Resmetirom: The First Food and Drug Administration-Approved Medication for Nonalcoholic Steatohepatitis (NASH).

OBJECTIVE: To review the literature leading to the Food and Drug Administration (FDA) approval of the first medication, resmetirom, for the treatment of nonalcoholic steatohepatitis (NASH), including the pharmacology, pharmacokinetics, clinical studies, dosing, and adverse effects. Relevant data will be used to discuss how resmetirom impacts clinical practice. DATA SOURCES: A literature search was conducted using MEDLINE from database inception to May 12, 2024. Keywords included non-alcoholic steatohepatitis, nonalcoholic fatty liver disease, and resmetirom. Study selection, data extraction and all English-language studies involving the use of resmetirom for nonalcoholic fatty liver disease (NAFLD)/NASH were included. DATA SYNTHESIS: Resmetirom, a thyroid hormone receptor agonist, is administered at daily doses of either 80 mg or 100 mg. The drug was shown to provide NASH resolution as assessed by the NAFLD activity score, 80 mg-24.2%, 100 mg-25.9% compared to 14.2% with the placebo group (P < 0.001). Resmetirom, improved liver fibrosis, 80 mg-25.9%, 100 mg-29.9% compared to 9.7% with the placebo group (P < 0.001). Resmetirom's ability to improve fibrosis in patients with F2-F3 fibrosis offers valuable benefit for patients at risk of progressing to cirrhosis. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Resmetirom expands the medication options available to treat patients with NASH which can be given alongside other medications to optimize metabolic factors such as glucagon-like peptide-1 and hydroxymethylglutaryl-coenzyme A reductase inhibitors. Resmetirom was well tolerated in studies. CONCLUSION: Resmetirom serves as an attractive option in patients diagnosed with NASH with evidence of advanced fibrosis (F2-F3) in combination with exercise, diet, and other multimodal therapies targeting metabolic risk factors.

Pharmacotherapeutic advances in fibromyalgia: what's new on the horizon?

INTRODUCTION: This review delves into Fibromyalgia Syndrome (FMS), a chronic pain condition demanding thorough understanding for precise diagnosis and treatment. Yet, a definitive pharmacological solution for FMS remains elusive. AREAS COVERED: In this article, we systematically analyze various pharmacotherapeutic prospects for FMS treatment, organized into sections based on the stage of drug development and approval. We begin with an overview of FDA-approved drugs, discussing their efficacy in FMS treatment. Next, we delve into other medications currently used for FMS but still undergoing further study, including opioids and muscle relaxants. Further, we evaluate the evidence behind medications that are currently under study, such as cannabinoids and naltrexone. Lastly, we explore new drugs that are in phase II trials. Our research involved a thorough search on PUBMED, Google Scholar, and clinicaltrials.gov. We also discuss the action mechanisms of these drugs and their potential use in specific patient groups. EXPERT OPINION: A focus on symptom-driven, combination therapy is crucial in managing FMS. There is also a need for ongoing research into drugs that target neuroinflammation, immunomodulation, and the endocannabinoid system. Bridging the gap between benchside research and clinical application is challenging, but it holds potential for more targeted and effective treatment strategies.

Voclosporin: A Novel Calcineurin Inhibitor for the Treatment of Lupus Nephritis.

OBJECTIVE: To describe the safety, efficacy, and potential role in therapy of voclosporin, an oral calcineurin inhibitor approved by the Food and Drug Administration (FDA) in January 2021 as an adjunct treatment for lupus nephritis. DATA SOURCES: A literature search was conducted using PubMed with the following terms: voclosporin, Lupkynis, and lupus nephritis (January 1, 2010, to December 1, 2021). FDA product labeling was also reviewed for pertinent data sources. STUDY SELECTION AND DATA EXTRACTION: All articles were considered for inclusion. English-language articles selected included preclinical and clinical studies examining the pharmacokinetics, efficacy, and/or safety of voclosporin. DATA SYNTHESIS: Voclosporin has been studied as an adjunct immunosuppressive agent in patients with lupus nephritis. Drug design allows for a more predictable pharmacokinetic profile than other calcineurin inhibitors. Data suggest that adding this newly approved calcineurin inhibitor to a regimen of mycophenolate mofetil and corticosteroids produces promising therapeutic results. As such, voclosporin has been approved for use in patients with active lupus nephritis who are maintained on immunosuppressive therapy with mycophenolate mofetil and a corticosteroid. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Voclosporin may be a favorable calcineurin inhibitor in patients with lupus nephritis, due to a predictable pharmacokinetic profile. This allows for decreased therapeutic drug monitoring and suggests a favorable adverse effect profile. However, cost remains a consideration with this new agent. CONCLUSIONS: Current available data suggest that voclosporin is a promising adjunct treatment option for patients with active lupus nephritis who are maintained on mycophenolate mofetil and a corticosteroid.

