RESUMO
This commentary explores how 2 recently published studies evaluating the clinical benefit of the FDA's accelerated approval program for oncology drugs came to different conclusions.
Assuntos
Antineoplásicos , Aprovação de Drogas , United States Food and Drug Administration , Humanos , Estados Unidos , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológicoRESUMO
Sterol regulatory element-binding protein (SREBP) transcription factors are central regulators of lipid homeostasis and are essential for lipid metabolic reprogramming that supports tumor growth in multiple cancers. SREBP pathway inhibitors have been identified, but bioavailable compounds are lacking. To address this need, we designed a novel approach for screening a collection of 4,474 FDA-approved drugs. SREBPs are conditionally essential and required under low lipid conditions. Leveraging this property, we screened for drugs that inhibited pancreatic cancer cell growth in lipid-poor, but not lipid-rich, medium. The primary screen identified 83 drugs that inhibited cell growth in a lipid-dependent manner. Secondary assays examining SREBP target gene expression, SREBP proteolytic cleavage, and effects on human breast cancer cells identified 13 FDA-approved drugs that inhibit SREBP pathway activation. Taken together, we demonstrated that our screening approach can identify SREBP inhibitors from a small library of compounds. This high-throughput screening platform enables screening of large compound collections to discover novel small molecule SREBP inhibitors.
Assuntos
Ensaios de Triagem em Larga Escala , Proteínas de Ligação a Elemento Regulador de Esterol , Humanos , Ensaios de Triagem em Larga Escala/métodos , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo , Proteínas de Ligação a Elemento Regulador de Esterol/antagonistas & inibidores , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Estados Unidos , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Aprovação de Drogas , Proliferação de Células/efeitos dos fármacos , United States Food and Drug Administration , Antineoplásicos/farmacologiaRESUMO
The dysregulation of kinases has emerged as a major class of targets for anticancer drug discovery given its node roles in the etiology of tumorigenesis, progression, invasion, and metastasis of malignancies, which is validated by the FDA approval of 28 small molecule kinase inhibitor (SMKI) drugs for cancer treatment at the end of 2015. While the preclinical and clinical data of these drugs are widely presented, it is highly essential to give an updated review on the medical indications, design principles and binding modes of these anti-tumor SMKIs approved by the FDA to offer insights for the future development of SMKIs with specific efficacy and safety.
Assuntos
Antineoplásicos , Aprovação de Drogas , Neoplasias , Inibidores de Proteínas Quinases , Bibliotecas de Moléculas Pequenas , United States Food and Drug Administration , Humanos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Neoplasias/tratamento farmacológico , Estados Unidos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Estrutura Molecular , Sítios de Ligação , Relação Estrutura-AtividadeAssuntos
N-Metil-3,4-Metilenodioxianfetamina , Transtornos de Estresse Pós-Traumáticos , United States Food and Drug Administration , Humanos , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Estados Unidos , Retratação de Publicação como Assunto , Aprovação de Drogas/legislação & jurisprudência , Alucinógenos/uso terapêuticoRESUMO
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.
Assuntos
Fármacos Anti-HIV , Humanos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/síntese química , Infecções por HIV/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , HIV-1/efeitos dos fármacos , Estrutura Molecular , Aprovação de DrogasRESUMO
Cervical Cancer remains a women's health concern worldwide and ranks among the most prevalent cancers, particularly in developing countries. Many women are diagnosed with cervical cancer, with a substantial number succumbing to the disease even after the availability of vaccines and drugs. The tumour microenvironment often exhibits immune evasion, including suppression of T-cell activity and altered cytokine, impacting the efficacy of therapeutic interventions and highlighting the need for treatments to modulate the immune response. Despite efforts to promote HPV vaccination and regular screenings, it causes many deaths, underscoring the urgent need for continued research, healthcare access, and rapid drug development or repurposing. In this study, we identified various proteins involved in cervical cancer cell cycle regulation and DNA replication proteins, performed the multitargeted docking with an FDA-approved library, and identified Oxidopamine HBr as a multitargeted drug. Studies extended with pharmacokinetics and compared with the standard values followed by DFT, which supported the compound as a multitargeted inhibitor. Further, the docked complexes were taken for the interaction fingerprints, and it was identified that there are many 9 polar, 5 hydrophobic, 2 aromatic, and 2 basic residues. We extended our studies for 100ns MD Simulation in water, and the computations explored the deviation and fluctuations under 2Å and many intermolecular interactions; the same trajectory files were used for the MM\GBSA studies. All the studies have supported the Oxidopamine HBr as a cervical cancer multitargeted inhibitor-however, experimental studies are needed before human use.
