Opicapone: A Review in Parkinson's Disease.

Oral opicapone (Ongentys®), a potent third-generation, peripheral catechol-O-methyltransferase (COMT) inhibitor, is approved as adjunctive therapy to preparations of levodopa/dopa-decarboxylase inhibitor (L-dopa/DDCI) in adults with Parkinson's disease (PD) and end-of dose (EoD) motor fluctuations. In pivotal global trials (BIPARK 1 and BIPARK 2; 14-15 weeks' duration), open-label extensions (OLEs) of BIPARK, and in the real-world setting (OPTIPARK; 3-6 months), opicapone 50 mg once daily was an effective and generally well tolerated adjunctive therapy to L-dopa/DDCI plus other PD therapy in adults with PD and EoD motor fluctuations. Adjunctive opicapone provided better efficacy than placebo for improvements in ON- and OFF-state time and fulfilled noninferiority to adjunctive entacapone for improvements in OFF time in BIPARK 1. These beneficial effects of adjunctive opicapone on motor fluctuations were maintained during 1 year of treatment in OLE studies. Given its efficacy and safety profile, adjunctive opicapone remains an important option in the management of adults with PD and EoD motor fluctuations who cannot be stabilized on preparations of L-dopa/DDCI.

Lumasiran: First Approval.

Lumasiran (Oxlumo™) is a subcutaneously administered small interfering RNA (siRNA) targeting the mRNA for hydroxyacid oxidase 1 gene (HAO1; encodes glycolate oxidase) and was developed by Alnylam Pharmaceuticals for the treatment of primary hyperoxaluria type 1 (PH1). By silencing the gene encoding glycolate oxidase, lumasiran depletes glycolate oxidase and thereby inhibits the synthesis of oxalate, which is the toxic metabolite that is directly associated with the clinical manifestations of PH1. On 19 November 2020, lumasiran received its first global approval in the EU for the treatment of PH1 in all age groups. On 23 November 2020, lumasiran was approved in the USA for the treatment of adult and paediatric patients with PH1. This article summarizes the milestones in the development of lumasiran leading to this first approval.

Darolutamide: A Review in Non-Metastatic Castration-Resistant Prostate Cancer.

Oral darolutamide (Nubeqa™) is a novel second-generation, nonsteroidal, selective androgen receptor (AR) inhibitor indicated for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). In the pivotal multinational, phase 3 ARAMIS trial in men with nmCRPC, relative to placebo plus ongoing androgen deprivation therapy (ADT), darolutamide (+ ADT) significantly prolonged metastasis-free survival (MFS) at the time of the primary analysis and overall survival (OS) at the time of the final OS analysis and was generally well tolerated in extended follow-up. Albeit long-term data from the real-world setting are required to fully define the safety profile of darolutamide, current evidence from the final ARAMIS analysis indicates that darolutamide has a low propensity for CNS-related adverse events (AEs) associated with other currently approved second-generation AR inhibitors. Given the efficacy and safety evidence from the final ARAMIS analysis and the key role of second-generation AR inhibitors in the management of nmCRPC, darolutamide + ADT represents an important emerging option for the treatment of men with nmCRPC who are at high risk of developing metastatic prostate cancer.

Siponimod: A Review in Secondary Progressive Multiple Sclerosis.

Oral siponimod (Mayzent®), a next-generation, selective sphingosine 1-phosphate receptor (S1PR) 1 and 5 modulator, is approved in several countries for the treatment of secondary progressive multiple sclerosis (SPMS), with specific indications varying between individual countries. In the pivotal EXPAND trial (median duration double-blind treatment 18 months) in a broad spectrum of patients with SPMS, once-daily oral siponimod 2 mg (initial dose titration over 6 days) was significantly more effective than placebo in reducing clinical and MRI-defined outcomes of disease activity and disability progression, including 3-month confirmed disability progression on the Expanded Disability Status Scale (EDSS), and was generally well tolerated in the core phase of the study. These beneficial effects of siponimod appeared to be sustained during up to 5 years of treatment in the ongoing open-label extension phase of EXPAND. The safety profile of siponimod is similar to that of other agents in its class, including adverse events of special interest (i.e. those known to be associated with S1PR modulators). No new safety signals were identified during up to 5 years' treatment in the open-label extension phase. Albeit further long-term efficacy and safety data from the real-world setting are required to fully define its role, given the paucity of current treatment options and its convenient dosage regimen, siponimod represents an important emerging option for the treatment of adult patients with SPMS with active disease evidenced by relapses or imaging-features of inflammatory activity.

Correction to: Romosozumab: A Review in Postmenopausal Osteoporosis.

