Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH.

BACKGROUND: Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. The efficacy and safety of pegozafermin in patients with biopsy-proven noncirrhotic NASH are not well established. METHODS: In this phase 2b, multicenter, double-blind, 24-week, randomized, placebo-controlled trial, we randomly assigned patients with biopsy-confirmed NASH and stage F2 or F3 (moderate or severe) fibrosis to receive subcutaneous pegozafermin at a dose of 15 mg or 30 mg weekly or 44 mg once every 2 weeks or placebo weekly or every 2 weeks. The two primary end points were an improvement in fibrosis (defined as reduction by ≥1 stage, on a scale from 0 to 4, with higher stages indicating greater severity), with no worsening of NASH, at 24 weeks and NASH resolution without worsening of fibrosis at 24 weeks. Safety was also assessed. RESULTS: Among the 222 patients who underwent randomization, 219 received pegozafermin or placebo. The percentage of patients who met the criteria for fibrosis improvement was 7% in the pooled placebo group, 22% in the 15-mg pegozafermin group (difference vs. placebo, 14 percentage points; 95% confidence interval [CI], -9 to 38), 26% in the 30-mg pegozafermin group (difference, 19 percentage points; 95% CI, 5 to 32; P = 0.009), and 27% in the 44-mg pegozafermin group (difference, 20 percentage points; 95% CI, 5 to 35; P = 0.008). The percentage of patients who met the criteria for NASH resolution was 2% in the placebo group, 37% in the 15-mg pegozafermin group (difference vs. placebo, 35 percentage points; 95% CI, 10 to 59), 23% in the 30-mg pegozafermin group (difference, 21 percentage points; 95% CI, 9 to 33), and 26% in the 44-mg pegozafermin group (difference, 24 percentage points; 95% CI, 10 to 37). The most common adverse events associated with pegozafermin therapy were nausea and diarrhea. CONCLUSIONS: In this phase 2b trial, treatment with pegozafermin led to improvements in fibrosis. These results support the advancement of pegozafermin into phase 3 development. (Funded by 89bio; ENLIVEN ClinicalTrials.gov number, NCT04929483.).

The Novel GlycoPEGylated FGF21 Analog Pegozafermin Activates Human FGF Receptors and Improves Metabolic and Liver Outcomes in Diabetic Monkeys and Healthy Human Volunteers.

Pegozafermin (also known as BIO89-100) is a glycoPEGylated analog of fibroblast growth factor 21 (FGF21) under development to treat nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia (SHTG). In cell-based assays, pegozafermin had a similar receptor engagement profile as recombinant FGF21, with approximately eightfold higher potency at fibroblast growth factor receptor 1c (FGFR1c). In diabetic monkeys, once-weekly and once-every-2-weeks regimens of subcutaneous pegozafermin provided rapid and robust benefits for an array of metabolic biomarkers, including triglycerides, cholesterol, fasting glucose, glycated hemoglobin, adiponectin, alanine aminotransferase, food intake, and body weight. In a single ascending dose study in healthy volunteers, subcutaneously administered pegozafermin was associated with statistically significant improvements in triglycerides, low- and high-density lipoprotein-cholesterol, and adiponectin, an insulin-sensitizing and anti-inflammatory adipokine. Pharmacokinetic half-lives ranged from 55 to 100 hours over the clinically relevant dose range, consistent with the expected half-life extension by glycoPEGylation. These findings provide evidence that pegozafermin is a promising candidate molecule for the treatment of patients with NASH or SHTG. SIGNIFICANCE STATEMENT: Fibroblast growth factor 21 (FGF21) is a stress-inducible hormone that has important roles in regulating energy balance and glucose and lipid homeostasis. Studies presented here demonstrate that a novel long-acting FGF21 analog, pegozafermin, has similar pharmacologic properties as FGF21 and that repeated, subcutaneous dosing of pegozafermin in diabetic monkeys and healthy humans improves lipid metabolism, glucose metabolism, weight, and liver transaminases. These results support future development of pegozafermin for the treatment of metabolic diseases, including nonalcoholic steatohepatitis and severe hypertriglyceridemia.

Enzalutamide in Japanese patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer: A post-hoc analysis of the placebo-controlled PREVAIL trial.

