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BackgroundImmune checkpoint inhibitor (ICI) therapies have become increasingly popular treatment options for patients with cancer, even for patients in non-metastatic settings. Survival and responses have been reported for individual tumor types, but little is known about these outcomes, collectively. We sought to provide an overview of overall survival (OS) and progression-free survival (PFS) in ICI drugs tested in registration trials.MethodsIn a cross-sectional analysis of US FDA oncology ICI drug approvals (2011-2023), we searched for supporting ICI registration trials. We characterized these trials, regarding differences in median OS and PFS between patients in intervention and control arm participants in ICI registration trials; percentage of patients who receive ICI crossover; and whether there is correlation between the percentage of crossover and differences in OS or PFS.ResultsFifty-six (54.4 %) approvals had trials that reported median OS for both intervention and control arms (median difference was 2.8 months; IQR: 2.2 to 5.0 months). Sixty-five (63.1 %) approvals had trials that reported PFS data for both arms (median of 0.9 months; IQR: -0.2 to 3.0 months). Subsequent therapy was common (median=18.9 %) and was significantly correlated with a higher difference in median OS in all studies with reported differences (R2 =0.15; p = 0.001).ConclusionICIs are increasingly used in the treatment of cancer, yet the median OS improvement is modest, and many ICIs have not been tested for OS benefit. OS is the outcome most meaningful for patients, and drug regulation should require better testing and reporting of these data.

BackgroundProject Orbis is a global initiative that aims to streamline regulatory review processes across international regulators in the USA, Canada, Australia, UK, Israel, Brazil, Singapore, and Switzerland to bring promising cancer drugs to patients earlier. We explored the clinical benefit, time to regulatory approval and health technology assessment recommendations, reimbursement outcomes, and monthly treatment prices of cancer drugs reviewed through this initiative.MethodsFor this retrospective, comparative analysis, we identified cancer drug approvals reviewed through Project Orbis in the USA, Canada, and the UK between May 1, 2019, and Nov 1, 2023. Approvals of cancer drugs reviewed Project Orbis were extracted from the Food and Drug Administration (FDA) Oncology Centre of Excellence and all other FDA approvals from the Drugs@FDA database. The co-primary outcomes were time of regulatory review, time from regulatory approval to health technology assessment recommendation (England, Scotland, and Canada), reimbursement outcomes, clinical benefit (defined as median gains in progression-free survival and overall survival) between cancer drug approvals reviewed by Project Orbis and other FDA approval processes, and monthly treatment prices. The Wilcoxon rank-sum and Fisher's Exact tests were used to examine statistical significance between approvals reviewed through Project Orbis and other FDA approvals during the same period.FindingsBetween May 1, 2019 and Nov 1, 2023, 81 (33%) of 244 cancer drugs approved by the FDA were reviewed through Project Orbis. The median overall survival gains were 4·1 months (IQR 3·3-5·1) compared with 2·7 months (2·1-3·9) for other FDA approvals. Similarly, progression-free survival gains were 2·6 months (IQR 1·7-4·9) for Project Orbis compared with 2·6 months (0·6-5·1) for other FDA approvals. Neither overall survival (p=0·11) nor progression-free survival (p=0·44) gains were significantly different between the two cohorts of approvals. Of the 14 UK Medicines and Healthcare products Regulatory Agency (MHRA) approvals reviewed by the Scottish Medicines Consortium (SMC), the agency gave positive recommendations for all 14 (100%). Of the 15 MHRA approvals reviewed by the National Institute for Health and Care Excellence (NICE), the agency gave positive recommendations for six (40%). Of the 49 approvals reviewed by the Canadian Agency for Drugs and Technologies in Health (CADTH), the agency conditionally recommended 44 (90%). The time between regulatory approval to NICE recommendation increased from a median of 137 days (IQR 102-172) in 2021 to 302 days (184-483) in 2023, SMC recommendation increased from 185 days (in 2021 for one drug only) to 368 days (IQR 313-476) in 2023, and CADTH decision increased from 97 days (in 2020 for one drug only) to 202 days (IQR 153-304) in 2023. The median monthly price of approvals reviewed through Project Orbis was US$20 000 per month (IQR 13 000-37 000).InterpretationClinical outcomes of Project Orbis were no different than other FDA approvals during the same time, and access, after a successful health technology assessment, was considerably delayed or absent, raising questions about whether Project Orbis participation translates into faster patient access to medicines with high clinical benefit and sustainable costs. Although future challenges might benefit from regulatory harmonisation, the advantages are currently unclear.FundingNone.

ImportanceIn oncology randomized clinical trials, suboptimal access to best available care at recurrence (or relapse) may affect overall survival results.ObjectiveTo assess the proportion and the quality of postrecurrence treatment received by patients enrolled in US Food and Drug Administration (FDA) registration trials of systemic therapy in the adjuvant or neoadjuvant setting.Evidence reviewFor this systematic review, all trials leading to an FDA approval from January 2018 through May 2023 were obtained from the FDA website and drug announcements. Randomized clinical trials of an anticancer drug in the neoadjuvant or the adjuvant setting were included. Trials of supportive care treatment and treatments given in combination with radiotherapy were excluded. Information abstracted for each trial included tumor type, setting, phase, type of sponsor, reporting and assessment of postrecurrence, and overall survival data.FindingsA total of 14 FDA trials met the inclusion criteria. Postrecurrence data were not available in 6 of 14 registration trials (43%). Of the 8 remaining trials, postrecurrence treatment was assessed as suboptimal in 6 (75%). Overall, only 2 of 14 trials (14%) had data assessed as appropriate.Conclusions and relevanceThis systematic review found that 43% of randomized clinical trials of anticancer treatment in the adjuvant or neoadjuvant context failed to present any assessable postrecurrence treatment data. In instances in which these data were shared, postrecurrence treatment was suboptimal 75% of the time. The findings suggest that regulatory bodies should enforce rules stipulating that patients have access to the best standard of care at recurrence.

We report our initial real-world experience with 177Lu-PSMA-617 radioligand therapy. Methods: We performed a retrospective review of patients treated with 177Lu-PSMA-617. Pretreatment PSMA PET, laboratory findings, overall survival, a fall in prostate-specific antigen by 50% (PSA50), and toxicities were evaluated. Results: Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%). Conclusion: At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from 177Lu-PSMA-617 radioligand therapy.

BACKGROUND: The US Food and Drug Administration (FDA) has expanded the use of surrogate markers in drugs approved for oncology/hematology indications. This has likely resulted in a greater number of approvals and possibly drugs coming to market faster, but it is unknown whether these drugs also improve overall survival (OS) for patients taking them. METHODS: We sought to estimate the percentage of oncology drugs that have shown to improve OS in a cross-sectional analysis of US FDA oncology drug approvals (2006-2023). We searched for OS data in registration trials and the peer-reviewed literature. RESULTS: We found 392 oncology drug approvals. Eighty-seven (22%) drug approvals were based on OS, 147 drug approvals were later tested for OS benefit (38% of all approvals and 48% of drugs approved on a surrogate), and 130 (33%) have yet to be tested for OS benefit. Of the 147 drug approvals later tested for OS, 109 (28% of all approvals and 74% of drugs later tested for OS) have yet to show OS benefit, whereas 38 (10% of all approvals and 26% of drugs later tested for OS benefit) were later shown to have OS benefit. In total, 125 out of 392 (32%) drugs approved for any indication have been shown to improve OS benefit at some point, and 267 (68%) have yet to show approval. CONCLUSION: About 32% of all oncology drug approvals have evidence for an improvement in OS. Higher standards are needed in drug regulation to ensure that approved drugs are delivering better patient outcomes, specifically in regards to survival.

Earlier this year, pro-lifers had high hopes for the Supreme Court as the justices considered the legality of the government's 2000 approval and subsequent protocol changes in FDA v. AHM. [...]

