Risankizumab for Ulcerative Colitis: Two Randomized Clinical Trials.

Importance: The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown.

Objective: To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis.

Design, Setting, And Participants: Two phase 3 randomized clinical trials were conducted.

Clinical Bridging From Prefilled Syringe to On-body Injector for Risankizumab in Crohn's Disease.

Purpose: This article describes the clinical development bridging strategy and key data to support the marketing application of the risankizumab on-body injection (OBI) system for the treatment of moderately to severely active Crohn's disease (CD), even though the OBI was not evaluated directly in the pivotal Phase III studies in CD.

Methods: Three studies were conducted as part of the clinical bridging strategy. The pilot pharmacokinetics (PK) study was a Phase I, single-dose, 4-arm, open-label, randomized, parallel-group exploratory PK and tolerability study that assessed the effect of rate and volume of administration on the bioavailability (BA) of risankizumab and the extent of injection site-related pain after subcutaneous (SC) administration in healthy subjects.

Risankizumab as maintenance therapy for moderately to severely active Crohn's disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial.

Background: There is a great unmet need for new therapeutics with novel mechanisms of action for patients with Crohn's disease. The ADVANCE and MOTIVATE studies showed that intravenous risankizumab, a selective p19 anti-interleukin (IL)-23 antibody, was efficacious and well tolerated as induction therapy. Here, we report the efficacy and safety of subcutaneous risankizumab as maintenance therapy.

Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials.

Background: Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease.

Methods: ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8.

Long-Term Safety and Efficacy of Risankizumab Treatment in Patients with Crohn's Disease: Results from the Phase 2 Open-Label Extension Study.

Background And Aims: Risankizumab, an interleukin-23 antibody, demonstrated efficacy and acceptable safety in a phase 2 study of patients with moderate-to-severe refractory Crohn's disease. This open-label extension investigated the long-term safety, pharmacokinetics, immunogenicity and efficacy of risankizumab in responders to risankizumab in the parent phase 2 study.

Methods: Enrolled patients had achieved clinical response [decrease in Crohn's Disease Activity Index from baseline ≥100] without clinical remission [Crohn's Disease Activity Index <150] at Week 26, or clinical response and/or remission at Week 52 in the parent phase 2 study and received open-label subcutaneous risankizumab 180 mg every 8 weeks.

Pharmacokinetic Comparability of Risankizumab Formulations in Prefilled Syringe and Auto-injector for Subcutaneous Injection.

Purpose: Risankizumab is a humanized immunoglobulin G1 monoclonal antibody that inhibits the p19 subunit of interleukin 23 from interacting with its receptor for the treatment of moderate to severe plaque psoriasis. The aim of this Phase I biopharmaceutics bridging study was to evaluate the pharmacokinetic comparability, immunogenicity, and tolerability of the risankizumab 90 mg/mL prefilled syringe (PFS) and the risankizumab 150 mg/mL PFS and auto-injector (AI) in healthy subjects.

Methods: Healthy subjects received one 150-mg dose of risankizumab in 1 of 3 ways (226 subjects randomized 3:3:1 to 3 treatment arms): 150 mg/mL by PFS × 1 SC injection, 90 mg/mL by PFS × 2 SC injections, or 150 mg/mL by AI × 1 SC injection, and were followed up for 140 days after dosing for the collection of pharmacokinetic, immunogenicity, and tolerability data.

Elagolix Pharmacokinetic Profiles in Women With Renal or Hepatic Impairment.

The aim of these studies was to assess the safety and pharmacokinetics of elagolix, an oral nonpeptide gonadotropin-releasing hormone antagonist following oral administration in women with renal or hepatic impairment. Two phase 1 studies were conducted in adult women with normal renal function versus renal impairment (reduced study), and normal hepatic function versus hepatic impairment (full study design). All women received a single dose of elagolix 200 mg (renal) or 150 mg (hepatic).

Elagolix Alone or With Add-Back Therapy in Women With Heavy Menstrual Bleeding and Uterine Leiomyomas: A Randomized Controlled Trial.

Objective: To evaluate elagolix, an oral gonadotropin-releasing hormone receptor antagonist, alone or with add-back therapy, in premenopausal women with heavy menstrual bleeding (greater than 80 mL per month) associated with uterine leiomyomas.

