Gefapixant: First Approval.

Gefapixant (Lyfnua®; Merck & Co.) is a first-in-class, non-narcotic, selective P2X3 receptor antagonist being developed for the treatment of refractory chronic cough or unexplained chronic cough. Marketing approval for gefapixant is being sought in the EU and USA, and the drug was recently approved for marketing in Japan as treatment for refractory or unexplained chronic cough. This article summarizes the milestones in the development of gefapixant leading to this first approval.

Daridorexant: First Approval.

Daridorexant (Quviviq™; Idorsia Pharmaceuticals Ltd.) is an orally administered dual orexin type 1 and type 2 (OX1 and OX2) receptor antagonist (DORA) being developed for the treatment of insomnia. It was selected from a pool of drug candidates on the basis of an expected effect duration of ≈ 8 h at a dose of 25 mg, with a half-life intended to minimize residual effects that might impair daytime functioning. Based on the results of two pivotal phase III trials, daridorexant was recently approved in the USA for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. This article summarizes the milestones in the development of daridorexant leading to this first approval.

Cabozantinib plus Nivolumab: A Review in Advanced Renal Cell Carcinoma.

Dual therapy with a tyrosine kinase inhibitor (TKI) and either a programmed death protein/ligand 1 (PD-1/PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor has proven efficacy as treatment for previously-untreated advanced renal cell carcinoma (RCC). The combination of the multi-targeted TKI cabozantinib (Cabometyx®) and the anti-PD-1 monoclonal antibody nivolumab (Opdivo®) is approved as first line treatment for RCC in the EU, USA and multiple other countries. In the CheckMate 9ER trial, combination therapy with cabozantinib and nivolumab was superior to sunitinib monotherapy as first line treatment for advanced RCC, demonstrating significantly longer progression-free survival and, importantly, improved overall survival. Patients receiving the combination were also more likely to respond than those treated with sunitinib monotherapy. In addition, health-related quality of life was significantly better with cabozantinib plus nivolumab at nearly all time points during the study. The tolerability profile of the combination was consistent with that seen in previous studies evaluating the two drugs as monotherapy, although more patients who received the combination had serious adverse events than those treated with sunitinib monotherapy. In summary, cabozantinib plus nivolumab is a recommended option for first-line treatment of previously-untreated advanced RCC.

Advanced renal cell carcinoma (RCC) is a difficult-to-treat disease with a poor prognosis. The introduction of targeted therapy and, subsequently, treatments that boost or restore the patient's natural immune response to cancer (immunotherapy), however, has led to improved outcomes. In particular, combination treatment with a targeted therapy drug and an immunotherapeutic agent has been shown to significantly improve overall survival compared to targeted therapy alone. Dual therapy with the tyrosine kinase inhibitor cabozantinib (Cabometyx^®) and the PD-1 inhibitor nivolumab (Opdivo^®) is approved for the first line treatment of advanced RCC in multiple countries. In the CheckMate 9ER trial, cabozantinib plus nivolumab significantly improved progression-free and overall survival in patients with previously untreated RCC compared to monotherapy with an older drug (sunitinib). The combination was also associated with better quality of life than sunitinib monotherapy. Although the tolerability profile of the combination was consistent with that seen in previous studies evaluating the two drugs as monotherapy, more patients who received the combination had serious adverse events than those treated with sunitinib. In summary, cabozantinib plus nivolumab is a recommended option for first-line treatment of previously-untreated advanced RCC.

Envafolimab: First Approval.

Envafolimab (®) is a subcutaneously (SC) administered single domain anti-programmed death ligand 1 (PD-L1) antibody being developed for the treatment of various solid tumours and chronic hepatitis B in China, and for soft tissue sarcomas and biliary tract cancer in the USA. Single-domain antibodies are more soluble and more rapidly penetrate tissues than full monoclonal antibodies, enabling SC administration. Based on the results of a pivotal phase II trial, SC envafolimab was recently approved in China for the treatment of adult patients with previously-treated microsatellite instability-high (MSI-H) or deficient MisMatch Repair (dMMR) advanced solid tumours. This article summarizes the milestones in the development of envafolimab leading to this first approval.

Tisotumab Vedotin: First Approval.

Tisotumab vedotin (Tivdak™) is an antibody-drug conjugate comprising a fully human monoclonal antibody specific for tissue factor (TF-011) conjugated to monomethyl auristatin E (MMAE) that has been engineered to target tissue factor expressing tumours. Based on the results of a phase II trial, tisotumab vedotin has been granted accelerated approval in the USA for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. This article summarizes the milestones in the development of tisotumab vedotin leading to this first approval.

Mobocertinib: First Approval.

