[Innovative therapies for treatment of invasive fungal diseases]. / Invasive Mykosen ­ Innovative Therapien.

Invasive fungal diseases (IFD) are difficult to treat and pose a significant threat to immunocompromised individuals. Current antifungal agents face limitations, including antifungal resistance and adverse effects. This review aims to give a comprehensive overview of emerging treatment strategies.Novel drugs in development are Ibrexafungerp, an orally available triterpenoid inhibiting glucan synthesis, and Rezafungin representing the echinocandins with extended half-life and improved tissue penetration, both recently licensed for certain indications. Fosmanogepix targets glycosylphosphatidylinositol biosynthesis, while Olorofim, an orotomide, inhibits fungal nucleic acid synthesis, both currently assessed in advanced clinical trials.Immunotherapeutic approaches include immune checkpoint inhibitors to enhance immune response in immunosuppressed individuals and fungal-specific allogeneic CAR-T cell therapy. For prophylactic purpose in high-risk populations to develop IFD, monoclonal antibodies against different virulence factors of Candida spp. have been discovered but are not yet seen in clinical trials. Vaccines against distinct fungal antigens as well as pan fungal vaccines to prevent IFD are under development in preclinical stages, notably for Candida spp., Cryptococcus spp., and Aspergillus spp., however, their clinical value is still discussed.In summary, major advances to treat IFD have been observed, but challenges for their establishment in the clinical routine persist.

Access to innovative therapies in pediatric oncology: Report of the nationwide experience in Canada.

BACKGROUND: The need for new therapies to improve survival and outcomes in pediatric oncology along with the lack of approval and accessible clinical trials has led to "out-of-trial" use of innovative therapies. We conducted a retrospective analysis of requests for innovative anticancer therapy in Canadian pediatric oncology tertiary centers for patients less than 30 years old between 2013 and 2020. METHODS: Innovative therapies were defined as cancer-directed drugs used (a) off-label, (b) unlicensed drugs being used outside the context of a clinical trial, or (c) approved drugs with limited evidence in pediatrics. We excluded cytotoxic chemotherapy, cellular products, and cytokines. RESULTS: We retrieved data on 352 innovative therapy drug requests. Underlying diagnosis was primary CNS tumor 31%; extracranial solid tumor 37%, leukemia/lymphoma 22%, LCH 2%, and plexiform neurofibroma 6%. RAS/MAP kinase pathway inhibitors were the most frequently requested innovative therapies in 28% of all requests followed by multi-targeted tyrosine kinase inhibitors (17%), inhibitors of the PIK3CA-mTOR-AKT pathway (8%), immune checkpoints inhibitors (8%), and antibody drug conjugates (8%). In 112 out of 352 requests, innovative therapies were used in combination with another anticancer agent. 48% of requests were motivated by the presence of an actionable molecular target. Compassionate access accounted for 52% of all requests while public insurance was used in 27%. Mechanisms of funding varied between provinces. CONCLUSION: This real-world data collection illustrates an increasing use of "out-of-trial" innovative therapies in pediatric oncology. This new field of practice warrants further studies to understand the impact on patient trajectory and equity in access to innovative therapies.

Regulating ethical experimentation: Impacts of the breakthrough therapy designation on drug R&D.

This article investigates patterns of pharmaceutical development activity around the 2012 creation of the FDA's Breakthrough Therapy Designation (BTD). The BTD introduced regulatory flexibility and support to avoid ethical challenges created by experimental therapies of exceptional performance in early stage clinical trials. We argue that the program's design indirectly created substantial incentives for the industry to pursue the designation. Consistent with this hypothesis, our evidence links the creation of the program with a substantial increase in the number of new drug indications entering the clinical trial process. This surge in introductions has resulted in a discernible increase in approvals, which has manifested with a lag and may strengthen in the future. Countering theoretical predictions, BTD incentives have not led to increased risk taking in project selection.

Myasthenia Gravis Treatment: From Old Drugs to Innovative Therapies with a Glimpse into the Future.

