Sara Freeman

LISBON – A delayed-release (DR) formulation of metformin produced improvements in glycated hemoglobin and fasting plasma glucose levels in a 16-week, dose-ranging, phase 2 trial performed in patients with type 2 diabetes mellitus and chronic kidney disease (CKD).

There was also a reduced incidence of gastrointestinal side effects with metformin DR versus immediate-release (IR) metformin (less than 16% at all doses tested vs. 28%), particularly with regard to nausea (1%-3% vs. 10%).

Sara Freeman/Frontline Medical News

[email protected]

LISBON – A delayed-release (DR) formulation of metformin produced improvements in glycated hemoglobin and fasting plasma glucose levels in a 16-week, dose-ranging, phase 2 trial performed in patients with type 2 diabetes mellitus and chronic kidney disease (CKD).

There was also a reduced incidence of gastrointestinal side effects with metformin DR versus immediate-release (IR) metformin (less than 16% at all doses tested vs. 28%), particularly with regard to nausea (1%-3% vs. 10%).

Sara Freeman/Frontline Medical News

[email protected]

LISBON – A delayed-release (DR) formulation of metformin produced improvements in glycated hemoglobin and fasting plasma glucose levels in a 16-week, dose-ranging, phase 2 trial performed in patients with type 2 diabetes mellitus and chronic kidney disease (CKD).

There was also a reduced incidence of gastrointestinal side effects with metformin DR versus immediate-release (IR) metformin (less than 16% at all doses tested vs. 28%), particularly with regard to nausea (1%-3% vs. 10%).

Sara Freeman/Frontline Medical News

[email protected]

LISBON – The mortality reductions that can be achieved with the sodium–glucose cotransporter 2 inhibitor empagliflozin versus placebo in people with type 2 diabetes remained after investigators controlled for traditional cardiovascular (CV) risk factors over time, analyses from the EMPA-REG OUTCOME trial showed.

The 38% reduction in CV deaths and 32% reduction in all-cause mortality that were observed in the main trial (N Engl J Med. 2015;373:2117-28) were “largely unchanged when adjusted for control of blood pressure, LDL cholesterol, and glycated hemoglobin (HbA_1c) during the study,” David Fitchett, MD, reported at the annual meeting of the European Association for the Study of Diabetes.

Sara Freeman/Frontline Medical News

*This article was updated Sept. 28, 2017.

LISBON – The mortality reductions that can be achieved with the sodium–glucose cotransporter 2 inhibitor empagliflozin versus placebo in people with type 2 diabetes remained after investigators controlled for traditional cardiovascular (CV) risk factors over time, analyses from the EMPA-REG OUTCOME trial showed.

The 38% reduction in CV deaths and 32% reduction in all-cause mortality that were observed in the main trial (N Engl J Med. 2015;373:2117-28) were “largely unchanged when adjusted for control of blood pressure, LDL cholesterol, and glycated hemoglobin (HbA_1c) during the study,” David Fitchett, MD, reported at the annual meeting of the European Association for the Study of Diabetes.

Sara Freeman/Frontline Medical News

*This article was updated Sept. 28, 2017.

LISBON – The mortality reductions that can be achieved with the sodium–glucose cotransporter 2 inhibitor empagliflozin versus placebo in people with type 2 diabetes remained after investigators controlled for traditional cardiovascular (CV) risk factors over time, analyses from the EMPA-REG OUTCOME trial showed.

The 38% reduction in CV deaths and 32% reduction in all-cause mortality that were observed in the main trial (N Engl J Med. 2015;373:2117-28) were “largely unchanged when adjusted for control of blood pressure, LDL cholesterol, and glycated hemoglobin (HbA_1c) during the study,” David Fitchett, MD, reported at the annual meeting of the European Association for the Study of Diabetes.

Sara Freeman/Frontline Medical News

*This article was updated Sept. 28, 2017.

LISBON – Pregnant women with type 1 diabetes mellitus should be offered continuous glucose monitoring, according to the investigators of a prospective, multicenter, randomized, controlled study who found that it improved a number of neonatal outcomes.

In the open-label Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes(CONCEPTT) study, infants born to mothers who had used continuous glucose monitoring (CGM) versus those who had not had a 49% lower chance of being large for gestational age (53% vs. 69%, odds ratio [OR] 0.51, P = .0210) and were 52% less likely to need neonatal intensive care lasting for longer than 24 hours (27% vs. 43%, OR 0.48, P = .0157).

