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Alan D Lopez - One of the best experts on this subject based on the ideXlab platform.

  • tobacco smoking and risk of 36 cardiovascular disease subtypes fatal and non fatal outcomes in a large prospective australian study
    BMC Medicine, 2019
    Co-Authors: Emily Banks, Grace Joshy, Rosemary J Korda, Bill Stavreski, Kay Soga, Sam Egger, Cathy Day, Naomi E Clarke, Sarah Lewington, Alan D Lopez
    Abstract:

    Tobacco smoking is a leading cause of cardiovascular disease (CVD) morbidity and mortality. Evidence on the relation of smoking to different subtypes of CVD, across fatal and non-fatal outcomes, is limited. A prospective study of 188,167 CVD- and cancer-free individuals aged ≥ 45 years from the Australian general population joining the 45 and Up Study from 2006 to 2009, with linked questionnaire, hospitalisation and death data up to the end of 2015. Hazard ratios (HRs) for hospitalisation with or mortality from CVD among current and past versus never smokers were estimated, including according to intensity and recency of smoking, using Cox regression, adjusting for age, sex, urban/rural residence, alcohol consumption, income and education. Population-attributable fractions were estimated. During a mean 7.2 years follow-up (1.35 million person-years), 27,511 (crude rate 20.4/1000 person-years) incident fatal and non-fatal major CVD events occurred, including 4548 (3.2) acute myocardial infarction (AMI), 3991 (2.8) cerebrovascular disease, 3874 (2.7) heart failure and 2311 (1.6) peripheral arterial disease (PAD) events. At baseline, 8% of participants were current and 34% were past smokers. Of the 36 most common specific CVD subtypes, event rates for 29 were increased significantly in current smokers. Adjusted HRs in current versus never smokers were as follows: 1.63 (95%CI 1.56–1.71) for any major CVD, 2.45 (2.22–2.70) for AMI, 2.16 (1.93–2.42) for cerebrovascular disease, 2.23 (1.96–2.53) for heart failure, 5.06 (4.47–5.74) for PAD, 1.50 (1.24–1.80) for Paroxysmal Tachycardia, 1.31 (1.20–1.44) for atrial fibrillation/flutter, 1.41 (1.17–1.70) for pulmonary embolism, 2.79 (2.04–3.80) for AMI mortality, 2.26 (1.65–3.10) for cerebrovascular disease mortality and 2.75 (2.37–3.19) for total CVD mortality. CVD risks were elevated at almost all levels of current smoking intensity examined and increased with smoking intensity, with HRs for total CVD mortality in current versus never smokers of 1.92 (1.11–3.32) and 4.90 (3.79–6.34) for 4–6 and ≥ 25 cigarettes/day, respectively. Risks diminished with quitting, with excess risks largely avoided by quitting before age 45. Over one third of CVD deaths and one quarter of acute coronary syndrome hospitalisations in Australia aged < 65 can be attributed to smoking. Current smoking increases the risk of virtually all CVD subtypes, at least doubling the risk of many, including AMI, cerebrovascular disease and heart failure. Paroxysmal Tachycardia is a newly identified smoking-related risk. Where comparisons are possible, smoking-associated relative risks for fatal and non-fatal outcomes are similar. Quitting reduces the risk substantially. In an established smoking epidemic, with declining and low current smoking prevalence, smoking accounts for a substantial proportion of premature CVD events.

A Difrancesco - One of the best experts on this subject based on the ideXlab platform.

  • a novel wnt pathway inhibitor sm04690 for the treatment of moderate to severe osteoarthritis of the knee results of a 24 week randomized controlled phase 1 study
    Osteoarthritis and Cartilage, 2017
    Co-Authors: Yusuf Yazici, Timothy E Mcalindon, Roy Fleischmann, Allan Gibofsky, Nancy E Lane, A Kivitz, N Skrepnik, E Armas, Christopher J Swearingen, A Difrancesco
    Abstract:

