Ezetimibe plus simvastatin for the treatment of hypercholesterolemia

Introduction: Cardiovascular disease is a major cause of death, and hypercholesterolemia is a major risk factor. Statins, with simvastatin among the most widely used, have ample evidence demonstrating prevention of cardiovascular events and mortality. Ezetimibe is effective at improving serum lipids in combination with statins or alone, but its role has been controversial.

Areas covered: Here, we provide an overview of the pharmacokinetics and pharmacodynamics of each component of the combination, as well as pharmacogenetic contributors. Regarding clinical efficacy, our focus will be on the post-marketing clinical trials of ezetimibe–simvastatin combination therapy. We broach the controversy around the role of ezetimibe, particularly in light of the results of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT).

Expert opinion: Ezetimibe in combination with simvastatin or other statins provides an excellent means of incremental lipid-lowering effect, although the clinical benefit has been uncertain. IMPROVE-IT is the first to demonstrate incremental cardiovascular risk reduction with the addition of ezetimibe to simvastatin. What the literature lacks is evidence around the common use of ezetimibe as monotherapy or add-on therapy to lower doses of statins in patients who fail to achieve adequate lipid lowering or do not tolerate high-dose statins.     

Importance of potent P2Y12 receptor blockade in acute myocardial infarction: focus on prasugrel

Introduction: Angiogenesis plays a crucial role in the proliferation and in the metastatic spread of tumour cells. Several agents with anti-angiogenic activity have been tested in advanced non-small-cell lung cancer (NSCLC) patients. Motesanib (AMG 706) is a promising anti-angiogenic multi-targeted tyrosine kinase inhibitor (TKI), which has been investigated as a monotherapy or in combination with chemotherapy, in several types of cancer.

Areas covered: We have reviewed the literature, and we have presented the results of clinical trials that have investigated the administration of motesanib in advanced NSCLC patients.

Expert opinion: Encouraging results have been described with the administration of motesanib as first-line treatment in combination with carboplatin and paclitaxel in Asian patients with non-squamous advanced NSCLC. Further studies are needed in order to identify the predictive biomarkers of response and to select patients who may benefit from this anti-angiogenic treatment.     

Future of combination therapy with dabrafenib and trametinib in metastatic melanoma

Introduction: Combination therapy with BRAF and MEK inhibitors is a recommended treatment strategy for metastatic melanoma patients with BRAF^V600 mutations. This treatment provides significant response rates and little added toxicity, with relatively improved survival outcomes compared to RAF/MEK inhibitor monotherapy and chemotherapy.

Areas covered: This review covers the pharmacology, efficacy, and toxicity data derived from clinical studies of dabrafenib, trametinib, and the combination thereof. The major downfall of combiDT is the limited durability of response, which is largely due to acquired resistance in the MAPK pathway.

Expert opinion: Future directions of combiDT concentrate on further combinations with immunotherapy or other targeted inhibitors, referred to triple-agent therapy, which may be essential to improving durability of responses and overcoming resistance.     

Safety analysis of sofosbuvir and ledipasvir for treating hepatitis C

Introduction: The approval of sofosbuvir (SOF), a nucleotide analogue NS5B polymerase inhibitor, and ledipasvir (LDV), a NS5A inhibitor, marked a new chapter in IFN and ribavirin-free treatment of hepatitis C virus (HCV). This drug reduces adverse events associated with IFN therapy.

Areas Covered: The purpose of this paper is to evaluate the safety and efficacy of LDV/SOF. Clinical trials illustrating safety and efficacy of LDV/SOF are reviewed and compared to other IFN and ribavirin-free treatment options available.

Expert Opinion: In trials enrolling more than 3000 patients, LDV/SOF is well tolerated with a good safety and side-effect profile in diverse cohorts, including previous direct-acting antiviral (DAA) treatment failures, liver transplant recipients, decompensated cirrhosis and HIV/HCV co-infection. As with all DAAs, the potential for drug–drug interactions must be carefully evaluated, as demonstrated by recent post-marketing reports of symptomatic bradycardia when LDV/SOF is co-administered with amiodarone. Currently, dose recommendations cannot be given for patients with advanced renal disease. Trials in this population are ongoing, more study is warranted. When surveying the DAA regimens available, efficacy, safety and tolerability of LDV/SOF is comparable or better, and LDV/SOF provides an option with convenient single-tablet, once daily, ribavirin-free dosing with relatively few significant drug–drug interactions.     