The two‐trials rule for drug approval requires "at least two adequate and well‐controlled studies, each convincing on its own, to establish effectiveness." This is usually implemented by requiring two significant pivotal trials and is the standard regulatory requirement to provide evidence for a new drug's efficacy. However, there is need to develop suitable alternatives to this rule for a number of reasons, including the possible availability of data from more than two trials. I consider the case of up to three studies and stress the importance to control the partial Type‐I error rate, where only some studies have a true null effect, while maintaining the overall Type‐I error rate of the two‐trials rule, where all studies have a null effect. Some less‐known P$$ P $$‐value combination methods are useful to achieve this: Pearson's method, Edgington's method and the recently proposed harmonic mean χ2$$ {\chi}^2 $$‐test. I study their properties and discuss how they can be extended to a sequential assessment of success while still ensuring overall Type‐I error control. I compare the different methods in terms of partial Type‐I error rate, project power and the expected number of studies required. Edgington's method is eventually recommended as it is easy to implement and communicate, has only moderate partial Type‐I error rate inflation but substantially increased project power. [ABSTRACT FROM AUTHOR]

News coverage of the human papillomavirus (HPV) vaccine grew rapidly in China in 2016 when the vaccine was approved. Drawing upon framing theory, the present study analyzed the content of 491 Chinese newspaper reports on the HPV vaccine published between June 2000 and December 2018 to investigate what and how information and valence about the vaccine was relayed to the public. The results indicated that, while the Chinese media failed to provide comprehensive and accurate information about HPV and the HPV vaccine, they showed a positive evaluation of the HPV vaccine demand and market. In addition, there was a decline in negative coverage after the vaccine was approved. This study extended the literature on HPV vaccine coverage by combining issue-specific framing and valence framing, considering the Chinese-specific vaccine market for presentation and the value of such products, which is rare in previous studies. Practical implications of the findings for health promotion were also discussed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: In response to activated patient communities' catalyzation, two significant efforts by the FDA to expedite treatments have now been in place for multiple decades. In 1983, the United States Congress passed the Orphan Drug Act to provide financial incentives for development of drugs for rare diseases. In 1992, partly in response to the HIV epidemic, the FDA implemented Accelerated Approval (AA) to expedite access to promising new therapies to treat serious conditions with unmet medical need based on surrogate marker efficacy while additional clinical data is confirmed. The uses of these regulatory approaches over time are assessed in this study. Methods: The following U.S. FDA CDER published lists were used in this analysis: 1. all orphan designations and approvals; 2. all AA and their details updated through December 31, 2022; new molecular entities (NMEs). Results: Orphan drug designations and approvals have increased several-fold over the past four decades. The largest increase recently has been in therapies targeting oncological diseases (comprised of both oncology and malignant hematology). Although orphan drug approvals based on NMEs are the minority of orphan drug designations, the count of approved orphan drug NMEs has increased in recent years. The characteristics of orphan drug approvals show notable differences by disease area with rare diseases and medical genetics (49%) having a relatively large fraction of orphan drug approvals with NMEs compared to the oncological diseases (32%). Similar to the use of orphan drug designation, oncological disease therapies have been the largest utilizers of AA. Many therapies targeting these diseases address unmet medical need and can leverage surrogate markers that have previously been used in similar trials. The timings of conversion of AA (confirmed or withdrawn) were assessed and found to be consistent across decades and to have some dependency upon the broad disease area (when assessed by three large groups: HIV conversions were fastest; followed by oncology; followed by all others). By the end of 2022, 98% of the first 105 (approved in 2010 or earlier) AA had been converted to confirmed or withdrawn. Conclusions: Although the typical timings for AA to be confirmed or withdrawn has not changed significantly over the decades, the disease areas utilizing orphan drug designation and AA have changed significantly over time. Both programs have had increases in their use for therapies targeting oncological diseases. The re-use of surrogate markers for oncological diseases has been an advantage in a way that may not be scientifically feasible in many other disease areas that have greater differentiation across disease etiology. For non-oncological diseases, applicability of AA is, in part, dependent upon greater focus on characterization and acceptance of novel surrogate markers. [ABSTRACT FROM AUTHOR]

Nab‐paclitaxel (Abraxane), an albumin‐bound solvent‐free paclitaxel (PTX) formulation that takes advantage of the endogenous albumin transport pathway, is the current gold standard for treatment of solid tumors with PTX. However, nab‐paclitaxel has several limitations, including complex manufacturing, immunogenicity, slow drug‐release, and a narrow therapeutic window. Nevertheless, no other PTX formulation has gained the Food and Drug Administration approval since Abraxane's 18‐year reign. Addressing these concerns, herein, a PTX‐loaded nanoparticle of a recombinant polypeptide that—like nab‐paclitaxel—capitalizes on the long in vivo half‐life of albumin is reported. This genetically engineered nanoparticle packages PTX in the core of the nanoparticle and displays an albumin‐binding domain on the exterior of the nanoparticle. Upon in vivo administration, the drug‐loaded nanoparticle binds albumin with nanomolar affinity, and acquires an albumin‐corona, which eliminates the need to use exogenous albumin. The nanoparticles can be stored at subzero temperature as lyophilized powder without any cryoprotectants for upto a year and can be reconstituted on‐demand in aqueous buffer at high concentration, thus greatly simplifying formulation processes. These albumin‐binding nanoparticles improve the therapeutic window by at least twofold compared to nonalbumin‐binding counterpart and outperform nab‐paclitaxel in multiple murine tumor models, results that have been independently replicated by a contract research organization. [ABSTRACT FROM AUTHOR]

The number of available antiseizure medications with demonstrated efficacy in cats is limited. As such, there is a need to evaluate the pharmacokinetics of newer medications so that proper dosing regimens can be made. Brivaracetam (BRV) is a more potent analogue of levetiracetam, and is Food and Drug Administration approved for use in people. The goal of this study was to describe the pharmacokinetics of intravenous and oral doses of BRV in healthy cats. A cross‐over study involving eight healthy cats, that were administered 10 mg of BRV intravenously as a bolus and orally in the fasted state. Blood samples were collected over 24 h. Analysis was performed using liquid chromatography‐mass spectrometry. Data were subjected to non‐compartmental analysis. Median (min–max) of maximal concentration, time to maximal concentration, area under the curve, elimination half‐life and oral absolute bioavailability were 902 (682–1036) ng/mL, 0.6 (0.5–2.0) h, 6.4 (5.2–7.2) h, 8145 (6669–9351) ng × h/mL and 100% (85–110) respectively. BRV appeared to be well tolerated by all cats. A single dose of BRV is well tolerated both orally and intravenously. Maximal concentrations are produced rapidly and within the human reference interval considered to be therapeutic. [ABSTRACT FROM AUTHOR]

Lotilaner ophthalmic solution 0.25% (XDEMVY®; henceforth referred to as lotilaner 0.25%) is a novel prescription eye drop indicated for the treatment of Demodex blepharitis. It is the first and currently the only US FDA-approved treatment for this condition. One drop of lotilaner 0.25% instilled in each eye twice daily for 6 weeks was associated with significantly higher rates of collarette reduction to ≤ 2 collarettes (primary endpoint), mite eradication and erythema cure compared to the vehicle control. Lotilaner 0.25% is generally well tolerated, with the most common ocular adverse reaction being instillation site stinging and burning (incidence 10%). The 6-week treatment remained durable with no safety issues during the observational period for up to a year. The eye drop was generally neutral or very comfortable for most patients. Plain Language Summary: Demodex blepharitis is a common eyelid margin disease caused by an infestation of Demodex mites. It is characterized by persistent cylindrical waxy dandruff (collarettes) in the eyelashes, eyelid margin inflammation, redness and eye irritation. Lotilaner ophthalmic solution 0.25% (XDEMVY®; henceforth referred to as lotilaner 0.25%) is a novel prescription eye drop that eradicates Demodex mites. It is FDA-approved in the USA for the treatment of Demodex blepharitis. One drop of lotilaner 0.25% in each eye twice daily for 6 weeks significantly reduces collarettes, decreases or eradicates Demodex mites and reduces eyelid redness in patients with Demodex blepharitis. The treatment is generally well tolerated, with the most common ocular adverse reactions being installation site stinging and burning (incidence 10%). Currently, lotilaner 0.25% is the only US FDA-approved treatment for Demodex blepharitis. [ABSTRACT FROM AUTHOR]

