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.

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.

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.

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.

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia.

Venetoclax (Venclyxto®; Venclexta®) is a first-in-class, oral, selective B cell lymphoma-2 (BCL-2) inhibitor. The drug is approved in numerous countries, including those of the EU and in the USA, for the treatment of adults with relapsed or refractory (RR) chronic lymphocytic leukemia (CLL); the specific indication(s) for venetoclax may vary between individual countries. Venetoclax monotherapy or combination therapy with rituximab was an effective treatment, provided durable responses, and had a manageable safety profile in pivotal clinical trials in adults with RR CLL, including in patients with adverse prognostic factors. In combination with 6 cycles of rituximab, venetoclax (fixed 24 months' treatment) was more effective than bendamustine plus rituximab (6 cycles) in prolonging progression-free survival (PFS) and inducing undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM), with these benefits sustained during 36 months' follow-up. Hence, with its novel mechanism of action and convenient oral once-daily regimen, venetoclax monotherapy or fixed 24-month combination therapy with rituximab represents an important option for treating RR CLL, including in patients with del(17p) or TP53 mutation and those failing a B cell receptor (BCR) inhibitor and/or chemotherapy.

Correction to: Osimertinib as first-line therapy in advanced NSCLC: a profile of its use.

[This corrects the article DOI: 10.1007/s40267-018-0536-9.].

Lenvatinib: A Review in Hepatocellular Carcinoma.

Lenvatinib (Lenvima®) is an oral small molecule inhibitor of multiple receptor tyrosine kinases, and is approved for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) in the USA, EU, Japan and China. The approval of lenvatinib was based on results of the randomized, open-label, multinational, non-inferiority phase III REFLECT trial in patients with unresectable HCC, who had not received treatment for advanced disease. In REFLECT, lenvatinib was non-inferior, but not superior, to sorafenib (current standard of care) for overall survival (OS). However, lenvatinib was associated with significant improvements compared with sorafenib in terms of all secondary endpoints [higher objective response rate (ORR), and longer progression-free survival (PFS) and time to progression (TTP)]. Lenvatinib had a generally manageable tolerability profile in REFLECT, with the most common treatment-emergent adverse events being hypertension, diarrhoea, decreased appetite and decreased weight. Given its non-inferior efficacy to sorafenib and manageable tolerability profile, lenvatinib represents a long-awaited alternative option to sorafenib for the first-line systemic treatment of patients with unresectable HCC. Further clinical experience may be required to fully define the position of lenvatinib in this setting.

Migalastat: A Review in Fabry Disease.

Fabry disease is a rare lysosomal disorder characterized by deficient or absent α-galactosidase A activity resulting from mutations in the GLA gene. Migalastat (Galafold™), a pharmacological chaperone, stabilizes and facilitates trafficking of amenable mutant forms of α-galactosidase A enzyme from the endoplasmic reticulum to lysosomes and increases its lysosomal activity. Oral migalastat is the first pharmacological chaperone approved for treating patients [aged ≥ 18 years (USA and Canada) or ≥ 16 years in other countries] with Fabry disease who have a migalastat-amenable GLA mutation. In the FACETS trial in enzyme replacement therapy (ERT)-naive patients with GLA mutations amenable or non-amenable to migalastat, there was no significant difference between the migalastat and placebo groups for the proportion of patients achieving a ≥ 50% reduction in the number of globotriaosylceramide (GL-3) inclusions/kidney interstitial capillary (KIC) at 6 months [primary endpoint; intent-to-treat (ITT) population]. In the modified ITT population (i.e. patients with migalastat-amenable GLA mutations), relative to placebo, migalastat treatment significantly reduced the mean number of GL-3 inclusions/KIC and plasma lyso-globotriaosylsphingosine levels at 6 months. Among evaluable patients, migalastat maintained renal function and reduced cardiac mass after ≤ 24 months' therapy. In the ATTRACT trial in ERT-experienced patients, renal function was maintained during 18 months of migalastat or ERT; however, migalastat significantly reduced cardiac mass compared with ERT. Migalastat was generally well tolerated in both of these trials. Given its convenient oral regimen and the limited therapeutic options available, migalastat is an important treatment option for Fabry disease in patients with migalastat-amenable GLA mutations.