OBJECTIVES: To evaluate the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients. METHODS: This was a post-hoc analysis of the phase 3, double-blind, placebo-controlled PREVAIL trial. Asymptomatic or mildly symptomatic chemotherapy-naïve patients with metastatic castration-resistant prostate cancer progressing on androgen deprivation therapy were randomized one-to-one to 160 mg/day oral enzalutamide or placebo until discontinuation on radiographic progression or skeletal-related event and initiation of subsequent antineoplastic therapy. Coprimary end-points were centrally assessed radiographic progression-free survival and overall survival. Secondary end-points were investigator-assessed radiographic progression-free survival, time to initiation of chemotherapy, time to prostate-specific antigen progression, prostate-specific antigen response (≥50% decline) and time to skeletal-related event. RESULTS: Of 1717 patients, 61 were enrolled in Japan (enzalutamide, n = 28; placebo, n = 33); hazard ratios (95% confidence interval) of 0.30 for centrally assessed radiographic progression-free survival (0.03-2.95), 0.59 for overall survival (0.20-1.8), 0.46 for time to chemotherapy (0.22-0.96) and 0.36 for time to prostate-specific antigen progression (0.17-0.75) showed the treatment benefit of enzalutamide over the placebo. Prostate-specific antigen responses were observed in 60.7% of enzalutamide-treated men versus 21.2% of placebo-treated men. Plasma concentrations of enzalutamide were higher in Japanese patients: the geometric mean ratio of Japanese/non-Japanese patients was 1.126 (90% confidence interval 1.018-1.245) at 13 weeks. Treatment-related adverse events grade ≥3 occurred in 3.6% of enzalutamide- and 6.1% of placebo-treated Japanese patients. CONCLUSION: Treatment effects and safety in Japanese patients were generally consistent with the overall results from PREVAIL.

Population Pharmacokinetics and Pharmacodynamics of Pegozafermin in Patients with Nonalcoholic Steatohepatitis.

Pegozafermin is a long-acting glycoPEGylated analog of fibroblast growth factor 21 (FGF21) in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. In a phase Ib/IIa placebo-controlled, double-blind, multiple ascending dose study in patients with NASH (NCT04048135), administration of pegozafermin resulted in clinically meaningful reductions in hepatic fat fraction (HFF), with a favorable safety and tolerability profile. We aimed to characterize the relationship between pegozafermin dosing, exposure and effects on HFF reduction. We used pharmacokinetic (PK) and pharmacodynamic (PD) modeling of data from the phase Ib/IIa study to identify model parameters and covariates affecting the exposure-response relationship. Clinical simulations were performed to help support dose selection for larger studies. Pegozafermin exposure was adequately described by a one compartment PK model, with one additional transit absorption compartment. PK/PD modeling demonstrated that HFF reduction was significantly related to pegozafermin exposure. HFF outcomes were correlated with average pegozafermin concentrations regardless of weekly dosing (q.w.) or dosing every 2 weeks (q2w). The significant PK/PD model covariates included baseline body weight, alanine aminotransferase level, and liver volume. Simulations showed that the 30 mg q.w. dose approximated the full PD effect; almost all patients would benefit from a greater than or equal to 30% HFF reduction, suggesting fibrosis regression. Furthermore, 44 mg q2w dosing (~22 mg q.w.) appeared to be an effective regimen for HFF reduction. Our modeling supports the feasibility of q.w. and q2w dosing for achieving favorable treatment outcomes in patients with NASH, and provides the rationale for dose selection for the phase IIb ENLIVEN study (NCT04929483).

Safety, pharmacokinetics, and pharmacodynamics of pegozafermin in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study.

