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.

In silico Screening of Food and Drug Administration-approved Compounds against Trehalose 2-sulfotransferase (Rv0295c) in Mycobacterium tuberculosis: Insights from Molecular Docking and Dynamics Simulations.

BACKGROUND: Tuberculosis (TB) remains a prominent global health challenge, distinguished by substantial occurrences of infection and death. The upsurge of drug-resistant TB strains underscores the urgency to identify novel therapeutic targets and repurpose existing compounds. Rv0295c is a potentially druggable enzyme involved in cell wall biosynthesis and virulence. We evaluated the inhibitory activity of Food and Drug Administration (FDA)-approved compounds against Rv0295c of Mycobacterium tuberculosis, employing molecular docking, ADME evaluation, and dynamics simulations. METHODS: The study screened 1800 FDA-approved compounds and selected the top five compounds with the highest docking scores. Following this, we subjected the initially screened ligands to ADME analysis based on their dock scores. In addition, the compound exhibited the highest binding affinity chosen for molecular dynamics (MD) simulation to investigate the dynamic behavior of the ligand-receptor complex. RESULTS: Dihydroergotamine (CHEMBL1732) exhibited the highest binding affinity (-12.8 kcal/mol) for Rv0295c within this set of compounds. We evaluated the stability and binding modes of the complex over extended simulation trajectories. CONCLUSION: Our in silico analysis demonstrates that FDA-approved drugs can serve as potential Rv0295c inhibitors through repurposing. The combination of molecular docking and MD simulation offers a comprehensive understanding of the interactions between ligands and the protein target, providing valuable guidance for further experimental validation. Identifying Rv0295c inhibitors may contribute to new anti-TB drugs.

Development and approval of novel injectables: enhancing therapeutic innovations.

INTRODUCTION: Novel injectables possess applications in both local and systemic therapeutics delivery. The advancement in utilized materials for the construction of complex injectables has tremendously upgraded their safety and efficacy. AREAS COVERED: This review focuses on various strategies to produce novel injectables, including oily dispersions, in situ forming implants, injectable suspensions, microspheres, liposomes, and antibody-drug conjugates. We herein present a detailed description of complex injectable technologies and their related drug formulations permitted for clinical use by the United States Food and Drug Administration (USFDA). The excipients used, their purpose and the challenges faced during manufacturing such formulations have been critically discussed. EXPERT OPINION: Novel injectables can deliver therapeutic agents in a controlled way at the desired site. However, several challenges persist with respect to their genericization. Astronomical costs incurred by innovator companies during product development, complexity of the product itself, supply limitations with respect to raw materials, intricate manufacturing processes, patent evergreening, product life-cycle extensions, relatively few and protracted generic approvals contribute to the exorbitant prices and access crunch. Moreover, regulatory guidance are grossly underdeveloped and significant efforts have to be directed toward development of effective characterization techniques.

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.

Health care decision-maker perceptions and trends in the utilization of preapproval information for formulary decision-making.

BACKGROUND: Preapproval information exchange (PIE) has increased between biopharma companies and health care decision-makers (HCDMs) over the last several years. However, there still exists a gap in what HCDMs need and what biopharma companies are providing. OBJECTIVE: To assess trends in the utilization of preapproval information by HCDMs and identify resources that may best support organizations in evaluating product information for formulary coverage prior to US Food and Drug Administration approval. METHODS: A double-blinded, web-based survey was fielded to a research panel of HCDMs from FormularyDecisions from May 16, 2022, to May 23, 2022. RESULTS: A total of 30 advisors were invited to take the survey and 17 responded to the survey, with representation largely from health plans (41%), pharmacy benefit managers (24%), and integrated delivery networks (12%) across commercial, Medicare, and Medicaid lines of business. Of the respondents, 47% noted that the availability of preapproval information has shortened the time to make a formulary decision. Almost all respondents (90%) ranked the availability of clinical and economic information in a timely manner to evaluate budget impact as a top benefit for PIE. Respondents noted that Academy of Managed Care Pharmacy (AMCP) preapproval dossiers (88%), AMCP PIE webinars (76%), preapproval presentations/videos (65%), and posters and abstracts of clinical trials results (59%) were the main resources used to facilitate PIE. CONCLUSIONS: The availability of preapproval information for HCDMs (particularly content related to anticipated place in therapy and product pricing) has an impact on shortening formulary decision-making timelines.

