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Grade 3 or 4 adverse events possibly related to refametinib or sorafenib, occurring in {greater than or equal to}2 patients in either cohort

Purpose: To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors.Experimental Design: BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal–regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes.Results: Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life ∼12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate–stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy.Conclusion: This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types. Clin Cancer Res; 19(5); 1232–43. ©2012 AACR.

Overview of dose-limiting toxicities and adverse events leading to discontinuation and relationship to study treatment

Refametinib geometric mean (% coefficient of variation) multiple-dose pharmacokinetic data on day 1 of course 2

Incidence of treatment-emergent adverse events, all grades, occurring in {greater than or equal to}20% of patients in either cohort

CTC enumeration and pERK analysis in course 1

Table S1: Dose-limiting toxicities; Table S2:Multiple-dose pharmacokinetic parameters (geometric mean (%CV) of BAY 86-9766 and metabolite M17 on Course 1, Day 22 (representing exposure after 15 days of continuous dosing) for once-daily dosing cohorts; Table S3: Multiple-dose pharmacokinetic parameters of BAY 86-9766 and metabolite M17 on Course 1, Day 22 (representing exposure after 15 days of continuous dosing) for twice-daily dosing cohorts

pERK levels in hair follicles by dose level and course

Legend for supplementary figure

Refametinib geometric mean (% coefficient of variation) single-dose pharmacokinetic data on day 1 of course 1

Treatment schema

Sorafenib geometric mean (% coefficient of variation) multiple-dose pharmacokinetic data on day 1 of course 2

Supplementary Figure 1 from RDEA119/BAY 869766: A Potent, Selective, Allosteric Inhibitor of MEK1/2 for the Treatment of Cancer

Objective The aim of this study was to examine whether serum urate-associated genetic variants are associated with early-onset gout. Methods Participants with gout in the Genetics of Gout in Aotearoa study with available genotyping were included (n = 1648). Early-onset gout was defined as the first presentation of gout Results In the Genetics of Gout in Aotearoa study, there were 638 (42.4%) participants with early-onset gout. The ABCG2 rs2231142 gout risk T-allele was present more frequently in participants with early-onset gout compared with the later-onset group. For the other SNPs tested, no differences in risk allele number were observed. In the allelic association analysis, the ABCG2 rs2231142 T-allele was associated with early-onset gout in unadjusted and adjusted models. Analysis of the replication cohorts confirmed the association of early-onset gout with the ABCG2 rs2231142 T-allele, but not with other serum urate-associated SNPs. In the meta-analysis, the odds ratio (95% CI) for early-onset gout for the ABCG2 rs2231142 T-allele was 1.60 (1.41, 1.83). Conclusion In contrast to other serum urate-raising variants, the ABCG2 rs2231142 T-allele is strongly associated with early-onset gout.

Lesinurad [Zurampic; 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)], a selective inhibitor of uric acid reabsorption transporters approved for the treatment of gout, is a racemate of two atropisomers. The objective of this investigation was to evaluate the stereoselectivity of metabolism, the inhibitory potency on kidney uric acid reabsorption transporters (URAT1 and OAT4), and the clinical pharmacokinetics of the lesinurad atropisomers. Incubations with human liver microsomes (HLM), recombinant CYP2C9, and recombinant CYP3A4 were carried out to characterize the stereoselective formation of three metabolites: M3 (hydroxylation), M4 (a dihydrodiol metabolite), and M6 (S-dealkylation). The formation of M3 in HLM with atropisomer 1 was approximately twice as much as that with atropisomer 2, whereas formation of M4 with atropisomer 1 was 8- to 12-fold greater than that with atropisomer 2. There were no significant differences in the plasma protein binding among lesinurad and the atropisomers. Following oral administration of 400 mg lesinurad once daily for 14 days to healthy human volunteers, the systemic exposure (Cmax at steady state and area under the concentration-time curve from time zero to the time of dosing interval) of atropisomer 1 was approximately 30% lower than that of atropisomer 2, whereas renal clearance was similar. In vitro cell-based assays using HEK293 stable cells expressing URAT1 and OAT4 demonstrated that atropisomer 2 was approximately 4-fold more potent against URAT1 than atropisomer 1 and equally active against OAT4. In conclusion, lesinurad atropisomers showed stereoselectivity in clinical pharmacokinetics, metabolism, and inhibitory potency against URAT1.

Jesse Hall,1 Michael Gillen,2 Sha Liu,1 Jeffrey N Miner,1 Shakti Valdez,1 Zancong Shen,1 Caroline Lee1 1Ardea Biosciences, Inc., San Diego, CA, USA; 2AstraZeneca, Gaithersburg, MD, USA Purpose: Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for treatment of gout and asymptomatic hyperuricemia. This study evaluated verinurad pharmacokinetics, pharmacodynamics, and tolerability in healthy Japanese and non-Asian adult male subjects.Methods: This was a Phase I, randomized, single-blind, placebo-controlled study. Panels of 8 Japanese subjects were randomized to receive oral verinurad (2.5–15 mg) or placebo administered as a single dose in a fasted and fed state and as once-daily doses for 7 days in a fed state. Eight non-Asian subjects received verinurad 10 mg as a single dose (fasted and fed) and multiple doses in the fed state. Serial plasma/serum and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse events and laboratory data.Results: Of 48 randomized subjects, 46 (Japanese, 39; non-Asian, 7) completed the study. Following single or multiple doses in Japanese subjects, maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) increased in a near dose-proportional manner. Time to Cmax (Tmax) was ~1.25–2.0 hours with fasting. A moderate-fat meal delayed Tmax (range 3.0–5.0 hours) and had a variable effect on AUC (0%–97% increase) and Cmax (0%–26% increase) across the dose groups. Following multiple verinurad 10 mg doses, Cmax and AUC were 38% and 23% higher, respectively, in Japanese vs non-Asian subjects, largely due to body weight differences. Mean reduction of serum urate following multiple verinurad 10 mg doses was 46% and 44% after 24 hours in Japanese and non-Asian subjects, respectively. Verinurad was well tolerated at all doses.Conclusion: Verinurad monotherapy lowered serum urate and was well tolerated in both healthy Japanese and non-Asian males, while small differences in plasma pharmacokinetics were observed. These data support further evaluation of once-daily verinurad as a treatment for gout and asymptomatic hyperuricemia. Keywords: pharmacokinetics, pharmacodynamics, selective uric acid reabsorption inhibitor, serum urate, urinary uric acid

