Spotlight on Denosumab in Postmenopausal Osteoporosis

Denosumab (Prolia®) is a human recombinant monoclonal antibody that is approved for the treatment of postmenopausal osteoporosis in women at high or increased risk of fracture in the US, the EU, and several other countries. Denosumab has a novel mechanism of action; it binds to receptor activator of nuclear factor κB ligand and inhibits bone resorption by inhibiting osteoclast formation, function, and survival. In postmenopausal women with osteoporosis, denosumab reduced the risk of vertebral, nonvertebral, and hip fractures compared with placebo over 3 years in the large, phase III FREEDOM study. In postmenopausal women with low bone mineral density (BMD) or osteoporosis, treatment with denosumab increased BMD and decreased markers of bone turnover more than alendronate in those who were essentially treatment-naive in the 1-year DECIDE study and also in the 1-year STAND study, in which women were switched from alendronate to denosumab or continued alendronate treatment. Denosumab was generally well tolerated in clinical trials, although long-term effects of very low bone turnover remain to be established. Denosumab is administered once every 6 months via subcutaneous injection, which may be a preferred method of administration and may improve adherence to treatment compared with other osteoporosis treatments. Denosumab is a valuable new option for the treatment of postmenopausal osteoporosis in women at increased or high risk of fractures, and may be useful as a first-line treatment in women at increased risk of fractures who are unable to take other osteoporosis treatments.     

Spotlight on avian coronaviruses

ABSTRACT

Coronaviruses (CoVs) mainly cause enteric and/or respiratory signs. Mammalian CoVs including COVID-19 (now officially named SARS-CoV-2) belong to either the Alphacoronavirus or Betacoronavirus genera. In birds, the majority of the known CoVs belong to the Gammacoronavirus genus, whilst a small number are classified as Deltacoronaviruses. Gammacoronaviruses continue to be reported in an increasing number of avian species, generally by detection of viral RNA. Apart from infectious bronchitis virus in chickens, the only avian species in which CoV has been definitively associated with disease are the turkey, pheasant and guinea fowl. Whilst there is strong evidence for recombination between gammacoronaviruses of different avian species, and between betacoronaviruses in different mammals, evidence of recombination between coronaviruses of different genera is lacking. Furthermore, the recombination of an alpha or betacoronavirus with a gammacoronavirus is extremely unlikely. For recombination to happen, the two viruses would need to be present in the same cell of the same animal at the same time, a highly unlikely scenario as they cannot replicate in the same host!     

Spotlight on Omalizumab in Allergic Asthma

Omalizumab (Xolair) is a humanized monoclonal antibody used in the treatment of adolescent and adult patients with moderate to severe allergic asthma inadequately controlled with inhaled corticosteroids (ICS). It selectively binds to circulating immunoglobulin E (IgE) and, thereby, prevents binding of IgE to mast cells and other effector cells. Without surface-bound IgE, these cells are unable to recognize allergens, thus preventing cellular activation by antigens and the subsequent allergic/asthmatic symptoms. Omalizumab decreases free serum IgE levels in a dose-dependent manner, reduces IgE receptor density on effector cells, and significantly improves airway inflammation parameters.Omalizumab is slowly absorbed after subcutaneous administration, and mean elimination half-life is 26 days, thus allowing infrequent administration of the drug. Omalizumab dosage is determined by bodyweight and pretreatment serum total IgE levels. Patients treated with subcutaneous omalizumab in clinical trials received a dosage that was approximately equal to 0.016 mg/kg/IgE (IU/mL) per 4 weeks. Thus, patients received 150 or 300 mg every 4 weeks, or 225, 300, or 375 mg every 2 weeks.In adults and adolescents (> or = 12 years of age) with moderate to severe allergic asthma, subcutaneous administration of omalizumab as add-on therapy with ICS improved the number of asthma exacerbations, rescue medication use, asthma symptom scores, and quality-of-life (QOL) scores compared with placebo during 28- and 32-week double-blind trials. In addition, concomitant ICS use was significantly decreased in patients receiving omalizumab, and in the two largest double-blind trials approximately 40% of omalizumab recipients completely withdrew from ICS therapy while maintaining effective asthma control. In general, results of extension studies showed that the beneficial effects of omalizumab were maintained over a total period of 52 weeks. Omalizumab was well tolerated as add-on therapy with ICS during treatment for up to 52 weeks. Common adverse events in clinical trials included injection site reaction, viral infection, upper respiratory tract infection, sinusitis, headache, and pharyngitis, although the incidence of adverse events with omalizumab was similar to that with placebo.In conclusion, omalizumab, as add-on therapy with ICS, is an effective and well tolerated agent for the treatment of moderate to severe allergic asthma in adolescents and adults. In addition to its symptomatic and QOL benefits, omalizumab therapy allows ICS dosage reduction or discontinuation of ICS in many patients. Comparisons of omalizumab with other asthma therapies have yet to be conducted; however, clinical efficacy and tolerability data indicate that omalizumab is a valuable option in the treatment of allergic asthma.     