Revefenacin, a once-daily, long-acting muscarinic antagonist, for nebulized maintenance therapy in patients with chronic obstructive pulmonary disease.

PURPOSE: This article reviews the efficacy and safety of revefenacin, the first once-daily, long-acting muscarinic antagonist, when delivered via a standard jet nebulizer in patients with chronic obstructive pulmonary disease (COPD). SUMMARY: Revefenacin 175 µg is indicated for the maintenance treatment of patients with moderate to very severe COPD. Preclinical studies showed that revefenacin is a potent and selective antagonist with similar affinity for the different subtypes of muscarinic receptors (M1-M5). Furthermore, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose dependent and lasted longer than 24 hours, demonstrating a long duration of action. In phase 2 and 3 trials, treatment with revefenacin was demonstrated to result in statistical improvements in pulmonary function (≥100 mL, P < 0.05) vs placebo, including among patients with markers of more severe disease and those who received concomitant long-acting ß-agonists or long-acting ß-agonists together with inhaled corticosteroids. Revefenacin was also demonstrated to have efficacy similar to that of tiotropium. The clinical trial findings indicated no significant difference between revefenacin and tiotropium with regard to rates of adverse events. Overall, revefenacin was well tolerated, with COPD worsening/exacerbation, dyspnea, headache, and cough among the most common adverse events noted in the clinical trials. CONCLUSIONS: Revefenacin treatment delivered via nebulization led to improvements in lung function in patients with COPD. It was also generally well tolerated, with no major safety concerns. Revefenacin provides a viable treatment option for patients with COPD and may be a suitable alternative for those with conditions that may impair proper use of traditional handheld inhalers.

Amisulpride: A New Drug for Management of Postoperative Nausea and Vomiting.

OBJECTIVE: To review the pharmacology, efficacy, and safety of amisulpride and determine its role in the management of postoperative nausea and vomiting (PONV). DATA SOURCES: A PubMed search (1946 to November 2020) using the terms amisulpride and APD421 was conducted. STUDY SELECTION AND DATA EXTRACTION: Relevant reports on intravenous amisulpride were included. DATA SYNTHESIS: Six clinical trials were evaluated. In 4 trials on the prevention of PONV, a greater percentage of patients who received amisulpride 5 mg compared with placebo experienced a complete response (44%-60% vs 31%-33%, respectively, when used as monotherapy; 58% vs 47%, respectively, when used in combination with another antiemetic). In 2 trials on the treatment of PONV, a significantly greater percentage of patients who received amisulpride 10 mg compared with placebo experienced a complete response (31.4% vs 21.5%, respectively, in patients who had not received prophylaxis; 41.7% vs 28.5%, respectively, in patients who had received prophylaxis). Adverse effects included infusion site pain, chills, hypokalemia, procedural hypotension, and abdominal distension. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Amisulpride is effective for the management of PONV and may be less likely to cause QT prolongation and extrapyramidal symptoms than other dopamine antagonists. Additional information is needed on its use for chemotherapy-induced nausea and vomiting and in children. CONCLUSIONS: Amisulpride is an important new option for the multimodal management of PONV in adults, and it may be the preferred dopamine antagonist because of the more favorable safety profile that results from its unique pharmacological properties.

Osilodrostat: A Novel Steroidogenesis Inhibitor to Treat Cushing's Disease.

