Drugs

Beecher, Grayson; Putko, Brendan; Wagner, Amanda; Siddiqi, Zaeem

doi: 10.1007/s40265-019-1065-0pmid: 30762205

Myasthenia gravis is a rare, heterogeneous, classical autoimmune disease characterized by fatigable skeletal muscle weakness, which is directly mediated by autoantibodies targeting various components of the neuromuscular junction, including the acetylcholine receptor, muscle specific tyrosine kinase, and lipoprotein-related protein 4. Subgrouping of myasthenia gravis is dependent on the age of onset, pattern of clinical weakness, autoantibody detected, type of thymic pathology, and response to immunotherapy. Generalized immunosuppressive therapies are effective in all subgroups of myasthenia gravis; however, approximately 15% remain refractory and more effective treatments with improved safety profiles are needed. In recent years, successful utilization of targeted B-cell therapies in this disease has triggered renewed focus in unraveling the underlying immunopathology in attempts to identify newer therapeutic targets. While myasthenia gravis is predominantly B-cell mediated, T cells, T cell–B cell interactions, and B-cell-related factors are increasingly recognized to play key roles in its immunopathology, particularly in autoantibody production, and novel therapies have focused on targeting these specific immune system components. This overview describes the current understanding of myasthenia gravis immunopathology before discussing B-cell-related therapies, their therapeutic targets, and the rationale and evidence for their use. Several prospective studies demonstrated efficacy of rituximab in various myasthenia gravis subtypes, particularly that characterized by antibodies against muscle-specific tyrosine kinase. However, a recent randomized control trial in patients with acetylcholine receptor antibodies was negative. Eculizumab, a complement inhibitor, has recently gained regulatory approval for myasthenia gravis based on a phase III trial that narrowly missed its primary endpoint while achieving robust results in all secondary endpoints. Zilucoplan is a subcutaneously administered terminal complement inhibitor that recently demonstrated significant improvements in functional outcome measures in a phase II trial. Rozanolixizumab, CFZ533, belimumab, and bortezomib are B-cell-related therapies that are in the early stages of evaluation in treating myasthenia gravis. The rarity of myasthenia gravis, heterogeneity in its clinical manifestations, and variability in immunosuppressive regimens are challenges to conducting successful trials. Nonetheless, these are promising times for myasthenia gravis, as renewed research efforts provide novel insights into its immunopathology, allowing for development of targeted therapies with increased efficacy and safety.

Pugh, Dan; Gallacher, Peter; Dhaun, Neeraj

doi: 10.1007/s40265-019-1064-1pmid: 30758803

Chronic kidney disease (CKD) is an increasingly prevalent condition globally and is strongly associated with incident cardiovascular disease (CVD). Hypertension is both a cause and effect of CKD and affects the vast majority of CKD patients. Control of hypertension is important in those with CKD as it leads to slowing of disease progression as well as reduced CVD risk. Existing guidelines do not offer a consensus on optimal blood pressure (BP) targets. Therefore, an understanding of the evidence used to create these guidelines is vital when considering how best to manage individual patients. Non-pharmacological interventions are useful in reducing BP in CKD but are rarely sufficient to control BP adequately. Patients with CKD and hypertension will often require a combination of antihypertensive medications to achieve target BP. Certain pharmacological therapies provide additional BP-independent renoprotective and/or cardioprotective action and this must be considered when instituting therapy. Managing hypertension in the context of haemodialysis and following kidney transplantation presents further challenges. Novel therapies may enhance treatment in the near future. Importantly, a personalised and evidence-based management plan remains key to achieving BP targets, reducing CVD risk and slowing progression of CKD.