Background: Gene and RNA therapies have potential to transform the treatment of rare inherited diseases, but there are concerns about the evidence supporting their use and high costs. Objective: We analyze the evidence supporting Food and Drug Administration (FDA) approval of gene and RNA therapies for rare inherited diseases and discuss implications for clinical practice and policy. Methods: We conducted a qualitative analysis of FDA documents outlining the basis of approval for gene and RNA therapies approved for rare inherited diseases between 2016 and 2023. For each drug, we gathered five characteristics of the evidence supporting FDA approval (no phase 3 trial, nonrandomized, no clinical endpoint, lack of demonstrated benefit, and significant protocol deviation) and four characteristics of the FDA approval process (prior rejection or complete response, negative committee vote, discrepancy between label and trial population, and boxed warning). The main outcome was the number of drugs with each characteristic. Results: Between 2016 and 2023, 19 gene and RNA therapies received FDA approval to treat rare inherited diseases. The most common limitations in the evidence supporting approval of these drugs were nonrandomized studies (8/19, 42%), no clinical endpoint (7/19, 37%), lack of demonstrated benefit or inconsistent results (4/19, 21%), and no phase 3 trial (4/19, 21%). Half (3/6) of accelerated approvals and 57% (5/9) of drugs with breakthrough designation had nonrandomized trials, and gene therapies with one-time dosing were overrepresented (5/7, 71%) among the drugs with nonrandomized trials. Five of six accelerated approvals (83%) and five of nine pediatric drugs (56%), most of which were indicated for Duchenne muscular dystrophy, had no clinical endpoint. Four of nine (44%) pediatric drugs and four of six (67%) accelerated approvals failed to demonstrate benefit compared with none of the nonpediatric drugs and none of the traditional approvals. Five drugs, which all had different indications and represented a mix of RNA and gene therapies, did not have any of these evidence characteristics. Among drugs that received prior rejections or negative committee opinions, all four had nonrandomized trials and lacked a clinical endpoint, and 75% (3/4) lacked demonstrated benefit. Five of nine (56%) pediatric drugs were indicated for broader age groups according to the drug label compared with the trial populations. Of the three drugs with boxed warnings, two had pediatric indications and nonrandomized studies, and one had no phase 3 trial. Conclusions: Issues related to trial design, outcome, and data integrity in the evidence supporting FDA approval of rare inherited disease gene and RNA therapies raise questions about whether this evidence is adequate to inform prescribing decisions. Gene and RNA therapies with accelerated approval and pediatric indications were overrepresented among drugs lacking clinical endpoints or demonstrated benefit and should be the focus of efforts to reduce uncertainty in the evidence. [ABSTRACT FROM AUTHOR]

Valbenazine is a highly potent and selective inhibitor of synaptic vesicular monoamine transporter 2. The current therapeutic doses of valbenazine for tardive dyskinesia (TD) are 40, 60, or 80 mg capsules, given orally, once daily (QD). While 40 and 80 mg were investigated in phase 3 KINECT® 3 trial and initially approved, the approval of valbenazine 60 mg was based on the analysis utilizing the Model‐informed drug development (MIDD) approach, facilitated through the US Food and Drug Administration's MIDD Pilot Program. This study aimed to demonstrate the efficacy of 60 mg QD dose through model simulations using an established exposure‐response (E‐R) relationship between valbenazine active metabolite [+]‐α‐dihydrotetrabenazine exposure and the change from baseline in Abnormal Involuntary Movement Scale total score (AIMS‐CFB). A longitudinal E–R model was constructed based on the 40 and 80 mg data from the KINECT 3 trial. The final Emax model adequately predicted dose‐dependent improvement in the primary endpoint and was used to interpolate AIMS‐CFB for 60 mg at week 6. The efficacy of the unstudied 60 mg dose regimen is expected to be within the range of doses studied clinically with predicted mean AIMS‐CFB (95% confidence interval) of −2.69 (−3.30, −2.13) between observed mean AIMS‐CFB for 40 mg of −1.92 and 80 mg of −3.39. Results from this analysis provided the key evidence to establish efficacy of 60 mg QD without the need for an additional clinical trial. The availability of valbenazine 60 mg dose fills an existing medical need for patients with TD who could benefit from this third effective dose. [ABSTRACT FROM AUTHOR]

This study explores the repurposing of Food and Drug Administration (FDA)-approved drugs as potential inhibitors of SARS-CoV-2 papain-like protease (PLpro), a critical enzyme for viral replication. Initially, 3009 FDA approved drugs were screened to identify candidates structurally similar to the co-crystallized ligand XT7 in the SARS-CoV-2 PLpro complex (PDB ID: 7LBR). A fingerprint analysis narrowed the selection to the top 5%)150 drugs) most structurally akin to XT7, followed by a more refined structural similarity test that identified the top 1% (30 drugs). Molecular docking studies highlighted several compounds with strong binding affinities to the SARS-CoV-2 PLpro. Notably, Fedratinib exhibited a particularly robust binding energy of − 2 0. 5 4 kcal/mol and was chosen for further investigation. Subsequent molecular dynamics (MD) simulations over 100 ns confirmed the stability and efficacy of Fedratinib's binding, as evidenced by favorable energetic and dynamic profiles. The molecular mechanics-generalized born surface area (MM-GBSA) calculations corroborated these findings, revealing a binding energy of − 2 4. 3 6 kcal/mol. Additionally, PLIP, ProLIF, and PCAT analyses further validated the stability and interactions of the PLpro-Fedratinib complex observed during the MD simulations. Overall, our results indicate that Fedratinib, an FDA-approved drug, demonstrates promising potential as an inhibitor of SARS-CoV-2 PLpro, warranting further in vitro and in vivo experimental validation as well as potential clinical evaluation. 3009 FDA-approved drugs subjected to ligand-based computational studies to select the most similar 30 drugs to the co-crystallized ligand, XT7, in of SARS-CoV-2 PLpro (PDB ID: 7LBR). Molecular docking studies highlighted Fedratinib's robust binding energy and excellent binding mode. MD simulations, MM-GBSA, PLIP, ProLIF, and PCAT analyses validated the stability and interactions of the PLpro-Fedratinib complex [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a chronic, burdensome, highly prevalent disease that is characterized by depressed mood and anhedonia. MDD is especially burdensome as approved monoamine antidepressant treatments have weeks-long delays before clinical benefit and low remission rates. In the past 2 decades, a promising target emerged to improve patient outcomes in depression treatment: glutamatergic signaling. This narrative review provides a high-level overview of glutamate signaling in synaptogenesis and neural plasticity and the implications of glutamate dysregulation in depression. Based on this preclinical evidence implicating glutamate in depression and the rapid improvement of depression with ketamine treatment in a proof-of-concept trial, a range of N-methyl-d-aspartate (NMDA)-targeted therapies have been investigated. While an array of treatments has been investigated in registered phase 2 or 3 clinical trials, the development of most of these agents has been discontinued. Multiple glutamate-targeted antidepressants are actively in development, and two are approved. Nasal administration of esketamine (Spravato®) was approved by the US Food and Drug Administration (FDA) in 2019 to treat adults with treatment-resistant depression and in 2020 for adults with MDD with acute suicidal ideation or behavior. Oral combination dextromethorphan–bupropion (AXS-05, Auvelity® extended-release tablet) was FDA approved in 2022 for the treatment of MDD in adults. These approvals bolster the importance of glutamate in depression and represent an exciting breakthrough in contemporary psychiatry, providing new avenues of treatment for patients as first-line therapy or with either poor response or unacceptable side effects to monoaminergic antidepressants. Plain Language Summary: Major depressive disorder (MDD) is a common disease defined by sadness and a loss of interest or pleasure in activities. Depression treatments include therapy and antidepressant medication. Most available antidepressants affect the same types of chemicals that communicate in the brain (neurotransmitters) called monoamines. Unfortunately, these medicines can take weeks to work for some people and many still have depression symptoms with treatment. To provide more treatment options, new medicines have been studied that impact a different neurotransmitter in the brain, that is, glutamate. Glutamate, the most abundant neurotransmitter, is important for the growth of new brain cell connections, and there are changes in glutamate in people with depression versus people without depression. In 2000, the first small study in people showed that ketamine, a medicine targeting glutamate, quickly improved depression symptoms. Safety risks, including dissociation and sedation, require supervised administration and management guidance. Since 2000, about 20 glutamate-targeted medicines have been tested in human clinical trials. Two of these are approved as antidepressants. The medicine esketamine, which is inhaled up the nose at a clinic under medical supervision, is approved for the adjunctive treatment of people with MDD whose symptoms do not improve with other treatments or who have suicidal thoughts or actions (brand name Spravato®). The combination medicine dextromethorphan–bupropion is a swallowed tablet taken twice daily that is an approved monotherapy to treat adults with MDD (brand name Auvelity®). The approval of these drugs helps show the importance of glutamate in depression and provides more options for people with depression. [ABSTRACT FROM AUTHOR]

Background: Single-arm clinical trials (SAT) are common in drug and biologic submissions for rare or life-threatening conditions, especially when no therapeutic options exist. External control arms (ECAs) improve interpretation of SATs but pose methodological and regulatory challenges. Objective: Through narrative reviews and expert input, we developed a framework for considerations that might influence regulatory use and likelihood of regulatory acceptance of an SAT, identifying non-oncology first indication approvals as an area of interest. We systematically analyzed FDA and EMA approvals using SATs as pivotal evidence. The framework guided outcome abstraction on regulatory responses. Methods: We examined all non-oncology FDA and EMA drug and biologic approvals for first indications from 2019 to 2022 to identify those with SAT as pivotal safety or efficacy evidence. We abstracted outcomes, key study design features, regulator responses to SAT and (where applicable) ECA design, and product label content. Results: Among 20 SAT-based FDA approvals and 17 SAT-based EMA approvals, most common indications were progressive rare diseases with high unmet need/limited therapeutic options and a natural history without spontaneous improvement. Of the types of comparators, most were natural history cohorts (45% FDA; 47% EMA) and baseline controls (40% FDA; 47% EMA). Common critiques were of non-contemporaneous ECAs, subjective endpoints, and baseline covariate imbalance between arms. Conclusion: Based on recent FDA and EMA approvals, the likelihood of regulatory success for SATs with ECAs depends on many design, analytic, and data quality considerations. Our framework is useful in early drug development when considering SAT strategies for evidence generation. [ABSTRACT FROM AUTHOR]

