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Alectinib (Alecensa ® ) is a second-generation, orally active, potent and highly selective inhibitor of anaplastic lymphoma kinase (ALK). Alectinib is approved for the treatment of ALK fusion-gene positive, unresectable, advanced or recurrent non-small cell lung cancer (NSCLC) in Japan, where it has been given orphan drug designation. Approval was based on a phase 1–2 study in ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC who received twice-daily alectinib 300 mg. In the phase 2 portion, 93.5 % of patients achieved an objective response. Treatment response was rapid, with a partial response achieved in two-thirds of patients within 3 weeks (cycle 1). Patient follow-up is ongoing, and after approximately 2 years, 19.6 % of patients had achieved a complete response, and the 2-year progression-free survival rate is 76 %. During treatment with alectinib (median follow-up approximately 8 months), there was no progression of CNS lesions among patients with known CNS metastases at baseline (although prior radiation therapy may have confounded results). In preclinical models, alectinib was active against most ALK fusion-gene mutations related to crizotinib resistance, and preliminary results from clinical trials indicate efficacy in crizotinib-refractory NSCLC. Alectinib was generally well tolerated in clinical trials, and there were no treatment-related grade 4 adverse events or deaths. The most common grade 3 treatment-related adverse events were decreased neutrophil counts and increased creatinine phosphokinase. While more data are needed to confirm the efficacy of alectinib and to evaluate its activity in crizotinib-resistant disease, the drug provides a very promising option for the treatment of ALK-rearranged advanced NSCLC.

Ravulizumab (ravulizumab-cwvz; ULTOMIRIS™), a humanized monoclonal antibody, is a complement C5 inhibitor developed by Alexion Pharmaceuticals for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS). Like the first-generation C5 inhibitor, eculizumab, ravulizumab binds specifically and with high affinity to the complement protein C5, thereby preventing formation of the terminal complement complex C5b-9, which mediates cell lysis. In December 2018, intravenous ravulizumab received its first global approval in the USA for the treatment of adults with PNH, and is under regulatory review in the European Union and Japan in this indication. Phase 3 development of intravenous ravulizumab for the treatment of aHUS is underway worldwide. The use of ravulizumab in myasthenia gravis and IgA nephropathy is also being evaluated in the USA in early-phase and preclinical studies, respectively. Clinical development of a subcutaneous formulation for PNH and aHUS is also underway. Ravulizumab has been developed using Xencor’s antibody half-life prolongation technology (Xtend™), which utilises antibody Fc variants to prolong half-life. Alexion is also evaluating the coadministration of subcutaneous ravulizumab with Halozyme’s ENHANZE ® drug-delivery technology (rHuPH20), which may have the potential to further extend the dosing interval. This article summarizes the milestones in the development of ravulizumab leading to this first approval for PNH.

Daratumumab (Darzalex™) is a first-in-class, humanized IgG1κ monoclonal antibody that targets the CD38 epitope and was developed by Janssen Biotech and Genmab. Intravenous daratumumab was recently approved via an accelerated approval programme in the USA for patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent. The drug is in preregistration for this indication in the EU and Canada. In a phase II trial in patients with previously treated (as described above) relapsed or refractory multiple myeloma, monotherapy with daratumumab 16 mg/kg achieved an overall response rate of approximately 30 %. This article summarizes the milestones in the development of daratumumab leading to this first approval for multiple myeloma.

Aflibercept is a recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF), a key regulator of angiogenesis. It binds to all isoforms of VEGF-A as well as VEGF-B and placental growth factor, and, thus, prevents them from binding to and activating their cognate receptors. In the USA and EU, intravenously administered aflibercept in combination with an infusion of leucovorin, fluorouracil and irinotecan (FOLFIRI) is approved for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed after treatment with an oxaliplatin-containing regimen. The efficacy of aflibercept in this indication was assessed in a multinational, pivotal phase 3 trial (VELOUR), in which the approved regimen of aflibercept 4 mg/kg every 2 weeks plus FOLFIRI significantly prolonged median overall survival by 1.44 months compared with FOLFIRI alone (primary endpoint). The addition of aflibercept also significantly prolonged progression-free survival and significantly increased the objective response rate compared with FOLFIRI alone. Addition of aflibercept to FOLFIRI was associated with anti-VEGF-related adverse events and an increased incidence of FOLFIRI-related adverse events, but the tolerability of the combination was generally acceptable in this pre-treated population. The most common grade 3 or 4 adverse events with aflibercept plus FOLFIRI included neutropenia, diarrhoea and hypertension. In conclusion, aflibercept plus FOLFIRI is a useful treatment option for patients with metastatic colorectal cancer previously treated with an oxaliplatin-containing regimen, with or without bevacizumab.

Trelagliptin (Zafatek ® ) is an orally active dipeptidyl peptidase (DPP)-4 inhibitor developed by Takeda and approved in Japan for the treatment of type 2 diabetes mellitus (T2DM). Unlike other approved agents of its class, which are usually administered once daily, trelagliptin can be administered once weekly. Phase II development of trelagliptin was discontinued in the USA and EU, as Takeda considered that the costs associated with obtaining approval in these markets were prohibitive. This article summarizes the milestones in the development of trelagliptin leading to this first approval for T2DM.

