To assess the safety, pharmacokinetics, and exploratory efficacy of SM04690, a novel Wnt pathway inhibitor, as a potential disease modifying treatment for knee osteoarthritis (OA).
Subjects with ...Kellgren-Lawrence grade 2–3 knee OA were randomized in successive dose-escalation cohorts to receive a knee intra-articular (IA) injection with 0.03, 0.07, or 0.23 mg SM04690, or placebo (PBO) (4:1 ratio). Safety, pharmacokinetics, efficacy (WOMAC Total/Function/Pain, Pain VAS, Physician Global Assessment MDGA, and OMERACT-OARSI Response), OA-related biomarker (P1NP, ß-CTX, and cartilage oligomeric matrix protein COMP), and radiographic/imaging data were collected at baseline and during 24-week follow-up.
61 subjects (SM04690 n = 50; PBO n = 11) enrolled. Two dose limiting toxicities (DLTs), increased pain following injection and paroxysmal tachycardia (also the single serious AE), were reported in the 0.07 mg cohort. A total of 72 AEs were reported; Sixteen (occurring in eight subjects) were considered related to study medication. There were three discontinuations; one due to an AE (0.03 mg cohort). Bone marrow edema (BME) remained constant for most subjects. No doses were excluded from further study due to DLT criteria. Plasma levels of SM04690 were below the limit of detection at all time points. At Week 24, improvements from baseline were seen in all cohorts for the exploratory measures WOMAC Total, WOMAC Function, WOMAC Pain, MDGA, Pain VAS, and OMERACT-OARSI response. Joint space width (JSW) improvement was observed in the 0.07 mg cohort (P = 0.02 vs PBO).
SM04690 appeared safe and well tolerated, with no evidence of systemic exposure. Exploratory efficacy analyses suggested positive trends for measurements of OA pain, function and disease-modifying osteoarthritis drug (DMOAD) properties.
NCT02095548.
Hip osteoarthritis (OA) is difficult to treat. Steroid injections reduce pain with short duration. With widespread adoption of office-based, image-guided injections, hyaluronic acid is a potentially ...relevant therapy. In the largest clinical trial to-date, we compared safety/efficacy of a single, 6-mL image-guided injection of hylan G-F 20 to saline in painful hip OA.
357 patients were enrolled in a multicenter, double-blind, randomized saline placebo- controlled trial. Subjects were ≥35 years of age, with painful (Western Ontario and McMaster Universities Osteoarthritis Index WOMAC-A1:5.0–8.0; numeric rating scale NRS: 0–10) mild-to-moderate hip OA (Kellgren–Lawrence grade II/III) and minimal contralateral hip pain (WOMAC-A1 < 4). Outcome measures included “pain on walking” (WOMAC-A1 and -A), Patient Global Self-Assessment (PTGA), WOMAC-A1 responder rate (+≥2 points on NRS), and adverse events (AEs) over 26 weeks.
357 patients (hylan G-F 20 single:182; saline:175) were enrolled. Both groups demonstrated significant pain improvement from baseline over 26 weeks (P < 0.0001); saline-induced pain reduction was a remarkable 35%. WOMAC-A and PTGA scores also significantly improved (P < 0.0001). No statistically significant difference was observed between groups in WOMAC-A1 scores (hylan G-F 20 single:−2.19 ± 0.16; saline:−2.26 ± 0.17) or WOMAC-A1 responders (41–52%). Treatment-related AE rates at target hip were similar (hylan G-F 20 single:23 patients 12.8%; saline:12 7.0%). Posthoc analysis found, despite protocol requirements, many patients had psychological (31%) or potential neuropathic pain (27.5%) conditions.
A single 6-mL hylan G-F 20 injection or saline for painful hip OA resulted in similar, statistically significant/clinically relevant pain and function improvements up to 6 months following injection; no differences between hylan G-F 20 and saline placebo were observed.
Lorecivivint (LOR; SM04690), an investigational Wnt pathway modulator, previously demonstrated patient-reported and radiographic outcome improvements vs placebo in clinically relevant subjects with ...moderate to severe knee osteoarthritis (OA). This study's objective was to identify effective LOR doses.
Subjects in this 24-week, Phase 2b, multicenter, randomized, double-blind, placebo (PBO)-controlled trial received an intra-articular injection of 2 mL LOR (0.03, 0.07, 0.15, or 0.23 mg), PBO, or dry-needle sham. The primary efficacy endpoints were changes in Pain NRS 0–10, WOMAC Pain 0–100, WOMAC Function 0–100, and radiographic mJSW outcomes, which were measured using baseline-adjusted analysis of covariance at Week 24. Multiple Comparison Procedure-Modeling (MCP-Mod) was performed for dose modeling.
