States Food and Drug Administration , Humanos , Trastornos por Estrés Postraumático/tratamiento farmacológico , Estados Unidos , Retractación de Publicación como Asunto , Aprobación de Drogas/legislación & jurisprudencia , Alucinógenos/uso terapéuticoRESUMEN
BACKGROUND: vaccines are complex products used in healthy populations. They should be carefully regulated, and benefits should clearly outweigh risks. OBJECTIVES: To describe the evidence used to support benefit-risk evaluations of vaccines centrally assessed by the European Medicines Agency (EMA), and to identify if real-world data (RWD) was used throughout the vaccine life cycle. METHODS: Cohort study of vaccines approved in the European Union. Inclusion criteria comprised having ATC code J07 and being centrally approved between 2012 and 2022. We collected data from regulatory documents, study protocols, and, when necessary, from scientific publications. Vaccines were followed from initial approval up to March 2023. RESULTS: We included 31 vaccines addressing 17 therapeutic areas. More than 390 studies were used in the process of initial marketing authorisation (MA) and monitoring, and 174 studies were listed in initial risk management plans. We also identified 93 studies in the EU PAS register. At MA, all vaccines had at least one pivotal trial and 27 vaccines had at least one supportive study. Most pivotal trials were randomized, double-blinded and active-controlled, with immunogenicity endpoints as primary outcome. RWD was used for extension of indications and monitoring of at least 4 vaccines, and the undertaking of RWE studies was foreseen in the RMP of at least 17 vaccines. DISCUSSION: Our study revealed an important reliance on randomized controlled trials with individual-level randomization, and a significant focus on immunogenicity endpoints. The use of RWD in vaccine assessments so far has been restricted to COVID-19, and despite its challenges and limitations, we believe that efforts to expand adoption of RWE in continuous benefit-risk assessments should be made. We further highlight the need to enhance data transparency and reporting standards since heterogeneity among regulatory documents made it difficult to identify all the studies considered in vaccine evaluations.
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Unión Europea , Vacunas , Humanos , Vacunas/administración & dosificación , Vacunas/inmunología , Aprobación de Drogas , Medición de Riesgo , COVID-19/prevención & control , Estudios de Cohortes , Vacunas contra la COVID-19/inmunología , SARS-CoV-2/inmunologíaRESUMEN
Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS) with high morbidity and mortality rates. Treatment of AIDS/HIV is being complicated by increasing resistance to currently used antiretroviral (ARV) drugs, mainly in low- and middle-income countries (LMICs) due to drug misuse, poor drug supply and poor treatment monitoring. However, progress has been made in the development of new ARV drugs, targeting different HIV components (Fig. 1). This review aims at presenting and discussing the progress made towards the discovery of new ARVs that are at different stages of clinical trials as of July 2024. For each compound, the mechanism of action, target biomolecule, genes associated with resistance, efficacy and safety, class, and phase of clinical trial are discussed. These compounds include analogues of nucleoside reverse transcriptase inhibitors (NRTIs) - islatravir and censavudine; non-nucleoside reverse transcriptase inhibitors (NNRTIs) - Rilpivirine, elsulfavirine and doravirine; integrase inhibitors namely cabotegravir and dolutegravir and chemokine coreceptors 5 and 2 (CC5/CCR2) antagonists for example cenicriviroc. Also, fostemsavir is being developed as an attachment inhibitor while lenacapavir, VH4004280 and VH4011499 are capsid inhibitors. Others are maturation inhibitors such as GSK-254, GSK3532795, GSK3739937, GSK2838232, and other compounds labelled as miscellaneous (do not belong to the classical groups of anti-HIV drugs or to the newer classes) such as obefazimod and BIT225. There is a considerable progress in the development of new anti-HIV drugs and the effort will continue since HIV infections has no cure or vaccine till now. Efforts are needed to reduce the toxicity of available drugs or discover new drugs with new classes which can delay the development of resistance.
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Fármacos Anti-VIH , Humanos , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/síntesis química , Infecciones por VIH/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , VIH-1/efectos de los fármacos , Estructura Molecular , Aprobación de DrogasRESUMEN
In July 2023, the U.S. Food and Drug Administration approved Opill (norgestrel 0.075 mg), a progestin-only tablet to prevent pregnancy to be used without a prescription. Although progestin-only birth control pills were approved in 1973, it has taken 50 years for the first oral contraceptive pills to be sold over the counter. In this column, I review the evidence on the barriers to access oral contraceptive pills, the efficacy, preferences and support of a nonprescription progestin-only pill, the cost, and policy implications for health insurance coverage. I conclude with recommendations from professional organizations on over-the-counter access to hormonal contraception.
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Medicamentos sin Prescripción , Humanos , Femenino , Estados Unidos , United States Food and Drug Administration , Anticonceptivos Orales/administración & dosificación , Accesibilidad a los Servicios de Salud , Aprobación de Drogas , EmbarazoRESUMEN
The NLRP3 inflammasome is dysregulated in autoinflammatory disorders caused by inherited mutations and contributes to the pathogenesis of several chronic inflammatory diseases. In this study, we discovered that disulfiram, a safe US Food and Drug Administration (FDA)-approved drug, specifically inhibits the NLRP3 inflammasome but not the NLRC4 or AIM2 inflammasomes. Disulfiram suppresses caspase-1 activation, ASC speck formation, and pyroptosis induced by several stimuli that activate NLRP3. Mechanistically, NLRP3 is palmitoylated at cysteine 126, a modification required for its localization to the trans-Golgi network and inflammasome activation, which was inhibited by disulfiram. Administration of disulfiram to animals inhibited the NLRP3, but not NLRC4, inflammasome in vivo. Our study uncovers a mechanism by which disulfiram targets NLRP3 and provides a rationale for using a safe FDA-approved drug for the treatment of NLRP3-associated inflammatory diseases.