Safety and Pharmacokinetics of Quizartinib Combination Therapy With Standard Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia: Results from Two Phase 1 Trials in Japan and China.

Quizartinib is a potent, oral, second-generation, selective type II FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor. It has shown improved overall survival in a randomized, multinational, Phase 3 (QuANTUM-First) study in patients with FLT3-internal tandem duplication (ITD)-positive newly diagnosed acute myeloid leukemia. We conducted 2 Phase 1b studies in Japan and China to evaluate the safety, pharmacokinetics, and efficacy of quizartinib in combination with standard induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Quizartinib was started at a dose level of 20 mg/day and then escalated to 40 mg/day, the dose used in the Phase 3 study. Seven patients were enrolled according to the 3 + 3 dose-escalation method in each study, including 3 patients who were FLT3-ITD positive. No dose-limiting toxicities were observed at dose levels up to 40 mg/day in both studies. Grade 3 or higher, quizartinib-related, treatment-emergent adverse events included febrile neutropenia, hematologic toxicities, and infections. QT prolongation on electrocardiogram was observed in 5 patients. The pharmacokinetics of quizartinib and its metabolite AC886 were similar between the studies and consistent with previous findings in the United States. We confirmed the tolerability of Japanese and Chinese patients to the dose of quizartinib and chemotherapy regimens used in the QuANTUM-First study.

Disaggregation of Islet Amyloid Polypeptide Fibrils as a Potential Anti-Fibrillation Mechanism of Tetrapeptide TNGQ.

Islet amyloid polypeptide (IAPP) fibrillation has been commonly associated with the exacerbation of type 2 diabetes prognosis. Consequently, inhibition of IAPP fibrillation to minimize ß-cell cytotoxicity is an important approach towards ß-cell preservation and type 2 diabetes management. In this study, we identified three tetrapeptides, TNGQ, MANT, and YMSV, that inhibited IAPP fibrillation. Using thioflavin T (ThT) fluorescence assay, circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), and molecular docking, we evaluated the potential anti-fibrillation mechanism of the tetrapeptides. ThT fluorescence kinetics and microscopy as well as transmission electron microscopy showed that TNGQ was the most effective inhibitor based on the absence of normal IAPP fibrillar morphology. CD spectroscopy showed that TNGQ maintained the α-helical conformation of monomeric IAPP, while DLS confirmed the presence of varying fibrillation species. Molecular docking showed that TNGQ and MANT interact with monomeric IAPP mainly by hydrogen bonding and electrostatic interaction, with TNGQ binding at IAPP surface compared to YMSV, which had the highest docking score, but interact mainly through hydrophobic interaction in IAPP core. The highly polar TNGQ was the most active and appeared to inhibit IAPP fibrillation by disaggregation of preformed IAPP fibrils. These findings indicate the potential of TNGQ in the development of peptide-based anti-fibrillation and antidiabetic nutraceuticals.

A critical appraisal of Japan's new drug approval process: a case study of FLT3-ITD inhibitor quizartinib.

In the last two decades, simultaneous global development of novel drugs become more common by conducting multiregional clinical trials. However, regulatory authorities of different regions often make different decisions on the approvals of the same new drugs. We would like to discuss the appropriateness of Japanese regulatory approach through a case study of quizartinib, a novel anti-leukemia drug developed in Japan. The pivotal clinical trial "QuANTUM-R" conducted in 19 countries showed a modest increase in median overall survival with quizartinib than the conventional chemotherapy. However, because several critical defects in this trial were pointed out by the United States Food and Drug Administration (US FDA) and the European Medicines Agency (EMA), quizartinib has not been approved in the US and Europe to date. On the contrary, the regulatory authority of Japan gave a notice of approval to quizartinib as a "standard of care", and the country becomes the sole country that granted market authorization. In our paper, we provide more detailed discussion about the methodology for scientific evaluation of the new drug.