Ixazomib for the treatment of multiple myeloma

Introduction: Proteasome inhibition is a mainstay in the treatment of multiple myeloma (MM). Bortezomib, the first proteasome inhibitor (PI) approved for MM therapy, has shown efficacy in relapsed/refractory patients and in the front-line setting. Among second-generation PIs, MLN9708 (ixazomib) is the first oral compound to be evaluated in MM treatment and has shown improvement in pharmacokinetic and pharmacodynamic parameters compared with bortezomib with a similar efficacy in the control of myeloma growth and in the prevention of bone loss.

Areas covered: In this review, the authors discuss the rationale for use of PIs. They then summarize the clinical development of ixazomib in MM, from initial Phase I to Phase II studies as a monotherapy and in combination with other chemotherapeutics.

Expert opinion: Preliminary data of Phase I/II trials showed that ixazomib had a good safety profile and exerted anti-myeloma activity as a single agent in relapsed/refractory patients. Furthermore, ixazomib also had efficacy in patients who were refractory to bortezomib. Its use in combination with lenalidomide and dexamethasone was shown to be an effective and well-tolerated regimen in up-front treatment leading to minimal residual disease negativity in a significant number of patients. Results of Phase III trials, evaluating ixazomib in induction or maintenance therapy, are awaited.     

An update on the use of lenalidomide for the treatment of multiple myeloma

Introduction: Lenalidomide, an immunomodulatory agent with unique mechanism of action, represents the cornerstone in the treatment of patients with multiple myeloma (MM) providing rapid and sustained control of the disease with a manageable safety profile.

Areas covered: This review article, synthesizing all available data coming from trials and evaluating the efficacy and safety of lenalidomide in patients with MM, tries to provide to the clinicians with an easy-to-grasp synopsis of recent and clinically meaningful advances on the field.

Expert opinion: Lenalidomide combined with dexamethasone is a safe and effective option for newly diagnosed MM patients ineligible for autologous stem cell transplantation (ASCT). Long-term administration of the agent as continuous treatment for ineligible for ASCT patients or maintenance therapy after ASCT has documented unprecedented progression-free survival improvements, whereas lenalidomide in combination with dexamethasone has shown deep and durable remissions for patients with relapsed and/or refractory disease.     

Apremilast as a treatment for psoriasis

Introduction: S-1 is an oral fluoropyrimidine that consists of tegafur, 5-chloro-2, 4-dihydroxypyridine and potassium oxonate. It has been developed as a prodrug of 5-fluorouracil with the goal of improving therapeutic efficacy and tolerability.

Areas covered: This review aims to provide an evidence-based update of clinical trials that have investigated the clinical efficacy, adverse-event profile, dosage and administration of S-1, given alone or in combination with conventional chemotherapeutics and new target-oriented drugs, in the management of colorectal cancer (CRC). Additionally, differences in the tolerability and pharmacokinetics of S-1 between Caucasians and Asians have been described. Finally, the therapeutic efficacy of S-1 regarding metastatic CRC or postoperative CRC has been discussed. Available data have stimulated further research, including Phase III trials for the treatment of advanced CRC.

Expert opinion: Treatment using S-1 combined with oxaliplatin (± bevacizumab) and irinotecan has achieved promising results in terms of feasibility, safety and effectiveness. Furthermore, S-1 is an acceptable treatment as adjuvant chemotherapy for colon cancer.     

Apatinib for the treatment of gastric cancer

Introduction: Antiangiogenesis therapy plays an important role in cancer treatment. Apatinib mesylate, a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, has been recommended as third-line treatment for metastatic gastric cancer patients.

Areas covered: The current review summarizes the publications and conference reports relating to apatinib from preclinical and clinical research in gastric cancer. Apatinib showed good safety, tolerance and treatment efficacy in Phase I/II studies. In a Phase III study, apatinib prolonged the median overall survival of patients with chemotherapy-refractory metastatic gastric cancer by 55 days and the median progression-free survival by 25 days compared with placebo.

Expert opinion: Apatinib is a new treatment option for advanced gastric cancer. Apatinib is expected to have a broader application when it has been evaluated worldwide. The key issues are to find biomarkers and overcome drug resistance.     

