Drugs

Ertl, Hildegund C. J.

doi: 10.1007/s40265-023-01836-1pmid: 36715794

Gene transfer with high doses of adeno-associated viral (AAV) vectors has resulted in serious adverse events and even death of the recipients. Toxicity could most likely be circumvented by repeated injections of lower and less toxic doses of vectors. This has not been pursued as AAV vectors induce potent neutralizing antibodies, which prevent cell transduction upon reinjection of the same vector. This review discusses different types of immune responses against AAV vectors and how they offer targets for the elimination or inhibition of vector-specific neutralizing antibodies. Such antibodies can be circumvented by using different virus serotypes for sequential injections, they can be removed by plasmapheresis, or they can be destroyed by enzymatic degradation. Antibody producing cells can be eliminated by proteasome inhibitors. Drugs that inhibit T-cell responses, B-cell signaling, or presentation of the vector’s antigens to B cells can prevent or reduce induction of AAV-specific antibodies. Combinations of different approaches and drugs are likely needed to suppress or eliminate neutralizing antibodies, which would then allow for repeated dosing. Alternatively, novel AAV vectors with higher transduction efficacy are being developed and may allow for a dose reduction, although it remains unknown if this will completely address the problem of high-dose adverse events.

Núñez, Paulina; Quera, Rodrigo; Yarur, Andres J.

doi: 10.1007/s40265-023-01840-5pmid: 36913180

In recent years, better knowledge of the pathophysiology of inflammatory bowel diseases (IBD) has led to a relevant expansion of the therapeutic arsenal for these conditions. Janus kinase (JAK) inhibitors are a family of small molecules that block one or more of the intracellular tyrosine kinases, including JAK-1, JAK-2, JAK-3 and TYK-2. Tofacitinib, a non-selective small molecule JAK inhibitor, and upadacitinib and filgotinib, which are selective JAK-1 inhibitors, have been approved by the US Food and Drug Administration (FDA) for moderate-to-severe active ulcerative colitis. Compared to biological drugs, JAK inhibitors have a short half-life, rapid onset of action, and no immunogenicity. Both clinical trials and real-world evidence support the use of JAK inhibitors in the treatment of IBD. However, these therapies have been linked with multiple adverse events (AEs) including infection, hypercholesterolemia, venous thromboembolism, major adverse cardiovascular events, and malignancy. While early studies recognized several potential AEs, post-marketing trials have shown that tofacitinib may increase the risk of thromboembolic diseases and major cardiovascular events. The latter are seen in patients aged 50 years or older with cardiovascular risk factors. Hence, the benefits of treatment and risk stratification need to be considered when positioning tofacitinib. Novel JAK inhibitors with a more selective effect on JAK-1 have proven to be effective in both Crohn’s disease and ulcerative colitis, offering a potentially safer and efficacious therapeutic option to patients, including those with previous non-response to other therapies such as biologics. Nevertheless, long-term effectiveness and safety data are required.

Yan, Vincent K. C.; Li, Hang-Long; Wei, Li; Knapp, Martin R. J.; Wong, Ian C. K.; Chan, Esther W.

doi: 10.1007/s40265-023-01837-0pmid: 36840892

BackgroundDirect oral anticoagulants (DOACs) have been increasingly utilised over warfarin. However, little is known about the relative consumption trends and costs of each DOAC at the global level.MethodsAn ecological study using pharmaceutical sales data from IQVIA-MIDAS database was used to estimate consumption and cost of individual DOACs in 65 countries from 2008 to 2019. Consumption was estimated from the volume of DOACs sold, expressed as defined-daily-dose/1000-inhabitants/day (DDDTID). Compound and absolute annual growth rates were reported to quantify consumption changes over time. Costs were estimated as manufacturer price per day-of-therapy.ResultsGlobal consumption of dabigatran, rivaroxaban, apixaban and edoxaban were 0.31, 1.05, 1.08 and 0.78 DDDTID, respectively, in Q2–2019, compared to 0.23, 0.54, 0.21 and 0.03 in Q2–2015, with highest consumption in Western Europe, Northern Europe and Oceania (18.2, 14.07, 13.14 DDDTID). In most countries (46/65, 70%), rivaroxaban contributed to most DOAC consumption (35%–100%), whereas dabigatran accounted for less than one-third. Edoxaban accounted for < 20% of the total in Northern America and Europe but contributed significant proportions in Japan (28.58%) and South Korea (31.37%). Longer median time-to-adoption from FDA approval for apixaban and edoxaban was observed. Costs of all DOACs were ~2–4 times higher in the USA, Puerto Rico and Thailand than in other countries.ConclusionsRegional differences exist in consumption pattern and trends of individual DOACs over the past decade. Consumption of rivaroxaban and apixaban overtook dabigatran in most countries, whereas use of edoxaban remains limited except in East Asian countries. The USA pays higher prices for DOACs than other countries.

Kang, Connie

doi: 10.1007/s40265-023-01844-1pmid: 36848032

Olutasidenib (REZLIDHIATM), an isocitrate dehydrogenase-1 (IDH1) inhibitor, is being developed by Rigel Pharmaceuticals for the treatment of relapsed or refractory (R/R) acute myeloid leukaemia (AML). Olutasidenib was recently approved in the USA for the treatment of adults with R/R AML with a susceptible IDH1 mutation as detected by a US Food and Drug Administration-approved test. This article summarizes the milestones in the development of olutasidenib leading to this first approval for R/R AML.

Heo, Young-A

doi: 10.1007/s40265-023-01845-0pmid: 36802324

Etranacogene dezaparvovec (etranacogene dezaparvovec-drlb; Hemgenix®) is an adeno-associated virus vector-based gene therapy being developed by uniQure and CSL Behring for the treatment of haemophilia B. In November 2022, etranacogene dezaparvovec was approved in the USA for the treatment of haemophilia B [congenital factor IX (FIX) deficiency] in adults who are currently using FIX prophylaxis therapy, have current or historical life-threatening haemorrhage or have repeated, serious spontaneous bleeding episodes. In December 2022, etranacogene dezaparvovec also received positive opinion in the EU for the treatment of haemophilia B. This article summarizes the milestones in the development of etranacogene dezaparvovec leading to this first approval.

Lee, Arnold

doi: 10.1007/s40265-023-01846-zpmid: 36856952

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.

Hoy, Sheridan M.

doi: 10.1007/s40265-023-01851-2pmid: 36856953

Lecanemab (lecanemab-irmb; LEQEMBI™) is a humanized immunoglobulin gamma 1 (IgG1) against aggregated soluble and insoluble forms of amyloid-β peptide. It is being developed by Eisai, under a global licence from BioArctic (formerly BioArctic Neuroscience), and in collaboration with Biogen, for the treatment of Alzheimer's disease, and received its first approval for this indication on 6 January 2023 in the USA under the Accelerated Approval Pathway. According to the US prescribing information, treatment should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, and a confirmed presence of amyloid beta pathology (i.e. the population in which treatment was initiated in clinical trials). There are no effectiveness or safety data on initiating treatment at earlier or later stages of the disease than were studied. Lecanemab is undergoing regulatory review in the EU, Japan and China, with clinical development underway in several other countries worldwide. This article summarizes the milestones in the development of lecanemab leading to this first approval for the treatment of Alzheimer’s disease.