Recent and anticipated novel drug approvals (3Q 2024 through 2Q 2025).

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Health-system pharmacists play a crucial role in monitoring the pharmaceutical pipeline to manage formularies, allocate resources, and optimize clinical programs for new therapies. This article aims to support pharmacists by sharing new and anticipated novel drug approvals. SUMMARY: Selected drug approvals anticipated in the 12-month period covering the third quarter of 2024 through the second quarter of 2025 are reviewed. The analysis emphasizes drugs expected to have significant clinical and financial impact in hospitals and clinics selected from 54 novel drugs awaiting US Food and Drug Administration approval. New cell therapies for treating cancers continue to enter the drug pipeline, while novel targeted therapies for biliary tract, gastric, pancreatic, and breast cancers, as well as 3 subcutaneous versions of already approved drugs given intravenously, are awaiting approval. Additionally, many novel drugs are being developed for treatment of rare and ultra-rare diseases such as hereditary angioedema, macular telangiectasia, congenital adrenal hyperplasia, and Barth syndrome. Two new subcutaneous drugs for hemophilia, a new oral medication for hereditary angioedema, a novel monoclonal antibody for atopic dermatitis, and the first oral penem antibiotic are also in the pipeline. CONCLUSION: New drugs with various indications for cancers and rare diseases continue to strengthen the drug pipeline.

Interstitial lung disease in patients enrolled in early-phase clinical trials: the ILDE study.

BACKGROUND: Interstitial lung disease (ILD) encompasses a heterogeneous group of disorders sharing pathophysiological inflammatory mechanisms, leading to parenchymal distortions. The prevalence of ILD with new cancer drugs is underreported: the identification of potential determinants is priority. MATERIALS AND METHODS: ILDE is a retrospective study aimed at describing the clinical course and potential determinants of ILD in patients receiving experimental treatments. RESULTS: We identified 226 eligible patients, of whom 5.3% (n = 12) had ILD. In five patients, the diagnosis was radiological, while seven patients had initial cough, dyspnea, fatigue or fever. ILD was graded as grade 1 (G1) in four, G2 in five and G3 in three patients. The first occurrence of ILD resolved completely in 50% of patients (n = 6/12). No patient had fatal ILD. Eight patients (66.7%) resumed the treatment after the first episode of ILD, while four patients (33.3%) had to discontinue the therapy. Five out of six patients had resolved the first ILD episode and then resumed treatment, experiencing a second ILD episode (n = 5/6; 83.3%). The second ILD event was G1 in three patients and G2 in two patients, resulting in three patients who eventually discontinued the treatment (n = 3/5; 60%). Correlation analysis showed a higher risk of ILD in older patients (P = 0.051), those who had received previous chest radiation therapy (P = 0.047) or those receiving antibody-drug conjugates (P = 0.006). In a survival analysis adjusted for immortal time bias, ILD was not independently prognostic (hazard ratio 0.50, 95% confidence interval 0.23-1.09, P = 0.082). CONCLUSIONS: In ILDE, patients experiencing ILD had generally good outcomes, and many could resume the cancer treatments. Implementing best practices to prompt diagnosis and management of ILD is critical to treat a potentially severe adverse effect of new drugs, while not affecting patients' outcomes. Research efforts to identify risk factors is warranted, to implement risk-based monitoring schedules and develop ad hoc strategies to improve the cure rates of ILD.

Cellulose Acetate Microparticles Synthesized from Agave sisalana Perrine for Controlled Release of Simvastatin.