Assuntos
Simulação de Acoplamento Molecular , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Feminino , Antineoplásicos/farmacologia , United States Food and Drug Administration , Simulação de Dinâmica Molecular , Estados Unidos , Aprovação de DrogasRESUMO
Generalized pustular psoriasis (GPP) is a chronic, rare, and potentially life-threatening inflammatory disease, characterized by the rapid and widespread eruption of small, sterile pustules with surrounding skin erythema. Abnormal signaling of the interleukin-36 (IL-36) pathway appears to have a central role in GPP immunopathology, and provides a rational therapeutic target. Spesolimab is a first-in-class humanized monoclonal antibody that binds specifically to the IL-36 receptor, and antagonizes IL-36 signaling. Spesolimab obtained regulatory approval in the United States (US) in September 2022 for use in the treatment of GPP flares in adults, and was subsequently approved for GPP flare treatment in many other countries across the world. Recently, regulatory approval was granted for subcutaneous dosing of spesolimab for treatment of GPP when not experiencing a flare. Here, we review data from two key clinical trials that supported the initial US regulatory approval; namely, the phase 1 proof-of-concept trial (ClinicalTrials.gov ID, NCT02978690), and Effisayil™ 1 (NCT03782792), which remains the largest and only randomized clinical trial in patients experiencing GPP flares published to date. In the phase 1 proof-of-concept trial, a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 (clear or almost clear skin) was attained in 5/7 (71%) patients by week 1 and in all 7 patients by week 4; and the mean percent improvement in the Generalized Pustular Psoriasis Area and Severity Index (GPPASI) score from baseline was 59.0% at week 1, 73.2% at week 2, and 79.8% at week 4. In Effisayil™ 1, a GPPGA pustulation subscore of 0 (no visible pustules) was achieved in 19/35 (54%) patients receiving spesolimab at the end of week 1, versus 1/18 (6%) receiving placebo (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P<0.001); and a GPPGA total score of 0 or 1 was achieved by 15/35 (43%) patients in the spesolimab group, versus 2/18 (11%) patients in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P = 0.02). Infections at week 1 were reported in 6/35 (17%) patients receiving spesolimab and in 1/18 (6%) patients receiving placebo. These data demonstrate the efficacy and safety of spesolimab in providing rapid and sustained clinical improvement for patients with GPP flares, which translates into improved quality of life, by offering a targeted therapy for GPP.
Assuntos
Anticorpos Monoclonais Humanizados , Aprovação de Drogas , Psoríase , Humanos , Psoríase/tratamento farmacológico , Estados Unidos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Adulto , Masculino , Feminino , Resultado do Tratamento , Pessoa de Meia-Idade , United States Food and Drug Administration , InterleucinasRESUMO
INTRODUCTION: The independent French drug bulletin Prescrire International rates the therapeutic innovation of new drug-indications approved for marketing in France using an ordinal scale with the lowest rating being "not acceptable". This study investigates whether these drugs were approved by Health Canada. METHODS: A list of "not acceptable" drug-indications was generated by handsearching all issues of Prescrire International between January 2013 and December 2022. The generic names, indications and reasons why Prescrire labeled them not acceptable were recorded. The approval date was determined by consulting the website of the European Medicines Agency (EMA). The status of these drug-indications in Canada was determined by searching multiple Health Canada websites. Therapeutic Evaluations for new drug-indications done by the Patented Medicine Prices Review Board (PMPRB) were recorded. RESULTS: Prescrire rated 57 new drug-indications and 42 new indications for existing drugs as not acceptable. Seventy of these drug-indications were available in Canada- 42 new drug-indications and 28 new indications for existing drugs. Twenty (90.9%) of the 22 new drugs evaluated by the PMPRB were rated as slight/no therapeutic improvement and 2 as moderate therapeutic improvement. The median difference, in days, between approval times by the EMA/ANSM and Health Canada was 129 (interquartile range -102, 341) in favour of the former. DISCUSSION: The majority of the not acceptable drug-indications were approved by Health Canada. The difference between when Prescrire and Health Canada examined the evidence for these drug-indications is unlikely to explain the difference in their evaluations. A change in regulatory standards at Health Canada may be one factor behind the presence of these drugs. To what degree those drugs led to more harms than benefits for patients who are taking them needs to be urgently investigated. Finally, the reasoning behind Health Canada's approval of these drugs should be interrogated.
