B.J. Riis

The effect of oral salmon calcitonin delivered with 5-CNAC on bone and cartilage degradation in osteoarthritic patients: a 14-day randomized study

BACKGROUND The aim of this study was to investigate the pharmacokinetic and pharmacodynamic parameters of oral salmon calcitonin (oSCT) administered over 14 days to men and women presenting with osteoarthritis (OA). MATERIALS AND METHODS The study was a phase-I, 2-week, placebo-controlled, double-blind, double-dummy, randomized, gender-stratified study including 73 subjects aged 57-75 years. Patients had painful OA with a Kellgren and Lawrence index score of I-III. Treatment allocations were; 0.6 mg, 0.8 mg of oSCT, or placebo. Treatment was given twice daily for 14 days. The morning dose was administered between 07:00 and 08:00 at least 30 min before breakfast. The second dose was administered 30 min before evening dinner. On treatment day 1 and 14, the morning dose was followed by 5h of fasting, and blood samples and urine were collected immediately prior to dosing and according to the protocol. Study parameters were: plasma sCT levels, bone resorption by CTX-I (serum C-terminal telopeptide of collagen type I), bone formation by osteocalcin (serum OC), and cartilage degradation by CTX-II (urine C-terminal telopeptide of collagen type II) (clinicaltrials.gov identifier: NCT00486369). RESULTS Doses of 0.8 mg compared with 0.6 mg produced significantly higher C(max) and AUC(0-4 hrs), of calcitonin, P=0.03. This resulted in significant reductions in CTX-I and CTX-II, [P<0.0001; P=0.007]. No differences were observed between baseline and follow-up at day 14 in pharmacokinetic and pharmacodynamic parameters. Gender had no observable influence on results. CONCLUSIONS oSCT given twice daily with a pre-dinner and morning fasting dosing resulted in reductions in markers of bone resorption and cartilage degradation.

Treatment of symptomatic knee osteoarthritis with oral salmon calcitonin: results from two phase 3 trials.

PURPOSE To evaluate the structure-modifying and symptom efficacy, as well as safety and tolerability of oral salmon calcitonin (sCT) formulated with a 5-CNAC carrier (a molecule based on Eligen(®) technology), in osteoarthritis (OA) patients with moderate to severe knee pain and joint structural damage classified as Kellgren and Lawrence (KL)2-3. METHODS AND DESIGN This is the combined reporting of two randomized, double-blind, multi-center, placebo-controlled trials (CSMC021C2301 and CSMC021C2302), evaluating the efficacy and safety of oral sCT in patients with painful knee OA with structural manifestations, enrolling 1176 and 1030 patients, respectively. Study subjects were randomized (1:1) to oral sCT 0.8 mg twice daily or placebo (PBO) for 24 months. The primary efficacy objectives were to examine the treatment effect compared to placebo on change over 24 months in joint space width (JSW) in the signal knee measured by X-ray, and to examine the change in pain and function using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) questionnaire. Other study parameters included patient and physician global assessment, and biochemical markers of bone (CTX-I) and cartilage degradation (CTX-II). RESULTS At the 24 month endpoint there was no statistically significant treatment effect on joint space narrowing (JSN) in any of the two studies. In CSMC021C2301 there was a treatment effect on WOMAC (sum of pain, function, stiffness, and total scores) as well as on the biomarkers of bone and joint metabolism, but due to the hierarchical testing procedure the treatment effect was not claimed statistically significant. CONCLUSIONS The present formulation of oral sCT did not provide reproducible clinical benefits in patients with symptomatic knee OA (NCT00486434, NCT00704847).

OA phenotypes, rather than disease stage, drive structural progression--identification of structural progressors from 2 phase III randomized clinical studies with symptomatic knee OA.

