Drugs

Anderson, Anna; Walker, Brian

doi: 10.1007/s40265-013-0112-5pmid: 23990334

Inhibition of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been proposed as a novel therapeutic target for the treatment of type 2 diabetes mellitus. Over 170 new compounds targeting 11β-HSD1 have been developed. This article reviews the current published literature on compounds that have reached phase II clinical trials in patients with type 2 diabetes, and summarises the preclinical evidence that such agents may be useful for associated conditions, including peripheral vascular disease, coronary artery disease and cognitive decline. In clinical trials, 11β-HSD1 inhibitors have been well tolerated and have improved glycaemic control, lipid profile and blood pressure, and induced modest weight loss. The magnitude of the effects are small relative to other agents, so that further development of 11β-HSD1 inhibitors for the primary therapeutic indication of type 2 diabetes has stalled. Ongoing programmes are focused on additional benefits for cognitive function and other cardiovascular risk factors.

Ujjani, Chaitra; Cheson, Bruce

doi: 10.1007/s40265-013-0092-5pmid: 23884816

Follicular lymphoma consists of a heterogeneous group of diseases that can vary dramatically in clinical course. As with other indolent lymphomas, follicular lymphoma is felt to be highly treatable, but ultimately incurable. The appropriate management of this disease ranges from close observation to chemoimmunotherapy based on presenting symptoms and comorbidities. In this article, we focus on the optimal management of follicular lymphoma, including prognostication, indications for treatment, and current treatment options. While a number of front-line chemoimmunotherapy options exist, R-CHOP (rituximab, cyclophosphamide, vincristine, prednisone) and BR (bendamustine, rituximab) tend to be favored due to efficacy and tolerability. Post-induction options include maintenance rituximab and radioimmunotherapy, but neither has demonstrated an overall survival benefit. In relapsed disease, patients can receive an alternative chemoimmunotherapy regimen or radioimmunotherapy, or participate in a clinical trial. There are a number of new biologic targeted therapies with promising activity in follicular lymphoma that have the potential to change our approach to this disease.

Fox, Susan

doi: 10.1007/s40265-013-0105-4pmid: 23917951

The pathological processes underlying Parkinson’s disease (PD) involve more than dopamine cell loss within the midbrain. These non-dopaminergic neurotransmitters include noradrenergic, serotonergic, glutamatergic, and cholinergic systems within cortical, brainstem and basal ganglia regions. Several non-dopaminergic treatments are now in clinical use to treat motor symptoms of PD, or are being evaluated as potential therapies. Agents for symptomatic monotherapy and as adjunct to dopaminergic therapies for motor symptoms include adenosine A2A antagonists and the mixed monoamine-B inhibitor (MAO-BI) and glutamate release agent safinamide. The largest area of potential use for non-dopaminergic drugs is as add-on therapy for motor fluctuations. Thus adenosine A2A antagonists, safinamide, and the antiepileptic agent zonisamide can extend the duration of action of levodopa. To reduce levodopa-induced dyskinesia, drugs that target overactive glutamatergic neurotransmission can be used, and include the non-selective N-methyl d-aspartate antagonist amantadine. More recently, selective metabotropic glutamate receptor (mGluR5) antagonists are being evaluated in phase II randomized controlled trials. Serotonergic agents acting as 5-HT2A/2C antagonists, such as the atypical antipsychotic clozapine, may also reduce dyskinesia. 5-HT1A agonists theoretically can reduce dyskinesia, but in practice, may also worsen PD motor symptoms, and so clinical applicability has not yet been shown. Noradrenergic α2A antagonism using fipamezole can potentially reduce dyskinesia. Several non-dopaminergic agents have also been investigated to reduce non-levodopa-responsive motor symptoms such as gait and tremor. Thus the cholinesterase inhibitor donepezil showed mild benefit in gait, while the predominantly noradrenergic re-uptake inhibitor methylphenidate had conflicting results in advanced PD subjects. Tremor in PD may respond to muscarinic M4 cholinergic antagonists (anticholinergics), but tolerability is often poor. Alternatives include β-adrenergic antagonists such as propranolol. Other options include 5-HT2A antagonists, and drugs that have mixed binding properties involving serotonin and acetylcholine, such as clozapine and the antidepressant mirtazapine, can be effective in reducing PD tremor. Many other non-dopaminergic agents are in preclinical and phase I/II early stages of study, and the reader is directed to recent reviews. While levodopa remains the most effective agent to treat motor symptoms in PD, the overall approach to using non-dopaminergic drugs in PD is to reduce reliance on levodopa and to target non-levodopa-responsive symptoms.