Simvastatin (SIM) is widely prescribed to treat hyperlipidemia, despite its limitations, such as a short half-life and low oral bioavailability. To overcome these drawbacks, the development of a controlled-release formulation is desirable. This study aims to develop a microparticulate system based on cellulose acetate (ACT) obtained from Agave sisalana Perrine to promote a controlled SIM release. SIM-loaded microparticles (SMP) were prepared using the solvent emulsification-evaporation method. Several parameters were evaluated, including particle size, surface charge, morphology, encapsulation efficiency, thermochemical characteristics, crystallinity, and in vitro release profile. ACT exhibited favorable flow properties after acetylation, with a degree of substitution values superior to 2.5, as confirmed by both the chemical route and H-NMR, indicating the formation of cellulose triacetate. The obtained SMP were spherical with an average size ranging from 1842 to 1857 nm, a zeta potential of -4.45 mV, and a high SIM incorporation efficiency (98%). Thermal and XRD analyses revealed that SIM was homogeneously dispersed into the polymeric matrix in its amorphous state. In vitro studies using dialysis bags revealed that the controlled SIM release from microparticles was higher under simulated intestinal conditions and followed the Higuchi kinetic model. Our results suggest that ACT-based microparticles are a promising system for SIM delivery, which can improve its bioavailability, and result in better patient compliance.

Evaluation of the Generic Drug User Fee Act (GDUFA) Program for Fiscal Years 2013-2022.

The effectiveness of the regulatory initiatives, strategies, and incentives put forth in the first two authorizations of the Generic Drug User Fees Act (GDUFA) were evaluated using factors including the number of Abbreviated New Drug Application (ANDA) withdrawals and first-cycle approvals. GDUFA was originally authorized in 2012 for FY 2013-2017 (GDUFA I) and reauthorized for FY 2018-2022 (GDUFA II). ANDA approvals were analyzed from the Drugs @ FDA database covering 2013-2022. From the applications, the approval time, dosage form and route of administration (ROA), product indication, market status of the product, first generic status, company and company size filing the ANDA were noted. Despite the COVID pandemic, there was more than a 40% increase in ANDA approvals during GDUFA II relative to GDUFA I. Oral and parenteral drugs were the two leading categories of approved generics during both iterations of GDUFA. There was more than a 120% increase in withdrawn applications during GDUFA II, which reflects the partial refund that is now offered to incentivize companies to withdraw inadequate applications prior to review. This also appears to have contributed to an increase in the number of first-cycle approvals, which increased by 100% between GDUFA I and II. Due to the COVID-19 public health emergency, there was a decrease in activity within the generic drug program and market. Therefore, it is important to consider this impact when observing actual trends from this study.

Combined Theoretical and Experimental Investigations: Design, Synthesis, Characterization, and In Vitro Cytotoxic Activity Assessment of a Complex of a Novel Ureacellobiose Drug Carrier with the Anticancer Drug Carmustine.

Drug delivery systems (DDSs) are used to transport drugs which are characterized by some pharmaceutical problems to the specific target site, enhancing therapeutic efficacy and reducing off-target accumulation in the body. In this work, one of the recently synthesized molecules, 1,10-N,N'-bis-(ß-ᴅ-ureidocellobiosyl)-4,7,13,16-tetraoxa-1,10-diazacyclooctadecane (TN), was tested as a potential drug carrier towards the anticancer drug carmustine. For this purpose, different techniques were used, from synthesis and calculations to cytotoxicity assessment. Our results showed that TN is characterized by a very compact geometry, which significantly impacts its complexation properties. Although it forms a very stable complex with carmustine, it adopts a non-inclusion geometry, as verified by both experimental and theoretical NMR analyses. The cytotoxicity study performed for all analyzed molecules (TN; carmustine; TN:carmustine complex) towards normal and cancer (breast and colon) cells revealed that TN is not toxic and that the formation of complexes with carmustine reduces the toxicity of carmustine to normal cells.

Oral Nanoformulations in Cardiovascular Medicine: Advances in Atherosclerosis Treatment.