Myasthenia gravis (MG) is a rare autoimmune disease that causes debilitating muscle weakness due to impaired neuromuscular transmission. Since most (about 80-90%) MG patients present autoantibodies against the acetylcholine receptor, standard medical therapy consists of symptomatic treatment with acetylcholinesterase inhibitors (e.g., pyridostigmine). In addition, considering the autoimmune basis of MG, standard therapy includes immunomodulating agents, such as corticosteroids, azathioprine, cyclosporine A, and cyclophosphamide. New strategies have been proposed for the treatment of MG and include complement blockade (i.e., eculizumab, ravulizumab, and zilucoplan) and neonatal Fc receptor antagonism (i.e., efgartigimod and rozanolixizumab). The aim of this review is to provide a detailed overview of the pre- and post-marketing evidence on the five pharmacological treatments most recently approved for the treatment of MG, by identifying both preclinical and clinical studies registered in clinicaltrials.gov. A description of the molecules currently under evaluation for the treatment of MG is also provided.

Academic challenges on advanced therapy medicinal products' development: a regulatory perspective.

Advanced therapy medicinal products (ATMPs) are becoming the new kid on the block for the treatment of a variety of indications with promising results. Despite the academic contribution to the basic and clinical research of ATMPs, undertaking a full product development process is extraordinarily challenging and demanding for academic institutions. Meeting regulatory requirements is probably the most challenging aspect of academic development, considering the limited experience and resources compared with pharmaceutical companies. This review aims to outline the key aspects to be considered when developing novel ATMPs from an academic perspective, based on the results of our own experience and interaction with the Spanish Agency of Medicines and Medical Devices (AEMPS) and European Medicine Agency (EMA) related to a number of academic ATMP initiatives carried out at our center during the last 5 years. Emphasis is placed on understanding the regulatory requirements during the early phases of the drug development process, particularly for the preparation of a Clinical Trial Application. Academic centers usually lack expertise in product-related documentation (such as the Investigational Medicinal Product Dossier), and therefore, early interaction with regulators is crucial to understand their requirements and receive guidance to comply with them. Insights are shared on managing quality, nonclinical, clinical, and risk and benefit documentation, based on our own experience and challenges. This review aims to empower academic and clinical settings by providing crucial regulatory knowledge to smooth the regulatory journey of ATMPs.

APOLLO 11 Project, Consortium in Advanced Lung Cancer Patients Treated With Innovative Therapies: Integration of Real-World Data and Translational Research.

INTRODUCTION: Despite several therapeutic efforts, lung cancer remains a highly lethal disease. Novel therapeutic approaches encompass immune-checkpoint inhibitors, targeted therapeutics and antibody-drug conjugates, with different results. Several studies have been aimed at identifying biomarkers able to predict benefit from these therapies and create a prediction model of response, despite this there is a lack of information to help clinicians in the choice of therapy for lung cancer patients with advanced disease. This is primarily due to the complexity of lung cancer biology, where a single or few biomarkers are not sufficient to provide enough predictive capability to explain biologic differences; other reasons include the paucity of data collected by single studies performed in heterogeneous unmatched cohorts and the methodology of analysis. In fact, classical statistical methods are unable to analyze and integrate the magnitude of information from multiple biological and clinical sources (eg, genomics, transcriptomics, and radiomics). METHODS AND OBJECTIVES: APOLLO11 is an Italian multicentre, observational study involving patients with a diagnosis of advanced lung cancer (NSCLC and SCLC) treated with innovative therapies. Retrospective and prospective collection of multiomic data, such as tissue- (eg, for genomic, transcriptomic analysis) and blood-based biologic material (eg, ctDNA, PBMC), in addition to clinical and radiological data (eg, for radiomic analysis) will be collected. The overall aim of the project is to build a consortium integrating different datasets and a virtual biobank from participating Italian lung cancer centers. To face with the large amount of data provided, AI and ML techniques will be applied will be applied to manage this large dataset in an effort to build an R-Model, integrating retrospective and prospective population-based data. The ultimate goal is to create a tool able to help physicians and patients to make treatment decisions. CONCLUSION: APOLLO11 aims to propose a breakthrough approach in lung cancer research, replacing the old, monocentric viewpoint towards a multicomprehensive, multiomic, multicenter model. Multicenter cancer datasets incorporating common virtual biobank and new methodologic approaches including artificial intelligence, machine learning up to deep learning is the road to the future in oncology launched by this project.