BACKGROUND: Management strategies for non-alcoholic steatohepatitis (NASH) are based predominantly on lifestyle modification, with no approved disease-modifying drugs yet available. We aimed to evaluate the safety, pharmacokinetics, and pharmacodynamics of pegozafermin (BIO89-100), a glycoPEGylated FGF21 analogue, in participants with NASH. METHODS: This randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study enrolled adults (aged 21-75 years) who had NASH with stage F1-F3 fibrosis, or non-alcoholic fatty liver disease and a high risk of NASH (referred to in this study as phenotypic NASH) due to central obesity with type 2 diabetes, or central obesity with increased alanine aminotransferase (ALT) or a Fibroscan score of 7 kPa or greater, across 12 specialist centres and clinics in the USA. Patients were centrally randomised by use of an interactive web response system to receive subcutaneously administered pegozafermin (3, 9, 18, or 27 mg once weekly; 18 or 36 mg once every 2 weeks) or placebo for 12 weeks. The primary endpoints were the safety, tolerability, and pharmacokinetics of pegozafermin. This trial is registered with ClinicalTrials.gov (NCT04048135). FINDINGS: Between July 29, 2019, and Aug 3, 2020, 275 participants were screened and 81 (15 [19%] with biopsy-confirmed NASH) were randomly assigned: 62 to pegozafermin (six to 3 mg once weekly, 12 to 9 mg once weekly, 11 to 18 mg once weekly, ten to 27 mg once weekly, 14 to 18 mg once every 2 weeks, and nine to 36 mg once every 2 weeks) and 19 to placebo; 63 received pegozafermin and 18 received placebo, as one participant in the placebo group inadvertently received 3 mg pegozafermin once weekly. Adverse events were reported in eight (44%) of 18 participants in the pooled placebo group, six (86%) of seven in the 3 mg once weekly pegozafermin group, four (33%) of 12 in the 9 mg once weekly group, seven (64%) of 11 in the 18 mg once weekly group, seven (70%) of ten in the 27 mg once weekly group, eight (57%) of 14 in the 18 mg once every 2 weeks group, and eight (89%) of nine in the 36 mg once every 2 weeks group. The most common treatment-related adverse event was mild increased appetite (in ten [16%] of 63 participants in the pooled pegozafermin group vs none of 18 in the pooled placebo group), which was not associated with bodyweight gain. Two patients discontinued treatment due to an adverse event (one each in the 27 mg once weekly and 18 mg once every 2 weeks groups). No treatment-related serious adverse events or deaths occurred. Dose-proportional pharmacokinetics were observed. Anti-drug antibodies were detected in 41 (65%) of 63 participants treated with pegozafermin. By week 13, pegozafermin significantly reduced the least squares mean (LSM) absolute differences in hepatic fat fraction versus pooled placebo (-8·9% [95% CI -14·8 to -3·1; p=0·0032] for 3 mg once weekly, -11·5% [-16·1 to -6·9; p<0·0001] for 9 mg once weekly, -8·9% [-13·7 to -4·2; p=0·0004] for 18 mg once weekly, -14·9% [-20·1 to -9·7; p<0·0001] for 27 mg once weekly, -10·4% [-14·7 to -6·1; p<0·0001] for 18 mg once every 2 weeks, and -11·1% [-16·2 to -6·0; p<0·0001] for 36 mg once every 2 weeks). At week 13, significant LSM relative reductions versus pooled placebo in ALT were observed for pegozafermin 9 mg once weekly, 18 mg once weekly, 27 mg once weekly, and 36 mg once every 2 weeks. At week 13, significant LSM relative reductions versus pooled placebo in aspartate aminotransferase were observed for pegozafermin 3 mg once weekly, 27 mg once weekly, and 36 mg once every 2 weeks. Significant improvements were also observed with pegozafermin treatment for triglycerides (9 mg once weekly, 27 mg once weekly, and 18 mg once every 2 weeks), LDL-C (9 mg once weekly and 27 mg once weekly), HDL-C (3 mg once weekly and 18 mg once every 2 weeks), non-HDL-C (9 mg once weekly and 27 mg once weekly), adiponectin (all doses except for 36 mg once every 2 weeks), PRO-C3 (27 mg once weekly), and bodyweight (27 mg once weekly). Changes in insulin resistance and HbA1c were not significant. INTERPRETATION: Pegozafermin was generally well tolerated and associated with clinically meaningful reductions in liver fat, measures of liver function, and circulating lipids. Further evaluation of pegozafermin in individuals with NASH is warranted. FUNDING: 89bio.

The FGF21 analog pegozafermin in severe hypertriglyceridemia: a randomized phase 2 trial.