ABCG2 rs2231142 (Q141K) has been reported to be associated with poor response to allopurinol, while there are conflicting data on the association between the genetically independent ABCG2 rs10011796 variant and allopurinol response. The aim of this study was to replicate the association of ABCG2 rs2231142 and rs10011796 with allopurinol response and perform a meta-analysis.Participants in the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO) (n = 299) were studied. In patients with evidence of adherence to allopurinol therapy (plasma oxypurinol20 μmol/l), good response was defined as serum urate6 mg/dl on allopurinol ⩽300 mg/day and poor response as serum urate ⩾ 6 mg/dl despite allopurinol300 mg/day. Association of rs2231142 and rs10011796 with poor response was tested in logistic regression models that included age, sex, BMI, ethnicity and estimated glomerular filtration rate. Results from the LASSO study and a subset of participants in the Genetics of Gout in Aotearoa New Zealand study (n = 296, including 264 from a previously published report) were combined by meta-analysis.There was evidence for association of rs2231142 with allopurinol response [odds ratio (OR) = 2.35, P = 7.3 × 10-4] but not for rs10011796 (OR = 1.21, P = 0.33) in the LASSO cohort using an adjusted logistic regression model. Meta-analysis provided evidence of a significant association of rs2231142 with allopurinol response (OR = 2.43, P = 6.2 × 10-7), but not rs10011796 (OR = 1.06, P = 0.69).This study has confirmed the significant association of ABCG2 rs2231142 with poor response to allopurinol.

Resume Objectif Le but de ce travail etait de determiner si un changement du taux serique d’acide urique (AUs) entrainait une modification de la fraction d’excretion de l’acide urique (FEAU) et si une reponse renale differente etait observee chez les patients atteints de goutte par rapport aux sujets sains. Methodes La FEAU a ete calculee sur la base d’etudes deja publiees et de quatre essais de phase I portant sur des sujets sains et/ou des patients goutteux, avant et apres un traitement visant a reduire ou augmenter le taux d’acide urique dans le sang. Les traitements comprenaient des inhibiteurs de la xanthine oxydase ayant pour role de reduire l’AUs ainsi que des injections d’acide urique et un regime riche en purines pour augmenter l’AUs. Des traces illustrant la FEAU et l’AUs avant et apres traitement ont ete realises. Pour les essais de phase I, le pourcentage de variation de la FEUA pour chaque modification de l’AUs en mg/dL a ete calcule separement pour les sujets sains et les patients goutteux, puis compare a l’aide du test t de Student. Resultats L’analyse des donnees publiees et celles des essais cliniques de phase I montre que la modification de l’AUs par un mecanisme non renal entraine une variation de la FEAU. On retrouve un changement de plus grande ampleur chez les sujets ayant une FEAU initiale elevee comparativement aux patients goutteux. La quantite d’urate excrete est plus importante chez les sujets sains que chez les patients goutteux lorsque la charge urique filtree est physiologique ; toutefois, cette difference disparait lorsque la charge filtree est reduite a ∼ 5000 mg/24 h. Conclusion Ces observations sont coherentes avec le systeme de reabsorption de l’urate moins sature chez les patients goutteux comparativement aux sujets sains, avec pour consequence une retention elevee de l’acide urique. Des analyses supplementaires pourraient permettre de decouvrir les mecanismes responsables de l’etiologie de l’hyperuricemie ou de la goutte.

Zancong Shen,1 Michael Gillen,2 Jeffrey N Miner,1 Gail Bucci,1 David M Wilson,1 Jesse W Hall1 1Ardea Biosciences, Inc., San Diego, CA, 2AstraZeneca, Gaithersburg, MD, USA Purpose: Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy adult males.Subjects and methods: This was a Phase I, randomized, double-blind, placebo-controlled, single and multiple ascending dose study. Panels of eight male subjects received a single oral dose of verinurad or placebo in either a fasted or fed state; panels of 10–12 male subjects received ascending doses of once-daily verinurad or placebo in a fasted state for 10days. Serial blood and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse event (AE) reports, laboratory tests, vital signs, and electrocardiograms (ECGs).Results: A total of 81 adult males completed the study. Following single doses of verinurad, maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) increased in a dose-proportional manner; Cmax occurred at 0.5–0.75hours and 1.25hours in the fasted and fed states, respectively. Food decreased AUC by 23% and Cmax by 37%-53%. There was a modest accumulation of verinurad following multiple daily doses. Verinurad reduced serum urate levels by up to 62% (40mg, single dose) and 61% (10mg, multiple dose). The increase in urinary excretion of uric acid was greatest in the first 6hours after dosing and was still evident ≥24hours for verinurad doses ≥2mg. Verinurad was well tolerated at all doses. No serious AEs, severe AEs, discontinuations due to AEs, or clinically significant laboratory or ECG abnormalities were reported.Conclusion: Single and multiple doses of verinurad were well tolerated, absorption was rapid, and exposure was dose proportional. Verinurad increased urinary uric acid elimination and resulted in sustained reductions in serum urate. These data support further clinical evaluation of once-daily verinurad as a treatment for gout. Keywords: fractional excretion of uric acid, selective uric acid reabsorption inhibitor, serum urate, urinary uric acid&nbsp

Uric acid is the highly insoluble end-product of purine metabolism in humans. Serum levels exceeding the solubility threshold can trigger formation of urate crystals resulting in gouty arthritis. Uric acid is primarily excreted through the kidneys with 90% reabsorbed back into the bloodstream through the uric acid transporter URAT1. This reabsorption process is essential for the high serum uric acid levels found in humans. We discovered that URAT1 proteins from humans and baboons have higher affinity for uric acid compared with transporters from rats and mice. This difference in transport kinetics of URAT1 orthologs, along with inability of modern apes to oxidize uric acid due to loss of the uricase enzyme, prompted us to ask whether these events occurred concomitantly during primate evolution. Ancestral URAT1 sequences were computationally inferred and ancient transporters were resurrected and assayed, revealing that affinity for uric acid was increased during the evolution of primates. This molecular fine-tuning occurred between the origins of simians and their diversification into New- and Old-World monkey and ape lineages. Remarkably, it was driven in large-part by only a few amino acid replacements within the transporter. This alteration in primate URAT1 coincided with changes in uricase that greatly diminished the enzymatic activity and took place 27-77 Ma. These results suggest that the modifications to URAT1 transporters were potentially adaptive and that maintaining more constant, high levels of serum uric acid may have provided an advantage to our primate ancestors.

