Drugs

Rosen, Natalie; Dawson, Samantha; Brooks, Melissa; Kellogg-Spadt, Susan

doi: 10.1007/s40265-019-01085-1pmid: 30847806

Vulvodynia is a common, recurrent, vulvar pain condition with debilitating consequences for affected women’s health and quality of life. The heterogeneity of women suffering from vulvodynia as well as its uncertain and likely multifactorial etiology pose a significant challenge to identifying any kind of “gold standard” treatment. Thus, treatment providers must be well versed in the various options and the evidence for each. In this review, we begin with pharmacological treatments, followed by non-pharmacological treatments, surgery, and finally multimodal treatments. For each approach, we briefly discuss the method, mechanism of action, and empirical support for the treatment. In sum, pharmacological treatments that may be beneficial but require further research include antinociceptive agents (lidocaine, capsaicin), anti-inflammatory agents (corticosteroids, interferon), neuromodulating medications (anticonvulsants and antidepressants), hormonal agents, and muscle relaxants (e.g., botulinum toxin). There is strong evidence to support and recommend non-pharmacological interventions including psychological therapy, pelvic floor physical therapy, as well as surgery (i.e., vestibulectomy for provoked vestibulodynia) for the treatment of vulvodynia. We conclude this review with a discussion of issues that may have hindered progress of treatment efficacy and effectiveness, and recommendations for moving the field forward.

Lichter-Konecki, Uta; Vockley, Jerry

doi: 10.1007/s40265-019-01079-zpmid: 30864096

Phenylalanine hydroxylase (PAH) deficiency is an inborn error of metabolism that results in elevated phenylalanine levels in blood. The classical form of the disease with phenylalanine level > 1200 µmol/L in blood is called phenylketonuria (PKU) and is associated with severe intellectual disability when untreated. In addition, phenylalanine levels above the therapeutic range in pregnant female patients lead to adverse fetal effects. Lowering the plasma phenylalanine level prevents intellectual disability, maintaining the level in the therapeutic range of 120–360 µmol/L is associated with good outcome for patients as well as their pregnancies. Patient phenotypes are on a continuous spectrum from mild hyperphenylalaninemia to mild PKU, moderate PKU, and severe classic PKU. There is a good correlation between the biochemical phenotype and the patient’s genotype. For over four decades the only available treatment was a very restrictive low phenylalanine diet. This changed in 2007 with the approval of cofactor therapy which is effective in up to 55% of patients depending on the population. Cofactor therapy typically is more effective in patients with milder forms of the disease and less effective in classical PKU. A new therapy has just been approved that can be effective in all patients with PAH deficiency regardless of their degree of enzyme deficiency or the severity of their phenotype. This article reviews the mainstay therapy, adjunct enzyme cofactor therapy, and the newly available enzyme substitution therapy for hyperphenylalaninemia. It also provides an outlook on emerging approaches for hyperphenylalaninemia treatment such as recruiting the microbiome into the therapeutic endeavor as well as therapies under development such as gene therapy.

Delos Santos, Rowena; Rossi, Ana; Coyne, Daniel; Maw, Thin

doi: 10.1007/s40265-019-01074-4pmid: 30811012

Significant advances in immunosuppressive therapies have been made in renal transplantation, leading to increased allograft and patient survival. Despite improvement in overall patient survival, patients continue to require management of persistent post-transplant hyperparathyroidism. Medications that treat persistent hyperparathyroidism include vitamin D, vitamin D analogues, and calcimimetics. Medication side effects such as hypocalcemia or hypercalcemia, and adynamic bone disease, may lead to a decrease in the drugs. When medical management fails to control persistent post-transplant hyperparathyroidism, treatment is a parathyroidectomy. Surgical techniques are not uniform between centers and surgeons. Undergoing the surgery may include a subtotal technique or a technique including total parathyroid gland resection with partial heterotopic gland reimplantation. In addition, there are possible post-surgical complications. The ideal treatment for persistent post-transplant hyperparathyroidism is the treatment and prevention of the condition while patients are being managed for their late-stage chronic kidney disease and end-stage renal disease.

