Drugs

Herr, Florence; Brunel, Melanie; Roders, Nathalie; Durrbach, Antoine

doi: 10.1007/s40265-016-0656-2pmid: 27785759

Long-term survival of solid allografts depends on both immunosuppressive efficacy and reducing the side effects associated with these therapies. Immunotherapies developed over the past 15 years to prevent organ rejection have greatly improved cardiovascular and renal function compared with classical therapies, such as calcineurin inhibitors and corticosteroids. Immunotherapies that target T cells through the co-stimulation blockade (CTLA-4-Ig) improve renal function and the survival of grafts and patients, but are associated with higher rates of T-cell-mediated acute rejection. Improvements to safe and efficacious therapeutic options could combine a co-stimulation blockade with a depleting immunotherapy. Herein, we describe the clinical outcomes and the likely causes of defects in the co-stimulation blockade, and comment on new therapeutic strategies to overcome these. Great progress has been made to optimize immunotherapy using the co-stimulation blockade, but the therapeutic combinations should be assessed further.

Brito-Zerón, Pilar; Retamozo, Soledad; Gheitasi, Hoda; Ramos-Casals, Manuel

doi: 10.1007/s40265-016-0659-zpmid: 27844414

Sjögren Syndrome (SS) is a systemic autoimmune disease with a wide clinical spectrum that extends from sicca symptoms of the mucosal surfaces to extra-glandular systemic manifestations. Understanding of the pathophysiology of primary SS has advanced over recent years, and this, in turn, has presented new targeted treatment options. We provide a brief, up-to-date description of the pathophysiology of SS and the main etiopathogenic pathways implicated in the disease process and review clinical evidence in support of new treatment options targeting these pathways, highlighting successes and failures, and concluding with a summary of gaps in knowledge and where future research should be focused. Direct and indirect B-cell targeted therapies are currently the most promising biological agents in primary SS, especially for systemic involvement, but other pathways (T-cell co-stimulation, cytokine-based therapies, intracellular pathways and gene therapies) are under development. The next 10 years may witness a disruptive therapeutic scenario in primary SS.

Anderholm, K. M.; Bierle, C. J.; Schleiss, M. R.

doi: 10.1007/s40265-016-0653-5pmid: 27882457

Congenital human cytomegalovirus (HCMV) infection can result in severe and permanent neurological injury in newborns, and vaccine development is accordingly a major public health priority. HCMV can also cause disease in solid organ transplant (SOT) and hematopoietic stem-cell transplant (HSCT) recipients, and a vaccine would be valuable in prevention of viremia and end-organ disease in these populations. Currently there is no licensed HCMV vaccine, but progress toward this goal has been made in recent clinical trials. A recombinant HCMV glycoprotein B (gB) vaccine has been shown to have some efficacy in prevention of infection in young women and adolescents, and has provided benefit to HCMV-seronegative SOT recipients. Similarly, DNA vaccines based on gB and the immunodominant T-cell target, pp65 (ppUL83), have been shown to reduce viremia in HSCT patients. This review provides an overview of HCMV vaccine candidates in various stages of development, as well as an update on the current status of ongoing clinical trials. Protective correlates of vaccine-induced immunity may be different for pregnant woman and transplant patients. As more knowledge emerges about correlates of protection, the ultimate licensure of HCMV vaccines may reflect the uniqueness of the target populations being immunized.

Shirley, Matt; Scott, Lesley

doi: 10.1007/s40265-016-0652-6pmid: 27766566

Isavuconazole is a second-generation triazole with activity against a broad spectrum of clinically important fungi. Its water-soluble prodrug, isavuconazonium sulfate (Cresemba®), available in interchangeable intravenous and oral formulations, is approved in the USA and EU for the treatment of adults with invasive aspergillosis and mucormycosis. In international phase III clinical trials, isavuconazole was efficacious and generally well tolerated in the treatment of these life-threatening diseases. In the phase III SECURE trial, isavuconazole was non-inferior to voriconazole for the primary treatment of invasive mould disease (primarily aspergillosis) and was associated with fewer drug-related treatment-emergent adverse events (TEAEs) than voriconazole. In addition, the single-arm, phase III VITAL trial and a matched case–control analysis of isavuconazole- versus amphotericin B-treated patients provided evidence of the efficacy of isavuconazole in the treatment of mucormycosis. The most commonly reported TEAEs among isavuconazole recipients were gastrointestinal disorders such as nausea, vomiting and diarrhoea. Isavuconazole has several other attributes that make it a useful new treatment option for these invasive mould diseases, including predictable pharmacokinetics, excellent bioavailability, no food effect with the oral formulation, and its potential utility in renally impaired patients given the absence of cyclodextrin in the intravenous formulation.