Spotlight on Tesamorelin in HIV-Associated Lipodystrophy

Tesamorelin (Egrifta?) is a synthetic analog of human growth hormone-releasing hormone (also known as growth hormone-releasing factor) that stimulates the synthesis and release of endogenous growth hormone. It is the first and, so far, only treatment indicated for the reduction of excess abdominal fat in patients with HIV-associated lipodystrophy. This article reviews the pharmacological properties, clinical efficacy and tolerability of tesamorelin in patients with HIV-associated central fat accumulation. Subcutaneous tesamorelin was effective in reducing visceral adipose tissue (VAT), but did not affect subcutaneous adipose tissue to a clinically significant extent in two 26-week, well designed, clinical trials in patients with HIV-associated central fat accumulation. This reduction in VAT was maintained in the longer term in patients who continued to receive tesamorelin until week 52 in the extension phases of the two trials. However, discontinuation of therapy during this period resulted in the reaccumulation of VAT. Tesamorelin therapy was also associated with significant improvements in other body composition measures (e.g. trunk fat and waist circumference) and improvements were generally seen in some body image parameters (e.g. belly image distress). Tesamorelin was generally well tolerated, with treatment-emergent serious adverse events occurring in <4% of patients during 26 weeks of therapy. Most of these events were injection-site reactions or events known to be associated with growth hormone therapy (e.g. arthralgia, headache and peripheral edema). Although long-term clinical experience is needed to further assess the benefits and risks of therapy, current evidence suggests that tesamorelin may be useful for reducing visceral adiposity in patients with HIV-associated lipodystrophy, thereby potentially improving self image.     

Spotlight on Pegfilgrastim in Chemotherapy-Induced Neutropenia

Pegfilgrastim (Neulasta), the sustained-duration form of filgrastim (recombinant human granulocyte colony-stimulating factor [G-CSF]), is created by the addition of a polyethylene glycol (PEG) moiety to filgrastim. Its approved indication in the US is to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy.A single subcutaneous injection of pegfilgrastim once per chemotherapy cycle was more effective than placebo as an adjunct to moderately myelosuppressive chemotherapy for breast cancer, no less effective than daily injections of filgrastim as an adjunct to highly myelosuppressive chemotherapy for breast cancer, and as effective as daily filgrastim as an adjunct to chemotherapy for lymphoma (predominantly non-Hodgkin lymphoma [NHL]) and acute myeloid leukemia. Pegfilgrastim has also successfully supported delivery of dose-dense chemotherapy, stem cell mobilization, and stem cell transplantation after high-dose chemotherapy in patients with non-myeloid or myeloid malignancies. By offering a convenient alternative to daily filgrastim, once-per-cycle administration of pegfilgrastim has the potential to simplify the management of chemotherapy-induced neutropenia, further improve patient health-related quality of life, and reduce total treatment costs in breast cancer and NHL, and possibly other cancer settings. Pegfilgrastim should, likewise, permit simplification of G-CSF-based stem cell mobilization and transplantation procedures.     

Spotlight on Sapropterin in Primary Hyperphenylalaninemia

Sapropterin dihydrochloride (Kuvan®) is a synthetic formulation of the active 6R-isomer of tetrahydrobiopterin, a naturally occurring co-factor for phenylalanine hydroxylase. In the EU, sapropterin is approved for the treatment of hyperphenylalaninemia in patients ≥4 years of age with tetrahydrobiopterin-responsive phenylketonuria (PKU), and in adults and children with tetrahydrobiopterin deficiency who have been shown to be responsive to such treatment. In the US, it is approved to reduce blood phenylalanine levels in patients with hyperphenylalaninemia due to tetrahydrobiopterin-responsive PKU. Oral sapropterin effectively lowers blood phenylalanine levels in a proportion of patients with PKU; to date, there are no published efficacy trials of the specific sapropterin formulation under review in patients with tetrahydrobiopterin deficiency. Sapropterin was well tolerated in patients with PKU, although longer-term tolerability data are required. Sapropterin is the first non-dietary treatment for patients with PKU that has been shown in randomized, double-blind trials to be effective in lowering blood phenylalanine levels. Thus, sapropterin provides a promising treatment option for patients with PKU who are tetrahydrobiopterin responsive.     