In total, 695/700 subjects were treated. Pain NRS showed significant improvements vs PBO after treatment with 0.07 mg and 0.23 mg LOR at Weeks 12 (−0.96, 95% CI −1.54, −0.37, P = 0.001; −0.78 −1.39, −0.17, P = 0.012) and 24 (−0.70 -1.34, −0.06, P = 0.031; −0.82 −1.51, −0.12, P = 0.022). Additionally, 0.07 mg LOR significantly improved WOMAC Pain and Function subscores vs PBO at Week 12 (P = 0.04, P = 0.021), and 0.23 mg LOR significantly improved both WOMAC subscores at Week 24 (P = 0.031, P = 0.017). No significant differences from PBO were observed for other doses. No radiographic progression was observed in any group at Week 24. MCP-Mod identified 0.07 mg LOR as the lowest effective dose.
This 24-week Phase 2b trial demonstrated the efficacy of LOR on PROs in knee OA subjects. The optimal dose for future studies was identified as 0.07 mg LOR.
Reactive oxygen species have been implicated in the gastrointestinal pathogenesis of septic and endotoxic shock. The objective of this study was to investigate the role of inducible nitric oxide ...synthase during endotoxin-induced formation of oxidants by cells of the small intestine. After intravenous Escherichia coli lipopolysaccharide (LPS) (1 mg/kg) injection, nitric oxide production was measured as nitrosyl complex formation in the ileum using electron paramagnetic resonance spectroscopy. Oxidative stress biomarkers were determined as duodenal mucosal-reduced thiols, the ileal lipid peroxidation and luminal free radical production using spin trapping methodology. Demonstration of nitrosyl complex formation commenced at 3 h and diminished 24 h post-LPS. Mucosal thiol levels were decreased at 3, 6, 12, and 18 h post-LPS treatment. At these time point, the ileal lipid peroxidation also increased as did luminal formation of hydroxyl radical adduct. Nitric oxide synthase inhibitors reversed the elevation of hydroxyl radical formation and reversed the decrease in mucosal-reduced thiol levels in the LPS-treated rats. Our data indicate that nitric oxide or its oxidant product(s), such as peroxynitrite, contribute to oxidative injury in the small intestine of rats treated with endotoxin.
The recombinant oncotoxin AR209 e23(Fv)PE38KDEL; formerly OLX-209 was developed to treat neoplasia that expresses the c-erbB-2
(HER-2/neu) protein product p185(erbB-2). The AR209 compound contains a ...single-chain antibody domain specific for p185(erbB-2),
coupled with a portion of the Pseudomonas exotoxin. The drug has been shown to be effective in inhibiting cells that overexpress
erbB-2 due to gene amplification and in cells that do not contain amplified erbB-2 but express slightly higher levels of the
protein than normal cells do. To test the efficacy of AR209 on human lung tumors, athymic nude mice were inoculated intrathoracically
with a cell line derived from a poorly differentiated lung adenocarcinoma. This cell line, termed 201T, expresses moderately
elevated levels of p185(erbB-2) 7.6-fold over normal bronchial epithelium. Mice treated with i.v. injections of AR209 for
5 weeks after orthotopic tumor implantation had smaller tumors and in 20% of cases showed no evidence of disease. The data
from this study indicate that AR209 may be an effective treatment for patients with non-small cell lung cancers that express
p185(erbB-2).
The aim of the present work was to test the effect of acute in vivo alcohol administration (180-190 mg/dl plasma for 3 h) on glucose utilization by tissues under basal conditions or after a ...hyperinsulinemic (100-130 microU/ml) euglycemic clamp in fasted rats. In vivo glucose use by individual tissues was assessed by the tracer 2-deoxy-D-glucose technique. Alcohol administration to saline-infused rats markedly inhibited glucose use by skeletal muscles, including the soleus, white and red quadriceps, and gastrocnemius, as well as by the heart. Ethanol infusion, however, had no effect on glucose use by the diaphragm, lung, liver, skin, ileum, brain, and adipose tissue. The insulin-stimulated glucose use was also inhibited by alcohol selectively in the muscles, with no effect on other tissues tested, except a moderate inhibition in the brain. Ethanol inhibited muscle glucose use by an average of approximately 50% under both basal and insulin-stimulated conditions. However, because insulin treatment more than doubled basal glucose use by these muscles, the 50% inhibition by ethanol treatment represents a greater inhibition of absolute glucose use under insulin-stimulated rather than under basal conditions. Our data demonstrate that acute alcohol intake attenuates basal and hormone-induced glucose utilization in a tissue-specific fashion. The inhibitory effect of alcohol on skeletal muscle glucose use could contribute to the previously observed decreased glucose recycling in humans after acute alcohol intake.
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