ObjectivesTo assess the efficacy and tolerability of lesinurad, an oral selective uric acid reabsorption inhibitor, in combination with allopurinol versus allopurinol alone in patients with gout and an inadequate response to allopurinol.MethodsPatients (N=227) with an inadequate response to allopurinol, defined as serum urate (sUA) ≥6 mg/dL on ≥2 occasions ≥2 weeks apart despite ≥6 weeks of allopurinol, were randomised 2:1 to 4 weeks of double-blind treatment with lesinurad (200, 400 or 600 mg/day) or matching placebo in combination with their prestudy allopurinol dose (200–600 mg/day). Colchicine prophylaxis for gout flares was required. The primary end point was percent reduction from baseline sUA levels at 4 weeks. A pharmacokinetic substudy was also conducted. Safety was assessed throughout.ResultsPatients (n=208) received ≥1 dose of blinded medication. Lesinurad 200, 400 and 600 mg in combination with allopurinol produced significant mean percent reductions from baseline sUA of 16%, 22% and 30%, respectively, versus a mean 3% increase with placebo (pConclusionsLesinurad achieves clinically relevant and statistically significant reductions in sUA in combination with allopurinol in patients who warrant additional therapy on allopurinol alone.Trial registration numberNCT01001338.

Background Ferritin positively associates with serum urate and an interventional study suggests that iron has a role in triggering gout flares. The objective of this study was to further explore the relationship between iron/ferritin and urate/gout. Methods European (100 cases, 60 controls) and Polynesian (100 cases, 60 controls) New Zealand (NZ) males and 189 US male cases and 60 male controls participated. The 10,727 participants without gout were from the Jackson Heart (JHS; African American = 1260) and NHANES III (European = 5112; African American = 4355) studies. Regression analyses were adjusted for age, sex, body mass index and C-reactive protein. To test for a causal relationship between ferritin and urate, bidirectional two-sample Mendelian randomization analysis was performed. Results Serum ferritin positively associated with gout in NZ Polynesian (OR (per 10 ng ml− 1 increase) = 1.03, p = 1.8E–03) and US (OR = 1.11, p = 7.4E–06) data sets but not in NZ European (OR = 1.00, p = 0.84) data sets. Ferritin positively associated with urate in NZ Polynesian (β (mg dl− 1) = 0.014, p = 2.5E–04), JHS (β = 0.009, p = 3.2E–05) and NHANES III (European β = 0.007, p = 5.1E–11; African American β = 0.011, p = 2.1E–16) data sets but not in NZ European (β = 0.009, p = 0.31) or US (β = 0.041, p = 0.15) gout data sets. Ferritin positively associated with the frequency of gout flares in two of the gout data sets. By Mendelian randomization analysis a one standard deviation unit increase in iron and ferritin was, respectively, associated with 0.11 (p = 8E–04) and 0.19 mg dl− 1 (p = 2E–04) increases in serum urate. There was no evidence for a causal effect of urate on iron/ferritin. Conclusions These data replicate the association of ferritin with serum urate. Increased ferritin levels associated with gout and flare frequency. There was evidence of a causal effect of iron and ferritin on urate. Electronic supplementary material The online version of this article (10.1186/s13075-018-1668-y) contains supplementary material, which is available to authorized users.

Background The uric acid (UA) level in patients with gout is a key factor in disease management and is typically measured in the laboratory using plasma samples obtained after venous puncture. This study aimed to assess the reliability of immediate UA measurement with capillary blood samples obtained by fingertip puncture with the HumaSensplus point-of-care meter. Methods UA levels were measured using both the HumaSensplus meter in the clinic and the routine plasma UA method in the biochemistry laboratory of 238 consenting diabetic patients. HumaSensplus capillary and routine plasma UA measurements were compared by linear regression, Bland-Altman plots, intraclass correlation coefficient (ICC), and Lin’s concordance coefficient. Values outside the dynamic range of the meter, low (LO) or high (HI), were analyzed separately. The best capillary UA thresholds for detecting hyperuricemia were determined by receiver operating characteristic (ROC) curves. The impact of potential confounding factors (demographic and biological parameters/treatments) was assessed. Capillary and routine plasma UA levels were compared to reference plasma UA measurements by liquid chromatography-mass spectrometry (LC-MS) for a subgroup of 67 patients. Results In total, 205 patients had capillary and routine plasma UA measurements available. ICC was 0.90 (95% confidence interval (CI) 0.87–0.92), Lin’s coefficient was 0.91 (0.88–0.93), and the Bland-Altman plot showed good agreement over all tested values. Overall, 17 patients showed values outside the dynamic range. LO values were concordant with plasma values, but HI values were considered uninterpretable. Capillary UA thresholds of 299 and 340 μmol/l gave the best results for detecting hyperuricemia (corresponding to routine plasma UA thresholds of 300 and 360 μmol/l, respectively). No significant confounding factor was found among those tested, except for hematocrit; however, this had a negligible influence on the assay reliability. When capillary and routine plasma results were discordant, comparison with LC-MS measurements showed that plasma measurements had better concordance: capillary UA, ICC 0.84 (95% CI 0.75–0.90), Lin’s coefficient 0.84 (0.77–0.91); plasma UA, ICC 0.96 (0.94–0.98), Lin’s coefficient 0.96 (0.94–0.98). Conclusions UA measurements with the HumaSensplus meter were reasonably comparable with those of the laboratory assay. The meter is easy to use and may be useful in the clinic and in epidemiologic studies.