Molecular Mechanisms in Pathophysiology of Mucopolysaccharidosis and Prospects for Innovative Therapy.

Mucopolysaccharidoses (MPSs) are a group of inborn errors of the metabolism caused by a deficiency in the lysosomal enzymes required to break down molecules called glycosaminoglycans (GAGs). These GAGs accumulate over time in various tissues and disrupt multiple biological systems, including catabolism of other substances, autophagy, and mitochondrial function. These pathological changes ultimately increase oxidative stress and activate innate immunity and inflammation. We have described the pathophysiology of MPS and activated inflammation in this paper, starting with accumulating the primary storage materials, GAGs. At the initial stage of GAG accumulation, affected tissues/cells are reversibly affected but progress irreversibly to: (1) disruption of substrate degradation with pathogenic changes in lysosomal function, (2) cellular dysfunction, secondary/tertiary accumulation (toxins such as GM2 or GM3 ganglioside, etc.), and inflammatory process, and (3) progressive tissue/organ damage and cell death (e.g., skeletal dysplasia, CNS impairment, etc.). For current and future treatment, several potential treatments for MPS that can penetrate the blood-brain barrier and bone have been proposed and/or are in clinical trials, including targeting peptides and molecular Trojan horses such as monoclonal antibodies attached to enzymes via receptor-mediated transport. Gene therapy trials with AAV, ex vivo LV, and Sleeping Beauty transposon system for MPS are proposed and/or underway as innovative therapeutic options. In addition, possible immunomodulatory reagents that can suppress MPS symptoms have been summarized in this review.

Challenges and opportunities in spinal muscular atrophy therapeutics.

Spinal muscular atrophy was the most common inherited cause of infant death until 2016, when three therapies became available: the antisense oligonucleotide nusinersen, gene replacement therapy with onasemnogene abeparvovec, and the small-molecule splicing modifier risdiplam. These drugs compensate for deficient survival motor neuron protein and have improved lifespan and quality of life in infants and children with spinal muscular atrophy. Given the lifelong implications of these innovative therapies, ways to detect and manage treatment-modified disease characteristics are needed. All three drugs are more effective when given before development of symptoms, or as early as possible in individuals who have already developed symptoms. Early subtle symptoms might be missed, and disease onset might occur in utero in severe spinal muscular atrophy subtypes; in some countries, newborn screening is allowing diagnosis soon after birth and early treatment. Adults with spinal muscular atrophy report stabilisation of disease and less fatigue with treatment. These subjective benefits need to be weighed against the high costs of the drugs to patients and health-care systems. Clinical consensus is required on therapeutic windows and on outcome measures and biomarkers that can be used to monitor drug benefit, toxicity, and treatment-modified disease characteristics.

Chloroquine and Chemotherapeutic Compounds in Experimental Cancer Treatment.

Chloroquine (CQ) and its derivate hydroxychloroquine (HCQ), the compounds with recognized ability to suppress autophagy, have been tested in experimental works and in clinical trials as adjuvant therapy for the treatment of tumors of different origin to increase the efficacy of cytotoxic agents. Such a strategy can be effective in overcoming the resistance of cancer cells to standard chemotherapy or anti-angiogenic therapy. This review presents the results of the combined application of CQ/HCQ with conventional chemotherapy drugs (doxorubicin, paclitaxel, platinum-based compounds, gemcitabine, tyrosine kinases and PI3K/Akt/mTOR inhibitors, and other agents) for the treatment of different malignancies obtained in experiments on cultured cancer cells, animal xenografts models, and in a few clinical trials. The effects of such an approach on the viability of cancer cells or tumor growth, as well as autophagy-dependent and -independent molecular mechanisms underlying cellular responses of cancer cells to CQ/HCQ, are summarized. Although the majority of experimental in vitro and in vivo studies have shown that CQ/HCQ can effectively sensitize cancer cells to cytotoxic agents and increase the potential of chemotherapy, the results of clinical trials are often inconsistent. Nevertheless, the pharmacological suppression of autophagy remains a promising tool for increasing the efficacy of standard chemotherapy, and the development of more specific inhibitors is required.