Pegozafermin, a long-acting glycopegylated analog of human fibroblast growth factor 21, is in development for the treatment of severe hypertriglyceridemia (SHTG) and nonalcoholic steatohepatitis. Here we report the results of a phase 2, double-blind, randomized, five-arm trial testing pegozafermin at four different doses (n = 67; 52 male) versus placebo (n = 18; 12 male) for 8 weeks in patients with SHTG (triglycerides (TGs), ≥500 mg dl-1 and ≤2,000 mg dl-1). Treated patients showed a significant reduction in median TGs for the pooled pegozafermin group versus placebo (57.3% versus 11.9%, difference versus placebo -43.7%, 95% confidence interval (CI): -57.1%, -30.3%; P < 0.001), meeting the primary endpoint of the trial. Reductions in median TGs ranged from 36.4% to 63.4% across all treatment arms and were consistent regardless of background lipid-lowering therapy. Results for secondary endpoints included significant decreases in mean apolipoprotein B and non-high-density lipoprotein cholesterol concentrations (-10.5% and -18.3% for pooled doses compared to 1.1% and -0.6% for placebo (95% CI: -21.5%, -2.0%; P = 0.019 and 95% CI: -30.7%, -5.1%; P = 0.007, respectively), as well as a significant decrease in liver fat fraction for pooled treatment (n = 17) versus placebo (n = 6; -42.2% pooled pegozafermin, -8.3% placebo; 95% CI: -60.9%, -8.7%; P = 0.012), as assessed in a magnetic resonance imaging sub-study. No serious adverse events were observed to be related to the study drug. If these results are confirmed in a phase 3 trial, pegozafermin could be a promising treatment for SHTG (ClinicalTrials.gov registration: NCT0441186).

Clinical trial: Effects of pegozafermin on the liver and on metabolic comorbidities in subjects with biopsy-confirmed nonalcoholic steatohepatitis.

BACKGROUND: An approved therapy for nonalcoholic steatohepatitis (NASH) and fibrosis remains a major unmet medical need. AIM: To investigate the histological and metabolic benefits of pegozafermin, a glycoPEGylated FGF21 analogue, in subjects with biopsy-confirmed NASH. METHODS: This proof-of-concept, open-label, single-cohort study, part 2 of a phase 1b/2a clinical trial, was conducted at 16 centres in the United States. Adults (age 21-75 years) with NASH (stage 2 or 3 fibrosis, NAS≥4) and magnetic resonance imaging proton density fat fraction (MRI-PDFF) ≥8% received subcutaneous pegozafermin 27 mg once weekly for 20 weeks. Primary outcomes were improvements in liver histology, and safety and tolerability. RESULTS: Of 20 enrolled subjects, 19 completed the study. Twelve subjects (63%) met the primary endpoint of ≥2-point improvement in NAFLD activity score with ≥1-point improvement in ballooning or lobular inflammation and no worsening of fibrosis. Improvement of fibrosis without worsening of NASH was observed in 26% of subjects, and NASH resolution without worsening of fibrosis in 32%. Least-squares mean relative change from baseline in MRI-PDFF was -64.7% (95% CI: -71.7, -57.7; p < 0.0001). Significant improvements from baseline were also seen in serum aminotransferases, noninvasive fibrosis tests, serum lipids, glycaemic control and body weight. Adverse events (AEs) were reported in 18 subjects (90%). The most frequently reported AEs were mild/moderate nausea and diarrhoea. There were no serious AEs, discontinuations due to AEs, or deaths. CONCLUSIONS: Pegozafermin treatment for 20 weeks had beneficial effects on hepatic and metabolic parameters and was well tolerated in subjects with NASH. CLINICALTRIALS: gov: NCT04048135.

GNE genotype explains 20% of phenotypic variability in GNE myopathy.

OBJECTIVE: To test the hypothesis that common GNE mutations influence disease severity; using statistical analysis of patient cohorts from different countries. METHODS: Systematic literature review identified 11 articles reporting 759 patients. GNE registry data were used as a second data set. The relative contributions of the GNE mutations, homozygosity, and country to the age at onset were explored using linear modeling, and relative importance measures were calculated. The rate of ambulation loss for GNE mutations, homozygosity, country, and age at onset was analyzed using Cox proportional hazards models. RESULTS: A spectrum of symptoms and large variability of age at onset and nonambulatory status was observed within families and cohorts. We estimated that 20% of variability is explained by GNE mutations. Individuals harboring p.Asp207Val have an expected age at onset 8.0 (s.e1.0) years later than those without and probability of continued ambulation at age 40 of 0.98 (95% confidence interval [CI] 0.96-1). In contrast, p.Leu539Ser results in onset on average 7.2 (s.e.2.7) years earlier than those without this mutation, and p.Val603Leu has a probability of continued ambulance of 0.61 (95% CI 0.50-0.74) at age 40, but has a nonsignificant effect on age at onset. CONCLUSIONS: GNE myopathy severity significantly varies in all cohorts, with 20% of variability explained by the GNE mutation. Atypical symptoms and clinical presentation suggest that physical and instrumental examination should include additional clinical tests. Proven and measurable effect of GNE mutations on the disease severity should be factored in patient management and clinical research study for a better data interpretation.

