Deucravacitinib: First Approval.

Deucravacitinib (SOTYKTU™) is a first-in-class, highly selective, oral tyrosine kinase 2 (TYK2) inhibitor. It acts via an allosteric mechanism, binding to the catalytically inactive pseudokinase regulatory domain of TYK2 and stabilizing an inhibitory interaction between the regulatory and catalytic domains. Deucravacitinib is being developed by Bristol Myers Squibb for the treatment of multiple immune-mediated diseases, including psoriasis, psoriatic arthritis, lupus and inflammatory bowel disease. It received its first approval (in the USA on 9 September 2022) for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. On 26 September 2022, it was subsequently approved in Japan for the treatment of plaque psoriasis, generalized pustular psoriasis and erythrodermic psoriasis. The Marketing Authorisation Application for deucravacitinib for the treatment of adults with moderate to severe plaque psoriasis has been validated in the EU, and clinical development of the drug for the treatment of multiple immune-mediated diseases is underway in numerous countries worldwide. This article summarizes the milestones in the development of deucravacitinib leading to this first approval for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Baricitinib: A Review in Moderate to Severe Atopic Dermatitis.

Baricitinib (Olumiant®) is an oral small molecule inhibitor of Janus kinase (JAK)1 and JAK2, which have been implicated in the pathogenesis of atopic dermatitis (AD). In phase III studies in adults with moderate to severe AD who were inadequately controlled with topical corticosteroids (TCS) or systemic treatments (e.g. ciclosporin), or for whom these therapies were not advisable, baricitinib, alone or in combination with TCS, achieved significant and/or clinically relevant improvements in multiple measures of disease severity, pruritus, skin pain, sleep disturbance and health-related quality of life (HR-QOL) over 16 weeks. Benefit onset was rapid, with efficacy generally sustained over the longer term (treatment duration ≤ 68 weeks). In this patient population, the safety profile of baricitinib was consistent with that established in the moderate to severe rheumatoid arthritis (RA) population. Although further longer-term data would be beneficial, current evidence indicates that baricitinib, alone or in combination with TCS, provides an oral alternative to subcutaneous biologics for the treatment of moderate to severe AD in adults who are candidates for systemic therapy.

A better understanding of the multiple factors that cause atopic dermatitis (AD; a chronic, relapsing, inflammatory skin disease often known as eczema) has led to the development of novel therapies that target various inflammatory pathways involved in the disease process. Baricitinib (Olumiant^®), a Janus kinase (JAK)1 and JAK2 inhibitor that targets inflammatory pathways in AD, is a once-daily oral treatment approved in the EU for moderate to severe AD in adults who are candidates for systemic therapy. In such patients, baricitinib, alone or in combination with topical corticosteroids, improved disease severity, pruritus, skin pain, sleep disturbance and health-related quality of life compared with placebo over 16 weeks. Benefit onset was rapid and generally sustained over the longer term (treatment duration ≤ 68 weeks). The safety profile of baricitinib in patients with moderate to severe AD is consistent with that seen in adults with moderate to severe rheumatoid arthritis treated with the drug. Thus, baricitinib provides a convenient oral alternative to subcutaneous biologics for the treatment of moderate to severe AD.

Obinutuzumab: a review of its use in patients with chronic lymphocytic leukaemia.