Homoharringtonine synergizes with quizartinib in FLT3-ITD acute myeloid leukemia by targeting FLT3-AKT-c-Myc pathway.

Acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) has a dismal prognosis. FLT3 inhibitors have been developed to treat patients with FLT3-ITD AML; however, when used alone, their efficacy is insufficient. FLT3 inhibitors combined with chemotherapy may be a promising treatment for FLT3-ITD AML. Homoharringtonine (HHT) is a classical anti-leukaemia drug with high sensitivity to FLT3-ITD AML cells. Here, we showed that HHT synergizes with a selective next-generation FLT3 inhibitor, quizartinib, to inhibit cell growth/viability and induce cell-cycle arrest and apoptosis in FLT3-ITD AML cells in vitro, significantly inhibit acute myeloid leukemia progression in vivo, and substantially prolong survival of mice-bearing human FLT3-ITD AML. Mechanistically, HHT and quizartinib cooperatively inhibit FLT3-AKT and its downstream targets GSK3ß, c-Myc, and cyclin D1, cooperatively up-regulate the pro-apoptosis proteins Bim and Bax, and down-regulate the anti-apoptosis protein Mcl1. Most strikingly, HHT and quizartinib cooperatively reduce the numbers of side-population (SP) and aldehyde dehydrogenase (ALDH)-positive cells, which reportedly are rich in LSCs. In conclusion, HHT combined with quizartinib may be a promising treatment strategy for patients with FLT3-ITD AML.

The safety profile of FLT3 inhibitors in the treatment of newly diagnosed or relapsed/refractory acute myeloid leukemia.

INTRODUCTION: FLT3 inhibitors are important drugs in the therapy of FLT3 positive acute myeloid leukemia (AML). Midostaurin was registered in combination with chemotherapy to treat newly diagnosed AML. Gilteritinib and quizartinib demonstrate effectiveness in a randomized trial in relapsed/refractory AML. Several promising FLT3 inhibitors are being evaluated in clinical research. AREAS COVERED: This review will report the safety of FLT3 inhibitors that are registered for acute myeloid leukemia induction and rescue therapy. EXPERT OPINION: In the near future, it is possible that all the FLT3 positive non M3-AML patients will receive a FLT3 inhibitor. Therapy adherence and strategies to mitigate adverse events must be pursued. The treatment with FLT3 inhibitors may be optimized in terms of toxicities with a rational evaluation of antifungal prophylaxis and concomitant therapy, cardiology monitoring, and keeping in mind rare adverse events. Future studies on unfit patients, special populations, and maintenance settings are warranted, together with post-market studies and real-life experiences. Whenever new FLT3 inhibitors will come to the clinic, we could face a scenario in which profound knowledge of effectiveness, toxicities, and off-target effects will be relevant to choose the best drug for each patient.

AS602801 sensitizes glioma cells to temozolomide and vincristine by blocking gap junction communication between glioma cells and astrocytes.

Previous studies showed that the chemotherapeutic effect of temozolomide (TMZ) and vincristine (VCR) against glioma might be blunted by the co-culture with astrocytes, and connexin-43 (CX43) was thought to play a vital role in the communication between glioma cells and astrocytes. In this study, we aimed to investigate the combined chemotherapeutic effect of AS602801 and TMZ/ VCR in glioma cells both. Dye transfer assay was used to evaluate the gap junction activity between U251 cells and astrocytes. Western blot and immunohistochemistry were carried out to analyse the expression of p-JNK, CX43 and CASP-3 proteins treated under different conditions. AS602801 significantly suppressed the gap junction activity between U251 cells and astrocytes. The expression of p-JNK and CX43 was remarkably inhibited by AS602801. TMZ/VCR-induced apoptosis of glioma cells was effectively enhanced by AS602801 treatment. Accordingly, the inhibitory role of TMZ/VCR in the expression of p-JNK, CX43 and CASP-3 in glioma cells was notably restored by AS602801. Furthermore, in a glioma cell xenograft, AS602801 showed an apparent capability to enhance TMZ/VCR-induced tumour cell apoptosis through altering the expression of p-JNK, CX43 and CASP-3. The findings of this study demonstrated that the co-culture of glioma cells with astrocytes blunted the tumour killing effect of TMZ and VCR. AS602801 down-regulated CX43 expression by inhibiting JNK. And AS602801 also sensitized glioma cells to TMZ/VCR by blocking the gap junction communication between glioma cells and astrocytes via down-regulating CX43, indicating its potential role as a novel adjuvant chemotherapeutic agent in the treatment of glioma.