Neonates born to mothers who used CGM during their pregnancy were also less likely to experience hypoglycemia (15% vs. 28%, OR 0.45, P = .0250) and were able to leave the hospital with their mother 1 day earlier (P = .0091) than those born to mothers who did not use CGM.However, these were secondary outcomes of the study, which first looked at how CGM affected the glycemic profile of the mother.“To the best of our knowledge, this is the first trial to demonstrate a benefit of CGM on health outcomes beyond glucose control,” Helen Murphy, MD, one of the CONCEPTT trial’s two principal investigators, said at the annual meeting of the European Association for the Study of Diabetes.

“We believe that the CONCEPTT results support CGM use during pregnancy for all women with type 1 diabetes,” they wrote, adding that the mother’s “time in [glycated hemoglobin, HbA_1C] range might become an important measure in pregnancies with type 1 diabetes.”

Dr. Garg and Dr. Polsky also suggested that endocrine and obstetric medical societies take note and perhaps revise accordingly their guidelines on the use of CGM during pregnancy in diabetic women.

CONCEPTT involved 325 women with type 1 diabetes; 215 were pregnant at the time of enrollment, and 110 were planning on becoming pregnant in the near future.

Co-principal investigator Denice Feig, MD, of Sinai Health System in Toronto, explained that women were eligible for inclusion in the trial if they had type 1 diabetes for at least 1 year, were aged between 18 and 40 years, and had been using daily insulin delivered by either an insulin pump or multiple daily injections (MDI). At enrollment, the participants’ insulin regimen had to been stable for at least 4 weeks before randomization to CGM with capillary glucose monitoring or capillary glucose monitoring alone and their glycemic control had to be suboptimal.

Two groups of women were studied: a “pre-pregnancy group” of women who were planning on pregnancy and wanted to optimize their glycemic control before conception, and a “pregnancy group” of women in their first trimester (less than 14 weeks’ gestation) who were due to have a live, singleton birth as confirmed by ultrasound.

The primary outcome of the trial was the change in HbA_1C from baseline to 34 weeks, with pre-specified secondary outcomes of various CGM measures, neoneonatal outcomes, and patient-reported outcomes.

Pregnant women using CGM had lower HbA_1C levels during the trial than women who did not have CGM monitoring, although the difference was small (–0.19%, P = .0207).

The use of CGM was associated with more time spent in target HbA1_C range (68% of women using CMG vs. 61% of those not using CGM, P = .0034), with less time being hyperglycemic (27% vs. 37%, P = .0279) and comparable rates of hypoglycemia (17 vs. 21 episodes) and time spent being hypoglycemic (2% vs. 4%, P = .10).“The CGM effects were very comparable among insulin pump and MDI users and across 31 international sites,” Dr. Murphy summarized, although she noted that there was no consistent benefit of using CGM seen in women who were planning a pregnancy. Dr. Feig noted that the strengths of the study were the large sample size and that CGM was used continuously from the first trimester until delivery. Women using both pumps and MDI were included at multiple centers and countries, and HbA1_C was centrally assessed, with detailed CGM measures used in an exclusively type 1 diabetes population.“Of note, one needed to treat only six women with CGM to prevent one episode of large for gestational age,” Dr. Feig reported. “One needed to treat only eight women to prevent one neonatal hypoglycemia, and six women to prevent one NICU [neonatal intensive care unit] admission over 24 hours.”

There were some limitations, of course, including: around 20% of women had missing data on their HbA_1C level; women using CGM also made more unscheduled visits to their health care providers although there are no data on the frequency of self-monitoring of blood glucose or frequency of insulin bolus dosing; and the study was open label.

In her independent précis of the trial, Dr. Mathiesen, professor of endocrinology and chief physician managing pregnant women with diabetes at the Rigshospitalet University Hospital in Copenhagen, noted that there were some other downsides to using CGM in the study.

The CONCEPTT study was funded by the Juvenile Diabetes Research Foundation, the Canadian Clinical Trial Network, the National Institute for Health Research, the Center for Mother, Infant, and Child Research, and the Jaeb Center for Health Research. Medtronic also supported the study by providing the CGM sensors and systems at a reduced cost. Dr. Feig declared she had no competing interests. Dr. Murphy disclosed sitting on an advisory board for Medtronic and receiving personal fees from Novo Nordisk and Roche, unrelated to the current study. Dr. Mathiesen was the invited EASD independent commentator for the trial and did not give any disclosures. Dr. Garg has received advisory board consulting fees and research grants from Medtronic and several other pharmaceutical companies specializing in diabetes care. Dr. Polsky has received research funding from DexCom for diabetes device use in patients with diabetes paid directly to the University of Denver.

