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Christine R West - One of the best experts on this subject based on the ideXlab platform.
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Development of pain therapies targeting nerve growth factor signal transduction and the strategies used to resolve safety issues
Journal of Toxicological Sciences, 2020Co-Authors: Patrice Belanger, Christine R West, Mark T BrownAbstract:Therapeutic agents commonly used in the management of chronic pain have limited effectiveness and may be associated with issues of dependence and tolerability. Thus, a large unmet medical need exists for the development of safe and effective therapeutics for treatment of chronic pain. A novel approach includes identification of intracellular signals involved in the pain transduction pathway, such as nerve growth factor (NGF). Monoclonal antibodies targeting NGF, such as Tanezumab, fulranumab and fasinumab, have been investigated for the treatment of chronic pain conditions. Due to unexpected joint adverse events in clinical studies and concerns about sympathetic nervous system toxicity in animals, these agents were placed on 2 separate partial clinical holds, which were subsequently lifted after rigorous evaluations were conducted to understand how inhibition of NGF impacts safety. To share learnings regarding the rigorous evaluation of clinical and nonclinical safety data which contributed to the removal of these partial clinical holds, this article reviews the rationale for developing agents that target NGF as potential treatments for chronic pain, describes nonclinical and clinical studies of these agents, and describes strategies used to evaluate whether inhibition of NGF has negative effects on joint or sympathetic nervous system safety.
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Tanezumab Reduces Osteoarthritic Hip Pain: Results of a Randomized, Double‐Blind, Placebo‐Controlled Phase III Trial
Arthritis & Rheumatism, 2020Co-Authors: Mark T Brown, Isabelle Davignon, Michael D Smith, Frederick T Murphy, David M Radin, Christine R WestAbstract:Objective To compare the efficacy of Tanezumab versus placebo for reducing pain and improving physical function in patients with osteoarthritis (OA) of the hip. Methods This was a 32-week, randomized, double-blind, placebo-controlled, phase III trial. Patients with baseline Western Ontario and McMaster Universities OA Index (WOMAC) Pain and Physical Function subscale scores of ≥5 and ≥4, respectively, and patient's global assessment of OA as “fair,” “poor,” or “very poor” were treated at baseline and weeks 8 and 16. Coprimary efficacy end points were change from baseline to week 16 in WOMAC Pain and Physical Function subscales and patient's global assessment, analyzed using analysis of covariance. Adverse events (AEs) were monitored throughout. Results Patients (n = 621) were randomized 1:1:1:1 to treatment with intravenous Tanezumab 2.5 mg, 5 mg, or 10 mg or placebo. Each Tanezumab group showed significant improvement for the 3 coprimary end points versus placebo (P ≤ 0.001 for all). AE incidence ranged from 55% to 58% across Tanezumab groups versus 44% for placebo. Safety findings were similar to those previously reported. The Tanezumab OA clinical program was temporarily placed on hold because of AEs leading to joint replacement. Total joint replacements were reported in 8 patients: 1 in the 10 mg, 2 in the 5 mg, 2 in the 2.5 mg, and 3 in the placebo group. A total of 9 joints were replaced (8 hips [7 index joints] and 1 shoulder). Conclusion Our findings indicate that Tanezumab provides superior pain relief and improvement in physical function and patient's global assessment versus placebo in patients with painful hip OA, and is generally well tolerated.
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subcutaneous Tanezumab for osteoarthritis of the hip or knee efficacy and safety results from a 24 week randomised phase iii study with a 24 week follow up period
Annals of the Rheumatic Diseases, 2020Co-Authors: Francis Berenbaum, Mark T Brown, Lars Viktrup, William Carey, F Blanco, Ali Guermazi, Kenji Miki, Takaharu Yamabe, Rod Junor, Christine R WestAbstract:Objective Tanezumab, a nerve growth factor inhibitor, was investigated for osteoarthritis (OA) of the hip or knee in a study with 24-week treatment and 24-week safety follow-up. Methods This double-blind, randomised, phase III study enrolled adults in Europe and Japan with moderate-to-severe OA who had not responded to or could not tolerate standard-of-care analgesics. Patients were randomised to Tanezumab 2.5 mg or 5 mg subcutaneously or matching placebo every 8 weeks (three doses). Co-primary end points were change from baseline to week 24 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and Patient’s Global Assessment of OA (PGA-OA). Joint safety and neurological assessments continued throughout the 48-week study. Results From March 2016 to December 2017, 849 patients were randomised and evaluated (placebo n=282, Tanezumab 2.5 mg n=283, Tanezumab 5 mg n=284). At week 24, there was a statistically significant improvement from baseline for Tanezumab 5 mg compared with placebo for WOMAC Pain (least squares mean difference±SE –0.62±0.18, p=0.0006), WOMAC Physical Function (–0.71±0.17, p Conclusion Tanezumab 5 mg statistically significantly improved pain, physical function and PGA-OA, but Tanezumab 2.5 mg only achieved two co-primary end points. RPOA occurred more frequently with Tanezumab 5 mg than Tanezumab 2.5 mg. TJRs were similarly distributed across all three groups. Trial registration number NCT02709486.