Atherosclerosis (AS) is the formation of atherosclerotic plaques on the walls of the arteries, causing them to narrow. If this occurs in the coronary arteries, the blood vessels may be completely blocked, resulting in myocardial infarction; if it occurs in the blood vessels of the brain, the blood vessels may be blocked, resulting in cerebral infarction, i.e., stroke. Studies have shown that the pathogenesis of atherosclerosis involves the processes of inflammation, lipid infiltration, oxidative stress, and endothelial damage, etc. SIRT, as a key factor regulating the molecular mechanisms of oxidative stress, inflammation, and aging, has an important impact on the pathogenesis of plaque formation, progression, and vulnerability. Statistics show that AS accounts for about 50 per cent of deaths in Western countries. Currently, oral medication is the mainstay of AS treatment, but its development is limited by side effects, low bioavailability and other unfavourable factors. In recent years, with the rapid development of nano-preparations, researchers have combined statins and natural product drugs within nanopreparations to improve their bioavailability. Based on this, this paper summarises the main pathogenesis of AS and also proposes new oral nanoformulations such as liposomes, nanoparticles, nanoemulsions, and nanocapsules to improve their application in the treatment of AS.

Recent and anticipated novel drug approvals (Q2 2024 through Q1 2025).

PURPOSE: Health-system pharmacists play a crucial role in monitoring the pharmaceutical pipeline to manage formularies, allocate resources, and optimize clinical programs for new therapies. This article aims to support pharmacists by providing periodic updates on new and anticipated novel drug approvals. SUMMARY: Selected drug approvals anticipated in the 12-month period covering the second quarter of 2024 through the first quarter of 2025 are reviewed. The analysis emphasizes drugs expected to have significant clinical and financial impact in hospitals and clinics, as selected from 52 novel drugs awaiting US Food and Drug Administration approval. New cellular and gene therapies for cancers continued to strengthen the pipeline, in addition to new drugs targeting previously untreatable conditions. Several novel drugs are being developed for rare and ultra-rare diseases such as hemophilia, Niemann-Pick disease type C, hereditary angioedema, and aromatic l-amino acid decarboxylase deficiency. CONCLUSION: The current drug pipeline includes new drugs with various indications for cancers and rare diseases as well as diabetes, acute coronary syndrome, chronic skin disorder, and chronic obstructive pulmonary disease.

Accelerated Predictive Stability Study of a Pediatric Drug Product for a Supplemental New Drug Application.

In this paper, we report two Accelerated Stability Assessment Program (ASAP) studies for a pediatric drug product. Whereas the first study using a generic design failed to establish a predictive model, the second one was successful after troubleshooting the first study and customizing the study conditions. This work highlighted important lessons learned from designing an ASAP study for formulations containing excipients that could undergo phase change at high humidity levels. The stability predictions by the second ASAP model were consistent with available long-term stability data of the drug product under various storage conditions in two different packaging configurations. The ASAP model was part of the justifications accepted by the health authority to submit a stability package with reduced long-term stability data from the primary stability batches for a Supplemental New Drug Application (sNDA).

[New drug discovery and prospect of small nucleic acids derived from traditional Chinese medicine and natural medicine].

Small nucleic acid drugs mainly include small interfering RNA(siRNA), antisense oligonucleotide(ASO), microRNA(miRNA), messenger RNA(mRNA), nucleic acid aptamer(aptamer), and so on. Its translation or regulation can be inhibited by binding to the RNA of the target molecule. Due to its strong specificity, persistence, and curability, small nucleic acid drugs have received considerable attention in recent years. Recent studies have shown that some miRNAs from animal and plant sources can stably exist in the blood, tissue, and organs of animals and human beings and exert pharmacological action by regulating the expression of various target proteins. This paper summarized the discovery of small nucleic acids derived from traditional Chinese medicine(TCM) and natural drugs and their cross-border regulatory mechanisms and discussed the technical challenges and regulatory issues brought by this new drug, which can provide new ideas and methods for explaining the complex mechanism of TCM, developing new drugs of small nucleic acids from TCM and natural medicine, and conducting regulatory scientific research.