    Summary Objective To assess the safety, pharmacokinetics, and exploratory efficacy of SM04690, a novel Wnt pathway inhibitor, as a potential disease modifying treatment for knee osteoarthritis (OA). Design Subjects with Kellgren-Lawrence grade 2–3 knee OA were randomized in successive dose-escalation cohorts to receive a knee intra-articular (IA) injection with 0.03, 0.07, or 0.23 mg SM04690, or placebo (PBO) (4:1 ratio). Safety, pharmacokinetics, efficacy (WOMAC Total/Function/Pain, Pain VAS, Physician Global Assessment [MDGA], and OMERACT-OARSI Response), OA-related biomarker (P1NP, s-CTX, and cartilage oligomeric matrix protein [COMP]), and radiographic/imaging data were collected at baseline and during 24-week follow-up. Results 61 subjects (SM04690 n  = 50; PBO n  = 11) enrolled. Two dose limiting toxicities (DLTs), increased pain following injection and Paroxysmal Tachycardia (also the single serious AE), were reported in the 0.07 mg cohort. A total of 72 AEs were reported; Sixteen (occurring in eight subjects) were considered related to study medication. There were three discontinuations; one due to an AE (0.03 mg cohort). Bone marrow edema (BME) remained constant for most subjects. No doses were excluded from further study due to DLT criteria. Plasma levels of SM04690 were below the limit of detection at all time points. At Week 24, improvements from baseline were seen in all cohorts for the exploratory measures WOMAC Total, WOMAC Function, WOMAC Pain, MDGA, Pain VAS, and OMERACT-OARSI response. Joint space width (JSW) improvement was observed in the 0.07 mg cohort ( P  = 0.02 vs PBO). Conclusion SM04690 appeared safe and well tolerated, with no evidence of systemic exposure. Exploratory efficacy analyses suggested positive trends for measurements of OA pain, function and disease-modifying osteoarthritis drug (DMOAD) properties. ClinicalTrials.gov registration NCT02095548.

  • sat0428 safety clinical and imaging outcomes of a novel intra articular injectable wnt inhibitor sm04690 in the treatment of osteoarthritis of the knee exploratory analysis of results from a 24 week randomized double blind placebo controlled phase 1 study
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Yusuf Yazici, Timothy E Mcalindon, Roy Fleischmann, Allan Gibofsky, Nancy E Lane, A Kivitz, S Majumdar, Vibeke Strand, C Swearingen, A Difrancesco
    Abstract:

