Tovorafenib: First Approval.

Tovorafenib (OJEMDA™) is a once-weekly oral, selective, brain-penetrant, type II RAF kinase inhibitor being developed by Day One Biopharmaceuticals, Inc., under a license from Takeda Oncology, for the treatment of paediatric low-grade glioma (pLGG) and solid tumours. Most pLGGs harbour alterations in the MAPK pathway, such as a BRAF mutation or BRAF fusion, which result in aberrant intracellular signalling. Tovorafenib is an inhibitor of mutant BRAF V600E, wild-type BRAF and wild-type CRAF kinases and BRAF fusions. In April 2024, tovorafenib received its first approval in the USA for the treatment of patients aged ≥ 6 months with relapsed or refractory pLGGs harbouring a BRAF fusion or rearrangement, or BRAF V600 mutation. It received accelerated approval for this indication based on the response rate and duration of response achieved in this population in the ongoing, pivotal, phase 2 FIREFLY-1 study. Clinical development of tovorafenib is underway in numerous countries worldwide. This article summarizes the milestones in the development of tovorafenib leading to this first approval for relapsed or refractory pLGG with an activating BRAF alteration.

Tarlatamab: First Approval.

Tarlatamab (tarlatamab-dlle: IMDELLTRA™) is a first-in-class, half-life extended bispecific delta-like ligand 3 (DLL3)-directed CD3 T-cell engager being developed by Amgen for the treatment of small cell lung cancer (SCLC) and neuroendocrine prostate cancer. Tarlatamab binds to DLL3 on the surface of tumour cells and CD3 on the surface of cytotoxic T lymphocytes (CTLs), resulting in T-cell activation, release of inflammatory cytokines and CTL-mediated cell death of DLL3-expressing tumour cells. In May 2024, tarlatamab received its first approval in the USA for the treatment of adults with extensive stage SCLC (ES-SCLC) with disease progression on or after platinum-based chemotherapy. Tarlatamab received accelerated approval for this indication based on overall response rate and duration of response in the pivotal phase 2 DeLLphi-301 study, and continued approval may be contingent on the demonstration of clinical benefit in a confirmatory trial(s). Tarlatamab is under regulatory review in Brazil, Canada, Israel and the UK, and clinical studies are underway in multiple countries. This article summarizes the milestones in the development of tarlatamab leading to this first approval for ES-SCLC with disease progression on or after platinum-based chemotherapy.

Zevorcabtagene Autoleucel: First Approval.

Zevorcabtagene autoleucel () is a fully humanised B cell maturation antigen (BCMA)-targeting specific chimeric antigen receptor (CAR) T-cell therapy being developed by CARsgen for the treatment of multiple myeloma. Zevorcabtagene autoleucel is an autologous CAR T cell comprising a fully human BCMA-specific scFv (25C2), a CD8α hinge region and transmembrane domain, a 4-1BB costimulatory domain and a CD3-ζ T cell activation domain. Zevorcabtagene autoleucel recognizes and induces selective toxicity against BCMA-expressing tumour cells leading to their elimination. In February 2024, zevorcabtagene autoleucel received its first approval in China for the treatment of adults with relapsed or refractory multiple myeloma who have progressed after ≥ 3 prior lines of therapy (including ≥ 1 proteasome inhibitor and an immunomodulatory agent). Clinical studies of zevorcabtagene autoleucel are underway in Canada and the US. This article summarizes the milestones in the development of zevorcabtagene autoleucel leading to this first approval for relapsed or refractory multiple myeloma.

Aprocitentan: First Approval.

Aprocitentan (TRYVIO™) is a once-daily oral dual endothelin A (ETA) and B (ETB) receptor antagonist developed by Idorsia Pharmaceuticals for the treatment of hypertension. The endothelin pathway has been implicated in hypertension. Aprocitentan inhibits the binding of endothelin-1 to ETA and ETB receptors, thereby preventing its deleterious effects and lowering blood pressure. In March 2024, aprocitentan received its first approval in the USA for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adults who are not adequately controlled on other drugs. This article summarizes the milestones in the development of aprocitentan leading to this first approval for hypertension not adequately controlled on other drugs.

Inotuzumab Ozogamicin: First Pediatric Approval.