Unfortunately the sections were published incorrectly in the original article.

Romosozumab: A Review in Postmenopausal Osteoporosis.

Romosozumab (Evenity®), a humanized monoclonal antibody, promotes bone formation and inhibits bone resorption by inhibiting sclerostin, a protein involved in the regulation of bone formation. Subcutaneous romosozumab is approved in several countries, including those of the EU for treating severe osteoporosis as well as in the USA for osteoporosis in postmenopausal women at high risk of fracture. In pivotal phase III trials (FRAME and ARCH), 12 months' once-monthly romosozumab 210 mg significantly reduced vertebral and clinical fracture risk versus placebo and oral alendronate in postmenopausal women with osteoporosis. After patients transitioned from romosozumab to 12-24 months of subcutaneous denosumab or oral alendronate, fracture risks were significantly improved versus placebo-to-denosumab and alendronate-only treatment. In these trials and a phase IIIb trial, romosozumab significantly increased bone mineral density (BMD) relative to placebo, alendronate and subcutaneous teriparatide at 12 months, with these benefits maintained 12-24 months after patients transitioned from romosozumab to alendronate or denosumab in pivotal trials. Romosozumab had a generally manageable tolerability profile. While further clinical experience is needed to more definitively establish its efficacy and safety, including its CV safety, romosozumab extends the treatment options in postmenopausal women with osteoporosis who have a high risk of fracture and in those who have failed or are intolerant to other available osteoporosis therapy.

Rivaroxaban: A Review for Secondary CV Prevention in CAD and PAD.

Secondary cardiovascular (CV) prevention in patients with vascular disease [e.g. coronary (CAD) and peripheral (PAD) artery disease] is crucial and typically involves antiplatelet therapy with aspirin; however, managing residual ischaemic and bleeding risks in CV disease (CVD) remains a challenge. Combining the oral anticoagulant rivaroxaban (Xarelto®) with aspirin targets both the platelet and thrombotic processes of atherosclerosis, a common pathophysiological process associated with CVD. In the global COMPASS trial (n > 27,000), rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily (vs aspirin alone) significantly reduced the risk of the primary composite major adverse CV event (MACE) outcome (i.e. myocardial infarction, stroke or CV death) in adults with stable CAD and/or PAD and, in those with PAD, significantly reduced the risk of the composite major adverse limb event (MALE) outcome. Rivaroxaban + aspirin treatment was generally well tolerated; however, the risk of the composite major bleeding outcome, but not intracranial or fatal bleeding, was significantly higher with rivaroxaban + aspirin than aspirin. The increased risk for the composite major bleeding outcome did not negate the composite net clinical benefits of rivaroxaban + aspirin for secondary CV prevention, with rivaroxaban + aspirin especially beneficial in those with a greater CV risk at baseline. Ongoing clinical experience is required to fully define the role of rivaroxaban + aspirin in secondary CV prevention. In the meantime, dual therapy with rivaroxaban + aspirin is an important emerging option for secondary CV prevention of atherothrombotic events in adults with CAD or symptomatic PAD who are at high risk of ischaemic events.

Correction to: Galcanezumab: A Review in the Prevention of Migraine and Treatment of Episodic Cluster Headache.

The name of the first reviewer which previously read.

Voretigene Neparvovec: A Review in RPE65 Mutation-Associated Inherited Retinal Dystrophy.

Voretigene neparvovec (Luxturna®), a recombinant adeno-associated virus vector-based gene therapy, delivers a functioning copy of the human retinal pigment epithelium-specific 65 kDa (RPE65) gene into retinal cells of patients with reduced or absent levels of RPE65 protein, providing the potential to restore the visual cycle. A single-dose subretinal injection of voretigene neparvovec administered in each eye is approved in several countries worldwide for the treatment of vision loss in adult and paediatric patients with confirmed biallelic RPE65 mutation-associated inherited retinal dystrophy (IRD) and with sufficient viable retinal cells. In the pivotal phase III trial, significant improvements from baseline were seen in the mean bilateral multi-luminance mobility test scores in the voretigene neparvovec group compared with the control group at 1 year. The beneficial effects of voretigene neparvovec treatment were maintained after up to 4 years of follow-up (with follow-up continuing for 15 years). Control recipients were eligible to receive voretigene neparvovec at 1 year, and showed improvements at subsequent follow-ups (≤ 3 years post injection) consistent with those in patients who received voretigene neparvovec at baseline. Most adverse reactions in voretigene neparvovec recipients were transient, asymptomatic and non-serious, and resolved without sequelae (may have been related to voretigene neparvovec, the subretinal injection procedure, concomitant corticosteroid use or a combination thereof). Retinal detachment occurred in one patient at year 4. Although ongoing additional long-term efficacy and safety data are required, voretigene neparvovec is an important novel gene therapy for patients with RPE65 mutation-associated IRD and sufficient viable retinal cells.