Objective Verinurad (RDEA3170) is a high-affinity, selective URAT1 inhibitor in development for treating gout and asymptomatic hyperuricaemia. This study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad in combination with febuxostat in adults with gout. Methods The phase IIa, open-label, multicentre study randomised 64 subjects into one of five cohorts to receive febuxostat (40 or 80 mg) alone or in combination with verinurad 2.5–20 mg. Serial plasma/serum and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse events, chemistry panels, ECGs and physical examinations. Results Serum pharmacodynamic data demonstrated the maximum percent decrease in serum urate (sUA) from baseline (Emax) at 8–12 hours after dosing. Verinurad with febuxostat decreased sUA in a dose-dependent manner. Emax for verinurad with febuxostat 40 mg ranged from 52% to 77% vs 42% for febuxostat 40 mg alone; Emax for verinurad with febuxostat 80 mg was 62%–82% vs 55% for febuxostat 80 mg alone. Urinary uric acid excretion rate was reduced below baseline by febuxostat alone and was comparable to baseline for verinurad with febuxostat. Verinurad plasma exposure increased with dose and was comparable when combined with febuxostat. No drug-drug interactions were observed. Verinurad was well tolerated with no clinically meaningful changes in laboratory values. Conclusion Verinurad administered with febuxostat produced dose-dependent decreases in sUA while maintaining urinary uric acid levels comparable to baseline. These dose combinations of verinurad and febuxostat were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout. Trial registration number NCT02246673

This study assesses the efficacy and exposure–response relationship of omega-3-carboxylic acids (OM-3 CA) in models of crystal-based inflammation. Human THP-1 macrophages and primary peripheral blood mononuclear cells exposed to multiple inflammatory crystal types were used to determine the anti-inflammatory potential of omega-3 (OM-3) fatty acids in vitro. Anti-inflammatory effects of OM-3 CA in vivo were tested in rat monosodium urate (MSU) crystal air pouch and rat knee intra-articular MSU injection models. Acute treatment with the OM-3 fatty acid docosahexaenoic acid suppressed MSU-, cholesterol crystal-, and calcium pyrophosphate crystal-mediated interleukin-1β (IL-1β) production in vitro. In vivo, OM-3 CA dose-dependently reduced crystal-mediated cell migration, exudate volume, and levels of IL-1β and prostaglandin E2. Following intra-articular injection of MSU, treatment with OM-3-CA (1 mL/kg) and indomethacin (1 mg/kg) resulted in similar mean reductions in pain (23% and 41%, respectively) and swelling (58% and 50%, respectively), compared with controls. Additionally, in complex formulations of OM-3 fatty acids, high levels of palmitic acid could reduce the in vivo effect on crystal-mediated IL-1β elevation. OM-3 CA has a broadly efficacious anti-inflammatory effect with a strong exposure–response relationship that could be beneficial in prevention and treatment of crystal arthritis, with potential applications in other IL-1β-mediated diseases.

Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for treatment of hyperuricemia and gout. This phase 1b, multiple‐dose, drug‐drug interaction study evaluated the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in combination with allopurinol. Adult males with gout were randomized to receive once‐daily oral doses of allopurinol 300 mg or verinurad 10 mg alone for 7 days, allopurinol 300 mg + verinurad 10 mg on days 8 to 14, and the alternative single agent on days 15 to 21. Colchicine 0.6 mg was taken prophylactically for gout flares. Plasma/serum and urine samples were assayed for verinurad, allopurinol, oxypurinol (allopurinol active metabolite), colchicine (plasma only), and uric acid. Safety was assessed by adverse events (AEs) and laboratory tests. Verinurad plasma exposure was unaffected by allopurinol. Verinurad increased the maximum observed plasma concentration (Cmax) for allopurinol by 33%; the area under the plasma concentration‐time curve (AUC) was unaffected. Oxypurinol Cmax and AUC were reduced 32% and 38%, respectively, by verinurad. Colchicine plasma exposure was unaltered by verinurad. The maximum decrease in serum urate was greater with verinurad + allopurinol (65%) than with verinurad (51%) or allopurinol (43%) alone. Compared with the baseline rate, the maximum rate of uric acid excreted in urine was +56% with verinurad, −46% with allopurinol, and unchanged with verinurad + allopurinol. No serious AEs, discontinuations due to AEs, or clinically significant laboratory abnormalities were noted. Despite decreased systemic exposure of allopurinol and oxypurinol in the presence of verinurad, the combination resulted in greater serum urate reduction compared with either drug alone and was well tolerated at the studied doses.

Background Verinurad (RDEA3170) is a high-affinity, selective URAT1 inhibitor in development for the treatment of gout and asymptomatic hyperuricemia. Objectives This Phase 2a, randomized, open-label, multicenter study investigated the multiple-dose pharmacodynamics (PD), pharmacokinetics (PK), and safety of oral verinurad in combination with allopurinol versus allopurinol alone in adults with gout (NCT02498652). Methods Patients aged ≥18 and ≤75 years with gout and serum uric acid (sUA) ≥8 mg/dL were randomized to 1 of 2 cohorts to receive allopurinol (300 mg) in combination with verinurad (dose range 2.5 mg to 20 mg) and allopurinol 300 mg or 600 mg alone (each treatment period was 7 days). Medications were administered once daily ∼30 min after breakfast (for allopurinol 300 mg b.i.d. group, the second allopurinol dose was in the evening). Colchicine 0.6 mg for gout flare prophylaxis was initiated at approximately Day -14 (start of urate-lowering therapy [ULT]) washout) or Day -7 if not on ULT. Serial blood and urine samples were measured on Days -1, 1, 7, 14, 21, 28, and 35 for PD and PK endpoints. Safety assessments included adverse events (AEs) and laboratory, electrocardiogram, and vital sign parameters. Results Forty-one patients were randomized (n=20–21 per cohort). Serum PD data pooled across cohorts demonstrated maximal % decrease in sUA from baseline (Emax)at 6–10 h after verinurad and allopurinol combination treatment. Addition of verinurad (2.5 mg to 20 mg) to allopurinol decreased sUA in dose-dependent manner (Figure). Greater sUA reductions were observed for dose combinations of verinurad ≥5 mg with allopurinol 300 mg versus allopurinol 600 mg alone, while allopurinol 600 mg once daily was equivalent to allopurinol 300 b.i.d. Emax was 46.9%, 58.9%, 59.9%, 67.1%, 68.4%, and 74.3% for verinurad at doses of 2.5, 5, 7.5, 10, 15, and 20 mg in combination with allopurinol 300 mg, versus 39.7%, 53.8%, and 54.4% with allopurinol 300 mg, allopurinol 600 mg, and allopurinol 300 mg b.i.d. alone. No drug-drug interaction on verinurad and allopurinol plasma PK parameters was observed. Conclusions Verinurad coadministered with allopurinol dose-dependently decreased sUA. All dose combinations of verinurad and allopurinol in this study were generally well tolerated with no serious AEs or renal-related events during combination treatment. Disclosure of Interest R. Fleischmann Grant/research support from: Ardea Biosciences, Inc., P. Winkle Employee of: Anaheim Clinical Trials, J. Miner Employee of: Ardea Biosciences, Inc., X. Yan Employee of: Ardea Biosciences, Inc., L. Hicks Employee of: Ardea Biosciences, Inc., S. Valdez Employee of: Ardea Biosciences, Inc., J. Hall Employee of: Ardea Biosciences, Inc., M. Hernandez-Illas: None declared

