Drugs

Amber, Kyle; Maglie, Roberto; Solimani, Farzan; Eming, Rüdiger; Hertl, Michael

doi: 10.1007/s40265-018-0976-5pmid: 30238396

Autoimmune bullous skin disorders are rare but meaningful chronic inflammatory diseases, many of which had a poor or devastating prognosis prior to the advent of immunosuppressive drugs such as systemic corticosteroids, which down-regulate the immune pathogenesis in these disorders. Glucocorticoids and adjuvant immunosuppressive drugs have been of major benefit for the fast control of most of these disorders, but their long-term use is limited by major side effects such as blood cytopenia, osteoporosis, diabetes mellitus, hypertension, and gastrointestinal ulcers. In recent years, major efforts were made to identify key elements in the pathogenesis of autoimmune bullous disorders, leading to the identification of their autoantigens, which are mainly located in desmosomes (pemphigus) and the basement membrane zone (pemphigoids). In the majority of cases, immunoglobulin G, and to a lesser extent, immunoglobulin A autoantibodies directed against distinct cutaneous adhesion molecules are directly responsible for the loss of cell-cell and cell-basement membrane adhesion, which is clinically related to the formation of blisters and/or erosions of the skin and mucous membranes. We describe and discuss novel therapeutic strategies that directly interfere with the production and regulation of pathogenic autoantibodies (rituximab), their catabolism (intravenous immunoglobulins), and their presence in the circulation and extravascular tissues such as the skin (immunoadsorption), leading to a significant amelioration of disease. Moreover, we show that these novel therapies have pleiotropic effects on various proinflammatory cells and cytokines. Recent studies in bullous pemphigoid suggest that targeting of immunoglobulin E autoantibodies (omalizumab) may be also beneficial. In summary, the introduction of targeted therapies in pemphigus and pemphigoid holds major promise because of the high efficacy and fewer side effects compared with conventional global immunosuppressive therapy.

Baldassari, Laura E.; Fox, Robert J.

doi: 10.1007/s40265-018-0984-5pmid: 30255442

Despite the fact that majority of patients with multiple sclerosis (MS) have relapsing-remitting disease, many transition to secondary progressive disease (SPMS) over time. This transition is thought to be related to neurodegenerative processes increasingly predominating over inflammatory processes as the driving forces of disability. However, some patients initially present with primary progressive disease (PPMS) that is characterized by a gradual accumulation of neurological symptoms and subsequent disability accumulation. The treatment of both PPMS and SPMS, collectively referred to as progressive MS, has proven quite challenging due to the multifactorial and poorly understood pathophysiology of multiple sclerosis in general, specifically that of progressive disease. The purpose of this article is to discuss important clinical and pathophysiologic differences between relapsing and progressive forms of MS, review previous notable trials of drugs in progressive MS, examine current literature regarding recent and promising progressive MS treatments, and discuss future considerations for progressive MS therapeutics and management. Specifically, the current evidence regarding treatment of progressive MS with ocrelizumab, simvastatin, ibudilast, alpha-lipoic acid, high-dose biotin, siponimod, and cell-based therapies are discussed.

Manolis, Antonis; Manolis, Theodora; Manolis, Antonis

doi: 10.1007/s40265-018-0985-4pmid: 30251174

Results from recent cardiovascular outcome trials have ushered in a new era in the management of type 2 diabetes mellitus, moving from a focus on glycemic control to the cardiovascular safety of antihyperglycemic agents. Several new antihyperglycemic drugs have been shown to exert either neutral or cardioprotective effects in patients with diabetes. Among them, the sodium–glucose co-transporter-2 (SGLT-2) inhibitors (gliflozins) and selected agents from the incretin mimetics or enhancers, such as the glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins), appear to confer cardiovascular safety and/or protection in patients with underlying, or at high risk for, cardiovascular disease. Metformin remains the standard first-line drug treatment for patients with diabetes because of its established effectiveness and cardiovascular safety. However, this initial drug therapy may not prove adequate as this disease appears to be progressive with a decline in function of the pancreatic beta cells, necessitating the addition of other agents to better control rising glucose levels. With the advent of several new classes of antihyperglycemic drugs and the completion of their respective cardiovascular outcome trials, the therapeutic armamentarium against this disease pandemic appears to be greatly expanding and moving closer to the direction of the Hippocratic aphorism “Do Good or Do No Harm”. In this review, we discuss all these issues and summarize the contemporary literature on cardiovascular safety and outcomes of the available glucose-lowering agents.

Vazouras, Konstantinos; Basmaci, Romain; Bielicki, Julia; Folgori, Laura; Zaoutis, Theoklis; Sharland, Mike; Hsia, Yingfen

doi: 10.1007/s40265-018-0988-1pmid: 30311096

Hoy, Sheridan

doi: 10.1007/s40265-018-0991-6pmid: 30306338

Sodium zirconium cyclosilicate (Lokelma™) [hereafter referred to as SZC] is a non-absorbed, non-polymer zirconium silicate compound that preferentially exchanges hydrogen and sodium for potassium and ammonium ions in the gastrointestinal tract (GIT), thereby increasing faecal potassium excretion and lowering serum potassium levels. It is available as a powder for oral suspension (in water) and is approved in the EU and the USA for the treatment of hyperkalaemia in adults. In two multinational, phase III studies in adults with hyperkalaemia, SZC 10 g three times daily lowered serum potassium levels to within the normal range (3.5–5.0 mmol/L) during the first 48 h of treatment, and SZC 5 and 10 g once daily maintained normokalaemia over ≤ 28 days’ therapy. These beneficial effects were consistent across all patient subgroups (e.g. chronic kidney disease, diabetes, heart failure, concomitant use of RAAS inhibitor therapy), and appeared to be maintained over the longer term (≤ 12 months). SZC was generally well tolerated in adults with hyperkalaemia. Its tolerability profile was generally similar to that seen with placebo over ≤ 28 day, and its safety profile appeared to remain consistent over the longer term (≤ 12 months). Moreover, the incidence of hypokalemia was low. Current evidence indicates that SZC is a promising therapy for the management of hyperkalaemia in adults.