Obinutuzumab (Gazyva(®); Gazyvaro(®)) is an intravenously administered, glycoengineered, humanized, type II, anti-CD20 monoclonal antibody of the IgG1 subclass. It is available in the EU and the USA as combination therapy with oral chlorambucil in adults with previously untreated chronic lymphocytic leukaemia (CLL). In a multinational phase III study in this patient population, obinutuzumab plus chlorambucil significantly prolonged progression-free survival compared with oral chlorambucil alone and intravenous rituximab plus oral chlorambucil. Significant advantages with obinutuzumab plus chlorambucil over chlorambucil alone and rituximab plus chlorambucil were also observed in event-free survival, the time to a new anti-leukaemia treatment and overall response. The overall survival benefit with obinutuzumab plus chlorambucil is as yet unclear, although the most recent analysis suggests a benefit over chlorambucil alone. In the phase III study, obinutuzumab plus chlorambucil had a manageable tolerability profile in accordance with what would be expected for an anti-CD20 antibody. Neutropenia and infusion-related reactions were the most frequently reported grade 3 or higher treatment-emergent adverse events. In the majority of patients, infusion-related reactions were mild to moderate in severity and occurred predominantly during the first infusion and were managed by slowing or temporarily halting the infusion. Thus, current evidence suggests that obinutuzumab plus chlorambucil is a welcome addition to the treatment options currently available for adults with previously untreated CLL and is recommended by the National Comprehensive Cancer Network guidelines as the preferred first option for some, including those with comorbidities.

Omega-3 ethylester concentrate: a review of its use in secondary prevention post-myocardial infarction and the treatment of hypertriglyceridaemia.

Oral omega-3 ethylester concentrate (omega-3 EEC) [Omacor; Lovaza] is indicated as an adjuvant therapy in adult patients for secondary prevention post-myocardial infarction (MI) and the treatment of hypertriglyceridaemia in the majority of European countries, and for the treatment of hypertriglyceridaemia (serum triglyceride levels > or =5.6 mmol/L [> or =500 mg/dL]) in the US. Each 1000 mg capsule of omega-3 EEC consists of 460 mg of ethyl eicosapentaenoic acid and 380 mg of ethyl docosahexaenoic acid. The addition of omega-3 EEC 1000 mg/day to standard medical therapy in the GISSI-Prevenzione study provided secondary prevention benefits in post-MI adult patients. The benefits were attributable to reductions in death and cardiovascular death (including sudden death). Additional data examining the extent and mechanisms of the cardiovascular benefit conferred by omega-3 EEC in secondary prevention would be useful. As an adjunct to diet, monotherapy with omega-3 EEC 4000 mg/day significantly reduced triglyceride levels in patients with hypertriglyceridaemia, although limited data suggest it was less effective than gemfibrozil. In addition, omega-3 EEC 4000 mg/day plus simvastatin or atorvastatin reduced triglyceride, non-high-density lipoprotein cholesterol (non-HDL-C) and/or very-low-density lipoprotein cholesterol (VLDL-C) levels to a significantly greater extent than placebo plus simvastatin or atorvastatin. Omega-3 EEC was generally well tolerated both as secondary prevention post-MI and in the treatment of hypertriglyceridaemia. Thus, omega-3 EEC is a useful option both in secondary prevention post-MI and the treatment of hypertriglyceridaemia.

Sodium picosulfate/magnesium citrate: a review of its use as a colorectal cleanser.