Drug safety evaluation of apremilast for treating psoriatic arthritis

Introduction: Apremilast is an orally available small molecule that targets PDE4. PDE4 modulates intracellular signaling and thereby can impact various proinflammatory and anti-inflammatory mediators. Apremilast has been approved by the USA FDA for the treatment of active psoriatic arthritis (PsA) and moderate-to-severe psoriasis (PsO). Although there are several therapies approved and used for the treatment of PsA, there is still an unmet need for additional effective and well-tolerated therapeutic options. In PsA clinical trials, apremilast has been shown to be efficacious and to have an acceptable safety profile.

Areas covered: This review article covers the mechanism of action of apremilast, its efficacy in clinical trials and a detailed focus on its safety profile, mainly from Phase III clinical trials.

Expert opinion: Based on the available literature, apremilast has proven to be an efficacious therapy for PsA and PsO. It may offer some advantage as compared to other therapeutic options given its favorable safety profile, including a lack of need for routine laboratory monitoring.     

Safety of vedolizumab in the treatment of Crohn’s disease and ulcerative colitis

Introduction: Vedolizumab is the latest FDA-approved anti-integrin therapy for treatment of moderate-to-severe inflammatory bowel disease (IBD). The safety and efficacy of vedolizumab have been studied in short-term clinical trials.

Areas covered: This paper reviews the safety profile of vedolizumab compared with other biologics. It also highlights the mechanism of action of the medication. We discuss the current position of vedolizumab in our current algorithm for IBD management and comment on future prospects of the drug.

Expert opinion: Vedolizumab appears to be a safe and effective option in the treatment of moderate-to-severe IBD in the short term. Long-term observational studies and post-marketing safety data are needed to ascertain the long-term efficacy and side effect profile.     

Delamanid when other anti-tuberculosis-treatment regimens failed due to resistance or tolerability

Introduction: The limited availability of effective drugs causes difficulties in the management of multidrug-resistant tuberculosis (MDR-TB) and novel therapeutic agents are needed. Delamanid, a new nitro-hydro-imidazooxazole derivative, inhibits mycolic acid synthesis. This review covers the efficacy and safety of delamanid for MDR-TB.

Area covered: This paper reviews the pharmacological profile of delamanid and the results of clinical trials evaluating its efficacy for treating MDR-TB in combination with other anti-TB drugs. The drug’s safety and tolerability profiles are also considered.

Expert opinion: Delamanid showed potent activity against drug-susceptible and -resistant Mycobacterium tuberculosis in both in vitro and in vivo studies. In clinical trials, the drug showed significant early bactericidal activity in pulmonary TB patients, and increased culture conversion after 2 months of treatment in combination with an optimized background regimen in MDR-TB patients. In addition, decreased mortality was observed in MDR-TB patients who received > 6 months of delamanid treatment. The drug was generally tolerable, but QT prolongation should be monitored carefully using electrocardiograms and potassium levels. Therefore, delamanid could be used as part of an appropriate combination regimen for pulmonary MDR-TB in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.     

Evaluation of dolutegravir safety for the treatment of HIV-1

Introduction: Dolutegravir (DGV) is the newest integrase inhibitor approved for the treatment of HIV-1 infection in both treatment-naive and experienced adults and adolescents. This article reviews the safety of DGV for the treatment of HIV-1 infection.

Areas covered: The PubMed database was searched using the keywords ‘DGV’ and ‘HIV’. In addition, conference proceedings from Conference on Retroviruses and Opportunistic Infections, International AIDS Society and European AIDS Clinical Society meetings were searched for presentations on DGV clinical studies.

Expert opinion: DGV has demonstrated a favorable safety profile and is well tolerated for the treatment of HIV-1 infection. Unlike raltegravir, DGV can be given once daily, and unlike elvitegravir, it does not require pharmacologic boosting to achieve consistent blood levels.     

Safety of infliximab for the treatment of inflammatory bowel disease: current understanding of the potential for serious adverse events

Introduction: Infliximab, a chimeric monoclonal antibody directed towards TNF-α, has revolutionized the treatment of inflammatory bowel disease (IBD). Since this therapy suppresses the immune system by neutralizing the immunological activity of TNF, concerns exist regarding the potential for infection, malignancy and immune disorders.

Areas covered: Comprehensive data from randomized controlled trials, meta-analyses and cohort studies have defined the risk of infection and malignancy with infliximab. Additional data regarding associations with immune disorders, such as drug-induced lupus, demyelinating syndromes and psoriaform skin disease have emerged, primarily from case reports. We report evidence from the most robust data sources that have examined these adverse events.