Spotlight on Rasburicase in Anticancer Therapy-Induced Hyperuricemia

Intravenous rasburicase (Elitek), Fasturtec) is the first recombinant uricolytic agent. It is indicated for the management of anticancer therapy-induced hyperuricemia in pediatric patients in the EU and US, and in adult patients in the EU. Rasburicase is effective and generally well tolerated in adult and pediatric patients with, or at risk of developing, anticancer therapy-induced hyperuricemia. It is associated with potentially serious hematologic adverse events and hypersensitivity reactions, which must be considered prior to and during administration; rasburicase is contraindicated in patients predisposed to hemolysis or methemoglobinemia and in patients with glucose-6-phosphate dehydrogenase deficiency. Unlike allopurinol, rasburicase acts on existing uric acid concentrations. Rasburicase treatment resulted in significantly less systemic exposure to uric acid and a quicker therapeutic response than allopurinol in pediatric patients; further studies are needed to determine the comparative efficacy and tolerability of rasburicase versus allopurinol in adult patients. Although further pharmacoeconomic data would be useful, rasburicase was most cost effective for the prevention of hyperuricemia in children and for treatment of this condition in adults. Thus, rasburicase is a useful option for the prophylaxis or treatment of anticancer therapy-induced hyperuricemia in both adult and pediatric patients.     

Spotlight on Bevacizumab in Metastatic Colorectal Cancel

Bevacizumab (Avastin((R))) is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor (VEGF) that is used to inhibit VEGF function in vascular endothelial cells and thereby inhibit tumor angiogenesis, upon which solid tumors depend for growth and metastasis.The addition of bevacizumab to fluoropyrimidine-based chemotherapy, with or without irinotecan or oxaliplatin, in both the first- and second-line treatment of metastatic colorectal cancer, significantly increased median progression-free survival or time to disease progression in most randomized controlled trials. Bevacizumab was generally, but not always, associated with a survival advantage; in phase III trials, the increases in median overall survival attributable to bevacizumab were 4.7 months with first-line therapy and 2.1 months with second-line therapy. In some studies, patients experienced clinical improvement without an apparent overall survival benefit. Bevacizumab had acceptable tolerability, with the majority of adverse events being generally mild and clinically manageable. However, from the UK National Health Service perspective, bevacizumab was not considered to be cost effective in combination with bolus fluorouracil/leucovorin (folinic acid) or irinotecan/bolus fluorouracil/leucovorin. Additional pharmacoeconomic analyses from different perspectives and using clinical data for combinations with the more efficacious infusional fluorouracil/leucovorin plus oxaliplatin or irinotecan chemotherapy regimens are required. Although cost effectiveness may be a concern, the combination of bevacizumab and fluoropyrimidine-based chemotherapy has potential in the treatment of metastatic colorectal cancer.     

Spotlight on Reteplase in Thrombotic Occlusive Disorders

Reteplase (Retavase) is a plasminogen activator, mimicking endogenous tissue plasminogen activator (t-PA), a serine protease, converting plasminogen to plasmin and thereby precipitating thrombolysis. It is a third-generation recombinant form of t-PA that operates in the presence of fibrin (i.e. it is fibrin specific).Reteplase can be administered as a bolus dose (nonweight-based), rather than an infusion, which promotes rapid and safe administration. The ease of administration of this reteplase dosage regimen (two 10U bolus doses, each over 2 minutes, 30 minutes apart) is conducive to prehospital initiation of thrombolytic treatment in patients with ST-segment elevation myocardial infarction (STEMI), which reduces the time to treatment, a critical factor in improving long-term survival.In large randomized clinical trials of patients with STEMI, reteplase was superior to alteplase for coronary artery patency (according to TIMI [thrombolysis in myocardial infarction] flow) at 60 and 90 minutes, but there was no significant difference between agents for mortality rate and incidence of intracranial bleeding. The 35-day mortality rates were equivalent for reteplase and streptokinase recipients; there was reduced incidence of some cardiac events with reteplase versus streptokinase, but a greater incidence of hemorrhagic stroke.Reteplase has also shown thrombolytic efficacy (in nonapproved indications) as a catheter-directed intra-arterial or intravenous infusion for peripheral vessel occlusions, as 5-minute bolus doses (in 1U increments) for acute ischemic stroke, as a low-dose solution for occluded catheters or grafts, and as an intravenous double bolus for massive pulmonary embolism. Across studies in these indications, the incidence of bleeding complications associated with reteplase treatment appeared to be similar to that associated with other fibrin-specific thrombolytic agents.With its efficacy, and the ease of administration of the bolus doses potentially minimizing dosage errors when treatment is administered under time pressure, reteplase is a valuable option for pre- or in-hospital thrombolytic treatment in patients with STEMI, and is a useful thrombolytic for the treatment of the other thrombotic occlusive disorders described.     