A review of dose escalation for FDA-approved products treating solid tumors and hematological malignancies in first-in-human trials.

First-in-human (FIH) dose-escalation trials on oncology should prioritize safety and emphasize efficacy. We reviewed the FIH trials of 67 anti-tumor products approved by the Food and Drug Administration between 2018 and 2023 and found that the "3 + 3" design remains the predominant dose-escalation method (66.2%). The number of patients receiving sub-therapeutic doses is positively correlated with the maximum tolerated dose (MTD) or maximum dose (MD) to starting dose ratio (P = 0.056) and the number of dose levels in trials (P < 0.001). In addition, the proportion of products with a high ratio in antibody drugs is higher than that in small molecules (P < 0.001). The MTD or MD exceeded the label dose by three or more doses in 22.03% of the products. In conclusion, optimizing the starting dose selection method, refining the way of determining doses, and finding alternative indicators to replace toxicity as the endpoints will increase the effectiveness and broaden the beneficiary scope.

Appropriate Relevancy and Reliability of Real-World Data for the Utilization of Regulatory Submission.

The extraction of data that contribute to regulatory approval from real-world data (RWD) is difficult because of the lack of a standardized data format and extraction methodology. Additionally, when real-world evidence (RWE) is used as an external control group, the similarity between internal and external control data is not evaluated. To investigate the data extraction methodology for the external control data of rare molecular subtypes, we have initiated the "REALISE" study. In this study, we aim to elucidate the "relevance" and "reliability" of RWD/RWE necessary for regulatory approval. As most databases are not designed for regulatory use in the creation phase, we will investigate retrospective methodologies to ensure RWD/RWE reliability. This study will compare the "relevance" and "reliability" of the ARCAD global database, SCRUM-Japan Registry, SCRUM-Japan observational study, and Flatiron Health RWD, and statistically analyze the differences and similarities among the four databases. We will also examine the methodology for extracting sufficiently relevant data from the SCRUM-Japan observational study. Additionally, if the reliability of the RWD/RWE does not reach the required level for regulatory approval, we will examine the methodologies to ensure the "reliability" of the SCRUM-Japan observational study for regulatory approval. The obtained results will be submitted to the "Consultation for Development of Registry" in the Pharmaceuticals and Medical Devices Agency, and we will discuss the standard methodology. The procedures and findings identified in the REALISE study will be organized from the perspectives of "database construction," "data analysis," and "outcome evaluation" and will be issued as "the draft guidelines."

Drug review process advancement and required manufacturer and contract research oraganization responses.

The United States Senate passed the "FDA Modernization Act 2.0." on September 29, 2022. Although the effectiveness of this Bill, which aims to eliminate the mandatory use of laboratory animals in new drug development, is limited, it represents a significant trend that will change the shape of drug applications in the United States and other countries. However, pharmaceutical companies have not taken major steps towards the complete elimination of animal testing from the standpoint of product safety, where they prioritize patient safety. Nonetheless, society is becoming increasingly opposed to animal testing, and efforts will be made to use fewer animals and conduct fewer animal tests as a natural and reasonable response. These changes eventually alter the shape of new drug applications. Based on the assumption that fewer animal tests will be conducted or fewer animals will be used in testing, this study explored bioinformatics and new technologies as alternatives to compensate for reduced information and provide a picture of how future new drug applications may look. The authors also discuss the directions that pharmaceutical companies and nonclinical contract research organizations should adopt to promote the replacement, reduction, and refinement of animals used in research, teaching, testing, and exhibitions.

A systematic review of real-world evidence (RWE) supportive of new drug and biologic license application approvals in rare diseases.

