Efficacy, safety, and target engagement of dazukibart, an IFNβ specific monoclonal antibody, in adults with dermatomyositis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial.

Background: Dermatomyositis is a chronic autoimmune disease with distinctive cutaneous eruptions and muscle weakness, and the pathophysiology is characterised by type I interferon (IFN) dysregulation. This study aims to assess the efficacy, safety, and target engagement of dazukibart, a potent, selective, humanised IgG1 neutralising monoclonal antibody directed against IFNβ, in adults with moderate-to-severe dermatomyositis.

Methods: This multicentre, double-blind, randomised, placebo-controlled, phase 2 trial was conducted at 25 university-based hospitals and outpatient sites in Germany, Hungary, Poland, Spain, and the USA.

A phase 2a trial of brepocitinib for cicatricial alopecia.

Background: Cicatricial alopecias are chronic, progressive scarring hair-loss conditions. Molecular dysregulation is not fully understood, hindering treatment development. Th1/IFNγ signaling and Janus kinase dysregulation has shown involvement, providing rationale for this phase 2a trial with Tyrosine kinase 2/Janus kinase 1 inhibitor brepocitinib.

Brepocitinib, Zimlovisertib, and Ropsacitinib in Hidradenitis Suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a debilitating, inflammatory skin disease with limited treatment options and partially understood pathophysiology. Using an umbrella trial design, three kinase inhibitor immunomodulators with different mechanisms of action were evaluated. METHODS: This phase 2a, double-blind, parallel-group trial enrolled adults with moderate to severe HS who were then randomly assigned (1:1:1:1) to once-daily brepocitinib 45 mg (a JAK1/TYK2 inhibitor), zimlovisertib 400 mg (an IRAK4 inhibitor), ropsacitinib 400 mg (a TYK2 inhibitor), or matching placebo for 16 weeks.

Safety, Tolerability, and Pharmacokinetics of PF-06823859, an Anti-Interferon β Monoclonal Antibody: A Randomized, Phase I, Single- and Multiple-Ascending-Dose Study.

This double-blind, randomized, placebo-controlled, dose-ascending, first-in-human study (NCT02766621) assessed the safety, tolerability, and pharmacokinetics (PK) of PF-06823859, an anti-interferon β monoclonal antibody. Healthy subjects were randomized to single ascending doses (SADs) of intravenous PF-06823859 30, 100, 300, 900, or 2000 mg or placebo; to multiple ascending doses (MADs) of subcutaneous PF-06823859 100 or 300 mg or placebo (once every 2 weeks for a total of 3 doses); or to MAD of intravenous PF-06823859 600 mg or placebo (once every 3 weeks or once every 4 weeks for a total of 2 doses). The incidence, severity, and causal relationship of adverse events (AEs) were assessed, along with immunogenicity and PK.

A phase I, randomized, double-blind study to assess the safety, tolerability and efficacy of the topical RORC2 inverse agonist PF-06763809 in participants with mild-to-moderate plaque psoriasis.

Background: Transcription factor retinoic acid-related orphan receptor 2 (RORC2/RORγT) mediates interleukin (IL)-17A and IL-17F expression. IL-17A plays a central role in the pathogenesis of several inflammatory disorders, including psoriasis. The RORC2 inhibitor PF-06763809 has been hypothesized to inhibit IL-17A production in T-helper 17 (Th17) cells, thereby reducing psoriasis symptoms.

Safety, Pharmacokinetic, and Pharmacodynamic Evaluation After Single and Multiple Ascending Doses of a Novel Selective Androgen Receptor Modulator in Healthy Subjects.

Purpose: Tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) properties of single ascending doses (SADs) and multiple ascending doses (MADs) of PF-06260414, a novel selective androgen receptor modulator, were assessed after oral administration in healthy subjects.

Methods: Range of SAD and MAD levels tested were 1 to 400 mg and 3 to 100 mg BID, respectively (n = 8 per cohort). In addition, a 60-mg once-daily (n = 8) cohort and a Japanese cohort receiving 30 mg BID (n = 7) also received PF-06260414.

OSKIRA-4: a phase IIb randomised, placebo-controlled study of the efficacy and safety of fostamatinib monotherapy.