Renal Reabsorptive Transport of Uric Acid Precursor Xanthine by URAT1 and GLUT9.

Xanthine and hypoxanthine are intermediate metabolites of uric acid and a source of reactive oxidative species (ROS) by xanthine oxidoreductase (XOR), suggesting that facilitating their elimination is beneficial. Since they are reabsorbed in renal proximal tubules, we investigated their reabsorption mechanism by focusing on the renal uric acid transporters URAT1 and GLUT9, and examined the effect of clinically used URAT1 inhibitor on their renal clearance when their plasma concentration is increased by XOR inhibitor. Uptake study for [3H]xanthine and [3H]hypoxanthine was performed using URAT1- and GLUT9-expressing Xenopus oocytes. Transcellular transport study for [3H]xanthine was carried out using Madin-Darby canine kidney (MDCK)II cells co-expressing URAT1 and GLUT9. In in vivo pharmacokinetic study, renal clearance of xanthine was estimated based on plasma concentration and urinary recovery. Uptake by URAT1- and GLUT9-expressing oocytes demonstrated that xanthine is a substrate of URAT1 and GLUT9, while hypoxanthine is not. Transcellular transport of xanthine in MDCKII cells co-expressing URAT1 and GLUT9 was significantly higher than those in mock cells and cells expressing URAT1 or GLUT9 alone. Furthermore, dotinurad, a URAT1 inhibitor, increased renal clearance of xanthine in rats treated with topiroxostat to inhibit XOR. It was suggested that xanthine is reabsorbed in the same manner as uric acid through URAT1 and GLUT9, while hypoxanthine is not. Accordingly, it is expected that treatment with XOR and URAT1 inhibitors will effectively decrease purine pools in the body and prevent cell injury due to ROS generated during XOR-mediated reactions.

Towards better combination regimens of cytarabine and FLT3 inhibitors in acute myeloid leukemia.

BACKGROUND: AML patients with FLT3/ITD mutations have poor response to cytarabine-based chemotherapy. FLT3 inhibitors (FLT3i) may resensitize cells to cytarabine (CYT). Improving treatment outcome of this combination may benefit from a mechanistic extrapolation approach from in vitro data. METHODS: The effects of CYT and several FLT3i on cell proliferation and cell cycle kinetics were examined in AML cell lines. The effect of FLT3i (quizartinib, midostaurin, sorafenib) on cell proliferation and cell cycle kinetics was assessed in AML cell lines with differing FLT3 status; HEL (negligible expression of wild-type FLT3), EOL1 (wild-type FLT3), MV4-11 (FLT3-ITD resulting in constitutively active isoform). Semi-mechanistic cell cycle models for CYT and FLT3i were developed. Clinical CYT and quizartinib pharmacokinetic dosage regimens were modeled. Survival of AML patients was described via a hazard model. Simulations exploring different CYT/quizartinib regimens were conducted with the goal of improving treatment outcome. RESULTS: FLT3 status was associated with sensitivity to CYT (HEL cells most sensitive > EOL1 > MV4-11 cells). This order of sensitivity is reversed for FLT3i. Cytarabine induced apoptosis in the S-phase while all FLT3i induced apoptosis and cell cycle arrest at G1 phase. Simulations of candidate clinical regimens predict better cell kill upon adding quizartinib simultaneously with or immediately after CYT exposure. Overall survival was predicted to be significantly better with quizartinib 200 mg administered every 48 h vs every 24 h in patients with FLT3 aberrations. CONCLUSION: Simultaneous administration of quizartinib and CYT every other day is a promising combination regimen for AML patients with FLT3 mutations.

