Karly P. Garnock-Jones

Omaveloxolone (SKYCLARYS™) is an orally active, small molecule semi-synthetic triterpenoid drug that increases antioxidant activity, which is being developed by Reata Pharmaceuticals, Inc. for the treatment of Friedreich’s ataxia. In patients with Friedreich’s ataxia, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway is suppressed, which is associated with oxidative stress, mitochondrial dysfunction and damage to cells, including central and peripheral neurones. The Nrf2 pathway may be activated by omaveloxolone as it blocks the ubiquitination and degradation of Nrf2. Omaveloxolone was approved in February 2023 in the USA for the treatment of Friedreich's ataxia. This article summarizes the milestones in the development of omaveloxolone leading to this first approval for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.

Ublituximab (ublituximab-xiiy; BRIUMVI^™) is a glycoengineered anti-CD20 monoclonal antibody developed by TG Therapeutics, Inc. for the treatment of multiple sclerosis (MS). The mechanism of action of ublituximab involves the depletion of B cells via antibody-dependent cellular cytotoxicity, as B cells have a key role in the pathogenesis of MS. Ublituximab is the first anti-CD20 treatment that is administered twice-yearly as one hour infusions, following the initial doses. In December 2022, ublituximab received its first global approval in the USA for the treatment of adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. This article summarizes the milestones in the development of ublituximab leading to this first approval in this indication.

Nadofaragene firadenovec (nadofaragene firadenovec-vncg; Adstiladrin^®) is a non-replicating adenoviral vector-based gene therapy developed by Ferring Pharmaceuticals for the treatment of high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC). Nadofaragene firadenovec constitutes vector DNA that encodes for interferon (IFN)-α2b and is the first approved gene therapy in bladder cancer. The production of IFN-α2b by transfected urothelial cells is associated with anticancer activity, including immunostimulatory, antiangiogenic and apoptotic effects. In December 2022, nadofaragene firadenovec received its first global approval in the USA for the treatment of high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumours in adults. This article summarizes the milestones in the development of nadofaragene firadenovec leading to this first approval for this indication.

Clazosentan (PIVLAZ^™) is a small molecule, endothelin (ET) A receptor-selective antagonist being developed by Idorsia Pharmaceuticals. ET_A receptor inhibition by clazosentan decreases ET-related cerebral vasospasm, which may occur after an aneurysmal subarachnoid haemorrhage. Clazosentan has been approved in Japan for use in the prevention of cerebral vasospasm, vasospasm-related cerebral infarction and cerebral ischaemic symptoms after aneurysmal subarachnoid haemorrhage, following the results from the JapicCTI163369 and JapicCTI163368 phase III trials. This article summarises the milestones in the development of clazosentan leading to this first approval in this indication.

Avacopan (TAVNEOS™) is a complement 5a receptor (C5aR) antagonist developed by ChemoCentryx for the treatment of autoimmune diseases including anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. The therapeutic effects of avacopan are attributed to the inhibition of C5aR activity on neutrophils, however, the exact mechanism of therapeutic efficacy in patients with ANCA-associated vasculitis has not been established. In September 2021, avacopan received its first approval in Japan for the treatment of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), the two most common forms of ANCA-associated vasculitis, where it is being commercialized by Kissei Pharmaceutical through a partnership with Vifor Pharma. In October 2021, avacopan was approved in the USA as an adjunctive treatment in adults for severe active ANCA-associated vasculitis (specifically MPA and GPA) in combination with standard therapy including glucocorticoids (avacopan does not eliminate glucocorticoid use). Avacopan has received a positive opinion in the EU, and is also undergoing regulatory review in Switzerland and Canada. Avacopan is being investigated for the treatment of complement component 3 glomerulopathy, hidradenitis suppurativa, lupus nephritis and IgA nephropathy. This article summarizes the milestones in the development of avacopan leading to these first approvals in Japan and the USA.

Ibrexafungerp (BREXAFEMME^®) is an orally active triterpenoid antifungal drug being developed by SCYNEXIS, Inc. for the treatment of fungal infections. The inhibition of β-1,3-d glucan synthetase by ibrexafungerp compromises the integrity of fungal cell walls. Ibrexafungerp has been recently approved for the treatment of vulvovaginal candidiasis (VVC), and it is the first novel antifungal drug class to be approved in more than 20 years. Development for the treatment of recurrent VVC and invasive fungal infections is ongoing. This article summarizes the milestones in the development of ibrexafungerp leading to this first approval for the treatment of VVC in adult and postmenarchal paediatric females.

Tucatinib is an oral, small molecule, selective HER2 inhibitor initially developed by Array BioPharma (a subsidiary of Pfizer) and subsequently developed by Seattle Genetics for the treatment of HER2-positive solid tumours, including breast cancer and colorectal cancer. Tucatinib was approved in the USA in April 2020 and in Switzerland in May 2020 for the treatment of HER2-positive breast cancer, and is pending regulatory review in the EU, Australia, Canada and Singapore. This article summarizes the milestones in the development of tucatinib leading to this first approval in patients with advanced unresectable or metastatic HER2-positive breast cancer.

Abstract Tislelizumab (百泽安^®;替雷利珠单抗; Tileilizhu Dankang Zhusheye) is an anti-human programmed death receptor-1 (PD-1) monoclonal IgG4 antibody that is being developed by BeiGene as an immunotherapeutic, anti-neoplastic drug. Tislelizumab has been investigated in haematological cancers and advanced solid tumours, leading to its approval in December 2019 in China for patients with relapsed or refractory classical Hodgkin’s lymphoma after at least second-line chemotherapy. This article summarises the major milestones in the development of tislelizumab for this first approval for classical Hodgkin’s lymphoma, and its potential upcoming approvals in other indications.