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To compare the pharmacokinetics (PK), safety, tolerability, and immunogenicity of single intravenous doses of FKB238, a proposed biosimilar of bevacizumab, with European Union (EU)-approved and United States (US)-licensed bevacizumab in healthy participants.In a randomized, double-blind, parallel-group study, 99 healthy men received 5 mg of FKB238, EU-bevacizumab, or US-bevacizumab in a 1 : 1 : 1 ratio by intravenous infusion. PK, immunogenicity, adverse events, local tolerability, vital signs, electrocardiogram, and safety tests of blood and urine were assessed before and up to 99 days after treatment.The 90% confidence interval for the ratios of the primary (area under the curve ((AUC)The study demonstrated the PK similarity of FKB238 to both EU-bevacizumab and US-bevacizumab after a single intravenous infusion. FKB238 was well tolerated in healthy participants, and there was no difference in ADA incidence among the 3 products.

Aims The objectives of this study were to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of ONO-7684, a novel activated factor XI (FXIa) inhibitor, in healthy subjects. Methods This was a first-in-human (FIH), randomised, placebo-controlled, double-blind, single and multiple dose study in healthy subjects under fed and fasted conditions. This study consisted of two parts: single ascending dose (Part A; 1, 5, 20, 80, 150 or 300 mg ONO-7684 or placebo) and multiple ascending doses (Part B; 80, 150 or 250 mg ONO-7684 or placebo daily for 14 days). In both parts, subjects were randomised in a 3:1 ratio to receive ONO-7684 or placebo. Results ONO-7684 was well tolerated at all dose levels tested following both single and repeated doses, with a low overall incidence of treatment-emergent adverse events. There was no evidence to suggest a bleeding risk. Dose proportionality in exposure was observed for the range of 1-300 mg ONO-7684 in Part A. In Part A, the half-life of ONO-7684 administered in the fasted state ranged from 16.0 to 19.8 hours. In Part B, the half-life of ONO-7684 administered in the fed state ranged from 22.1 to 27.9 hours, supporting once daily oral dosing. ONO-7684 strongly inhibited factor XI coagulation activity (FXI:C) and increased activated partial thromboplastin time (aPTT), with a mean maximum on treatment percentage inhibition versus baseline of 92% and a mean maximum on treatment ratio-to-baseline of 2.78, respectively, at 250 mg ONO-7684 daily. Conclusions The data generated in this FIH study demonstrate the promising potential of oral FXIa inhibition and ONO-7684 for indications requiring anticoagulation.

Introduction/Study objectives: FKB327 is a biosimilar of the adalimumab reference product. Studies in healthy subjects and patients with rheumatoid arthritis demonstrated biosimilarity between FKB327 and the reference product in safety profile, efficacy and immunogenicity. FKB327 formulation excipients differ from the citrate-containing formulation of the reference product, and injection-site pain differences have been reported. The current analysis examines pooled data to assess the amount of injection-site pain resulting from injecting FKB327 using a prefilled syringe, autoinjector, or vial/syringe versus the reference product. Methods: Data from four studies were pooled to compare injection-site pain upon subcutaneous administration of FKB327 versus the reference product. Pooled data were analysed to compare FKB327 with the reference product and to compare the autoinjector, pre-filled syringe and vial/syringe. Results: Data were analysed from 2007 assessments in 1,001 subjects. A linear mixed model of the injection-site pain visual analogue scale score across all studies showed a 12.6-point lower pain score for FKB327 versus the reference product (95% confidence interval, –14.3 to –10.8; p > 0.001). The autoinjector pain score was 4.4 points lower than the vial/syringe (95% confidence interval, –5.9 to –2.8; p > 0.001) and 1.7 points lower than the pre-filled syringe (95% confidence interval, –3.3 to –0.1; p = 0.035). No statistically significant differences were identified for gender, age, body weight, needle gauge, or injection site. Conclusion: FKB327 showed less injection-site pain compared with the reference product. No statistically significant differences were seen in injection-site reactions or related adverse events between FKB327 and the reference product or among FKB327 injection methods.

Summary Background To address the unmet medical need for an effective prophylactic vaccine against Ebola virus we assessed the safety and immunogenicity of three different two-dose heterologous vaccination regimens with a replication-deficient adenovirus type 26 vector-based vaccine (Ad26.ZEBOV), expressing Zaire Ebola virus glycoprotein, and a non-replicating, recombinant, modified vaccinia Ankara (MVA) vector-based vaccine, encoding glycoproteins from Zaire Ebola virus, Sudan virus, and Marburg virus, and nucleoprotein from the Tai Forest virus. Methods This randomised, observer-blind, placebo-controlled, phase 2 trial was done at seven hospitals in France and two research centres in the UK. Healthy adults (aged 18–65 years) with no history of Ebola vaccination were enrolled into four cohorts. Participants in cohorts I–III were randomly assigned (1:1:1) using computer-generated randomisation codes into three parallel groups (randomisation for cohorts II and III was stratified by country and age), in which participants were to receive an intramuscular injection of Ad26.ZEBOV on day 1, followed by intramuscular injection of MVA-BN-Filo at either 28 days (28-day interval group), 56 days (56-day interval group), or 84 days (84-day interval group) after the first vaccine. Within these three groups, participants in cohort II (14:1) and cohort III (10:3) were further randomly assigned to receive either Ad26.ZEBOV or placebo on day 1, followed by either MVA-BN-Filo or placebo on days 28, 56, or 84. Participants in cohort IV were randomly assigned (5:1) to receive one dose of either Ad26.ZEBOV or placebo on day 1 for vector shedding assessments. For cohorts II and III, study site personnel, sponsor personnel, and participants were masked to vaccine allocation until all participants in these cohorts had completed the post-MVA-BN-Filo vaccination visit at 6 months or had discontinued the trial, whereas cohort I was open-label. For cohort IV, study site personnel and participants were masked to vaccine allocation until all participants in this cohort had completed the post-vaccination visit at 28 days or had discontinued the trial. The primary outcome, analysed in all participants who had received at least one dose of vaccine or placebo (full analysis set), was the safety and tolerability of the three vaccination regimens, as assessed by participant-reported solicited local and systemic adverse events within 7 days of receiving both vaccines, unsolicited adverse events within 42 days of receiving the MVA-BN-Filo vaccine, and serious adverse events over 365 days of follow-up. The secondary outcome was humoral immunogenicity, as measured by the concentration of Ebola virus glycoprotein-binding antibodies at 21 days after receiving the MVA-BN-Filo vaccine. The secondary outcome was assessed in the per-protocol analysis set. This study is registered at ClinicalTrials.gov , NCT02416453 , and EudraCT, 2015-000596-27. Findings Between June 23, 2015, and April 27, 2016, 423 participants were enrolled: 408 in cohorts I–III were randomly assigned to the 28-day interval group (123 to receive Ad26.ZEBOV and MVA-BN-Filo, and 13 to receive placebo), the 56-day interval group (124 to receive Ad26.ZEBOV and MVA-BN-Filo, and 13 to receive placebo), and the 84-day interval group (117 to receive Ad26.ZEBOV and MVA-BN-Filo, and 18 to receive placebo), and 15 participants in cohort IV were assigned to receive Ad26.ZEBOV and MVA-BN-Filo (n=13) or to receive placebo (n=2). 421 (99·5%) participants received at least one dose of vaccine or placebo. The trial was temporarily suspended after two serious neurological adverse events were reported, one of which was considered as possibly related to vaccination, and per-protocol vaccination was disrupted for some participants. Vaccinations were generally well tolerated. Mild or moderate local adverse events (mostly pain) were reported after 206 (62%) of 332 Ad26.ZEBOV vaccinations, 136 (58%) of 236 MVA-BN-Filo vaccinations, and 11 (15%) of 72 placebo injections. Systemic adverse events were reported after 255 (77%) Ad26.ZEBOV vaccinations, 116 (49%) MVA-BN-Filo vaccinations, and 33 (46%) placebo injections, and included mostly mild or moderate fatigue, headache, or myalgia. Unsolicited adverse events occurred after 115 (35%) of 332 Ad26.ZEBOV vaccinations, 81 (34%) of 236 MVA-BN-Filo vaccinations, and 24 (33%) of 72 placebo injections. At 21 days after receiving the MVA-BN-Filo vaccine, geometric mean concentrations of Ebola virus glycoprotein-binding antibodies were 4627 ELISA units (EU)/mL (95% CI 3649–5867) in the 28-day interval group, 10 131 EU/mL (8554–11 999) in the 56-day interval group, and 11 312 mL (9072–14106) in the 84-day interval group, with antibody concentrations persisting at 1149–1205 EU/mL up to day 365. Interpretation The two-dose heterologous regimen with Ad26.ZEBOV and MVA-BN-Filo was safe, well tolerated, and immunogenic, with humoral and cellular immune responses persisting for 1 year after vaccination. Taken together, these data support the intended prophylactic indication for the vaccine regimen. Funding Innovative Medicines Initiative and Janssen Vaccines & Prevention BV. Translation For the French translation of the abstract see Supplementary Materials section.