Expert opinion: A modest increase in the incidence of serious infection with infliximab and TNF-antagonists has been observed in methodologically rigorous studies. Combination therapy with an immunosuppressant does not confer a higher risk of serious infection than infliximab monotherapy. TNF-antagonist therapy alone with an immunosuppressant is not associated with higher rates of malignancy. Additional data are required to define causality, the magnitude and determinants of risk for other immune-related complications. Available data suggest the therapeutic index of infliximab is favorable for treatment of moderate-to-severe IBD.     

Perindopril arginine + amlodipine for the treatment of hypertension in the USA

Introduction: Controlling blood pressure is a global health priority; single-pill combinations of antihypertensive agents are often prescribed to improve adherence, persistence, and outcomes.

Areas covered: A novel preparation of perindopril arginine and amlodipine besylate was approved by the US Food and Drug Administration on 21 Jan 2015, based primarily on a 837-subject, 6-week, randomized, multicenter, prospective, clinical trial. The maximal marketed dose of the combination (14/10 mg daily) lowered both systolic and diastolic blood pressure significantly more than either monotherapy, with a reduction in adverse effects (especially ankle edema), compared to amlodipine alone.

Expert opinion: Substantial clinical trial experience with amlodipine or perindopril suggests that these two agents effectively lower blood pressure, and may reduce the risk of major adverse cardiovascular events. In the Anglo-Scandinavian Cardiac Outcomes Trial, hypertensive subjects randomized to receive these two drugs (in sequence) had a significantly lower incidence of several types of clinical events, compared to those who received atenolol ± bendroflumethiazide. The new formulation of perindopril arginine protects its ethyl ester, without requiring physical separation from amlodipine in a single pill, and is less hydroscopic than perindopril erbumine. These and other attributes may make this combination an attractive addition to the antihypertensive armamentarium.     

Ezatiostat hydrochloride for the treatment of myelodysplastic syndromes

Introduction: Myelodysplastic syndromes (MDSs) are associated with significant morbidity due to ineffective hematopoiesis. Given the limited number of drugs approved by the FDA, there is a need for new therapeutic options. Ezatiostat is a novel agent targeting oxidative stress via inhibition of glutathione S-transferase 1.

Areas covered: Herein, the authors summarize the standard of care in order to build the framework for therapeutic advancements. The purpose of this paper is to review the body of preclinical and clinical research literature on the investigational agent ezatiostat hydrochloride (TLK199) for the treatment of MDSs. The article includes details of the pathophysiology, pharmacology, toxicity and efficacy of ezatiostat hydrochloride from controlled studies in patients with myelodysplasia.

Expert opinion: MDS clonal heterogeneity and clonal architecture complexity has presented a significant technical challenge in developing effective therapies. Ezatiostat offers a unique and specific mechanism to improve the transfusion burden associated with myelodysplasia. Since it is tolerable as a monotherapy, combining ezatiostat with agents such as lenalidomide may have the most potential benefit.     

Linagliptin for the treatment of type 2 diabetes mellitus: a drug safety evaluation

Introduction: Established treatments for type 2 diabetes mellitus (T2DM) have side effects that limit their use in specific populations. New therapies with improved safety profiles are needed, especially because of the chronic and progressive nature of T2DM.

Areas covered: This review describes the overall safety and tolerability of linagliptin – a dipeptidyl peptidase-4 inhibitor that improves glycemic control without increasing risk for hypoglycemia and without weight gain. Specifically, the safety of linagliptin is evaluated in difficult-to-treat patients with T2DM, in relation to risk of cardiovascular (CV) events and acute pancreatitis, and in comparison with other antihyperglycemic drugs.

Expert opinion: Linagliptin is generally well tolerated in a broad range of patient populations. It can be used in patients with renal impairment without dose titration and may be a rational alternative treatment in this vulnerable population. Ongoing long-term trials are fully evaluating the CV and renal safety profile of linagliptin.     

Rasagiline for the treatment of Parkinson’s disease: an update

Introduction: Rasagiline is a potent, selective, irreversible Monoamine Oxidase-B (MAO-B) inhibitor, developed to prolong the action of dopamine in the brain. It has been demonstrated that rasagiline can improve motor and some non-motor symptoms (NMS) in both early and advanced Parkinson’s disease (PD) patients, and it also exhibits neuroprotective and antiapoptotic properties.