Objectives: OSKIRA-4 evaluated the efficacy of fostamatinib monotherapy versus placebo on the signs and symptoms of rheumatoid arthritis over 6 weeks by Disease Activity Score C reactive protein (DAS-28(CRP)) and assessed non-inferiority to adalimumab monotherapy at Week 24 by DAS-28(CRP).

Methods: Overall, 279 patients not currently taking disease-modifying antirheumatic drugs were randomised to: (A) fostamatinib 100 mg twice daily for 24 weeks plus placebo injection every 2 weeks (PBOI); (B) fostamatinib 100 mg twice daily for 4 weeks, then 150 mg once daily up to Week 24, plus PBOI; (C) fostamatinib 100 mg twice daily for 4 weeks, then 100 mg once daily up to Week 24, plus PBOI; (D) adalimumab 40 mg every 2 weeks for 24 weeks, plus oral placebo twice daily; or (E) oral placebo twice daily for 6 weeks, plus PBOI, then a switch to arm A or B.

Results: Fostamatinib demonstrated a significant improvement in DAS-28(CRP) score from baseline versus placebo at Week 6 for arms A and B, but not C.

Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial: Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II).

Background And Purpose: A previous randomized, placebo-controlled, double-blind study suggested that abciximab may be safe and effective in treatment of acute ischemic stroke. The current phase 3 study was planned to test the relative efficacy and safety of abciximab in patients with acute ischemic stroke with planned treatment within 5 hours since symptoms onset.

Methods: An international, randomized, placebo-controlled, double-blind phase 3 trial tested intravenous administration of abciximab in 2 study cohorts using stratification variables of time since onset and stroke severity.

Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement.

Rationale: Evidence suggests that tumor necrosis factor (TNF)-alpha plays an important role in the pathophysiology of sarcoidosis.

Objectives: To assess the efficacy of infliximab in sarcoidosis.

Methods: A phase 2, multicenter, randomized, double-blind, placebo-controlled study was conducted in 138 patients with chronic pulmonary sarcoidosis.

Static pressure regulates connective tissue growth factor expression in human mesangial cells.

Connective tissue growth factor (CTGF) is overexpressed in a variety of fibrotic disorders such as renal fibrosis and atherosclerosis. Fibrosis is a common final pathway of renal diseases of diverse etiology, including inflammation, hemodynamics, and metabolic injury. Mechanical strains such as stretch, shear stress, and static pressure are possible regulatory elements in CTGF expression.

Connective tissue growth factor induces apoptosis in human breast cancer cell line MCF-7.

Connective tissue growth factor (CTGF) is a member of an emerging CCN gene family that is implicated in various diseases associated with fibro-proliferative disorder including scleroderma and atherosclerosis. The function of CTGF in human cancer is largely unknown. We now show that CTGF induces apoptosis in the human breast cancer cell line MCF-7.

Overexpression of connective tissue growth factor gene induces apoptosis in human aortic smooth muscle cells.

Background: Connective tissue growth factor (CTGF) is expressed at very high levels particularly in the shoulder of human atherosclerotic lesions but not in normal blood vessels. Thus, CTGF may be important in the regulation of vascular smooth muscle cell function in atherosclerosis, but its precise role remains elusive.

Methods And Results: Full-length CTGF cDNA driven by a cytomegalovirus promoter was transiently transfected into cultured human aortic smooth muscle cells (HASCs).

Platelet-derived growth factor-induced vasodilatation in mesenteric resistance arteries by nitric oxide: blunted response in spontaneous hypertension.

Platelet-derived growth factor (PDGF) is a potent mitogen for vascular smooth-muscle cells, but its effects on vasomotion remain controversial. Both vasoconstriction and vasodilatation of isolated rat aortic rings have been reported. The effects of PDGF on responses of perfused mesenteric resistance arteries from normotensive Wistar-Kyoto and spontaneously hypertensive rats were studied by using a video dimension analyzer.

Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis.

Background: NO regulates vascular tone and structure, platelets, and monocytes. NO is synthesized by endothelial NO synthase (eNOS). Endothelial dysfunction occurs in atherosclerosis.

Expression of connective tissue growth factor in human renal fibrosis.

Chronic renal failure may occur in etiologically diverse renal diseases and can be caused by hemodynamic, immunologic and metabolic factors. Initial damage may evoke irreversible scarring, which involves production of a number of proinflammatory and fibrogenic cytokines, including platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-beta). Connective tissue growth factor (CTGF), a cytokine of the family of growth regulators comprising sef10, cyr61, CTGF and nov, has recently been described in association with scleroderma and other scarring conditions.

