Zevorcabtagene Autoleucel: First Approval.

Zevorcabtagene autoleucel () is a fully humanised B cell maturation antigen (BCMA)-targeting specific chimeric antigen receptor (CAR) T-cell therapy being developed by CARsgen for the treatment of multiple myeloma. Zevorcabtagene autoleucel is an autologous CAR T cell comprising a fully human BCMA-specific scFv (25C2), a CD8α hinge region and transmembrane domain, a 4-1BB costimulatory domain and a CD3-ζ T cell activation domain. Zevorcabtagene autoleucel recognizes and induces selective toxicity against BCMA-expressing tumour cells leading to their elimination. In February 2024, zevorcabtagene autoleucel received its first approval in China for the treatment of adults with relapsed or refractory multiple myeloma who have progressed after ≥ 3 prior lines of therapy (including ≥ 1 proteasome inhibitor and an immunomodulatory agent). Clinical studies of zevorcabtagene autoleucel are underway in Canada and the US. This article summarizes the milestones in the development of zevorcabtagene autoleucel leading to this first approval for relapsed or refractory multiple myeloma.

Pharmacotherapeutic advances in fibromyalgia: what's new on the horizon?

INTRODUCTION: This review delves into Fibromyalgia Syndrome (FMS), a chronic pain condition demanding thorough understanding for precise diagnosis and treatment. Yet, a definitive pharmacological solution for FMS remains elusive. AREAS COVERED: In this article, we systematically analyze various pharmacotherapeutic prospects for FMS treatment, organized into sections based on the stage of drug development and approval. We begin with an overview of FDA-approved drugs, discussing their efficacy in FMS treatment. Next, we delve into other medications currently used for FMS but still undergoing further study, including opioids and muscle relaxants. Further, we evaluate the evidence behind medications that are currently under study, such as cannabinoids and naltrexone. Lastly, we explore new drugs that are in phase II trials. Our research involved a thorough search on PUBMED, Google Scholar, and clinicaltrials.gov. We also discuss the action mechanisms of these drugs and their potential use in specific patient groups. EXPERT OPINION: A focus on symptom-driven, combination therapy is crucial in managing FMS. There is also a need for ongoing research into drugs that target neuroinflammation, immunomodulation, and the endocannabinoid system. Bridging the gap between benchside research and clinical application is challenging, but it holds potential for more targeted and effective treatment strategies.

THPdb2: compilation of FDA approved therapeutic peptides and proteins.

During the past 20 years, there has been a significant increase in the number of protein-based drugs approved by the US Food and Drug Administration (FDA). This paper presents THPdb2, an updated version of the THPdb database, which holds information about all types of protein-based drugs, including peptides, antibodies, and biosimilar proteins. THPdb2 contains a total of 6,385 entries, providing comprehensive information about 894 FDA-approved therapeutic proteins, including 354 monoclonal antibodies and 85 peptides or polypeptides. Each entry includes the name of therapeutic molecule, the amino acid sequence, physical and chemical properties, and route of drug administration. The therapeutic molecules that are included in the database target a wide range of biological molecules, such as receptors, factors, and proteins, and have been approved for the treatment of various diseases, including cancers, infectious diseases, and immune disorders.

Application of the ESMO Magnitude of Clinical Benefit Scale to assess the clinical benefit of antibody drug conjugates in solid cancer: a systematic descriptive analysis of phase III and pivotal phase II trials.

OBJECTIVE: The aim of this study was to assess the clinical benefit value of approved antibody drug conjugates (ADCs) for solid tumours using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) V.1.1. DESIGN: Systematic descriptive analysis. DATA SOURCES: PubMed was searched for publications from 1 January 2000 to 18 October 2023. ELIGIBILITY CRITERIA: We included the phase III randomised controlled trials or phase II pivotal trials leading to approval of ADCs in solid tumours. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and discrepancies were resolved by consensus in the presence of a third investigator. RESULTS: ESMO-MCBS Scores were calculated for 16 positive clinical trials of eight ADCs, which were first approved by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the China National Medical Products Administration and the Japanese Pharmaceuticals and Medical Devices Agency for solid cancers. Among 16 trials, 4 (25%) met the ESMO-MCBS benefit threshold grade, while 12 (75%) of the regimens did not meet the ESMO-MCBS benefit threshold grade. 5 (31%) of the 16 trials had no published scorecard on the ESMO website due to the approval by other jurisdictions but not by the FDA or EMA. Discrepancies between our results and the ESMO scorecard were observed in 4 (36%) of 11 trials, mostly owing to integration of more recent data. CONCLUSIONS: ESMO-MCBS is an important tool for assessing the clinical benefit of cancer drugs, but not all drugs met the meaningful benefit threshold.