Context SJX-653 is a novel neurokinin 3 receptor (NK3R) antagonist. The NK3 pathway is a central regulator of gonadotropin releasing hormone (GnRH) secretion and has also been implicated in the generation of hot flashes. Therefore, decreases of luteinizing hormone (LH) and testosterone in men serve as sensitive pharmacodynamic (PD) markers of central NK3 antagonism. Objective To characterize the safety, tolerability, pharmacokinetics, and pharmacodynamic activity of SJX-653 in healthy men. Design A randomized, placebo-controlled, double-blind, single ascending dose study. Setting Phase 1 unit. Patients or Other Participants Seven cohorts of 6 healthy men 18–45 years of age (4:2 randomization to SJX-653/placebo per cohort). Intervention(s) Single oral doses of 0.5–90 mg SJX-653. Main Outcome Measure(s) Safety assessments and serial pharmacokinetic (PK)/PD measurements. Results SJX-653 was well tolerated at all dose levels. Cmax and AUC0-24 increased in a dose-proportional manner. The terminal elimination half-life ranged between 9.8 and 12.5 hours independent of dose. A statistically significant, dose-dependent, reversible reduction of LH and testosterone was observed with near maximal effect after 15 mg and little to no effect at 4.5 mg. Maximal LH reduction was 70 ± 7% (mean ± sd) at 6 hours after 30 mg SJX-653 versus 10 ± 43% for placebo (P = 0.0006); maximal T reduction was of 68 ± 5% at 8 hours after 60 mg SJX-653 versus 18 ± 11% for placebo (P Conclusions These data demonstrate clinical proof-of-mechanism for SJX-653 as a potent centrally-acting NK3R antagonist.

Background & Aims In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR or CCK2R), eradicated some type 1 gNETs in patients. We investigated the mechanisms by which netazepide induced gNET regression using gene expression profiling. Methods We obtained serum samples and gastric corpus biopsy specimens from 8 patients with hypergastrinemia and type 1 gNETs enrolled in a phase 2 trial of netazepide. Control samples were obtained from 10 patients without gastric cancer. We used amplified and biotinylated sense-strand DNA targets from total RNA and Affymetrix (Thermofisher Scientific, UK) Human Gene 2.0 ST microarrays to identify differentially expressed genes in stomach tissues from patients with type 1 gNETs before, during, and after netazepide treatment. Findings were validated in a human AGSGR gastric adenocarcinoma cell line that stably expresses human CCK2R, primary mouse gastroids, transgenic hypergastrinemic INS-GAS mice, and patient samples. Results Levels of pappalysin 2 (PAPPA2) messenger RNA were reduced significantly in gNET tissues from patients receiving netazepide therapy compared with tissues collected before therapy. PAPPA2 is a metalloproteinase that increases the bioavailability of insulin-like growth factor (IGF) by cleaving IGF binding proteins (IGFBPs). PAPPA2 expression was increased in the gastric corpus of patients with type 1 gNETs, and immunohistochemistry showed localization in the same vicinity as CCK2R-expressing enterochromaffin-like cells. Up-regulation of PAPPA2 also was found in the stomachs of INS-GAS mice. Gastrin increased PAPPA2 expression with time and in a dose-dependent manner in gastric AGSGR cells and mouse gastroids by activating CCK2R. Knockdown of PAPPA2 in AGSGR cells with small interfering RNAs significantly decreased their migratory response and tissue remodeling in response to gastrin. Gastrin altered the expression and cleavage of IGFBP3 and IGFBP5. Conclusions In an analysis of human gNETS and mice, we found that gastrin up-regulates the expression of gastric PAPPA2. Increased PAPPA2 alters IGF bioavailability, cell migration, and tissue remodeling, which are involved in type 1 gNET development. These effects are inhibited by netazepide., Graphical abstract

Background This double-blind, first-in-human Phase I study evaluated pharmacokinetics, safety and tolerability of AL-794 (prodrug of ALS-033719), a potent endonucle-ase inhibitor of influenza A and B in healthy volunteers. Methods Healthy adult volunteers were randomized to AL-794 (50–2,000 mg single ascending doses, fasting) or placebo (5 cohorts, n=6:2 AL-794: placebo/cohort) in part 1, and AL-794 (50–600 mg multiple ascending doses, twice-daily, fed or fasted) or placebo (3 cohorts, n=8:2 AL-794: placebo/cohort) for 7 days in part 2. In part 3, 8 healthy volunteers from part 1 received 450 mg AL-794 ( n=6) or placebo ( n=2) following a high-fat meal. All dosing was done with an oral suspension. Blood and urine samples for pharmacokinetics were collected at scheduled times and analysed for ALS-033719 and ALS-033927 (inactive glucuronide) plasma concentrations using LC-MS/MS. Results ALS-033719 plasma concentrations increased dose proportionately up to 150 mg but less than proportionately above 150 mg. Steady-state was generally achieved by the third dose. ALS-033719 exposure increased following administration with a standard meal (19%–33%) or high-fat meal (3–3.6-fold). ALS-033927 was the major metabolite observed. Renal elimination was negligible (0.2%). Seventeen AL-794-treated healthy volunteers reported ≥1 treatment-emergent adverse event (TEAE; part 1: n=6, 24%; part 2: n=11, 69%). The most common TEAEs were headache (part 1: n=3; part 2: n=5) and dizziness (part 1: n=2; part 2: n=6). Conclusions AL-794 up to 200 mg twice daily achieved ALS-033719 exposures which are expected to be efficacious and were generally tolerated. Further studies are planned to characterize safety and antiviral activity.

Background Nalmefene (Selincro®) is a µ- and δ- opioid receptor antagonist, κ-opioid receptor partial agonist that has recently been approved in Europe for treating alcohol dependence. It offers a treatment approach for alcohol dependent individuals with “high risk drinking levels” to reduce their alcohol consumption. However, the neurobiological mechanism underpinning its effects on alcohol consumption remains to be determined. Using a randomised, double blind, placebo controlled within subject cross-over design we aimed to determine the effect of a single dose of nalmefene on striatal BOLD (blood oxygen level dependent) signal change during anticipation of monetary reward using the Monetary Incentive Delay Task following alcohol challenge. Methods and Materials 22 currently heavy drinking, non-treatment seeking alcohol dependent males were recruited. The effect of single dose nalmefene (18mg; Selincro®) on changes in a priori defined striatal region of interest (ROI) BOLD signal change during reward anticipation compared with placebo were investigated using functional MRI (magnetic resonance imaging). Both conditions were performed under intravenous alcohol administration (6% v/v infusion to achieve a target level of 80mg%). Results Datasets from 18 participants were available and showed that in the presence of the alcohol infusion, nalmefene significantly reduced the BOLD response in the striatal ROI compared with placebo. Nalmefene did not alter brain perfusion. Discussion Nalmefene blunts BOLD response in the mesolimbic system during anticipation of monetary reward and an alcohol infusion. This is consistent with nalmefene’s actions on opiate receptors, which modulate the mesolimbic dopaminergic system, and provides a neurobiological basis for its efficacy.