Background A key factor in the success of gout management is the long-term lowering of uricemia below predetermined targets (300 or 360μ mol/l). Monitoring of uricemia in gout patients is therefore important, and is presently done in the laboratory on plasma samples obtained after venous puncture. An accurate uric acid (UA) meter allowing rapid testing by the health care professionals and self-measurement by the patient should improve management of gout. Objectives This study aimed to assess the reliability of immediate UA measurement in capillary blood samples obtained from fingertip puncture using the HumaSens Plus point-of-care meter (meter) compared with that of a standard laboratory assay (lab). Methods Capillary UA levels were measured from 236 consenting diabetic patients using the commercially available HumaSens Plus UA meter (European Conformity marked and approved for EU market use). Each patient also had a plasma UA measurement in the biochemistry laboratory using an uricase automated colorimetric assay. Since the UA meter has a dynamic range of 180–1190μ mol/l, when the values were out-ranged (meter reading LO or HI), they were individually compared to corresponding plasma measurements. Agreement between capillary and plasma UA levels was assessed by Intraclass Correlation Coefficient (ICC) and Bland-Altman graphic representation. Best capillary UA threshold for detection of hyperuricemia (plasma UA>360μmol/l) was determined from a ROC curve, relationship between methods were identified by regression. Impact of potential confounding factors (biological parameters/treatments) was searched. A total of 206 paired measurements were required for estimation of an ICC of 0.80 with a precision of 0.10 at alpha risk of 0.05%. To better understand discrepancies between meter and lab, results were compared to reference plasma UA measurements by liquid chromatography-mass spectrometry (LC-MS) in a subgroup of 77 patients who gave complementary consent. Results Fourteen capillary samples were read LO by the meter: 11 were confirmed by lab to be below 180μmol/l and 3 were above (189, 206 and 428μmol/l). Two capillary samples were read HI and were measured at 303 and 213μmol/l by lab. In the remaining 222 samples with meter and lab values, ICC was 0.90 [0.87–0.92] and Bland-Altman curve showed acceptable agreement over all the tested values. Best meter threshold for detection of hyperuricemia by the HumaSens Plus meter was 330μmol/l (sensitivity 0.89, specificity 0.89, area under the ROC curve 0.95). Based on regression, plasma uricase of 360μmol/l corresponded to 343μmol/l. Among the biological parameters tested, only hematocrit impacted capillary uric acid measurements, however negligibly. No medication appeared to significantly affect test results. Plasma uricase measurements were better correlated to LC-MS measurements (r=0.98 [0.96–0.99]) than capillary measurements (r=0.84 [0.75–0.90]). Conclusions Results of the HumaSens Plus meter were reasonably comparable to those of the laboratory assay. It is easy to use and may be useful in clinic and in epidemiologic studies. Disclosure of Interest None declared

Background Chronic gout is a significant clinical problem in Asia, including Japan, where many patients remain suboptimally treated with currently available therapies. Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. Objectives The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy Japanese and non-Asian adult male subjects. Methods This was a Phase 1, randomized, single-blind, placebo-controlled study (NCT01872832). Panels of 8 Japanese male subjects were randomized in a 3:1 ratio to receive a modified-release formulation of oral verinurad (2.5 mg, 5 mg, 10 mg, 15 mg) or placebo administered as a single dose in a fasted state and as multiple once-daily doses in a fed state for 7 days. A panel of 8 non-Asian male subjects received single and multiple doses of oral verinurad (10 mg) or placebo. Serial plasma/serum and urine samples were assayed for verinurad and uric acid at predetermined time points. Safety was assessed by adverse event (AE) reports, laboratory tests, vital signs, and electrocardiograms (ECGs). Results Of 48 randomized subjects, 46 (Japanese: 39, non-Asian: 7) completed the study. Treatment groups were generally well balanced; however, mean body weight and body mass index were approximately 14% and 7% lower, respectively, in Japanese than non-Asian subjects. Following single- or multiple-oral doses of verinurad in Japanese subjects, exposure (maximum plasma concentration [C max ] and area under the plasma concentration-time curve [AUC]) increased in a near dose-proportional manner under fasted or fed conditions. The time to C max (T max ) was approximately 1.25–2.0 hours post-dose under fasted conditions. A moderate-fat meal delayed T max up to 5 hours post-dose and increased plasma verinurad exposures up to 109%. Following once-daily multiple doses, there was modest accumulation of verinurad. C max and AUC were 38% and 23% higher, respectively, in Japanese versus non-Asian subjects, largely due to the difference in body weight. Mean reductions in serum uric acid following once-daily multiple dosing of verinurad 10 mg were 62% and 58% at maximum reduction and 46% and 44% at 24 hours post-dose in Japanese and non-Asian subjects, respectively. Verinurad was well tolerated at all doses. One Japanese subject discontinued verinurad due to an AE of urticaria that resolved after 11 days. No serious AEs, Grade 3 or 4 AEs, or clinically significant laboratory or ECG abnormalities were noted. Conclusions Verinurad significantly lowered serum uric acid and was well tolerated in both healthy Japanese and non-Asian males, despite small differences in plasma pharmacokinetics. These data support further evaluation of once-daily verinurad as a treatment for hyperuricemia with or without gout in the Japanese population. Acknowledgements The authors thank Caroline Lee and Zancong Shen of Ardea Biosciences, Inc., for critical review of the abstract. Disclosure of Interest M. Gillen Employee of: AstraZeneca, J. Miner Employee of: Ardea Biosciences, Inc., S. Valdez Employee of: Ardea Biosciences, Inc.