Despite regulatory changes designed to stimulate investment in therapies for rare diseases, many of these conditions lack government-approved treatments. Advanced regenerative medicines, which are therapies and clinical interventions aimed at healing or replacing damaged or defective human cells, tissues, and organs, offer great promise for addressing many rare diseases. A major challenge facing advanced regenerative medicines for rare diseases is securing financial support to assist in bringing a therapy to market. This paper describes the factors cited by pharmaceutical industry players globally for sponsoring the development of advanced regenerative medicines for rare diseases. The paper examines the motivations of 53 sponsors that meet the latter criteria. The motivations behind investments were broadly similar amongst sponsors and map closely onto regulatory requirements for clinical development and marketing authorization of advanced therapeutic products, including the presence of accelerated or attenuated pathways for regulatory approval, use for indications with high unmet medical needs, and/or that have advantages over existing therapies, and robust preclinical data. Other factors include availability of investment incentives and opportunities for off-label use in the post-approval stages. [ABSTRACT FROM AUTHOR]

Post-approval changes (PACs) to the control and manufacturing processes of medicines and vaccines are routinely undertaken and critical to enable both innovation and secure sustained supply. In a world of global supply chains, the existence of divergent national PAC requirements (with additional countries introducing new requirements with potential differences) and other factors including document preparation and response timelines, can lead to long delays in approval (of up to 3–5 years) increasing the risk of disruption and shortages. We undertook an Industry survey in 2023 to assess implementation of ICH Q12, PAC procedures (change categorisation and review timelines) and use of reliance mechanisms across different countries (9 selected ICH Members and 19 Observers). Although this survey revealed limited implementation of Q12 in ICH Member countries, when comparing the data collected with those of a previous survey performed in 2020, we observed a broader adoption of risk-based approaches to variation categorisation (in all countries). This, however, was not reflected in improved timelines for approval. With regards to ICH Q12 adoption, the uptake of Post-Approval Change Management Protocols (PACMPs) was unchanged (with only one country reporting in-use) and implementation gaps were evident for Established Conditions (EC) and the Product Life Cycle Management document (PLCM). The survey found greater awareness of ICH Q12 and its tools compared to 2020, potentially illustrating the positive impact of training efforts. This illustrates the challenges being faced to broaden its implementation and use globally. In the same Industry survey, we also assessed PAC processes across different international countries. Long unpredictable timelines were the major concern across the countries surveyed together with limited capacity of the regulators. Four different CMC changes were selected and categorized by the respondents according to current knowledge of national classifications and timelines in the selected countries and compared with a reference classification and timeline from the European Medicines Agency and the World Health Organisation. This highlighted the lack of harmonisation of many countries with EU/WHO requirements, especially within the ICH Observer group. Last, this survey showed that some use of unilateral forms of reliance to Reference Authorities for PACs is starting. This is a mechanism all countries can employ, regardless of convergence of requirements and expertise, to enhance capacity building and reduce duplication of reviews, streamline variations approval, whilst accelerating patient access to innovation and securing supply. [ABSTRACT FROM AUTHOR]

Post-approval changes (PACs) to marketed products are routinely introduced to continuously enhance the product lifecycle management. However, bringing a chemistry, manufacturing and control (CMC) change through the global health authorities can be a complex and lengthy process taking up to several years, therefore negatively impacting supply continuity. In order to accelerate the review and approval of regulatory submissions and ensure continuous supply to patients, the World Health Organization (WHO) is strongly supporting the implementation of reliance among National Regulatory Authorities (NRAs). While some promising developments have been made with the use of reliance pathways for initial marketing authorizations, reliance is still not widely used for PACs. With the support of the European Medicines Agency (EMA) and WHO, Roche launched a reliance pilot based on EMA approval to file a supply critical variation for a monoclonal antibody. The variation constitutes major changes to the approved manufacturing process. Sameness of the product is ensured by submitting to all participants the same variation package as in the EU. The objectives of the pilot are to ensure continuous supply of this critical medicine by targeting global approval in 6.5 months, to promote regulatory convergence by waiving country specific requirements, and enhance greater transparency by sharing EMA Committee for Medicinal Products for Human Use (CHMP) final assessment report and Q&As to participating NRAs. Globally 48 NRAs have agreed to join the pilot. This article outlines the process of establishing the pilot project, including a planning phase and an engagement phase with the EMA, WHO and the participating NRAs. [ABSTRACT FROM AUTHOR]

Objective: The aims of this article are to review the clinical aspects of rozanolixizumab, to describe clinical trial results that led to the drug's approval, and to examine the impact on patient care to aid clinical decision making. Data Sources: A PubMed search was conducted using the terms Rystiggo ™, rozanolixizumab, rozanolixizumab therapy, and myasthenia gravis. The most recent prescribing information was also used for information relating to the drug and for identification of pertinent studies. Study Selection/Data Extraction: Phase I, II, and III randomized controlled trials were all eligible for inclusion. Meeting abstracts and articles focusing on the use of rozanolixizumab or any indication other than generalized myasthenia gravis were excluded from this article. Data Synthesis: Food and Drug Administration approval of rozanolixizumab is based on the phase III MycarinG study in patients with generalized myasthenia gravis. A phase II trial explored initial clinical efficacy and safety pertaining to the dose and frequency of rozanolixizumab across 2 treatment periods in patients with moderate to severe myasthenia gravis. Relevance to Patient Care and Clinical Practice in Comparison to Existing Agents: Rozanolixizumab is the first therapy approved to treat patients positive for both types of antibodies, anti-acetylcholine receptor or anti-muscle-specific tyrosine kinase, in generalized myasthenia gravis. Conclusion/Relevance: The approval of rozanolixizumab represents an advancement in therapy for generalized myasthenia gravis. The provision of individualized, targeted, and well-tolerated treatment is valuable for the patients whose myasthenia gravis is not well controlled and who are seeking a medication with a rapid onset of action to improve their symptoms and overall quality of life. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion Currently, there are two approved single chamber leadless pacemakers (LP) in the United States (US), Micra VR™; approved since 2016 and AVEIR VR™; approved in 2022. A potential complication of LPs is dislodgement and/or embolization (D/E) during or after implant. According to the IDE trials, there appears to be a significant difference in D/E rates between the two LPs that have different fixation mechanisms; Micra uses nitinol tines, while AVEIR uses an active screw helix. The aim of this study was to determine if the AVEIR VR LP has continued to exhibit D/E in the United States since it was approved by the Food and Drug Administration (FDA) in April 2022.The FDA Manufacturer and User Facility Device Experience (MAUDE) database was searched for US D/E reports communicated by the manufacturers of both LP devices. For AVEIR VR we reviewed reports from approval till December 2023, and for Micra VR we looked at reports from approval to April 2024. Excluded were reports based on information indirectly obtained from registries, journals, social media, or volunteers. Total number of US implants was acquired from the manufacturers' product performance reports.During a period of 21 months, 5990 AVEIR VR implants had been registered in the United States, of which 53 (0.88%) encountered D/E both during and after the procedure. More D/E (32; 60.4%) occurred during the implantation procedure, with device release problems being the most prominent procedural issue involved with these events. Within a 8‐year period, 72 237 Micra VR implants have been registered in the United States, of which 211 (0.29%) showed D/E. The rate of D/E since the US approval of both devices was significantly higher for AVEIR VR compared to Micra VR (0.88% vs 0.29%; p < .0001).AVEIR VR implants may be complicated by dislodgement with or without embolization. Currently, the estimated incidence is about 0.9%, which is significantly higher than Micra VR. Fixation issues and separation problems of the device from the delivery catheter appear to be responsible for most of these D/E events. [ABSTRACT FROM AUTHOR]