    Background Wnt signaling pathway plays a central role in joint tissue formation and altered Wnt signaling has been associated with cartilage loss in preclinical/clinical studies. 1 SM04690 is an IA small molecule inhibitor of the Wnt pathway. Objectives To report safety, clinical and imaging efficacy results from a 24 week phase 1 randomized, double-blind, placebo-controlled, dose-escalation clinical trial of a small molecule Wnt pathway inhibitor, SM04690, in knee OA. Methods Subjects with symptomatic, radiographic knee OA were randomized to receive a single IA injection in the target knee with either 0.03, 0.07, 0.23 mg SM04690 or vehicle (volume 2mLs) in a 4:1 SM04690 (N=16): vehicle (N=4) ratio. Safety, pharmacokinetics, WOMAC Total, Function, Pain subscales and strict OARSI responses 2 , and radiographs were collected at baseline and during the 24 week trial. Analyses of efficacy outcomes were conducted using a modified Intention-To-Treat (mITT) baseline-adjusted analysis of covariance (ANCOVA) and logistic regression. Results A total of 61 subjects (female N=41, mean age 62.6 yrs, BMI 30.4 kg/m 2 ) were enrolled. Serum levels of SM04690 in all subjects were below limits of detection at all time points. Two dose limiting toxicities (DLTs), Paroxysmal Tachycardia, (also an SAE), and increased pain were reported in 0.07 mg cohort. A total of 72 AEs were reported in 28 (46%) subjects; 16 AEs in 8 subjects were considered possibly or probably related to study drug. At Week 24, improved WOMAC Total Score was seen for both 0.03 mg and 0.07 mg cohorts (change from baseline, -27.4 and -26.6 respectively) compared to placebo (-21.7) (Figure 1). Odds of having an OMERACT-OARSI strict response in 0.07 mg cohort were higher than in the placebo cohort at week 12 (odds ratio=5.7, 95% CI: 1.1, 30.0, P=0.04); odds of an OMERACT-OARSI strict response in 0.03 mg cohort were higher than in the placebo cohort at week 24 (odds ratio=4.8, 95% CI: 0.9, 25.8, P=0.07) (Figure 2). Joint space width by radiographs showed no change from baseline to Week 24 in the 0.03 mg cohort (0.00 mm), an increase in the 0.07 mg cohort (0.49 mm), and a decrease in the 0.23 mg cohort (-0.15 mm), with the placebo cohort exhibiting a larger decrease (-0.33 mm). Compared to placebo, the change in joint space width seen in 0.07 mg cohort was statistically significant (P=0.02). Conclusions These phase 1 data suggested that an intra-articular injection with a novel Wnt inhibitor SM04690 into the knee of OA patients was safe and well-tolerated. SM04690 appeared to potentially improve function, pain and knee joint space width. Additional studies are underway to further evaluate safety, tolerability, efficacy and potential DMOAD properties. References Gelse K. Osteoarthr Cartil 2002; 20(2): 162–71. Pham T, et al. J Rheumatol. 2003;30(7):1648–1654 Disclosure of Interest Y. Yazici Employee of: Samumed, LLC, T. McAlindon Consultant for: Pfizer, Regeneron, Flexion, Fidia, R. Fleischmann Grant/research support from: Samumed, LLC, A. Gibofsky Shareholder of: AbbVie, Amgen, J&J, GSK, Regeneron, Consultant for: AbbVie, Pfizer, Horizon, Iroko, Celgene, Novartis/Sandoz, Speakers bureau: AbbVie, Amgen, Celgene, Pfizer, N. Lane Consultant for: Samumed, LLC, A. Kivitz Grant/research support from: Samumed, LLC, Consultant for: Samumed, LLC, S. Majumdar Consultant for: Samumed, LLC, V. Strand Consultant for: Abbvie, Afferent, Bioventus, Carbylan, Eupraxia, Iroko, Pfizer, Regeneron, SKK, C. Swearingen Employee of: Samumed, LLC, A. DiFrancesco Employee of: Samumed, LLC, J. Tambiah Employee of: Samumed, LLC, J. Hood Employee of: Samumed, LLC, M. Hochberg Consultant for: Bioiberica, EMD Serono, Novartis Pharma AG, Plexxikon, Regeneron, Samumed, Theralogix LLC

Emily Banks - One of the best experts on this subject based on the ideXlab platform.

  • tobacco smoking and risk of 36 cardiovascular disease subtypes fatal and non fatal outcomes in a large prospective australian study
    BMC Medicine, 2019
    Co-Authors: Emily Banks, Grace Joshy, Rosemary J Korda, Bill Stavreski, Kay Soga, Sam Egger, Cathy Day, Naomi E Clarke, Sarah Lewington, Alan D Lopez
    Abstract:

    Tobacco smoking is a leading cause of cardiovascular disease (CVD) morbidity and mortality. Evidence on the relation of smoking to different subtypes of CVD, across fatal and non-fatal outcomes, is limited. A prospective study of 188,167 CVD- and cancer-free individuals aged ≥ 45 years from the Australian general population joining the 45 and Up Study from 2006 to 2009, with linked questionnaire, hospitalisation and death data up to the end of 2015. Hazard ratios (HRs) for hospitalisation with or mortality from CVD among current and past versus never smokers were estimated, including according to intensity and recency of smoking, using Cox regression, adjusting for age, sex, urban/rural residence, alcohol consumption, income and education. Population-attributable fractions were estimated. During a mean 7.2 years follow-up (1.35 million person-years), 27,511 (crude rate 20.4/1000 person-years) incident fatal and non-fatal major CVD events occurred, including 4548 (3.2) acute myocardial infarction (AMI), 3991 (2.8) cerebrovascular disease, 3874 (2.7) heart failure and 2311 (1.6) peripheral arterial disease (PAD) events. At baseline, 8% of participants were current and 34% were past smokers. Of the 36 most common specific CVD subtypes, event rates for 29 were increased significantly in current smokers. Adjusted HRs in current versus never smokers were as follows: 1.63 (95%CI 1.56–1.71) for any major CVD, 2.45 (2.22–2.70) for AMI, 2.16 (1.93–2.42) for cerebrovascular disease, 2.23 (1.96–2.53) for heart failure, 5.06 (4.47–5.74) for PAD, 1.50 (1.24–1.80) for Paroxysmal Tachycardia, 1.31 (1.20–1.44) for atrial fibrillation/flutter, 1.41 (1.17–1.70) for pulmonary embolism, 2.79 (2.04–3.80) for AMI mortality, 2.26 (1.65–3.10) for cerebrovascular disease mortality and 2.75 (2.37–3.19) for total CVD mortality. CVD risks were elevated at almost all levels of current smoking intensity examined and increased with smoking intensity, with HRs for total CVD mortality in current versus never smokers of 1.92 (1.11–3.32) and 4.90 (3.79–6.34) for 4–6 and ≥ 25 cigarettes/day, respectively. Risks diminished with quitting, with excess risks largely avoided by quitting before age 45. Over one third of CVD deaths and one quarter of acute coronary syndrome hospitalisations in Australia aged < 65 can be attributed to smoking. Current smoking increases the risk of virtually all CVD subtypes, at least doubling the risk of many, including AMI, cerebrovascular disease and heart failure. Paroxysmal Tachycardia is a newly identified smoking-related risk. Where comparisons are possible, smoking-associated relative risks for fatal and non-fatal outcomes are similar. Quitting reduces the risk substantially. In an established smoking epidemic, with declining and low current smoking prevalence, smoking accounts for a substantial proportion of premature CVD events.

Yusuf Yazici - One of the best experts on this subject based on the ideXlab platform.

  • a novel wnt pathway inhibitor sm04690 for the treatment of moderate to severe osteoarthritis of the knee results of a 24 week randomized controlled phase 1 study
    Osteoarthritis and Cartilage, 2017
    Co-Authors: Yusuf Yazici, Timothy E Mcalindon, Roy Fleischmann, Allan Gibofsky, Nancy E Lane, A Kivitz, N Skrepnik, E Armas, Christopher J Swearingen, A Difrancesco
    Abstract:

    Summary Objective To assess the safety, pharmacokinetics, and exploratory efficacy of SM04690, a novel Wnt pathway inhibitor, as a potential disease modifying treatment for knee osteoarthritis (OA). Design Subjects with Kellgren-Lawrence grade 2–3 knee OA were randomized in successive dose-escalation cohorts to receive a knee intra-articular (IA) injection with 0.03, 0.07, or 0.23 mg SM04690, or placebo (PBO) (4:1 ratio). Safety, pharmacokinetics, efficacy (WOMAC Total/Function/Pain, Pain VAS, Physician Global Assessment [MDGA], and OMERACT-OARSI Response), OA-related biomarker (P1NP, s-CTX, and cartilage oligomeric matrix protein [COMP]), and radiographic/imaging data were collected at baseline and during 24-week follow-up. Results 61 subjects (SM04690 n  = 50; PBO n  = 11) enrolled. Two dose limiting toxicities (DLTs), increased pain following injection and Paroxysmal Tachycardia (also the single serious AE), were reported in the 0.07 mg cohort. A total of 72 AEs were reported; Sixteen (occurring in eight subjects) were considered related to study medication. There were three discontinuations; one due to an AE (0.03 mg cohort). Bone marrow edema (BME) remained constant for most subjects. No doses were excluded from further study due to DLT criteria. Plasma levels of SM04690 were below the limit of detection at all time points. At Week 24, improvements from baseline were seen in all cohorts for the exploratory measures WOMAC Total, WOMAC Function, WOMAC Pain, MDGA, Pain VAS, and OMERACT-OARSI response. Joint space width (JSW) improvement was observed in the 0.07 mg cohort ( P  = 0.02 vs PBO). Conclusion SM04690 appeared safe and well tolerated, with no evidence of systemic exposure. Exploratory efficacy analyses suggested positive trends for measurements of OA pain, function and disease-modifying osteoarthritis drug (DMOAD) properties. ClinicalTrials.gov registration NCT02095548.