Objective. The aim of this study was to evaluate the pharmacodynamics (PDs), pharmacokinetics (PKs) and safety of lesinurad (selective uric acid reabsorption inhibitor) in combination with febuxostat (xanthine oxidase inhibitor) in patients with gout. Methods. This study was a phase IB, multicentre, open-label, multiple-dose study of gout patients with serum uric acid (sUA) >8 mg/dl following washout of urate-lowering therapy with colchicine flare prophylaxis. Febuxostat 40 or 80 mg/day was administered on days 121, lesinurad 400 mg/day was added on days 814 and then lesinurad was increased to 600 mg/day on days 1521. sUA, urine uric acid and PK profiles were evaluated at the end of each week. Safety was assessed by adverse events, laboratory tests and physical examinations. Results. Initial treatment with febuxostat 40 or 80 mg/day monotherapy resulted in 67% and 56% of subjects, respectively, achieving a sUA level

Gout is caused by elevated serum urate levels, which can be treated using inhibitors of the uric acid transporter, URAT1. We exploited affinity differences between the human and rat transporters to map inhibitor binding sites in URAT1. Human-rat transporter chimeras revealed that human URAT1 serine-35, phenylalanine-365 and isoleucine-481 are necessary and sufficient to provide up to a 100-fold increase in affinity for inhibitors. Moreover, serine-35 and phenylalanine-365 are important for high-affinity interaction with the substrate urate. A novel URAT1 binding assay provides support for direct interaction with these amino acids; thus, current clinically important URAT1 inhibitors likely bind the same site in URAT1. A structural model suggests that these three URAT1 residues are in close proximity potentially projecting within the channel. Our results indicate that amino acids from several transmembrane segments functionally cooperate to form a high-affinity URAT1 inhibitor binding site that, when occupied, prevents substrate interactions.

Background Excess body burden of uric acid promotes gout. Diminished renal clearance of uric acid causes hyperuricemia in most patients with gout, and the renal urate transporter (URAT)1 is important for regulation of serum uric acid (sUA) levels. The URAT1 inhibitors probenecid and benzbromarone are used as gout therapies; however, their use is limited by drug–drug interactions and off-target toxicity, respectively. Here, we define the mechanism of action of lesinurad (Zurampic®; RDEA594), a novel URAT1 inhibitor, recently approved in the USA and Europe for treatment of chronic gout. Methods sUA levels, fractional excretion of uric acid (FEUA), lesinurad plasma levels, and urinary excretion of lesinurad were measured in healthy volunteers treated with lesinurad. In addition, lesinurad, probenecid, and benzbromarone were compared in vitro for effects on urate transporters and the organic anion transporters (OAT)1 and OAT3, changes in mitochondrial membrane potential, and human peroxisome proliferator-activated receptor gamma (PPARγ) activity. Results After 6 hours, a single 200-mg dose of lesinurad elevated FEUA 3.6-fold (p

Objective Our objectives were to determine whether a change in serum uric acid (sUA) resulted in a corresponding change in the fractional excretion of uric acid (FEUA) and whether the renal response was different in patients with gout versus healthy subjects. Methods FEUA was calculated from previously published studies and four new phase I studies in healthy subjects and/or patients with gout before and after treatment to lower or raise sUA. Treatments included xanthine oxidase inhibitors to lower sUA as well as infusion of uric acid and provision of a high-purine diet to raise sUA. Plots were created of FEUA versus sUA before and after treatment. For the phase I studies, percent change in FEUA per mg/dL change in sUA was calculated separately for healthy subjects and patients with gout, and compared using Student's t test. Results Analysis of previously published data and the new phase I clinical data indicates that changing sUA by a non-renal mechanism leads to a change in FEUA. The magnitude of change is greater in subjects with higher baseline FEUA versus patients with gout. Healthy subjects excrete more urate than do patients with gout at physiological urate-filtered load; this difference disappears when the urate-filtered load is decreased to ∼5000 mg/24 hours. Conclusion These observations are consistent with a less saturated urate reabsorption system in patients with gout versus healthy subjects, resulting in elevated retention of uric acid. Further investigation could lead to the discovery of mechanisms responsible for the etiology of hyperuricemia/gout.

A key goal in gout treatment is achieving sustained serum uric acid (sUA) lowering. Point-of-care test (PoCT) meters provide convenient, rapid measures of sUA levels to monitor/adjust therapy. Four commercially available sUA PoCT meters were compared qualitatively (ease of use) and quantitatively (precision/accuracy).Liquid chromatography mass spectrometry (LC-MS) analysis was used as a laboratory reference method to compare precision of PoCT devices using blood samples from 20 healthy volunteers. Accuracy was compared against the LC-MS reference method and a laboratory clinical chemistry platform.Qualitatively, EasyTouch(®) GU and UASure were least user-friendly, requiring repeated attempts for accurate use. HumaSens and BeneCheck provided good usability and assay precision. Cross-validation of meter precision with laboratory-based uricase assay gave good correlations between both methods (R(2) = 0.8061 and 0.7605, respectively).UA PoCT meters can be important in managing gout, and the characteristics compared herein may enhance successful patient uptake.

A series of tetrahydroquinoline derivatives were synthesized and profiled for their ability to act as glucocorticoid receptor selective modulators. Structure-activity relationships of the tetrahydroquinoline B-ring lead to the discovery of orally available GR-selective agonists with high in vivo activity.

the development of new drugs over the last few decades has targeted specific proteins thought to be a key to the disease state. MAPK kinases 1 and 2 (commonly known as MEK1-2) represent such proteins as they lie downstream of important drug targets for oncology, such as EGFR, RAS and RAF. Several MEK1-2 inhibitors are currently in Phase I and II clinical trials in oncology.this review of current literature and recent conferences provides a background on the RAS-RAF-MEK-ERK signaling pathway and a discussion of early MEK inhibitors. The potential of MEK1-2 inhibitors for the treatment of inflammation is briefly presented. Preclinical and early clinical results are discussed for MEK inhibitors currently in development. Completed clinical trials of MEK inhibitors in oncology include some disappointments as well as some promising signs of the value of these compounds and we discuss the potential for MEK inhibitors as monotherapy and their use in drug combinations.the utility of MEK inhibitors as anticancer agents will depend on careful patient selection based on the presence of mutations in genes such as KRAS and BRAF, the identification of additional predictive biomarkers, and an improved understanding of the benefit of drug combinations utilizing both established and emerging therapeutics.