Aims To compare the pharmacokinetics, safety, tolerability and immunogenicity of FKB327, a biosimilar of adalimumab, with European Union (EU)-approved Humira and US-licensed Humira after single subcutaneous doses in healthy subjects. Methods In a randomized, double-blind, parallel-group study, 180 healthy subjects received by subcutaneous injection 40 mg of EU-Humira, or US-Humira, or FKB327, in a 1:1:1 ratio, stratified by bodyweight. Pharmacokinetics, local tolerability, immunogenicity, adverse events, vital signs, electrocardiography and laboratory safety tests were assessed prior to and up to 1536 h after treatment. Results The pharmacokinetics of FKB327 were similar to those of both EU- and US-Humira. The 90% confidence interval for the ratios of AUC0–t, AUC0–inf, and Cmax geometric means were in the acceptance range for bioequivalence of 0.80–1.25 for all three pairwise comparisons by analysis of covariance with baseline characteristics age, body weight and (for Cmax only) sex as covariates. Tolerability of all three treatments was equally acceptable, and there were no differences in safety profile or immunogenicity among the three treatments. Overall, antidrug antibodies were detected in approximately 70% of subjects who received each treatment; higher titres were associated with faster elimination of adalimumab. Conclusions The study demonstrated pharmacokinetic similarity of FKB327 with EU- and US-Humira. FKB327 was well tolerated by healthy subjects, with adverse effects similar to Humira. If clinical similarity to Humira, including efficacy, can be shown in patients, FKB327 will meet the criteria for biosimilarity to Humira.

Advancement of RNAi-based therapeutics depends on effective delivery to the site of protein synthesis. Although intravenously administered, multi-component delivery vehicles have enabled small interfering RNA (siRNA) delivery and progression into clinical development, advances of single-component, systemic siRNA delivery have been challenging. In pre-clinical models, attachment of a triantennary N -acetylgalactosamine (GalNAc) ligand to an siRNA mediates hepatocyte uptake via the asialoglycoprotein receptor enabling RNAi-mediated gene silencing. In this phase 1 study, we assessed translation of this delivery approach by evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of a GalNAc-siRNA conjugate, revusiran, targeting transthyretin (TTR). Subjects received a placebo or ascending doses of revusiran subcutaneously ranging from 1.25–10 mg/kg in the single and 2.5–10 mg/kg in the multiple ascending dose phases. Revusiran was generally well tolerated, with transient, mild to moderate injection site reactions the most common treatment-emergent adverse events. Doses of 2.5–10 mg/kg revusiran elicited a significant reduction of serum TTR versus the placebo (p 0.01), with mean TTR reductions of approximately 90% observed with multiple dosing. These results demonstrate translation of this novel delivery platform, enabling clinical development of subcutaneously administered GalNAc-siRNAs for liver-based diseases.

Gastrin controls gastric acid secretion and mucosal cell growth, especially of enterochromaffin-like cells, via gastrin/cholecystokinin-2 receptor (CCK2R) binding and downstream signalling. Studies in animal models, healthy subjects and patients with gastric neuroendocrine tumours provide compelling evidence to justify developing a CCK2R antagonist (CCK2RA) for preventing or treating the trophic effects of hypergastrinaemia or conditions expressing CCK2R, and with or without a proton pump inhibitor, for treating gastric acid-related conditions. Many compounds have been studied, but most have had problems with potency, selectivity for CCK2 versus CCK1 receptor, solubility or oral bioavailability. None has yet been marketed. Netazepide and Z-360 are currently undergoing clinical development, for treatment of gastric neuroendocrine tumours and pancreatic cancer, respectively. There are several other potential indications for a CCK2RA and an unmet need.

Background FKB327 is a proposed biosimilar of the adalimumab reference product (RP). Several studies in both healthy volunteers and patients with active rheumatoid arthritis (RA) were undertaken, the results of which have been reported elsewhere. The formulation excipients of the biosimilar product differ from those of the RP, and different injection-site pain intensity with subcutaneous injection has been reported. Objectives The current meta-analysis examines pooled data from these studies in relation to the amount of injection-site pain resulting from using a prefilled syringe (PFS) versus an auto-injector (AI) versus a regular syringe (RS), and the proposed biosimilar, FKB327, versus the RP. Methods Data from 4 studies, FKB327-001, -002, -003, and -004, were pooled in an effort to compare injection-site pain upon subcutaneous administration of FKB327 versus the RP (citrate-containing formulation of the RP [40 mg/0.8 mL]). Study FKB327-001, in healthy volunteers (n = 180), involved a single subcutaneous dose of either FKB327 or the RP. Study FKB327-004 was a similar study in healthy Japanese volunteers (n = 130). Study FKB327-002 was a randomized (FKB327 with RS or the RP), double-blind, multiple-dose study in patients with active RA. This was followed by Study FKB327-003, in which patients were rerandomized to receive either FKB327 with PFS or the RP in the randomization phase, followed by an open-label extension phase of the study, in which AI was introduced. As patients continued receiving treatment or switched treatments during the course of the FKB327-002 and -003 studies, injection-site pain was assessed at the first dosing occasion of FKB327 or the RP (n = 691). Data from all 4 studies were examined by meta-analysis of the visual analog scale (VAS) using a 100-mm horizontal scale for FKB327 versus the RP and for comparison of AI, PFS, and RS. Results Data were analyzed from a total of 2007 assessments in 1001 subjects. A linear mixed model of the VAS in mm for the RP versus FKB327 across all 4 studies showed a 12.6-point lower pain score for FKB327 versus the RP (95% confidence interval [CI], –14.3 to –10.8; P Conclusion FKB327 showed a significant advantage in terms of injection-site pain intensity compared with the RP, as well as lack of inferiority for both AI and PFS versus RS. Disclosure of Interests: Rieke Alten Grant/research support from: Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb, Mark C. Genovese Grant/research support from: Sanofi/Genzyme, Genentech/Roche, RPharm, Consultant for: Sanofi/Genzyme, Genentech/Roche, RPharm, Malcolm Boyce: None declared, Takuma Yonemura Grant/research support from: I have received a research grant from FKB for conducting the clinical study., Takahiro Ito Employee of: I am an employee of Fujifilm Kyowa Kirin Biologics., Herbert Kellner Grant/research support from: Roche, Consultant for: Roche