ABSTRACT An informed estimate of subject‐level variance is a key determinate for accurate estimation of the required sample size for clinical trials. Evaluating completed adult Type 2 diabetes studies submitted to the FDA for accuracy of the variance estimate at the planning stage provides insights to inform the sample size requirements for future studies. From the U.S. Food and Drug Administration (FDA) database of new drug applications containing 14,106 subjects from 26 phase 3 randomized studies submitted to the FDA in support of drug approvals in adult type 2 diabetes studies reviewed between 2013 and 2017, we obtained estimates of subject‐level variance for the primary endpoint—change in glycated hemoglobin (HbA1c) from baseline to 6 months. In addition, we used nine additional studies to examine the impact of clinically meaningful covariates on residual standard deviation and sample size re‐estimation. Our analyses show that reduced sample sizes can be used without interfering with the validity of efficacy results for adult type 2 diabetes drug trials. This finding has implications for future research involving the adult type 2 diabetes population, including the potential to reduce recruitment period length and improve the timeliness of results. Furthermore, our findings could be utilized in the design of future endocrinology clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: Despite their dangerous side effects, opioid drugs remain a standard of care for moderate to severe pain with few alternatives. Strategies to maintain the analgesic effects of opioids while minimizing the associated risks are needed. Pre-clinical studies have shown using a dopamine 3 receptor (D3R) agonist as an adjuvant to morphine provides superior analgesia against painful stimuli compared to morphine alone. Our objective was to test if adjunct treatment with a D3R agonist can lead to a reduction in opioid use while maintaining effective analgesia. Patients and methods: This study was set up as a double-blinded, placebocontrolled randomized trial. Enrollment included acute renal colic patients presenting to the emergency department, from which patients were randomized to either the "control" or "study arm". The control group received standard treatment of care (morphine, 0.1 mg/kg; i.v.) and an oral placebo pill. The experimental group received half-dosed morphine and oral pramipexole pill (0.25 mg). Pain measurements including a numerical pain scale and visual analog scale were collected from enrollees at baseline and every subsequent 15 min. Results: A total of 19 patients completed the study, 10 in the experimental arm and 9 in the control arm. During the study period, effective analgesia (50% decrease from baseline) was achieved in 80% of patients in the experimental arm vs. 33.3% in the control arm. Conclusion: Our pilot clinical trial demonstrated that D3R recruitment can serve as an effective adjuvant to low-dose morphine for control of renal colic pain and potentially other acute pain conditions. [ABSTRACT FROM AUTHOR]

Background: The cost of cancer drugs presents a significant challenge to accessibility of treatment worldwide. Projections indicate that by 2040, two-thirds of cancer cases will occur in low- and middle- income countries. Paradoxically, despite this impending burden, LMICs command less than 5% share of global resources for treating cancer. Morocco, like many LMICs, faces significant obstacles in providing innovative cancer treatments to its population. Aim: Firstly, we aimed to conduct an original research investigating the availability and affordability of innovative cancer drugs in Morocco. Secondly, we sought to review the broader market dynamics, pricing, and reimbursement policies in the country. Methods: For the first objective, we identified a preliminary list of medicines approved for oncological indications in the Moroccan market based on resources from ANAM (National Agency for Health Insurance), pharmacy regulators, and online resources that compile information on approved medicines. For the second objective, we exhaustively reviewed the regulatory documents, legal texts and grey literature reports. All the informations were examined by pharma delegates and local experts. Results: As of January 2024, Morocco has 39 innovative anticancer medicines with market authorization. 30% of these drugs were approved after 2020. The majority of approved drugs were for breast, lung, colorectal, and prostate cancer. The period between FDA approval and entry into the Moroccan market ranges from 2 to 7 years, with a median of 3 years for breast cancer drugs and 7 years for more expensive drugs like Olaparib and Osimertinib. 22 out of the 39 drugs are not reimbursed, with an average reimbursement time of 4 years. Compared to prices in France, the most notable pricing disparities concern immunotherapy agents, priced 600 to 900 euros lower in France, while drugs like Pazopanib and Erlotinib cost 50% less in Morocco. Conclusion: Our study reveals significant disparities in the availability and affordability of innovative cancer drugs in Morocco. Regulatory hurdles, importation challenges, and pricing strategies contribute to this inequitable landscape. Addressing systemic barriers, fostering collaborations between stakeholders, and adopting a value-based pricing approach are imperative steps toward ensuring equitable access to high-quality interventions for patients, regardless of their geographical location. [ABSTRACT FROM AUTHOR]

Repurposing generic drugs as new treatments for life-threatening diseases such as cancer is an exciting yet largely overlooked opportunity due to a lack of market-driven incentives. Nonprofit organizations and other non-manufacturers have been ramping up efforts to repurpose widely available generic drugs and rapidly expand affordable treatment options for patients. However, these nonmanufacturers find it difficult to obtain regulatory approval in the U.S. Without a straightforward path for approval and updating drug labeling, non-manufacturers have relied on off-label use of repurposed drugs. This limits the broad clinical adoption of these drugs and patient access. In this paper, we explore the regulatory landscape for repurposing of small molecule generic drugs within the U.S. We describe case studies of repurposed drugs that have been successfully incorporated into clinical treatment guidelines for cancer without regulatory approval. To encourage greater adoption of generic drugs in clinical practice-that is, to encourage the repurposing of these drugs-we examine existing Food and Drug Administration (FDA) pathways for approval of new uses or indications for generic drugs. We show how non-manufacturers, who are generally more active in generic drug repurposing than manufacturers, could utilize existing regulatory authorities and pathways, and we describe the challenges they face. We propose an extension of the existing 505(b)(2) new drug application (NDA) approval pathway, called a "labeling-only" 505(b)(2) NDA, that would enable non-manufacturers to seek approval of new indications for well-established small molecule drugs when multiple generic products are already available. It would not require new chemistry, manufacturing, and controls (CMC) data or introducing new drug products into the marketplace. This pathway would unlock innovation broadly and enable patients to benefit from the enormous potential of low-cost generic drugs. [ABSTRACT FROM AUTHOR]

Nuclear Medicine is witnessing a revolution across a large spectrum of patient care applications, hardware, software and novel radiopharmaceuticals. We propose to offer a framework of the nuclear medicine practice of the future that incorporates multiple novelties and coined as the NEW (nu) Clear medicine. All these new developments offer a significant clarity and real clinical impact, and we need a concerted effort from all stakeholders in the field for bedside implementation and success. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with ovarian cancer often have higher levels of platelets in their blood than are normally found in healthy individuals. Ovarian cancer cells form clumps called spheroids that travel throughout the abdomen in a fluid that contains platelets. Previously, we showed that platelets cause ovarian cancer spheroids to become smaller and denser. In this study, we found that an antiplatelet inhibitor called eptifibatide can prevent this effect of platelets on ovarian cancer spheroids. We also discovered that the molecule called liver X receptor appears to be involved in how platelets affect ovarian cancer spheroids and how eptifibatide can prevent this. These findings suggest that eptifibatide could be repurposed to treat ovarian cancer, and that drugs that affect the liver X receptor could be developed to enhance the anti-cancer activity of eptifibatide. Background: Platelets have been shown to promote ovarian cancer; however, the mechanism is poorly understood. Previously, we demonstrated that platelets reduce the size and increase the density of multi-cellular ovarian cancer spheroids in cell cultures. The objectives of this study were to determine if platelet inhibitors could counteract these effects, and to explore the mechanisms involved. Methods: FDA-approved platelet inhibitors were screened for their abilities to alter platelet effects on ovarian cancer spheroids. Mass spectrometry was used to identify proteins significantly altered in cancer cells upon exposure to platelets. The effects of platelets and/or liver x receptor agonists or antagonists on LXR activity were measured using ES-2 ovarian cancer cells transduced with an LXR-reporter vector. Results: Eptifibatide, a GPIIB-IIIA integrin inhibitor, and dipyridamole, an adenosine reuptake inhibitor, reduced and enhanced platelet effects on ovarian cancer spheroids, respectively. Proteomic studies identified the LXR/RXR and integrin pathways as mediators of platelet effects on ovarian cancer, and downstream effectors of eptifibatide. Conclusions: Integrin pathways and their downstream LXR/RXR effectors are implicated in how platelets alter ovarian cancer spheroid morphology. These results support studying eptifibatide and LXR/RXR agonists as candidate drugs for repurposing as therapeutic strategies to counteract platelet promotion of ovarian cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic graft vs. host disease (cGVHD) is a major complication that appears after allogeneic hematopoietic cell transplantation. As result, this has a significant and detrimental impact on both the quality of life and survival of patients after transplantation. In recent years, three novel therapies have been approved by the FDA for the management of cGVHD. To date, previous studies have not analyzed the effect of these novel drugs on other health-associated conditions such as metabolic syndrome, bone health, return to employment, mental health, and other para-medical outcomes. In this study, during three different time periods, we aimed to assess and highlight the association between novel advanced treatments for cGVHD and their impact on the quality of life of patients after allogeneic transplantation. Objectives—chronic graft vs. host disease (cGVHD) is associated with substantial morbidity and mortality. We aimed to analyze advances in treatment strategy and outcomes during the last decade due to the incorporation of novel immunosuppressive therapy (IST) drugs in the armamentarium. Methods—we retrospectively analyzed all patients > 18 years with cGVHD after their first hematopoietic cell transplantation (HCT) between 2012 and 2020 (n = 91), divided into three treatment periods: 2012–2014, 2015–2017, and 2018–2020 (groups 1, 2, and 3, respectively). Results—mean cumulative steroid dose and dose/total cGVHD-treatment days was lower in groups 2–3 compared to 1 (p = 0.008 and p = 0.042, respectively). The median IST-free survival was 79 (95%CI54–94) months, with more patients in group 3 (47% (95%CI 25–54%) discontinuing IST at 3 years, p = 0.1). Groups 2–3 compared to 1 had better glycemic control (p < 0.01), higher bone density (p = 0.06), and fewer cardiovascular events. The number of admissions/patient dropped from 0.7/year in group 1 to 0.24/year and 0.36/year in groups 2–3, respectively (p = 0.36). Employment reintegration was higher in groups 2–3 compared with 1 (p = 0.05) and so was earlier return to work (p = 0.01). There were no differences in survival outcomes. Conclusions—the incorporation of novel agents appears to be associated with reduced overall steroid burden, improved cGVHD control, and fewer long-term side effects. [ABSTRACT FROM AUTHOR]