Inotuzumab ozogamicin (BESPONSA™) is a CD22-targeted monoclonal antibody drug conjugate (ADC) developed by Pfizer for the treatment of CD22-postive B-cell precursor acute lymphoblastic leukaemia (ALL). Inotuzumab ozogamicin comprises a humanized IgG4 anti-CD22 monoclonal antibody covalently linked to the potent DNA-binding cytotoxic agent N-acetyl-gamma-calicheamicin dimethylhydrazide (CalichDMH) via a linker. Inotuzumab ozogamicin binds to CD22-expressing tumour cells, facilitating the delivery of conjugated CalichDMH, which after intracellular activation induces double strand DNA breaks, ultimately leading to cell cycle arrest and apoptotic cell death. Inotuzumab ozogamicin is approved in the USA, Europe and several countries worldwide for the treatment of relapsed or refractory CD22-positive B-cell precursor ALL in adults. On 6 March 2024, inotuzumab ozogamicin received its first pediatric approval in the USA for this indication in patients aged ≥ 1 years. Inotuzumab ozogamicin has since been approved in Japan in March 2024 for the same indication in pediatric patients. This article summarizes the milestones in the development of inotuzumab ozogamicin leading to this first approval for the treatment of relapsed or refractory CD22-positive B-cell precursor ALL in pediatric patients.

Crovalimab: First Approval.

Crovalimab (®; PiaSky) is a humanized, anti-complement component C5 (anti-C5) recycling monoclonal antibody developed by Chugai Pharmaceutical, in collaboration with Roche, which is being investigated for the treatment of complement-mediated diseases, including paroxysmal nocturnal haemoglobinuria (PNH), atypical haemolytic uremic syndrome, lupus nephritis and sickle cell disease. Crovalimab targets C5, inhibiting its cleavage to C5a and C5b, thus blocking the terminal complement pathway and preventing intravascular haemolysis in PNH. Crovalimab is designed to bind to the antigen repeatedly, resulting in sustained complement inhibition at a lower dosage, and allowing for once-monthly subcutaneous administration. In February 2024, subcutaneous crovalimab received its first approval in China for the treatment of adolescents and adults (aged ≥ 12 years) with PNH who have not been previously treated with complement inhibitors. Crovalimab has since been approved in Japan in March for use in the treatment of PNH, including in treatment-naïve and previously treated patients. Crovalimab is also under regulatory review for the treatment of naïve and previously treated patients with PNH in multiple countries, including the USA and the European Union. This article summarizes the milestones in the development of crovalimab leading to this first approval in China for the treatment of PNH.

Tegileridine: First Approval.

Tegileridine () is a small molecule µ-opioid receptor biased agonist developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd for the treatment of postoperative pain. Tegileridine selectively activates the G-protein-coupled pathway, which mediates strong central analgesic effects and only weakly activates the ß-arrestin-2 pathway implicated in adverse events like respiratory depression and gastrointestinal dysfunction. In January 2024, tegileridine received its first approval in China for the treatment of moderate to severe pain after abdominal surgery. This article summarizes the milestones in the development of tegileridine leading to this first approval for the treatment of moderate to severe pain after abdominal surgery.

Aponermin: First Approval.

Aponermin () is a recombinant circularly permuted human tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) developed by Beijing Sunbio Biotech (a wholly owned subsidiary of Wuhan Hiteck Biological Pharma CO., LTD) for the treatment of multiple myeloma. Aponermin binds to and activates the death receptors 4 and/or 5 on tumour cells, triggering intracellular caspase reactions and inducing apoptosis, thereby exerting antitumor effects. In November 2023, aponermin in combination with thalidomide and dexamethasone received its first approval in China for the treatment of patients with relapsed or refractory multiple myeloma who have received at least two prior therapies. This article summarizes the milestones in the development of aponermin leading to this first approval for relapsed or refractory multiple myeloma.

Fidanacogene Elaparvovec: First Approval.

Fidanacogene elaparvovec (PrBEQVEZ™) is an adeno-associated viral (AAV) vector-based gene therapy developed by Spark Therapeutics (a subsidiary of Roche) and Pfizer (under a license from Spark Therapeutics) for the treatment of haemophilia B. In December 2023, fidanacogene elaparvovec received its first approval for the treatment of adults (aged ≥ 18 years) with moderately severe to severe haemophilia B (congenital factor IX deficiency) who are negative for neutralizing antibodies to variant AAV serotype Rh74 (AAVRh74var). Fidanacogene elaparvovec is under regulatory review in the USA and the European Union and clinical studies are ongoing in multiple countries. This article summarizes the milestones in the development of fidanacogene elaparvovec leading to this first approval for moderately severe to severe (factor IX activity ≤ 2%) haemophilia B who are negative for neutralizing antibodies to AAVRh74var.