McKay, Rana; Choueiri, Toni; Taplin, Mary-Ellen

doi: 10.1007/s40265-013-0107-2pmid: 23943203

Despite state of the art local therapy, a significant portion of men with high-risk prostate cancer develop progressive disease. Neoadjuvant systemic therapy prior to radical prostatectomy (RP) is an approach that can potentially maximize survival outcomes in patients with localized disease. This approach is under investigation with a wide array of agents and provides an opportunity to assess pathologic and biologic activity of novel treatments. The aim of this review is to explore the past and present role of neoadjuvant therapy prior to definitive therapy with RP in patients with high-risk localized or locally advanced disease. The results of neoadjuvant androgen-deprivation therapy (ADT), including use of newer agents such as abiraterone, are promising. Neoadjuvant chemotherapy, primarily with docetaxel, with or without ADT has also demonstrated efficacy in men with high-risk disease. Other novel agents targeting the vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), clusterin, and the immune system are currently under investigation and have led to variable results in early clinical trials. Despite optimistic data, approval of neoadjuvant therapy prior to RP in patients with high-risk prostate cancer will depend on positive results from well designed phase III trials.

Guaraldi, Giovanni; Stentarelli, Chiara; Zona, Stefano; Santoro, Antonella

doi: 10.1007/s40265-013-0108-1pmid: 24002702

In the late 1990s, reports of unusual changes in body fat distribution named ‘lipodystrophy’ (LD) began to appear in HIV patients mitigating the enormous enthusiasm about improvement of survival and quality of life provided by the combinations of antiretroviral (ARV) drug classes, the so-called highly active antiretroviral therapy (HAART), which had just become available at that time. The objective of this paper is to critically review the literature on LD and to discuss the impact of newer ARV agents, namely atazanavir, darunavir and raltegravir, as well as strategies of the late HAART era, including single-tablet regimens and nucleoside-sparing regimens. Studies in which LD was measured by dual-energy x-ray absorptiometry or by abdominal computed tomography or magnetic resonance imaging scan only, were included. We were unable to identify studies depicting a negative impact of drugs or ARV regimens on limb fat loss. On the contrary, a few studies identified a negative impact of atazanavir/ritonavir or darunavir/ritonavir on trunk fat increase. It should be noted that this anthropometric measure is a poor instrument since it cannot distinguish between subcutaneous and visceral fat. We conclude that presumably the body fat changes currently observed in HIV-infected patients is the net result of competing phenomena: on one side the natural history of lipohypertrophy as a result of HIV and HAART impact, and on the other side the physiological body fat changes observed in the aging population.

Dhillon, Sohita

doi: 10.1007/s40265-013-0098-zpmid: 23881669

Eplerenone (Inspra®) is a selective mineralocorticoid receptor antagonist (MRA). In the EU, it is approved for use (in addition to standard optimal therapy) to reduce the risk of cardiovascular (CV) mortality and morbidity in adult patients with chronic systolic heart failure (HF) and mild symptoms. This article reviews the efficacy and tolerability of eplerenone in this indication and briefly summarizes its pharmacology. In the EMPHASIS-HF study, relative to placebo, the addition of eplerenone to optimal background therapy significantly reduced the risk of death from CV causes or hospitalization for HF in patients with chronic systolic HF and mild symptoms. Benefits of eplerenone therapy over placebo were also observed in several secondary outcomes, including: death from any cause or hospitalization for HF; death from any cause; hospitalization for any reason; or hospitalization for HF. Eplerenone was generally well tolerated in this study, with the most frequent adverse event being hyperkalaemia, which is a known adverse event of the drug class. Sexual adverse events (e.g. gynecomastia) occurred in <1 % of eplerenone recipients, reflecting the selectivity of eplerenone for mineralocorticoid receptors. Based on these results, European guidelines have been updated and recommend the use of an MRA to reduce the risk of HF hospitalization and premature death in all patients with persisting symptoms (New York Heart Association class II–IV) and a left-ventricular ejection fraction of ≤35 %, despite treatment with ACE inhibitor (or an angiotensin receptor blocker if an ACE inhibitor is not tolerated) and a β-blocker.

McCormack, Paul L.

doi: 10.1007/s40265-013-0102-7pmid: 23912625

Natalizumab (Tysabri®) is a humanized monoclonal antibody against the α4 chain of integrins and was the first targeted therapy to be approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Natalizumab acts as a selective adhesion molecule antagonist, which binds very late antigen (VLA)-4 and inhibits the translocation of activated VLA-4-expressing leukocytes across the blood–brain barrier into the CNS. In a pivotal phase III clinical trial, natalizumab 300 mg intravenously every 4 weeks for 2 years in adults with RRMS significantly reduced the annualized relapse rate and the risk of sustained progression of disability compared with placebo, as well as significantly increasing the proportion of relapse-free patients at 1 and 2 years. Natalizumab also significantly reduced the number of T2-hyperintense, gadolinium-enhancing and T1-hypointense lesions on magnetic resonance imaging, and significantly reduced the volume of T2-hyperintense and T1-hypointense lesions compared with placebo. Natalizumab recipients generally experienced improved health-related quality of life at 1–2 years. Natalizumab was generally well tolerated in pivotal trials. The only adverse events that were more frequent with natalizumab monotherapy than with placebo were fatigue and allergic reactions. The main safety and tolerability issue with natalizumab is the incidence of progressive multifocal leukoencephalopathy (PML). As long as the risk of PML is managed effectively, natalizumab is a valuable therapeutic option for adults with highly active relapsing forms of multiple sclerosis.