Acute myeloid leukemia (AML) is an aggressive hematologic disease that is characterized by the accumulation of immature myeloid precursor cells. Treatment options for patients are selected based on factors such as age, comorbidities, and cytogenetics. For patients deemed ineligible for standard intensive induction chemotherapy, treatments include either low-dose cytarabine (LDAC) or hypomethylating agents (e.g., azacitidine and decitabine) but when used as single agents, relapses are inevitable. Polo-like Kinase 1 (PLK1), a serine/threonine kinase that is a master regulator of cell-cycle progression, is overexpressed in a number of cancer types including AML. Depletion of PLK1 preferentially induces cell death in tumor versus normal cells. Inhibition of PLK1 in preclinical AML models results in significant efficacy. PCM-075, a highly selective PLK1 inhibitor, is currently in a phase 1b/2 trial (NCT03303339) in combination with standard-of care (LDAC or decitabine) for AML. Collection and processing of blood and bone marrow samples from patients is being performed pre- and post-treatment to assess 1) the inhibition of PLK1 kinase activity and downstream effects by measurement of pharmacodynamic (PD) and mechanism of action (MOA) biomarkers (blood), and 2) the genomic profile of blast cell population(s) from individual patients (blood and bone marrow). For each patient, blood is collected into CellSave, EDTA, and PAXgene blood RNA tubes at various time points as per the clinical protocol schedule of events. PBMCs isolated from CellSave blood tubes are used to assess the phosphorylation status of PD biomarkers using Western blot and phospho-flow cytometry. DNA extracted from blasts (EDTA tube) is used to detect somatic alterations and RNA extracted from the total cell population (PAXgene) is used to detect fusions and determine gene expression profiles by next-generation sequencing. To identify potential PD biomarkers that would enable assessment of PLK1 inhibition in AML patients treated with PCM-075, nine candidate substrates phosphorylated by PLK1 were screened in the AML cell line MV4-11 by Western blot using selected phospho-antibodies. Of these, phosphorylation of Translational Control Tumor Protein (TCTP) at Ser46 was both time- and dose-dependently inhibited by PCM-075. pTCTP detection by Western blot and phospho-flow cytometry was first optimized in PBMCs isolated from healthy donors and later in blast cells from AML patients resulting in a functional biomarker. Additional downstream MOA biomarkers of PCM-075 activity (DNA content, phospho-histone H3, cleaved caspase 3) and tumor DNA biomarkers that enable categorization of AML molecular subtypes have been validated. We present preliminary patient data from the ongoing phase 1b/2 trial and describe biomarker assays that will be used to evaluate target engagement of PCM-075 in AML patients. Citation Format: Maya Ridinger, Karena Kosco, Latifa Hassaine, Jeffrey N. Miner, Mark Erlander. Pharmacodynamic and tumor biomarker analysis of a PLK1 inhibitor, PCM-075, in a phase 1b/2 trial for acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4833.

First generation FLT3 inhibitors have been useful in treating AML (sorafenib, midostaurin). Second generation inhibitors with more selectivity are currently in P3 trials in AML (quizartinib, gilteritinib). Despite the advances, resistance to FLT3 inhibitors and disease progression while on FLT3 inhibitors remains an important problem for patient care. We analyzed the activity of a highly-selective PLK1 inhibitor, PCM-075 (formerly NMS-1286937), in models of acute myeloid leukemia (AML) alone and in combination with various chemotherapies and targeted therapeutics including FLT3 inhibitors. PCM-075 is a potent, highly-selective adenosine triphosphate competitive inhibitor of PLK1, a serine/threonine kinase, which is over-expressed in hematologic malignancies and solid tumors such as AML, breast, prostate, ovarian, lung, gastric and colon. PCM-075 is highly active in blocking proliferation and inducing G2/M arrest in multiple AML cell lines. In a therapeutic model, PCM-075 was capable of inducing significant tumor growth inhibition (TGI)1, and increasing survival in an in vivo disseminated leukemia model (AML-NS8 Cells)2. Orally administered PCM-075 is currently in development for multiple tumor types and is in clinical trials for the treatment of AML (NCT03303339). Synergistic interactions between Quizartinib, other FLT3 inhibitors and PCM-075 were examined in cell culture models. In vivo, combination studies in an AML FLT3 mutant 21 day treatment xenograft model (MV4-11) revealed synergistic interactions between Quizartinib and PCM-075. PCM-075 (dosed orally 30 mg/kg, QD for days 1-10 and 12 -21) in combination with Quizartinib (1 mg/kg, QD for 21 days) resulted in 97.3% (96.2-98.4) TGI, compared to 77.9% (70.0-85.8) with Quizartinib and 80.2% (70.4-90.0) with PCM-075 as monotherapy. Body weight in treated mice remained within 20% of controls. To better understand the mechanism of the synergistic activity of PCM-075, we have conducted in vitro RNA-based profiling studies examining the combination of PCM-075 with FLT3 inhibitors for impact on specific gene pathways in AML cell lines and this will be presented. Combination therapy is the mainstay of current oncology treatment regimens and these results suggest that combining PCM-075 with FLT3 inhibitors could be useful in the treatment of AML and a potential next step for patients developing resistance to FLT3 inhibitors. 1 Mol Cancer Ther. 2012 Apr;11(4):1006-162 PLoS One. 2013;8(3):e58424 Citation Format: Karena Kosco, Maya Ridinger, Penn Whitley, Peter Croucher, Jeffrey N. Miner, Mark Erlander. Selective Polo-like Kinase 1 (PLK1) inhibitor PCM-075 is highly active alone and shows synergy when combined with FLT3 inhibitors in models of acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1885.