LISBON – Pregnant women with type 1 diabetes mellitus should be offered continuous glucose monitoring, according to the investigators of a prospective, multicenter, randomized, controlled study who found that it improved a number of neonatal outcomes.

In the open-label Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes(CONCEPTT) study, infants born to mothers who had used continuous glucose monitoring (CGM) versus those who had not had a 49% lower chance of being large for gestational age (53% vs. 69%, odds ratio [OR] 0.51, P = .0210) and were 52% less likely to need neonatal intensive care lasting for longer than 24 hours (27% vs. 43%, OR 0.48, P = .0157).

Neonates born to mothers who used CGM during their pregnancy were also less likely to experience hypoglycemia (15% vs. 28%, OR 0.45, P = .0250) and were able to leave the hospital with their mother 1 day earlier (P = .0091) than those born to mothers who did not use CGM.However, these were secondary outcomes of the study, which first looked at how CGM affected the glycemic profile of the mother.“To the best of our knowledge, this is the first trial to demonstrate a benefit of CGM on health outcomes beyond glucose control,” Helen Murphy, MD, one of the CONCEPTT trial’s two principal investigators, said at the annual meeting of the European Association for the Study of Diabetes.

“We believe that the CONCEPTT results support CGM use during pregnancy for all women with type 1 diabetes,” they wrote, adding that the mother’s “time in [glycated hemoglobin, HbA_1C] range might become an important measure in pregnancies with type 1 diabetes.”

Dr. Garg and Dr. Polsky also suggested that endocrine and obstetric medical societies take note and perhaps revise accordingly their guidelines on the use of CGM during pregnancy in diabetic women.

CONCEPTT involved 325 women with type 1 diabetes; 215 were pregnant at the time of enrollment, and 110 were planning on becoming pregnant in the near future.

Co-principal investigator Denice Feig, MD, of Sinai Health System in Toronto, explained that women were eligible for inclusion in the trial if they had type 1 diabetes for at least 1 year, were aged between 18 and 40 years, and had been using daily insulin delivered by either an insulin pump or multiple daily injections (MDI). At enrollment, the participants’ insulin regimen had to been stable for at least 4 weeks before randomization to CGM with capillary glucose monitoring or capillary glucose monitoring alone and their glycemic control had to be suboptimal.

Two groups of women were studied: a “pre-pregnancy group” of women who were planning on pregnancy and wanted to optimize their glycemic control before conception, and a “pregnancy group” of women in their first trimester (less than 14 weeks’ gestation) who were due to have a live, singleton birth as confirmed by ultrasound.

The primary outcome of the trial was the change in HbA_1C from baseline to 34 weeks, with pre-specified secondary outcomes of various CGM measures, neoneonatal outcomes, and patient-reported outcomes.

Pregnant women using CGM had lower HbA_1C levels during the trial than women who did not have CGM monitoring, although the difference was small (–0.19%, P = .0207).

The use of CGM was associated with more time spent in target HbA1_C range (68% of women using CMG vs. 61% of those not using CGM, P = .0034), with less time being hyperglycemic (27% vs. 37%, P = .0279) and comparable rates of hypoglycemia (17 vs. 21 episodes) and time spent being hypoglycemic (2% vs. 4%, P = .10).“The CGM effects were very comparable among insulin pump and MDI users and across 31 international sites,” Dr. Murphy summarized, although she noted that there was no consistent benefit of using CGM seen in women who were planning a pregnancy. Dr. Feig noted that the strengths of the study were the large sample size and that CGM was used continuously from the first trimester until delivery. Women using both pumps and MDI were included at multiple centers and countries, and HbA1_C was centrally assessed, with detailed CGM measures used in an exclusively type 1 diabetes population.“Of note, one needed to treat only six women with CGM to prevent one episode of large for gestational age,” Dr. Feig reported. “One needed to treat only eight women to prevent one neonatal hypoglycemia, and six women to prevent one NICU [neonatal intensive care unit] admission over 24 hours.”

There were some limitations, of course, including: around 20% of women had missing data on their HbA_1C level; women using CGM also made more unscheduled visits to their health care providers although there are no data on the frequency of self-monitoring of blood glucose or frequency of insulin bolus dosing; and the study was open label.

