Comparing the disease modifying effects of alendronate to risedronate in the rat anterior cruciate ligament transection model of osteoarthritis

s / Osteoarthritis and Cartilage 22 (2014) S57–S489 S463 between subjects receivingABT-981orplacebo. A trend towardsdecreased absolute neutrophil count (ANC) was observed in subjects receiving ABT981. TheANCaveragedemonstratedadose-dependentdecrease; thus,ANC has potential utility as a PD biomarker. There were 2 transient grade 2 neutropenia events observed in the MAD study; both resolved spontaneously. Several inflammation (Fig A) and joint destruction/remodeling (Fig B) biomarkers decreased after ABT-981 treatment; some of these markers exhibited dose-dependent changes (eg, hsCRP, C3M, CRPM). The phase 1 results supported initiation of a phase 2a proof-of-concept study. This is a randomized, DB, parallel-group, placebo-controlled trial to evaluate the safety, tolerability, efficacy and PK/PD effect of ABT-981 in patients with symptomatic, radiographic, and inflammatory knee OA. Approximately 320 patients will be randomized to 4 treatment groups receiving ABT-981 or placebo E2W for 50 weeks (treatment period). Patients will discontinue all analgesic medications during the washout period through week 26. Afterwards, oral standard-of-care medications will be permitted. The primary objective of the trial is to assess the effect of ABT-981 on OA knee pain using the Western Ontario and McMaster Universities OA Index from baseline to week 16, and synovitis/effusion volume of the index knee using magnetic resonance imaging (MRI) from baseline to week 26. The secondary objectives include evaluating the safety and tolerability of ABT-981 and the effect of ABT-981 on physical function, index knee resting and intermittent pain, patient global assessment, and MRI structure parameters over 52 weeks. The change in joint space narrowing will also be assessed on radiographs at week 52. Conclusions: Results of the phase 1 trials demonstrated that ABT-981 was well tolerated in healthy subjects and knee OA patients, and support further investigation of ABT-981 in an OA population in the phase 2 trial. 847 COMPARING THE DISEASE MODIFYING EFFECTS OF ALENDRONATE TO RISEDRONATE IN THE RAT ANTERIOR CRUCIATE LIGAMENT TRANSECTION MODEL OF OSTEOARTHRITIS T. Hayami y,z, G. Wesolowski y, Z. Ya y, M. Pickarski y, L.T. Duong y. yBone Biology. Merck Res Labs., West Point, PA. USA; z Saiseikai Niigata Daini Hosp., Niigata, Japan Purpose: Osteoarthritis (OA) is considered to be a disease of the whole joint and subchondral bone remodeling has been proposed to contribute to the initiation and progression of OA. We previously demonstrated the bisphosphonate (BIS) alendronate (ALN) partially prevented cartilage degradation and reduced periarticular bone remodeling in the rat anterior cruciate ligament transection (ACLT) model of OA. Considering the osteoporosis doses of risedronate (RIS) and ALN are 35mg and 70 mg once-weekly, respectively, the clinical evaluation of RIS at 5 mg/ d, 15 mg/d, 35 mg/wk and 50 mg/wk for 2 years failed to demonstrate disease modifying efficacy in human OA. Hence, the purpose of the current study is to directly compare efficacy of ALN versus RIS in the rat ACLT model. Method: Skeletally mature male Sprague-Dawley rats (20-wks old) were subjected to anterior cruciate ligament transection (ACLT, n 1⁄4 42) or sham (ShamþV, n 1⁄4 7) surgery in the right knee. ACLT rats were randomized into 5 treatment groups (n 1⁄4 7/group): vehicle (ACLTþV), low dose ALN (0.06 mg/kg/wk, ACLTþL-ALN), high dose ALN (0.12 mg/kg/wk, ACLTþH-ALN), low dose RIS (0.06 mg/kg/wk, ACLTþL-RIS), or high dose RIS (0.12 mg/kg/wk, ACLTþH-RIS). The BIS were administered at one week prior to the ACLT surgery via SQ, twice-weekly for 10-weeks. Disarticulated femora were scored for incidence of osteophyte formation. Proximal tibiae were trimmed into anterior and posterior halves. Paraffin sections of the anterior tibia were subjected to histological Mankin scoring. Plastic sections of the posterior halves were stained with Masson’s trichrome and subjected to histomorphometric assessments for osteophyte area. Levels of urinary C-terminal telopeptide type II collagen (CTX-II) and type I collagen (CTX-I) were determined to evaluate cartilage and bone turnover. Results: Historically, ALN at 0.03 mg/kg/wk is an effective dose to fully prevent estrogen-deficient bone loss in ovariectomized rats. Hence, the two doses of ALN used in this study were w2and 4-fold of the equivalent osteoporosis dose in this species. Both doses of ALN and RIS significantly reduced the histological Mankin score of cartilage damage by 20-35% as compared to ACLTþV. The BIS also significantly reduced osteophyte score and