OBJECTIVE: To review data on efficacy and safety of osilodrostat (Isturisa), a novel oral steroidogenesis inhibitor for treatment of Cushing's disease (CD), a life-threatening endocrine disorder. DATA SOURCES: A PubMed/CINAHL search from inception to September 25, 2020, was performed using the following keywords: osilodrostat, 11-beta hydroxylase, pituitary, ACTH hypersecretion, and Cushing's disease. STUDY SELECTION AND DATA EXTRACTION: Phase 2 and 3 clinical trials and supplementary documents investigating osilodrostat were obtained from a primary literature search, the manufacturer's website, and the Food and Drug Administration website. These articles evaluated the clinical pharmacology, efficacy, safety, adverse events, warnings, and precautions for osilodrostat. DATA SYNTHESIS: Osilodrostat was efficacious and safe in the treatment of CD in mostly middle-aged Caucasian women. A pivotal phase 3 study revealed a significant difference in 24-hour mean urinary free cortisol (primary end point) between osilodrostat and placebo (86% vs 29%; P < 0.001). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Osilodrostat provides a potent and consistent effect in reducing life-threatening supraphysiological levels of cortisol in patients with CD. Hypocortisolism adverse effects can be mitigated by slowly increasing osilodrostat's dose at ≥2-week intervals. QT interval prolongation was noted; therefore, the QT interval must be monitored by the electrocardiogram. Increased levels of cortisol precursors during treatment with osilodrostat may increase the risk of hypokalemia, edema, and hypertension. CONCLUSIONS: Osilodrostat was efficacious in decreasing cortisol levels and safe in treating patients who have failed or are ineligible for pituitary surgery. Although risks exist, a pivotal clinical trial revealed efficacy in 86% of participants.

Doing More With Less: Review of Dolutegravir-Lamivudine, a Novel Single-Tablet Regimen for Antiretroviral-Naïve Adults With HIV-1 Infection.

OBJECTIVE: To review data on efficacy and safety of dolutegravir (DTG) and lamivudine (3TC) in treatment-naïve adults with HIV-1 infection. DATA SOURCES: Phase III clinical trials and review articles were identified through PubMed (1996 to March 2020) and ClinicalTrials.gov (2000 to May 2020) using the keywords dolutegravir, lamivudine, and HIV. STUDY SELECTION AND DATA EXTRACTION: Relevant clinical trials and review articles available in English evaluating efficacy and safety of DTG and 3TC were included. DATA SYNTHESIS: The once-daily, single-tablet regimen of DTG/3TC is the first dual antiretroviral therapy (ART) recommended for initial therapy in treatment-naïve adults with HIV-1 infection. DTG and 3TC were compared with a regimen of DTG and tenofovir disoproxil fumarate/emtricitabine in the GEMINI studies and demonstrated noninferiority for the primary end point of virological suppression at up to 96 weeks. No treatment-emergent resistance mutations were identified in a small group of participants who did not reach virological suppression. The regimen is well tolerated, and the most common adverse events reported in trials include headache, diarrhea, nausea, insomnia, and fatigue. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This dual-ART regimen is a favorable treatment option for ART-naïve patients with HIV-1 RNA <500 000 copies/mL, absence of hepatitis B virus, and no resistance to DTG or 3TC. Benefits of dual ART include reduction in treatment-related adverse events and toxicities, drug interactions, and cost. In addition, the once-daily, single-tablet formulation promotes adherence. CONCLUSIONS: DTG/3TC has demonstrated efficacy in maintaining virological suppression in ART-naïve patients at up to 96 weeks while minimizing treatment-related adverse events and toxicities.

Lifitegrast: a novel drug for patients with dry eye disease.