Garnock-Jones, Karly

doi: 10.1007/s40265-013-0104-5pmid: 23912626

The sumatriptan iontophoretic transdermal system (ZECUITY®) [hereafter referred to as sumatriptan TDS] is the first transdermal treatment for migraine to be approved by the US FDA. This article reviews the available pharmacologic properties of sumatriptan TDS and its clinical efficacy and tolerability for the acute treatment of adult patients with migraine with or without aura. Sumatriptan, a selective 5-hydroxy-tryptamine receptor subtype 1 (5-HT1) agonist, is presumed to exert its therapeutic effect on migraine patients by binding to the 5-HT1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, resulting in cranial vessel constriction and the inhibition of the release of pro-inflammatory neuropeptides and plasma extravasation. In a well designed, phase III clinical trial, sumatriptan TDS was shown to be more effective than placebo at treating a single migraine attack, with significantly more sumatriptan TDS than placebo recipients being headache pain free and nausea free at 2 hours. These data were supported by a long-term, repeat-use study over 12 months. Additionally, sumatriptan TDS was generally well tolerated in clinical trials; the most common adverse events were application-site reactions. The sumatriptan TDS formulation avoids the gastrointestinal tract, and has a controlled, sustained delivery, allowing for patients with migraine-associated nausea and vomiting to receive treatment without the risk of inconsistent absorption or avoidance of tablet use (associated with oral delivery of the drug in these patients). Moreover, it may offer a useful alternative to the nasal spray or subcutaneous sumatriptan formulations. However, definitive conclusions on the comparative efficacy and tolerability of sumatriptan TDS versus other sumatriptan formulations or other migraine drugs are not as yet possible, and data from comparative trials would be of great interest. Sumatriptan TDS is a useful addition to the treatment options available to migraine patients.

McCormack, Paul

doi: 10.1007/s40265-013-0109-0pmid: 23982598

Pertuzumab (Perjeta®) is a humanized anti-HER2 monoclonal antibody that binds to the extracellular dimerization subdomain of the HER2 receptor and reduces HER2 intracellular signalling by preventing HER2 from forming heterodimers with other HER receptors. Inhibition of HER2 signalling results in a reduction of tumour cell proliferation, invasiveness and survival. Pertuzumab and trastuzumab bind to different sites on the HER2 receptor and have complementary antitumour activities; they act synergistically in inhibiting the growth of HER2-overexpressing breast cancer cell lines in vitro. The efficacy of intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) in combination with trastuzumab plus docetaxel in the first-line treatment of HER2-positive metastatic breast cancer was demonstrated in the randomized, double-blind, placebo-controlled, multinational, phase III CLEOPATRA trial. Pertuzumab in combination with trastuzumab and docetaxel significantly increased independently assessed median progression-free survival (primary endpoint), objective response rate and overall survival compared with placebo in combination with trastuzumab and docetaxel. Pertuzumab had an acceptable tolerability profile when added to trastuzumab and docetaxel in the pivotal CLEOPATRA trial. Thus, pertuzumab is a valuable addition to the growing list of anti-HER2 targeted therapies for breast cancer.

Dungo, Rosselle; Keating, Gillian

doi: 10.1007/s40265-013-0111-6pmid: 23982599

Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases, is under development with Boehringer Ingelheim for the once-daily, oral treatment of cancer. Afatinib downregulates ErbB signalling by covalently binding to epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER) 2 and HER4, irreversibly inhibiting tyrosine kinase autophosphorylation. It also inhibits transphosphorylation of HER3. Oral afatinib (Gilotrif™) has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) who have tumours with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test. Afatinib has also been approved in Taiwan for the first-line treatment of patients with EGFR mutation-positive NSCLC. In addition, the European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the approval of afatinib (Giotrif®) for the treatment of patients with locally advanced or metastatic NSCLC with activating EGFR mutations who are EGFR tyrosine kinase inhibitor naïve. Afatinib is also under regulatory review in Canada, Japan and other Asian countries. This article summarizes the milestones in the development of afatinib, leading to this first approval in patients with metastatic NSCLC.