Simple Summary: Bruton's tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of various B-cell lymphoid malignancies. However, acquisition of resistance to BTKi has emerged as an important clinical challenge. Herein, we provide a detailed review, describing the clinical trials that led to the FDA approval of the BTK inhibitors for management of Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma, Marginal Zone Lymphoma (MZL), Follicular Lymphoma (FL) and Waldenstrom Macroglobulinemia (WM). We describe the mechanism of intrinsic and extrinsic resistance to the BTKi with main emphasis on the functional description of BTK mutations in CLL. Finally, we review the latest updates of the PROTACs BTK degraders, an evolving treatment modality for the management of the BTKi refractory B-cell malignancies. B-cell lymphoid malignancies are a heterogeneous group of hematologic cancers, where Bruton's tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling. Resistance to covalent BTK inhibitors (BTKi) can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLCγ2) resulting in downstream signaling. To bypass the C481S mutation, non-covalent BTKi, such as Pirtobrutinib, were developed and are active against both wild-type and the C481S mutation. In this review, we discuss the molecular and genetic mechanisms which contribute to acquisition of resistance to covalent and non-covalent BTKi. In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTKi and the development of new therapeutic strategies highlight the ongoing advances being made towards the pursuit of a cure for B-cell lymphoid malignancies. [ABSTRACT FROM AUTHOR]

Vorasidenib (VORANIGO®; Servier) is an orally administered, first-in-class, highly brain-penetrant dual inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1/2) enzymes being developed for use in IDH-mutant diffuse glioma. Vorasidenib received its first approval on 6 August 2024, in the USA, for the treatment of adult and pediatric patients aged 12 years and older with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation following surgery, including biopsy, sub-total resection, or gross total resection. Approval was based on results from the multinational phase III INDIGO trial, in which vorasidenib significantly improved progression-free survival and time to the next anticancer intervention relative to placebo. In the EU and other countries worldwide, regulatory review of vorasidenib in IDH-mutant glioma is currently underway. This article summarizes the milestones in the development of vorasidenib leading to this first approval for glioma. [ABSTRACT FROM AUTHOR]

Golidocitinib (高瑞哲®) is an oral, potent, selective Janus kinase 1 (JAK1) inhibitor being developed by Dizal (Jiangsu) Pharmaceutical Co., Ltd for the treatment of cancer, including peripheral T cell lymphoma (PTCL). In June 2024, golidocitinib received conditional approval in China for the treatment of adult patients with relapsed or refractory (r/r) PTCL who have received at least one line of systemic treatment. This article summarizes the milestones in the development of golidocitinib leading to this first approval for the treatment of adults with PTCL. [ABSTRACT FROM AUTHOR]

Donanemab (donanemab-azbt; KisunlaTM) is an amyloid β-directed antibody developed by Eli Lilly and Company for the treatment of Alzheimer's disease. Donanemab recently received approval in the USA for the treatment of adults with early symptomatic Alzheimer's disease (patients with mild cognitive impairment or mild dementia stage of disease). This article summarizes the milestones in the development of donanemab leading to this first approval for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

RNA and protein‐based therapeutics constitute almost half of recent drug approvals and receive considerable attention within biotechnology industries. Ensuring their stability and longevity in the context of heat, freezing, and lyophilization processes are paramount to a successful deployment. However, the advancement of formulations designed to achieve this goal is still in its nascent phase. To address these challenges, a new class of semi‐dendritic hydrophilic polymer with extended linear units is reported, which showcase very high hydration. These novel polymers demonstrated exceptional efficacy in preserving messenger RNA‐ (mRNA‐) and self‐amplifying RNA‐ (saRNA‐) lipid nanoparticles during freezing and lyophilization. Additionally, they have been found to protect therapeutic proteins against external stressors such as freezing, heat, and lyophilization. These polymers are non‐toxic, which enables their utilization at high concentrations and eliminates the requirement for removal prior to administration. It is found that their unique topology contributes to the high hydration. These excipients are anticipated to create new prospects in biotechnology, food science, and cryopreservation. [ABSTRACT FROM AUTHOR]

Targeted biologic drugs and small molecules have transformed the psoriasis treatment landscape in recent years. The Belgian healthcare system, in common with many others across Europe, must balance the burgeoning use of these transformative, yet expensive, drugs with the sustainable use of limited resources. Drawing on recent updates to the EuroGuiDerm and the German S2 psoriasis guidelines, eight Belgian dermatologists experienced in treating patients with psoriasis undertook a quasi‐Delphi initiative to provide perspectives on the current opportunities and challenges in psoriasis. This update focuses on responsible ways to rationalize the use of innovative treatments (e.g. biologics and small molecules). Inherently, this required viewpoints on the International Psoriasis Council's new definition of severe psoriasis, defining psoriasis severity and the concept of treating to target. It discusses the appropriateness of using older biologics classes, biosimilars and personalized dosing and lastly, how teledermatology may play a role in providing sustainable, patient‐centric psoriasis care. In addition, this manuscript includes the updated Belgian evidence‐based treatment advice in psoriasis (BETA‐PSO) to reflect recent data and drug approvals. The recommendations reflect the best practices for clinicians when using systemic and biologic therapies to treat patients with psoriasis and offer guidance on how they may prescribe these drugs sustainably and efficiently. [ABSTRACT FROM AUTHOR]

Wearables offer a promising solution for enhancing remote monitoring (RM) of heart failure (HF) patients by tracking key physiological parameters. Despite their potential, their clinical integration faces challenges due to the lack of rigorous evaluations. This review aims to summarize the current evidence and assess the readiness of wearables for clinical practice using the Medical Device Readiness Level (MDRL). A systematic search identified 99 studies from 3112 found articles, with only eight being randomized controlled trials. Accelerometery was the most used measurement technique. Consumer-grade wearables, repurposed for HF monitoring, dominated the studies with most of them in the feasibility testing stage (MDRL 6). Only two of the described wearables were specifically designed for HF RM, and received FDA approval. Consequently, the actual impact of wearables on HF management remains uncertain due to limited robust evidence, posing a significant barrier to their integration into HF care. [ABSTRACT FROM AUTHOR]

ABSTRACT Minimal residual disease (MRD) is one of the most important prognostic factors in multiple myeloma (MM) and a valid surrogate for progression‐free survival (PFS) and overall survival (OS). Recently, MRD negativity was approved as an early clinical endpoint for accelerated drug approval in MM. Nevertheless, there is limited evidence of MRD utility in real‐world setting. In this retrospective multicenter study, we report outcomes of 331 newly diagnosed MM patients with MRD evaluation at Day+100 after autologous stem cell transplantation using flow cytometry with a median limit of detection of 0.001%. MRD negativity was reached in 47% of patients and was associated with significantly prolonged median PFS (49.2 months vs. 18.4 months; hazard ratios (HR) = 0.37; p < 0.001) and OS (not reached vs. 74.9 months; HR = 0.50; p = 0.007). Achieving MRD negativity was associated with PFS improvements regardless of age, International Staging System (ISS) stage, lactate dedydrogenase (LDH) level, or cytogenetic risk. Importantly, MRD positive patients benefited from lenalidomide maintenance versus no maintenance (18‐months PFS: 81% vs. 46%; HR = 0.24; p = 0.002) while in MRD negative patients such benefit was not observed (p = 0.747). The outcomes of our real‐world study recapitulate results from clinical trials including meta‐analyses and support the idea that MRD positive patients profit more from lenalidomide maintenance than MRD negative ones. [ABSTRACT FROM AUTHOR]