Pagliuca, Martina; Buonerba, Carlo; Fizazi, Karim; Lorenzo, Giuseppe

doi: 10.1007/s40265-019-1060-5pmid: 30742279

Prostate cancer (PC) is a major health issue in developed countries, with, on the one hand, men suffering from sequelae related to unnecessary treatment of non-lethal PC, and, on the other hand, still dying because of advanced PC that progresses to castration-resistant disease. Systemic treatment is the mainstay of therapy of castration-resistant PC (CRPC). To date, a multitude of systemic agents have been tested and many of these have failed to provide a clinically meaningful benefit in CRPC, while others have been approved by the US Food and Drug Administration and/or the European Medicines Agency, including antiandrogen hormonal drugs (abiraterone, enzalutamide, apalutamide), chemotherapy (docetaxel and cabazitaxel), immunotherapy (Sipuleucel-T), and radiopharmaceutical (Radium-223) agents. In this review, systemic treatments regarded as most likely to have an impact in clinical practice are presented and discussed. In addition to the pivotal clinical studies, selected retrospective and non-randomized clinical trials are also discussed if deemed to have an impact on clinical practice or future research. A comprehensive appraisal of the expanding landscape of systemic therapies for advanced PC is provided from an expert perspective, with a focus on novel classification and diagnostic tools that have been paving the way for the development of precision medicine in PC.

Mata, Melinda; Gottschalk, Stephen

doi: 10.1007/s40265-019-01071-7pmid: 30796733

While impressive clinical responses have been observed using chimeric antigen receptor (CAR) T cells targeting CD19+ hematologic malignancies, limited clinical benefit has been observed using CAR T cells for a variety of solid tumors. Results of clinical studies have highlighted several obstacles which CAR T cells face in the context of solid tumors, including insufficient homing to tumor sites, lack of expansion and persistence, encountering a highly immunosuppressive tumor microenvironment, and heterogeneous antigen expression. In this review, we review clinical outcomes and discuss strategies to improve the antitumor activity of CAR T cells for solid tumors.

Lattanzi, Simona; Brigo, Francesco; Trinka, Eugen; Vernieri, Fabrizio; Corradetti, Tommaso; Dobran, Mauro; Silvestrini, Mauro

doi: 10.1007/s40265-019-01069-1pmid: 30793254

BackgroundNovel therapeutic options with improved efficacy and safety profiles are needed for the prophylaxis of migraine. In recent years, the inhibition of calcitonin gene-related peptide (CGRP) signaling has attracted growing interest in the pharmacological research on migraine. Erenumab is the first fully human monoclonal antibody directed against the CGRP receptor to be approved for use in migraineurs.ObjectiveTo evaluate the efficacy and safety of erenumab as preventive treatment in patients with migraine using meta-analytical techniques.MethodsRandomized, placebo-controlled, single- or double-blinded trials were identified through a systematic literature search (October week 4, 2018). Main outcomes included the changes from baseline in monthly migraine days (MMD) and monthly acute migraine-specific medication days (MSMD) at week 12, and the incidence of adverse events (AEs), severe AEs (SAEs) and treatment withdrawal due to AEs. Mean difference (MD) and risk ratio (RR) with 95% confidence intervals (95% CIs) were estimated.ResultsAcross the five included trials, erenumab given as a subcutaneous injection at a monthly dosage of 70 mg and 140 mg was associated with a significantly greater reduction in baseline MMD (70 mg: MD − 1.3, 95% CI − 1.7 to − 1.0, p < 0.001; 140 mg: MD − 1.9, 95% CI − 2.3 to − 1.4, p < 0.001) and MSMD (70 mg: MD − 1.0, 95% CI − 1.6 to − 0.4, p < 0.001; 140 mg: MD − 1.8, 95% CI − 2.5 to − 1.1, p < 0.001) than placebo. There were no differences in the occurrence of AEs, SAEs, and drug withdrawal due to AEs between the erenumab and placebo groups.ConclusionsErenumab is an efficacious and well tolerated preventive treatment in adult patients with episodic and chronic migraine.

Blair, Hannah

doi: 10.1007/s40265-019-01075-3pmid: 30793255

Secukinumab (Cosentyx®), a first-in-class fully human monoclonal antibody against interleukin-17A, is approved in several countries, including the USA and those of the EU, for the treatment of ankylosing spondylitis (AS). Subcutaneous secukinumab significantly improved the clinical signs and symptoms of AS versus placebo in three of four phase III trials. The benefits of secukinumab were generally seen regardless of whether patients had or had not received previous tumour necrosis factor (TNF) inhibitor therapy, and were sustained during longer-term (up to 5 years) treatment. Secukinumab was also associated with improvements in spinal mobility, physical function, health-related quality of life and work productivity in some of the trials. In MEASURE 1, secukinumab reduced inflammation in the sacroiliac joint, and slowed radiographic progression. Secukinumab was generally well tolerated during up to 5 years’ treatment; the most commonly reported adverse event was nasopharyngitis. In the minority of patients who developed anti-drug antibodies (ADAs), ADAs did not decrease efficacy or increase adverse events. In conclusion, secukinumab is an effective therapy for TNF inhibitor-naive patients with active AS, and provides a useful treatment option for patients who have an inadequate response to or are intolerant of TNF inhibitors.