Yang, Ming; Huo, Xiaochuan; Miao, Zhongrong; Wang, Yongjun

doi: 10.1007/s40265-019-01078-0pmid: 30838514

Tirofiban is a non-peptide selective glycoprotein (GP) IIb/IIIa receptor inhibitor that reversibly inhibits fibrinogen-dependent platelet aggregation and subsequent formation of thrombi, which contribute to the major atherosclerotic complications in the development, progression, and resolution of ischemic stroke. The adjunctive use of tirofiban has been extensively evaluated in progressive stroke, combined intravenous thrombolysis (IVT), and endovascular treatment (EVT) in both preclinical and clinical studies. A body of evidence has been accumulated on the risks and benefits associated with tirofiban in terms of prevention of stroke progression, stent thrombosis, improvement in functional independence, and mortality, especially among high-risk ischemic stroke patients as a further strategy alongside conventional treatment. In general, tirofiban has a favorable tolerability and efficacy profile in the improvement of vascular recanalization and long-term functional outcome, although the optimum dosage, application setting, and precise target patients are not yet well-established. However, its specific inhibition of ongoing platelet aggregation and thrombus formation rather than absolute thrombolysis suggests that tirofiban, one of the most widely used GP IIb/IIIa inhibitors, with high affinity and a short plasma/biologic half-life, may have great potential in the acute treatment of ischemic stroke. Substantial practical progress is likely as our understanding of the mechanism of action and pharmacological actions of tirofiban in atherosclerotic ischemic disease improves. Therefore, we classify and summarize the available findings regarding tirofiban in acute ischemic stroke to stimulate and guide further research and clinical practice.

Gupta, Manik; Singh, Jasvinder

doi: 10.1007/s40265-019-01081-5pmid: 30868398

Cardiovascular disease affects more than 90 million Americans. Recent studies support an increased cardiovascular disease risk in inflammatory conditions, such as gout. Increased serum urate levels, or hyperuricemia, are a precursor to gout. Data from meta-analyses have shown hyperuricemia to be linked to hypertension and coronary heart disease. Similarly, gout has been associated with an increased risk of myocardial infarction, cerebrovascular accidents, and death from cardiovascular disease in randomized clinical trials. Urate-lowering therapy reduces serum urate and may decrease systemic inflammation, generation of oxidative species, and reverses endothelial dysfunction through hyperuricemia-dependent or hyperuricemia-independent pathways. Cardioprotective benefits of allopurinol, a first-line agent for the treatment of gout, have been demonstrated to potentially prevent myocardial infarction, stroke, atrial fibrillation, and other cardiovascular diseases in observational studies in select populations. Randomized controlled trials (RCTs) have also examined the role of newer urate-lowering therapies, such as febuxostat and lesinurad, and their risk of cardiovascular-specific mortality in comparison to allopurinol. A large post-marketing study of febuxostat vs. allopurinol showed higher all-cause and cardiovascular-specific mortality in the febuxostat group than in the allopurinol group; a major study limitation was that large numbers of patients were lost to follow-up or discontinued treatment. RCTs are required to assess the comparative effectiveness of urate-lowering therapies, validate findings of observational studies, and to determine which subgroup populations of gout are most likely to benefit from appropriate long-term urate-lowering therapy. This review examines the data for increased cardiovascular disease in gout and potential underlying mechanisms (including hyperuricemia, inflammation, endothelial dysfunction, oxidative stress) and the effect of urate-lowering therapy on cardiovascular disease.

McCafferty, Emma; Scott, Lesley

doi: 10.1007/s40265-019-01090-4pmid: 30875019

Fabry disease is a rare lysosomal disorder characterized by deficient or absent α-galactosidase A activity resulting from mutations in the GLA gene. Migalastat (Galafold™), a pharmacological chaperone, stabilizes and facilitates trafficking of amenable mutant forms of α-galactosidase A enzyme from the endoplasmic reticulum to lysosomes and increases its lysosomal activity. Oral migalastat is the first pharmacological chaperone approved for treating patients [aged ≥ 18 years (USA and Canada) or ≥ 16 years in other countries] with Fabry disease who have a migalastat-amenable GLA mutation. In the FACETS trial in enzyme replacement therapy (ERT)-naive patients with GLA mutations amenable or non-amenable to migalastat, there was no significant difference between the migalastat and placebo groups for the proportion of patients achieving a ≥ 50% reduction in the number of globotriaosylceramide (GL-3) inclusions/kidney interstitial capillary (KIC) at 6 months [primary endpoint; intent-to-treat (ITT) population]. In the modified ITT population (i.e. patients with migalastat-amenable GLA mutations), relative to placebo, migalastat treatment significantly reduced the mean number of GL-3 inclusions/KIC and plasma lyso-globotriaosylsphingosine levels at 6 months. Among evaluable patients, migalastat maintained renal function and reduced cardiac mass after ≤ 24 months’ therapy. In the ATTRACT trial in ERT-experienced patients, renal function was maintained during 18 months of migalastat or ERT; however, migalastat significantly reduced cardiac mass compared with ERT. Migalastat was generally well tolerated in both of these trials. Given its convenient oral regimen and the limited therapeutic options available, migalastat is an important treatment option for Fabry disease in patients with migalastat-amenable GLA mutations.