In her independent précis of the trial, Dr. Mathiesen, professor of endocrinology and chief physician managing pregnant women with diabetes at the Rigshospitalet University Hospital in Copenhagen, noted that there were some other downsides to using CGM in the study.

The CONCEPTT study was funded by the Juvenile Diabetes Research Foundation, the Canadian Clinical Trial Network, the National Institute for Health Research, the Center for Mother, Infant, and Child Research, and the Jaeb Center for Health Research. Medtronic also supported the study by providing the CGM sensors and systems at a reduced cost. Dr. Feig declared she had no competing interests. Dr. Murphy disclosed sitting on an advisory board for Medtronic and receiving personal fees from Novo Nordisk and Roche, unrelated to the current study. Dr. Mathiesen was the invited EASD independent commentator for the trial and did not give any disclosures. Dr. Garg has received advisory board consulting fees and research grants from Medtronic and several other pharmaceutical companies specializing in diabetes care. Dr. Polsky has received research funding from DexCom for diabetes device use in patients with diabetes paid directly to the University of Denver.

LISBON – Pregnant women with type 1 diabetes mellitus should be offered continuous glucose monitoring, according to the investigators of a prospective, multicenter, randomized, controlled study who found that it improved a number of neonatal outcomes.

In the open-label Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes(CONCEPTT) study, infants born to mothers who had used continuous glucose monitoring (CGM) versus those who had not had a 49% lower chance of being large for gestational age (53% vs. 69%, odds ratio [OR] 0.51, P = .0210) and were 52% less likely to need neonatal intensive care lasting for longer than 24 hours (27% vs. 43%, OR 0.48, P = .0157).

Neonates born to mothers who used CGM during their pregnancy were also less likely to experience hypoglycemia (15% vs. 28%, OR 0.45, P = .0250) and were able to leave the hospital with their mother 1 day earlier (P = .0091) than those born to mothers who did not use CGM.However, these were secondary outcomes of the study, which first looked at how CGM affected the glycemic profile of the mother.“To the best of our knowledge, this is the first trial to demonstrate a benefit of CGM on health outcomes beyond glucose control,” Helen Murphy, MD, one of the CONCEPTT trial’s two principal investigators, said at the annual meeting of the European Association for the Study of Diabetes.

“We believe that the CONCEPTT results support CGM use during pregnancy for all women with type 1 diabetes,” they wrote, adding that the mother’s “time in [glycated hemoglobin, HbA_1C] range might become an important measure in pregnancies with type 1 diabetes.”

Dr. Garg and Dr. Polsky also suggested that endocrine and obstetric medical societies take note and perhaps revise accordingly their guidelines on the use of CGM during pregnancy in diabetic women.

CONCEPTT involved 325 women with type 1 diabetes; 215 were pregnant at the time of enrollment, and 110 were planning on becoming pregnant in the near future.

Co-principal investigator Denice Feig, MD, of Sinai Health System in Toronto, explained that women were eligible for inclusion in the trial if they had type 1 diabetes for at least 1 year, were aged between 18 and 40 years, and had been using daily insulin delivered by either an insulin pump or multiple daily injections (MDI). At enrollment, the participants’ insulin regimen had to been stable for at least 4 weeks before randomization to CGM with capillary glucose monitoring or capillary glucose monitoring alone and their glycemic control had to be suboptimal.

Two groups of women were studied: a “pre-pregnancy group” of women who were planning on pregnancy and wanted to optimize their glycemic control before conception, and a “pregnancy group” of women in their first trimester (less than 14 weeks’ gestation) who were due to have a live, singleton birth as confirmed by ultrasound.

The primary outcome of the trial was the change in HbA_1C from baseline to 34 weeks, with pre-specified secondary outcomes of various CGM measures, neoneonatal outcomes, and patient-reported outcomes.

Pregnant women using CGM had lower HbA_1C levels during the trial than women who did not have CGM monitoring, although the difference was small (–0.19%, P = .0207).