Shirley, Matt

doi: 10.1007/s40265-018-0995-2pmid: 30317521

Dinoprostone vaginal insert (Cervidil®; Propess®), a retrievable vaginal pessary containing 10 mg of dinoprostone [prostaglandin E2 (PGE2)] in a controlled-release drug delivery device, is approved in many countries worldwide for the initiation (or continuation) of cervical ripening in patients at term prior to labour induction. The device is designed to provide a constant and sustained release of dinoprostone to the cervix to promote the complex processes involved in cervical ripening. The vaginal insert is attached to a retrieval system that facilitates easy removal of the device at the onset of labour or in the event of complications. The effectiveness of dinoprostone vaginal insert has been demonstrated in a vast range of randomized clinical trials in women at term. The agent is well tolerated, with a generally favourable safety profile, both maternal and foetal/neonatal. As with all prostaglandin agents used in cervical ripening, dinoprostone vaginal insert is associated with a risk of uterine hyperstimulation. However, this is generally rapidly reversible upon removal of the insert. The demonstrated effectiveness and safety of the device, combined with the benefits of controlled drug release from a simple, single application, and efficient dose control, suggest that dinoprostone vaginal insert is a valuable option for promoting cervical ripening in patients with an unfavourable cervix at term.

Hoy, Sheridan

doi: 10.1007/s40265-018-0983-6pmid: 30251172

Patisiran (ONPATTRO™) is a double-stranded small interfering RNA encapsulated in a lipid nanoparticle for delivery to hepatocytes. By specifically binding to a genetically conserved sequence in the 3′ untranslated region of mutant and wild-type transthyretin (TTR) messenger RNA, patisiran causes its degradation (via RNA interference) and subsequently a reduction in serum TTR protein levels and tissue TTR protein deposits. Patisiran has been developed by Alnylam Pharmaceuticals; it was recently approved in the USA for the treatment of the polyneuropathy of hereditary TTR-mediated amyloidosis (hATTR) in adults and subsequently approved in the EU for the treatment of hATTR in adults with stage 1 or 2 polyneuropathy. The recommended dosage, administered as a single intravenous infusion over approximately 80 min, is 0.3 mg/kg once every 3 weeks for patients weighing < 100 kg and 30 mg once every 3 weeks for patients weighing ≥ 100 kg. This article summarizes the milestones in the development of patisiran leading to these approvals.

Syed, Yahiya

doi: 10.1007/s40265-018-0987-2pmid: 30267321

Shire is developing lanadelumab (Takhzyro™) for the prevention of hereditary angioedema (HAE) attacks. Lanadelumab is a fully human monoclonal antibody that inhibits plasma kallikrein. Mutations in the SERPING1 gene lead to C1 inhibitor deficiency or dysfunction, resulting in uncontrolled plasma kallikrein activity, which in turn produces excessive bradykinin, a vasodilator thought to cause angioedema symptoms. Subcutaneous administration of lanadelumab significantly reduced HAE attacks versus placebo in patients aged ≥ 12 years with type I or II HAE in a phase III trial. Based on these results, lanadelumab is recently approved in the USA for the prevention of HAE attacks in patients aged ≥ 12 years. It is also preregistered in the EU, Canada, Australia and Switzerland. This article summarizes the milestones in the development of lanadelumab leading to this first approval.

Duggan, Sean

doi: 10.1007/s40265-018-0989-0pmid: 30298461

Ablynx, a Sanofi Company, has developed the anti-von Willebrand factor Nanobody® caplacizumab (Cablivi™) for the treatment of acquired thrombotic thrombocytopenic purpura (aTTP). Based on positive results in phase II and III trials in patients with aTTP, caplacizumab was recently approved in the EU for the treatment of adults experiencing an episode of aTTP, in conjunction with plasma exchange and immunosuppression. This article summarizes the milestones in the development of caplacizumab leading to this first approval.

Deeks, Emma

doi: 10.1007/s40265-018-0993-4pmid: 30341683

Doravirine is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) developed by Merck & Co for the treatment of HIV-1 infection. The drug is approved in the USA both as a single-agent tablet (Pifeltro™) and as a fixed-dose combination tablet with the nucleos(t)ide reverse transcriptase inhibitors lamivudine and tenofovir disoproxil fumarate (Delstrigo™). Each formulation is indicated in the USA for treating HIV-1 infection in adults with no prior antiretroviral treatment, has received a positive opinion in the EU for treating HIV-1 infection in adults without resistance to NNRTIs or (in the case of the fixed-dose combination tablet) lamivudine or tenofovir, and is also under regulatory review for the treatment of HIV-1 infection in Canada. This article summarizes the milestones in the development of doravirine leading to this first approval for the treatment of HIV-1 infection in treatment-naïve adults.