Osteoporosis is a chronic disease with high unmet medical need. It is characterized by low bone mass and deteriorated bone architecture, leading to increased risk of fragility fractures, with vertebral and hip fractures representing the highest risk of morbidity and mortality. The baseline therapeutic approach to osteoporosis treatment has been based on adequate intake of calcium and supplementation of vitamin D. In this review, we focus on two approved monoclonal antibodies, romosozumab and denosumab, which have been shown to be efficient and safe options to prevent patient fractures. Romosozumab is a humanized monoclonal antibody IgG2 isotype that extracellularly binds sclerostin with high affinity and specificity. Denosumab is a fully human monoclonal antibody IgG2 isotype that binds RANK ligand (RANKL) and prevents the interaction of RANKL with its receptor RANK. Denosumab is an antiresorptive that has been used for more than a decade, and romosozumab has recently been approved for clinical practice worldwide.

On January 25, 2022, the U.S. Food and Drug Administration (FDA) approved the use of tebentafusp, a bispecific glycoprotein 100 (gp100) peptide-human leukocyte antigen (HLA)-directed CD3 T-cell activator, for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma (mUM). Pharmacodynamic data indicate that tebentafusp targets a specific HLA-A*02:01/gp100 complex, activating both CD4+/CD8+ effector and memory T cells that induce tumor cell death. Tebentafusp is administered to patients via intravenous infusion daily or weekly, depending on the indication. Phase III trials have documented a 1-year overall survival of 73%, overall response rate of 9%, progression-free survival of 31% and disease control rate of 46%. Common adverse events reported are cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache and vomiting. Compared to other types of melanomas, mUM presents with a distinct profile of genetic mutations, which phenotypically results in limited survival efficacy when using traditional melanoma treatments. The low current treatment efficacy for mUM, alongside a poor long-term prognosis and high mortality rates, gives precedence for the approval of tebentafusp to be groundbreaking in its clinical impact. This review will discuss the pharmacodynamic and pharmacokinetic profile, and the clinical trials used to evaluate the safety and efficacy of tebentafusp.

Nearly two-thirds of patients with non-small cell lung cancer (NSCLC) have locally advanced or metastatic disease at the time of diagnosis, and many patients with early-stage disease will eventually experience metastatic recurrence. In the absence of a known driver alteration, treatment of metastatic NSCLC is limited to immunotherapy with or without cytotoxic chemotherapy. For most patients with locally advanced unresectable NSCLC, the standard of care involves concurrent chemoradiation followed by consolidative immunotherapy. Several immune checkpoint inhibitors have been developed and approved for NSCLC in both the metastatic and adjuvant settings. This review will discuss sugemalimab, a novel programmed cell death 1 ligand 1 (PD-L1) inhibitor, for the treatment of advanced NSCLC.

In recent years, the role of interleukin-17 (IL-17) in orchestrating and manipulating proinflammatory immune responses has received special attention. It has become apparent from murine studies and clinical trials that due to its inhibitory effect on immunoregulation and its stimulatory action on promoting proinflammatory responses, IL-17 is an ideal cytokine to target for drug development, in order to cease its induction or eliminate IL-17-producing cells of any kind. Several monoclonal antibodies have been developed and tested as potent inhibitors of IL-17 in various inflammatory diseases. This review summarizes data from relevant clinical trials on recent developments of the application of inhibitors of IL-17 in psoriasis and psoriatic arthritis, namely secukinumab, ixekizumab, bimekizumab and brodalumab.

Mitapivat, an oral first-in-class activator of erythrocyte pyruvate kinase (PKR), was first investigated in patients with pyruvate kinase deficiency (PKD), where it was found to improve hemoglobin (Hb) concentrations in patients who did not regularly receive transfusions and to reduce transfusion burden in patients who receive regular transfusions. It was approved in 2022 for the treatment of PKD and is being explored in other hereditary chronic conditions that are associated with hemolytic mechanisms of anemia, such as sickle cell disease (SCD) and thalassemia. In a proof-of-concept phase I study in SCD, treatment with mitapivat demonstrated efficacy in increasing Hb concentrations, but also restored the thermostability of PKR, increasing its activity and decreasing 2,3-diphosphoglycerate (2,3-DPG) levels in sickle erythrocytes, which decreases Hb polymerization by increasing the affinity of Hb to oxygen. In thalassemia, mitapivat is hypothesized to increase adenosine triphosphate (ATP) production and mitigate harmful effects on red blood cells. This hypothesis is supported by preclinical data showing that mitapivat ameliorated ineffective erythropoiesis, iron overload and anemia in the Hbbth3/+ murine model of β-thalassemia intermedia. The efficacy and safety of mitapivat were confirmed in an open-label, multicenter, phase II study of patients with non-transfusion-dependent α-thalassemia or β-thalassemia, where activation of PKR improves anemia, and the drug showed a tolerable safety profile comparable to that in previous studies in other hemolytic anemias. Together, these efficacy and safety results provide rationale for continuing investigation of mitapivat for the treatment of thalassemia and SCD, developing other PK activators and starting investigational studies in other acquired diseases characterized by dyserythropoiesis and hemolytic anemia.