BACKGROUND: Real-world evidence (RWE) generated using real-world data (RWD) presents the potential to contextualize and/or supplement traditional clinical trials for regulatory approval of rare diseases (RDs). This systematic review evaluated the use of RWD for non-oncologic RD therapies with orphan drug designation (ODD) to support efficacy outcomes in regulatory application packages to the US Food and Drug Administration (FDA). New drug applications (NDAs) and biologic license applications (BLAs) submitted between January 2017 and October 2022 were obtained from publicly available FDA drug approval websites. NDAs and BLAs of non-oncologic RD therapies were screened, and manually reviewed using RWE-related keywords. Quantitative summary of number/proportion of study types was provided, whereas qualitative synthesis focused on key categories of output assessing the use of RWD in overall drug approval process, including agency's feedback on its strengths and key challenges. RESULTS: A total of 868 NDAs and BLAs were identified, of which 243 were screened for non-oncologic RDs with ODD, and 151 were subsequently reviewed for the RWD used to support efficacy outcomes. Twenty (12 NDAs, 8 BLAs) applications met the review inclusion criteria. Most (19; 95%) applications used only retrospective RWD, while one (5%) collected RWD both retrospectively and prospectively. RWD studies included natural history including registry-based/retrospective historical controls (14; 70%), retrospective medical chart-reviews (4; 20%), and external RWD controls from other studies (2; 10%). The FDA generally accepted RWD studies demonstrating a large effect size despite the noted concerns and criticisms. However, the agency expressed concerns about overall quality and comparability of RWD with trial data for some applications, including RWD study designs with respect to differences in patients' baseline characteristics, missing information, and potential bias and measurement errors. CONCLUSIONS: This systematic review highlights potential benefits of appropriately conducted RWE studies in RD, which can strengthen the clinical evidence for efficacy comparison and contextualization to support product approval efforts, particularly when a large magnitude of effect is observed for the new intervention. Nonetheless, quality and completeness of RWD and its comparability with trial data remain areas of concern that can serve as valuable learnings for advancing future science and regulatory approvals.

Novel drugs approved by the EMA, the FDA, and the MHRA in 2023: A year in review.

In 2023, seventy novel drugs received market authorization for the first time in either Europe (by the EMA and the MHRA) or in the United States (by the FDA). Confirming a steady recent trend, more than half of these drugs target rare diseases or intractable forms of cancer. Thirty drugs are categorized as "first-in-class" (FIC), illustrating the quality of research and innovation that drives new chemical entity discovery and development. We succinctly describe the mechanism of action of most of these FIC drugs and discuss the therapeutic areas covered, as well as the chemical category to which these drugs belong. The 2023 novel drug list also demonstrates an unabated emphasis on polypeptides (recombinant proteins and antibodies), Advanced Therapy Medicinal Products (gene and cell therapies) and RNA therapeutics, including the first-ever approval of a CRISPR-Cas9-based gene-editing cell therapy.

Medical research without patents: It's preferable, it's profitable, and it's practicable.

This article addresses the question of the possibility of medical research without patents, a major issue in healthcare research and policy. We discuss and evaluate the relevant scientific, economic, societal, and moral aspects of our system of funding and organizing the research, development, manufacture and sale of prescription drugs. The focus is on the patent practices of big pharmaceutical companies. We analyze and critically assess the main features and impacts of these practices. In a positive sense, we propose an approach to organizing and funding drug research that prioritizes its public interest rather than its privatization through patenting. For these purposes, we first demonstrate that producing prescription drugs through patenting has serious drawbacks. Second, we develop a concrete alternative (medical research without patents) that is shown to be scientifically, socially and morally preferable, economically and financially profitable, and socio-politically and organizationally practicable.

The Requirements of Managing Phase I Clinical Trials Risks: The British and Italian Case Studies.