Precarious hope: Ethical considerations for offering experimental fetal therapies outside of research after initial studies in humans.

OBJECTIVE: Risks and benefits of experimental fetal therapies can remain uncertain after initial clinical studies, especially long-term effects. Nevertheless, pregnant individuals may request them, hoping to benefit their future child. Guidance about offering experimental fetal therapies outside research (as "innovative therapy") is limited, despite their ethical complexity. We propose points for clinicians and reviewers to consider when deciding whether and how to offer experimental fetal therapies as innovative therapies after initial clinical studies. METHOD: We used conceptual analysis and a current case to develop points for consideration, grounded in broader debates on innovative therapy and the unique challenges associated with experimental fetal therapies. RESULTS: Clinicians should evaluate whether offering experimental fetal therapies as innovative therapy is appropriate for a pregnant individual and their fetus. The anticipated risk-benefit ratio for the fetus should be favorable. For the pregnant individual, risks may outweigh benefits, within reasonable limits. Medical resources should be sufficient to ensure appropriate care. Clinicians should support pregnant individuals in making informed choices. Clinicians offering innovative therapies with more than minimal risk should collect and report data on outcomes. Independent review should take place. CONCLUSION: Considering these points may advance the interests of fetuses, future children, and their families.

Restoration of vision by combined experimental antithymocyte therapy, and orbital radiation with high-dose steroids for severe, acute, steroid-refractory, congestive thyroid orbitopathy.

PURPOSE: We report diagnostic and therapeutic dilemmas in the difficult case of compressive optic neuropathy with severe visual acuity and visual field loss with subsequent visual recovery in both eyes, in a patient with Graves' orbitopathy (GO) by a combination of experimental antithymocyte therapy, orbital radiotherapy with high-dose steroids. METHODS: A 72-year-old man presented with severe vision loss in both eyes. The visual symptoms had appeared over a year before the GO diagnosis. He was initially misdiagnosed with neuroborreliosis and optic neuritis based on brain and orbital magnetic resonance imaging. There was no exophthalmos. The ophthalmological examination included visual acuity, visual field, tonometry in primary and upgaze eye position, optical coherence tomography (OCT), pattern electroretinogram (PERG), pattern, and flash visual evoked potentials (PVEP and FVEP). The patient received experimental therapy with ATG, followed by high-dose of intravenous steroids and orbital radiotherapy. RESULTS: Delayed VEP peaks became shorter after treatment. After systemic and local therapy lowering of intraocular pressure was achieved. Abnormal PERG has been found three months before ganglion cells atrophy was detected in OCT. Visual acuity and visual field improvement occurred in both eyes after therapy, despite partial left optic nerve atrophy. The patient regained full decimal visual acuity (1.0 right from as poor as 0.3  to 1.0 in the right eye and from hand movements to 0.9 in the left. Severe visual field loss with advanced absolute scotomata has improved to slight relative scotomata. The duration of follow-up time after the treatment was 4 months. CONCLUSIONS: Intensive treatment of steroid-resistant Graves' orbitopathy (GO) may prevent total optic nerve atrophy. Despite severely advanced optic neuropathy, this report emphasizes the necessity of therapy even with nearly complete visual function loss hence there is always a possibility to regain full visual acuity and visual field. Patients with tense orbital septum may not present with significant exophthalmos, thus delaying the correct diagnosis of orbitopathy. A supporting sign of GO was the difference in intraocular pressure in the primary and upgaze eye positions. Electrophysiological examinations are helpful in the diagnosis and monitoring of GO therapy. To our knowledge, this is the first report of this kind presenting visual function restoration and structural recovery in a patient with advanced optic neuropathy in GO.

[Place of innovative therapies in the management of cervical cancer]. / Place des thérapies innovantes dans la prise en charge des cancers du col de l'utérus.

Despite optimized screening and prevention strategies, cervical cancer remains a major public health problem, even in developed countries. In France, the incidence is estimated at 3159 cases per year in 2023. While the management of early-stage cases is now highly standardized, few therapeutic advances were made in the treatment of metastatic stages before 2021, before the therapeutic arsenal that we know today took off. The aim of this review is to summarize these advances.