BACKGROUND/PURPOSE The aim of this study was to identify key characteristics of disease progression through investigation of the association of radiographic progression over two years with baseline Joint Space Width (JSW), Kellgren-Lawrence (KL) grade, Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain, Joint Space Narrowing (JSN), and BMI. METHODS Data from 2206 subjects (4390 knees) were combined for this post-hoc analysis of two randomized, double-blind, multi-center, placebo-controlled phase III trials (NCT00486434 and NCT00704847) that evaluated the efficacy and safety of 2-years treatment with oral salmon calcitonin of subjects with painful knee osteoarthritis (OA). RESULTS There was a clear positive and significant correlation between KL grade and WOMAC pain and total WOMAC, albeit the variance in pain measures was from min-to-max for all KL categories, emphasizing the heterogeneity of this patient population and pain perception. 32% of target knees did not progress, and only 51% had changes over minimum significant change (MSC). BMI, KL-Score and WOMAC pain was diagnostic, but only KL-score and pain had prognostic value, albeit pain in a non-linear manner. CONCLUSION These data clearly describe significant associations between KL grade, JSW, pain and BMI in patients with symptomatic knee OA. KL grade, BMI and WOMAC pain were diagnostically associated with OA based on JSW but only KL-score and pain in a non-linier fashion was prognostic. 50% of patients did not progress more than MSC, highlighting the importance for identification of structural progressors and the phenotypes associated with these. These results suggest that disease phenotypes, rather than disease status, are responsible for disease progression.

338 INVESTIGATIONS OF INTER- AND INTRA-INDIVIDUAL RELATIONSHIPS BETWEEN ABSORPTION OF ORAL SALMON CALCITONIN AND A SURROGATE MARKER OF PHARMACODYNAMIC EFFICACY

Purpose: The aim of the study was to compare interand intraindividual bioavailability of 0.8 mg of oral salmon calcitonin (sCT) given once before or after food intake to assess the relationship between bioavailability and levels of the bone resorption biomarker, serum C-terminal telopeptide of collagen type I (CTX-I). Methods: Participants were from two randomized, double-blind, placebo-controlled studies. Study I was a cross-over trial including healthy postmenopausal women receiving a single dose of 0.8 mg of oral sCT or placebo pre-breakfast at 08:00 (n=42), predinner at 17:00 (n=20), or post-dinner at 22:00 (n=19). Blood samples were taken before drug intake, and at 5, 10, 15, 30, 45 minutes, 1, 11⁄2, 2, 21⁄2, 3 hours, and every subsequent hour until 24 hours after dosing. Study II investigated the pharmacokinetics and pharmacodynamics of oral sCT administered on days 1 and 14 to postmenopausal women and men (n=73) suffering from osteoarthritis (OA). In one treatment arm, 0.8 mg of oral sCT was given twice daily with one dose in the morning at 08:00 and one dose given pre-dinner at 17:00 (n=26). On treatment day 1 and day 14, blood samples were taken before drug intake, and at 10, 15, 30, 45 minutes, and 1, 2, and 4 hours post-dose. In both studies the absorption of calcitonin was assessed by plasma sCT concentrations, and bone resorption by the biochemical marker of serum CTX-I. Results: Irrespective of dosing time, a single dose of 0.8 mg oral sCT was rapidly absorbed, reaching Cmax between 15 to 30 minutes in both low and high absorbers. Following Cmax, sCT was eliminated from plasma with a half-life between 9 and 15 minutes. Overall, a single dose of 0.8 mg oral sCT resulted in significant suppression of serum CTX-I compared with placebo irrespective of the level of absorption of sCT. At all three dosing times a significantly higher suppression of sCTX-I was observed in subjects with the highest intestinal absorption of sCT. The effect of increased absorption of sCT was a marked prolongation of serum CTX-1 suppression whereas acute suppression 1 to 2 hours after dosing was unaffected. A high degree of correlation between the level of absorption of sCT and the suppression of serum CTX-I was observed at all three dosing times, i.e. a Pearson correlation coefficient of r = -0.74, r = -0.94, and r = -0.78, was found at the dose times 08:00, 17:00, and 22:00. A weak association of borderline significance was found in the intra-individual absorption of sCT on dosing days 1 and 14 with r = 0.40 and r = 0.38 at the dose times 08:00 and 17:00. As expected, the intra-individual response in serum CTX-I levels was statistically non-significantly associated on dosing days 1 and 14 with r = 0.34 and r = 0.27 at the dose times 08:00 and 17:00. Conclusions: Increased bioavailability of orally administered 0.8 mg sCT is highly correlated with suppression of the bone resorption marker, serum CTX-I. Moreover, the effect is highly controlled with a minimum of individual variability in serum CTX-I. The variable absorption of the drug demonstrates the importance of determining the optimal conditions for ensuring a most beneficial drug uptake. 339