Background: NK3 antagonism is a clinically validated mechanism of action for treating menopausal vasomotor symptoms (“hot flashes”). In men, reductions of LH and T are sensitive pharmacodynamic markers of central NK3 antagonism, due to the known inhibitory effect of NK3 antagonists on GnRH pulsatility. Here we present results of a first-in-human study with SJX-653, a novel and selective NK3 antagonist, in healthy adult men. Objective: To characterize the safety, tolerability, pharmacokinetics, and pharmacodynamic activity (as measured by LH and T reductions) of single ascending oral doses of SJX-653 in healthy adult men. Methods: The study was a randomized, placebo-controlled, double-blind, single ascending dose study of orally administered SJX-653 in healthy adult men. Seven cohorts of 6 men were enrolled (4 SJX-653: 2 placebo). Subjects were confined to a Phase 1 unit from Day -1 to Day 3 with a follow-up visit on Day 8. Safety assessments (labs, ECG, vitals) and serial PK/PD samples were collected pre- and post-dose at multiple timepoints. Results: 42 male subjects were randomized and completed the study. Dose levels of 0.5 to 90 mg SJX-653 were evaluated. The median ages of subjects in the SJX-653 and placebo groups were 32.0 and 27.0 years, respectively. Subjects receiving SJX-653 and placebo had comparable mean height, weight, and BMI measurements. There were no serious adverse events (SAEs) or clinically meaningful changes in clinical laboratory values, vital sign measurements, or ECG parameters. AEs were mostly mild and the incidence of adverse events (AEs) was similar between subjects treated with SJX-653 and placebo. Across the 180-fold dose range (0.5 to 90 mg) mean Cmax and AUC0-24 values increased in a dose‑proportional manner with 175-fold and 143-fold increases, respectively. The mean terminal elimination half-life for SJX-653 was 10 to 13 hours. Reductions in LH and T levels were reversible and dose-dependent. LH reductions preceded T reductions by 2-3 hours, as expected. Statistically significant reductions in LH and T from baseline were observed at doses ≥15 mg SJX-653. The maximum mean LH reduction of 70% at 6 hours was in subjects treated with 30 mg SJX-653, versus 10% in placebo-treated subjects at the corresponding timepoint (p = 0.0006). The maximum mean T reduction of 68% at 8 hours was in subjects treated with 60 mg SJX-653, versus 18% in placebo-treated subjects at the corresponding timepoint (p < 0.0001). Conclusions: Single ascending doses of SJX-653 were well tolerated in healthy adult men. There were no SAEs and the incidence of AEs was similar between subjects treated with SJX-653 and placebo. The plasma half-life for SJX-653 was 10-13 hours, consistent with once-daily (QD) dosing. SJX-653 demonstrated clinical proof-of-mechanism as a central NK3 antagonist by causing statistically significant, dose-dependent, and reversible reductions in LH and T. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Netazepide, a gastrin/CCK2 receptor antagonist, once daily for 12 weeks reduced the number of tumours and size of the largest one in 16 patients with autoimmune chronic atrophic gastritis (CAG), achlorhydria, hypergastrinaemia and multiple gastric neuroendocrine tumours (type 1 gastric NETs), and normalised circulating chromogranin A (CgA) produced by enterochromaffin-like cells, the source of the tumours. The aim was to assess whether longer-term netazepide treatment can eradicate type 1 gastric NETs.After a mean 14 months off netazepide, 13 of the 16 patients took it for another 52 weeks. Assessments were: gastroscopy; gene-transcript expression in corpus biopsies using qPCR; blood CgA and gastrin concentrations; and safety assessments.While off-treatment, the number of tumours, the size of the largest one, and CgA all increased again. Netazepide for 52 weeks: cleared all tumours in 5 patients; cleared all but one tumour in one patient; reduced the number of tumours and size of the largest one in the other patients; normalised CgA in all patients; and reduced mRNA abundances of CgA and histidine decarboxylase in biopsies. Gastrin did not increase further, confirming that the patients had achlorhydria. Netazepide was safe and well tolerated.A gastrin/CCK2 receptor antagonist is a potential medical and targeted treatment for type 1 gastric NETs, and an alternative to regular gastroscopy or surgery. Treatment should be continuous because the tumours will regrow if it is stopped. Progress can be monitored by CgA in blood or biomarkers in mucosal biopsies. This article is protected by copyright. All rights reserved.

Netazepide (YF476) is a recently developed, orally active gastrin receptor antagonist that, in short trials in patients with type 1 gastric enterochromaffin-like cell neuroendocrine tumours, has been shown to induce a significant reduction in the number and size of tumours as well as serum chromogranin A (CgA). The aim of this review is to evaluate the long-term effect and safety of netazepide.Five patients previously treated with netazepide in an open-label trial were offered continuous treatment with netazepide 25 mg once daily. Upper endoscopy was performed every 6 months. The tumours were counted and measured, and tissue samples were obtained from the flat corpus mucosa. Enterochromaffin-like cell hyperplasia was classified according to Solcia and colleagues and volume density of CgA immunoreactive (IR) cells was calculated. Fasting serum CgA and fasting serum gastrin were measured every 3 months.All tumours regressed completely in three of five patients; time until total disappearance was 3, 9 and 12 months. In the other two patients, the number of tumours was reduced from 13 to 5 and from 14 to 3. Serum CgA showed a rapid and sustained decrease (P0.001). The mean reduction in serum CgA was 4.1±0.5 nmol/l. Similarly, volume density of CgA IR cells in the flat corpus mucosa decreased (P0.001), with the mean change being 2.0±0.4%. Serum gastrin and volume density of gastrin IR cells in the antral part of the stomach remained unchanged (P=0.2 and 0.7, respectively).Long-term administration of netazepide is effective and safe.

Epidemiological studies suggest an increased fracture risk in patients taking proton pump inhibitors (PPIs) for long term. The underlying mechanism, however, has been disputed. By binding to the gastric proton pump, PPIs inhibit gastric acid secretion. We have previously shown that proton pump (H+/K+ATPase beta subunit) KO mice exhibit reduced bone mineral density (BMD) and inferior bone strength compared with WT mice. Patients using PPIs as well as these KO mice exhibit gastric hypoacidity, and subsequently increased serum concentrations of the hormone gastrin. In this study, we wanted to examine whether inhibition of the gastrin/CCK2 receptor influences bone quality in these mice. KO and WT mice were given either the gastrin/CCK2 receptor antagonist netazepide dissolved in polyethylene glycol (PEG) or only PEG for 1year. We found significantly lower bone mineral content and BMD, as well as inferior bone microarchitecture in KO mice compared with WT. Biomechanical properties by three-point bending test also proved inferior in KO mice. KO mice receiving netazepide exhibited significantly higher cortical thickness, cortical area fraction, trabecular thickness and trabecular BMD by micro-CT compared with the control group. Three-point bending test also showed higher Young’s modulus of elasticity in the netazepide KO group compared with control mice. In conclusion, we observed that the gastrin receptor antagonist netazepide slightly improved bone quality in this mouse model, suggesting that hypergastrinemia may contribute to deteriorated bone quality during acid inhibition.

// Yoomi Lee 1, * , Aleksandra M. Urbanska 2, * , Yoku Hayakawa 2 , Hongshan Wang 2, 3 , Andrew S. Au 2 , Aesis M. Luna 4 , Wenju Chang 2, 3 , Guangchun Jin 2 , Govind Bhagat 4 , Julian A. Abrams 2 , Richard A. Friedman 5, 6 , Andrea Varro 7 , Kenneth K. Wang 8 , Malcolm Boyce 9 , Anil K. Rustgi 10 , Antonia R. Sepulveda 4 , Michael Quante 11 , Timothy C. Wang 2 1 Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, New York, NY, USA 2 Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA 3 Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China 4 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA 5 Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center, New York, NY, USA 6 Department of Biomedical Informatics, Columbia University Medical Center, New York, NY, USA 7 Department of Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, England 8 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA 9 Hammersmith Medicines Research, Central Middlesex Hospital, London, UK 10 Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 11 Medical Clinic II, Clinic of the Right Bank, Technical University of Munich, Munich, Germany * These authors contributed equally to this work Correspondence to: Timothy C. Wang, email: tcw21@columbia.edu Keywords: Barrett’s esophagus, esophageal cancer, gastrin, gastrin receptors, stem cells Received: March 15, 2016 Accepted: June 13, 2016 Published: July 18, 2016 ABSTRACT Objective: The incidence of esophageal adenocarcinoma (EAC) is increasing, but factors contributing to malignant progression of its precursor lesion, Barrett’s esophagus (BE), have not been defined. Hypergastrinemia caused by long-term use of proton pump inhibitors (PPIs), has been suggested as one possible risk factor. The gastrin receptor, CCK2R, is expressed in the cardia and upregulated in BE, suggesting the involvement of the gastrin-CCK2R pathway in progression. In the L2-IL-1β mouse model, Barrett’s-like esophagus arises from the gastric cardia. Therefore, we aimed to analyze the effect of hypergastrinemia on CCK2R+ progenitor cells in L2-IL-1β mice. Design: L2-IL-1β mice were mated with hypergastrinemic ( INS-GAS ) mice or treated with PPIs to examine the effect of hypergastrinemia in BE progression. CCK2R-CreERT crossed with L2-IL-1β mice were used to analyze the lineage progenitor potential of CCK2R+ cells. Cardia glands were cultured in vitro , and the effect of gastrin treatment analyzed. L2-IL-1β mice were treated with a CCK2R antagonist YF476 as a potential chemopreventive drug. Results: Hypergastrinemia resulted in increased proliferation and expansion of Barrett’s-like esophagus. Lineage tracing experiments revealed that CCK2R+ cells are long-lived progenitors that can give rise to such lesions under chronic inflammation. Gastrin stimulated organoid growth in cardia culture, while CCK2R inhibition prevented Barrett’s-like esophagus and dysplasia. Conclusions: Our data suggest a progression model for BE to EAC in which CCK2R+ progenitor cells, stimulated by hypergastrinemia, proliferate to give rise to metaplasia and dysplasia. Hypergastrinemia can result from PPI use, and the effects of hypergastrinemia in human BE should be studied further.