Medical oncology is a rapidly evolving field, with new medications being discovered yearly, contributing to increased survival rates. However, accessing drugs in a timely manner can be challenging. In Quebec, Canada, a physician can prescribe an unlisted anticancer treatment through a regulated pathway under exceptional circumstances. We conducted a quality improvement study describing the outcomes of incurable cancer patients receiving unlisted anticancer therapy at the Jewish General Hospital between 2018 and 2019. Though our study did not include a comparator arm, unlisted anticancer therapies were associated with interesting median progression-free survival (11 months) and overall survival (25 months). Moreover, a large proportion of treatments, 44%, were subsequently reimbursed in the province of Quebec. Given the delay in anticancer drug reimbursement, this pathway is essential for timely access to oncology drugs. Such 'special access' programs will likely become increasingly important as precision medicine becomes the standard of practice. [ABSTRACT FROM AUTHOR]

Objectives: Thyroid eye disease (TED) treatment has been recently revolutionized with the approval of teprotumumab, a targeted insulin growth factor 1 receptor (IGF1R) inhibitor. To date, teprotumumab is the only FDA-approved drug for treating TED. In this article, we would like to temper the current enthusiasm around IGF1R inhibitors. Methods: critical review of the literature by independent academic practitioners. Results: several questions should be raised. First, "how an orphan drug has become a blockbuster with annual sales exceeding $1 billion?" Teprotumumab infusions are expensive, costing about USD 45,000 for one infusion and USD 360,000 for eight infusions in a 75 kg patient. Teprotumumab approval was based on two randomized clinical trials investigating active (clinical activity score ≥ 4) TED patients. Despite this, teprotumumab was approved by the FDA for "the treatment of TED" without distinguishing between active and inactive forms. The second question is as follows: "how can a new drug, compared only to a placebo, become the new standard without being compared to historically established gold standard medical or surgical treatments?" Teprotumumab has never been compared to other medical treatments in active TED nor to surgery in chronic TED. Up to 75% of patients may experience proptosis regression after treatment discontinuation. Finally, ototoxicity has emerged as a potentially devastating side effect requiring frequent monitoring. Investigation into the long-term side effects, especially in women of childbearing age, is also warranted. Conclusions: Teprotumumab is undoubtedly a major treatment option in TED. However, before prescribing a drug, practitioners should assess its benefit/risk ratio based on the following: (i) evidence-based medicine; (ii) their empirical experience; (iii) the cost/benefit analysis; (iv) the long-term outcomes and safety profile. [ABSTRACT FROM AUTHOR]

Maternal medication use may expose the developing fetus through placental transfer or the infant through lactational transfer. Because pregnant and lactating individuals have been historically excluded from early drug development trials, there is often limited to no human data available to inform pharmacokinetics (PK) and safety in these populations at the time of drug approval. We describe the known mechanisms of placental or lactational transfer of IgG‐based therapeutic proteins and use clinical examples to highlight the potential for fetal or infant exposure during pregnancy and lactation. Placental transfer of IgG‐based therapeutic proteins may result in systemic exposure to the developing fetus. A lactational transfer may be associated with local gastrointestinal (GI) exposure in the infant and may also result in systemic exposure, although data are very limited as proteins have shown instability in the GI tract. Understanding of PK and pharmacodynamic (PD) effects of IgG‐based therapeutic proteins in infants exposed in utero as well as the potential exposure through human milk and its clinical implications is critical for developing treatment strategies for pregnant or lactating individuals. We share the current knowledge gaps and considerations for future evaluations to inform PK, PD, and the safety of IgG‐based therapeutic proteins for safe use during pregnancy and lactation. With the increasing use of IgG‐based therapeutic proteins in treating chronic diseases during pregnancy and lactation, there is a need to improve the quantity and quality of data to inform the safe use in pregnant and lactating individuals. [ABSTRACT FROM AUTHOR]

Pregnancy is a period in a woman's life during which she experiences physiological, psychological, and social changes. These changes can lead to various mental illnesses, including postpartum depression (PPD), which is common during the perinatal period. Postpartum depression is a significant cause of morbidity and mortality for both the mother and baby. A peripartum-onset major depressive episode is defined as PPD when it occurs during pregnancy or up to 4 weeks postpartum. The frequency of this condition is extremely high. Its etiology is influenced by biological, psychological, and sociocultural factors. Depressed mood, anhedonia, feelings of guilt, irritability, lack of concentration, psychomotor agitation or retardation, sleep disturbance, and changes in appetite and weight can all be symptoms of PPD. There are various treatment options available, many of which are adapted from those used for major depression. Selective serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors, tricyclic antidepressants, estradiol, progesterone, psychothera- pies, electroconvulsive therapy, and brexanolone can be used to treat PPD. In addition, the newest drug approved by the FDA (Food and Drug Administration) for this condition is oral zuranolone. This review aims to analyze recent developments on zuranolone, the latest drug approved by the FDA for PPD, based on current studies. [ABSTRACT FROM AUTHOR]

Lecanemab (also known as lecanemab-irmb in the USA; LEQEMBI®), an immunoglobulin (Ig)G1 monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid-β, is an emerging treatment option for patients with Alzheimer's disease. Lecanemab is approved for the treatment of Alzheimer's disease in multiple countries worldwide, including the USA. Lecanemab is administered as an intravenous infusion once every 2 weeks, with treatment initiated early in the disease process (i.e. when patients have mild cognitive impairment or mild dementia). In the phase 3 Clarity AD trial in patients with early Alzheimer's disease, lecanemab reduced brain amyloid-β levels and was associated with significantly less decline in measures of cognition and function than placebo. The benefits of lecanemab on clinical progression were maintained over the longer term, with the drug demonstrating a disease-modifying effect. Lecanemab was associated with relatively preserved health-related quality of life and less worsening of caregiver burden than placebo. However, lecanemab was also associated with adverse events (AEs), the most common being infusion-related reactions and amyloid-related imaging abnormalities (ARIA). Plain Language Summary: Alzheimer's disease is a progressive neurodegenerative disorder that disrupts memory, behaviour and thinking skills. Accumulation of amyloid-β in the brain is known to play an important role in the development and progression of Alzheimer's disease. Lecanemab (also known as lecanemab-irmb in the USA; LEQEMBI®) is a monoclonal antibody that targets amyloid-β and has been approved for the treatment of Alzheimer's disease. It is infused intravenously every 2 weeks. In clinical trials in patients with early Alzheimer's disease, lecanemab decreased the amount of amyloid-β in the brain and reduced clinical decline on a global cognitive and functional scale compared with placebo. Over the longer term, lecanemab appeared to slow progression of the disease. Lecanemab was associated with adverse events (AEs) in clinical trials. The most common AEs with lecanemab were infusion-related reactions and amyloid-related imaging abnormalities, which usually occurred early in treatment and were of mild to moderate severity. Lecanemab is an emerging treatment option for patients with Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Sodium oxybate extended-release suspension (LUMRYZ™; hereafter referred to as sodium oxybate ER) represents a promising novel option for the treatment of narcolepsy. It is the first once-nightly sodium oxybate formulation to be approved in the USA for the treatment of cataplexy or excessive daytime sleepiness (EDS) in adults with narcolepsy. Sodium oxybate ER has a pharmacokinetic profile that supports a single bedtime dose. In a pivotal phase 3 trial, once-nightly sodium oxybate ER dose-dependently increased sleep latency during the daytime, reduced cataplexy and daytime sleepiness, and improved disrupted nighttime sleep (DNS) compared with placebo in patients aged ≥ 16 years with narcolepsy. These improvements were statistically significant and clinically meaningful. Most patients who switched from twice-nightly immediate-release sodium oxybate (hereafter referred to as sodium oxybate IR) to once-nightly sodium oxybate ER in an open-label extension/switching study preferred the once-nightly formulation. Once-nightly sodium oxybate ER was generally well tolerated, including over the longer term, with a tolerability profile consistent with that of twice-nightly sodium oxybate IR. Plain Language Summary: Narcolepsy, a disorder of sleep-wake instability, is a lifelong condition characterized primarily by overwhelming and persistent daytime sleepiness. Other symptoms include sudden muscle weakness associated with strong emotions (cataplexy), disturbed nighttime sleep, sleep paralysis, and vivid hallucinations when falling asleep or when awakening. The standard of care for patients with narcolepsy has been sodium oxybate, which requires twice-nightly dosing. Patients take their first dose at bedtime and must then awaken 2.5–4 h later to take their second dose. A less burdensome once-nightly formulation, sodium oxybate extended-release suspension (LUMRYZ™; hereafter referred to as sodium oxybate ER), has been approved for the treatment of cataplexy or excessive daytime sleepiness in patients with narcolepsy. In a clinical trial, patients treated with once-nightly sodium oxybate ER were able to stay awake longer during the day, felt less sleepy in the daytime, had fewer cataplexy attacks, and had less disruption to nighttime sleep than placebo recipients. Sodium oxybate ER was generally well tolerated. Nausea, dizziness, bed-wetting, headache, and vomiting were the most common treatment-related adverse events. Thus, once-nightly sodium oxybate ER represents a promising new option for the treatment of narcolepsy. [ABSTRACT FROM AUTHOR]