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onset and maintenance of efficacy of subcutaneous Tanezumab in patients with moderate to severe osteoarthritis of the knee or hip a 16 week dose titration study
Seminars in Arthritis and Rheumatism, 2020Co-Authors: Thomas J Schnitzer, Arifulla Khan, Louis Bessette, Isabelle Davignon, Mark T Brown, Glenn C Pixton, William R Prucka, L Tive, Lars Viktrup, Christine R WestAbstract:Abstract Objective To examine the onset and maintenance of efficacy of subcutaneous Tanezumab for pain relief and functional improvement in difficult-to-treat patients with moderate-to-severe osteoarthritis (OA) in a 16-week dose-titration study (NCT02697773). Methods Patients were randomized to placebo (placebo group) or Tanezumab 2.5 mg at baseline and week 8 (Tanezumab 2.5 mg group), or Tanezumab 2.5 mg at baseline and Tanezumab 5 mg at week 8 (Tanezumab 2.5/5 mg group). Analyses included change from baseline in average daily index joint pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and treatment responses (WOMAC Pain improvement criteria and Outcome Measures in Rheumatology-Osteoarthritis Research Society International [OMERACT-OARSI] criteria). Results The 696 patients received placebo (n = 232), Tanezumab 2.5 mg (n = 231), or Tanezumab 2.5/5 mg (n = 233). Average daily index joint pain was statistically significantly improved within the first week (day 3–5) with Tanezumab 2.5 mg compared with placebo. On first post-randomization WOMAC measurement (week 2), both Tanezumab groups had statistically significant improvements compared with placebo in WOMAC Pain and Physical Function, and more Tanezumab-treated patients achieved treatment response criteria (≥30%, ≥50%, or ≥70% reduction in WOMAC Pain or OMERACT-OARSI response). Efficacy was generally maintained throughout the 16-week treatment period. Conclusion Subcutaneous Tanezumab provided statistically significant improvements compared with placebo in average daily index joint pain within the first week and WOMAC Pain and Physical Function (week 2) that were generally maintained throughout the 16-week treatment period. Tanezumab 5 mg provided only modest additional efficacy over Tanezumab 2.5 mg.
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effect of Tanezumab on joint pain physical function and patient global assessment of osteoarthritis among patients with osteoarthritis of the hip or knee a randomized clinical trial
JAMA, 2019Co-Authors: Thomas J Schnitzer, Isabelle Davignon, Mark T Brown, Glenn C Pixton, Lars Viktrup, Christine R West, Richard Easton, Shirley Pang, Dennis J Levinson, Kenneth M VerburgAbstract:Importance Patients with osteoarthritis (OA) may remain symptomatic with traditional OA treatments. Objective To assess 2 subcutaneous Tanezumab dosing regimens for OA. Design, Setting, and Participants A randomized, double-blind, multicenter trial from January 2016 to May 14, 2018 (last patient visit). Patients enrolled were 18 years or older with hip or knee OA, inadequate response to OA analgesics, and no radiographic evidence of prespecified joint safety conditions. Interventions Patients received by subcutaneous administration either Tanezumab, 2.5 mg, at day 1 and week 8 (n = 231); Tanezumab, 2.5 mg at day 1 and 5 mg at week 8 (ie, Tanezumab, 2.5/5 mg; n = 233); or placebo at day 1 and week 8 (n = 232). Main Outcomes and Measures Co–primary end points were change from baseline to week 16 in Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) Pain (0-10, no to extreme pain), WOMAC Physical Function (0-10, no to extreme difficulty), and patient global assessment of osteoarthritis (PGA-OA) (1-5, very good to very poor) scores. Results Among 698 patients randomized, 696 received 1 or more treatment doses (mean [SD] age, 60.8 [9.6] years; 65.1% women), and 582 (83.6%) completed the trial. From baseline to 16 weeks, mean WOMAC Pain scores decreased from 7.1 to 3.6 in the Tanezumab, 2.5 mg, group; 7.3 to 3.6 in the Tanezumab, 2.5/5 mg, group; and 7.3 to 4.4 in the placebo group (least squares mean differences [95% CI] vs placebo were −0.60 [−1.07 to −0.13;P = .01] for Tanezumab, 2.5 mg, and −0.73 [−1.20 to −0.26;P = .002] for Tanezumab, 2.5/5 mg). Mean WOMAC Physical Function scores decreased from 7.2 to 3.7 in the 2.5-mg group, 7.4 to 3.6 in the 2.5/5-mg group, and 7.4 to 4.5 with placebo (differences vs placebo, −0.66 [−1.14 to −0.19;P = .007] for Tanezumab, 2.5 mg, and −0.89 [−1.37 to −0.42;P Conclusions and Relevance Among patients with moderate to severe OA of the knee or hip and inadequate response to standard analgesics, Tanezumab, compared with placebo, resulted in statistically significant improvements in scores assessing pain and physical function, and in PGA-OA, although the improvements were modest and Tanezumab-treated patients had more joint safety events and total joint replacements. Further research is needed to determine the clinical importance of these efficacy and adverse event findings. Trial Registration ClinicalTrials.gov Identifier:NCT02697773
Mark T Brown - One of the best experts on this subject based on the ideXlab platform.
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Development of pain therapies targeting nerve growth factor signal transduction and the strategies used to resolve safety issues
Journal of Toxicological Sciences, 2020Co-Authors: Patrice Belanger, Christine R West, Mark T BrownAbstract:Therapeutic agents commonly used in the management of chronic pain have limited effectiveness and may be associated with issues of dependence and tolerability. Thus, a large unmet medical need exists for the development of safe and effective therapeutics for treatment of chronic pain. A novel approach includes identification of intracellular signals involved in the pain transduction pathway, such as nerve growth factor (NGF). Monoclonal antibodies targeting NGF, such as Tanezumab, fulranumab and fasinumab, have been investigated for the treatment of chronic pain conditions. Due to unexpected joint adverse events in clinical studies and concerns about sympathetic nervous system toxicity in animals, these agents were placed on 2 separate partial clinical holds, which were subsequently lifted after rigorous evaluations were conducted to understand how inhibition of NGF impacts safety. To share learnings regarding the rigorous evaluation of clinical and nonclinical safety data which contributed to the removal of these partial clinical holds, this article reviews the rationale for developing agents that target NGF as potential treatments for chronic pain, describes nonclinical and clinical studies of these agents, and describes strategies used to evaluate whether inhibition of NGF has negative effects on joint or sympathetic nervous system safety.