A phase 3 randomized study evaluating sialic acid extended-release for GNE myopathy.

OBJECTIVE: To investigate the efficacy and safety of aceneuramic acid extended-release (Ace-ER), a treatment intended to replace deficient sialic acid, in patients with GNE myopathy. METHODS: UX001-CL301 was a phase 3, double-blind, placebo-controlled, randomized, international study evaluating the efficacy and safety of Ace-ER in patients with GNE myopathy. Participants who could walk ≥200 meters in a 6-minute walk test at screening were randomized 1:1, and stratified by sex, to receive Ace-ER 6 g/d or placebo for 48 weeks and assessed every 8 weeks. The primary endpoint was change in muscle strength over 48 weeks measured by upper extremity composite (UEC) score. Key secondary endpoints included change in lower extremity composite (LEC) score, knee extensor strength, and GNE myopathy-Functional Activity Scale (GNEM-FAS) mobility domain score. Safety assessments included adverse events (AEs), vital signs, and clinical laboratory results. RESULTS: Eighty-nine patients were randomized (Ace-ER n = 45; placebo n = 44). Change from baseline to week 48 for UEC score between treatments did not differ (least square mean [LSM] Ace-ER -2.25 kg vs placebo -2.99 kg; LSM difference confidence interval [CI] 0.74 [-1.61 to 3.09]; p = 0.5387). At week 48, there was no significant difference between treatments for the change in key secondary endpoints: LEC LSM difference (CI) -1.49 (-5.83 to 2.86); knee extension strength -0.40 (-2.38 to 1.58); and GNEM-FAS mobility domain score -0.72 (-2.01 to 0.57). Gastrointestinal events were the most common AEs. CONCLUSIONS: Ace-ER was not superior to placebo in improving muscle strength and function in patients with GNE myopathy. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with GNE myopathy, Ace-ER does not improve muscle strength compared to placebo.

Phenotypic stratification and genotype-phenotype correlation in a heterogeneous, international cohort of GNE myopathy patients: First report from the GNE myopathy Disease Monitoring Program, registry portion.

GNE myopathy is a rare distal myopathy, caused by mutations in the GNE gene, affecting sialic acid synthesis. Clinical presentation varies from asymptomatic early stage patients to severely debilitating forms. This first report describes clinical presentations and severity of the disease, using data of 150 patients collected via the on-line, patient-reported registry component of the GNE Myopathy Disease Monitoring Program (GNEM-DMP). Disease progression was prospectively analysed, over a 2-year period, using the GNE myopathy functional activity scale (GNEM-FAS). The average annual rates of decline in function were estimated at -9.6% and -3.2% in ambulant and non-ambulant patients respectively. 4.3% of participants became non-ambulant within one year. The mean time from onset to required use of a wheelchair was 11.9 years. Mean delay of genetic diagnosis from symptom onset was 5.2 years. Mutation specific analysis demonstrated genotype-phenotype relationships; i.e. p.Ala662Val may be associated with a more severe phenotype, compared to p.Val727Met. Patients with compound heterozygous mutation in epimerase and kinase domain appeared to have a more severe phenotype compared to patients with both mutations located within one domain. Acknowledging the limitations of the study, these findings suggest that the severity of the GNE mutations affects disease severity. The GNEM-DMP is a useful data collection tool, prospectively measuring the progression of GNE myopathy, which could play an important role in translational and clinical research and further understanding of genotype-phenotype correlations.

Effect of Visceral Disease Site on Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Enzalutamide in the PREVAIL Trial.

