Drugs

Bichoupan, Kian; Dieterich, Douglas T.

doi: 10.1007/s40265-014-0232-6pmid: 24866024

Approximately 30 % of HIV-infected patients are co-infected with hepatitis C virus (HCV). After the release of highly active antiretroviral therapy, liver disease has become the leading cause of morbidity and mortality in HIV patients. Prior to 2011, HCV treatment with pegylated-interferon and ribavirin in HCV/HIV co-infected patients only allowed 14–38 % of patients with HCV genotype 1 to achieve a sustained virologic response (SVR). Additionally, treatment was commonly discontinued as a result of adverse events. Recently, simeprevir and sofosbuvir have been approved by the US Food and Drug Administration (FDA) for HCV mono-infection. Sofosbuvir has been given FDA approval in co-infected patients offering unprecedented SVR rates and the potential for interferon-free therapy. HCV therapies that are in the pipeline offer improved treatment times, safety profiles, and rates of SVR. Despite these improvements, several new issues including adherence, drug–drug interactions with antiretroviral therapies, adverse events, resistance, and patient selection may complicate therapy. This article reviews the current status of direct-acting antivirals (DAA)-containing regimens for HIV/HCV co-infected patients in the USA. New results investigating telaprevir and boceprevir are also discussed as they are relevant for locations where new DAAs are not available. The impact future interferon-free therapies may have on co-infected patients is also discussed.

Qasim, Waseem; Gennery, Andrew

doi: 10.1007/s40265-014-0223-7pmid: 24848753

Gene therapy using autologous haematopoietic stem cells offers a valuable treatment option for patients with primary immunodeficiencies who do not have access to an HLA-matched donor, although such treatments have not been without their problems. This review details gene therapy trials for X-linked and adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID), Wiskott–Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). X-linked SCID was chosen for gene therapy because of previous ‘natural’ genetic correction through a reversion event in a single lymphoid precursor, demonstrating limited thymopoiesis and restricted T-lymphocyte receptor repertoire, showing selective advantage of progenitors possessing the wild-type gene. In early studies, patients were treated with long terminal repeats-intact gamma-retroviral vectors, without additional chemotherapy. Early results demonstrated gene-transduced cells, sustained thymopoiesis, and a diverse T-lymphocyte repertoire with normal function. Serious adverse effects were subsequently reported in 5 of 20 patients, with T-lymphocyte leukaemia developing, secondary to the viral vector integrating adjacent to a known oncogene. New trials using self-inactivating gamma-retroviral vectors are progressing. Trials for ADA-SCID using gamma-retroviral vectors have been successful, with no similar serious adverse effects reported; trials using lentiviral vectors are in progress. Patients with WAS and CGD treated with early gamma-retroviral vectors have developed similar lymphoproliferative adverse effects to those seen in X-SCID—current trials are using new-generation vectors. Targeted gene insertion using homologous recombination of corrected gene sequences by cellular DNA repair pathways following targeted DNA breakage will improve efficacy and safety of gene therapy. A number of new techniques are discussed.

Chrusciel, Piotr; Rysz, Jacek; Banach, Maciej

doi: 10.1007/s40265-014-0233-5pmid: 24902800

Trimetazidine is a cytoprotective drug whose cardiovascular effectiveness, especially in patients with stable ischemic heart disease, has been the source of much controversy in recent years; some have gone so far as to treat the medication as a ‘placebo drug’ whose new side effects, such as Parkinsonian symptoms, outweigh its benefits. This article is an attempt to present the recent key studies, including meta-analyses, on the use of trimetazidine in chronic heart failure, also in patients with diabetes mellitus and arrhythmia, as well as in peripheral artery disease. This paper also includes the most recent European Society of Cardiology guidelines, including those of 2013, on the use of trimetazidine in cardiovascular disease.

Hornung, Thorsten; Wenzel, Joerg

doi: 10.1007/s40265-014-0240-6pmid: 24939511

Dermatomyositis (DM) is an autoimmune disease mainly affecting muscle and skin. Typical clinical and laboratory findings include muscle weakness with elevated muscle enzymes, characteristic skin lesions (e.g., Gottron papules, heliotrope erythema, Shawl sign), and specific serum autoantibodies. Recent studies have highlighted the activation of the innate immune system, including high expression of interferons (IFNs) and IFN-regulated proteins, as an important pathological hallmark of DM. These findings have changed our understanding of the disease fundamentally, since inappropriate activation of the innate immune system with secondary dysregulation of the adaptive immune response is now considered to be a central pathogenetic feature of DM. In this article, we review current guidelines and standards in diagnosis and treatment. We detail evidence-based and pathophysiology-based treatment strategies, with a focus on skin as well as on muscle lesions. Particularly, we discuss how the recent advances in the understanding of the pathomechanisms of DM have altered our conception of the mode of action of established drugs such as chloroquine and methotrexate. Finally, we outline possible future treatment strategies, with a focus on the innate immune system, e.g., targeting the IFN system with the anti-IFN-α antibody sifalimumab.