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Tanezumab Reduces Osteoarthritic Hip Pain: Results of a Randomized, Double‐Blind, Placebo‐Controlled Phase III Trial
Arthritis & Rheumatism, 2020Co-Authors: Mark T Brown, Isabelle Davignon, Michael D Smith, Frederick T Murphy, David M Radin, Christine R WestAbstract:Objective To compare the efficacy of Tanezumab versus placebo for reducing pain and improving physical function in patients with osteoarthritis (OA) of the hip. Methods This was a 32-week, randomized, double-blind, placebo-controlled, phase III trial. Patients with baseline Western Ontario and McMaster Universities OA Index (WOMAC) Pain and Physical Function subscale scores of ≥5 and ≥4, respectively, and patient's global assessment of OA as “fair,” “poor,” or “very poor” were treated at baseline and weeks 8 and 16. Coprimary efficacy end points were change from baseline to week 16 in WOMAC Pain and Physical Function subscales and patient's global assessment, analyzed using analysis of covariance. Adverse events (AEs) were monitored throughout. Results Patients (n = 621) were randomized 1:1:1:1 to treatment with intravenous Tanezumab 2.5 mg, 5 mg, or 10 mg or placebo. Each Tanezumab group showed significant improvement for the 3 coprimary end points versus placebo (P ≤ 0.001 for all). AE incidence ranged from 55% to 58% across Tanezumab groups versus 44% for placebo. Safety findings were similar to those previously reported. The Tanezumab OA clinical program was temporarily placed on hold because of AEs leading to joint replacement. Total joint replacements were reported in 8 patients: 1 in the 10 mg, 2 in the 5 mg, 2 in the 2.5 mg, and 3 in the placebo group. A total of 9 joints were replaced (8 hips [7 index joints] and 1 shoulder). Conclusion Our findings indicate that Tanezumab provides superior pain relief and improvement in physical function and patient's global assessment versus placebo in patients with painful hip OA, and is generally well tolerated.
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subcutaneous Tanezumab for osteoarthritis of the hip or knee efficacy and safety results from a 24 week randomised phase iii study with a 24 week follow up period
Annals of the Rheumatic Diseases, 2020Co-Authors: Francis Berenbaum, Mark T Brown, Lars Viktrup, William Carey, F Blanco, Ali Guermazi, Kenji Miki, Takaharu Yamabe, Rod Junor, Christine R WestAbstract:Objective Tanezumab, a nerve growth factor inhibitor, was investigated for osteoarthritis (OA) of the hip or knee in a study with 24-week treatment and 24-week safety follow-up. Methods This double-blind, randomised, phase III study enrolled adults in Europe and Japan with moderate-to-severe OA who had not responded to or could not tolerate standard-of-care analgesics. Patients were randomised to Tanezumab 2.5 mg or 5 mg subcutaneously or matching placebo every 8 weeks (three doses). Co-primary end points were change from baseline to week 24 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and Patient’s Global Assessment of OA (PGA-OA). Joint safety and neurological assessments continued throughout the 48-week study. Results From March 2016 to December 2017, 849 patients were randomised and evaluated (placebo n=282, Tanezumab 2.5 mg n=283, Tanezumab 5 mg n=284). At week 24, there was a statistically significant improvement from baseline for Tanezumab 5 mg compared with placebo for WOMAC Pain (least squares mean difference±SE –0.62±0.18, p=0.0006), WOMAC Physical Function (–0.71±0.17, p Conclusion Tanezumab 5 mg statistically significantly improved pain, physical function and PGA-OA, but Tanezumab 2.5 mg only achieved two co-primary end points. RPOA occurred more frequently with Tanezumab 5 mg than Tanezumab 2.5 mg. TJRs were similarly distributed across all three groups. Trial registration number NCT02709486.
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onset and maintenance of efficacy of subcutaneous Tanezumab in patients with moderate to severe osteoarthritis of the knee or hip a 16 week dose titration study
Seminars in Arthritis and Rheumatism, 2020Co-Authors: Thomas J Schnitzer, Arifulla Khan, Louis Bessette, Isabelle Davignon, Mark T Brown, Glenn C Pixton, William R Prucka, L Tive, Lars Viktrup, Christine R WestAbstract:Abstract Objective To examine the onset and maintenance of efficacy of subcutaneous Tanezumab for pain relief and functional improvement in difficult-to-treat patients with moderate-to-severe osteoarthritis (OA) in a 16-week dose-titration study (NCT02697773). Methods Patients were randomized to placebo (placebo group) or Tanezumab 2.5 mg at baseline and week 8 (Tanezumab 2.5 mg group), or Tanezumab 2.5 mg at baseline and Tanezumab 5 mg at week 8 (Tanezumab 2.5/5 mg group). Analyses included change from baseline in average daily index joint pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and treatment responses (WOMAC Pain improvement criteria and Outcome Measures in Rheumatology-Osteoarthritis Research Society International [OMERACT-OARSI] criteria). Results The 696 patients received placebo (n = 232), Tanezumab 2.5 mg (n = 231), or Tanezumab 2.5/5 mg (n = 233). Average daily index joint pain was statistically significantly improved within the first week (day 3–5) with Tanezumab 2.5 mg compared with placebo. On first post-randomization WOMAC measurement (week 2), both Tanezumab groups had statistically significant improvements compared with placebo in WOMAC Pain and Physical Function, and more Tanezumab-treated patients achieved treatment response criteria (≥30%, ≥50%, or ≥70% reduction in WOMAC Pain or OMERACT-OARSI response). Efficacy was generally maintained throughout the 16-week treatment period. Conclusion Subcutaneous Tanezumab provided statistically significant improvements compared with placebo in average daily index joint pain within the first week and WOMAC Pain and Physical Function (week 2) that were generally maintained throughout the 16-week treatment period. Tanezumab 5 mg provided only modest additional efficacy over Tanezumab 2.5 mg.