BACKGROUND: The Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy (PREVAIL) trial was unique as it included patients with visceral disease. This analysis was designed to describe outcomes for the subgroup of men from PREVAIL with specific sites of visceral disease to help clinicians understand how these patients responded to enzalutamide prior to chemotherapy. PATIENTS AND METHODS: Prespecified analyses examined the coprimary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) only. All other efficacy analyses were post hoc. The visceral subgroup was divided into liver or lung subsets. Patients with both liver and lung metastases were included in the liver subset. RESULTS: Of the 1717 patients in PREVAIL, 204 (12%) had visceral metastases at screening (liver only or liver/lung metastases, n = 74; lung only metastases, n = 130). In patients with liver metastases, enzalutamide was associated with an improvement in rPFS (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.22-0.90) but not OS (HR, 1.04; 95% CI, 0.57-1.87). In patients with lung metastases only, the HR for rPFS (0.14; 95% CI, 0.06-0.36) and the HR for OS (0.59; 95% CI, 0.33-1.06) favored enzalutamide over placebo. Patients with liver metastases had worse outcomes than those with lung metastases, regardless of treatment. Enzalutamide was well tolerated in patients with visceral disease. CONCLUSIONS: Enzalutamide is an active first-line treatment option for men with asymptomatic or mildly symptomatic chemotherapy-naive metastatic castration-resistant prostate cancer and visceral disease. Patients with lung-only disease fared better than patients with liver disease, regardless of treatment.

The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer.

BACKGROUND: Enzalutamide, an oral androgen receptor inhibitor, significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) versus placebo in the PREVAIL trial of men with chemotherapy-naïve metastatic castration-resistant prostate cancer. OBJECTIVE: To assess the effects of enzalutamide versus placebo in patients from PREVAIL based on site and extent of baseline disease. DESIGN, SETTING, AND PARTICIPANTS: One thousand seven hundred and seventeen asymptomatic or minimally symptomatic patients were randomized to enzalutamide (n=872) or placebo (n=845). Subgroup analyses included nonvisceral (only bone and/or nodal; n=1513), visceral (lung and/or liver; n=204), low-volume bone disease (<4 bone metastases; n=867), high-volume bone disease (≥4 bone metastases; n=850), lymph node only disease (n=195). INTERVENTION: Oral enzalutamide (160mg) or placebo once daily while continuing androgen deprivation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Coprimary endpoints (rPFS, OS) were prospectively evaluated in nonvisceral and visceral subgroups. All other efficacy analyses were post hoc. RESULTS AND LIMITATIONS: Enzalutamide improved rPFS versus placebo in patients with nonvisceral disease (hazard ratio [HR], 0.18; 95% confidence interval [CI], 0.14-0.22), visceral disease (HR, 0.28; 95% CI, 0.16-0.49), low- or high-volume bone disease (HR, 0.16; 95% CI, 0.11-0.22; HR, 0.22; 95% CI, 0.16-0.29, respectively), and lymph node only disease (HR, 0.09; 95% CI, 0.04-0.19). For OS, HRs favored enzalutamide (<1) across all disease subgroups, although 95% CI was >1 in patients with visceral disease (HR, 0.82; 95% CI, 0.55-1.23). Enzalutamide was well tolerated in patients with or without visceral disease. CONCLUSIONS: Enzalutamide provided clinically significant benefits in men with chemotherapy-naïve metastatic castration-resistant prostate cancer, with or without visceral disease, low- or high-volume bone disease, or lymph node only disease. PATIENT SUMMARY: Patients with metastatic castration-resistant prostate cancer-including those with or without visceral disease or widespread bone disease-benefitted from enzalutamide, an active well-tolerated therapy.

Bioavailability of intranasal vs. rectal diazepam.

There remains an unmet medical need in the out-of-hospital management of seizure emergencies because older children and adults often refuse treatment with diazepam rectal gel due to social objections. We have previously reported that intranasal diazepam (DZP) administration is feasible, with maximum plasma concentrations (C(max)) and time to maximum concentration (T(max)) that are comparable to rectal DZP; but tolerability was poor. In the present study, the tolerability and pharmacokinetics of two investigational nasal formulations were compared with DZP rectal gel. Twelve healthy volunteers were enrolled into an active-control, double-blind, four-period, crossover pharmacokinetic and tolerability study. Three intranasal treatments (Nas-A 10mg, Nas-B 10mg and Nas-B 13.4 mg) were compared to a 10mg dose of the rectal gel. A single dose of each formulation was administered followed by at least a 14 day washout period. Blood samples for plasma DZP concentration-time characterization were collected pre-dose and at regular intervals to 240 h post-dose. Tolerability and sedation were assessed using visual analog scales. Mean DZP C(max) (±SD) was 181.8 ± 84.16, 151.3 ± 108.1 and 180.7 ± 82.1 ng/mL for Nas-A 10mg, Nas-B 10 and Nas-B 13.4 mg respectively; in comparison the C(max) for the rectal gel was 160.9 ± 109.4 ng/mL. Median T(max) was 0.75 h for all treatments. Both intranasal formulations were well tolerated and exhibited relatively rapid, but variable, absorption with bioavailability of 70-90% relative to DZP rectal gel. This study shows that the development of a well-tolerated nasal formulation is possible and that the rate and extent of absorption approximates that of DZP rectal gel. We conclude that intranasal DZP offers a viable alternative to rectal administration, but enhancement of formulations is needed to improve the extent and consistency of absorption.