Galcanezumab: A Review in the Prevention of Migraine and Treatment of Episodic Cluster Headache.

Galcanezumab (Emgality®) is a humanized monoclonal antibody targeting the calcitonin gene-related peptide (CGRP), thereby inhibiting its physiological activity, with CGRP playing a key role in the pathophysiology of migraine and headache disorders. In pivotal phase 3 trials, recommended dosages of subcutaneous galcanezumab once monthly were significantly more effective than placebo as preventive therapy in adults with episodic (EVOLVE-1 and -2; over 6 months) or chronic (REGAIN; over 3 months) migraine (±  aura), including in patients who had failed several prior preventive migraine drugs (CONQUER; over 3 months). The beneficial effects of galcanezumab preventive treatment in reducing the number of monthly migraine headache days (MHDs) and improving health-related quality of life (HR-QOL) were sustained during up to 1 year of treatment. In adults with episodic cluster headache, galcanezumab treatment was associated with a significant reduction in the weekly frequency of cluster headache attacks across weeks 1-3 compared with placebo (primary endpoint), albeit during weeks 4-8, there was a convergence of results between these treatment groups. Although further evidence from the clinical setting is required to determine its long-term safety profile, given its convenient administration regimen, efficacy and short-term tolerability profile, monthly galcanezumab represents an important emerging option for the prevention of episodic and chronic migraine (±  aura) and the treatment of episodic cluster headache.

Rimegepant: First Approval.

The orally disintegrating tablet (ODT) formulation of rimegepant (NURTEC ODT®) is a small molecule, highly-selective, calcitonin gene-related peptide antagonist that was developed by Biohaven Pharmaceutical Holding Company Ltd as an acute treatment for migraine. A conventional tablet formulation of the drug is being investigated for the acute treatment (under FDA review in the USA) and prevention of migraine and the treatment of refractory trigeminal neuralgia. In February 2020, rimegepant ODT received its first global approval in the USA for the acute treatment of migraine (± aura) in adults. This article summarizes the milestones in the development of rimegepant leading to its first global approval for acute treatment of migraine (± aura) in adults.

Certolizumab Pegol: A Review in Moderate to Severe Plaque Psoriasis.

Certolizumab pegol (Cimzia®) is a PEGylated, Fab'-only, recombinant humanized antibody against TNF-α. Subcutaneous certolizumab pegol is indicated for the treatment of various immune-mediated inflammatory diseases (IMIDs), including moderate to severe plaque psoriasis. In pivotal phase III trials in adults with moderate to severe plaque psoriasis, significantly more patients receiving certolizumab pegol 200 mg or 400 mg once every 2 weeks than placebo recipients achieved a ≥ 75% reduction in PASI score (PASI75 responder) and a PGA score of clear/mostly clear with a ≥ 2 point improvement from baseline (PGA0/1 responder) at week 12 (CIMPACT) or 16 (CIMPASI-1 and -2). In CIMPACT, certolizumab pegol 400 mg once every 2 weeks was superior to etanercept (highest recommended dosage) at 12 weeks, with certolizumab pegol 200 mg once every 2 weeks demonstrating non-inferiority, but not superiority, to etanercept. The clinical benefits of certolizumab pegol were maintained during the maintenance phase (to week 48) and the open-label extension phase of these trials. Certolizumab pegol is unique among the biologics, with the absence of an Fc fragment conferring pharmacokinetic advantages; most notably, its minimal transfer across the placenta, and low relative infant dose during breastfeeding in conjunction with its low oral bioavailability. Certolizumab pegol was generally well tolerated and no new safety signals were identified in these phase III trials, which complements its established safety profile in other IMIDs. Certolizumab pegol is a useful option for the treatment of moderate to severe plaque psoriasis and provides an important treatment option for women of childbearing age, for whom there are limited options available.

Correction to: Ubrogepant: First Approval.

The article Ubrogepant: First Approval, written by Lesley J. Scott, was originally published published Online First without Open Access. After publication online Allergan Sales, LLC requested that the article be Open Choice to make the article an open access publication. Post-publication open access was funded by Allergan Sales, LLC. The article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.

Lemborexant: First Approval.