Methods: This double-blind, randomized, placebo-controlled, parallel-group study evaluated efficacy and safety of elagolix in cohorts 1 (300 mg twice daily) and 2 (600 mg daily) with four arms per cohort: placebo, elagolix alone, elagolix with 0.5 mg estradiol/0.

Long-Term Outcomes of Elagolix in Women With Endometriosis: Results From Two Extension Studies.

Objective: To evaluate the efficacy and safety of elagolix, an oral, nonpeptide gonadotropin-releasing hormone antagonist, over 12 months in women with endometriosis-associated pain.

Methods: Elaris Endometriosis (EM)-III and -IV were extension studies that evaluated an additional 6 months of treatment after two 6-month, double-blind, placebo-controlled phase 3 trials (12 continuous treatment months) with two elagolix doses (150 mg once daily and 200 mg twice daily). Coprimary efficacy endpoints were the proportion of responders (clinically meaningful pain reduction and stable or decreased rescue analgesic use) based on average monthly dysmenorrhea and nonmenstrual pelvic pain scores.

Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist.

Background: Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies.

Methods: We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix - 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) - as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain.

A Randomized, Double-Blind, Placebo-Controlled, Crossover Study of the T-Type Calcium Channel Blocker ABT-639 in an Intradermal Capsaicin Experimental Pain Model in Healthy Adults.

Objective: This randomized, double-blind, placebo-controlled, crossover trial evaluated the pharmacodynamic effects of a single 100-mg dose of ABT-639, a peripherally active, selective T-type Ca3.2 channel blocker, with the intradermal capsaicin pain model using pregabalin 300 mg as a positive control.

Subjects: Healthy adult males (aged 21 to 55 years) were randomly assigned to receive single oral doses of ABT-639, pregabalin, and placebo.

A randomized double-blind, placebo-, and active-controlled study of T-type calcium channel blocker ABT-639 in patients with diabetic peripheral neuropathic pain.

T-type Cav3.2 calcium channels represent a novel target for neuropathic pain modulation. Preclinical studies with ABT-639, a peripherally acting highly selective T-type Cav3.

Effects of a T-type calcium channel blocker, ABT-639, on spontaneous activity in C-nociceptors in patients with painful diabetic neuropathy: a randomized controlled trial.

T-type calcium channels are a potential novel target for treatment of neuropathic pain such as painful diabetic neuropathy. ABT-639 is a peripherally acting highly selective T-type Ca(v)3.2 calcium channel blocker that has demonstrated analgesic efficacy in preclinical models and may have the potential to reduce spontaneous fiber activity.

Population pharmacokinetics and exposure-uric acid analyses after single and multiple doses of ABT-639, a calcium channel blocker, in healthy volunteers.

ABT-639 is a selective T-type calcium channel blocker with efficacy in a wide range of preclinical models of nociceptive and neuropathic pain. In the current first-in-human (FIH) study, the pharmacokinetics, tolerability, and safety of ABT-639 after single- (up to 170 mg) and multiple doses (up to 160 mg BID) were evaluated in healthy volunteers in a randomized, double-blinded, placebo-controlled manner. ABT-639 demonstrated acceptable safety and pharmacokinetic profiles in human.

An oral TRPV1 antagonist attenuates laser radiant-heat-evoked potentials and pain ratings from UV(B)-inflamed and normal skin.

Aims: Laser (radiant-heat) evoked potentials (LEPs) from vertex-EEG peak-to-peak (PtP) amplitude were used to determine acute antinociceptive/antihyperalgesic efficacy of ABT-102, a novel TRPV1 antagonist efficacious in preclinical pain models, compared with active controls and placebo in normal and UV(B)-inflamed skin.

Methods: This was a randomized, placebo- and active-controlled, double-blind, intra-individual, crossover trial. Twenty-four healthy subjects received six sequences of single doses of ABT-102 (0.

Efficacy and safety of the α4β2 neuronal nicotinic receptor agonist ABT-894 in patients with diabetic peripheral neuropathic pain.