Quizartinib for the treatment of acute myeloid leukemia.

INTRODUCTION: . Up to 30% of patients with acute myeloid leukemia (AML) have a mutation in the FLT3 receptor. Molecular targets have acquired a significant interest in the treatment of AML and are changing patient outcomes, including improvement of overall survival (OS) and remission rates. FLT3 inhibitors have obtained a central role in how we treat AML. AREAS COVERED: . This article reviews the mechanism of action, pharmacology, clinical efficacy, and safety of quizartinib, a FLT3 inhibitor, for the treatment of acute myeloid leukemia. EXPERT OPINION: . Quizartinib yielded an improvement in OS and complete remission (CR) rates in a phase 3 trial for relapsed/refractory FLT3-mutated AML. The toxicities are manageable; however, it is associated with significant QTc prolongation and myelosuppression. The FDA and EMA did not grant drug approval to quizartinib in the relapsed/refractory setting due to the lack of a significant benefit - to-risk ratio, safety concerns and concerns with credibility and generalizability of the trial data. Results from the frontline phase 3 study evaluating quizartinib with intensive chemotherapy are eagerly awaited. Ongoing studies are investigating its toxicity and efficacy with other therapeutic agents and will help to clarify its role in the treatment of FLT3-ITD-mutated AML.

Population Pharmacokinetic Analysis of Quizartinib in Healthy Volunteers and Patients With Relapsed/Refractory Acute Myeloid Leukemia.

Quizartinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown robust clinical activity in patients with FLT3-internal tandem duplication-mutated relapsed/refractory acute myeloid leukemia (AML). This analysis evaluated the population pharmacokinetics (PK) of quizartinib and its active metabolite, AC886, in a pooled analysis of data from 649 healthy volunteers or patients with AML from 8 clinical trials including the phase 3 QuANTUM-R study. Quizartinib was given as a single dose or multiple once-daily doses of 20, 30, 60, or 90 mg. Nonlinear mixed-effects modeling was performed using observed concentrations of quizartinib and AC886. Strong CYP3A inhibitor use resulted in an 82% increase in the area under the curve (AUC) and a 72% increase in the maximum concentration (Cmax ) of quizartinib. Albumin level, age, and body surface area were statistically significant covariates on quizartinib PK. However, their individual effects on quizartinib AUC and Cmax were <20%. For AC886, strong CYP3A inhibitor use, body surface area and black/African American race were significant covariates. Except for strong CYP3A inhibitor use, the effects on the overall exposure (AUC of quizartinib + AC886) were <20%. The population PK model provided an adequate description of the observed concentrations of quizartinib and AC886 in both healthy volunteers and patients with AML. Only concomitant use of strong CYP3A inhibitors had a clinically meaningful effect on quizartinib PK exposure.

New Treatments in Renal Cancer: The AhR Ligands.

Kidney cancer rapidly acquires resistance to antiangiogenic agents, such as sunitinib, developing an aggressive migratory phenotype (facilitated by c-Metsignal transduction). The Aryl hydrocarbon receptor (AhR) has recently been postulated as a molecular target for cancer treatment. Currently, there are two antitumor agent AhR ligands, with activity against renal cancer, that have been tested clinically: aminoflavone (AFP 464, NSC710464) and the benzothiazole (5F 203) prodrug Phortress. Our studies investigated the action of AFP 464, the aminoflavone pro-drug currently used in clinical trials, and 5F 203 on renal cancer cells, specifically examining their effects on cell cycle progression, apoptosis and cell migration. Both compounds caused cell cycle arrest and apoptosis but only 5F 203 potently inhibited the migration of TK-10, Caki-1 and SN12C cells as well as the migration signal transduction cascade, involving c-Met signaling, in TK-10 cells. Current investigations are focused on the development of nano-delivery vehicles, apoferritin-encapsulated benzothiazoles 5F 203 and GW610, for the treatment of renal cancer. These compounds have shown improved antitumor effects against TK-10 cells in vitro at lower concentrations compared with a naked agent.