Background Interleukin-13 (IL-13) is a key mediator of T-helper-cell-type-2 (Th-2)-driven asthma, the inhibition of which may improve treatment outcomes. We examined the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of VR942, a dry-powder formulation containing CDP7766, a high-affinity anti-human-IL-13 antigen-binding antibody fragment being developed for the treatment of asthma. Methods We conducted a phase 1, randomized, double-blind, placebo-controlled, ascending-dose study at Hammersmith Medicines Research, London, UK, which is now complete. Healthy adults aged 18–50 years (n = 40) were randomized 3:1 to a single inhaled dose of VR942 0.5, 1.0, 5.0, 10, or 20 mg, or placebo. Adults aged 18–50 years who were diagnosed with asthma for ≥6 months before screening, and had forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) values ≥70% of the predicted values at screening (n = 45), were randomized to once-daily inhaled VR942 0.5 or 10 mg, or placebo (2:2:1), or VR942 20 mg or placebo (3:2), for 10 days. All participants were randomized to receive VR942 or placebo based on a randomization list prepared by an independent HMR statistician using SAS® software ( SAS Institute , Cary, NC). The primary outcome was safety and tolerability of VR942 (safety population, defined as all who received at least one dose of VR942 or placebo). This study is listed on ClinicalTrials.gov (NCT02473939). Findings In the VR942 and placebo groups, treatment-emergent adverse events (TEAEs) were reported in 10/30 (33%) and 0/10 (0%) healthy participants, and in 16/29 (55%) and 9/16 (56%) participants with asthma, respectively. Mild intermittent wheezing occurred in 7 participants (VR942 20 mg, n = 4; corresponding placebo, n = 3), resolving spontaneously within 1 h. All TEAEs were mild or moderate; there were no deaths, serious adverse events, or clinically significant changes in vital signs, electrocardiograms, or laboratory parameters. There was no clinically significant immunogenicity, with only one participant with asthma considered positive for treatment-related immunogenicity for CDP7766. Interpretation This study, considered to be the only example of a dry powder anti-IL-13 fragment antibody being administered via inhalation, demonstrated that single and repeat doses were well tolerated over a period of up to 10 days in duration. Rapid and durable inhibition of fractional exhaled nitric oxide (FeNO) (secondary outcome) provided evidence of pharmacological engagement with the IL-13 target in the airways of participants diagnosed with mild asthma. These data, together with the numerical improvements observed for predose FEV1, justify further clinical evaluation of VR942 in a broader population of patients with asthma, and continue to support the development of an inhaled anti-IL-13 antibody fragment as a potential future treatment that is alternative to monoclonal antibodies delivered via the parenteral route. Funding Study funding and funding for the medical writing and editorial support for preparation of the manuscript were split equally between the two study co-funders (Vectura Ltd and UCB Pharma).

Background AL-794 is an orally active prodrug of ALS-033719, which selectively inhibits the endonuclease domain of influenza virus A and B polymerase. Methods In a phase 1, double-blinded, randomized, placebo-controlled study, healthy subjects were inoculated intranasally with influenza virus (A/Perth/16/2009 H3N2) after confirmation of infection or on day 4. Subjects received 50 mg of AL-794, 150 mg of AL-794, or placebo twice daily for 5 days. Viral load, influenza symptoms, pharmacokinetics, and safety were evaluated. Results A total of 61 subjects were inoculated. In 42 infected subjects, the mean peak viral load for 50-mg AL-794 recipients, 150-mg AL-794 recipients, and placebo recipients was 3.54, 2.77, and 3.72 log10 50% tissue culture infectious doses (TCID50)/mL, respectively. The mean influenza viral load area under the curve in the corresponding treatment groups was 137, 87.5, and 142 log10 TCID50/mL·h, respectively, and the median time to virus nondetection was 117, 75.3, and 108 hours, respectively. AL-794 was well tolerated, and no viral resistance to ALS-033719 was identified. Conclusion Following oral administration of AL-794, significant dose-dependent antiviral activity was noted, with a greater decrease in viral load, symptoms, and mucus weight at the 150-mg dose, compared with the 50-mg dose, and no safety concerns for either dose or placebo. Clinical trials registration NCT02588521.

SummaryBackground It is thought that asthmatics who smoke cigarettes respond less well to inhaled corticosteroid (ICS) therapy than asthmatics who do not smoke. Objective To evaluate the effects of smoking on allergen-induced airway responses in asthmatics treated with ICS. Methods Randomized, double-blind, crossover study evaluating twice daily fluticasone propionate (FP) 100 μg, FP 500 μg and placebo, for 7 days, on allergen-induced asthmatic responses in 18 non-smoking and 17 smoking atopic asthmatics (NCT01400906). At 1 h post-morning dose on Day 6, forced expiratory volume in 1 sec (FEV1) was measured up to 10 h post-challenge. Exhaled nitric oxide (eNO), induced sputum cell counts, and responsiveness to methacholine were assessed the following day. Results The late asthmatic response (LAR) was suppressed by FP in smokers and non-smokers; with placebo, the LAR was also attenuated in smokers versus non-smokers (adjusted mean minimum change in FEV1 (L) over 4–10 h [95% CI] in non-smokers: placebo −1.01 [1.31, 0.70], FP 100 μg −0.38 [0.54, 0.22], FP 500 μg −0.35 [0.54–0.22]; and in smokers: placebo −0.63 [0.84, 0.43]; FP 100 μg −0.44 [0.65, 0.23]; FP 500 μg −0.46 [0.59–0.32]). The Early AR was suppressed by FP treatment in non-smokers, but was not impacted in smokers. The reduction in methacholine hyperresponsiveness after FP was greater in non-smokers (1.5- and twofold doubling dose difference from placebo after FP 100 μg and FP 500 μg) than smokers (1.0 and 1.3 difference, respectively). Allergen-induced increases in eNO and sputum eosinophils were lower in smokers than non-smokers and were suppressed in both groups by FP. Conclusion and Clinical Relevance Allergen-induced LARs were of a similar amplitude in both smoking and non-smoking atopic asthmatics at the end of ICS treatment, but attenuation of the LAR in smokers was only partly associated with ICS treatment. The marked attenuation of the LAR observed in smokers in the absence of ICS treatment is a novel observation.

Aims To compare gastric acid suppression by netazepide, a gastrin/CCK2 receptor antagonist, with that by a proton pump inhibitor (PPI), and to determine if netazepide can prevent the trophic effects of PPI-induced hypergastrinaemia. Methods Thirty healthy subjects completed a double-blind, randomized, parallel group trial of oral netazepide and rabeprazole, alone and combined, once daily for 6 weeks. Primary end points were: basal and pentagastrin-stimulated gastric acid and 24 h circulating gastrin and chromogranin A (CgA) at baseline, start and end of treatment, gastric biopsies at baseline and end of treatment and basal and pentagastrin-stimulated gastric acid and dyspepsia questionnaire after treatment withdrawal. Results All treatments similarly inhibited pentagastrin-stimulated gastric acid secretion. All treatments increased serum gastrin, but the combination and rabeprazole did so more than netazepide alone. The combination also reduced basal acid secretion. Rabeprazole increased plasma CgA, whereas netazepide and the combination reduced it. None of the biopsies showed enterochromaffin-like (ECL) cell hyperplasia. Withdrawal of treatments led neither to rebound hyperacidity nor dyspepsia. Conclusions Netazepide suppressed pentagastrin-stimulated gastric acid secretion as effectively as did rabeprazole. The reduction in basal acid secretion and greater increase in serum gastrin by the combination is consistent with more effective acid suppression. Despite our failure to show rabeprazole-induced ECL cell hyperplasia and rebound hyperacidity, the increase in plasma CgA after rabeprazole is consistent with a trophic effect on ECL cells, which netazepide prevented. Thus, netazepide is a potential treatment for the trophic effects of hypergastrinaemia and, with or without a PPI, is a potential treatment for acid-related conditions.