Mobocertinib (EXKIVITY™) is a first-in-class EGFR tyrosine kinase inhibitor being developed for the treatment of EGFR exon 20 insertion (EGFRex20ins) -positive non-small cell lung cancer (NSCLC). Based on efficacy in patients whose disease had progressed on or after platinum-based therapy in a phase I/II trial, mobocertinib was recently granted accelerated approval in the USA in this indication. The drug is also being assessed for marketing approval in various other countries and territories including the EU and China. This article summarizes the milestones in the development of mobocertinib leading to this first approval in the USA for locally advanced or metastatic EGFRex20ins-positive NSCLC that has progressed on or after platinum-based chemotherapy.

Avatrombopag: A Review in Thrombocytopenia.

Avatrombopag (Doptelet®) is an orally administered second generation thrombopoietin receptor agonist (TPO-RA) approved for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory or have an unsatisfactory response to other treatments, as well as for the treatment of thrombocytopenia in adult patients with chronic liver disease (CLD) scheduled to undergo an invasive procedure. In phase III studies, avatrombopag was associated with a significantly greater platelet response than placebo in patients with chronic ITP, and was superior to placebo in reducing the requirement for platelet transfusion or rescue procedures for bleeding caused by surgery in patients with CLD with a platelet count < 50 × 109/L at baseline. Longer term data indicate that avatrombopag is associated with high durable response rates in ITP and may have corticosteroid-sparing effects. The drug was generally well tolerated in both indications. Avatrombopag thus represents a convenient and effective second-line treatment for patients with chronic ITP and can prevent bleeding events in patients with CLD scheduled to undergo a procedure, offering a useful alternative to other available treatments in both indications.

Avatrombopag (Doptelet^®) is an orally administered drug that mimics the natural compound (thrombopoietin) responsible for stimulating the production of platelets, an essential component of the clotting process that prevents excessive bleeding. Several conditions can cause reduced platelet levels (thrombocytopenia) to the point that intervention is needed to prevent excessive blood loss. Avatrombopag is approved for the treatment of primary chronic immune thrombocytopenia (ITP) and to prevent bleeding caused by surgery in patients with low platelet levels caused by chronic liver disease (CLD). Clinical trials in patients with ITP show that avatrombopag quickly increases platelet levels and that this increase is maintained in the longer term in many patients. Similarly, clinical trials in patients with low platelet levels because of CLD showed that giving avatrombopag prior to surgery reduced the need for platelet transfusions or rescue procedures for bleeding. Avatrombopag is thus a convenient and effective treatment for patients with chronic ITP and can prevent bleeding events in patients with CLD scheduled to undergo a procedure. In both indications avatrombopag offers a useful alternative to other available treatments.

Zimberelimab: First Approval.

Zimberelimab (®) is an anti-programmed cell death protein-1 (PD-1) monoclonal antibody being developed by Gloria Biosciences, Arcus Biosciences and Taiho Pharmaceutical Co. for the treatment of various cancers including cervical cancer, non-small cell lung cancer and classical Hodgkin's lymphoma. Based on the results of a phase II trial, zimberelimab was recently approved for marketing in China as treatment for relapsed or refractory classical Hodgkin's lymphoma. This article summarizes the milestones in the development of zimberelimab leading to this first approval.

Savolitinib: First Approval.

Savolitinib (Orpathys®; HUTCHMED, AstraZeneca) is a receptor tyrosine kinase mesenchymal epithelial transition factor (MET) inhibitor being developed for the treatment of metastatic non-small cell lung cancer (NSCLC), papillary and clear cell renal cell carcinoma (RCC), gastric cancer and colorectal cancer. Based on the results of a pivotal phase II trial in patients with NSCLC/pulmonary sarcomatoid carcinoma, savolitinib was recently granted approval in China (conditional on the results of a phase III trial) for the treatment of metastatic NSCLC with MET exon 14-skipping alterations in patients who have progressed after or who are unable to tolerate platinum-based chemotherapy. This article summarizes the milestones in the development of savolitinib leading to this first approval.

Pamiparib: First Approval.

Pamiparib (PARTRUVIX™; BeiGene Ltd.) is a selective poly (ADP-ribose) polymerase 1 and 2 (PARP1 and PARP2) inhibitor being developed for the treatment of various cancers. Based on the results from the pivotal phase II portion of a phase I/II trial (NCT03333915) pamiparib was recently approved in China for the treatment of germline BRCA mutation-associated recurrent advanced ovarian, fallopian tube or primary peritoneal cancer previously treated with two or more lines of chemotherapy. This article summarizes the milestones in the development of pamiparib leading to this first approval.

Dostarlimab: First Approval.

Dostarlimab (Jemperli™; GlaxoSmithKline) is a humanized monoclonal antibody programmed death-1 (PD-1) receptor antagonist being developed for the treatment of various cancers. Based on preliminary results from the GARNET trial dostarlimab has recently been approved in the EU and USA for the treatment of adult patients with mismatch repair deficient recurrent or advanced endometrial cancer. This article summarizes the milestones in the development of dostarlimab leading to these first approvals.

