A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy.

This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference (P = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10.3 meters in favor of drisapersen was observed at week 48. Key secondary efficacy endpoints (North Star Ambulatory Assessment, 4-stair climb ascent velocity, and 10-meter walk/run velocity) gave consistent findings. Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity. The increased standard deviation alone, due to less stringent inclusion/exclusion criteria, reduced the statistical power from pre-specified 90% to actual 53%. Therefore, a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300-400 meters and ability to rise from floor. A statistically significant improvement in 6MWD of 35.4 meters (P = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects.

Healthcare resource utilization and costs by age and joint location among osteoarthritis patients in a privately insured population.

AIMS: To compare healthcare resource utilization and costs between patients aged 18-64 years with osteoarthritis (OA) and matched controls without OA in a privately insured population. METHODS: Patients with OA were selected from de-identified US-based employer claims (Q1:1999-Q3:2011). The index date was defined as the first OA diagnosis indicated by ICD-9-CM codes. One year before and after the index date were defined as the baseline and study periods, respectively. A second OA diagnosis during the study period was also required. Patients with OA were matched one-to-one on age, gender, index date, and minimum length of follow-up to controls without OA. Baseline characteristics and study period resource utilization and costs (2016 USD) were compared between cohorts. RESULTS: This study identified 199,539 patients with OA (knee: 87,271, hip: 19,953, hand: 15,670, spine: 12,496). The average age was 54 years, and 58% were female. OA patients had higher healthcare resource utilization than matched controls in inpatient, emergency room, and outpatient settings (p < .001 for all). Further, patients with OA had 4-times the excess total medical costs of their matched controls ($14,521 vs $3,629; p < .001). Patients with hip OA had the highest medical costs among all joint locations. Outpatient and pharmacy costs were similar among patients with knee, hip, and hand OA, but higher in patients with spine OA. In sub-group analyses, older patients (45-64 years old) had higher costs. LIMITATIONS: This sample, obtained using claims data, only includes patients who were actively seeking care for OA and were likely symptomatic. Asymptomatic patients would likely not be captured in this analysis. CONCLUSIONS: Patients with OA incur greater healthcare resource utilization and costs than patients without OA, with substantial variation by joint location.

Predictive validity of biochemical biomarkers in knee osteoarthritis: data from the FNIH OA Biomarkers Consortium.

OBJECTIVE: To investigate a targeted set of biochemical biomarkers as predictors of clinically relevant osteoarthritis (OA) progression. METHODS: Eighteen biomarkers were measured at baseline, 12 months (M) and 24 M in serum (s) and/or urine (u) of cases (n=194) from the OA initiative cohort with knee OA and radiographic and persistent pain worsening from 24 to 48 M and controls (n=406) not meeting both end point criteria. Primary analyses used multivariable regression models to evaluate the association between biomarkers (baseline and time-integrated concentrations (TICs) over 12 and 24 M, transposed to z values) and case status, adjusted for age, sex, body mass index, race, baseline radiographic joint space width, Kellgren-Lawrence grade, pain and pain medication use. For biomarkers with adjusted p<0.1, the c-statistic (area under the curve (AUC)), net reclassification index and the integrated discrimination improvement index were used to further select for hierarchical multivariable discriminative analysis and to determine the most predictive and parsimonious model. RESULTS: The 24 M TIC of eight biomarkers significantly predicted case status (ORs per 1 SD change in biomarker): sCTXI 1.28, sHA 1.22, sNTXI 1.25, uC2C-HUSA 1.27, uCTXII, 1.37, uNTXI 1.29, uCTXIα 1.32, uCTXIß 1.27. 24 M TIC of uCTXII (1.47-1.72) and uC2C-Human Urine Sandwich Assay (HUSA) (1.36-1.50) both predicted individual group status (pain worsening, joint space loss and their combination). The most predictive and parsimonious combinatorial model for case status consisted of 24 M TIC uCTXII, sHA and sNTXI (AUC 0.667 adjusted). Baseline uCTXII and uCTXIα both significantly predicted case status (OR 1.29 and 1.20, respectively). CONCLUSIONS: Several systemic candidate biomarkers hold promise as predictors of pain and structural worsening of OA.

Pharmacokinetics and Tolerability of a Dual Variable Domain Immunoglobulin ABT-981 Against IL-1α and IL-1ß in Healthy Subjects and Patients With Osteoarthritis of the Knee.

The interleukin (IL)-1 family of proinflammatory cytokines are thought to play a significant role in the structural progression of osteoarthritis and its associated symptoms. IL-1α and IL-1ß are 2 distinct cytokines found in the cartilage, synovial membrane, and synovial fluid of patients with osteoarthritis. The aim of these studies was to evaluate the pharmacokinetics of ABT-981, a dual variable domain immunoglobulin (DVD-Ig) capable of simultaneously binding IL-1α and IL-1ß, in healthy subjects and patients with osteoarthritis of the knee. Fifty-six healthy adult subjects were randomized to receive single doses of ABT-981 intravenously (0.3, 1, 3, or 10 mg/kg), subcutaneously (0.3, 1, 3 mg/kg), or matching placebo in a 3:1 ratio. Thirty-six patients with osteoarthritis of the knee were randomized to receive 4 subcutaneous ABT-981 doses of 0.3, 1, or 3 mg/kg administered every 2 weeks, 3 subcutaneous doses of ABT-981 3 mg/kg every 4 weeks, or matching placebo in a 7:2 active:placebo ratio. ABT-981 behaved similarly to conventional monoclonal antibodies following single or multiple doses with mean maximum serum concentrations 2 to 9 days after subcutaneous doses, mean terminal half-lives of 10 to 14 days, and an absolute subcutaneous bioavailability of 46%. Exposure of ABT-981 was approximately linear following single or multiple doses every 2 weeks with monoexponential decline of terminal-phase concentrations. The most common adverse events associated with ABT-981 were diarrhea and headache in healthy subjects and injection site erythema in subjects with osteoarthritis of the knee. Decreased absolute neutrophil counts were observed in response to ABT-981 administration.