  • sat0428 safety clinical and imaging outcomes of a novel intra articular injectable wnt inhibitor sm04690 in the treatment of osteoarthritis of the knee exploratory analysis of results from a 24 week randomized double blind placebo controlled phase 1 study
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Yusuf Yazici, Timothy E Mcalindon, Roy Fleischmann, Allan Gibofsky, Nancy E Lane, A Kivitz, S Majumdar, Vibeke Strand, C Swearingen, A Difrancesco
    Abstract:

    Background Wnt signaling pathway plays a central role in joint tissue formation and altered Wnt signaling has been associated with cartilage loss in preclinical/clinical studies. 1 SM04690 is an IA small molecule inhibitor of the Wnt pathway. Objectives To report safety, clinical and imaging efficacy results from a 24 week phase 1 randomized, double-blind, placebo-controlled, dose-escalation clinical trial of a small molecule Wnt pathway inhibitor, SM04690, in knee OA. Methods Subjects with symptomatic, radiographic knee OA were randomized to receive a single IA injection in the target knee with either 0.03, 0.07, 0.23 mg SM04690 or vehicle (volume 2mLs) in a 4:1 SM04690 (N=16): vehicle (N=4) ratio. Safety, pharmacokinetics, WOMAC Total, Function, Pain subscales and strict OARSI responses 2 , and radiographs were collected at baseline and during the 24 week trial. Analyses of efficacy outcomes were conducted using a modified Intention-To-Treat (mITT) baseline-adjusted analysis of covariance (ANCOVA) and logistic regression. Results A total of 61 subjects (female N=41, mean age 62.6 yrs, BMI 30.4 kg/m 2 ) were enrolled. Serum levels of SM04690 in all subjects were below limits of detection at all time points. Two dose limiting toxicities (DLTs), Paroxysmal Tachycardia, (also an SAE), and increased pain were reported in 0.07 mg cohort. A total of 72 AEs were reported in 28 (46%) subjects; 16 AEs in 8 subjects were considered possibly or probably related to study drug. At Week 24, improved WOMAC Total Score was seen for both 0.03 mg and 0.07 mg cohorts (change from baseline, -27.4 and -26.6 respectively) compared to placebo (-21.7) (Figure 1). Odds of having an OMERACT-OARSI strict response in 0.07 mg cohort were higher than in the placebo cohort at week 12 (odds ratio=5.7, 95% CI: 1.1, 30.0, P=0.04); odds of an OMERACT-OARSI strict response in 0.03 mg cohort were higher than in the placebo cohort at week 24 (odds ratio=4.8, 95% CI: 0.9, 25.8, P=0.07) (Figure 2). Joint space width by radiographs showed no change from baseline to Week 24 in the 0.03 mg cohort (0.00 mm), an increase in the 0.07 mg cohort (0.49 mm), and a decrease in the 0.23 mg cohort (-0.15 mm), with the placebo cohort exhibiting a larger decrease (-0.33 mm). Compared to placebo, the change in joint space width seen in 0.07 mg cohort was statistically significant (P=0.02). Conclusions These phase 1 data suggested that an intra-articular injection with a novel Wnt inhibitor SM04690 into the knee of OA patients was safe and well-tolerated. SM04690 appeared to potentially improve function, pain and knee joint space width. Additional studies are underway to further evaluate safety, tolerability, efficacy and potential DMOAD properties. References Gelse K. Osteoarthr Cartil 2002; 20(2): 162–71. Pham T, et al. J Rheumatol. 2003;30(7):1648–1654 Disclosure of Interest Y. Yazici Employee of: Samumed, LLC, T. McAlindon Consultant for: Pfizer, Regeneron, Flexion, Fidia, R. Fleischmann Grant/research support from: Samumed, LLC, A. Gibofsky Shareholder of: AbbVie, Amgen, J&J, GSK, Regeneron, Consultant for: AbbVie, Pfizer, Horizon, Iroko, Celgene, Novartis/Sandoz, Speakers bureau: AbbVie, Amgen, Celgene, Pfizer, N. Lane Consultant for: Samumed, LLC, A. Kivitz Grant/research support from: Samumed, LLC, Consultant for: Samumed, LLC, S. Majumdar Consultant for: Samumed, LLC, V. Strand Consultant for: Abbvie, Afferent, Bioventus, Carbylan, Eupraxia, Iroko, Pfizer, Regeneron, SKK, C. Swearingen Employee of: Samumed, LLC, A. DiFrancesco Employee of: Samumed, LLC, J. Tambiah Employee of: Samumed, LLC, J. Hood Employee of: Samumed, LLC, M. Hochberg Consultant for: Bioiberica, EMD Serono, Novartis Pharma AG, Plexxikon, Regeneron, Samumed, Theralogix LLC