The objective of this article is to review the pharmacology, efficacy, and safety of lifitegrast and determine its role relative to other agents in the management of dry eye disease. A PubMed search (1946 to December 2018) using the terms lifitegrast and SAR 1118 was conducted to identify relevant articles. In vitro or in vivo evaluations of lifitegrast published in the English language were eligible for inclusion. Phase II and III trials were selected for review of efficacy and safety. Four randomized controlled trials evaluated the efficacy and safety of lifitegrast 0.5% ophthalmic solution for 12 weeks, and 1 additional trial assessed safety for 1 year. In a majority of the trials, lifitegrast caused statistically significant improvements in inferior corneal fluorescein staining scores and eye dryness scores. The most common adverse effects were eye irritation, dysgeusia, and reduced visual acuity, and most were mild to moderate in severity. Lifitegrast has a novel mechanism of action and is safe and effective for the treatment of dry eye disease. At this time, lifitegrast may be considered as an option for patients who have an inadequate response to artificial tears.

Apalutamide: A new agent in the management of prostate cancer.

Apalutamide is a competitive inhibitor of the androgen receptor and binds directly to the ligand-binding domain. The US Food and Drug Administration approved apalutamide on 14 February 2018 for use in patients with nonmetastatic castration-resistant prostate cancer based upon results from the phase III SPARTAN trial demonstrating significantly longer metastasis-free survival over placebo. The SPARTAN trial evaluated 1207 patients with nonmetastatic castration-resistant prostate cancer who were randomized 2:1 to apalutamide or placebo in combination with androgen deprivation therapy. Patients who received apalutamide experienced statistically significantly longer metastasis-free survival (40.5 versus 16.2 months, hazard ratio 0.28 (95% confidence interval = 0.23-0.35); P < 0.0001), which was the major efficacy outcome. Rash, hypothyroidism, and fracture were reported to occur more frequently with apalutamide than placebo. Based upon these results, apalutamide was deemed a safe and effective treatment option for patients with nonmetastatic castration-resistant prostate cancer. Clinical trials are ongoing to expand its indication in the metastatic setting, and identify additional roles for apalutamide in the management of prostate cancer such as in the castrate-sensitive metastatic setting.

Baricitinib: The Second FDA-Approved JAK Inhibitor for the Treatment of Rheumatoid Arthritis.

Objective: To review the pharmacology, pharmacokinetics, safety, and efficacy of baricitinib, a recently approved selective Janus Kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA), and explore its potential role in therapy. Data Sources: Articles were identified using a PubMed search from inception through January 2019 using the terms rheumatoid arthritis, Olumiant, baricitinib, and LY3009104, its molecular name. Study Selection and Data Extraction: Articles relating to randomized clinical trials, pharmacology, pharmacokinetics, efficacy, and safety of baricitinib were evaluated. Data Synthesis: Baricitinib exerts its effects by inhibiting JAK1 and JAK2 enzymes, targeting cytokine and growth factor receptor stimulation, thus reducing downstream immune cell function. Four trials have demonstrated the efficacy of baricitinib with or without methotrexate in patients naïve to disease-modifying antirheumatic drugs (DMARDs) and those who had an inadequate response to or intolerance to both conventional and biological DMARDs. Furthermore, baricitinib was associated with delayed radiographic progression. Despite baricitinib 4 mg often demonstrating greater efficacy compared with the 2 mg dose, only the 2 mg dose is Food and Drug Administration approved because of safety concerns with the 4 mg dose, primarily thromboembolism. Relevance to Patient Care and Clinical Practice: Baricitinib provides an oral treatment option for patients failing tumor necrosis factor inhibitors (TNFis). Safety, cost, and comparative effectiveness to tofacitinib should be considered prior to prescribing baricitinib. Conclusion: Baricitinib is the second medication in its class and has been proven efficacious for the treatment of RA. Given concerns for adverse effects associated with baricitinib, it should be reserved for patients who have failed one or more TNFis.

Exploratory analysis of comparative clinical trials used for marketing approval in patients with type 2 diabetes in Japan.

