Netazepide, an Antagonist of Cholecystokinin Type 2 Receptor, Prevents Vincristine-Induced Sensory Neuropathy in Mice.

Among the vinca-alkaloid class, vincristine is a potent chemotherapeutic agent with significant neurotoxic effects and is employed to address a wide spectrum of cancer types. Recently, the therapeutic potential of the cholecystokinin type 2 receptor (CCK2R) as a target for vincristine-induced peripheral neuropathy (VIPN) was demonstrated. In this study, the impact of preventive CCK2R blockade using netazepide (Trio Medicines Ltd., London, UK) was investigated in a mouse model of vincristine-induced peripheral neuropathy. Netazepide is a highly selective CCK2R antagonist under development for the treatment of patients with gastric neuroendocrine tumors caused by hypergastrinemia secondary to chronic autoimmune atrophic gastritis. Vincristine-induced peripheral neuropathy was induced by intraperitoneal injections of vincristine at 100 µg/kg/d for 7 days (D0 to D7). Netazepide (2 mg/kg/d or 5 mg/kg/d, per os) was administered one day before vincristine treatment until D7. Vincristine induced a high tactile allodynia from D1 to D7. VIPN was characterized by dorsal root ganglion neuron (DRG) and intraepidermal nerve fiber (IENF) loss, and enlargement and loss of myelinated axons in the sciatic nerve. Netazepide completely prevented the painful symptoms and nerve injuries induced by vincristine. In conclusion, the fact that netazepide protected against vincristine-induced peripheral neuropathy in a mouse model strongly supports the assessment of its therapeutic potential in patients receiving such chemotherapy.

SLN124, a GalNAc conjugated 19-mer siRNA targeting tmprss6, reduces plasma iron and increases hepcidin levels of healthy volunteers.

SLN124, an N-acetylgalactosamine conjugated 19-mer short interfering RNA, is being developed to treat iron-loading anemias (including beta-thalassemia and myelodysplastic syndromes) and myeloproliferative neoplasms (polycythemia vera). Through hepatic targeting and silencing of the TMPRSS6 gene, SLN124 increases endogenous hepcidin synthesis. This is the first clinical report of an siRNA targeting a component of iron homeostasis. This first-in-human, phase 1 study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of SLN124 (1.0, 3.0, and 4.5 mg/kg) in healthy volunteers. Twenty-four participants were randomized in three sequential cohorts of eight subjects, each to receive a single dose of either SLN124 or placebo (6:2 randomization), administered subcutaneously. There were no serious or severe adverse events, or discontinuations due to adverse events, and most treatment-emergent adverse events were mild, including transient mild injection site reactions, resolving without intervention. SLN124 was rapidly absorbed, with a median tmax of 4-5 h across all treatment groups, and largely eliminated from plasma by 48 h. Plasma concentrations increased in a greater than dose proportional fashion between treatment groups. In all SLN124 groups, a dose-related effect was observed across iron metabolism markers, and across erythroid markers, SLN124 resulted in increased plasma hepcidin levels, peaking around Day 29, and consequent dose-related sustained reductions in plasma iron and transferrin saturation with decreased reticulocyte production, MCHC, and MCV. Results suggest duration of action lasting up to 56 days after a single SLN124 dose, on hepcidin and hematological parameters of iron metabolism (serum iron and TSAT).

Neuroendocrine mechanism of gastric acid secretion: Historical perspectives and recent developments in physiology and pharmacology.

The physiology of gastric acid secretion is one of the earliest subjects in medical literature and has been continuously studied since 1833. Starting with the notion that neural stimulation alone drives acid secretion, progress in understanding the physiology and pathophysiology of this process has led to the development of therapeutic strategies for patients with acid-related diseases. For instance, understanding the physiology of parietal cells led to the developments of histamine 2 receptor blockers, proton pump inhibitors (PPIs), and recently, potassium-competitive acid blockers. Furthermore, understanding the physiology and pathophysiology of gastrin has led to the development of gastrin/CCK2 receptor (CCK2 R) antagonists. The need for refinement of existing drugs in patients have led to second and third generation drugs with better efficacy at blocking acid secretion. Further understanding of the mechanism of acid secretion by gene targeting in mice has enabled us to dissect the unique role for each regulator to leverage and justify the development of new targeted therapeutics for acid-related disorders. Further research on the mechanism of stimulation of gastric acid secretion and the physiological significances of gastric acidity in gut microbiome is needed in the future.

Ensovibep, a SARS-CoV-2 antiviral designed ankyrin repeat protein, is safe and well tolerated in healthy volunteers: Results of a first-in-human, ascending single-dose Phase 1 study.