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effect of Tanezumab on joint pain physical function and patient global assessment of osteoarthritis among patients with osteoarthritis of the hip or knee a randomized clinical trial
JAMA, 2019Co-Authors: Thomas J Schnitzer, Isabelle Davignon, Mark T Brown, Glenn C Pixton, Lars Viktrup, Christine R West, Richard Easton, Shirley Pang, Dennis J Levinson, Kenneth M VerburgAbstract:Importance Patients with osteoarthritis (OA) may remain symptomatic with traditional OA treatments. Objective To assess 2 subcutaneous Tanezumab dosing regimens for OA. Design, Setting, and Participants A randomized, double-blind, multicenter trial from January 2016 to May 14, 2018 (last patient visit). Patients enrolled were 18 years or older with hip or knee OA, inadequate response to OA analgesics, and no radiographic evidence of prespecified joint safety conditions. Interventions Patients received by subcutaneous administration either Tanezumab, 2.5 mg, at day 1 and week 8 (n = 231); Tanezumab, 2.5 mg at day 1 and 5 mg at week 8 (ie, Tanezumab, 2.5/5 mg; n = 233); or placebo at day 1 and week 8 (n = 232). Main Outcomes and Measures Co–primary end points were change from baseline to week 16 in Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) Pain (0-10, no to extreme pain), WOMAC Physical Function (0-10, no to extreme difficulty), and patient global assessment of osteoarthritis (PGA-OA) (1-5, very good to very poor) scores. Results Among 698 patients randomized, 696 received 1 or more treatment doses (mean [SD] age, 60.8 [9.6] years; 65.1% women), and 582 (83.6%) completed the trial. From baseline to 16 weeks, mean WOMAC Pain scores decreased from 7.1 to 3.6 in the Tanezumab, 2.5 mg, group; 7.3 to 3.6 in the Tanezumab, 2.5/5 mg, group; and 7.3 to 4.4 in the placebo group (least squares mean differences [95% CI] vs placebo were −0.60 [−1.07 to −0.13;P = .01] for Tanezumab, 2.5 mg, and −0.73 [−1.20 to −0.26;P = .002] for Tanezumab, 2.5/5 mg). Mean WOMAC Physical Function scores decreased from 7.2 to 3.7 in the 2.5-mg group, 7.4 to 3.6 in the 2.5/5-mg group, and 7.4 to 4.5 with placebo (differences vs placebo, −0.66 [−1.14 to −0.19;P = .007] for Tanezumab, 2.5 mg, and −0.89 [−1.37 to −0.42;P Conclusions and Relevance Among patients with moderate to severe OA of the knee or hip and inadequate response to standard analgesics, Tanezumab, compared with placebo, resulted in statistically significant improvements in scores assessing pain and physical function, and in PGA-OA, although the improvements were modest and Tanezumab-treated patients had more joint safety events and total joint replacements. Further research is needed to determine the clinical importance of these efficacy and adverse event findings. Trial Registration ClinicalTrials.gov Identifier:NCT02697773
Michael D Smith - One of the best experts on this subject based on the ideXlab platform.
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Tanezumab Reduces Osteoarthritic Hip Pain: Results of a Randomized, Double‐Blind, Placebo‐Controlled Phase III Trial
Arthritis & Rheumatism, 2020Co-Authors: Mark T Brown, Isabelle Davignon, Michael D Smith, Frederick T Murphy, David M Radin, Christine R WestAbstract:Objective To compare the efficacy of Tanezumab versus placebo for reducing pain and improving physical function in patients with osteoarthritis (OA) of the hip. Methods This was a 32-week, randomized, double-blind, placebo-controlled, phase III trial. Patients with baseline Western Ontario and McMaster Universities OA Index (WOMAC) Pain and Physical Function subscale scores of ≥5 and ≥4, respectively, and patient's global assessment of OA as “fair,” “poor,” or “very poor” were treated at baseline and weeks 8 and 16. Coprimary efficacy end points were change from baseline to week 16 in WOMAC Pain and Physical Function subscales and patient's global assessment, analyzed using analysis of covariance. Adverse events (AEs) were monitored throughout. Results Patients (n = 621) were randomized 1:1:1:1 to treatment with intravenous Tanezumab 2.5 mg, 5 mg, or 10 mg or placebo. Each Tanezumab group showed significant improvement for the 3 coprimary end points versus placebo (P ≤ 0.001 for all). AE incidence ranged from 55% to 58% across Tanezumab groups versus 44% for placebo. Safety findings were similar to those previously reported. The Tanezumab OA clinical program was temporarily placed on hold because of AEs leading to joint replacement. Total joint replacements were reported in 8 patients: 1 in the 10 mg, 2 in the 5 mg, 2 in the 2.5 mg, and 3 in the placebo group. A total of 9 joints were replaced (8 hips [7 index joints] and 1 shoulder). Conclusion Our findings indicate that Tanezumab provides superior pain relief and improvement in physical function and patient's global assessment versus placebo in patients with painful hip OA, and is generally well tolerated.