Alirocumab: Pediatric First Approval.

Alirocumab (Praluent®), a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor that has been co-developed by Regeneron Pharmaceuticals, Inc. and Sanofi (formerly sanofi-aventis), is approved globally for use in adults with established cardiovascular disease, primary hyperlipidemia [including heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH)]. In November 2023, based on clinical data in patients aged 8-17 years, alirocumab received its first pediatric approval in the EU as an adjunct to diet alone, or in combination with a statin and/or other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, in pediatric patients aged ≥ 8 years with HeFH. Alirocumab was approved a few months later in the US for use as an adjunct to diet and other LDL-C-lowering therapies in pediatric patients aged ≥ 8 years with HeFH to reduce LDL-C. This article summarizes the milestones in the development of alirocumab leading to this first pediatric approval for HeFH.

Inotuzumab Ozogamicin: First Pediatric Approval.

Inotuzumab ozogamicin (BESPONSA™) is a CD22-targeted monoclonal antibody drug conjugate (ADC) developed by Pfizer for the treatment of CD22-postive B-cell precursor acute lymphoblastic leukaemia (ALL). Inotuzumab ozogamicin comprises a humanized IgG4 anti-CD22 monoclonal antibody covalently linked to the potent DNA-binding cytotoxic agent N-acetyl-gamma-calicheamicin dimethylhydrazide (CalichDMH) via a linker. Inotuzumab ozogamicin binds to CD22-expressing tumour cells, facilitating the delivery of conjugated CalichDMH, which after intracellular activation induces double strand DNA breaks, ultimately leading to cell cycle arrest and apoptotic cell death. Inotuzumab ozogamicin is approved in the USA, Europe and several countries worldwide for the treatment of relapsed or refractory CD22-positive B-cell precursor ALL in adults. On 6 March 2024, inotuzumab ozogamicin received its first pediatric approval in the USA for this indication in patients aged ≥ 1 years. Inotuzumab ozogamicin has since been approved in Japan in March 2024 for the same indication in pediatric patients. This article summarizes the milestones in the development of inotuzumab ozogamicin leading to this first approval for the treatment of relapsed or refractory CD22-positive B-cell precursor ALL in pediatric patients.

Tegileridine: First Approval.

Tegileridine () is a small molecule µ-opioid receptor biased agonist developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd for the treatment of postoperative pain. Tegileridine selectively activates the G-protein-coupled pathway, which mediates strong central analgesic effects and only weakly activates the ß-arrestin-2 pathway implicated in adverse events like respiratory depression and gastrointestinal dysfunction. In January 2024, tegileridine received its first approval in China for the treatment of moderate to severe pain after abdominal surgery. This article summarizes the milestones in the development of tegileridine leading to this first approval for the treatment of moderate to severe pain after abdominal surgery.

Lifileucel: the first cellular therapy approved for solid tumours.

The US Food and Drug Administration (FDA) approval of lifileucel, for advanced melanoma, represents the first cellular therapy to reach the clinic for solid cancers. Here, we summarise this landmark approval, consider the associated regulatory pathway, and evaluate the challenges that remain to ensure effective implementation of this advanced 'living' therapy.

Overall survival benefits of cancer drugs initially approved by the US Food and Drug Administration on the basis of immature survival data: a retrospective analysis.

BACKGROUND: New cancer drugs can be approved by the US Food and Drug Administration (FDA) on the basis of surrogate endpoints while data on overall survival are still incomplete or immature, with too few deaths for meaningful analysis. We aimed to evaluate whether clinical trials with immature survival data generated evidence of overall survival benefit during the period after marketing authorisation, and where that evidence was reported. METHODS: In this retrospective analysis, we searched Drugs@FDA to identify cancer drug indications approved between Jan 1, 2001, and Dec 31, 2018, on the basis of immature survival data. We systematically collected publicly available data on postapproval overall survival results in labelling (Drugs@FDA), journal publications (MEDLINE via PubMed), and clinical trial registries (ClinicalTrials.gov). The primary outcome was availability of statistically significant overall survival benefits during the period after marketing authorisation (until March 31, 2023). Additionally, we evaluated the availability and timing of overall survival findings in labelling, journal publications, and ClinicalTrials.gov records. FINDINGS: During the study period, the FDA granted marketing authorisation to 223 cancer drug indications, 95 of which had overall survival as an endpoint. 39 (41%) of these 95 indications had immature survival data. After a minimum of 4·3 years of follow-up during the period after marketing authorisation (and median 8·2 years [IQR 5·3-12·0] since FDA approval), additional survival data from the pivotal trials became available in either revised labelling or publications, or both, for 38 (97%) of 39 indications. Additional data on overall survival showed a statistically significant benefit in 12 (32%) of 38 indications, whereas mature data yielded statistically non-significant overall survival findings for 24 (63%) indications. Statistically significant evidence of overall survival benefit was reported in either labelling or publications a median of 1·5 years (IQR 0·8-2·3) after initial approval. The median time to availability of statistically non-significant overall survival results was 3·3 years (2·2-4·5). The availability of overall survival results on ClinicalTrials.gov varied considerably. INTERPRETATION: Fewer than a third of indications approved with immature survival data showed a statistically significant overall survival benefit after approval. Notable inconsistencies in timing and availability of information after approval across different sources emphasise the need for better reporting standards. FUNDING: None.