Blair, Hannah A.

doi: 10.1007/s40265-019-01089-xpmid: 30859412

The article Secukinumab: A Review in Ankylosing Spondylitis, written by Hannah A. Blair, was originally published Online First without open access. After online publication Novartis Pharma AG requested that the article be Open Choice to make the article an open access publication.

Syed, Yahiya Y.

doi: 10.1007/s40265-019-01080-6pmid: 30830601

Intravenous daratumumab (DARZALEX®) is a human CD38 monoclonal antibody approved as combination therapy (with bortezomib, melphalan and prednisone) for patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplantation (ASCT). The approval was based on results of the phase 3 ALCYONE trial in which the addition of daratumumab to bortezomib, melphalan and prednisone significantly prolonged median progression-free survival (PFS) relative to bortezomib, melphalan and prednisone alone (primary endpoint). Daratumumab addition was also associated with deeper and durable responses relative to the comparator. The addition of daratumumab did not increase overall toxicity, with the exception of infusion-related reactions and increased rates of infections. The incidences of the most common grade 3 or 4 adverse events in the daratumumab group (neutropenia, thrombocytopenia and anaemia) were largely similar to those in the comparator group. Thus, daratumumab in combination with bortezomib, melphalan and prednisone represents a promising treatment option for patients with NDMM who are ineligible for ASCT.

Paik, Julia; Duggan, Sean; Keam, Susan

doi: 10.1007/s40265-019-01083-3pmid: 30847805

Triamcinolone acetonide extended-release (ER) 32 mg (Zilretta®) is approved in the USA for the management of osteoarthritis (OA) pain of the knee and is administered as a single, 5 mL intra-articular (IA) injection. Although the therapeutic effects from IA corticosteroids are typically short-lived, triamcinolone acetonide ER is formulated in poly (lactic-co-glycolic acid) (PLGA) microspheres that slowly release triamcinolone acetonide in the synovium, enabling their prolonged presence in the joint. This reduces systemic exposure and lessens corticosteroid-related systemic adverse reactions, such as blood glucose elevations. In a 24-week, randomized, phase III clinical trial, triamcinolone acetonide ER 32 mg significantly improved mean average daily pain intensity in patients with knee OA relative to placebo, and pain, stiffness and physical function (according to WOMAC criteria) relative to placebo and triamcinolone acetonide crystalline suspension (CS). Triamcinolone acetonide ER was generally well tolerated, with a tolerability profile similar to that of triamcinolone acetonide CS and placebo. Findings from a single-arm phase IIIb study indicated that a repeat administration of triamcinolone acetonide ER may be similarly efficacious to an initial injection without having deleterious effects on cartilage or other aspects of joint structure. Thus, triamcinolone acetonide ER expands the treatment options available for the management of OA pain of the knee.

Deeks, Emma D.

doi: 10.1007/s40265-019-01070-8pmid: 30778848

Mirogabalin besylate (hereafter mirogabalin) [Tarlige®] is an orally administered gabapentinoid developed by Daiichi Sankyo for the treatment of peripheral neuropathic pain (PNP), including diabetic PNP and post-herpetic neuralgia. The drug binds to and modulates the α2δ-1 subunit of the voltage-gated calcium channels widely found in the nervous system in areas that mediate pain transmission and processing. Mirogabalin has a unique binding profile and long duration of action. The drug is approved in Japan for the treatment of PNP and is in clinical development for this indication elsewhere in Asia. Clinical development of the drug for fibromyalgia pain was discontinued in the USA and EU after the primary endpoint was not met in phase 3 trials. No recent reports of development have been identified for PNP in the USA or India or for fibromyalgia pain in Australia, India, New Zealand, Russia, Argentina, Belarus, Chile, Colombia, Israel, Mexico, Switzerland, Canada, Serbia or South Africa. This article summarizes the milestones in the development of mirogabalin leading to this first approval for PNP.