AIMS: This study aimed to assess safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of ensovibep, a designed ankyrin repeat protein antiviral being evaluated as a COVID-19 treatment, in healthy volunteers in a first-in-human ascending single-dose study. METHODS: Subjects were dosed intravenously, in a randomized double-blinded manner, with either ensovibep at 3, 9 or 20 mg/kg or with placebo, and followed until Day 100. PK and safety were assessed throughout the study duration. Immunogenicity and PD via viral neutralization in serum were also assessed. RESULTS: All adverse events were of mild to moderate severity, and no serious adverse events were observed. One subject who received the 20-mg/kg dose presented with moderate hypersensitivity vasculitis 3 weeks after infusion, which fully resolved using standard procedures. In most subjects ensovibep showed expected mono-exponential decline with a half-life of around 2 weeks. Anti-drug antibodies were detected in 15 of 17 subjects, with the earliest onset detected on Day 29. Viral neutralization assays on subject serum showed effective viral neutralization over the first 3 weeks following dosing with titre values in a dose dependent manner. CONCLUSION: Ensovibep proved safe in this first-in-human safety study and exhibited PK and PD parameters consistent with the expected treatment period required for acute COVID-19 infection.

Evaluation of NTP42, a novel thromboxane receptor antagonist, in a first-in-human phase I clinical trial.

Background: The thromboxane receptor (TP) antagonist NTP42 is in clinical development for treatment of cardiopulmonary diseases, such as pulmonary arterial hypertension. In this randomized, placebo-controlled Phase I clinical trial, NTP42, administered as the oral formulation NTP42:KVA4, was evaluated for safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy males. Methods: The first-in-human trial had three Parts: A, single ascending dose (SAD) study with seven groups given 0.25-243 mg NTP42:KVA4 or placebo; B, food effect study where one SAD group (9 mg) was also given NTP42:KVA4 or placebo after a high-fat breakfast; C, multiple ascending dose study with three groups given 15-135 mg NTP42:KVA4 or placebo once-daily for 7 days. Results: Seventy-nine volunteers participated. No serious adverse events occurred, where any drug- or placebo-related adverse events were mild to moderate, with no correlation to NTP42:KVA4 dose. NTP42 was rapidly absorbed, yielding dose proportional increases in exposure after single and repeat dosing. PK confirmed that, with a clearance (T1/2) of 18.7 h, NTP42:KVA4 is suited to once-daily dosing, can be taken with or without food, and does not accumulate on repeat dosing. At doses ≥1 mg, NTP42 led to complete and sustained inhibition of thromboxane-, but not ADP-, induced platelet aggregation ex vivo, with direct correlation between NTP42 exposure and duration of PD effects. Conclusion: Orally administered NTP42:KVA4 was well tolerated, with favorable PK/PD profiles and evidence of specific TP target engagement. These findings support continued clinical development of NTP42:KVA4 for cardiopulmonary or other relevant diseases with unmet needs. Clinical Trial Registration: clinicaltrials.gov, identifier NCT04919863.

Safety, tolerability, pharmacodynamic and wellbeing effects of SPL026 (dimethyltryptamine fumarate) in healthy participants: a randomized, placebo-controlled phase 1 trial.

Background: Due to their potential impact on mood and wellbeing there has been increasing interest in the potential of serotonergic psychedelics such as N,N-dimethyltryptamine (DMT) in the treatment of major depressive disorder (MDD). Aim: The aim of Part A of this study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) profile of escalating doses of SPL026 (DMT fumarate) in psychedelic-naïve healthy participants to determine a dose for administration to patients with MDD in the subsequent Phase 2a part of the trial (Part B: not presented in this manuscript). Methods: In the Phase 1, randomized, double-blind, placebo-controlled, parallel-group, single dose-escalation trial, psychedelic-naïve participants were randomized to placebo (n = 8) or four different escalating doses [9, 12, 17 and 21.5 mg intravenously (IV)] of SPL026 (n = 6 for each dose) together with psychological support from 2 therapy team members. PK and acute (immediately following dosing experience) psychometric measures [including mystical experience questionnaire (MEQ), ego dissolution inventory (EDI), and intensity rating visual analogue scale (IRVAS)] were determined. Additional endpoints were measured as longer-term change from baseline to days 8, 15, 30 and 90. These measures included the Warwick and Edinburgh mental wellbeing scale and Spielberger's state-trait anxiety inventory. Results: SPL026 was well tolerated, with an acceptable safety profile, with no serious adverse events. There was some evidence of a correlation between maximum plasma concentration and increased IRVAS, MEQ, and EDI scores. These trends are likely to require confirmation in a larger sample size. Using the analysis of the safety, tolerability, PD, PK results, doses of 21.5 mg SPL026 were the most likely to provide an intense, tolerated experience. Conclusion: Based on the data obtained from this part of the trial, a dose of 21.5 mg SPL026 given as a 2-phase IV infusion over 10 min (6 mg/5 min and 15.5 mg/5 min) was selected as the dose to be taken into patients in Part B (to be presented in a future manuscript).Clinical trial registration:www.clinicaltrials.gov, identifier NCT04673383; https://www.clinicaltrialsregister.eu, identifier 2020-000251-13; https://www.isrctn.com/, identifier ISRCTN63465876.

Pharmacokinetics, safety, tolerability, and immunogenicity of FKB238, a new biosimilar of bevacizumab, in healthy participants.

OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: The 90% confidence interval for the ratios of the primary (area under the curve ((AUC)0-t and AUC0-inf) and secondary (maximum concentration (Cmax) and elimination half-life (T1/2)) geometric mean PK parameters were entirely within the acceptance range for bioequivalence of 0.80 - 1.25 for all 3 pairwise comparisons by analysis of covariance, with baseline characteristics of age and body weight as covariates. FKB238 was well tolerated in healthy participants, and anti-drug antibody (ADA) incidence was low and similar in all treatment groups. CONCLUSION: 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.

ONO-7684 a novel oral FXIa inhibitor: Safety, tolerability, pharmacokinetics and pharmacodynamics in a first-in-human study.

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.

Pharmacodynamic Activity of the Novel Neurokinin-3 Receptor Antagonist SJX-653 in Healthy Men.

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 ±â€…7% (mean ±â€…sd) at 6 hours after 30 mg SJX-653 versus 10 ±â€…43% for placebo (P = 0.0006); maximal T reduction was of 68 ±â€…5% at 8 hours after 60 mg SJX-653 versus 18 ±â€…11% for placebo (P < 0.0001). The plasma IC50 for LH reduction was 33 ng/mL. CONCLUSIONS: These data demonstrate clinical proof-of-mechanism for SJX-653 as a potent centrally-acting NK3R antagonist.

Immunogenicity of an adalimumab biosimilar, FKB327, and its reference product in patients with rheumatoid arthritis.

AIM: This study, FKB327-003, is a phase 3, open-label extension (OLE) study comparing the long-term immunogenicity of an adalimumab biosimilar, FKB327 (F), with the reference product (RP). METHODS: In the OLE, patients completing 24 weeks of an initial randomized, double-blind (DB) study (Period 1) with clinical response and no safety concerns were rerandomized to F or RP, so that two-thirds of patients remained on the same treatment and one-third switched to the alternate treatment for weeks 24 through 54 (OLE weeks 0-30; Period 2), then all received F through week 100 (OLE week 76; Period 3). Treatment sequences were F-F-F (no switch), RP-F-F and RP-RP-F (single switch), and F-RP-F (double switch). Patients who entered the OLE study were evaluated for immunogenicity across switching sequences. RESULTS: The proportion of patients with positive antidrug antibody (ADA) status at the end of Period 1 was 61.7% and 60.0% for F and RP, respectively. The proportion of patients with positive ADA status did not increase throughout Period 1, and was similar for F and RP at all time points. At the end of Period 3, the proportion of patients with positive ADA status was lower in all treatment sequences, at 51.1%, 54.4%, 48.1%, and 42.5% for F-F-F, F-RP-F, RP-F-F, and RP-RP-F, respectively. CONCLUSION: The RP and F showed comparable immunogenicity characteristics after long-term administration. Development of ADAs with the RP and F was similar, and was not impacted by switching and double switching between F and RP treatment.

Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine Tumors.

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.

Antiviral Activity, Safety, and Pharmacokinetics of AL-794, a Novel Oral Influenza Endonuclease Inhibitor: Results of an Influenza Human Challenge Study.

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.

Randomized study of the safety and pharmacodynamics of inhaled interleukin-13 monoclonal antibody fragment VR942.

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).

Phase I study on safety and pharmacokinetics of a novel influenza endonuclease inhibitor, AL-794 (JNJ-64155806), following single- and multiple-ascending doses in healthy adults.

BACKGROUND: This double-blind, first-in-human Phase I study evaluated pharmacokinetics, safety and tolerability of AL-794 (prodrug of ALS-033719), a potent endonuclease 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.

Epithelial desquamation observed in a phase I study of an oral cathepsin C inhibitor (GSK2793660).

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 from 0.5 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 h 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.

Nalmefene Reduces Reward Anticipation in Alcohol Dependence: An Experimental Functional Magnetic Resonance Imaging Study.

BACKGROUND: Nalmefene 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 randomized, double-blind, placebo-controlled, within-subject crossover design we aimed to determine the effect of a single dose of nalmefene on striatal blood oxygen level-dependent (BOLD) signal change during anticipation of monetary reward using the monetary incentive delay task following alcohol challenge. METHODS: Twenty-two currently heavy-drinking, non-treatment-seeking alcohol-dependent males were recruited. The effect of single dose nalmefene (18 mg) on changes in a priori defined striatal region of interest BOLD signal change during reward anticipation compared with placebo was investigated using functional magnetic resonance imaging. Both conditions were performed under intravenous alcohol administration (6% vol/vol infusion to achieve a target level of 80 mg/dL). 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 region of interest compared with placebo. Nalmefene did not alter brain perfusion. CONCLUSIONS: 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 opioid receptors, which modulate the mesolimbic dopaminergic system, and provides a neurobiological basis for its efficacy.

Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate.

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.

Pharmacokinetics, safety, tolerability and immunogenicity of FKB327, a new biosimilar medicine of adalimumab/Humira, in healthy subjects.

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.

Gastrin stimulates a cholecystokinin-2-receptor-expressing cardia progenitor cell and promotes progression of Barrett's-like esophagus.

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-1ß 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-1ß mice. DESIGN: L2-IL-1ß 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-1ß 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-1ß 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.