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Safety and efficacy of subcutaneous Tanezumab in patients with knee or hip osteoarthritis
Journal of Pain Research, 2018Co-Authors: Charles A. Birbara, Mark T Brown, Christine R West, Michael D Smith, Eugene J Dabezies, Aimee M. Burr, Robert J Foutaine, Rosalin H Arends, Kenneth M VerburgAbstract:The objective of this study was to investigate the safety and efficacy of subcutaneous (SC) and intravenous (IV) Tanezumab administration in osteoarthritis (OA) patients. Study 1027 (NCT01089725), a placebo-controlled trial, evaluated the efficacy of SC Tanezumab (ie, 2.5, 5, and 10 mg) and the therapeutic equivalence of 10 mg Tanezumab given subcutaneously versus intravenously every 8 weeks in the symptomatic treatment of OA. Coprimary endpoints were: change from baseline in Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) Pain and Physical Function indices, and Patient's Global Assessment (PGA) of OA. Study 1043 (NCT00994890) was a long-term, noncontrolled safety study of Tanezumab (ie, 2.5, 5, and 10 mg) subcutaneously administered every 8 weeks. Both studies were discontinued prematurely due to a US Food and Drug Administration partial clinical hold. Due to the clinical hold, Study 1027 was underpowered, and no statistical analyses were performed. Mean (standard error [SE]) change from baseline to week 8 in WOMAC Pain in Tanezumab groups ranged from -3.59 (0.26) to -3.89 (0.32), versus -2.74 (0.25) with placebo. Mean (SE) change from baseline to week 8 in WOMAC Physical Function ranged from -3.13 (0.25) to -3.51 (0.28) with Tanezumab and was -2.26 (0.24) with placebo. PGA mean (SE) change from baseline to week 8 ranged from -0.90 (0.11) to -1.08 (0.12) with Tanezumab and was -0.78 (0.10) with placebo. Similar effectiveness was associated with Tanezumab in Study 1043. Few patients in either study (1.4%-5.2%) discontinued due to adverse events. Five patients required total joint replacements in Study 1027 (placebo, n=2 [2.8%]; Tanezumab 2.5 mg, n=3 [4.1%]) and 34 patients in Study 1043 (Tanezumab 2.5 mg, n=11 [4.8%]; Tanezumab 5 mg, n=8 [3.6%]; Tanezumab 10 mg, n=15 [6.6%]). Preliminary results show similar efficacy and safety for both SC and IV administration of Tanezumab based on the direct comparisons reported here and indirect comparisons with published results, confirming pharmacokinetic/pharmacodynamic modeling predictions.
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Tanezumab Reduces Pain in Women with Interstitial Cystitis/Bladder Pain Syndrome and Patients with Nonurological Associated Somatic Syndromes
The Journal of Urology, 2016Co-Authors: J. Curtis Nickel, Michael D Smith, Ian W Mills, Tim J Crook, Anamaria Jorga, Gary A Atkinson, John N KriegerAbstract:Purpose: We performed pooled analyses from 3 small, clinical trials of Tanezumab in patients with urological chronic pelvic pain, including chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis/bladder pain syndrome, to identify patient subpopulations more likely to benefit from Tanezumab treatment.Materials and Methods: Pooled analyses included data from 208 patients with interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome randomized to placebo (104, 65 [62.5%] female) or Tanezumab (104, 63 [60.6%] female) who received 1 dose or more of study medication. Data on Tanezumab were from study A4091010 (interstitial cystitis/bladder pain syndrome) on 200 μg/kg intravenous, study A4091019 (chronic prostatitis/chronic pelvic pain syndrome) on 20 mg intravenous and study A4091035 (interstitial cystitis/bladder pain syndrome) on 20 mg subcutaneous. Primary study end points were evaluated using analysis of covariance with gender, study and baseline pa...
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Tanezumab reduces pain in women with interstitial cystitis bladder pain syndrome and patients with nonurological associated somatic syndromes
The Journal of Urology, 2016Co-Authors: Curtis J Nickel, Michael D Smith, Ian W Mills, Tim J Crook, Anamaria Jorga, Gary A Atkinson, John N KriegerAbstract:Purpose: We performed pooled analyses from 3 small, clinical trials of Tanezumab in patients with urological chronic pelvic pain, including chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis/bladder pain syndrome, to identify patient subpopulations more likely to benefit from Tanezumab treatment.Materials and Methods: Pooled analyses included data from 208 patients with interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome randomized to placebo (104, 65 [62.5%] female) or Tanezumab (104, 63 [60.6%] female) who received 1 dose or more of study medication. Data on Tanezumab were from study A4091010 (interstitial cystitis/bladder pain syndrome) on 200 μg/kg intravenous, study A4091019 (chronic prostatitis/chronic pelvic pain syndrome) on 20 mg intravenous and study A4091035 (interstitial cystitis/bladder pain syndrome) on 20 mg subcutaneous. Primary study end points were evaluated using analysis of covariance with gender, study and baseline pa...
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when is osteonecrosis not osteonecrosis adjudication of reported serious adverse joint events in the Tanezumab clinical development program
Arthritis & Rheumatism, 2016Co-Authors: Marc C Hochberg, L Tive, Christine R West, Michael D Smith, Kenneth M Verburg, E Vignon, Steven B Abramson, David S HungerfordAbstract:Objective Tanezumab, a monoclonal antibody against nerve growth factor, has demonstrated efficacy in clinical trials of chronic pain in osteoarthritis (OA) and chronic low back pain. Unexpected adverse events (AEs) described as osteonecrosis (ON) occurred during Tanezumab development, leading the US Food and Drug Administration to impose a partial clinical hold for all indications except cancer pain. A blinded Adjudication Committee (AC) including orthopedic surgeons, rheumatologists, and an orthopedic pathologist reviewed and adjudicated joint-related AEs in the Tanezumab clinical program. Methods The AC adjudicated all reported cases of ON as well as cases of total joint replacements (TJRs) not reported as ON for which radiographs obtained within 9 months of the surgery were available. The AC prespecified categories for joint safety events including primary ON, worsening OA (rapid progression of OA [RPOA], normal progression of OA, insufficient information to distinguish between rapid and normal progression of OA), other, or insufficient information to distinguish between primary ON and worsening OA or another diagnosis. Results The AC reviewed events in 249 of 386 patients with an investigator-reported AE of ON and/or a TJR. Two events were adjudicated as primary ON, 200 events were adjudicated as worsening OA (68 of which were classified as RPOA), 29 events had another diagnosis, 11 had insufficient information to distinguish primary ON from worsening OA, and 7 did not have committee member consensus. Conclusion Despite initial reports, Tanezumab treatment was not associated with an increase in ON but was associated with an increase in RPOA. Higher doses of Tanezumab, Tanezumab administered with nonsteroidal antiinflammatory drugs, and preexisting subchondral insufficiency fractures were risk factors for RPOA in this cohort.