Establishing a multi-specialty consensus in the clinical need for hypercholesterolemia management and its implication for patients access to innovative therapies.

BACKGROUND: Increased level of blood LDL-C has a causal and cumulative effect on advancing atherosclerotic cardiovascular diseases (ASCVD). European guidelines for treating high LDL-C levels have been recently updated. However, in France, several challenges (e.g., physician and patient awareness, healthcare management) limit the application of management guidelines. The aim of this study was to understand the current opinions and perceived unmet clinical needs in recognising and managing hypercholesterolemia as an ASCVD risk factor, and to explore consensus around factors that support the effective management of elevated LDL-C. METHODS: An expert group of cardiologists, endocrinologists, biology/genetics researchers, and a health technology assessments expert, from France was convened. The current management of hypercholesterolemia and barriers to achieving LDL-C goals in France were discussed and 44 statements were developed. Wider consensus was assessed by sending the statements as a 4-point Likert Scale questionnaire to cardiologists and endocrinologists across France. The consensus threshold was defined as ≥75%. RESULTS: A total of 101 responses were received. Consensus was very high (>90%) in 25 (57%) statements, high (≥75%) in 18 (41%) statements and was not achieved (<75%) only in 1 (2%) of statements. Overall, 43 statements achieved consensus. CONCLUSIONS: Based on consensus levels, key recommendations for improving current guidelines and approaches to care have been developed. Implementation of these recommendations will lead to better concordance with international treatment guidelines and increase levels of education for healthcare practitioners and patients. In turn, this will improve the available treatment pathways for cardiovascular diseases, potentially creating improved patient outcomes in the future.

[CAR-T cells, an innovative therapy]. / Les CAR-Tcells, une thérapie innovante.

CAR-T cell therapy for patients with hematological malignancies has been practiced at the Basse-Normandie Hematology Institute since November 2022. This treatment requires the care pathway to be coordinated by the nurse coordinator. Nurses play a key role in the early diagnosis of side effects induced by this drug. Interdisciplinary collaboration and the value of teamwork are also emphasized.

Investigational treatment strategies in glioblastoma: progress made and barriers to success.

INTRODUCTION: Glioblastoma, isocitrate dehydrogenase wildtype (IDHwt), remains an incurable disease despite considerable research effort. The current standard of care since 2005 comprises maximal safe resection followed by radiation with concurrent and adjuvant temozolomide; more recently, the addition of tumor treating fields was approved in the newly diagnosed and recurrent disease settings. AREAS COVERED: Searches of PubMed, Cochrane Library, and ClinicalTrials.gov provided a foundation for this review. We first describe early research including carmustine wafers, brachytherapy, anti-angiogenesis, and immune checkpoint inhibition for glioblastoma. Next, we discuss challenges precluding the translation of preclinical successes. This is followed by a description of promising treatments such as chimeric antigen receptor T-cell therapy as well as the recent qualified successes of cancer vaccinations. Non-immunotherapy trials are also highlighted, and ongoing or pending phase 2 and 3 clinical trials are codified in study tables. EXPERT OPINION: Unfortunately, hundreds of trials, including of agents effective in systemic malignancy, have not drastically changed management of glioblastoma. This may reflect unique resistance mechanisms and highlights a need for multimodality treatments beyond surgery, radiation, and conventional chemotherapy. Novel techniques, such as those in the emerging field of cancer neuroscience, may help uncover tolerable and effective regimens for this lethal malignancy.

The Therapeutic Potential of CDK4/6 Inhibitors, Novel Cancer Drugs, in Kidney Diseases.