The use of CGM was associated with more time spent in target HbA1_C range (68% of women using CMG vs. 61% of those not using CGM, P = .0034), with less time being hyperglycemic (27% vs. 37%, P = .0279) and comparable rates of hypoglycemia (17 vs. 21 episodes) and time spent being hypoglycemic (2% vs. 4%, P = .10).“The CGM effects were very comparable among insulin pump and MDI users and across 31 international sites,” Dr. Murphy summarized, although she noted that there was no consistent benefit of using CGM seen in women who were planning a pregnancy. Dr. Feig noted that the strengths of the study were the large sample size and that CGM was used continuously from the first trimester until delivery. Women using both pumps and MDI were included at multiple centers and countries, and HbA1_C was centrally assessed, with detailed CGM measures used in an exclusively type 1 diabetes population.“Of note, one needed to treat only six women with CGM to prevent one episode of large for gestational age,” Dr. Feig reported. “One needed to treat only eight women to prevent one neonatal hypoglycemia, and six women to prevent one NICU [neonatal intensive care unit] admission over 24 hours.”

There were some limitations, of course, including: around 20% of women had missing data on their HbA_1C level; women using CGM also made more unscheduled visits to their health care providers although there are no data on the frequency of self-monitoring of blood glucose or frequency of insulin bolus dosing; and the study was open label.

In her independent précis of the trial, Dr. Mathiesen, professor of endocrinology and chief physician managing pregnant women with diabetes at the Rigshospitalet University Hospital in Copenhagen, noted that there were some other downsides to using CGM in the study.

The CONCEPTT study was funded by the Juvenile Diabetes Research Foundation, the Canadian Clinical Trial Network, the National Institute for Health Research, the Center for Mother, Infant, and Child Research, and the Jaeb Center for Health Research. Medtronic also supported the study by providing the CGM sensors and systems at a reduced cost. Dr. Feig declared she had no competing interests. Dr. Murphy disclosed sitting on an advisory board for Medtronic and receiving personal fees from Novo Nordisk and Roche, unrelated to the current study. Dr. Mathiesen was the invited EASD independent commentator for the trial and did not give any disclosures. Dr. Garg has received advisory board consulting fees and research grants from Medtronic and several other pharmaceutical companies specializing in diabetes care. Dr. Polsky has received research funding from DexCom for diabetes device use in patients with diabetes paid directly to the University of Denver.

LISBON – Additional data released from the ODYSSEY DM clinical trials program show that the PCSK9 inhibitor alirocumab lowers lipid levels works just as well in patients with type 1 diabetes as it does in those with type 2 diabetes, plus it may have an edge over using older, add-on lipid-lowering therapies such as fibrates.

The findings were presented at the annual meeting of the European Association for the Study of Diabetes.

In one study involving 76 insulin-treated patients with T1DM, treatment with alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) reduced low-density lipoprotein cholesterol levels by a mean of 47.8% versus placebo from baseline to week 24 (P less than .0001), the primary endpoint of the study.

Furthermore, in a separate study involving 413 patients with T2DM with mixed hyperlipidemia, alirocumab decreased levels of non–high-density lipoprotein cholesterol (non-HDL-C) by 33.3% compared with fenofibrate (P less than .0001).

These new results from the ODYSSEY DM-INSULIN and ODYSSEY DM-DYSLIPIDEMIA trials, respectively, add to those already presented this year at the annual scientific sessions of the American Diabetes Association.

Sara Freeman/Frontline Medical News

Efficacy unaffected by co-administration with insulin use

Helen Colhoun, MD, AXA chair of medical informatics and life course epidemiology at the University of Edinburgh, presented the updated findings of the ODYSSEY DM-INSULIN study, which recruited 517 patients, the majority (n = 441) of whom had T2DM.

In the study, alirocumab, a monoclonal antibody that targets proprotein convertase subtilisin–kexin type 9 (PCSK9), was compared with placebo in patients with established atherosclerotic cardiovascular disease or other cardiovascular risk factors, and in whom LDL-C was 70 mg/dL (1.8 mmol/L) or higher.

The percentage change in LDL-C from baseline to week 24 was similarly reduced in T1DM and T2DM, Dr. Colhoun observed, and commensurate with data seen across the ODYSSEY phase III trials program. Of note, the majority of type 2 (80%) and type 1 (63%) patients did not need the dose of alirocumab to be increased and remained on the starting dose of 75 mg every 2 weeks.

Sara Freeman/Frontline Medical News

Alirocumab beats fenofibrate as add-on lipid-lowering therapy

Presenting the ODYSSEY DM-DYSLIPIDEMIA data, which involved patients with T2DM, Dr. Del Prato observed that alirocumab was “generally well tolerated” and did not affect HbA_1c or fasting plasma glucose levels.