Effects of selenium on the proliferation and apoptosis of sheep spermatogonial stem cells in vitro.

The objective of this study was to investigate effects of selenium (Se) on proliferation and apoptosis of sheep spermatogonial stem cells (SSC) in vitro. The SSC were assigned to five treatment groups (0, 2.0, 4.0, 8.0 and 16.0 µmol/L Se). After treatment with Se for 96 h, cell proliferation and apoptosis were evaluated. The relative abundance of P53 mRNA transcript and protein, cell cycle and apoptosis-related genes were detected using real-time PCR and Western blot quantifications, respectively. The results indicate there were the least cell proliferation rates in the Se16.0 group. Treatments with relatively greater Se concentrations (8.0 and 16.0 µmol/L) resulted in a greater percentage of apoptotic cells, which was consistent with the relative abundances of P53, P21, P27 and pro-apoptosis mRNA transcripts. There were relatively greater ROS concentrations in the control, Se8.0 and Se16.0 groups. Compared with the control group, treatment with the Se concentration of 16.0 µmol/L resulted in an increased abundance of P53, P21, P27 and BAX proteins. Treatment with Pifithrin-α suppressed the increase in abundance of P53 and P21 proteins induced by the relatively greater concentration of Se (16.0 µmol/L), however, did not result in a change in abundances of P27 and BAX proteins. These results indicate the regulatory functions of Se on proliferation and apoptosis of sheep SSC is associated with the P21-mediated P53 signalling pathway. The P27 and BAX proteins have limited functions during the apoptotic process of SSC induced by the relatively greater concentrations of Se.

Effect of Food on the Pharmacokinetics of Quizartinib.

Quizartinib is an oral, highly potent, and selective type II FMS-like tyrosine kinase 3 inhibitor in development for acute myeloid leukemia. This parallel-group study evaluated potential food effects on quizartinib absorption in healthy subjects who received a single 30-mg dose after overnight fasting (n = 34) or a high-fat, high-calorie meal (n = 30). Blood samples were collected through 504 hours after dosing, and pharmacokinetic parameters calculated were maximum observed concentration (Cmax ) and area under plasma concentration-time curve from time 0 to last quantifiable concentration (AUClast ) and from time 0 to infinity (AUCinf ). Mean quizartinib pharmacokinetic profiles were similar under fasted and fed conditions. The geometric least squares means ratios (%) for fed/fasted and associated 90% confidence intervals (CIs) for Cmax , AUClast , and AUCinf were 91.58 (82.15-102.08), 105.39 (90.79-122.35), and 108.39 (91.54-128.34), respectively. The 90%CI for the ratio fell within the 80% to 125% limits for Cmax and AUClast , with 90%CI for AUCinf slightly outside the limits (ie, 128%). Food delayed quizartinib time to Cmax by 2 hours. All adverse events were either mild or moderate; no discontinuations due to adverse events occurred. Based on these results, quizartinib can be administered without regard to food.

Practical Considerations for Treatment of Relapsed/Refractory FLT3-ITD Acute Myeloid Leukaemia with Quizartinib: Illustrative Case Reports.