Lemborexant (DAYVIGO™) is an orally administered, dual orexin receptor (OXR) antagonist that exhibits reversible competitive antagonism at OXR1 and OXR2 (> affinity at OXR2) that was discovered and developed by Eisai Inc. for the treatment of adult patients with insomnia. In December 2019, lemborexant received its first approval (with final interim scheduling) in the USA for the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. In January 2020, lemborexant also received approval in Japan for the treatment of insomnia. It is also being investigated for the treatment of irregular sleep-wake rhythm disorder (ISWRD) associated with mild to moderate Alzheimer's disease. This article summarizes the milestones in the development of lemborexant leading to its first global approval.

Dulaglutide: A Review in Type 2 Diabetes.

Subcutaneous dulaglutide (Trulicity®) is a once-weekly glucagon-like peptide-1 receptor agonist that is approved in numerous countries as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes (T2D). In the clinical trial and real-world settings, once-weekly subcutaneous dulaglutide, as monotherapy or add-on therapy to other antihyperglycaemic agents (including oral antihyperglycaemic drugs and insulin), was an effective and generally well tolerated treatment in adults with inadequately controlled T2D, including in high-risk patients [e.g. obese and elderly patients, those with stage 3 or 4 chronic kidney disease (CKD) and/or cardiovascular (CV) disease]. In the REWIND CV outcomes trial in patients with T2D with or without CV disease, dulaglutide was associated with a significant reduction in the risk of a major adverse cardiac event (MACE; primary composite outcome comprising CV death, nonfatal myocardial infarction or nonfatal stroke) at a median of 5.4 years' follow-up. Given its durable glycaemic efficacy, beneficial effects on bodyweight and MACE outcomes, low inherent risk of hypoglycaemia and convenient once-weekly regimen, dulaglutide remains an important option in the management of T2D.

Ubrogepant: First Approval.

Ubrogepant (Ubrelvy™) is an orally administered, small molecule, highly-selective, calcitonin gene-related peptide (CGRP) antagonist that was developed by Allergan under license to Merck & Co. as an acute treatment for migraine. In December 2019, ubrogepant received its first global approval in the USA for the acute treatment of migraine (± aura) in adults. This article summarizes the milestones in the development of ubrogepant leading to its first global approval for the acute treatment of migraine (± aura) in adults.

Givosiran: First Approval.

Givosiran (Givlaari™) is an aminolevulinate synthase 1 (ALAS1)-directed small interfering RNA (siRNA) covalently linked to a ligand to enable specific delivery of the siRNA to hepatocytes. This results in downregulation of ALAS1 mRNA and prevents accumulation of neurotoxic δ-aminolevulinic acid and porphobilinogen levels that are associated with acute porphyria attacks. Givosiran is being developed by Alnylam Pharmaceuticals for the treatment of acute hepatic porphyria (AHP). In November 2019, givosiran was approved in the USA for the treatment of adults with AHP based on the positive results from the multinational, phase III ENVISION trial. In the EU, givosiran received a positive opinion in January 2020 for the treatment of AHP in adults and adolescents aged 12 years and older. This article summarizes the milestones in the development of givosiran leading to this first approval for the treatment of adults with AHP.

Dolutegravir/Lamivudine Single-Tablet Regimen: A Review in HIV-1 Infection.

The oral once-daily, fixed-dose single-tablet regimen (STR) of dolutegravir/lamivudine (Dovato®), combining a second generation integrase single-strand transfer inhibitor (INSTI) and a nucleoside reverse transcriptase inhibitor (NRTI), is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents (> 12 years of age weighing at least 40 kg) with no known or suspected resistance to the INSTI class or lamivudine. In GEMINI trials in antiretroviral therapy (ART)-naïve HIV-1-infected adults, treatment with dolutegravir plus lamivudine provided rapid and sustained virological suppression and was noninferior to dolutegravir plus tenofovir disoproxil fumarate/emtricitabine at 48 weeks, irrespective of baseline patient or disease characteristics. Virological suppression was sustained at 96 weeks in these ongoing trials. In patients with HIV-1 with sustained virological suppression on their current tenofovir alafenamide (AF)-based ART regimen (≥ 3 drugs), switching to treatment with dolutegravir/lamivudine was noninferior to continuing on a tenofovir AF-based regimen at 48 weeks in the ongoing TANGO trial. No resistance mutations to dolutegravir or lamivudine were detected in patients who met criteria for confirmed virological withdrawal in GEMINI and TANGO trials. Hence, the dolutegravir/lamivudine STR is an effective, generally well tolerated and convenient initial and subsequent ART option for adolescents and adults with HIV-1 infection with no known or suspected resistance to the INSTI class or lamivudine.