Stereologic analysis of tibial-plateau cartilage and femoral cancellous bone in guinea pigs with spontaneous osteoarthritis.

BACKGROUND: Two strains of guinea pig develop spontaneous osteoarthritis of the knee. Although the disease evolves at different rates in the two strains, it is not known whether these differences are reflected in the structure of the cartilage and cancellous bone. QUESTIONS/PURPOSES: We determined whether the three-dimensional structure of the tibial-plateau cartilage and femoral cancellous bone differed between the two strains. METHODS: Six Dunkin-Hartley and six GOHI/SPF guinea pigs were evaluated. The animals were sacrificed at 11 months of age. The 24 proximal tibias were used for a stereologic histomorphometric analysis of the tibial-plateau cartilage. The 24 femurs were used for a site-specific, three-dimensional quantitative analysis of the cancellous bone by micro-CT. RESULTS: Compared to the GOHI/SPF guinea pigs, the tibial-plateau cartilage of the Dunkin-Hartley strain had a larger lesion volume (3.8% versus 1.5%) and a thicker uncalcified cartilage layer (0.042 versus 0.035 mm), but a thinner calcified cartilage zone (0.008 versus 0.01 mm) and a thinner subchondral cortical bone plate (0.035 versus 0.039 mm). The femoral cancellous bone in the Dunkin-Hartley strain had a lower bone mineral density (477 versus 509 mg/cm(3)). However, the trabeculae were thicker (3.91 versus 3.53 pixels) and farther apart (7.8 versus 5.6 pixels). The osteoarthritic changes in the cartilage were topographically mirrored in the subchondral bone. They were most severe on the medial side of the joint, particularly in the anterior region. CONCLUSIONS: Spontaneous osteoarthritis in the guinea pig is associated with site-specific changes in the articular cartilage layer, which are topographically mirrored in the underlying subchondral bone. CLINICAL RELEVANCE: Three-dimensional structural information not revealed by two-dimensional radiography may help characterize the stages of osteoarthritis.

The effects of glucosamine hydrochloride on subchondral bone changes in an animal model of osteoarthritis.

OBJECTIVE: To quantify periarticular subchondral bone changes in a rabbit model of experimental osteoarthritis (OA), and to determine the effects of continuous administration of a clinically relevant dose of glucosamine HCl on subchondral bone changes in this model. METHODS: Anterior cruciate ligament transection (ACLT) was performed on the left femorotibial joints of 16 rabbits to induce OA. Ten rabbits that did not undergo ACLT served as unoperated controls. Eight rabbits that underwent ACLT and 6 control rabbits were treated with 100 mg of glucosamine daily, and the others were given a placebo. The articular cartilage was evaluated macroscopically and graded at the time of necropsy, 8 weeks after ACLT. Bone mineral density (BMD) was measured using dual-energy x-ray absorptiometry on the dissected distal femur and proximal tibia. Subchondral trabecular bone turnover, architecture, and connectivity, as well as subchondral plate thickness and mineralization were studied on the undecalcified tibia sections from each animal. RESULTS: Eight weeks after ACLT, most of the operated joints had various degrees of cartilage damage and fibrillation. Compared with the control group, the ACLT group had significantly increased subchondral bone turnover and lower BMD, bone volume, connectivity, and bone mineralization. The high bone turnover was significantly reduced in glucosamine-treated animals that underwent ACLT. In fact, there were no significant differences between the ACLT/glucosamine group and the control/glucosamine group in most of the bone parameters studied. CONCLUSION: This study shows that subchondral bone turnover, structure, and mineralization are significantly altered in the early stages of experimental OA, and that these changes are attenuated by glucosamine treatment.

Disease modifying effects of N-butyryl glucosamine in a streptococcal cell wall induced arthritis model in rats.

OBJECTIVE: To evaluate the effect of different doses of N-butyryl glucosamine (GlcNBu) on joint preservation and subchondral bone density and quality in a streptococcal cell wall (SCW) induced arthritis model in Lewis rats. METHODS: Chronic arthritis was induced in 36 female Lewis rats by a single intraperitoneal injection of SCW antigen. The 4 groups studied were: (1) no arthritis, no drug treatment; (2) arthritis, no drug treatment; (3) arthritis, oral GlcNBu 20 mg/kg/day; and (4) arthritis, oral GlcNBu 200 mg/kg/day. Inflammation (ankle swelling) was quantified throughout the clinical course; bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry on dissected distal femurs and proximal tibiae, in user defined regions of interest. Qualitative and quantitative 3-D bone architecture changes were determined using microcomputerized tomography on the left tibiae. Subchondral plate thickness and trabecular bone connectivity were studied on the proximal tibia epiphyses from the central coronal sections of each scanned tibia. RESULTS: GlcNBu inhibited inflammatory ankle swelling at both 20 and 200 mg/kg/day, the latter being statistically significant, with an average reduction of 33%. GlcNBu preserved or enhanced BMD and bone connectivity and prevented further bone loss at both the high and the low dose. Comparisons of the isosurfaces and the architectural measures in the different groups showed that GlcNBu effectively protected the joint surfaces from further erosion in this model of chronic inflammatory arthritis. For some of the bone measurements, increasing doses of GlcNBu showed increasing protective effects, while for other measurements, effects were maximal at the lower dose. CONCLUSION: These data indicate that GlcNBu provides antiinflammatory and antierosive effects by preserving BMD, joint integrity, and bone architecture in involved joints of the SCW model.