Kenneth M Verburg - One of the best experts on this subject based on the ideXlab platform.
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effect of Tanezumab on joint pain physical function and patient global assessment of osteoarthritis among patients with osteoarthritis of the hip or knee a randomized clinical trial
JAMA, 2019Co-Authors: Thomas J Schnitzer, Isabelle Davignon, Mark T Brown, Glenn C Pixton, Lars Viktrup, Christine R West, Richard Easton, Shirley Pang, Dennis J Levinson, Kenneth M VerburgAbstract:Importance Patients with osteoarthritis (OA) may remain symptomatic with traditional OA treatments. Objective To assess 2 subcutaneous Tanezumab dosing regimens for OA. Design, Setting, and Participants A randomized, double-blind, multicenter trial from January 2016 to May 14, 2018 (last patient visit). Patients enrolled were 18 years or older with hip or knee OA, inadequate response to OA analgesics, and no radiographic evidence of prespecified joint safety conditions. Interventions Patients received by subcutaneous administration either Tanezumab, 2.5 mg, at day 1 and week 8 (n = 231); Tanezumab, 2.5 mg at day 1 and 5 mg at week 8 (ie, Tanezumab, 2.5/5 mg; n = 233); or placebo at day 1 and week 8 (n = 232). Main Outcomes and Measures Co–primary end points were change from baseline to week 16 in Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) Pain (0-10, no to extreme pain), WOMAC Physical Function (0-10, no to extreme difficulty), and patient global assessment of osteoarthritis (PGA-OA) (1-5, very good to very poor) scores. Results Among 698 patients randomized, 696 received 1 or more treatment doses (mean [SD] age, 60.8 [9.6] years; 65.1% women), and 582 (83.6%) completed the trial. From baseline to 16 weeks, mean WOMAC Pain scores decreased from 7.1 to 3.6 in the Tanezumab, 2.5 mg, group; 7.3 to 3.6 in the Tanezumab, 2.5/5 mg, group; and 7.3 to 4.4 in the placebo group (least squares mean differences [95% CI] vs placebo were −0.60 [−1.07 to −0.13;P = .01] for Tanezumab, 2.5 mg, and −0.73 [−1.20 to −0.26;P = .002] for Tanezumab, 2.5/5 mg). Mean WOMAC Physical Function scores decreased from 7.2 to 3.7 in the 2.5-mg group, 7.4 to 3.6 in the 2.5/5-mg group, and 7.4 to 4.5 with placebo (differences vs placebo, −0.66 [−1.14 to −0.19;P = .007] for Tanezumab, 2.5 mg, and −0.89 [−1.37 to −0.42;P Conclusions and Relevance Among patients with moderate to severe OA of the knee or hip and inadequate response to standard analgesics, Tanezumab, compared with placebo, resulted in statistically significant improvements in scores assessing pain and physical function, and in PGA-OA, although the improvements were modest and Tanezumab-treated patients had more joint safety events and total joint replacements. Further research is needed to determine the clinical importance of these efficacy and adverse event findings. Trial Registration ClinicalTrials.gov Identifier:NCT02697773
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serological biomarker profiles of rapidly progressive osteoarthritis in Tanezumab treated patients
Osteoarthritis and Cartilage, 2019Co-Authors: M.a. Karsdal, Christine R West, Kenneth M Verburg, D S Keller, A C Bayjensen, R.h.g.p. ArendsAbstract:Summary There is a need for efficacious and safe pain treatments for OA (osteoarthritis). The nerve growth factor (NGF) antibody Tanezumab is associated with high efficacy, but when combined with chronic NSAID treatment shows an increased risk of rapidly progressive osteoarthritis (RPOA) in a small group of patients. Aim The aim of this study was to phenotype with biochemical biomarkers of bone, cartilage, soft tissue, synovial metabolism OA patients who are at risk of developing RPOA type-2, for both limited and chronic NSAIDs users. Material and methods The dataset consisted of OA patients participating in Tanezumab trials who used NSAIDs Results By use of two biomarkers at baseline the receiver operating characteristic (ROC) curve area for RPOA type-2 in limited NSAID users was 71%, [CI] (60–83%). OA subjects with this biomarker phenotype had 8-fold higher confidence interval [CI][(2–33)] relative risk of developing RPOA type-2 as compared to OA patients without this phenotype. The AUC of the model in chronic NSAIDs users based on 5 biomarkers was 78%, [CI](69–88%), with 4-fold [CI (2–6)] relative risk of developing RPOA type-2. Conclusion In this hypothesis generating and exploratory study, we identified combinations of biomarkers associated with OA patients who develop RPOA type-2, which may be related to the pathology of the RPOA type-2 joint.