BACKGROUND/OBJECTIVES: The results of phase 2 and 3 clinical trials, which justify decisions regarding marketing approval for new drugs, are used for comparison of drugs in the post-marketing phase. A number of meta-analyses of approved antidiabetics have been performed, but the heterogeneity of trials has not been fully examined. The aim of this study was to explore factors that may influence baseline HbA1c in trial samples and treatment outcomes (i.e. HbA1c reductions and effect sizes), with the goal of providing unbiased and fair retrospective comparisons between different antidiabetics. METHOD: We conducted three meta-regression analyses using 78 randomized or non-randomized comparative phase 2 or 3 trials of 24 approved antidiabetics in Japan, conducted from 1987 to 2012. RESULTS: Baseline HbA1c of each arm was higher in phase 2 trials, trials with a greater number of subjects, trials with a lower proportion of male subjects, trials of combination therapy, or trials with longer subject disease duration. Entry criteria were different among drug classes and caused variations in baseline HbA1c. HbA1c reductions were larger in non-randomized trials, trials with a shorter treatment period, or trials with a lower proportion of male subjects. Effect sizes were larger in phase 2 trials, or trials of combination therapy. Larger effect sizes were observed in drugs with later market entry for alpha-glucosidase inhibitors and glinides. CONCLUSION: Baseline HbA1c, an important characteristic of subjects enrolled in trials of antidiabetics, differed significantly across trials. Differences in features of study subjects were caused by explicit stipulations in eligibility criteria of HbA1c and also by other conditions (e.g. trial design, regulatory guidance, treatment guideline) and/or interventions of investigators and pharmaceutical companies that were specific to drugs and trials. Healthcare professionals should carefully consider these heterogeneities in trials used for marketing approval review when making a retrospective comparison to select the best treatment option for patients.

Glycopyrrolate/eFlow CS: The First Nebulized Long-Acting Muscarinic Antagonist Approved to Treat Chronic Obstructive Pulmonary Disease.

OBJECTIVE: To review the pharmacology, efficacy, and safety of the first nebulized long-acting muscarinic antagonist (LAMA), glycopyrrolate (GLY)/eFlow closed system (CS) nebulizer, approved for maintenance treatment of chronic obstructive pulmonary disease (COPD). DATA SOURCES: A PubMed search was conducted (January 2000 to July 2018) using the following terms/phrases: nebulized glycopyrrolate, inhalation devices in COPD, long-acting muscarinic antagonists COPD, and COPD survey. Retrieved articles were reviewed to identify additional references. STUDY SELECTION AND DATA EXTRACTION: Primary and review articles on GLY/eFlow CS and other treatment options for patients with COPD were selected. DATA SYNTHESIS: Guidelines recommend the use of LAMAs, alone or in combination with long-acting ß2-agonists, as maintenance therapy for the majority of patients with COPD. With the range of different devices and bronchodilators now available, treatment can be tailored based on individual needs. The eFlow CS nebulizer delivers GLY rapidly over a 2- to 3-minute period and provides bronchodilation within 30 minutes, lasting 12 hours. Phase 2 dose-finding and phase 3 studies demonstrated sustained statistically significant and clinically important improvements in pulmonary function and patient-reported outcomes with GLY/eFlow CS. Relevance to Patient Care and Clinical Practice: GLY/eFlow CS provides a novel, portable, efficient, and rapid drug delivery system. CONCLUSIONS: The recently approved GLY/eFlow CS drug-device combination provides a viable treatment option for patients with COPD, particularly those with conditions that may impair proper use of traditional handheld inhalers.

Avelumab: A Review of Its Application in Metastatic Merkel Cell Carcinoma.

OBJECTIVE: To summarize the clinical development of avelumab and its clinical relevance in metastatic Merkel cell carcinoma (MCC). DATA SOURCES: An English-language literature search using PubMed was performed using the terms avelumab, anti-PD-1, anti-PD-L1, and MCC from January of 1950 to March 2018. Data were also obtained from package inserts, meeting abstracts, and clinical registries. STUDY SELECTION/DATA EXTRACTION: All relevant published articles of avelumab were reviewed. Clinical trial registries and meeting abstracts were used for information about ongoing trials. DATA SYNTHESIS: Avelumab is a fully human monoclonal antibody that inhibits programmed death ligand-1, which reverses T-cell exhaustion and induces antitumor responses. Avelumab is safe and effective in previously treated metastatic MCC based on a phase II trial of previously treated patients with objective response rates in 28 of 88 patients, including 10 complete responses and 19 partial responses. Median overall survival (OS) was 12.9 months, and 1-year progression-free survival and OS were 30% and 52%, respectively. Grade 3 treatment-related side effects included lymphopenia (2 patients), serum creatine phosphokinase increase (1 patient), aminotransferase elevation (1 patient), and serum cholesterol increase (1 patient). Relevance to Patient Care and Clinical Practice: This review outlines the pharmacology and clinical trial data for avelumab in metastatic MCC and guides clinicians on avelumab's place in therapy. CONCLUSIONS: Avelumab is the first Food and Drug Administration-approved medication for metastatic MCC and provides an advantage of durable responses and possibly improved tolerability compared with traditional platinum-based chemotherapy. Clinical trials are under way to expand its utility into the adjuvant and frontline settings.