Polo-like kinase 1 (PLK1) is a serine-threonine kinase which regulates various cellular processes, including mitosis, DNA replication, and the stress response, and is over-expressed in many malignancies. PCM-075, a PLK1 selective inhibitor, is currently in a phase1b/2 clinical trial in AML in combination therapy with low dose cytarabine (LDAC) (NCT03303339). To identify potential drug relationships and biomarkers associated with response to PCM-075, a two-step computational approach was conducted. Using a modification of the ‘imputed drug-wide association study' (IDWAS) method(1), we first performed ridge regression model training on IC50 values and gene expression signatures for PCM-075 and 138 other drugs from the Genomics of Drug Sensitivity in Cancer (GDSC) database . In the second step, we applied these models to clinical patient datasets (The Cancer Genome Atlas (TCGA) populations containing 32 Cancer types and 9,968 total patients), generating a predicted sensitivity value to all drugs for each patient. Hierarchical clustering of imputed sensitivities across all patients showed that the PCM-075 activity profile is most closely related to cytarabine, etoposide and cisplatin, all of which are compounds that impact DNA replication and lead to apoptosis. Correlation of predicted response values was significant both within and between cancer types, with the acute myeloid leukemia (AML) cohort showing highest increased sensitivity to PCM-075, cytarabine and etoposide relative to the other 31 cancer types examined. Interestingly, other PLK1 inhibitors present in the GDSC (BI-2536 and GW843682X) do not closely cluster with PCM-075. Association of imputed TCGA sensitivity values with somatic variant data shows a high degree of concordance between predicted biomarkers, including TP53 mutation status, further suggesting a functional relationship. Given that this computational analysis suggests that similar pathways are affected by both cytarabine and PCM-075, we tested this experimentally by assessing the level of interaction between these two compounds within an AML cell line (HL-60). The combination resulted in statistically significant synergy (BRAID, k~2.7(1.31-4.25)) for anti-proliferative activity. The mechanistic cause of synergy may be related to DNA damage caused by cytarabine which is known to inhibit and degrade the PLK1 protein. In conclusion, we have identified a pathway signature that clusters PCM-075 with a subset of current oncology therapeutics. Synergy between these compounds in combination suggests the potential for use in treating AML and potentially other cancer types. 1.Genome Res. 27: 1743-1751 (2017). Citation Format: Penn Whitley, Peter J. Croucher, Barbara Valsasina, Dario Ballinari, Italo Beria, Jeffrey N. Miner, Mark G. Erlander. Computationally predicted sensitivity of clinical cohorts identifies drug relationships and biomarkers associated with response to PCM-075, a PLK1 selective inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2810.

Objectives Verinurad (RDEA3170) is a high affinity, selective uric acid transporter (URAT1) inhibitor indevelopment for treating gout and asymptomatic hyperuricaemia. This phase IIa study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad combined with allopurinol versus allopurinol alone in adults with gout. Methods Forty-one subjects were randomised into two cohorts of verinurad (2.5–20 mg) plus allopurinol (300 mg once daily) versus allopurinol 300 mg once daily, 600 mg once daily or 300 mg twice daily alone. Each treatment period was 7 days. Serial plasma/serum and urine samples were assayed for verinurad, allopurinol, oxypurinol and uric acid. Results Serum pharmacodynamic data pooled across cohorts demonstrated maximum per cent decreases in serum urate (sUA) from baseline (Emax) at 7–12 hours after verinurad plus allopurinol treatment. Combination treatment decreased sUA in dose-dependent manner: least-squares means Emax was 47%, 59%, 60%, 67%, 68% and 74% for verinurad doses 2.5, 5, 7.5, 10, 15 and 20 mg plus allopurinol 300 mg once daily, versus 40%, 54% and 54% for allopurinol 300 mg once daily, 600 mg once daily and 300 mg twice daily. Verinurad had no effect on allopurinol plasma pharmacokinetics, but decreased oxypurinol Cmax by 19.0%–32.4% and area under the plasma concentration–time curve from time zero to the last measurable time point by 20.8%–39.2%. Verinurad plus allopurinol was well tolerated with no serious adverse events (AEs), AE-related withdrawals or renal-related events. Laboratory values showed no clinically meaningful changes. Conclusion Verinurad coadministered with allopurinol produced dose-dependent decreases in sUA. All dose combinations of verinurad and allopurinol were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout. Trial registration number NCT02498652.

The RAS-RAF-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway provides numerous opportunities for targeted oncology therapeutics. In particular, the MEK enzyme is attractive due to high selectivity for its target ERK and the central role that activated ERK plays in driving cell proliferation. The structural, pharmacologic, and pharmacokinetic properties of RDEA119/BAY 869766, an allosteric MEK inhibitor, are presented. RDEA119/BAY 869766 is selectively bound directly to an allosteric pocket in the MEK1/2 enzymes. This compound is highly efficacious at inhibiting cell proliferation in several tumor cell lines in vitro. In vivo, RDEA119/BAY 869766 exhibits potent activity in xenograft models of melanoma, colon, and epidermal carcinoma. RDEA119/BAY 869766 exhibits complete suppression of ERK phosphorylation at fully efficacious doses in mice. RDEA119/BAY 869766 shows a tissue selectivity that reduces its potential for central nervous system–related side effects. Using pharmacokinetic and pharmacodynamic data, we show that maintaining adequate MEK inhibition throughout the dosing interval is likely more important than achieving high peak levels because greater efficacy was achieved with more frequent but lower dosing. Based on its longer half-life in humans than in mice, RDEA119/BAY 869766 has the potential for use as a once- or twice-daily oral treatment for cancer. RDEA119/BAY 869766, an exquisitely selective, orally available MEK inhibitor, has been selected for clinical development because of its potency and favorable pharmacokinetic profile. [Cancer Res 2009;69(17):6839–47]

The spinal nucleus of the bulbocavernosus (SNB) neuromuscular system is a highly conserved and well-studied model of sexual differentiation of the vertebrate nervous system. Sexual differentiation of the SNB is currently thought to be mediated by the direct action of perinatal testosterone on androgen receptors (ARs) in the bulbocavernosus/levator ani muscles, with concomitant motoneuron rescue. This model has been proposed based on surgical and pharmacological manipulations of developing rats as well as from evidence that male rats with the testicular feminization mutation (Tfm), which is a loss of function AR mutation, have a feminine SNB phenotype. We examined whether genetically replacing AR in muscle fibers is sufficient to rescue the SNB phenotype of Tfm rats. Transgenic rats in which wild-type (WT) human AR is driven by a human skeletal actin promoter (HSA-AR) were crossed with Tfm rats. Resulting male HSA-AR/Tfm rats express WT AR exclusively in muscle and nonfunctional Tfm AR in other tissues. We then examined motoneuron and muscle morphology of the SNB neuromuscular system of WT and Tfm rats with and without the HSA-AR transgene. We observed feminine levator ani muscle size and SNB motoneuron number and size in Tfm males with or without the HSA-AR transgene. These results indicate that AR expression in skeletal muscle fibers is not sufficient to rescue the male phenotype of the SNB neuromuscular system and further suggest that AR in other cell types plays a critical role in sexual differentiation of this system.