Scott, Lesley

doi: 10.1007/s40265-016-0654-4pmid: 27766567

Intravenous ceftaroline fosamil (Zinforo™), a prodrug that is rapidly converted to its active metabolite ceftaroline, is approved for use in adults and children (from 2 months of age) with complicated skin and soft tissue infections (cSSTIs) or community-acquired pneumonia (CAP). In several multinational trials, ceftaroline fosamil was an effective and generally well tolerated treatment in adult and paediatric patients with cSSTIs or CAP. In the phase 3 CANVAS trials, ceftaroline fosamil treatment was noninferior to vancomycin plus aztreonam in adults with cSSTIs. Based on a meta-analysis of three similarly designed, phase 3 trials (FOCUS 1, FOCUS 2 and an Asian trial), ceftaroline fosamil treatment was superior to ceftriaxone in adults with CAP of Pneumonia Outcomes Research Teams (PORT) risk class III or IV. Ceftaroline fosamil was also associated with high clinical cure rates in hospitalized children (aged 2 months to 17 years) with cSSTIs or CAP. With its broad spectrum of in vitro activity against clinically relevant Gram-positive [including methicillin-resistant Staphylococcus aureus (MRSA) and drug-resistant Streptococcus pneumoniae isolates] and Gram-negative pathogens implicated in cSSTIs and CAP, ceftaroline fosamil is an important treatment option for cSSTI and CAP in adults and children from the age of 2 months.

Frampton, James

doi: 10.1007/s40265-016-0655-3pmid: 27807822

Vortioxetine (Brintellix®; Trintellix®), a generally efficacious and well tolerated antidepressant agent, is approved in the EU and USA for the treatment of major depressive disorder (MDD) in adults. The drug has a distinctive pharmacological profile (combining inhibition of the serotonin transporter with modulation of multiple serotonin receptors) and has been shown to enhance cognitive performance in various animal models and clinical trials. Across three large, placebo-controlled studies in adults with recurrent MDD, short-term treatment with vortioxetine almost always resulted in statistically significant and clinically meaningful improvements in performance on two objective measures (the Digit Symbol Substitution Test and Rey Auditory Verbal Learning Test) that together cover a broad range of cognitive domains, including executive function, attention, processing speed, learning and memory. Vortioxetine also significantly improved a subjective measure of cognitive function (the Perceived Deficits Questionnaire) and an objective measure of functional capacity (the University of San Diego performance-based skills assessment). In general, the beneficial effects of vortioxetine on these measures were largely independent of its effect on improving depressive symptoms. Based on the available data, therefore, vortioxetine is a useful treatment option in patients with MDD where impaired cognitive function is apparent.

Dhillon, Sohita

doi: 10.1007/s40265-016-0662-4pmid: 27864686

Zoledronic acid (Reclast®, Aclasta®) is an intravenous, highly potent aminobisphosphonate approved worldwide, including in the USA, EU and Japan for use in patients with primary or secondary osteoporosis or low bone mass (approved indications vary between countries). Its high affinity to and long half-life in bone, and long duration of action, allow for once-yearly administration, which has the potential to improve adherence to therapy. Zoledronic acid once yearly for up to 3 years improved bone mineral density (BMD) at several skeletal sites, reduced fracture risk and bone turnover, and/or preserved bone structure and mass relative to placebo in clinical studies in patients with primary or secondary osteoporosis. While additional benefits were seen when treatment was continued for up to 6 years, as evidenced by a reduced risk of vertebral fractures and higher BMD relative to 3 years’ therapy, there was minimal advantage of treatment beyond 6 years. Therefore, in patients with low fracture risk, treatment discontinuation should be considered after approximately 5 years’ therapy. Zoledronic acid administered annually or once in 2 years was also effective in preventing bone loss in patients with low bone mass. Zoledronic acid was generally well tolerated, with the most common adverse events (AEs) being transient, mild-to-moderate post-infusion symptoms, which decreased with subsequent infusions. To conclude, zoledronic acid once yearly is an effective and generally well tolerated treatment option for patients with osteoporosis.

Syed, Yahiya

doi: 10.1007/s40265-016-0657-1pmid: 27807823

Eteplirsen (Exondys 51) is an antisense oligonucleotide designed to induce exon 51 skipping that is developed by Sarepta Therapeutics. Intravenous eteplirsen has received accelerated approval from the US FDA for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation of the DMD gene amenable to exon 51 skipping. Eteplirsen has orphan drug designation in the USA and EU, and rare paediatric disease designation in the USA for use in DMD. In the phase III PROMOVI trial, eteplirsen significantly increased dystrophin levels from baseline in muscle tissues of 12 evaluable patients with DMD after 48 weeks of treatment. This finding is supported by data from phase II trials. Long-term treatment with eteplirsen was associated with a decrease in the rate of decline in ambulation and pulmonary function in an open-label extension of a phase II trial. Eteplirsen was generally well tolerated in clinical trials. This article summarizes the milestones in the development of eteplirsen leading to this first approval for DMD.