Could nerve growth factor inhibitors have a place in the treatment of knee osteoarthritis?: Impact of joint destruction and means of administration ossn the value of Tanezumabs

Abstract

s / Osteoarthritis and Cartilage 23 (2015) A82eA416 A394 findings clearly indicate that even in low-risk group, it is cost-effective to co-prescribe PPIs along with traditional or COX-2-selective NSAIDs. Our results should be interpreted with caution due to their short time horizon and may not generalize beyond 3 months. 655 COULD NERVE GROWTH FACTOR INHIBITORS HAVE A PLACE IN THE TREATMENT OF KNEE OSTEOARTHRITIS?: IMPACT OF JOINT DESTRUCTION AND MEANS OF ADMINISTRATION OSSN THE VALUE OF TANEZUMABS E. Losina y, G. Michl y, J. Collins y, D.J. Hunter z, J.M. Jordan x, E. Yelin k, A.D. Paltiel ¶, J.N. Katz y. yBrigham and Women's Hosp., Boston, MA, USA; zUniv. of Sydney, Sydney, Australia; xUNC Sch. of Med., Chapel Hill, NC, USA; kUniv. of California, San Francisco, San Francisco, CA, USA; Yale Sch. of Publ. Hlth., New Haven, CT, USA Purpose: Tanezumab is a nerve growth factor inhibitor in development as an analgesic for patients with knee osteoarthritis (OA). While several studies show promising pain relief with Tanezumab, reports of joint destruction have led to temporary suspension of further studies. We sought to establish cost and toxicity (joint destruction) thresholds that would make Tanezumab a cost-effective treatment for moderate to severe knee OA. Methods: We used the Osteoarthritis Policy (OAPol) model, a validated computer simulation model of the natural history and management of knee OA, to estimate the cost-effectiveness of using Tanezumab in patients with persistent pain despite currently available pharmacologic therapy. Population characteristics and efficacy were derived from Lane et al. (2010). Mean age was 59 years, 59% were female and 88% were white. Baseline WOMAC Pain (0-100, with 1001⁄4worst) was 67 (SD 13). Mean pain reduction from Tanezumabwas 34 (SD 20) in the first year of treatment. In the absence of long-term data, we estimated Tanezumab annual discontinuation rate after the first year at 10% using data on Enbrel in RA. In the base case, we assumed joint destruction in 1% of subjects based on data from Pfizer’s 2012 Arthritis Advisory Committee Briefing Document. In subjects with a destroyed joint, we assumed a 50% decrease in pain reduction and structural efficacy for primary and revision total knee replacement surgery (TKR). We included drug, administration, and monitoring costs of Tanezumab. The price of one dose of Tanezumab (delivered every 8 weeks) was varied from $200 to $1,000. For each dose price, we considered self-administered subcutaneous injections vs. provider-administered IV infusion. The cost of an IV infusion varies by setting (non-hospital vs. hospital) and by whether it is billed as chemotherapy. Administrative costs therefore varied from $0 to $346 per dose in this analysis. Annual monitoring costs for IV infusions were fixed at $250 and included 2x/yr MD visits, 1x/yr blood tests, and biannual X-rays to check for OA progression. Monitoring costs for subcutaneous injections were $442, for two additional MD visits/yr. Cost-effectiveness was estimated as the ratio of incremental costs to incremental effectiveness (quality-adjusted life years, QALYs) when Tanezumab was added to current treatment for knee OA prior to primary TKR. Costs and QALYs were discounted at 3% per year. We defined a program as “cost-effective” if its cost-effectiveness ratio was below $100,000/QALY. In sensitivity analyses we varied efficacy, discontinuation, joint destruction rates and costs of Tanezumab. Results: In the base case analysis, Tanezumab led to an additional 0.27 quality-adjusted life years. It reduced primary TKR utilization by 17% and revision TKR utilization by 29%, and increased mean age at TKR from 67 to 70 years. Green shading in the Table indicates scenarios in which Tanezumab was cost-effective. Subcutaneous Tanezumab at $600/dose remained cost-effective when efficacy decreased by 20% and when discontinuation increased to 20%. Subcutaneous Tanezumab at $600/dose also remained cost-effective at a 2% joint destruction rate, but not when the joint destruction rate was increased to 5%. At joint destruction rates above 10%, Tanezumab decreased quality-adjusted life expectancy and did not represent a viable treatment option. Conclusions: Tanezumab (a promising NGF inhibitor in development) could be a cost-effective treatment for moderate to severe knee OA pain depending on the price of the drug and the delivery means. The value of Tanezumab depends on the rate of joint destruction. 