Novel Parathyroid Hormone-Based Bone Graft, KUR-113, in Treatment of Acute Open Tibial Shaft Fracture: A Phase-2 Randomized Controlled Trial.

BACKGROUND: Treatment of an open tibial shaft fracture (TSF) is complex, and many cases are associated with delayed bone union or malunion. Parathyroid hormone (PTH) plays a key role in bone metabolism. A peptide fragment of PTH (PTH1-34) has been shown to promote bone healing. The objective of this study was to evaluate the safety and efficacy of a novel PTH-based bone graft (KUR-113) in the treatment of subjects with an open TSF. METHODS: The study was a randomized, controlled, open-label (dose-blinded), dose-finding study of 200 subjects who had an open TSF secondary to trauma. Subjects were randomized into 1 of 4 groups to receive the standard of care (SoC) alone (control) or the SoC plus a single application of 4 mL of KUR-113 containing TGplPTH1-34 in fibrin at a concentration of 0.133 mg/mL (KUR-113-low), 0.4 mg/mL (KUR-113-mid), or 1.0 mg/mL (KUR-113-high). KUR-113 was administered at the fracture site after internal fracture fixation and before wound closure. Subjects were followed for up to 12 months after treatment. The primary outcome measure was fracture healing at 6 months assessed by the study investigator using radiographic and clinical measures. The primary end point was the proportion of subjects with fracture healing at 6 months. RESULTS: A total of 200 subjects were enrolled and randomized to 1 of the 4 treatments. The primary end point was met in the KUR-113-mid group, which showed a significantly higher prevalence of healing at 6 months than the control group (37 of 46; 80.4% versus 31 of 48; 64.6%). By 12 months, healing had occurred in the majority of subjects in all treatment groups, with the control group requiring more surgical interventions to achieve fracture healing. Adverse events occurred at similar frequencies between the KUR-113 groups and the SoC group. No ectopic bone formation or abnormal bone resorption at the fracture site was observed in any of the treatment groups. CONCLUSIONS: KUR-113 has the potential to be a good adjunctive therapy in the treatment of open TSFs. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

First Clinical Experience with ONO-4232: A Randomized, Double-blind, Placebo-controlled Healthy Volunteer Study of a Novel Lusitropic Agent for Acutely Decompensated Heart Failure.

PURPOSE: The aim of this study was to evaluate the safety, tolerability, and pharmacokinetic parameters of up to 15 dose levels of ONO-4232, a selective agonist for the EP4 subtype of the prostaglandin E2 receptor, with a dual left ventricular lusitropic and venodilatory action, in healthy, adult, male and female volunteers. METHODS: In this randomized, single-center, double-blind, placebo-controlled, single-dose, sequential-group escalation, first in human study, ONO-4232 (0.001, 0.003, 0.01, 0.02, 0.04, 0.08, 0.12, 0.15, 0.18, or 0.27 ng/kg/min) or placebo was administered as a continuous intravenous infusion over 3 hours. Safety, tolerability, and pharmacokinetic data were collected during dosing and over a period of 3 days (Day -1 to Day 2), and at the follow-up visit (Day 7 [±2 days]). FINDINGS: Fifty-seven subjects received ONO-4232 and 19 subjects received placebo. Ten of the planned 15 cohorts (dose range, 0.001-0.27 ng/kg/min) were conducted. A total of 34 treatment-emergent adverse events (TEAEs) were reported in 23 subjects. Overall, the majority of TEAEs were mild. No serious TEAEs or deaths were reported and no subjects discontinued due to adverse events. The most frequently reported TEAE was infusion site erythema. A decrease in systolic blood pressure from baseline occurred for ONO-4232 subjects compared with placebo that was statistically significant for the 0.08 ng/kg/min dose, and a dose-dependent increase in heart rate starting at 0.04 ng/kg/min and achieving statistical significance compared with placebo at 0.15 ng/kg/min and above. More orthostatic events occurred in the higher-dose groups and the dose escalation was terminated due to increasing occurrences of orthostatic hypotension/intolerance. Plasma concentrations of ONO-4232 reached steady state approximately 2 hours after the start of infusion and then declined rapidly after the end of infusion, and systemic exposure appeared to increase in a dose-proportional manner. Approximately 30% of the administered dose of ONO-4232 was excreted in the urine. IMPLICATIONS: In healthy adults ONO-4232 was generally well tolerated in the dose range of 0.001 to 0.27 ng/kg/min. There were dose-related changes in systolic blood pressure and heart rate. Infusion site erythema, which was likely associated with a venodilatory effect and possible evidence for the pharmacologic effects of ONO-4232, occurred increasingly with increasing dose. Pharmacokinetic parameters appeared to be dose-proportional. The study results support further evaluation of the cardiovascular effects of this first-in-class selective left ventricular lusitropic and venodilatory drug in patients with acutely decompensated heart failure.

A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies.

We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255.

Mechanical stability in a human radius fracture treated with a novel tissue-engineered bone substitute: a non-invasive, longitudinal assessment using high-resolution pQCT in combination with finite element analysis.

The clinical gold standard in orthopaedics for treating fractures with large bone defects is still the use of autologous, cancellous bone autografts. While this material provides a strong healing response, the use of autografts is often associated with additional morbidity. Therefore, there is a demand for off-the-shelf biomaterials that perform similar to autografts. Biomechanical assessment of such a biomaterial in vivo has so far been limited. Recently, the development of high-resolution peripheral quantitative computed tomography (HR-pQCT) has made it possible to measure bone structure in humans in great detail. Finite element analysis (FEA) has been used to accurately estimate bone mechanical function from three-dimensional CT images. The aim of this study was therefore to determine the feasibility of these two methods in combination, to quantify bone healing in a clinical case with a fracture at the distal radius which was treated with a new bone graft substitute. Validation was sought through a conceptional ovine model. The bones were scanned using HR-pQCT and subsequently biomechanically tested. FEA-derived stiffness was validated relative to the experimental data. The developed processing methods were then adapted and applied to in vivo follow-up data of the patient. Our analyses indicated an 18% increase of bone stiffness within 2 months. To our knowledge, this was the first time that microstructural finite element analyses have been performed on bone-implant constructs in a clinical setting. From this clinical case study, we conclude that HR-pQCT-based micro-finite element analyses show high potential to quantify bone healing in patients.