Quizartinib is a tyrosine kinase inhibitor selectively targeting the FMS-like tyrosine kinase 3 (FLT3) receptor that has been developed for the treatment of acute myeloid leukaemia (AML). The Phase 3 QuANTUM-R study investigated the efficacy of quizartinib monotherapy in patients with relapsed/refractory FLT3-ITD mutation-positive AML. The clinical course of four QuANTUM-R participants exemplifies issues specific to quizartinib treatment and is described here. Patient 1 was FLT3-ITD mutation-negative at AML diagnosis, but became FLT3-ITD mutation-positive during treatment that included several lines of chemotherapy and was therefore a suitable candidate for quizartinib. Because of the clonal shifts of AML during treatment, retesting genetic alterations at each relapse or resistance may help to identify candidates for targeted treatment options. Patient 2 developed QTc prolongation during quizartinib treatment, but the QTc interval normalised after dose reduction, allowing the patient to continue treatment and eventually resume the recommended dose. Patient 3 responded to quizartinib and was scheduled for haematopoietic stem cell transplant (HSCT), but developed febrile neutropenia and invasive aspergillosis during conditioning and subsequently died (to avoid drug-drug interactions, no azole antifungal was administered concomitantly). Care is required when selecting concomitant medications, and if there is potential for interactions (e.g. if prophylactic azole antifungals are required) the quizartinib dose should be reduced to minimise the risk of QTc prolongation. Patient 4 was able to undergo HSCT after responding to quizartinib and experienced a durable response after HSCT while on quizartinib maintenance therapy. Together, these cases illustrate the main issues to be addressed when managing patients under quizartinib, allowing for adequate scheduling and tolerability, bridging to HSCT, and durable remission on maintenance therapy in some patients.

p97: An Emerging Target for Cancer, Neurodegenerative Diseases, and Viral Infections.

The AAA+ ATPase, p97, also referred to as VCP, plays an essential role in cellular homeostasis by regulating endoplasmic reticulum-associated degradation (ERAD), mitochondrial-associated degradation (MAD), chromatin-associated degradation, autophagy, and endosomal trafficking. Mutations in p97 have been linked to a number of neurodegenerative diseases, and overexpression of wild type p97 is observed in numerous cancers. Furthermore, p97 activity has been shown to be essential for the replication of certain viruses, including poliovirus, herpes simplex virus (HSV), cytomegalovirus (CMV), and influenza. Taken together, these observations highlight the potential for targeting p97 as a therapeutic approach in neurodegeneration, cancer, and certain infectious diseases. This Perspective reviews recent advances in the discovery of small molecule inhibitors of p97, their optimization and characterization, and therapeutic potential.

Enhanced noninvasive imaging of oncology models using the NIS reporter gene and bioluminescence imaging.

Noninvasive bioluminescence imaging (BLI) of luciferase-expressing tumor cells has advanced pre-clinical evaluation of cancer therapies. Yet despite its successes, BLI is limited by poor spatial resolution and signal penetration, making it unusable for deep tissue or large animal imaging and preventing precise anatomical localization or signal quantification. To refine pre-clinical BLI methods and circumvent these limitations, we compared and ultimately combined BLI with tomographic, quantitative imaging of the sodium iodide symporter (NIS). To this end, we generated tumor cell lines expressing luciferase, NIS, or both reporters, and established tumor models in mice. BLI provided sensitive early detection of tumors and relatively easy monitoring of disease progression. However, spatial resolution was poor, and as the tumors grew, deep thoracic tumor signals were massked by overwhelming surface signals from superficial tumors. In contrast, NIS-expressing tumors were readily distinguished and precisely localized at all tissue depths by positron emission tomography (PET) or single photon emission computed tomography (SPECT) imaging. Furthermore, radiotracer uptake for each tumor could be quantitated noninvasively. Ultimately, combining BLI and NIS imaging represented a significant enhancement over traditional BLI, providing more information about tumor size and location. This combined imaging approach should facilitate comprehensive evaluation of tumor responses to given therapies.

Open-label study of long-term administration of dotinurad in Japanese hyperuricemic patients with or without gout.