A Blast From the Past: Revival of Angiotensin II for Vasodilatory Shock.

OBJECTIVE: To review and summarize data on angiotensin II (AT-II), approved by the Food and Drug Administration (FDA) in December 2017 to increase blood pressure in adults with septic or other distributive shock. DATA SOURCES: A PubMed/MEDLINE search was conducted using the following terms: (angiotensin ii OR angiotensin 2) AND (shock) from 1966 to February 2018. STUDY SELECTION AND DATA EXTRACTION: A total of 691 citations were reviewed with only relevant clinical data extracted. DATA SYNTHESIS: AT-II is a peptide hormone with a multitude of physiological effects-namely, vasoconstriction of venous and arterial smooth muscle. The priority approval granted by the FDA was secondary to a phase 3 study of patients receiving at least 0.2 µg/kg/min of norepinephrine or equivalent for vasodilatory shock. Compared with placebo, AT-II had a significantly higher rate of response, defined as a mean arterial pressure of 75 mm Hg or an increase of 10 mm Hg. No significant difference was found in death by day 28. CONCLUSIONS: AT-II is a newly available vasoactive agent with a novel mechanism for the treatment of distributive shock. Further research is needed to define its exact role in therapy of shock states, identify patients most likely to benefit, and further study its safety profile in critical illness.

Lesinurad: A Novel Agent for Management of Chronic Gout.

OBJECTIVE: To review the pharmacology, efficacy, and safety of lesinurad and determine its role relative to other agents in the management of chronic gout. DATA SOURCES: A PubMed search (1946 to February 2018) using the terms lesinurad and RDEA594 was conducted to identify relevant articles. STUDY SELECTION AND DATA EXTRACTION: In vitro or in vivo evaluations of lesinurad published in the English language were eligible for inclusion. Phase II and III trials were selected for review of efficacy and safety. DATA SYNTHESIS: Five clinical trials were evaluated. In 4 trials in which lesinurad was used in combination with a xanthine oxidase inhibitor (XOI), a greater percentage of patients receiving lesinurad 200 mg (54.0%-63.0%) compared with placebo (23.3%-46.8%) achieved a serum uric acid (sUA) level of <6 mg/dL at 1 to 6 months. In one trial involving lesinurad used as monotherapy, a sUA level of <6 mg/dL was achieved by a significantly greater percentage of patients receiving lesinurad 400 mg (29.9%) compared with placebo (1.9%) at 6 months. When used as combination therapy, the drug had an acceptable safety profile, with upper-respiratory-tract infection, nasopharyngitis, and hypertension occurring most commonly and transient renal-related events detected less frequently. CONCLUSIONS: Lesinurad has a novel mechanism of action and is safe and effective for the treatment of chronic gout. At this time, lesinurad may be considered as an add-on therapy for patients who have an inadequate response to maximum tolerated doses of a XOI.