Cathy Day - One of the best experts on this subject based on the ideXlab platform.

  • tobacco smoking and risk of 36 cardiovascular disease subtypes fatal and non fatal outcomes in a large prospective australian study
    BMC Medicine, 2019
    Co-Authors: Emily Banks, Grace Joshy, Rosemary J Korda, Bill Stavreski, Kay Soga, Sam Egger, Cathy Day, Naomi E Clarke, Sarah Lewington, Alan D Lopez
    Abstract:

    Tobacco smoking is a leading cause of cardiovascular disease (CVD) morbidity and mortality. Evidence on the relation of smoking to different subtypes of CVD, across fatal and non-fatal outcomes, is limited. A prospective study of 188,167 CVD- and cancer-free individuals aged ≥ 45 years from the Australian general population joining the 45 and Up Study from 2006 to 2009, with linked questionnaire, hospitalisation and death data up to the end of 2015. Hazard ratios (HRs) for hospitalisation with or mortality from CVD among current and past versus never smokers were estimated, including according to intensity and recency of smoking, using Cox regression, adjusting for age, sex, urban/rural residence, alcohol consumption, income and education. Population-attributable fractions were estimated. During a mean 7.2 years follow-up (1.35 million person-years), 27,511 (crude rate 20.4/1000 person-years) incident fatal and non-fatal major CVD events occurred, including 4548 (3.2) acute myocardial infarction (AMI), 3991 (2.8) cerebrovascular disease, 3874 (2.7) heart failure and 2311 (1.6) peripheral arterial disease (PAD) events. At baseline, 8% of participants were current and 34% were past smokers. Of the 36 most common specific CVD subtypes, event rates for 29 were increased significantly in current smokers. Adjusted HRs in current versus never smokers were as follows: 1.63 (95%CI 1.56–1.71) for any major CVD, 2.45 (2.22–2.70) for AMI, 2.16 (1.93–2.42) for cerebrovascular disease, 2.23 (1.96–2.53) for heart failure, 5.06 (4.47–5.74) for PAD, 1.50 (1.24–1.80) for Paroxysmal Tachycardia, 1.31 (1.20–1.44) for atrial fibrillation/flutter, 1.41 (1.17–1.70) for pulmonary embolism, 2.79 (2.04–3.80) for AMI mortality, 2.26 (1.65–3.10) for cerebrovascular disease mortality and 2.75 (2.37–3.19) for total CVD mortality. CVD risks were elevated at almost all levels of current smoking intensity examined and increased with smoking intensity, with HRs for total CVD mortality in current versus never smokers of 1.92 (1.11–3.32) and 4.90 (3.79–6.34) for 4–6 and ≥ 25 cigarettes/day, respectively. Risks diminished with quitting, with excess risks largely avoided by quitting before age 45. Over one third of CVD deaths and one quarter of acute coronary syndrome hospitalisations in Australia aged < 65 can be attributed to smoking. Current smoking increases the risk of virtually all CVD subtypes, at least doubling the risk of many, including AMI, cerebrovascular disease and heart failure. Paroxysmal Tachycardia is a newly identified smoking-related risk. Where comparisons are possible, smoking-associated relative risks for fatal and non-fatal outcomes are similar. Quitting reduces the risk substantially. In an established smoking epidemic, with declining and low current smoking prevalence, smoking accounts for a substantial proportion of premature CVD events.