Areas covered: The objective of this review, performed by a Medline search on the most recent papers investigating the therapeutic effects of rasagiline, is to describe the role of rasagiline in the schedule of treatment of early and advanced PD patients. It will then focus on its role in treating NMS, fatigue, early morning off and cognitive decline, which heavily affect quality of life for PD patients.

Expert opinion: Rasagiline is an efficacious, well-tolerated, easy to use drug. The drug has been extensively studied and has proven its efficacy in monotherapy and in combination with any other antiparkinsonian therapy. It proved to be efficacious in reducing ‘off’ time and in improving early morning ‘off’ but also some NMS, thus enhancing the therapeutic approach to PD.     

Selumetinib for the treatment of cancer

Introduction: The MAPK pathway is essential for regulation of cellular proliferation, differentiation and survival. Multiple human cancers have demonstrated activation of Raf-mitogen-activated kinase kinase (MEK)–extracellular signal-related kinase signaling, a hallmark of these tumors. Efforts to inhibit various protein kinases in this pathway have led to the development of MEK inhibitors. Selumetinib is one such drug, functioning as an oral, selective non-ATP-competitive MEK1/2 inhibitor.

Areas covered: In this article, the authors discuss the underlying biology of MEK inhibition and its rationale in cancer treatment. Furthermore, the authors summarize the clinical development of selumetinib in various tumor types, from initial Phase I studies to randomized Phase II studies, both as monotherapy or in combination with other chemotherapeutics.

Expert opinion: Given the frequency of activated MAPK signaling in multiple tumor types, the potent MEK inhibitor selumetinib had strong preclinical and early clinical rationale, particularly in those tumors harboring KRAS or BRAF mutations. While efficacy signals have been seen in various tumor types treated with selumetinib, better biomarkers are needed to select patients most likely to respond favorably to this agent. Furthermore, combinatorial therapy with selumetinib and other targeted agents can likely be optimized to maximize the antitumor effect of inhibiting RAS/MAPK signaling.     

Ibrutinib in B lymphoid malignancies

Introduction: Most lymphomas and lymphoid leukemias are of B cell origin. Indolent B cell lymphomas, most commonly follicular lymphoma but including Waldenstrom’s macroglobulinemia and mantle cell lymphoma, as well as chronic lymphocytic leukemia, are incurable with standard therapy. New treatments are needed. Survival of normal and many abnormal B cells depends on signals through the B-cell receptor, and a key element of this pathway is Bruton’s tyrosine kinase (BTK). The oral BTK inhibitor ibrutinib is already US FDA approved in four different indications based on marked treatment benefit in indolent B cell lymphoma/leukemia.

Areas covered: This review covers the clinical pharmacology of ibrutinib, its efficacy in clinical trials in chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia, as well as safety and toxicity. Future directions are discussed.

Expert opinion: Ibrutinib is a well-tolerated once-daily oral BTK inhibitor with impressive activity in treating indolent B cell lymphoproliferative disorders. As a single agent, it is already altering treatment paradigms in its approved indications. Ongoing studies will determine its movement to the front-line setting in these and other B cell disorders, as well as combination approaches.     

Buparlisib,an oral pan-PI3K inhibitor for the treatment of breast cancer

Introduction: Deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) intracellular signaling pathway is common in breast cancer (BC) and has been found to be potentially implicated in resistance to endocrine and anti-HER2 therapies. Targeting the PI3K/Akt/mTOR pathway may remove this inhibition and restore sensitivity to these compounds. Buparlisib (BKM120) is a potent oral pan-class I PI3K inhibitor that is being extensively evaluated in multiple tumor types.

Areas covered: This review briefly summarizes the pharmacodynamics and pharmacokinetics of buparlisib, focusing on preclinical and clinical data in BC and on ongoing randomized trials.

Expert opinion: Overall, buparlisib is a safe and tolerable drug and, despite its peculiar toxicity profile, it is suitable for studies in combination with other anticancer agents in BC. Early-phase clinical trials in BC have provided evidence of antitumor activity. Several trials are being conducted in all the biological subsets of BC, including combinations with endocrine therapy, anti-HER2 agents, PARP-inhibitors and chemotherapy. While clinical results are eagerly awaited, biological material suitable for both genomic and non-genomic analyses is being collected. The authors expect an intense investigation of the potential biomarkers that explain response or resistance to buparlisib and inspire strategies to rationally explore the therapeutic potential of this drug.