He presented new data from a prespecified analysis that looked at the subgroup of 72 patients who were randomized into an alirocumab (n = 48) or fenofibrate (n = 24) as usual care arm. Dr. Del Prato reminded the audience that the choice of usual treatment was decided by the study investigators prior to randomizing patients, and that other usual care treatments included in the study were ezetimibe, omega-3 fatty acids, nicotinic acid, or no lipid-lowering therapy.

As in the insulin study, the majority (63.6%) of patients treated with alirocumab remained on the starting dose of 75 mg every 2 weeks and did not need up-titration.

Changes in the percentage of non-HDL-C from baseline over time were greater in the alirocumab group than in the usual care group, both in the overall population and in the fenofibrate subanalysis.

Higher percentages of patients treated with alirocumab achieved non-HDL-C compared with those given usual care (66.9% vs. 17.7% in overall population, 65.2% vs. 10.1% in fenofibrate sub-analysis) and LDL-C (70.8% vs. 16.3% and 71.9% vs. 17.5%, respectively) goals at week 24.

Alirocumab also significantly reduced levels of Apo B, total cholesterol, and Lp(a) versus the overall usual care group and also versus the fenofibrate usual care group, Dr. Del Prato said.

Taking the two studies together, he concluded: “These data support alirocumab as a treatment option in people with diabetes mellitus and hypercholesterolemia despite maximally tolerated statins,” Dr. Del Prato said.
 

Will the lipid-benefits translate into improved cardiovascular outcomes?

The question now is whether the lipid-lowering effects of alirocumab in patients with diabetes will translate into improved cardiovascular outcomes in patients with diabetes.

The results of the ODYSSEY OUTCOMES trial, which is evaluating cardiovascular outcomes during treatment with alirocumab after an acute coronary syndrome, are expected next year. While the trial is not being conducted specifically in patients with diabetes, it is expected that there will be subpopulations of T1DM and T2DM patients included.

Cardiovascular outcomes data on the PCSK9 inhibitor, evolocumab (Repatha, Amgen) in the FOURIER trial were published in March (N Engl J Med 2017;376:1713-22) and provide some evidence that a reduction in major cardiovascular events may be possible with these agents.

Providing independent comment on the study, Angelo Avogaro, MD, of the University of Padova, Italy, said that the additional LDL-C lowering effect of alirocumab on top of statins could theoretically halve the projected 10-year risk of cardiovascular disease using data from the two ODYSSEY studies and the UKPDS Risk Engine. Using a baseline 10-year cardiovascular risk of around 26%-28%, this could be reduced to 11%-13%, he suggested.

Of note, Dr. Avogaro said, was that, at baseline, not all patients were on high intensity statins, the majority received moderate doses, with a good number of patients taking none or who were intolerant to statins included. “This, I like,” he observed.

A reassuring point was that there was no signal of having a detrimental effect on neurocognitive dysfunction, Dr. Avogaro observed, which concurs with recent data published on evolocumab (N Engl J Med 2017; 377:633-43).

Nevertheless, longer-follow-up is needed to examine adverse effects, “especially in those insulin-treated patients experiencing severe hypoglycemic reactions.”

The ODYSSEY DM studies were funded by Sanofi and Regeneron Pharmaceuticals.

Dr. Colhoun has received research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Pfizer, Regeneron Pharmaceuticals, Roche Pharmaceuticals, and Sanofi. She has also been a consultant for Eli Lilly, Regeneron Pharmaceuticals, and Sanofi.

Dr. Del Prato has received research funding from AstraZeneca, Boehringer Ingelheim, Novartis, Merck Sharpe & Dohme, and Novo Nordisk. He is a consultant for or has received honoraria from the preceding companies, as well as from Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, Laboratoires Servier, Sanofi-Aventis, and Takeda Pharmaceuticals.

LISBON – Additional data released from the ODYSSEY DM clinical trials program show that the PCSK9 inhibitor alirocumab lowers lipid levels works just as well in patients with type 1 diabetes as it does in those with type 2 diabetes, plus it may have an edge over using older, add-on lipid-lowering therapies such as fibrates.

The findings were presented at the annual meeting of the European Association for the Study of Diabetes.

In one study involving 76 insulin-treated patients with T1DM, treatment with alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) reduced low-density lipoprotein cholesterol levels by a mean of 47.8% versus placebo from baseline to week 24 (P less than .0001), the primary endpoint of the study.