BACKGROUND: Dotinurad is a novel selective urate reabsorption inhibitor (SURI) which reduces serum uric acid levels by selectively inhibiting urate transporter 1 (URAT1). This study was intended to verify the efficacy and safety of dotinurad following treatment for 34 or 58 weeks in hyperuricemic patients with or without gout. METHODS: This long-term study had an open-label design with dose escalation. The dose of dotinurad started at 0.5 mg/day and was increased progressively to 2 mg/day. If the serum uric acid level of patients did not reach ≤ 6 mg/dL at week 14, the dose was increased to 4 mg/day. The primary endpoint was the percent change in serum uric acid level from the baseline to each visit. RESULTS: At a dose of 2 mg, serum uric acid levels at week 34 and 58 were reduced from the baseline by 46.73% and 47.17%, respectively; at 4 mg, the respective values were 54.92% and 57.35%. At week 34 and 58, the percentages of patients achieving a serum uric acid levels ≤ 6.0 mg/dL with 2-mg dose were 89.11% and 91.30%, respectively; with 4 mg, the respective rates were 97.50% and 100.00%. In addition, the incidences of adverse events and adverse drug reactions were 65.2% and 21.8%, respectively. CONCLUSION: Dotinurad at doses of 2-4-mg sufficiently reduced serum uric acid levels in hyperuricemic patients with or without gout, and its efficacy and safety were verified for long-term administration. ClinicalTrials.gov Identifier: NCT03006445.

Clinical efficacy and safety of dotinurad, a novel selective urate reabsorption inhibitor, in Japanese hyperuricemic patients with or without gout: randomized, multicenter, double-blind, placebo-controlled, parallel-group, confirmatory phase 2 study.

BACKGROUND: Dotinurad, a novel selective urate reabsorption inhibitor (SURI), reduces serum uric acid levels by selectively inhibiting urate transporter 1 (URAT1) for the treatment of hyperuricemia with or without gout. We confirmed the serum uric acid lowering effect and safety of dotinurad. METHODS: This was a confirmatory, 12-week, randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose escalation, late phase 2 study. The study arms were dotinurad 0.5, 1, 2, or 4 mg and placebo. The primary endpoint was the percent change in serum uric acid level from the baseline to the final visit. The secondary endpoint was the percentage of patients achieving a serum uric acid level ≤ 6.0 mg/dL at the final visit. RESULTS: The study drugs were administered to 200 Japanese hyperuricemic patients with or without gout. The mean percent change in serum uric acid level from the baseline to the final visit in the dotinurad 0.5, 1, 2, and 4 mg groups and the placebo group was 21.81%, 33.77%, 42.66%, 61.09%, and - 2.83%, respectively. The percentage of patients achieving a serum uric acid level ≤ 6.0 mg/dL at the final visit in each group was 23.1%, 65.9%, 74.4%, 100%, and none, respectively. Regarding safety, the incidence of adverse events did not increase with dose escalation in the dotinurad groups. No significant differences were observed in the incidence of gouty arthritis in each group. CONCLUSION: The serum uric acid lowering effect and safety of dotinurad were confirmed in hyperuricemic patients with or without gout. CLINICALTRIALS. GOV IDENTIFIER: NCT02416167.

Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation.

Neutrophilic inflammation with prolonged neutrophil survival is common to many inflammatory conditions, including chronic obstructive pulmonary disease (COPD). There are few specific therapies that reverse neutrophilic inflammation, but uncovering mechanisms regulating neutrophil survival is likely to identify novel therapeutic targets. Screening of 367 kinase inhibitors in human neutrophils and a zebrafish tail fin injury model identified ErbBs as common targets of compounds that accelerated inflammation resolution. The ErbB inhibitors gefitinib, CP-724714, erbstatin and tyrphostin AG825 significantly accelerated apoptosis of human neutrophils, including neutrophils from people with COPD. Neutrophil apoptosis was also increased in Tyrphostin AG825 treated-zebrafish in vivo. Tyrphostin AG825 decreased peritoneal inflammation in zymosan-treated mice, and increased lung neutrophil apoptosis and macrophage efferocytosis in a murine acute lung injury model. Tyrphostin AG825 and knockdown of egfra and erbb2 by CRISPR/Cas9 reduced inflammation in zebrafish. Our work shows that inhibitors of ErbB kinases have therapeutic potential in neutrophilic inflammatory disease.