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Safety and efficacy of subcutaneous Tanezumab in patients with knee or hip osteoarthritis
Journal of Pain Research, 2018Co-Authors: Charles A. Birbara, Mark T Brown, Christine R West, Michael D Smith, Eugene J Dabezies, Aimee M. Burr, Robert J Foutaine, Rosalin H Arends, Kenneth M VerburgAbstract:The objective of this study was to investigate the safety and efficacy of subcutaneous (SC) and intravenous (IV) Tanezumab administration in osteoarthritis (OA) patients. Study 1027 (NCT01089725), a placebo-controlled trial, evaluated the efficacy of SC Tanezumab (ie, 2.5, 5, and 10 mg) and the therapeutic equivalence of 10 mg Tanezumab given subcutaneously versus intravenously every 8 weeks in the symptomatic treatment of OA. Coprimary endpoints were: change from baseline in Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) Pain and Physical Function indices, and Patient's Global Assessment (PGA) of OA. Study 1043 (NCT00994890) was a long-term, noncontrolled safety study of Tanezumab (ie, 2.5, 5, and 10 mg) subcutaneously administered every 8 weeks. Both studies were discontinued prematurely due to a US Food and Drug Administration partial clinical hold. Due to the clinical hold, Study 1027 was underpowered, and no statistical analyses were performed. Mean (standard error [SE]) change from baseline to week 8 in WOMAC Pain in Tanezumab groups ranged from -3.59 (0.26) to -3.89 (0.32), versus -2.74 (0.25) with placebo. Mean (SE) change from baseline to week 8 in WOMAC Physical Function ranged from -3.13 (0.25) to -3.51 (0.28) with Tanezumab and was -2.26 (0.24) with placebo. PGA mean (SE) change from baseline to week 8 ranged from -0.90 (0.11) to -1.08 (0.12) with Tanezumab and was -0.78 (0.10) with placebo. Similar effectiveness was associated with Tanezumab in Study 1043. Few patients in either study (1.4%-5.2%) discontinued due to adverse events. Five patients required total joint replacements in Study 1027 (placebo, n=2 [2.8%]; Tanezumab 2.5 mg, n=3 [4.1%]) and 34 patients in Study 1043 (Tanezumab 2.5 mg, n=11 [4.8%]; Tanezumab 5 mg, n=8 [3.6%]; Tanezumab 10 mg, n=15 [6.6%]). Preliminary results show similar efficacy and safety for both SC and IV administration of Tanezumab based on the direct comparisons reported here and indirect comparisons with published results, confirming pharmacokinetic/pharmacodynamic modeling predictions.
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Identification of serological biomarker profiles associated with total joint replacement in osteoarthritis patients
Osteoarthritis and Cartilage, 2017Co-Authors: R.h.g.p. Arends, Christine R West, Kenneth M Verburg, M.a. Karsdal, A.c. Bay-jensen, D S KellerAbstract:Summary Objective Establish a biomarker panel associated with all-cause total joint replacement (TJR) through identification of patients with osteoarthritis (OA) who do or do not progress to TJR and investigate effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Design Serum samples from patients enrolled in phase III trials of Tanezumab who experienced TJR ( n = 174) or matched patients who did not ( n = 321) were analyzed for bone, cartilage, soft tissue, and inflammation markers. Classification and Regression Tree (CART) analysis was used to identify biomarker phenotypes associated with TJR. Results At baseline, biomarker combinations for patients who did not use NSAIDs before starting Tanezumab and used NSAIDs during Tanezumab treatment Conclusions Although validation on other cohorts is necessary, biomarkers may assist in identifying patients who will need TJR. The profiles suggest NSAID use increases importance of bone metabolism in TJR pathology.
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when is osteonecrosis not osteonecrosis adjudication of reported serious adverse joint events in the Tanezumab clinical development program
Arthritis & Rheumatism, 2016Co-Authors: Marc C Hochberg, L Tive, Christine R West, Michael D Smith, Kenneth M Verburg, E Vignon, Steven B Abramson, David S HungerfordAbstract:Objective Tanezumab, a monoclonal antibody against nerve growth factor, has demonstrated efficacy in clinical trials of chronic pain in osteoarthritis (OA) and chronic low back pain. Unexpected adverse events (AEs) described as osteonecrosis (ON) occurred during Tanezumab development, leading the US Food and Drug Administration to impose a partial clinical hold for all indications except cancer pain. A blinded Adjudication Committee (AC) including orthopedic surgeons, rheumatologists, and an orthopedic pathologist reviewed and adjudicated joint-related AEs in the Tanezumab clinical program. Methods The AC adjudicated all reported cases of ON as well as cases of total joint replacements (TJRs) not reported as ON for which radiographs obtained within 9 months of the surgery were available. The AC prespecified categories for joint safety events including primary ON, worsening OA (rapid progression of OA [RPOA], normal progression of OA, insufficient information to distinguish between rapid and normal progression of OA), other, or insufficient information to distinguish between primary ON and worsening OA or another diagnosis. Results The AC reviewed events in 249 of 386 patients with an investigator-reported AE of ON and/or a TJR. Two events were adjudicated as primary ON, 200 events were adjudicated as worsening OA (68 of which were classified as RPOA), 29 events had another diagnosis, 11 had insufficient information to distinguish primary ON from worsening OA, and 7 did not have committee member consensus. Conclusion Despite initial reports, Tanezumab treatment was not associated with an increase in ON but was associated with an increase in RPOA. Higher doses of Tanezumab, Tanezumab administered with nonsteroidal antiinflammatory drugs, and preexisting subchondral insufficiency fractures were risk factors for RPOA in this cohort.
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effects of Tanezumab on satellite glial cells in the cervicothoracic ganglion of cynomolgus monkeys a 26 week toxicity study followed by an 8 week recovery period
Autonomic Neuroscience: Basic and Clinical, 2019Co-Authors: Mark Evans, Patrice Belanger, Mark T. Butt, Thomas Cummings, Jessicalyn Gremminger, Mark ZorbasAbstract:Abstract Tanezumab, a humanized monoclonal anti-NGF antibody, has demonstrated efficacy and safety profiles in Phase III clinical trials of chronic pain. In a 24-week study in non-human primates, morphological observations of sympathetic ganglia showed decreased ganglia volume, decreased neuronal size, and increased glial cell density compared with controls after 3 Tanezumab treatments. Using stereological techniques to quantify glial cells, the present 26-week study found no significant difference after weekly treatments in total cervicothoracic ganglia satellite glial cell number between placebo- or Tanezumab-treated cynomolgus monkeys. These findings suggest that Tanezumab treatment does not result in a true gliosis in sympathetic ganglia.