Repotrectinib: First Approval.

Repotrectinib (AUGTYRO™) is a next-generation, oral, small-molecule kinase inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC. It is being developed by Turning Point Therapeutics, a wholly owned subsidiary of Bristol-Myers Squibb (BMS), for the treatment of locally advanced or metastatic solid tumours, including non-small cell lung cancer (NSCLC). Repotrectinib is a next-generation tyrosine kinase inhibitor rationally designed to inhibit ROS1 and TRK fusion, including in the presence of resistance mutations such as solvent-front mutations. In November 2023, repotrectinib received its first approval in the USA for the treatment of adults with locally advanced or metastatic ROS1-positive NSCLC. Repotrectinib is under regulatory review in China and the EU for NSCLC. Clinical studies of repotrectinib are ongoing in several countries in patients with NSCLC and other solid tumours (including primary central nervous system cancer) across both adult and paediatric patient populations. In addition, preclinical investigation of repotrectinib in multiple myeloma is underway in the USA. This article summarizes the milestones in the development of repotrectinib leading to this first approval for the treatment of locally advanced or metastatic ROS1-positive NSCLC.

Narlumosbart: First Approval.

Narlumosbart () is a recombinant, fully human, anti-receptor activator of nuclear factor kappa-Β ligand (RANKL) IgG4 monoclonal antibody being developed by CSPC Pharmaceutical and its wholly owned subsidiary Shanghai Jinmante Biotechnology for the treatment of giant cell tumour of bone (GCTB), bone metastases from solid tumours and osteoporosis. The RANK/RANKL signalling pathway plays a pivotal role in osteoclastogenesis and in the pathogenesis of GCTB. Narlumosbart specifically binds to RANKL and blocks the interaction of RANKL with RANK, thus inhibiting osteoclastogenesis and bone resorption by osteoclasts. In September 2023, narlumosbart received conditional first approval in China for the treatment of adults with GCTB that is unresectable or when surgical resection would result in severe functional disability. Clinical studies of narlumosbart for bone metastases, postmenopausal osteoporosis and glucocorticoid-induced osteoporosis are underway in China. This article summarizes the milestones in the development of narlumosbart leading to this first approval for the treatment of adults with GCTB.

Sunvozertinib: First Approval.

Sunvozertinib (®) is an oral, irreversible, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) being developed by Dizal Pharmaceuticals (a joint venture company formed by AstraZeneca and the Chinese Future Industry Investment Fund) for the treatment of non-small cell lung cancer (NSCLC). Sunvozertinib has potent activity against EGFR mutations, including EGFR exon 20 insertion (exon20ins), and weak activity against wild-type EGFR. In August 2023, sunvozertinib received its first approval for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon20ins mutations whose disease has progressed on or after, or who are intolerable to, platinum-based chemotherapy. Sunvozertinib was granted conditional approval based on the overall response rates and duration of response in a single-arm phase 2 trial. Its full approval is contingent on results from ongoing confirmatory phase 3 randomized trials. Clinical studies of sunvozertinib are underway in several countries worldwide. This article summarizes the milestones in the development of sunvozertinib leading to this first approval for metastatic NSCLC with EGFR exon20ins.

Elranatamab: First Approval.

Elranatamab (elranatamab-bcmm; ELREXFIO™) is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T cell engager being developed by Pfizer for the treatment of multiple myeloma (MM). Elranatamab bridges CD3 on T cells with BCMA expressed on multiple myeloma cells, thereby activating T cells to induce T cell-mediated cytotoxicity against myeloma cells. In August 2023, elranatamab received its first approval in the USA for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior lines of therapy including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody. Elranatamab received accelerated approval for this indication based on response rate and durability of response, and continued approval may be contingent on the demonstration of clinical benefit in a confirmatory trial(s). Elranatamab has also received a positive opinion in the EU for RRMM and is under regulatory review in Japan and several other countries worldwide. Clinical studies of elranatamab are also underway in countries around the world. This article summarizes the milestones in the development of elranatamab leading to this first approval for the treatment of RRMM.

Beremagene Geperpavec: First Approval.