area compared to the vehicle treated ACLT-rats. Comparison of equivalent BIS doses demonstrated ALN treatment was consistently more effective than RIS in cartilage protection and reduction of osteophyte formation. Both BIS displayed dose-related reductions of the cartilage degradation (CTXII) and bone resorption (CTX-I) markers. However, ALN at both doses significantly reduced these markers to a higher extent than the respective RIS doses. Conclusions: The results from this study suggest that a BIS at a dose exceeding its osteoporosis dose is required to achieve inhibition of cartilage matrix degradation and osteophyte formation in preclinical models of OA. At the same administered dosages, ALN treatment was more effective than RIS on cartilage protection and reduction of osteophyte formation. 848 A SINGLE INTRA-ARTICULAR DOSE OF FX006, AN EXTENDEDRELEASE FORMULATION OF TRIAMCINOLONE ACETONIDE, HAS A SIMILAR EFFECT ON CARTILAGE IN HEALTHY DOGS AS THE COMMONLY USED KENALOG-40 SUSPENSION A. Kumar y, A. Walz z, D. Garlick x, C. Spainhour z, N. Bodick y. y Flexion Therapeutics, Burlington, MA, USA; zCalvert Lab., Olyphant, PA, USA; xHisto-Scientific Res. Lab., Mt. Jackson, VA, USA Purpose: FX006 is an extended-release poly(lactic-co-glycolic acid) (PLGA) microsphere formulation of triamcinolone acetonide (TCA). Following a single intra-articular (IA) injection, FX006 delivers TCA to the knee joint for about 3 months as PLGA slowly biodegrades by hydrolysis. It has been demonstrated that this prolonged delivery of TCA from FX006 results in enhanced analgesic effect in patients with osteoarthritis (OA). As part of the assessment of safety of FX006, single IA doses of an approved injectable suspension of TCA (Kenalog-40 ; TCA IR) or FX006 were injected into the knees of healthy dogs and the effect on cartilage was evaluated over a period of time. Methods: Anesthetized, healthy, male and female Beagle dogs received 1mL IA injections under aseptic conditions. Treatment groups included: FX006, which contains 25% (w/w) TCA, at TCA doses of 18.75 mg (maximum feasible high-dose; human equivalent dose about 60 mg), 6.2 mg or 2.1 mg; TCA IR to match high-dose FX006 (18.75 mg); blank PLGA microspheres to match the total microsphere content of highdose FX006 (75 mg) and vehicle/diluent (1 mL). FX006 is reconstituted with diluent to form a sterile suspension prior to IA injection. Groups of animals were sacrificed at the following time points post-dosing: 3 days, 4 weeks, 6 weeks, 3, 4, 6 and 9 months, to assess acute and late effects and the recovery of the same. At each time point, knee joints were collected, processed, decalcified, embedded in paraffin, and sectioned to include the patella, distal femoral articular cartilage (condyle), and proximal tibial articular cartilage (tibial plateau). One section was stained with hematoxylin and eosin and a second section with Safranin O for glycosaminoglycans (GAGs) in the extracellular matrix. These were evaluated to assess articular cartilage morphology by employing the Mankin scale. In this semi-quantitative scoring system, cartilage structure, cellularity, Safranin O staining and tidemark integrity are scored on scales of 0-6, 0-3, 0-4 and 0-1 respectively to yield a total Mankin score from 0-14, with 0 indicating normal. Results: Total Joint Average Mankin Scores from the proximal tibia, distal femur and patellar bone sections are summarized in Table 1 below for all time points evaluated. Overall the Mankin scores were low and the only change resulting in an increase from the normal score of 0 was due to a loss in Safranin O staining, indicating loss of GAGs in the extracellular matrix of articular cartilage, in all TCA-treated joints. The scores were comparable in TCA IR and FX006-treated knees with no dose-dependence in the FX006 groups. The loss of Safranin O appeared 3 days after IA injection of either TCA IR or FX006 and peaked at 4-6 weeks. This effect was still apparent 3 months post-injection and starting to recover but was still notable at 4 months. By 6 months, Safranin O staining was clearly recovering indicating a restoration of, or increase in secretion of matrix by chondrocytes. This recovery also was comparable between the TCA IR and FX006 treatment groups at all dose levels. By 9 months after dosing with either TCA IR or FX006, normal Safranin O staining was restored. No adverse effects on cartilage cellularity, structure (such as appearance of surface irregularities, pannus, clefts), tidemark integrity or on sub-chondral bone were evident in joints treated with either TCA IR or FX006 at any time point. No effect on cartilage as judged by any component of the Mankin score was noted following injection of blank PLGA microspheres or diluent at