Larotrectinib: First Global Approval.

Larotrectinib (VITRAKVI®) is an orally administered, small molecule, highly-selective, tropomyosin receptor kinase (TRK) inhibitor that was developed by Loxo Oncology in collaboration with Bayer AG as a treatment for adult and paediatric patients whose cancers harbour neurotrophic receptor tyrosine kinase (NTRK) gene fusions. In November 2018 larotrectinib received its first global approval in the USA for the treatment of adult and paediatric patients with solid tumours that have a NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. A registration application for the use of larotrectinib in paediatric and adult patients with locally advanced or metastatic solid tumours with NTRK gene fusion proteins has been submitted in the EU. This article summarizes the milestones in the development of larotrectinib leading to its first approval for the treatment of adult and paediatric patients with solid tumours that have NTRK gene fusion.

Enzalutamide: A Review in Castration-Resistant Prostate Cancer.

Oral enzalutamide (Xtandi®), a second generation androgen receptor inhibitor, is indicated for the treatment of castration-resistant prostate cancer (CRPC) in numerous countries worldwide, with specific indications in this patient population varying between individual countries. Based on extensive experience in the clinical trial and/or real-world settings, oral enzalutamide 160 mg once daily is an effective and generally well tolerated treatment in a broad spectrum of patients with CRPC, including in nonmetastatic and metastatic disease and in chemotherapy-naive and -experienced metastatic CRPC. Enzalutamide is an emerging option for the treatment of men with nonmetastatic CRPC who are at high-risk for developing metastatic disease, and remains an important first-line option in chemotherapy-naive or -experienced patients with metastatic CRPC.

Darvadstrocel: A Review in Treatment-Refractory Complex Perianal Fistulas in Crohn's Disease.

Darvadstrocel (Alofisel®) consists of a suspension of expanded human allogeneic adipose-derived mesenchymal stem cells (eASCs). It is the first mesenchymal stem cell (MSC) advanced therapy approved in the EU for the treatment of complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn's disease, when fistulas have shown an inadequate response to ≥ 1 conventional or biologic therapy. In the pivotal phase 3 ADMIRE-CD trial in this difficult-to-treat patient population, after standard-of-care fistula conditioning, add-on therapy with a single dose of darvadstrocel (120 million eASC) administered into the tissue surrounding complex perianal fistulas was significantly more effective than placebo (saline), with the darvadstrocel group having a higher combined remission rate (i.e. clinically-assessed fistula closure plus MRI-assessed absence of abscesses) at 24 weeks in intent-to-treat (ITT primary analysis), modified ITT and per-protocol analyses. Clinical remission was maintained in > 50% of patients at 52 weeks' follow-up. Given the very limited treatment options available for this difficult-to-treat rare condition, darvadstrocel is a promising, novel, minimally invasive therapy that represents an important advance in the therapeutic options for complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn's disease when fistulas have shown an inadequate response to ≥ 1 conventional or biologic therapy.

Correction to: Apatinib: A Review in Advanced Gastric Cancer and Other Advanced Cancers.

An Online First version of this article was made available online at http://link.springer.com/journal/40265/onlineFirst/page/1 on 16 April 2018. Errors were subsequently identified in the article, and the following corrections should be noted.

Apatinib: A Review in Advanced Gastric Cancer and Other Advanced Cancers.