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Aprovação de Drogas , Canadá , Humanos , Estudos de Coortes , França , Medicamentos GenéricosRESUMO
Real-world evidence (RWE) has an increasing role in preapproval settings to support the approval of new medicines and indications. The main objectives of this study were to identify and characterize regulatory use cases that utilized RWE and other related observational approaches through targeted review of publications and regulatory review documents. After screening and inclusion/exclusion, the review characterized 85 regulatory applications with RWE. A total of 31 were in oncology and 54 were in non-oncology therapeutic areas. Most were for indications in adults only (N = 42, 49.4%), while 13 were in pediatrics only (15.3%), and 30 were in both (35.3%). In terms of regulatory context, 59 cases (69.4%) were for an original marketing application, 24 (28.2%) were for label expansion, and 2 (2.4%) were for label modification. Most also received special regulatory designations (e.g., orphan indication, breakthrough therapy, fast track, conditional, and accelerated approvals). There were 42 cases that utilized RWE to support single-arm trials. External data to support single-arm trials were utilized in various ways across use cases, including direct matching, benchmarking, natural history studies as well as literature or previous trials. A variety of data sources were utilized, including electronic health records, claims, registries, site-based charts. Endpoints in oncology use cases commonly included overall survival, progression-free survival. In 13 use cases, RWE was not considered supportive/definitive in regulatory decision-making due to design issues (e.g., small sample size, selection bias, missing data). Overall, RWE is utilized in regulatory approval processes for new indications/label expansion across various therapeutic areas with wide range of approaches. Multifaceted cross-sector efforts are needed to further improve the quality and utility of RWE in regulatory decision-making.
Assuntos
Aprovação de Drogas , Humanos , Aprovação de Drogas/legislação & jurisprudência , Estados Unidos , United States Food and Drug Administration/normas , United States Food and Drug Administration/legislação & jurisprudênciaRESUMO
The Food and Drug Administration's (FDA's) breakthrough therapy designation (BTD) program was created to increase patient access to safe and effective therapies by supporting the efficient clinical development of qualifying, clinically meaningful therapies. Using a new data set of key development milestones for drugs approved between 2006 and 2020, including both BTD drugs and a set of comparator drugs identified by FDA experts, we estimated the BTD program's impact on time spent in late-stage clinical development, measured as the elapsed time between a drug's end-of-Phase-II meeting with regulators and its approval for marketing. Our analysis suggests that the BTD program lowers late-stage clinical development time by 30 percent. Our findings provide insight into future regulatory and innovation policies aimed at driving efficiency in medical product development to ensure timely patient access to the most clinically meaningful therapies.
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Aprovação de Drogas , Desenvolvimento de Medicamentos , United States Food and Drug Administration , Estados Unidos , Humanos , Fatores de TempoRESUMO
Over recent years, dozens of legal challenges have been instituted in response to government action during the COVID-19 pandemic. While public health orders have been challenged on several grounds, few cases have succeeded. Fewer cases still have called into question decisions made by the Therapeutic Goods Administration (TGA) to approve the COVID-19 vaccines. This section provides a brief update on one recent, partially successful COVID-19 health directions case before examining two applications in the Federal Court of Australia seeking judicial review of the TGA's approval of the COVID-19 vaccines. The section argues that, while both TGA applications were dismissed for lack of standing, they illustrate how and why third parties will ordinarily not be entitled to challenge administrative decisions about therapeutic goods.