Beyond the Label: Real-World Side Effects Experienced With FDA-Approved Drugs for Non-Melanoma Skin Cancers.

With immunotherapy historically focused on cutaneous melanoma, there has been a new wave of systemic medications available for treating non-melanoma skin cancers including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and Merkel cell carcinoma (MCC). The immune checkpoint inhibitors approved by the FDA target programmed cell death protein 1 (PD-1) and the Hedgehog (Hh) signaling pathway. These medications have expanded treatment options; however, side effects are an important consideration. We used the FDA Adverse Events Reporting System (FAERS) to characterize the most prevalent, real-world side effects experienced by patients on these agents. Muscle spasms (23.45%), alopecia (16.06%), ageusia (12.02%), taste disorder (11.91%), and fatigue (11.67%) were the five most common side effects reported with medications used for BCC treatment. Logistic regression analysis showed males on vismodegib for BCC having greater odds of experiencing muscle spasms (aOR 1.33, P<0.001) and ageusia (aOR 1.34,  P<0.001) versus females, who were more likely to exhibit alopecia (aOR 1.82, P<0.001) and nausea (aOR 1.96, P<0.001). With SCC treatment, the 5 most reported adverse events were fatigue (5.58%), rash (3.59%), asthenia (3.59%), pruritus (3.19%), and pyrexia (2.79%). Patients taking cemiplimab-rwlc for BCC compared to SCC were more likely to experience disease progression (aOR 10.98, P=0.02). With medication labels providing an excessively daunting list of side effects, we characterize practical side effects seen in patients receiving systemic treatments for non-melanoma skin cancers.  J Drugs Dermatol. 2024;23(5):301-305. doi:10.36849/JDD.7968.

Small molecule anticancer drugs approved during 2021-2022: Synthesis and clinical applications.

Drugs have structural homology across similar biological targets. Small molecule drugs have the efficacy to target specific molecular targets within the cancer cells with enhanced cell membrane permeability, oral administration, selectivity, and specific affinity. The objective of this review is to highlight the clinical importance and synthetic routes of new small molecule oncology drugs approved by the FDA during the period 2021-2022. These marketed drugs are listed based on the month and year of approval in chronological order. We believed that an in-depth insight into the synthetic approaches for the construction of these chemical entities would enhance the ability to develop new drugs more efficiently.

Premarket Evidence and Postmarketing Requirements for Real-Time Oncology Review Indication Approvals.

This cross-sectional study evaluates the use of the US Food and Drug Administration's Real-Time Oncology Review (RTOR) program in confirming the effectiveness of cancer drugs.

Gene therapy in pediatrics - Clinical studies and approved drugs (as of 2023).

Gene therapy in pediatrics represents a cutting-edge therapeutic strategy for treating a range of genetic disorders that manifest in childhood. Gene therapy involves the modification or correction of a mutated gene or the introduction of a functional gene into a patient's cells. In general, it is implemented through two main modalities namely ex vivo gene therapy and in vivo gene therapy. Currently, a noteworthy array of gene therapy products has received valid market authorization, with several others in various stages of the approval process. Additionally, a multitude of clinical trials are actively underway, underscoring the dynamic progress within this field. Pediatric genetic disorders in the fields of hematology, oncology, vision and hearing loss, immunodeficiencies, neurological, and metabolic disorders are areas for gene therapy interventions. This review provides a comprehensive overview of the evolution and current progress of gene therapy-based treatments in the clinic for pediatric patients. It navigates the historical milestones of gene therapies, currently approved gene therapy products by the U.S. Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) for children, and the promising future for genetic disorders. By providing a thorough compilation of approved gene therapy drugs and published results of completed or ongoing clinical trials, this review serves as a guide for pediatric clinicians to get a quick overview of the situation of clinical studies and approved gene therapy products as of 2023.