Pathway to Approval of Innovative Radiopharmaceuticals in China.

Since the late 1950s, radiopharmaceuticals have been used for diagnosis and treatment in clinical nuclear medicine in China. Over the decades, China has successfully established a relatively sophisticated system for radiopharmaceutical production and management, supported by state-of-the-art facilities. With the rapid growth of the national economy, the radiopharmaceutical market in China is expanding at a remarkable pace. This burgeoning market has led to an escalating demand for clinical-stage radiopharmaceuticals, either produced domestically or imported. Despite this positive trajectory, the development and application of radiopharmaceuticals in China have been hindered by several challenges that persist, such as inadequate research, insufficient investment, limited availability of radionuclides, shortage of trained personnel in related fields, and imperfections in policies and regulations. In an exciting development, the regulation reforms implemented since 2015 have positively affected China's drug regulatory system. The introduction of the "Mid- and Long-Term Development Plan (2021-2035) for Medical Isotopes" created concurrently an opportune environment for the advancement of innovative radiopharmaceuticals. In this review, we aim to provide an overview of the approval process for novel radiopharmaceuticals by the National Medical Products Administration and the status of radiopharmaceuticals in research and development in China. Preclinical development and clinical translation of radiopharmaceuticals are undergoing rapid evolution in China. As practitioners in the field in China, we provide several practical suggestions to stimulate open discussions and thoughtful consideration.

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.

A Comprehensive Analysis of Biopharmaceutical Products Listed in the FDA's Purple Book.

Although biopharmaceuticals constitute around 10% of the drug landscape, eight of the ten top-selling products were biopharmaceuticals in 2023. This study did a comprehensive analysis of the FDA's Purple Book database. Firstly, our research uncovered market trends and provided insights into biologics distributions. According to the investigation, although biotechnology has advanced and legislative shifts have made the approval process faster, there are still challenges to overcome, such as molecular instability and formulation design. Moreover, our research comprehensively analyzed biological formulations, pointing out significant strategies regarding administration routes, dosage forms, product packaging, and excipients. In conjunction with biologics, the widespread integration of innovative delivery strategies will be implemented to confront the evolving challenges in healthcare and meet an expanding array of treatment needs.

Akt Inhibitor Advancements: From Capivasertib Approval to Covalent-Allosteric Promises.

Akt kinase is vital in cell growth, survival, metabolism, and migration. Dysregulation of Akt signaling is implicated in cancer and metabolic disorders. In the context of cancer, overactive Akt promotes cell survival and proliferation. This has spurred extensive research into developing Akt inhibitors as potential therapeutic agents to disrupt aberrant Akt signaling. Akt inhibitors are classified into three main types: ATP-competitive, allosteric, and covalent-allosteric inhibitors (CAAIs). ATP-competitive inhibitors compete with ATP for binding to Akt, allosteric inhibitors interact with the Pleckstrin homology (PH) domain, and covalent-allosteric inhibitors form covalent bonds, making them more potent and selective. Notably, capivasertib (AZD5363), a potent ATP-competitive Akt inhibitor, received FDA approval in November 2023 for use in combination with the estrogen receptor degrader fulvestrant to treat breast cancer. Challenges remain, including improving selectivity, identifying biomarkers to tailor treatments, and enhancing therapeutic efficacy while minimizing adverse effects. Particularly covalent-allosteric inhibitors hold promise for future more effective and personalized treatments.

Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval.