656 EFFECTS OF DOXYCYCLINE AS AN ADJUVANT THERAPY ON THE WOMAC INDEX OF PATIENTS WITH PRIMARY KNEE OSTEOARTHRITIS S. Salman, A.M. Ahmed. Coll. of Med., Baghdad, Iraq Purpose: To examine the short-term effects of doxycycline compared with placebo on the WOMAC index (Western Ontario and McMaster Universities) of knee osteoarthritis during a 3-month treatment course. Methods:One hundred forty patients were enrolled in this randomized, placebo-controlled, double blind study. Half the patients (70) were randomly assigned to receive oral doxycycline capsule 100 mg twice daily in the drug group and the other half received a starch containing capsule (the placebo group). The efficacy outcome measure was the change in the WOMAC index. Results: There were no significant differences between the drug and placebo groups in pain score at the baseline visit (P1⁄40.63) or at the first visit one month later (P1⁄40.29). However, at the second visit, there was a significant reduction in pain score in the drug group compared to both placebo group (P1⁄40.028) and the baseline scores. At the third visit, three months later, the difference between both groups became more significant (P1⁄40.013). Stiffness and physical function scores in all comparisons in different visits showed no significant differences between both study groups.Mean WOMAC scores were reduced at each visit compared to its baseline value in drug group compared to the placebo group, and the reduction in mean score of baseline vs. third visit was significantly much higher in the treatment group (8.37±2.1) vs. (3.83±3.1) respectively, P<0.001. Conclusions: Doxycycline at the oral twice-daily dosage of 100 mg has symptomatic benefit in patients with primary osteoarthritis of the knees in terms of pain reduction and total WOMAC score. 657 MRI ANALYSIS FROM TWO PHASE 3 RANDOMIZED CLINICAL TRIALS; TREATMENT OF SYMPTOMATIC KNEE OSTEOARTHRITIS WITH ORAL SALMON CALCITONIN M.A. Karsdal y, E.B. Dam z, I. Byrjalsen y, A. Bihlet y, J.R. Andersen y, B.J. Riis y, P. Alexandersen x, A.-C. Bay-Jensen y, C. Christiansen y. , CSMC021C2301/2 investigatorsyNordic BioSci., Herlev, Denmark; zBiomediq, Copenhagen, Denmark; xCCBR, Ballerup, Denmark Purpose: To evaluate the structuremodification efficacy in two phase III studies by MRI of Oral Salmon Calcitonin (sCT) in osteoarthritis (OA) patients with moderate to severe knee pain and joint structural damage classified as Kellgren-Lawrence 2-3. Methods: This is the combined reporting of two randomized, doubleblind, multi-center, placebo-controlled trials (CSMC021C2301 and CSMC021C2302), evaluating the efficacy and safety of sCT in patients with painful knee OA, enrolling 1,176 and 1,030 patients, respectively, total of 2206, of which 858 were included in the MRI knee subpopulation (demographics table 1). sCT was formulated with a 5-CNAC carrier (a molecule based on Eligen® technology). MRIs were acquired at four investigator sites using a Turbo 3D T1 sequence on a 0.18T Esaote scanner (40 FA, TR 50ms, TE 16ms, scan time 10 minutes, resolution 0.7mm x 0.7mm x 0.8mm). The sequence was optimized for cartilage visualization. Cartilage volumes were automatically quantified in the medial tibial and the medial femoral compartments using a computerbased method (KneeIQ). The volume scores were corrected for scanner drift. The subjects had painful knee OA with structural manifestations. Study subjects were randomized (1:1) to oral sCT 0.8 mg twice daily or placebo for 24 months. This is the first reporting of the combined studies on the first secondary endpoint, MRI. Results: At the 24 month endpoint there was a significant protection of MRI total cartilage volume loss (P<0.02) in CSMC021C2301 albeit not in CSMC021C2302 (P1⁄40.67), and not combined, figure 1. Conclusions: The present formulation of oral calcitonin did not provide reproducible clinical benefits in patients with symptomatic knee OA (NCT00486434, NCT00704847). Other formulations of calcitonin receptor agonists in a selected subpopulation fitting the mode of action