Different proliferative properties of smooth muscle cells of human arterial and venous bypass vessels: role of PDGF receptors, mitogen-activated protein kinase, and cyclin-dependent kinase inhibitors.

Background: Internal mammary artery (IMA) bypass grafts have a higher patency than saphenous vein (SV) grafts. Intimal hyperplasia of SV grafts is due to smooth muscle cell (SMC) proliferation and migration. We hypothesized that different SMC growth activity exists in IMA and SV, which may explain the different patencies of arterial and venous grafts.

Pulsatile stretch stimulates superoxide production and activates nuclear factor-kappa B in human coronary smooth muscle.

There is increasing evidence that oxidative stress is of pathophysiological importance in cardiovascular disease. Mechanical forces such as pulsatility may also contribute. Using human coronary artery smooth muscle cells (HCAS), we tested the hypothesis that stretch-induced cell proliferation is associated with oxidative stress.

Connective tissue growth factor. Friend or foe?

Connective tissue growth factor (CTGF) is a novel cysteine-rich, secreted peptide, which is implicated in human atherosclerosis and fibrotic disorders such as systemic scleroderma. CTGF is a member of the peptide family that includes serum-induced immediate early gene products, a v-src-induced peptide, and a putative proto-oncogene. The CTGF gene family is a modular protein and is conserved throughout evolution.

Bimodal effects of angiotensin II on migration of human and rat smooth muscle cells. Direct stimulation and indirect inhibition via transforming growth factor-beta 1.

Angiotensin II may be an important mediator of neointima formation in vascular disease. This study was designed to examine the mechanisms involved in angiotensin II-stimulated migration of human and rat aortic vascular smooth muscle cells (VSMCs). VSMCs were seeded in one corner of Nunc four-well culture chambers; angiotensin II within filter paper was glued onto the wall of the opposite side.

Human connective tissue growth factor is expressed in advanced atherosclerotic lesions.

Background: Atherosclerosis affects certain but not all vascular beds of the human circulation. Its molecular mechanisms are only partially understood. Human connective tissue growth factor (hCTGF) is a novel cysteine-rich, secreted polypeptide.

[Molecular and cellular mechanisms of arteriosclerosis and restenosis: possibilities of gene therapy].

Atherosclerosis and its consequences account for most of morbidity and mortality in Western countries. Atherosclerosis develops over a period of decades and has a complex pathogenesis. It is a disease of the intima and primarily involves four cell types, i.

17 beta-Estradiol and smooth muscle cell proliferation in aortic cells of male and female rats.

The low incidence of cardiovascular disease in women before menopause or during hormone replacement therapy suggests a protective effect of estrogens. The mechanism(s) are uncertain but may involve effects on lipids, coagulation and the endothelium. Vascular smooth muscle cell (VSMC) proliferation also contributes to atherosclerosis.

[Molecular medicine and gene therapy as exemplified with arteriosclerosis and restenosis].

Atherosclerosis and its consequences account for most morbidity and mortality in Western countries. Atherosclerosis develops over a period of decades and has a complex pathogenesis. It is a disease of the intima and primarily involves four cell types, i.

Molecular and cellular mechanisms of atherosclerosis.

At least three distinct cellular mechanisms are currently thought to be responsible for the initiation of atherosclerotic lesions in humans: (1) accumulation of lipids and plasma-derived lipoproteins in the arterial intima; (2) smooth muscle cell migration from the media into the intima, and smooth muscle cell proliferation or accumulation, or both, within the intima; and (3) accumulation of platelet and/or fibrin deposits in the intima. Independent of the triggering factor, it appears that the first step in atherogenesis involves activation of repair mechanisms in the blood vessel in an attempt to restore vascular homeostasis, which involves a delicate balance of growth promoting and growth inhibitory activities of the vascular wall cells. The healing process involves a series of specific and temporally coordinated events, such as platelet aggregation, monocyte adhesion and migration across endothelial cells, and migration and proliferation of vascular smooth muscle cells, which are normally orchestrated by a variety of growth factors, cytokines, adhesion molecules, and extracellular matrix proteins in a controlled, although not yet fully understood, manner.