Furthermore, in a separate study involving 413 patients with T2DM with mixed hyperlipidemia, alirocumab decreased levels of non–high-density lipoprotein cholesterol (non-HDL-C) by 33.3% compared with fenofibrate (P less than .0001).

These new results from the ODYSSEY DM-INSULIN and ODYSSEY DM-DYSLIPIDEMIA trials, respectively, add to those already presented this year at the annual scientific sessions of the American Diabetes Association.

Sara Freeman/Frontline Medical News

Efficacy unaffected by co-administration with insulin use

Helen Colhoun, MD, AXA chair of medical informatics and life course epidemiology at the University of Edinburgh, presented the updated findings of the ODYSSEY DM-INSULIN study, which recruited 517 patients, the majority (n = 441) of whom had T2DM.

In the study, alirocumab, a monoclonal antibody that targets proprotein convertase subtilisin–kexin type 9 (PCSK9), was compared with placebo in patients with established atherosclerotic cardiovascular disease or other cardiovascular risk factors, and in whom LDL-C was 70 mg/dL (1.8 mmol/L) or higher.

The percentage change in LDL-C from baseline to week 24 was similarly reduced in T1DM and T2DM, Dr. Colhoun observed, and commensurate with data seen across the ODYSSEY phase III trials program. Of note, the majority of type 2 (80%) and type 1 (63%) patients did not need the dose of alirocumab to be increased and remained on the starting dose of 75 mg every 2 weeks.

Sara Freeman/Frontline Medical News

Alirocumab beats fenofibrate as add-on lipid-lowering therapy

Presenting the ODYSSEY DM-DYSLIPIDEMIA data, which involved patients with T2DM, Dr. Del Prato observed that alirocumab was “generally well tolerated” and did not affect HbA_1c or fasting plasma glucose levels.

He presented new data from a prespecified analysis that looked at the subgroup of 72 patients who were randomized into an alirocumab (n = 48) or fenofibrate (n = 24) as usual care arm. Dr. Del Prato reminded the audience that the choice of usual treatment was decided by the study investigators prior to randomizing patients, and that other usual care treatments included in the study were ezetimibe, omega-3 fatty acids, nicotinic acid, or no lipid-lowering therapy.

As in the insulin study, the majority (63.6%) of patients treated with alirocumab remained on the starting dose of 75 mg every 2 weeks and did not need up-titration.

Changes in the percentage of non-HDL-C from baseline over time were greater in the alirocumab group than in the usual care group, both in the overall population and in the fenofibrate subanalysis.

Higher percentages of patients treated with alirocumab achieved non-HDL-C compared with those given usual care (66.9% vs. 17.7% in overall population, 65.2% vs. 10.1% in fenofibrate sub-analysis) and LDL-C (70.8% vs. 16.3% and 71.9% vs. 17.5%, respectively) goals at week 24.

Alirocumab also significantly reduced levels of Apo B, total cholesterol, and Lp(a) versus the overall usual care group and also versus the fenofibrate usual care group, Dr. Del Prato said.

Taking the two studies together, he concluded: “These data support alirocumab as a treatment option in people with diabetes mellitus and hypercholesterolemia despite maximally tolerated statins,” Dr. Del Prato said.
 

Will the lipid-benefits translate into improved cardiovascular outcomes?

The question now is whether the lipid-lowering effects of alirocumab in patients with diabetes will translate into improved cardiovascular outcomes in patients with diabetes.

The results of the ODYSSEY OUTCOMES trial, which is evaluating cardiovascular outcomes during treatment with alirocumab after an acute coronary syndrome, are expected next year. While the trial is not being conducted specifically in patients with diabetes, it is expected that there will be subpopulations of T1DM and T2DM patients included.

Cardiovascular outcomes data on the PCSK9 inhibitor, evolocumab (Repatha, Amgen) in the FOURIER trial were published in March (N Engl J Med 2017;376:1713-22) and provide some evidence that a reduction in major cardiovascular events may be possible with these agents.

Providing independent comment on the study, Angelo Avogaro, MD, of the University of Padova, Italy, said that the additional LDL-C lowering effect of alirocumab on top of statins could theoretically halve the projected 10-year risk of cardiovascular disease using data from the two ODYSSEY studies and the UKPDS Risk Engine. Using a baseline 10-year cardiovascular risk of around 26%-28%, this could be reduced to 11%-13%, he suggested.