Inflammation is a crucial pathological feature in cancers and kidney diseases, playing a significant role in disease progression. Cyclin-dependent kinases CDK4 and CDK6 not only contribute to cell cycle progression but also participate in cell metabolism, immunogenicity and anti-tumor immune responses. Recently, CDK4/6 inhibitors have gained approval for investigational treatment of breast cancer and various other tumors. Kidney diseases and cancers commonly exhibit characteristic pathological features, such as the involvement of inflammatory cells and persistent chronic inflammation. Remarkably, CDK4/6 inhibitors have demonstrated impressive efficacy in treating non-cancerous conditions, including certain kidney diseases. Current studies have identified the renoprotective effect of CDK4/6 inhibitors, presenting a novel idea and potential direction for treating kidney diseases in the future. In this review, we briefly reviewed the cell cycle in mammals and the role of CDK4/6 in regulating it. We then provided an introduction to CDK4/6 inhibitors and their use in cancer treatment. Additionally, we emphasized the importance of these inhibitors in the treatment of kidney diseases. Collectively, growing evidence demonstrates that targeting CDK4 and CDK6 through CDK4/6 inhibitors might have therapeutic benefits in various cancers and kidney diseases and should be further explored in the future.

The complement system: a novel therapeutic target for age-related macular degeneration.

INTRODUCTION: With the recent FDA approvals of pegcetacoplan (SYFOVRE, Apellis Pharmaceuticals) and avacincaptad pegol (IZERVAY, Astellas Pharmaceuticals), modulation of the complement system has emerged as a promising therapeutic approach for slowing progression of geographic atrophy (GA) in AMD. AREAS COVERED: This article reviews the current understanding of the complement system, its role in AMD, and the various complement-targeting therapies in development for the treatment of GA, including monoclonal antibodies, aptamers, protein analogs, and gene therapies. Approved and investigational agents have largely focused on interfering with the activity of complement components 3 and 5, owing to their central roles in the classical, lectin, and alternative complement pathways. Other investigational therapies have targeted formation of membrane attack complex (a terminal step in the complement cascade which leads to cell lysis), complement factors H and I (which serve regulatory functions in the alternative pathway), complement factors B and D (within the alternative pathway), and complement component 1 (within the classical pathway). Clinical trials investigating these agents are summarized, and the potential benefits and limitations of these therapies are discussed. EXPERT OPINION: Targeting the complement system is a promising therapeutic approach for slowing the progression of GA in AMD, potentially improving visual outcomes. However, increased risk of exudative conversion must be considered, and further research is required to identify clinical criteria and best practices for initiating complement inhibitor therapy for GA.

Protecting Medicare's Discretion to Say No to Unproven Therapies.

In this Viewpoint, Kesselheim and coauthors discuss 2 bills in Congress that would curtail Medicare's ability to decline, limit, or conditionally cover medical products that lack robust evidence and argue that officials should distinguish between better and worse therapies when determining reimbursement.

Metastasis organotropism in colorectal cancer: advancing toward innovative therapies.

Distant metastasis remains a leading cause of mortality among patients with colorectal cancer (CRC). Organotropism, referring to the propensity of metastasis to target specific organs, is a well-documented phenomenon in CRC, with the liver, lungs, and peritoneum being preferred sites. Prior to establishing premetastatic niches within host organs, CRC cells secrete substances that promote metastatic organotropism. Given the pivotal role of organotropism in CRC metastasis, a comprehensive understanding of its molecular underpinnings is crucial for biomarker-based diagnosis, innovative treatment development, and ultimately, improved patient outcomes. In this review, we focus on metabolic reprogramming, tumor-derived exosomes, the immune system, and cancer cell-organ interactions to outline the molecular mechanisms of CRC organotropic metastasis. Furthermore, we consider the prospect of targeting metastatic organotropism for CRC therapy.

Advances in the Pathogenesis and Treatment of Resistant Hypertension.

Hypertension is a prevalent chronic disease associated with an increased risk of cardiovascular (CV) premature death, and its severe form manifests as resistant hypertension (RH). The accurate prevalence of resistant hypertension is difficult to determine due to the discrepancy in data from various populations, but according to recent publications, it ranges from 6% to 18% in hypertensive patients. However, a comprehensive understanding of the pathogenesis and treatment of RH is essential. This review emphasizes the importance of identifying the causes of treatment resistance in antihypertensive therapy and highlights the utilization of appropriate diagnostic methods. We discussed innovative therapies such as autonomic neuromodulation techniques like renal denervation (RDN) and carotid baroreceptor stimulation, along with invasive interventions such as arteriovenous anastomosis as potential approaches to support patients with inadequate medical treatment and enhance outcomes in RH.