Risankizumab (Skyrizi ® ), a humanised IgG monoclonal antibody that targets the p19 subunit of IL-23, was developed by AbbVie in collaboration with Boehringer Ingelheim for the treatment of immunological and inflammatory disorders. In March 2019, risankizumab received its first global approval in Japan for the treatment of adults with psoriasis vulgaris, psoriatic arthritis, generalized pustular psoriasis and erythrodermic psoriasis. Risankizumab has also received approval in the USA, Canada and the EU for the treatment of moderate-to-severe plaque psoriasis, and is in phase 3 development for this indication as well as psoriatic arthritis in several countries worldwide. Phase 2 and 3 clinical evaluation of risankizumab is ongoing in several countries in the treatment of Crohn’s disease and ulcerative colitis. Risankizumab is also in phase 2 development for the treatment of atopic dermatitis globally. This article summarizes the milestones in the development of risankizumab leading to this first approval for psoriasis vulgaris, psoriatic arthritis, generalized pustular psoriasis and erythrodermic psoriasis.

Finafloxacin is a fluoroquinolone antimicrobial agent that exhibits optimum efficacy in slightly acidic environments. It is being developed by MerLion Pharmaceuticals to treat serious bacterial infections associated with an acidic environment, including urinary tract infections and Helicobacter pylori infections. An otic suspension of finafloxacin (Xtoro™), developed by Alcon (a division of Novartis), was recently approved in the USA for the treatment of acute otitis externa, and a Common Technical Document for this indication was also filed in Canada. Oral and/or intravenous formulations are in phase I and II evaluation in uncomplicated urinary tract infections (Germany and Singapore), complicated urinary tract infections and pyelonephritis (Germany and Poland) and H. pylori infection (Germany). This article summarizes the milestones in the development of finafloxacin leading to this first approval for otitis externa.

CT-P13 (Remsima™; Inflectra™), a biosimilar of reference infliximab (Remicade ® ), is approved by the European Medicines Agency for use in all indications for which reference infliximab is approved, including rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriatic arthritis and psoriasis. Infliximab is a chimeric human-murine monoclonal antibody against the proinflammatory cytokine tumour necrosis factor-α. The CT-P13 infliximab formulation is identical to that of reference infliximab and it has similar physiochemical characteristics. The approval of CT-P13 was based on the results of a rigorous, comparability exercise. This article reviews the results of that exercise, focusing on the clinical evaluation programme. In two well-designed clinical trials, CT-P13 was equivalent to reference infliximab in terms of pharmacokinetic properties in patients with ankylosing spondylitis and in terms of efficacy in patients with rheumatoid arthritis. In both studies, CT-P13 was generally well tolerated with a similar tolerability profile to that of reference infliximab. Immunogenicity evaluations demonstrated that the proportion of patients developing anti-drug antibodies was similar with each agent. Preliminary data from trial extensions demonstrated that in patients who switched from reference infliximab to CT-P13, efficacy was sustained and similar to those who were treated continuously with CT-P13. As with all biosimilar and generic agents, CT-P13 has the potential to reduce treatment costs compared with those of reference infliximab, and modelled analyses predict significant cost savings compared with reference infliximab. In conclusion, CT-P13 is an infliximab biosimilar that provides a useful alternative to reference infliximab in patients requiring infliximab therapy.

Secukinumab (Cosentyx™) is a fully human monoclonal antibody against interleukin-17A, formulated for intravenous and subcutaneous administration. It received its first global approval in Japan on 26 December 2014 for the treatment of psoriasis and psoriatic arthritis in adults who are not adequately responding to systemic therapies (except for biologic agents). In the USA and the EU, secukinumab was approved in early 2015 for the treatment of patients with moderate-to-severe plaque psoriasis. Secukinumab is also being investigated in patients with ankylosing spondylitis and rheumatoid arthritis. This article summarizes the milestones in the development of secukinumab leading to its first approval for the treatment of adult patients with psoriasis and psoriatic arthritis.

Oral fostamatinib is an orally administered small molecule spleen tyrosine kinase (SYK) inhibitor approved for the treatment of adults with chronic immune thrombocytopenia (ITP) who have an inadequate response to a previous treatment. Fostamatinib has a unique mechanism of action, whereby its active metabolite targets the SYK-mediated pathway of platelet destruction. In clinical trials, fostamatinib provided durable responses in adults with chronic ITP who had not responded or had relapsed following treatment with one or more prior ITP therapies, including corticosteroids, thrombopoietin receptor agonists, rituximab, and/or splenectomy. Most patients who respond to fostamatinib maintain platelet counts of > 50 × 10 9 /L for periods of ≥ 12 months. The most common adverse events reported with fostamatinib in clinical trials were diarrhea, hypertension, nausea, and increased transaminase levels.