Ocrelizumab: A New B-cell Therapy for Relapsing Remitting and Primary Progressive Multiple Sclerosis.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of ocrelizumab, a new B-cell-targeted therapy for multiple sclerosis (MS). DATA SOURCES: A comprehensive search of PubMed and OVID/MEDLINE was conducted using search terms ocrelizumab and multiple sclerosis using the date range of 1946 through October 2017. STUDY SELECTION AND DATA EXTRACTION: All English-language, human-subject articles related to ocrelizumab and MS were evaluated. DATA SYNTHESIS: Ocrelizumab was approved in March 2017 for the treatment of relapsing or primary progressive MS (PPMS). A phase II trial established 600 mg intravenously every 6 months as the preferred dosing schedule. Two phase III trials evaluated the efficacy of ocrelizumab in patients with relapsing remitting MS, and individual and pooled analysis demonstrated a significant reduction in annualized relapse rate ( P < 0.001 pooled), disability progression at 12 weeks ( P < 0.001 pooled), and gadolinium-enhancing lesions on magnetic resonance imaging (MRI; P < 0.001). Patients with PPMS were evaluated in a third phase III trial, which showed a significant decrease in disease progression at 12 weeks ( P = 0.03) and volume of T2-weighted lesions on MRI ( P < 0.001). As with other monoclonal antibodies, adverse effects seen with ocrelizumab were primarily infusion-related reactions and infection. CONCLUSIONS: Ocrelizumab demonstrated efficacy in the treatment of relapsing and PPMS and is the first therapy approved for patients with PPMS.

Sofosbuvir/Velpatasvir/Voxilaprevir: A Pan-Genotypic Direct-Acting Antiviral Combination for Hepatitis C.

OBJECTIVES: To review the efficacy and safety of sofosbuvir/velpatasvir/voxilaprevir in the treatment of hepatitis C virus (HCV) infection. DATA SOURCES: A literature search through PubMed was conducted (August 2010 to August 2017) using the terms GS-9857, voxilaprevir, and NS3/4A protease inhibitor. STUDY SELECTION/DATA EXTRACTION: Studies of sofosbuvir/velpatasvir/voxilaprevir were identified. DATA SYNTHESIS: Sofosbuvir/velpatasvir/voxilaprevir is indicated for adult patients with chronic HCV without cirrhosis or with compensated cirrhosis who have (1) genotype 1 through 6 and have previously been treated with an NS5A inhibitor or (2) genotype 1a or 3 and have previously been treated with sofosbuvir without an NS5A inhibitor. POLARIS-1 demonstrated that sofosbuvir/velpatasvir/voxilaprevir for 12 weeks was highly effective in patients with HCV genotype 1 through 6 who had prior exposure to an NS5A inhibitor. POLARIS-2 failed to demonstrate that sofosbuvir/velpatasvir/voxilaprevir for 8 weeks was noninferior to sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 1 through 6 who had no prior exposure to direct-acting antivirals (DAAs). POLARIS-3 demonstrated that sofosbuvir/velpatasvir/voxilaprevir for 8 weeks was as effective as sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 3 and compensated cirrhosis who had no prior exposure to DAAs. POLARIS-4 demonstrated that sofosbuvir/velpatasvir/voxilaprevir was as effective as sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 1 through 3 who had prior exposure to DAAs but not an NS5A inhibitor. The most common adverse reactions were headache, fatigue, diarrhea, and nausea. CONCLUSIONS: Sofosbuvir/velpatasvir/voxilaprevir is safe and effective to treat HCV in patients who have previously been treated with DAAs.

Olaratumab: A Novel Platelet-Derived Growth Factor Receptor α-Inhibitor for Advanced Soft Tissue Sarcoma.

OBJECTIVE: To review and summarize data on olaratumab, which was approved by the US Food and Drug Administration (FDA) in October 2016, in combination with doxorubicin, for the treatment of advanced soft tissue sarcoma. DATA SOURCES: A literature search using PubMed was conducted using the search terms olaratumab, IMC-3G3, and advanced soft tissue sarcoma from January 2005 to June 2017. STUDY SELECTION AND DATA EXTRACTION: The literature search was confined to human studies published in English. Trials of olaratumab for advanced soft tissue sarcomas were prioritized. DATA SYNTHESIS: Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody. Its accelerated FDA approval was based on a phase II randomized trial of olaratumab plus doxorubicin (n = 66) versus doxorubicin monotherapy (n = 67) in patients with advanced soft tissue sarcoma. Olaratumab 15 mg/kg was administered intravenously (IV) on days 1 and 8 in combination with doxorubicin 75 mg/m2 IV on day 1 every 21 days for a total of 8 cycles compared to doxorubicin 75 mg/m2 IV monotherapy. The response rate was 18.2% with combination therapy versus 11.9% with monotherapy and median progression-free survival of 6.6 and 4.1 months, respectively. Additionally, overall survival was increased by 11.8 months in the olaratumab arm (26.5 months vs 14.7 months). Clinically relevant adverse effects in the olaratumab + doxorubicin arm included neutropenia (58%), mucositis (53%), nausea (73%), vomiting (45%), and diarrhea (34%). CONCLUSION: Olaratumab, in combination with doxorubicin, represents a novel treatment strategy for advanced soft tissue sarcoma and provides a significant survival advantage for this rare disease state with limited treatment options.