Phase I clinical trials represent a critical point in drug development because the investigational medicinal product is being tested in humans for the first time. For this reason, it is essential to evaluate and identify the Maximum Tolerated Dose (MTD) and the safety of the new compound. To mitigate the possible risks associated with drug administration and treatment, the European Competent Authority issued various guidelines to provide provisions and harmonize risk management processes. In the UK and Italy, particular attention should be paid to the Medicines & Healthcare Products Regulatory Agency (MHRA) phase I accreditation scheme and the specific rules set by the Italian Drug Authority through the AIFA Determination no. 809/2015. Both reference documents are based on the concept of quality risk management while conducting phase I clinical studies. Moreover, the AIFA determination outlines specific requirements for those sites that want to conduct non-profit phase I clinical trials. Indeed, the document reports peculiar activities to the "Clinical Trial Quality Team", which is a team that should support the clinical site researchers in designing, starting, performing, and closing non-profit phase I studies. In this paper, we provide a general overview of the main European guidelines concerning the management of risks during phase I trials, focusing on the main peculiarities of the schemes and rules set by the MHRA and AIFA.

Artificial Intelligence and Anticancer Drug Development-Keep a Cool Head.

Artificial intelligence (AI) is progressively spreading through the world of health, particularly in the field of oncology. AI offers new, exciting perspectives in drug development as toxicity and efficacy can be predicted from computer-designed active molecular structures. AI-based in silico clinical trials are still at their inception in oncology but their wider use is eagerly awaited as they should markedly reduce durations and costs. Health authorities cannot neglect this new paradigm in drug development and should take the requisite measures to include AI as a new pillar in conducting clinical research in oncology.

[Pharmaceutical changes and countermeasures for transformation of traditional Chinese medicine preparations in medical institutions into new drugs based on human use experience].

Traditional Chinese medicine(TCM) preparations in medical institutions, as a unique and important form of preparations in China, have a long history of human use and serve as a bridge between clinical experience prescriptions and new Chinese medicine preparations. The state encourages medical institutions to transform their preparations into new traditional Chinese medicines, emphasizing their role as "incubators". Since the proposal of the traditional Chinese medicine registration and evaluation evidence system with the integration of TCM theory, human use experience(HUE), and clinical experience, the idea of transforming preparations used in medical institutions into new drugs based on HUE has been increasingly valued by drug research and development organizations. In the transformation process, pharmaceutical changes should be concerned from multiple aspects. This paper discusses the pharmaceutical changes and countermeasures based on the transformation of traditional Chinese medicine preparations in medical institutions into new drugs based on HUE from the aspects of excipients, dosage forms, production technology, production scale, packaging materials and containers, production sites, and registration standards. It is emphasized that scientific decisions should be made according to the characteristics and clinical needs of drugs to ensure the stability of drug quality. The impacts of pharmaceutical changes on drug quality should be objectively assessed based on appropriate evaluation indexes and detection methods. The layout should be carried out in advance, and the key pharmaceutical information of the preparations should be kept stable, so as to underpin the transformation of traditional Chinese medicine preparations in medical institutions into new drugs based on HUE.

Recent and anticipated novel drug approvals for 2024.

PURPOSE: Health-system pharmacists play a crucial role in monitoring the pharmaceutical pipeline to manage formularies, allocate resources, and optimize clinical programs for new therapies. This article aims to support pharmacists by providing periodic updates on new and anticipated novel drug approvals. SUMMARY: Selected drug approvals anticipated in the 12-month period covering the first quarter of 2024 through the fourth quarter of 2024 are reviewed. The analysis emphasizes drugs expected to have significant clinical and financial impact in hospitals and clinics, as selected from 59 novel drugs awaiting US Food and Drug Administration approval. This year's pipeline includes recently added drugs with various indications including oncology, infectious diseases, genetic disorders, and rare diseases. New cellular and gene therapies are rapidly evolving and being studied for several rare diseases and cancers. CONCLUSION: More oncology agents, including gene therapies, oral agents, and monoclonal antibodies, are in the pipeline this year. Additional diseases targeted by new novel drugs, including cellular and gene therapies, are hemophilia, nonalcoholic steatohepatitis, Alzheimer's disease, and rare diseases such as galactosemia and epidermolysis bullosa.