Apatinib [Aitan® (brand name in China)], also known as rivoceranib, is a novel, small molecule, selective vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor and is the second anti-angiogenic drug to be approved in China for the treatment of advanced or metastatic gastric cancer. This article summarizes the pharmacological properties of apatinib and reviews its clinical use in chemotherapy-experienced patients with advanced gastric adenocarcinoma, including gastroesophageal adenocarcinoma (GEA), or with other advanced cancers such as non-small cell lung cancer (NSCLC), breast cancer, gynaecological cancers, hepatocellular carcinoma (HCC), thyroid cancer and sarcomas. As third- or subsequent-line therapy, oral apatinib significantly prolonged median progression-free survival (PFS) and overall survival (OS) compared with placebo and had a manageable safety profile in Chinese patients with advanced or metastatic gastric cancer or GEA participating in randomized, double-blind, multicentre, phase 2 and 3 trials. More limited evidence also supports it use as subsequent-line treatment in Chinese patients with other advanced or metastatic solid tumours, including NSCLC, breast cancer and HCC. Further clinical experience and long-term pharmacovigilance data are required to more definitively establish the efficacy and safety profile of apatinib, including its use in combination with other chemotherapy agents and its role in the management of other types of advanced or metastatic solid tumours. In the meantime, given its convenient administration regimen and the limited treatment options and poor prognosis for patients with advanced or metastatic solid tumours, apatinib is an important, emerging treatment option for adult patients with advanced gastric adenocarcinoma or GEA who have progressed or relapsed after chemotherapy.

Ferric Carboxymaltose: A Review in Iron Deficiency.

Intravenous ferric carboxymaltose (Ferinject®; Injectafer®) is a colloidal solution of nanoparticles which consist of a polynuclear iron (III)-(oxyhydr)oxide core stabilized by carboxymaltose and may be given as a single high-dose, 15-min infusion. This article reviews the clinical use of ferric carboxymaltose in various patient populations with iron deficiency (ID) [± anaemia] and briefly summarizes its pharmacological properties. Based on extensive experience in the clinical trial and real-world settings, ferric carboxymaltose is an effective and generally well tolerated treatment for rapidly replenishing iron stores and correcting anaemia in patients with ID (± anaemia) of various aetiologies, including patients with chronic heart failure (CHF), chronic kidney disease, inflammatory bowel disease or perioperative anaemia, and women with ID during pregnancy, postpartum or associated with heavy uterine bleeding. As it may be given as a single high-dose infusion, ferric carboxymaltose has the potential to provide cost savings from a healthpayer perspective. Thus, ferric carboxymaltose remains an important option for the treatment of ID in adults and, where approved, children aged ≥ 14 years, when oral iron preparations are ineffective or cannot be used.

Osimertinib as first-line therapy in advanced NSCLC: a profile of its use.

Osimertinib (Tagrisso®) is an oral, CNS-active, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that selectively inhibits EGFR TKI-activating mutations over wild-type EGFR in patients with advanced non-small cell lung cancer (NSCLC), including the T790M mutation that often underlies acquired resistance to earlier generation EGFR TKIs. Relative to standard of care first-generation EGFR TKIs (erlotinib or gefitinib) as first-line treatment of EGFR activating mutation-positive advanced NSCLC, osimertinib significantly prolongs median progression-free survival (PFS), with separation of the Kaplan-Meier PFS survival curves evident by the first assessment timepoint of 6 weeks. Osimertinib prolongs PFS relative to standard EGFR TKI therapy in all prespecified groups, irrespective of the EGFR mutation present at study entry and presence of CNS metastases at study entry. Overall survival data are not yet mature. Osimertinib has a generally manageable tolerability profile.

Abiraterone Acetate: A Review in Metastatic Castration-Resistant Prostrate Cancer.