Predicting the response to sumatriptan: the Sumatriptan Naratriptan Aggregate Patient Database.

OBJECTIVE: The efficacy and tolerability profiles of sumatriptan and other 5HT(1B/1D) agonists (triptans) have been well established. However, the determinants for optimal response to sumatriptan are unknown. The Sumatriptan Naratriptan Aggregate Patient (SNAP) database contains data from 128 clinical trials including 28,407 migraine sufferers treating over 130,000 attacks. The authors analyzed these data to identify factors predicting response (headache relief and pain-free response) to sumatriptan. METHODS: The authors assessed 24 possible univariate predictors of headache response in 3,706 patients (18 years and older) receiving sumatriptan tablets 100 mg or placebo in a double-blind study using recursive partitioning and logistic regression techniques. RESULTS: The authors found seven predictors of headache relief 2 hours postdose. Moderate pain at baseline was the strongest predictor (adjusted p = 3.32 x 10(-35)), followed by absence of a disability requiring bedrest (adjusted p = 3.11 x 10(-18)). Other predictors included absence at baseline of vomiting, pulsating pain, nausea, or photophobia/phonophobia, and onset of headache during daytime hours. Logistic regression confirmed that treatment with sumatriptan was the strongest predictor of headache relief, with significant baseline covariates being pain severity, level of disability, and presence or absence of vomiting. A similar pattern of results was reported for predictors of pain-free response 2 hours after taking sumatriptan. CONCLUSIONS: Pretreatment pain severity is the most important predicting factor for response to sumatriptan in migraine attacks: the lower baseline severity, the better.

Prevalence and diagnosis of migraine in patients consulting their physician with a complaint of headache: data from the Landmark Study.

CONTEXT: Headache experts have suggested that to improve the recognition of migraine, patients with a stable pattern of episodic, disabling headache and a normal physical exam should be considered to have migraine in the absence of contradictory evidence. The premise upon which this approach is based-that is, that episodic, recurrent primary headache in the clinic is usually migraine-has not been evaluated in prospective clinical studies. OBJECTIVES: To (1) evaluate the diagnoses of patients consulting their physician with primary episodic headache and (2) compare clinic diagnoses and patient self-diagnoses with International Headache Society (IHS) headache diagnoses assigned on the basis of longitudinal data from patient diaries. DESIGN: Prospective, open-label study. During the screening visit, patients self-reported a headache diagnosis and then were assigned a headache diagnosis by their physician following his or her customary practice. Patients with a new physician diagnosis of migraine or nonmigraine primary headache were given diaries to record headache symptoms for up to 3 months or 6 attacks. Members of an expert panel, unaware of the clinic diagnosis, used diary data to assign a headache diagnosis to each attack and to each patient. SETTING: One hundred twenty-eight (128) practices in 15 countries including the United States. PATIENTS: A total of 1203 male and female patients between 18 and 65 years of age who consulted their physician with headache as a primary or secondary complaint. RESULTS: Overall, 94% of patients with a physician diagnosis of nonmigraine primary headache or a new clinic diagnosis of migraine had IHS-defined migraine (76%) or probable migraine (migrainous) (18%) headache on the basis of longitudinal diary data. A new clinic diagnosis of migraine was almost always correct: 98% of patients with a clinic diagnosis of migraine had IHS-defined migraine (87% of patients) or probable migraine (11% of patients) headache on the basis of longitudinal diary data. On the other hand, review of diaries of patients with a clinic diagnosis of nonmigraine revealed that 82% of these patients had IHS-defined migraine (48%) or probable migraine (34%) headache. Altogether, one in four patients (25%) with IHS-defined migraine according to longitudinal diary data did not receive a clinic diagnosis of migraine. CONCLUSIONS: These findings support the diagnostic approach of considering episodic, disabling primary headaches with an otherwise normal physical exam to be migraine in the absence of contradictory evidence. If in doubt of diagnosis or when assigning a nonmigraine diagnosis, strong consideration should be given to the use of a diary to confirm primary headache diagnosis.