Chemists are involved in much of the work that paves the way for clinical studies of a potential new medicine: synthesis and characterisation of the drug substance, method development, formulation of a medicinal product, and analysis. Chemistry continues to play an important role during the early clinical phases of drug development and beyond: clinical studies may lead to the development of a new drug candidate, guide formulation development, or reveal one or more metabolites, which must be identified and characterised. So, although clinical pharmacology is traditionally the realm of physicians, biologists and biochemists, it is important that medicinal chemists are involved in, and understand, the clinical development of potential new medicines. This chapter describes the chemistry data needed to support “first-in-human” clinical trials. It explains the aims and design of the classical single ascending-dose study, and outlines special considerations for those studies, such as choice of population, starting dose, and dose-escalation strategy. Flexibility of the study design and the ability to work within tight timelines in a highly regulated environment are essential, so the logistical challenges are substantial. The chapter closes with case studies that demonstrate how the value of early clinical studies can be maximised to show proof-of-concept and guide dosing regimens in patients.

Aims Cathepsin C (CTSC) is necessary for the activation of several serine proteases including neutrophil elastase (NE), cathepsin G, and proteinase 3. GSK2793660 is an oral, irreversible inhibitor of CTSC that is hypothesized to provide an alternative route to achieve NE inhibition and was tested in a Phase I study. Methods Single escalating oral doses of GSK2793660 0.5 mg to 20 mg or placebo were administered in a randomized crossover design to healthy male subjects; a separate cohort received once daily doses of 12 mg or placebo for 21 days. Data were collected on safety, pharmacokinetics, CTSC enzyme inhibition and blood biomarkers. Results Single, oral doses of GSK2793660 were able to dose-dependently inhibit whole blood CTSC activity. Once daily dosing of 12 mg GSK2793660 for 21 days achieved > 90% inhibition (95% CI: 56, 130) of CTSC within 3 hours on day 1. Only modest reductions of whole blood enzyme activity of approximately 20% were observed for NE, cathepsin G, and proteinase 3. Seven of 10 subjects receiving repeat doses of GSK2793660 manifested epidermal desquamation on palmar and plantar surfaces beginning 7–10 days after dosing commencement. There were no other clinically important safety findings. Conclusions GSK2793660 inhibited CTSC activity but not the activity of downstream neutrophil serine proteases. The palmar-plantar epidermal desquamation suggests a previously unidentified role for CTSC or one of its target proteins in the maintenance and integrity of the epidermis at these sites, with some similarities to the phenotype of CTSC-deficient humans.

The intravenous (iv) formulation of levetiracetam has been available in clinical practice worldwide for several years, but not in Japan. Two open-label studies were conducted: Study A evaluated the bioequivalence of iv and oral tablet formulations in healthy Japanese volunteers; and Study B subsequently compared the pharmacokinetics of iv levetiracetam in healthy Japanese and Caucasian volunteers. Study A had a randomised, two-way crossover design; a single 1,500 mg levetiracetam dose was administered as a 15-min iv infusion and as 3 × 500 mg oral tablets to Japanese volunteers. In Study B, 1,500 mg levetiracetam was administered as single and repeated 15-min iv infusions to Japanese and Caucasian volunteers. Overall, 26/27 volunteers completed Study A and 32/32 (16 Japanese; 16 Caucasian) completed Study B. In Study A, the point estimate and 90 % confidence interval (CI) for the geometric least squares mean (LSM) ratio (iv vs oral) were fully included within the acceptance range for bioequivalence (0.85–1.25) for the area under plasma concentration–time curve from 0 to last quantifiable observation (AUClast 0.97 [0.95, 0.99]), but not for the maximum plasma concentration (C max 1.64 [1.47, 1.83]). In Study B, after a single iv infusion, the point estimates (90 % CI) for the geometric LSM ratio (Japanese vs Caucasian) for body weight-normalised C max and AUClast were 1.21 (1.07, 1.36) and 0.97 (0.90, 1.04), respectively. Corresponding values after repeated iv infusions were C max,ss 1.01 (0.91, 1.12) and AUCτ,ss 0.89 (0.83, 0.96). Levetiracetam was well tolerated in both studies. Study A did not demonstrate the bioequivalence of single doses of levetiracetam 1,500 mg administered as an iv infusion and as oral tablets in healthy Japanese adults. Study B, however, showed that pharmacokinetic profiles were generally similar between Japanese and Caucasian adults after single and repeated iv infusions of levetiracetam 1,500 mg.

Aims Two double-blind, randomized studies were conducted to assess the tolerability, pharmacokinetics and pharmacodynamics of oral TA-8995, a new cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. Methods Study 1: Subjects received single doses of TA-8995 or placebo (fasted). Doses were 5, 10, 25, 50 (fed/fasted), 100 and 150 mg (Caucasian males, 18–55 years), 25 mg (Caucasian males, > 65 years and Caucasian females, 18–55 years), 25, 50, 100 and 150 mg (Japanese males, 18–55 years). Study 2: Caucasian males (18–55 years) received 1, 2.5, 10 or 25 mg once daily TA-8995 or placebo for 21–28 days. Blood and urine for pharmacokinetics and/or pharmacodynamics were collected. Tolerability was assessed by adverse events, vital signs, electrocardiograms and laboratory safety tests. Results Peak TA-8995 concentrations occurred approximately 4 h post-dose. Mean half-lives ranged from 81 to 166 h, without an obvious dose relationship. Exposure increased less than proportionally to dose. TA-8995 was not excreted in urine. Following 2.5 to 25 mg once daily dosing, TA-8995 demonstrated nearly complete inhibition of CETP activity (92–99%), increased high density lipoprotein-cholesterol (HDL-C) by 96 to 140% and decreased low density liporotein-cholesterol (LDL-C) by 40% to 53%. There were dose-related increases in apolipoproteins A-1 and E, HDL2-C and HDL3-C, and decreases in apolipoprotein B and lipoprotein A. There was no evidence of significant effects of age, gender, ethnicity or food on pharmacokinetics or pharmacodynamics. All doses were well tolerated. Conclusions TA-8995 is a potent CETP inhibitor and warrants further investigation.

Aim To administer repeated oral doses of netazepide to healthy subjects for the first time, to assess safety, tolerability, pharmacokinetics and effect on 24 h gastric pH and plasma gastrin. Method We did two randomized, double-blind, parallel group studies. The first compared netazepide 25 and 100 mg 12 hourly, omeprazole 20 mg once daily and placebo for 7 days. On day 7 only, we measured pH and assayed plasma gastrin. The second study compared netazepide 5, 10 and 25 mg and placebo once daily for 14 days. We measured pH on days 1, 7 and 14 and assayed plasma gastrin on days 1 and 14. We compared treatments by time gastric pH ≥ 4 during 0–4, 4–9, 9–13 and 13–24 h after the morning dose, and by plasma gastrin. P < 0.05 was significant. Results Netazepide was well tolerated. On day 7 of the first study, netazepide increased pH significantly only during 9–13 h after the 100 mg dose, whereas omeprazole raised pH significantly during all periods. Both netazepide and omeprazole increased plasma gastrin significantly. Netazepide had linear pharmacokinetics. In the second study, netazepide caused dose-dependent, sustained increases in pH on day 1, but as in the first study, netazepide had little effect on pH on days 7 and 14. Again, netazepide increased plasma gastrin significantly. Conclusion Although repeated doses of netazepide led to tolerance to its effect on pH, the accompanying increase in plasma gastrin is consistent with continued inhibition of acid secretion, via gastrin receptor antagonism and gene up-regulation.