Oral abiraterone acetate (Zytiga®) is a selective inhibitor of CYP17 and thereby inhibits androgen biosynthesis, with androgen signalling crucial in the progression from primary to metastatic prostate cancer (PC) and subsequently, in the development of metastatic castration-resistant PC (mCRPC). In large phase 3 trials and in the clinical practice setting, oral abiraterone acetate in combination with prednisone was an effective treatment and had an acceptable, manageable tolerability and safety profile in chemotherapy-naive and docetaxel-experienced men with mCRPC. In the pivotal global phase 3 trials, relative to placebo (+prednisone), abiraterone acetate (+prednisone) prolonged overall survival (OS) at data maturity (final analysis) and radiographic progression-free survival (rPFS) at all assessed timepoints. Given its efficacy in prolonging OS and its convenient once-daily oral regimen, in combination with prednisone, abiraterone acetate is an important first-line option for the treatment of mCRPC.

SB2: An Infliximab Biosimilar.

SB2 is a biosimilar of the reference anti-TNF-α antibody infliximab. In May 2015, it was approved in the EU for use in all indications for which reference infliximab is approved, including rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriatic arthritis and psoriasis. It is also approved in these indications in several other countries, including Korea, the USA and Australia. Characterization of SB2 in preclinical studies showed that it is similar to reference infliximab. SB2 demonstrated pharmacokinetic biosimilarity to reference infliximab in healthy volunteers, and clinically equivalent efficacy in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy. SB2 was generally well tolerated; the safety and immunogenicity profiles were similar to those of reference infliximab with no additional safety concerns identified. Switching from reference infliximab to SB2 did not impact clinical efficacy, safety or immunogenicity. The role of reference infliximab in the management of autoimmune inflammatory conditions is well established, and SB2 provides an effective biosimilar alternative for patients requiring infliximab therapy.

Osimertinib: A Review in T790M-Positive Advanced Non-Small Cell Lung Cancer.

Osimertinib (Tagrisso™) is an oral, CNS-active, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets EGFR TKI-sensitizing mutations and, crucially, the T790M mutation that often underlies acquired resistance to EGFR TKI therapy. Osimertinib has been approved in numerous countries for use in patients with T790M-positive advanced NSCLC. In the pivotal, international AURA3 trial in patients with T790M-positive advanced NSCLC who had disease progression after EGFR TKI therapy, osimertinib treatment significantly prolonged progression-free survival (PFS; primary endpoint) compared with platinum-pemetrexed therapy at the time of the primary analysis. PFS results were consistent across predefined subgroups of patients, including those with CNS metastases at baseline. There was no difference between treatment groups in overall survival at 26% maturity. Objective response rates (ORRs) and patient-reported outcomes for prespecified symptoms were also significantly improved with osimertinib relative to platinum-pemetrexed, with CNS ORRs in patients with CNS metastases more than twofold higher in the osimertinib than in the platinum-pemetrexed group. Osimertinib had a manageable tolerability profile, with relatively few patients permanently discontinuing treatment because of adverse events (AEs). With limited treatment options available in this setting, osimertinib is an important option in adult patients with advanced EGFR T790M-positive NSCLC.

Insulin Glargine/Lixisenatide: A Review in Type 2 Diabetes.

Subcutaneous insulin glargine/lixisenatide (Suliqua™) is a titratable, fixed-ratio combination of a long-acting basal insulin analogue and a glucagon-like peptide-1 (GLP-1) receptor agonist for the treatment of adult patients with inadequately controlled type 2 diabetes. Once-daily insulin glargine/lixisenatide, in combination with metformin, provided effective glycaemic control and was generally well tolerated in the 30-week, multinational, phase 3 LixiLan-O and LixiLan-L trials in insulin-naive and -experienced adult patients with inadequately controlled type 2 diabetes. Although long-term clinical experience with this fixed-ratio combination is currently lacking, given its convenient once-daily regimen and beneficial effects on glycaemic control and bodyweight loss in the absence of an increase in the incidence of hypoglycaemia, insulin glargine/lixisenatide is an emerging option for the treatment of adult patients with type 2 diabetes to improve glycaemic control when this has not been provided by metformin alone or metformin combined with another OAD or basal insulin.