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Effects of Monoclonal Antibodies against Nerve Growth Factor on Healthy Bone and Joint Tissues in Mice, Rats, and Monkeys: Histopathologic, Biomarker, and Microcomputed Tomographic Assessments:
Toxicologic Pathology, 2018Co-Authors: Kathryn E Gropp, Susan Hurst, David L Shelton, Mark Evans, Cedo M Bagi, Cathy S. Carlson, William J. Reagan, Mark ZorbasAbstract:Tanezumab, an anti-nerve growth factor (NGF) antibody, is in development for management of chronic pain. During clinical trials of anti-NGF antibodies, some patients reported unexpected adverse eve...
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nerve growth factor inhibition with Tanezumab influences weight bearing and subsequent cartilage damage in the rat medial meniscal tear model
Annals of the Rheumatic Diseases, 2017Co-Authors: Timothy P Labranche, Susan Hurst, David L Shelton, Thomas Cummings, Alison M Bendele, Brian C Omura, Kathryn E Gropp, Cedo M Bagi, Lonnie E Grantham, Mark ZorbasAbstract:Objective To investigate whether the effects of nerve growth factor (NGF) inhibition with Tanezumab on rats with medial meniscal tear (MMT) effectively model rapidly progressive osteoarthritis (RPOA) observed in clinical trials. Methods Male Lewis rats underwent MMT surgery and were treated weekly with Tanezumab (0.1, 1 or 10 mg/kg), isotype control or vehicle for 7, 14 or 28 days. Gait deficiency was measured to assess weight-bearing on the operated limb. Joint damage was assessed via histopathology. A second arm, delayed onset of treatment (starting 3–8 weeks after MMT surgery) was used to control for analgesia early in the disease process. A third arm, mid-tibial amputation, evaluated the dependency of the model on weight-bearing. Results Gait deficiency in untreated rats was present 3–7 days after MMT surgery, with a return to normal weight-bearing by days 14–28. Prophylactic treatment with Tanezumab prevented gait deficiency and resulted in more severe cartilage damage. When onset of treatment with Tanezumab was delayed to 3–8 weeks after MMT surgery, there was no increase in cartilage damage. Mid-tibial amputation completely prevented cartilage damage in untreated MMT rats. Conclusions These data suggest that analgesia due to NGF inhibition during the acute injury phase is responsible for increased voluntary weight-bearing and subsequent cartilage damage in the rat MMT model. This model failed to replicate the hypotrophic bone response observed in Tanezumab-treated patients with RPOA.
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morphologic stereologic and morphometric evaluation of the nervous system in young cynomolgus monkeys macaca fascicularis following maternal administration of Tanezumab a monoclonal antibody to nerve growth factor
Toxicological Sciences, 2014Co-Authors: Mark Butt, David L Shelton, Mark Evans, Thomas Cummings, Christopher N Bowman, Satoru Oneda, Mark ZorbasAbstract:Tanezumab, an antibody to nerve growth factor, was administered to pregnant cynomolgus monkeys at 0, 0.5, 4, and 30 mg/kg weekly, beginning gestation day (GD) 20 through parturition (� GD165). Maternal Tanezumab administration appeared to increase stillbirths and infant mortality, but no consistent pattern of gross and/or microscopic change was detected to explain the mortality. Offspring exposed in utero were evaluated at 12 months of age using light microscopy (all tissues), stereology (basal forebrain cholinergic and dorsal root ganglia neurons), and morphometry (sural nerve). Light microscopy revealed decreased number of neurons in sympathetic ganglia (superior mesenteric, cervicothoracic, and ganglia in the thoracic sympathetic trunk). Stereologic assessment indicated an overall decrease in dorsal root ganglion (thoracic) volume and number of neurons in animals exposed to Tanezumab 4 mg/kg (n ¼ 9) and 30 mg/kg (n ¼ 1). At all Tanezumab doses, the sural nerve was small due to decreases in myelinated and unmyelinated axons. Existing axons/ myelin sheaths appeared normal when viewed with light and transmission electron microscopy. There was no indication of Tanezumab-related, active neuron/nerve fiber degeneration/necrosis in any tissue, indicating decreased sensory/ sympathetic neurons and axonal changes were due to hypoplasia or atrophy. These changes in the sensory and sympathetic portions of the peripheral nervous system suggest some degree of developmental neurotoxicity, although what effect, if any, the changes had on normal function and survival was not apparent. Overall, these changes were consistent with published data from rodent studies.
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developmental toxicity assessment of Tanezumab an anti nerve growth factor monoclonal antibody in cynomolgus monkeys macaca fascicularis
Reproductive Toxicology, 2014Co-Authors: Christopher N Bowman, Susan Hurst, David L Shelton, Mark Evans, Mark Butt, Thomas Cummings, Jessicalyn Gremminger, Satoru Oneda, Cris Kamperschroer, Mark ZorbasAbstract:Abstract Two intravenous studies with Tanezumab, an anti-nerve growth factor monoclonal antibody, were conducted in pregnant cynomolgus monkeys to assess potential effects on pregnancy and pre- and postnatal development. Study 1 evaluated infants up to 12 months of age following weekly maternal dosing (0, 0.5, 4 or 30 mg/kg; 18 per group) from gestation day (GD) 20 through parturition. Study 2 evaluated infants 2 months postnatally following weekly maternal dosing (0, 0.5 or 30 mg/kg; 20–21 per group) from GD 20 through 48. In the absence of maternal toxicity, Tanezumab increased stillbirth and post-birth infant mortality/morbidity, decreased infant growth and resulted in microscopic changes in the peripheral sympathetic and sensory nervous system of the infants at all doses. Decreased primary antibody responses and increased incidences in skin changes in infants were also observed. The no-observed-adverse-effect-level for maternal toxicity was 30 mg/kg and