Shirley, Matt

doi: 10.1007/s40265-019-01095-zpmid: 30877642

Amikacin liposome inhalation suspension (ALIS; Arikayce®) [formerly known as liposomal amikacin for inhalation, or LAI] is a liposomal formulation of the aminoglycoside antibacterial drug amikacin. The ALIS formulation, administered via inhalation following nebulization, is designed to facilitate targeted and localized drug delivery to the lungs while minimizing systemic exposure. Based on the prespecified primary endpoint analysis of the ongoing phase III CONVERT trial, ALIS has been approved in the USA for use as part of a combination antibacterial drug regimen against Mycobacterium avium complex (MAC) lung disease that is treatment refractory (i.e. an active infection present despite ≥ 6 consecutive months of a multidrug regimen) in adult patients who have limited or no alternative treatment options. In the CONVERT trial, once-daily ALIS as an add-on to guidelines-based therapy (GBT) significantly increased the odds of achieving sputum culture conversion by month 6 compared with GBT alone in patients with treatment-refractory MAC lung disease. The addition of ALIS to GBT was associated with an increased risk of respiratory adverse events compared with GBT alone; however, serious adverse events were experienced by a similar proportion of patients in the two treatment groups. In conclusion, although current evidence for efficacy is limited to microbiological outcomes (with clinical benefit yet to be established), available data suggest that ALIS is a useful option for the treatment of patients with MAC lung disease who have not responded to conventional therapy and for whom there are limited or no alternative treatment options available.

Dhillon, Sohita

doi: 10.1007/s40265-019-01077-1pmid: 30805897

Roxadustat (Ai Rui Zhuo® in China) is an orally administered, small molecule hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that is being developed by FibroGen, in collaboration with Astellas and AstraZeneca, for the treatment of anaemia in patients with dialysis-dependent chronic kidney disease (CKD), non-dialysis-dependent CKD and in patients with myelodysplastic syndromes. The drug reversibly binds to and inhibits HIF-prolyl hydroxylase enzymes that are responsible for the degradation of transcription factors in the HIF family under normal oxygen conditions. Inhibition of these enzymes reduces HIF breakdown and promotes HIF activity, leading to an increase in endogenous erythropoietin production, thereby enhancing erythropoiesis. It also reduces the expression of the peptide hormone hepcidin, improves iron availability and increases haemoglobin levels. HIF regulates the expression of genes in response to reduced oxygen levels, including genes required for erythropoiesis and iron metabolism. Roxadustat is approved in China and is under regulatory review in Japan for the treatment of anaemia in patients with dialysis-dependent CKD. Studies are underway to investigate long-term cardiovascular outcomes with roxadustat versus placebo (for non-dialysis-dependent CKD) or standard of care (for dialysis-dependent CKD). This article summarizes the milestones in the development of roxadustat leading to this first approval.

Keam, Susan J.

doi: 10.1007/s40265-019-01076-2pmid: 30805896

Toripalimab, a recombinant, humanized programmed death receptor-1 (PD-1) monoclonal antibody that binds to PD-1 and prevents binding of PD-1 with programmed death ligands 1 (PD-L1) and 2 (PD-L2), is being developed by Shanghai Junshi Bioscience Co., Ltd in China for the treatment of various cancers. In December 2018, based on positive efficacy results of a phase 2 trial and safety data from several clinical studies, toripalimab received conditional approval in China for the treatment of unresectable or metastatic melanoma that has failed previous systemic therapy. This article summarizes the milestones in the development of toripalimab leading to this first global approval for the treatment of unresectable or metastatic melanoma.

Syed, Yahiya

doi: 10.1007/s40265-019-01087-zpmid: 30859413

Tagraxofusp (tagraxofusp-erzs) [Elzonris™] is an intravenously administered CD123-directed cytotoxin (composed of human interleukin-3 and a truncated diphtheria toxin payload) that was developed by Stemline Therapeutics, Inc. for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). In December 2018, tagraxofusp received its first global approval in the USA for the treatment of BPDCN in adults and in paediatric patients aged 2 years and older. A centralized registration application for the use of tagraxofusp in patients with BPDCN is under review in the EU. This article summarizes the milestones in the development of tagraxofusp leading to its first global approval for the treatment of BPDCN.