Cobimetinib.

OBJECTIVE: To review and summarize data on cobimetinib, which was approved by the US Food and Drug Administration (FDA) in November 2015 for use in combination with vemurafenib for unresectable or metastatic melanoma with a BRAFV600E or V600K mutation. DATA SOURCES: A literature search using PubMed was conducted using the terms cobimetinib, MEK inhibitor, and melanoma from January 2000 to June 2016. STUDY SELECTION AND DATA EXTRACTION: The literature search was confined to human studies published in English. Trials of cobimetinib for melanoma were prioritized. DATA SYNTHESIS: Cobimetinib is a reversible inhibitor of MEK1 and MEK2. Its FDA approval was based on a phase III, randomized trial of vemurafenib monotherapy (n = 248) or vemurafenib and cobimetinib (n = 247) in unresectable stage IIIC or IV melanoma with a BRAFV600 mutation. Cobimetinib was administered as 60 mg orally daily for 21 days/7 days off, whereas vemurafenib was administered as 960 mg twice daily. Vemurafenib and cobimetinib were associated with an objective response rate of 68%, and median progression-free survival of 9.9 months. The overall survival was not reached at the time of first interim analysis. Clinically relevant grade ≥3 adverse events were diarrhea (6%), rash (6%), photosensitivity (2%), elevated liver function tests (LFTs) (8%-12%), increased creatine kinase (11%), and retinal detachment (3%). CONCLUSION: Cobimetinib combined with vemurafenib is an alternative BRAF/MEK inhibitor therapy for unresectable or metastatic melanoma with BRAFV600 mutation. The role of cobimetinib in melanoma and other solid tumors is likely to expand as the results from ongoing studies become available.

Assessing the Quality of Economic Evaluations of FDA Novel Drug Approvals: A Systematic Review.

OBJECTIVE: To systematically review and assess the quality of the novel drugs' economic evaluation literature in print during the drugs' early commercial availability following US regulatory approval. DATA SOURCES: MEDLINE and the United Kingdom National Health Service Economic Evaluation Database were searched from 1946 through December 2011 for economic evaluations of the 50 novel drugs approved by the FDA in 2008 and 2009. STUDY SELECTION AND DATA EXTRACTION: The inclusion criteria were English-language, peer-reviewed, original economic evaluations (cost-utility, cost-effectiveness, cost-minimization, and cost-benefit analyses). We extracted and analyzed data from 36 articles considering 19 of the 50 drugs. Two reviewers assessed each publication's quality using the Quality of Health Economic Studies (QHES) instrument and summarized study quality on a 100-point scale. DATA SYNTHESIS: Study quality had a mean of 70.0 ± 16.2 QHES points. The only study characteristics associated with QHES score (with P < 0.05) were having used modeling or advanced statistics, 75.1 versus 61.9 without; using quality-adjusted life years as an outcome, 75.9 versus 64.7 without; and cost-utility versus cost-minimization analysis, 75.9 versus 58.7. Studies most often satisfied quality aspects about stating study design choices and least often satisfied aspects about justifying design choices. CONCLUSION: The reviewed literature considered a minority of the 2008-2009 novel drugs and had mixed study quality. Cost-effectiveness stakeholders might benefit from efforts to improve the quality and quantity of literature examining novel drugs. Editors and reviewers may support quality improvement by stringently imposing economic evaluation guidelines about justifying study design choices.