Simple Summary: There has recently been an interest in drugs that work across the pan-cancer spectrum and show antitumor activity based on biomarkers rather than histology. In this article, we discuss one of these biomarkers, NTRK fusions, which, if present, can predict sensitivity to treatment with inhibitors of the NTRK molecular pathway. Currently, there are three drugs that have been approved by the United States Food and Drug Administration (FDA) in patients with NTRK fusions, regardless of the tumor tissue of origin. These are larotrectinib, entrectinib, and repotrectinib. Herein, we discuss what NTRK fusions are and how to detect them, alongside data on each drug, from a clinical perspective. NTRK fusions are oncogenic drivers for multiple tumor types. Therefore, the development of selective tropomyosin receptor kinase (TRK) inhibitors, including larotrectinib and entrectinib, has been transformative in the context of clinical management, given the high rates of responses to these drugs, including intracranial responses in patients with brain metastases. Given their promising activity in pan-cancer cohorts, larotrectinib and entrectinib received U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for tissue-agnostic indications in patients with advanced solid tumors harboring NTRK fusions. The safety profiles for both drugs are quite manageable, although neurotoxicity driven by the on-target inhibition of normal NTRK can be a concern. Also, on- and off-target resistance mechanisms can arise during therapy with TRK inhibitors, but they can be addressed with the use of combination therapy and next-generation TRK inhibitors. More recently, the FDA approved the use of repotrectinib, a second-generation TRK inhibitor, in patients with NTRK fusions, based on data suggesting clinical efficacy and safety, which could offer another tool for the treatment of NTRK-altered cancers. In this review, we summarize the current evidence related to the use of TRK inhibitors in the tissue-agnostic setting. We also elaborate on the safety profiles and resistance mechanisms from a practical perspective. [ABSTRACT FROM AUTHOR]

Simple Summary: Survival for patients with biliary tract cancer (BTC) is poor, especially in the advanced stage, where curative treatments are not available. While chemotherapy and immunotherapy are used in standard practice, antibody–drug conjugates (ADCs) have emerged as a novel therapy option. ADCs potentially enhance cancer cell death and reduce side effects. The anti-HER2 ADC Trastuzumab Deruxtecan (T-Dxd) has shown survival benefit for patients whose tumours are HER2-positive, including a subgroup of BTCs. In April 2024, the regulatory authority FDA approved T-Dxd for adults with unresectable or metastatic HER2-positive solid tumours, including BTCs, lacking other treatment options. Ongoing trials are exploring other potentially actionable BTC molecular alterations. This review will discuss the current evidence and ongoing research in this subject area. Background: Biliary tract cancers (BTCs) are aggressive in nature, often presenting asymptomatically until they are diagnosed at an advanced stage. Surgical resection or liver transplantation are potential curative options. However, a large proportion of patients present with incurable locally advanced or metastatic disease and most of these patients are only eligible for palliative chemotherapy or best supportive care. More recently, targeted therapies have proven beneficial in a molecularly selected subgroup of patients with cholangiocarcinoma who have progressed on previous lines of systemic treatment. However, only a minority of patients with BTCs whose tumours harbour specific molecular alterations can access these therapies. Methods: In relation to ADCs, studies regarding use of antibody–drug conjugates in cancer, particularly in BTCs, were searched in Embase (1974 to 2024) and Ovid MEDLINE(R) (1946 to 2024) to obtain relevant articles. Examples of current clinical trials utilising ADC treatment in BTCs were extracted from the ClinicalTrials.gov trial registry. Conclusions: Overall, this review has highlighted that ADCs have shown encouraging outcomes in cancer therapy, and this should lead to further research including in BTCs, where treatment options are often limited. The promising results observed with ADCs in various cancers underscore their potential as a transformative approach in oncology, warranting continued exploration and development and the need for education on the management of their specific toxicities. By addressing current challenges and optimising ADC design and application, future studies could potentially improve treatment outcomes for patients with BTCs and beyond, potentially in both early and advanced stage settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has changed the way we treat triple-negative breast cancer (TNBC), a type of breast cancer that does not have common markers like estrogen, progesterone, or HER2. TNBC has the worst outlook among breast cancers, but it may respond better to immunotherapy because it often shows higher levels of PD-L1 and has more immune cells attacking the tumor. Recently, the FDA approved pembrolizumab (Keytruda) combined with chemotherapy for advanced TNBC, offering new hope for patients. However, not all patients respond equally well, mainly because not everyone has high PD-L1 levels. To improve treatment success, combining immunotherapy with other treatments like chemotherapy, targeted therapies, or radiation seems promising. This review explains TNBC and immunotherapy, discusses current and future combination treatment strategies, and explores the challenges and potential new approaches that might soon be available for treating TNBC. Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptors (ERs), human epidermal growth factor receptor 2 (HER2), and progesterone receptors (PRs). TNBC has the poorest prognosis among breast cancer subtypes and is more likely to respond to immunotherapy due to its higher expression of PD-L1 and a greater percentage of tumor-infiltrating lymphocytes. Immunotherapy has revolutionized TNBC treatment, especially with the FDA's approval of pembrolizumab (Keytruda) combined with chemotherapy for advanced cases, opening new avenues for treating this deadly disease. Although immunotherapy can significantly improve patient outcomes in a subset of patients, achieving the desired response rate for all remains an unmet clinical goal. Strategies that enhance responses to immune checkpoint blockade, including combining immunotherapy with chemotherapy, molecularly targeted therapy, or radiotherapy, may improve response rates and clinical outcomes. In this review, we provide a short background on TNBC and immunotherapy and explore the different types of immunotherapy strategies that are currently being evaluated in TNBC. Additionally, we review why combination strategies may be beneficial, provide an overview of the combination strategies, and discuss the novel immunotherapeutic opportunities that may be approved in the near future for TNBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) are the most recent breakthrough in cancer treatments. Several drugs have been approved by the FDA including anti-PD-1 antibodies (Nivolumab, Pembrolizumab, and Cemiplimab). Their treatment is most effective for melanoma, non-small cell lung cancer, or bladder cancer. However, ICI response rates are very low for breast cancer patients, even for those with triple negative breast cancer (TNBC) who are expected to be more responsive to ICI treatment. Improved treatments are in demand for patient benefits. Our armed oncolytic virus is one therapeutic agent that can improve the outcome of TNBC treatment, especially in combination with ICIs, as demonstrated by this study. It has been shown that the response rate of TNBC is dependent on the level of PD-L1 and the tumor microenvironment (TME). Approaches that alter the TME can improve the efficacy of ICIs. Background: We have engineered a Smac-armed oncolytic virus by inserting a Smac transgene into the genome of a vesicular stomatitis virus to generate VSV-S. Our previous study shows that the anticancer efficacy of VSV-S is more potent than that of wild-typed VSV in a subcutaneous TNBC mouse model. VSV-S treatment reverts the immunosuppressive TME by reducing MDSCs and TAMs, while increasing infiltration of neutrophils and CD8+ T cells. Methods: VSV-S was used to treat TNBC in an orthotopic mouse model, and in a combination therapy with an anti-PD-1 antibody to treat metastatic TNBC in a mouse model. Changes in the TME were evaluated. Results: In this current study, we show that neoadjuvant VSV-S treatment of primary orthotopic TNBC tumors in mice drastically lowered lung metastasis after surgical removal of the primary tumor, and significantly increased the survival rate. The mechanism of action and changes to the TME were delineated, among which one significant marker is the elevation of PD-L1 expression in tumors. In the TNBC lung metastasis mouse model, pulmonary treatment with VSV-S greatly enhanced the efficacy of ICI treatment. Conclusions: Our results suggest that the combination of oncolytic virus and ICI therapies has the potential to substantially improve the outcome of TNBC treatment. [ABSTRACT FROM AUTHOR]