Beremagene geperpavec-svdt (VYJUVEK™) is a topically applied, redosable, live, replication defective herpes simplex virus-1 (HSV-1) vector -based gene therapy that is being developed by Krystal Biotech to deliver functional human collagen type VII alpha 1 chain (COL7A1) genes in patients with both, dominant and recessive dystrophic epidermolysis bullosa. Beremagene geperpavec can transduce both keratinocytes and fibroblasts and restore functional COL7 protein. In May 2023, beremagene geperpavec received its first approval in the US for the treatment of wounds in patients ≥ 6 months of age with dystrophic epidermolysis bullosa with mutation(s) in the COL7A1 gene. A Marketing Authorization Application for beremagene geperpavec in Europe is planned for the second half of 2023. This article summarizes the milestones in the development of beremagene geperpavec leading to this first approval for dystrophic epidermolysis bullosa.

Zavegepant: First Approval.

Zavegepant is a third generation, small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist being developed by Pfizer, under a license from Bristol-Myers Squibb, for the prevention and treatment of chronic and episodic migraine. In March 2023, zavegepant nasal spray (ZAVZPRET™) received its first approval in the USA for the acute treatment of migraine with or without aura in adults. Clinical development of an oral formulation of zavegepant is currently underway. This article summarizes the milestones in the development of zavegepant leading to this first approval for the acute treatment of migraine with or without aura in adults.

Adagrasib: First Approval.

Adagrasib (KRAZATI™) is an orally available, potent, irreversible, small molecule inhibitor of KRAS G12C mutant isoform being developed by Mirati Therapeutics for the treatment of solid tumours harbouring KRAS G12C oncogenic driver mutation, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Adagrasib covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive state, thereby preventing downstream signalling without affecting wild-type KRAS protein. In December 2022, adagrasib received its first approval in the USA for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic NSCLC (as determined by an FDA approved test) who have received ≥ 1 prior systemic therapy. It was approved under accelerated approval based on objective response rate and duration of response, and its continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s). The drug is under regulatory review for NSCLC in the European Union and is in development for CRC in the US. Clinical studies of adagrasib in solid tumours, including CRC, are underway in several countries. This article summarizes the milestones in the development of adagrasib leading to this first approval for KRAS G12C-mutated locally advanced or metastatic NSCLC.

Sodium Thiosulfate: Pediatric First Approval.

Sodium thiosulfate (Pedmark®) is a chemoprotectant/antioxidant developed by Fennec Pharmaceuticals (formerly Adherex Technologies) to reduce to risk of hearing loss associated with cisplatin. Sodium thiosulfate reduces the risk of ototoxicity by interacting directly with cisplatin to produce inactive platinum species, as well as by causing intracellular effects (such as increasing antioxidant glutathione levels and inhibition of oxidative stress) after entering the cells through the sodium sulfate cotransporter 2. In September 2022, sodium thiosulfate received its first approval in the USA for reducing the risk of ototoxicity associated with cisplatin in pediatric patients 1 month of age and older with localized, non-metastatic solid tumours. Sodium thiosulfate is under regulatory review in the EU for the prevention of ototoxicity induced by cisplatin chemotherapy in patients 1 month to < 18 years of age with localised, non-metastatic, solid tumours. This article summarizes the milestones in the development of sodium thiosulfate leading to this pediatric first approval for reducing the risk of ototoxicity associated with cisplatin in pediatric patients.

Pucotenlimab: First Approval.

Pucotenlimab (Puyouheng™) is a humanised immunoglobulin (Ig) G4 monoclonal antibody (mAb) being developed by Lepu Biopharma for the treatment of solid tumours, including gastrointestinal cancer, metastatic melanoma, liver cancer, bladder cancer, non-small cell lung cancer and breast cancer. Pucotenlimab binds to PD-1 and blocks its interaction with its ligands, PD-L1 and PD-L2, thereby restoring the ability of immune cells to target cancer cells. In July 2022, pucotenlimab received conditional first approval in China for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumours, including patients with advanced colorectal cancer who have experienced disease progression after previous therapy with fluorouracil, oxaliplatin and irinotecan, as well as patients with other advanced solid tumours who have experienced disease progression after previous first-line therapy and have no satisfactory treatment alternatives. In September 2022, pucotenlimab was approved in China for the treatment of unresectable or metastatic melanomas after the failure of previous systemic therapy. This article summarizes the milestones in the development of pucotenlimab leading to the first approval for the treatment of MSI-H/dMMR advanced solid tumours.