Spotlight on Panitumumab in Metastatic Colorectal Cancer

Panitumumab (Vectibix®) is a recombinant, fully human, IgG2 anti-epidermal growth factor receptor (EGFR) monoclonal antibody. This spotlight reviews the clinical efficacy of intravenous panitumumab in combination with chemotherapy in the first- and second-line treatment of metastatic colorectal cancer and as monotherapy in chemotherapy-refractory metastatic colorectal cancer, as well as summarizing its pharmacologic properties and tolerability. Panitumumab is indicated for use in patients with wild-type rather than mutant KRAS tumors. The efficacy of intravenous panitumumab 6 mg/kg administered every 2 weeks was examined in randomized, open-label, multicenter, phase III trials in patients with metastatic colorectal cancer. When administered as first- or second-line treatment in combination with chemotherapy, panitumumab plus chemotherapy prolonged progression-free survival to a significantly greater extent than chemotherapy alone in patients with wild-type KRAS tumors; no significant between-group difference in overall survival was seen in the second-line treatment trial. In patients with mutant KRAS tumors, progression-free survival was significantly shorter with panitumumab plus oxaliplatin-based chemotherapy (FOLFOX4) than with FOLFOX4 alone in the first-line treatment trial, with no significant difference between patients receiving panitumumab plus irinotecan-based chemotherapy (FOLFIRI) and those receiving FOLFIRI alone in the second-line treatment trial. In chemotherapy-refractory patients with metastatic colorectal cancer, panitumumab monotherapy plus best supportive care prolonged progression-free survival to a significantly greater extent than best supportive care alone in both the overall population and in patients with wild-type KRAS tumors, but not in those with mutant KRAS tumors. Intravenous panitumumab has an acceptable tolerability profile when administered as monotherapy or in combination with chemotherapy. It is associated with the skin-related toxicities characteristic of EGFR inhibitors and appears to have a low risk of immunogenicity. In conclusion, in patients with wild-type KRAS tumors, panitumumab is a useful option in combination with chemotherapy for the first- and second-line treatment of metastatic colorectal cancer or as monotherapy for the treatment of chemotherapy-refractory metastatic colorectal cancer.     

Spotlight on Agalsidase Beta in Fabry Disease1

Agalsidase beta (Fabrazyme) is a recombinant human alpha-galactosidase A enzyme approved for intravenous use in the treatment of Fabry disease. Fabry disease is a progressive, multisystemic, potentially life-threatening disorder caused by a deficiency of alpha-galactosidase A. This deficiency results in accumulation of glycosphingolipids, particularly globotriaosylceramide (GL-3), in the lysosomes of various tissues. This accumulation is the underlying driver of disease progression. Agalsidase beta provides an exogenous source of alpha-galactosidase A. Intravenous agalsidase beta is effective and well tolerated in patients with Fabry disease. In a phase III trial, agalsidase beta was shown to clear GL-3 from various target cells and, in a subsequent extension of this trial, prevent GL-3 reaccumulation. In a post-approval trial, agalsidase beta was shown to provide significant clinical benefit by reducing the risk of a major clinical event. Thus, agalsidase beta represents an important advance in the treatment of Fabry disease, and agalsidase beta therapy should be strongly considered in patients with Fabry disease who are suitable candidates.     

Spotlight on Gemtuzumab Ozogamicin in Acute Myeloid Leukaemia

Gemtuzumab ozogamicin (Mylotarg) is a conjugate of a monoclonal antibody and calicheamicin, which targets the membrane antigen CD33 in CD33-positive acute myeloid leukaemia (AML) and, after cell internalization, releases a derivative of the cytotoxic calicheamicin component. In the US, it is approved as monotherapy in patients aged>or=60 years with a first relapse of AML who are ineligible for other cytotoxic therapy.Monotherapy with gemtuzumab ozogamicin results in complete remission (CR) or CR with incomplete platelet recovery (CRp) in approximate, equals 25% of adults (including those aged>or=60 years) with CD33-positive AML in first relapse. Preliminary data indicate a potential role for gemtuzumab ozogamicin as a component of induction or consolidation regimens in adults and, based on an early study, in the treatment of children with AML, although randomized, controlled studies are needed. Serious adverse events, notably hepatotoxicity, characterize its tolerability profile, but gemtuzumab ozogamicin is comparatively well tolerated by most patients. Gemtuzumab ozogamicin is a valuable new treatment option for patients aged>or=60 years with CD33-positive AML in first relapse for whom other cytotoxic chemotherapy is not considered appropriate; patients with a first CR (CR1) of >12 months are likely to have the best outcome.