Dry eye disease (DED) is the most common ocular surface disorder affecting millions of people worldwide. Due to its chronic nature, the management of DED still represents a challenge in the ophthalmic practice. Nerve growth factor (NGF), which is expressed along with its high-affinity TrkA receptor on the ocular surface complex, has been widely studied for the treatment of neurotrophic keratopathy, and a novel recombinant human NGF (rhNGF) has recently received full market authorization in this setting. Since NGF has shown in both in vitro and in vivo studies to promote corneal healing, to enhance conjunctival epithelium differentiation and mucin secretion, and to stimulate tear film production and functionality, it could provide potential benefits also in patients with DED. A recent phase II clinical trial has assessed the role of rhNGF in DED patients, demonstrating significant improvements of DED signs and symptoms after 4 weeks of treatment. Further clinical evidence will be provided by the 2 ongoing phase III clinical trials. This review aims at comprehensively illustrating the rationale of use along with the efficacy and safety profile of topical NGF in patients with DED.

On November 8, 2022, the United States Food and Drug Administration (FDA) issued an emergency use authorization for the interleukin-1 (IL-1) inhibitor anakinra for the treatment of patients with COVID-19 pneumonia. The authorization was specifically intended for patients requiring supplemental oxygen who are at risk of progression to respiratory failure and are likely to have an elevated plasma soluble urokinase plasminogen activator receptor. Anakinra is a modified, recombinant human IL-1 receptor antagonist used to treat rheumatoid arthritis, neonatal-onset multisystem inflammatory disease and other inflammatory diseases. This manuscript examines what is known about the role of IL-1 receptor antagonism in the treatment of patients with COVID-19 and examines how anakinra may be used in the future to address the SARS-CoV-2 infection pandemic.

The Organization for Professionals in Regulatory Affairs (TOPRA) celebrated its 2022 Annual Symposium, which took place in Vienna, Austria, from October 17 to 19, 2022, to discuss most relevant current issues and debate the future of healthcare regulatory affairs for medicinal products, medical devices/in vitro diagnostics (IVDs) and veterinary medicines.

On March 23, 2022, the U.S. Food and Drug Administration (FDA) approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan), also known as 177Lu-PSMA-617, for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) who have highly expressed prostate-specific membrane antigen (PSMA) and have at least one metastatic lesion. It is the first FDA-approved targeted radioligand therapy for eligible men with PSMA-positive mCRPC. Lutetium Lu 177 vipivotide tetraxetan is a radioligand that strongly binds to PSMA, making it ideal for treating cancers of the prostate by targeted radiation, resulting in DNA damage and cell death. PSMA is overexpressed in cancer cells while being lowly expressed in normal tissues, which makes it an ideal theranostic target. As precision medicine advances, this is a thrilling turning point for highly individualized treatments. This review aims to summarize the pharmacology and clinical studies of the novel drug lutetium Lu 177 vipivotide tetraxetan for the treatment of mCRPC, emphasizing its mechanism of action, pharmacokinetics and safety.

Savolitinib is a highly selective MET tyrosine kinase inhibitor. MET is involved in numerous cellular processes such as proliferation, differentiation and the formation of distant metastases. MET amplification and MET overexpression are quite common in many cancers, but MET exon 14 skipping alteration is most common in non-small cell lung cancer (NSCLC). The role of MET signaling as a bypass pathway in the development of acquired resistance to tyrosine kinase inhibitor (TKI) epidermal growth factor receptor (EGFR) therapy in cancer patients with EGFR gene mutation was documented. Potential beneficiaries of savolitinib therapy are patients with NSCLC and initial diagnosis of MET ex 14 skipping mutation. Savolitinib therapy can be effective in NSCLC patients with EGFR-mutant MET with progression during first-line treatment with an EGFR-TKI. Antitumor activity of savolitinib in combination with osimertinib is very promising as first-line therapy of patients with advanced EGFR-mutated NSCLC, initially with MET expression. The safety profile of savolitinib as monotherapy and in combination with osimertinib or gefitinib is so favorable in all available studies that this drug has become a very promising therapeutic option and is being intensively investigated in ongoing clinical trials.