Importance: The US Food and Drug Administration's (FDA) accelerated approval pathway allows approval of investigational drugs treating unmet medical needs based on changes to surrogate measures considered "reasonably likely" to predict clinical benefit. Postapproval clinical trials are then required to confirm whether these drugs offer clinical benefit. Objective: To determine whether cancer drugs granted accelerated approval ultimately demonstrate clinical benefit and to evaluate the basis of conversion to regular approval. Design, Setting, and Participants: In this cohort study, publicly available FDA data were used to identify cancer drugs granted accelerated approval from 2013 to 2023. Main Outcomes and Measures: Demonstrated improvement in quality of life or overall survival in accelerated approvals with more than 5 years of follow-up, as well as confirmatory trial end points and time to conversion for drug-indication pairs converted to regular approval. Results: A total of 129 cancer drug-indication pairs were granted accelerated approval from 2013 to 2023. Among 46 indications with more than 5 years of follow-up (approved 2013-2017), approximately two-thirds (29, 63%) were converted to regular approval, 10 (22%) were withdrawn, and 7 (15%) remained ongoing after a median of 6.3 years. Fewer than half (20/46, 43%) demonstrated a clinical benefit in confirmatory trials. Time to withdrawal decreased from 9.9 years to 3.6 years, and time to regular approval increased from 1.6 years to 3.6 years. Among 48 drug-indication pairs converted to regular approval, 19 (40%) were converted based on overall survival, 21 (44%) on progression-free survival, 5 (10%) on response rate plus duration of response, 2 (4%) on response rate, and 1 (2%) despite a negative confirmatory trial. Comparing accelerated and regular approval indications, 18 of 48 (38%) were unchanged, while 30 of 48 (63%) had different indications (eg, earlier line of therapy). Conclusions and Relevance: Most cancer drugs granted accelerated approval did not demonstrate benefit in overall survival or quality of life within 5 years of accelerated approval. Patients should be clearly informed about the cancer drugs that use the accelerated approval pathway and do not end up showing benefits in patient-centered clinical outcomes.

Breakthrough Therapy Cancer Drugs and Indications With FDA Approval: Development Time, Innovation, Trials, Clinical Benefit, Epidemiology, and Price.

BACKGROUND: The breakthrough therapy designation (BTD) facilitates the development of drugs with a large preliminary benefit in treating serious or life-threatening diseases. This study analyzes the FDA approval, trials, benefits, unmet needs, and pricing of breakthrough and nonbreakthrough therapy cancer drugs and indications. PATIENTS AND METHODS: We analyzed 355 cancer indications with FDA approval (2012-2022). Breakthrough and nonbreakthrough indications were compared regarding their FDA approval, innovativeness, clinical trials, epidemiology, and price. Data were extracted from FDA labels, the Global Burden of Disease study, and the Centers for Medicare & Medicaid Services. Hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), and relative risk (RR) of tumor response were meta-analyzed across randomized controlled trials. Objective response rates (ORRs) were meta-analyzed for single-arm trials. RESULTS: We identified 137 breakthrough and 218 nonbreakthrough cancer indications. The median clinical development time was 3.2 years shorter for breakthrough drugs than for nonbreakthrough drugs (5.6 vs 8.8 years; P=.002). The BTD was more frequently granted to biomarker-directed indications (46% vs 34%; P=.025) supported by smaller trials (median, 149 vs 326 patients; P<.001) of single-arm (53% vs 27%; P<.001) and phase I or II design (61% vs 31%; P<.001). Breakthrough indications offered a greater OS (HR, 0.69 vs 0.74; P=.031) and tumor response (RR, 1.48 vs 1.32; P=.006; ORR, 52% vs 40%; P=.004), but not a PFS benefit (HR, 0.53 vs 0.58; P=.212). Median improvements in OS (4.8 vs 3.2 months; P=.002) and PFS (5.4 vs 3.3 months; P=.005) but not duration of response (8.7 vs 4.7 months; P=.245) were higher for breakthrough than for nonbreakthrough indications. The BTD was more frequently granted to first-in-class drugs (42% vs 28%; P=.001) and first-in-indication treatments (43% vs 29%; P<.001). There were no differences in treatment and epidemiologic characteristics between breakthrough and nonbreakthrough drugs. Breakthrough drugs were more expensive than nonbreakthrough drugs (mean monthly price, $38,971 vs $22,591; P=.0592). CONCLUSIONS: The BTD expedites patient access to effective and innovative, but also expensive, new cancer drugs and indications.