Aims To confirm by means of pentagastrin, a synthetic gastrin agonist, that netazepide is a gastrin/CCK2 receptor antagonist in healthy subjects, and that antagonism persists during repeated dosing. Methods We did two studies in which we infused pentagastrin (0.6 μg kg−1 h−1 intravenously), aspirated gastric secretion and measured the volume, pH and H+ secretion rate of the gastric aspirate. First, we did a double-blind, five-way crossover study (n = 10) to assess the effect of single oral doses of netazepide (1, 5, 25 and 100 mg) and placebo on the response to pentagastrin. Then, we did a single-blind, placebo-controlled study (n = 8) to assess the effect of the first and last oral doses of netazepide (100 mg) twice daily for 13 doses on the response to pentagastrin. Results Netazepide was well tolerated. After placebo, pentagastrin increased the volume and H+ secretion rate and reduced the pH of gastric aspirate. Compared with placebo, single doses of netazepide caused dose-dependent inhibition of the pentagastrin response (P < 0.02); netazepide (100 mg) abolished the response. After 13 doses, the reduction in volume and H+ secretion rate persisted (P < 0.001), but the pH effect was mostly lost. Conclusions Netazepide is an orally active, potent, competitive antagonist of human gastrin/CCK2 receptors. Antagonism is dose dependent and persists during repeated dosing, despite tolerance to the effect on pH. Further studies are required to explain that tolerance. Netazepide is a tool to study the physiology and pharmacology of gastrin, and merits studies in patients to assess its potential to treat gastric acid-related conditions and the trophic effects of hypergastrinaemia.

Many monoclonal antibodies (MAbs) have been studied in healthy volunteers in phase 1, but few data have been published on the safety of that practice. We aimed to review the available data, and thereby to estimate the risks of participation in phase 1 trials of MAbs. We searched PubMed, the ClinicalTrials.gov database and Google, using the search terms ‘monoclonal antibody’, ‘phase 1’ and ‘healthy volunteers’. We identified 70 completed trials of MAbs in healthy volunteers, but the published data were too sparse to allow confident assessment of the risks of MAbs in healthy volunteers. Our best estimate of risk of a life-threatening adverse event was between 1 : 425 and 1 : 1700 volunteer-trials, but all such events occurred in a single trial (of TGN1412). In a phase 1 trial of a small molecule, the risk of death or a life-threatening adverse event appears to be 1 : 100 000–1 000 000 volunteer-trials, which is similar to the risk of many ordinary daily activities. Most people would consider that level of risk to be ‘minimal’ or ‘negligible’ and, therefore, acceptable. On that basis, the safety record of MAbs in healthy volunteers has been ruined by the TGN1412 disaster. However, that experience is unlikely to be repeated, because of improvements in governance and practice of phase 1 trials. If the experience of TGN1412 is disregarded, it seems reasonable to continue using healthy volunteers in phase 1 trials of MAbs, provided that there are scientific and medical reasons to conclude that the risk is truly minimal.

The aim of the study was to characterize performance of a complementary set of assays to measure antigen-specific immune responses in subjects immunized with a neoantigen. Healthy volunteers (HV) (n = 8) and patients with systemic lupus erythematosus (SLE) (n = 6) were immunized with keyhole limpet haemocyanin (KLH) on days 1 and 29. Serum antibodies were detected using a flow cytometric bead array (CBA) that multiplexed the KLH response alongside pre-existing anti-tetanus antibodies. Peripheral blood mononuclear cells were studied by B cell ELISPOT. These assays were built upon precedent assay development in cynomolgus monkeys, which pointed towards their utility in humans. Primary anti-KLH IgG responses rose to a mean of 65-93-fold above baseline for HV and SLE patients, respectively, and secondary responses rose to a mean of 260-170-fold above baseline. High levels of anti-tetanus IgG were detected in pre-immunization samples and their levels did not change over the course of study. Anti-KLH IgG1-4 subclasses were characterized by a predominant IgG1 response, with no significant differences in subclass magnitude or distribution between HV and SLE subjects. Anti-KLH IgM levels were detectable, although the overall response was lower. IgM was not detected in two SLE subjects whodid generate an IgG response. All subjects responded to KLH by B cell ELISPOT, with no significant differences observed between HV and SLE subjects. The CBA and B cell ELISPOT assays reliably measured anti-KLH B cell responses, supporting use of this approach and these assays to assess the pharmacodynamic and potential safety impact of marketed/investigational immune-therapeutics.

Objective Long-term Helicobacter pylori infection causes gastritis leading to hypergastrinemia and predisposes to gastric cancer. Our aim was to assess the role of gastrin in oxyntic mucosal inflammation in H. pylori-infected Mongolian gerbils by means of the gastrin receptor antagonist netazepide (YF476). Design We studied 60 gerbils for 18 months and left five animals uninfected (control group), inoculated 55 with H. pylori, and treated 28 of the infected animals with netazepide (Hp+YF476 group). Twenty-seven infected animals were given no treatment (Hp group). We measured plasma gastrin and intraluminal pH. H. pylori detection and histologic evaluations of the stomach were carried out. Results All 55 inoculated animals were H. pylori positive at termination. Eighteen animals in the Hp group had gastritis. There was a threefold increase in mucosal thickness in the Hp group compared to the Hp+YF476 group, and a threefold increase in oxyntic neuroendocrine cells in the Hp group compared to the Hp+YF476 group (p

CHF6001 is an inhaled phosphodiesterase 4 (PDE4) inhibitor in development for the treatment of obstructive lung diseases. The efficacy and safety of CHF6001 were investigated in a double blind, placebo controlled, 3-way cross-over study using the allergen challenge model. Thirty-six atopic asthmatics who were not taking inhaled corticosteroids and who demonstrated a late asthmatic response (LAR) to inhaled allergen at screening were randomised to receive CHF6001 400 μg or 1200 μg or placebo administered once a day using a dry powder inhaler. The three treatment periods were 9 days; allergen challenges were performed on day 9 and induced sputum was obtained after 10 h from challenge. Washout periods between treatments were up to 5 weeks. Both CHF6001 doses significantly attenuated the LAR; the primary endpoint analysis showed that CHF6001 400 μg and 1200 μg caused reductions of 19.7% (p = 0.015) and 28.2% (p < 0.001) respectively of the weighted FEV1 AUC4-10h compared with placebo. The difference between the CHF6001 doses was not statistically significant (p = 0.223). Compared with placebo, CHF6001 caused greater reduction in sputum eosinophil counts, although these changes were not statistically significant. CHF6001 was well tolerated, with similar numbers of adverse events in each treatment period. This inhaled PDE4 inhibitor has the potential to provide clinical benefits in patients with atopic asthma.

Gastrin controls gastric acid secretion and mucosal cell growth, especially of enterochromaffin-like cells, via gastrin/cholecystokinin-2 receptor (CCK

Summary Background Patients with chronic atrophic gastritis have long-term gastric hypoacidity, and secondary hypergastrinaemia. Some also develop gastric ECL cells carcinoids (type 1 GC). Most type 1 GC remain indolent, but some metastasise. Patients undergo surveillance, and some are treated with somatostatin analogues, endoscopic resection or surgery. Netazepide (YF476) is a highly selective, potent and orally active gastrin receptor antagonist, which has anti-tumour activity in various rodent models of gastric neoplasia driven by hypergastrinaemia. Netazepide has been studied in healthy volunteers. Aim To assess the effect of netazepide on type 1 GC. Methods Eight patients with multiple type 1 GC received oral netazepide once daily for 12 weeks, with follow-up at 12 weeks in an open-label, pilot trial. Upper endoscopy was performed at 0, 6, 12 and 24 weeks, and carcinoids were counted and measured. Fasting serum gastrin and chromogranin A (CgA) and safety and tolerability were assessed at 0, 3, 6, 9, 12 and 24 weeks. Results Netazepide was well tolerated. All patients had a reduction in the number and size of their largest carcinoid. CgA was reduced to normal levels at 3 weeks and remained so until 12 weeks, but had returned to pre-treatment levels at 24 weeks. Gastrin remained unchanged throughout treatment. Conclusions The gastrin receptor antagonist netazepide is a promising new medical treatment for type 1 gastric carcinoids, which appear to be gastrin-dependent. Controlled studies and long-term treatment are justified to find out whether netazepide treatment can eradicate type 1 gastric carcinoids.