Ponesimod: First Approval.

Ponesimod (PONVORY™) is an orally administered selective sphingosine-1-phosphate (S1P) receptor 1 (S1P1) agonist being developed by the Janssen Pharmaceutical Companies of Johnson & Johnson for the treatment of multiple sclerosis (MS). Based on the results of the phase III OPTIMUM trial, ponesimod was recently approved in the USA for the treatment of relapsing forms of MS and has received a positive CHMP opinion in the EU for this indication. This article summarizes the milestones in the development of ponesimod leading to this first US approval.

Evinacumab: First Approval.

The recombinant human monoclonal antibody evinacumab (evinacumab-dgnb, EVKEEZA™) is an angiopoietin-like protein three (ANGPTL3) inhibitor that has been developed by Regeneron Pharmaceuticals for the treatment of homozygous familial hypercholesterolaemia (HoFH), refractory hypercholesterolemia (both familial and non-familial) and severe hypertriglyceridaemia. Based on the results of the phase III ELIPSE HoFH trial, evinacumab was recently approved in the USA as an adjunct to other LDL-C lowering therapies for the treatment of adult and paediatric patients aged 12 years and older with HoFH, and has received a positive opinion in the EU. This article summarizes the milestones in the development of evinacumab leading to this first approval for HoFH.

Vericiguat: First Approval.

Vericiguat (VERQUVO™; Merck & Co, Bayer AG) is a soluble guanylate cyclase (sGC) stimulator being developed for the treatment of chronic heart failure. Vericiguat stimulates sGC and cGMP production independent of nitric oxide (NO) and enhances the effects of NO by stabilizing the NO-sGC binding. Based on the results of the phase III VICTORIA trial vericiguat was recently approved in the USA for risk reduction in patients with heart failure and ejection fraction < 45%. This article summarizes the milestones in the development of vericiguat leading to this first approval.

Margetuximab: First Approval.

The second-generation anti-human epidermal growth factor receptor2 protein (HER2) monoclonal antibody margetuximab (MARGENZA™, margetuximab-cmkb) is being developed for the treatment of HER2-positive breast cancer, gastric cancer and gastro-oesophageal junction cancer. The antibody has been engineered for increased binding to activating Fcγ receptor IIIA (CD16A) and decreased binding to inhibitory Fcγ receptor IIB (CD32B) relative to trastuzumab with the aim of improving response rates. Based on the results of the phase III SOPHIA trial margetuximab has been approved in the USA for use in combination with chemotherapy as treatment of previously-treated metastatic HER2-positive breast cancer. This article summarizes the milestones in the development of margetuximab leading to this first approval.

Tirbanibulin: First Approval.

Tirbanibulin (Klisyri®) is a first-in-class Src kinase signaling inhibitor and tubulin polymerisation inhibitor being developed by Athenex in conjunction with global partners for the topical treatment of actinic keratosis, and psoriasis. Based on the data from two pivotal phase III trials the drug was recently approved for marketing in the US as a topical treatment for actinic keratosis. This article summarizes the milestones in the development of tirbanibulin leading to this first approval.

Setmelanotide: First Approval.

Setmelanotide (IMCIVREE™, Rhythm Pharmaceuticals) is a melanocortin-4 (MC4) receptor agonist developed for the treatment of obesity arising from proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. The drug has received its first approval in the USA for chronic weight management in patients 6 years and older with obesity caused by POMC, PCSK1 and LEPR deficiency and has been granted PRIority MEdicines (PRIME) designation by the European Medicines Agency for the treatment of obesity and the control of hunger associated with deficiency disorders of the MC4 receptor pathway. Setmelanotide is also being developed in other rare genetic disorders associated with obesity including Bardet-Biedl Syndrome, Alström Syndrome, POMC and other MC4R pathway heterozygous deficiency obesities, and POMC epigenetic disorders. This article summarizes the milestones in the development of setmelanotide leading to this first approval for obesity caused by POMC, PCSK1 and LEPR deficiency.

Naxitamab: First Approval.

Naxitamab (DANYELZA®, naxitamab-gqgk) is a humanised (IgG1) anti-GD2 (hu3F8) monoclonal antibody was developed by the Memorial Sloan Kettering Cancer Center (with commercial rights licenced to Y-mAbs therapeutics Inc.) for the treatment of neuroblastoma, osteosarcoma and other GD2-positive cancers. Naxitamab was recently granted accelerated approval by the US FDA for marketing as treatment (in combination with granulocyte-macrophage colony-stimulating factor) for paediatric patients at least one year of age and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow demonstrating a partial response, minor response, or stable disease to prior therapy. This article summarizes the milestones in the development of naxitamab leading to this first approval.