While treatment options for multiple myeloma (MM) are continuing to expand, this disease remains one characterized by requiring multiple lines of therapy, with generally decreasing effectiveness of each subsequent line. The development of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy has proven an exception to this rule. In the trial that led to approval of the BCMA CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel) by the U.S. Food and Drug Administration (FDA), deep and durable response rates were observed in heavily pretreated patients. In this review we summarize the available clinical trial data for cilta-cel, including discussion on notable adverse events, as well as discuss ongoing studies that are likely to lead to paradigm changes in the management of MM. In addition, we discuss the issues that currently surround the real-world utilization of cilta-cel.

Melanoma is a highly lethal type of skin cancer. Although an early diagnosis, in combination with surgery for nonmetastatic melanomas, significantly increases the probability of survival, there are no efficacious treatments for metastatic melanoma. Nivolumab and relatlimab are monoclonal antibodies that selectively interact with and block the proteins programmed cell death protein 1 (PD-1) and lymphocyte activation protein 3 (LAG-3), respectively, and thus, their activation by their cognate ligands. The combination of these immunotherapy drugs was approved in 2022 by the United States Food and Drug Administration (FDA) for the treatment of melanoma. Data from clinical trials indicated that, compared to nivolumab monotherapy, nivolumab and relatlimab produced more than a 2-fold median increase in progression-free survival (PFS) and a higher response rate in melanoma patients. This is an important finding as the response of patients to immunotherapies is limited due to dose-limiting toxicities and secondary drug resistance. This review article will discuss the pathogenesis of melanoma and the pharmacology of nivolumab and relatlimab. In addition, we will provide i) a summary of the anticancer drugs that inhibit LAG-3 and PD-1 in cancer patients and ii) our perspective about the use of nivolumab in combination with relatlimab to treat melanoma.

Hepatocellular carcinoma (HCC) is a global healthcare problem, with a high prevalence in nonindustrialized countries and a rising incidence in industrialized countries. Sorafenib demonstrated its efficacy as the first therapeutic agent for unresectable HCC in 2007. Since then, other multitarget tyrosine kinase inhibitors have demonstrated efficacy in HCC patients. Still, the tolerability of these drugs remains an unsolved problem, with 5-20% of patients permanently discontinuing their therapies due to adverse events. Donafenib is a deuterated form of sorafenib exploiting the increased bioavailability derived from the deuterium-for-hydrogen replacement. In the multicenter, randomized, controlled phase II-III trial ZGDH3, donafenib outperformed sorafenib in terms of overall survival, with favorable safety and tolerability. As a result, donafenib was approved as a possible first-line treatment of unresectable HCC by the National Medical Products Administration (NMPA) of China in 2021. In this monograph, we review the main preclinical and clinical evidence that emerged in the trials of donafenib.

Clascoterone is a novel topical antiandrogen medication approved for the treatment of acne. Conventional oral antiandrogen treatments targeting acne such as combined oral contraceptives and spironolactone exert systemic hormonal effects which commonly preclude their usage in male patients while hampering their application in certain female patients. In contrast, clascoterone is a first-in-class antiandrogen proven to be both safe and effective for female and male patients above the age of 12. Outside of occasional localized skin irritation, clascoterone is usually well tolerated, however, some adolescents in a phase II clinical trial experienced biochemical evidence of HPA suppression, which resolved after discontinuing treatment. In this review, we provide an overview of clascoterone including its preclinical pharmacology, pharmacokinetics and metabolism, safety, clinical studies and indications.

Metachromatic leukodystrophy (MLD) is a rare autosomal recessive disorder of sphingolipid metabolism, due to a deficiency of the enzyme arylsulfatase A (ARSA). The main clinical signs of the disease are secondary to central and peripheral nervous system demyelination. MLD is subdivided into early- and late-onset subtypes based upon the onset of neurological disease. The early-onset subtype is associated with a more rapid progression of the disease that leads to death within the first decade of life. Until recently, no effective treatment was available for MLD. The blood-brain barrier (BBB) prevents systemically administered enzyme replacement therapy from reaching target cells in MLD. The evidence for the efficacy of hematopoietic stem cell transplantation is limited to the late-onset MLD subtype. Here, we review the preclinical and clinical studies that facilitated the approval of the ex vivo gene therapy atidarsagene autotemcel for early-onset MLD by the European Medicines Agency (EMA) in December 2020. This approach was studied in an animal model first and then in a clinical trial, eventually proving its efficacy in preventing disease manifestations in presymptomatic patients and stabilizing its progression in paucisymptomatic subjects. This new therapeutic consists of patients' CD34+ hematopoietic stem/progenitor cells (HSPCs) transduced with a lentiviral vector encoding functional ARSA cDNA. The gene-corrected cells get reinfused into the patients after a cycle of chemotherapy conditioning.