Dhillon, Sohita

doi: 10.1007/s40265-014-0239-zpmid: 24919863

Certolizumab pegol (Cimzia®) is a polyethylene glycolylated antigen-binding fragment of a recombinant human monoclonal antibody that binds to and selectively neutralizes tumour necrosis factor (TNF) α. In the EU, subcutaneous certolizumab pegol is indicated for the treatment of adults with severe active axial spondyloarthritis (axSpA), comprising ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA), and for adults with active psoriatic arthritis (PsA). In the USA it is indicated for the treatment of adults with active AS or active PsA. This article reviews the efficacy and tolerability of certolizumab pegol in these patients and briefly summarizes its pharmacology. In two ongoing, well-designed studies, data at 12 and 24 weeks showed that treatment with certolizumab pegol (200 mg every 2 weeks or 400 mg every 4 weeks) was effective in improving the clinical signs and symptoms of disease, health-related quality of life and productivity in patients with axSpA (the RAPID-axSpA study) or PsA (the RAPID-PsA study), with the improvements maintained during longer-term (48 weeks) treatment. Within the axSpA population, clinical benefits with certolizumab pegol were seen both in patients with AS and in those with nr-axSpA. In addition, 12 weeks’ treatment with certolizumab pegol reduced inflammation in the sacroiliac joints and spine in patients with axSpA and 24 weeks’ treatment with the agent slowed radiographic disease progression in patients with PsA. Certolizumab pegol was generally well tolerated in these studies, with a tolerability profile consistent with that seen in previous clinical trials in other indications. Although additional long-term and comparative data are needed to position certolizumab pegol with respect to other TNFα antagonists, current evidence indicates that certolizumab pegol is an effective option for the treatment of axSpA (including AS and nr-axSpA) and PsA.

Shirley, Matt; Plosker, Greg

doi: 10.1007/s40265-014-0238-0pmid: 24919862

Deferasirox (Exjade®) is a once-daily orally administered iron chelator which has been approved for use in the treatment of transfusional-dependent chronic iron overload since 2005. Based primarily on the findings of the THALASSA (Assessment of Exjade® in Non-Transfusion-Dependent THALASSemiA) trial, the approval for deferasirox has recently been expanded to include the management of chronic iron overload in patients with non-transfusion-dependent thalassaemia (NTDT) syndromes. Despite the lack of regular blood transfusions, NTDT patients can still develop clinically relevant iron overload, primarily due to increased gastrointestinal absorption secondary to ineffective erythropoiesis, and may require chelation therapy. The THALASSA trial, the first placebo-controlled clinical trial of an iron chelator in NTDT patients, demonstrated that deferasirox was effective in reducing liver iron and serum ferritin levels in this population. Deferasirox has an acceptable tolerability profile, with the most common adverse events reported in the THALASSA trial being related to mild to moderate gastrointestinal disorders. Although further long-term studies will be required to clearly demonstrate the clinical benefit of chelation therapy in NTDT patients, deferasirox presents a useful tool in the management of iron overload in this population.

McKeage, Kate

doi: 10.1007/s40265-014-0242-4pmid: 24919864

Ustekinumab (Stelara®) is a human monoclonal antibody that binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, blocking signalling of their cognate receptors. It is established in the treatment of moderate-to-severe plaque psoriasis, but recently received approval in adults with active psoriatic arthritis. Tumour necrosis factor (TNF) inhibitors remain first-line biological agents for the treatment of psoriatic arthritis, but alternative agents are needed. This article summarises the pharmacology of ustekinumab and reviews its use in phase 3 trials in psoriatic arthritis. In these trials, subcutaneous ustekinumab 45 or 90 mg was significantly more effective than placebo, as determined by American College of Rheumatology response criteria at week 24. The drug was also associated with significantly greater efficacy than placebo with regard to secondary endpoints, including the Psoriasis Area and Severity Index ≥75 % response, enthesitis and dactylitis scores, radiographic progression and Health Assessment Questionnaire-Disability Index scores. Response to ustekinumab was maintained during long-term therapy (up to week 100), and was achieved with and without concomitant methotrexate. Ustekinumab was generally well tolerated, and the tolerability profile in psoriatic arthritis was similar to that reported in plaque psoriasis. Throughout long-term ustekinumab treatment, serious infection or major cardiovascular adverse events occurred rarely. More data are needed to clearly define the place of ustekinumab in psoriatic arthritis treatment algorithms. Meanwhile the drug is a valuable additional option for patients with psoriatic arthritis in whom the response to previous non-biological disease-modifying antirheumatic drugs has been inadequate, or for those who have failed anti-TNF therapy.

Ryan, Nicola; Lo, Jin

doi: 10.1007/s40265-014-0241-5pmid: 24923253

Delamanid, a nitro-dihydro-imidazooxazole derivative, has been developed by Otsuka Pharmaceutical for the treatment of multidrug-resistant tuberculosis (MDR-TB). Delamanid received its first global approval for the treatment of MDR-TB in the European Union (EU), for use in combination with optimised background therapy. It is also under review for marketing in Japan for MDR-TB, the first drug application filed in Japan for this indication. Delamanid has been granted orphan drug status in both the EU and Japan. This article summarizes the milestones in the development of delamanid leading to this first approval for MDR-TB.

Poole, Raewyn; Vaidya, Asha

doi: 10.1007/s40265-014-0244-2pmid: 24916147

Ramucirumab (Cyramza™ [US]), a fully human immunoglobulin G1 (IgG1) monoclonal antibody that inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), has been developed by Eli Lilly (formerly ImClone Systems) for the treatment of cancer. Ramucirumab has received its first global approval in the US for use as monotherapy in the treatment of advanced or metastatic gastric cancer or gastro-oesophageal junction adenocarcinoma in patients who experience disease progression on or after fluoropyrimidine- or platinum-containing chemotherapy. Ramucirumab is the first treatment to be approved by the US FDA for this setting. This article summarizes the milestones in the development of ramucirumab leading to this first approval for the treatment of gastric cancer and gastro-oesophageal junction adenocarcinoma.

Nowlan, Mary; Scott, Lesley

doi: 10.1007/s40265-014-0236-2pmid: N/A