Preclinical and clinical studies suggest that neuronal nicotinic receptor (NNR) agonists may be a novel and effective therapy for numerous painful conditions. Analgesic efficacy and safety of the highly selective α(4)β(2) NNR agonist ABT-894 was evaluated in 2 separate randomized, double-blind, multicenter, placebo-controlled clinical trials in patients with diabetic peripheral neuropathic pain (DPNP). Study 1 (280 patients randomized) tested 1, 2, and 4 mg ABT-894 twice daily compared with placebo and 60 mg duloxetine once per day over 8 weeks of treatment.

Oral and cutaneous thermosensory profile of selective TRPV1 inhibition by ABT-102 in a randomized healthy volunteer trial.

The capsaicin receptor (TRPV1) antagonist ABT-102 demonstrates efficacy in multiple preclinical pain models. However, evolving clinical data for this compound class suggest potentially profound drug-induced thermosensory impairment. Safety and tolerability of ABT-102 were assessed in a multiple-dose, double-blind, placebo-controlled, randomized healthy volunteer trial.

The stimulation of HSD17B7 expression by estradiol provides a powerful feed-forward mechanism for estradiol biosynthesis in breast cancer cells.

Our laboratory has previously cloned and purified an ovarian protein found to be a novel 17β-hydroxysteroid dehydrogenase type 7 enzyme (HSD17B7) (formerly prolactin receptor-associated protein) that converts the weak estrogen, estrone, to the highly potent estradiol. The regulation of this enzyme has not yet been explored. In this report, we show high expression of HSD17B7 in human ductal carcinoma and breast cancer cell lines and present evidence for a strong up-regulation of this enzyme by estradiol at the level of mRNA, protein expression, and promoter activity in MCF-7 cells.

A randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain.

ABT-594 is a neuronal nicotinic acetylcholine receptor (NNR) agonist that exhibits potent analgesic activity in preclinical models of acute, chronic, and neuropathic pain. The purpose of this phase 2, randomized, multicenter, double-blind, placebo-controlled study was to evaluate the safety and analgesic efficacy of ABT-594 in patients with diabetic peripheral neuropathic pain (DPNP). A total of 266 DPNP patients were randomized 1:1:1:1 to receive placebo, ABT-594 150 microg BID, ABT-594 225 microg BID, or ABT-594 300 microg BID.

A 14-week, randomized, double-blinded, placebo-controlled monotherapy trial of pregabalin in patients with fibromyalgia.

Unlabelled: The purpose of the study was to assess the efficacy and safety of pregabalin monotherapy in patients with fibromyalgia in a randomized, double-blinded, placebo-controlled trial. After 1 week of single-blinded administration of placebo, 750 patients meeting American College of Rheumatology criteria for fibromyalgia were randomly assigned to pregabalin (300 mg/d, 450 mg/d, 600 mg/d) or placebo, administered twice daily for 14 weeks. The primary outcome variable was comparison of end point mean pain scores, derived from daily diary ratings of pain intensity (0 to 10 scale), between each of the pregabalin groups and the placebo group.

A multitargeted receptor tyrosine kinase inhibitor, SU6668, does not affect the healing of cutaneous full-thickness incisional wounds in SKH-1 mice.

Disturbances of angiogenesis have been suggested to result in the impaired healing of skin wounds. Using a murine incisional wound model, we evaluated the effects of SU6668, an inhibitor of the receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF), on the healing of skin wounds. Mice were administered vehicle, SU6668 (100 or 400 mg/kg/day, b.

Comparison of immunohistochemistry for activated caspase-3 and cleaved cytokeratin 18 with the TUNEL method for quantification of apoptosis in histological sections of PC-3 subcutaneous xenografts.

The terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labelling (TUNEL) technique has been extensively used for the detection and quantification of apoptosis in histological tissue sections. However, the interpretation and specificity of this assay have been controversial. With accumulating knowledge of the molecular mechanisms of cell death and the discovery of the caspases as key mediators of apoptosis, more direct and earlier measurements of apoptosis in tissue sections have emerged.

Estrogen regulates a tissue-specific calpain in the anterior pituitary.

A PCR-based cDNA subtraction hybridization was performed to identify the genes stimulated by estrogen in the pituitary. A novel tissue-specific calpain (nCL-2'), previously shown to be expressed mainly in the stomach, was markedly induced in the pituitary after estrogen treatment. The 5'-flanking region of the calpain nCL-2' gene was analyzed to assess the molecular mechanism of estrogen regulation.