Oral sodium picosulfate/magnesium citrate (CitraFleet; Picolax), consisting of sodium picosulfate (a stimulant laxative) and magnesium citrate (an osmotic laxative), is approved for use in adults (CitraFleet; Picolax) and/or adolescents and children (Picolax) as a colorectal cleansing agent prior to any diagnostic procedure (e.g. colonoscopy or x-ray examination) requiring a clean bowel and/or surgery. It is dispensed in powder form (sodium picosulfate 0.01 g, magnesium oxide 3.5 g, citric acid 12.0 g per sachet), with the magnesium oxide and citric acid components forming magnesium citrate when the powder is dissolved in water. In adult patients, two sachets of sodium picosulfate/magnesium citrate was at least as effective and well tolerated as oral magnesium citrate 17.7 or 35.4 g, or oral polyethylene glycol 236 g in adult patients undergoing a double-contrast barium enema procedure in three large, randomized, comparative clinical studies. In contrast, sodium picosulfate/magnesium citrate was less effective than a sodium phosphate enema preparation in two studies in patients undergoing flexible sigmoidoscopy. A similar number of patients receiving two sachets of sodium picosulfate/magnesium citrate or two 45 mL doses of oral sodium phosphate the day before a double-contrast barium enema procedure achieved satisfactory barium coating and none/minimal faecal residue in one study. However, the data from three of these studies should be interpreted with caution because the administrative regimens used differed from that recommended. Sodium picosulfate/magnesium citrate is also an effective and generally well tolerated colorectal cleansing agent in children and adolescents; the preparation was more effective than oral bisacodyl 0.01 or 0.02 g plus a sodium phosphate enema preparation in this population. Further research is thus required to accurately position sodium picosulfate/magnesium citrate and fully establish its efficacy and tolerability prior to various exploratory or surgical procedures. Nevertheless, oral sodium picosulfate/magnesium citrate provides a useful option in the preparation of the colon and rectum in adults, adolescents and children undergoing any diagnostic procedure (e.g. colonoscopy or x-ray examination) requiring a clean bowel and/or surgery. Oral sodium picosulfate/magnesium citrate acts locally in the colon as both a stimulant laxative, by increasing the frequency and the force of peristalsis (sodium picosulfate component), and an osmotic laxative, by retaining fluids in the colon (magnesium citrate component), to clear the colon and rectum of faecal contents. It is not absorbed in any detectable quantities. Sodium picosulfate is a prodrug: it is hydrolyzed by bacteria in the colon to the active metabolite 4,4'-dihydroxydiphenyl-(2-pyridyl)methane. Sodium picosulfate/magnesium citrate may be associated with a dehydrating effect, as evidenced by a reduction in bodyweight and increased haemoglobin levels; some at-risk patients may experience postural hypotension and older patients may require additional electrolytes. In three large (n >100), randomized, single-blind clinical studies, two sachets of oral sodium picosulfate/magnesium citrate was at least as effective as oral magnesium citrate 17.7 or 35.4 g, or oral polyethylene glycol 236 g as a colorectal cleansing agent in adult patients undergoing a double-contrast barium enema procedure. In contrast, sodium picosulfate/magnesium citrate was less effective than a sodium phosphate enema preparation in two studies in patients undergoing flexible sigmoidoscopy. A similar number of patients receiving two sachets of sodium picosulfate/magnesium citrate or two 45 mL doses of oral sodium phosphate the day before a double-contrast barium enema procedure achieved satisfactory barium coating and none/minimal faecal residue in one study. However, the data from three of these studies should be interpreted with caution because the administrative regimens used differed from that recommended. In children and adolescents, sodium picosulfate/magnesium citrate was significantly more effective as a colorectal cleansing agent than oral bisacodyl 0.01 or 0.02 g plus a sodium phosphate enema preparation in a randomized, single-blind study; dosages were adjusted for age in this study. Oral sodium picosulfate/magnesium citrate is generally well tolerated in adult patients undergoing various investigational colorectal procedures. Adverse events were generally mild to moderate in intensity and mainly gastrointestinal in nature (e.g. abdominal cramps/pain, nausea); other common treatment-emergent adverse events included disturbance of daily activity, headache and sleep disturbance. This combination is at least as well tolerated as oral sodium phosphate or oral polyethylene glycol, with moderate/severe nausea and vomiting occurring less frequently in sodium picosulfate/magnesium citrate recipients than in those receiving oral sodium phosphate, and abdominal bloating/pain and nausea developing less often with sodium picosulfate/magnesium citrate than polyethylene glycol therapy. The incidence of abdominal pain and sleep disturbance in sodium picosulfate/magnesium citrate versus oral magnesium citrate recipients was similar in one study, but significantly lower with sodium picosulfate/magnesium citrate in another. While the incidence of most adverse events was similar in recipients of sodium picosulfate/magnesium citrate and a sodium phosphate enema preparation, more patients receiving sodium picosulfate/magnesium citrate reported moderate/severe flatulence, incontinence and sleep disturbance, and more patients receiving the enema preparation reported rectal soreness. The tolerability profile of sodium picosulfate/magnesium citrate in patients aged >70 years is reportedly similar to that in patients aged <70 years. Abdominal pain also occurred less frequently with sodium picosulfate/magnesium citrate than with oral bisacodyl plus a sodium phosphate enema preparation in children and adolescents.