Aim Our aim was to set up a system to help UK clinical research units to prevent healthy volunteers from participating in more than one non-therapeutic trial simultaneously, or from starting a second trial too soon after the first. Methods TOPS (The Over-volunteering Prevention System) is internet-based, simple and quick to use, free to users and a charity run by a Board of Trustees. Users enter only two or three pieces of information: (1) ‘National Insurance number’ (NINO) of UK citizens, or ‘passport number’ and country of origin of non-UK citizens, as their identifier, (2) ‘date of last dose’ of trial medicine or (3) ‘never dosed’. Subjects must consent, but TOPS collects only non-personal data, so it does not require Ethics Committee approval and is not covered by the Data Protection Act. Results A total of 55 research units (29 clinical research organisations, 5 pharmaceutical companies, 13 universities and 8 hospitals) throughout the UK have registered to use TOPS, and have entered 124,906 volunteers since we launched it. All commercial and many non-commercial units now use TOPS. In our unit, no subject has to the best of our knowledge participated in two trials simultaneously. TOPS has reduced to

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Domperidone, a dopamine antagonist metabolized mainly by CYP3A, has been used as an anti-emetic and prokinetic agent by mouth for over 30 years. • Domperidone has a good safety record. However, early studies of high dose intravenous domperidone were associated with QTc prolongation and arrhythmias, including torsade de pointes. • There have been no thorough QTc studies of domperidone. WHAT THIS STUDY ADDS • We assessed the effect on QTc of oral domperidone and ketoconazole, alone and in combination. • •Ketoconazole, a CYP3A inhibitor, tripled domperidone concentrations, whilst domperidone did not affect ketoconazole concentrations. • •Domperidone and ketoconazole, alone and in combination, increased QTc significantly in men, and there was a positive correlation between increased QTc and concentrations of domperidone and ketoconazole in both sexes. • The effect of domperidone alone on QTc was small and not clinically important, but domperidone should not be co-administered with ketoconazole. AIMS To assess the steady-state pharmacokinetic and QTc effects of domperidone and ketoconazole, given alone and together. METHODS A randomized, placebo-controlled, double-blind, crossover study was carried out. Healthy subjects (14 men, 10 women; age 18–39 years; mean weight 73.5 kg, range 53.8–98.8 kg; 23 Europid, 1 Afro-Caribbean) received orally, for 7 days each, placebo, domperidone 10 mg, four doses daily, at 4 h intervals, ketoconazole 200 mg 12-hourly and domperidone and ketoconazole together. The washout period was 15 days. Pharmacokinetics and serial 12-lead ECGs were assessed on day 7, and serial ECGs on day −1 and at follow-up. Two subjects withdrew before the third treatment period, so data were available for 22–24 subjects. RESULTS Ketoconazole tripled domperidone concentrations at steady-state. Domperidone, ketoconazole and their combination significantly increased QTcF in men. Overall adjusted mean differences from placebo were 4.20 (95% CI 0.77, 7.63), 9.24 (95% CI 5.85, 12.63) and 15.90 (95% CI 12.47, 19.33) ms, respectively. In women, QTcF was not significantly different from placebo on either domperidone or ketoconazole alone, or in combination. However, QTc was positively correlated with plasma drug concentrations, in both men and women. ΔQTcF increased by about 2 ms per 10 ng ml–1 rise in domperidone concentration, and per 1 µg ml–1 rise in ketoconazole concentration. CONCLUSIONS Ketoconazole tripled the plasma concentrations of domperidone. Domperidone and ketoconazole increased QTcF in men, whether given together or separately. The effect of domperidone alone was below the level of clinical importance. The negative result in women is unexplained.

Interferon beta-1a (IFNβ-1a) 30 μg weekly by intramuscular (IM) injection is used to treat relapsing forms of multiple sclerosis. We assessed if it can be given safely by inhalation. Twenty-one healthy volunteers inhaled IFNβ-1a 300 μg, formulated for deep delivery to the lungs, in a randomized, parallel-group, repeat-dose trial. Comparators were room air and placebo. The primary outcome measure was carbon monoxide transfer factor corrected for hemoglobin (TLCOc), which measures the CO transfer from inspired gas to pulmonary capillary blood. After 3 and 4 once-weekly doses, IFNβ-1a significantly reduced TLCOc compared with room air: after the third dose, mean standard deviation (SD) change in percent predicted TLCOc was-10.9 (2.8), and after the fourth dose was-12.1 (2.7). After 2, 3, and 4 doses, IFNβ-1a significantly reduced TLCOc compared with placebo: after the second dose, mean (SD) change in percent predicted TLCOc was-8.8 (5.5), after the third dose was-10.9 (2.8), and after the fourth dose was-12.1 (2.7). Circulating IFNβ-1a concentrations were about one-third those of the intramuscular dose regimen. Tolerability of IFNβ-1a and the comparators was equally good. In conclusion, IFNβ-1a reduced TLCOc, whereas placebo and room air did not. A dose of IFNβ-1a 300 μg by inhalation may not be safe for general use.

Objective: This study aimed to assess the pharmacokinetics and tolerability of once-and twice-daily frovatriptan given for 6 days, a regimen that has previously been reported to reduce the incidence and severity of menstrual migraine when administered during the perimenstrual period. Methods: This was a double-blind, placebo-controlled, two-period crossover study carried out in healthy premenopausal female volunteers aged ≥18 years (equal number taking or not taking estrogen-containing contraceptives [ECCs]) who were admitted to a clinical pharmacology unit. Women alternately received frovatriptan once daily (day 1: 5mg; days 2–6: 2.5mg) and twice daily (day 1: 5mg [10mg total]; days 2–6: 2.5mg [5mg total]) in a randomized treatment sequence. Dosing was also random with respect to the menstrual cycle. Whole blood samples were obtained on days 1 and 6 (predose and at 0.5, 1, 2, 4, 6, 8, 12 [before evening dose], 13, 14, 16 and 18 hours post-dose) and on days 2–5 (samples were taken before the morning dose). A final sample was drawn at 24 hours after the last treatment on day 6. A fully validated liquid chromatography assay coupled to a tandem mass spectroscopy assay measured drug concentrations (simultaneous measurement of frovatriptan and its metabolites). Pharmacokinetic parameters were determined using a noncompartmental approach. Safety and tolerability were measured by monitoring adverse events, haematology and biochemistry, vital signs, ECG results and physical examination findings. Results: Twenty-six healthy women participated in the study and 24 (12 ECC users and 12 ECC nonusers) completed the study. One ECC user during period 1 and one nonuser during period 2 withdrew before completion; both were taking frovatriptan once daily. Most women were White (n = 21), three were Black, and one each was Hispanic or Asian; mean ±SD age was 25.4 ±4.9 years; and mean ±SD weight was 61.9 ±6.5 kg. For both once-and twice-daily dosing, time to reach maximum blood concentration (Cmax) [tmax] was in the range of 2–4 hours. The loading dose enabled steady state (defined as constant trough blood concentration [Cmin]) to be reached by day 2 with both regimens. Geometric mean Cmax and area under the blood concentration-time curve from 0 to 12 hours (AUC12) were higher with twice-versus once-daily dosing (day 1: p