Of note, Dr. Avogaro said, was that, at baseline, not all patients were on high intensity statins, the majority received moderate doses, with a good number of patients taking none or who were intolerant to statins included. “This, I like,” he observed.

A reassuring point was that there was no signal of having a detrimental effect on neurocognitive dysfunction, Dr. Avogaro observed, which concurs with recent data published on evolocumab (N Engl J Med 2017; 377:633-43).

Nevertheless, longer-follow-up is needed to examine adverse effects, “especially in those insulin-treated patients experiencing severe hypoglycemic reactions.”

The ODYSSEY DM studies were funded by Sanofi and Regeneron Pharmaceuticals.

Dr. Colhoun has received research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Pfizer, Regeneron Pharmaceuticals, Roche Pharmaceuticals, and Sanofi. She has also been a consultant for Eli Lilly, Regeneron Pharmaceuticals, and Sanofi.

Dr. Del Prato has received research funding from AstraZeneca, Boehringer Ingelheim, Novartis, Merck Sharpe & Dohme, and Novo Nordisk. He is a consultant for or has received honoraria from the preceding companies, as well as from Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, Laboratoires Servier, Sanofi-Aventis, and Takeda Pharmaceuticals.

LISBON – Additional data released from the ODYSSEY DM clinical trials program show that the PCSK9 inhibitor alirocumab lowers lipid levels works just as well in patients with type 1 diabetes as it does in those with type 2 diabetes, plus it may have an edge over using older, add-on lipid-lowering therapies such as fibrates.

The findings were presented at the annual meeting of the European Association for the Study of Diabetes.

In one study involving 76 insulin-treated patients with T1DM, treatment with alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) reduced low-density lipoprotein cholesterol levels by a mean of 47.8% versus placebo from baseline to week 24 (P less than .0001), the primary endpoint of the study.

Furthermore, in a separate study involving 413 patients with T2DM with mixed hyperlipidemia, alirocumab decreased levels of non–high-density lipoprotein cholesterol (non-HDL-C) by 33.3% compared with fenofibrate (P less than .0001).

These new results from the ODYSSEY DM-INSULIN and ODYSSEY DM-DYSLIPIDEMIA trials, respectively, add to those already presented this year at the annual scientific sessions of the American Diabetes Association.

Sara Freeman/Frontline Medical News

Efficacy unaffected by co-administration with insulin use

Helen Colhoun, MD, AXA chair of medical informatics and life course epidemiology at the University of Edinburgh, presented the updated findings of the ODYSSEY DM-INSULIN study, which recruited 517 patients, the majority (n = 441) of whom had T2DM.

In the study, alirocumab, a monoclonal antibody that targets proprotein convertase subtilisin–kexin type 9 (PCSK9), was compared with placebo in patients with established atherosclerotic cardiovascular disease or other cardiovascular risk factors, and in whom LDL-C was 70 mg/dL (1.8 mmol/L) or higher.

The percentage change in LDL-C from baseline to week 24 was similarly reduced in T1DM and T2DM, Dr. Colhoun observed, and commensurate with data seen across the ODYSSEY phase III trials program. Of note, the majority of type 2 (80%) and type 1 (63%) patients did not need the dose of alirocumab to be increased and remained on the starting dose of 75 mg every 2 weeks.

Sara Freeman/Frontline Medical News

Alirocumab beats fenofibrate as add-on lipid-lowering therapy

Presenting the ODYSSEY DM-DYSLIPIDEMIA data, which involved patients with T2DM, Dr. Del Prato observed that alirocumab was “generally well tolerated” and did not affect HbA_1c or fasting plasma glucose levels.

He presented new data from a prespecified analysis that looked at the subgroup of 72 patients who were randomized into an alirocumab (n = 48) or fenofibrate (n = 24) as usual care arm. Dr. Del Prato reminded the audience that the choice of usual treatment was decided by the study investigators prior to randomizing patients, and that other usual care treatments included in the study were ezetimibe, omega-3 fatty acids, nicotinic acid, or no lipid-lowering therapy.

As in the insulin study, the majority (63.6%) of patients treated with alirocumab remained on the starting dose of 75 mg every 2 weeks and did not need up-titration.

Changes in the percentage of non-HDL-C from baseline over time were greater in the alirocumab group than in the usual care group, both in the overall population and in the fenofibrate subanalysis.

Higher percentages of patients treated with alirocumab achieved non-HDL-C compared with those given usual care (66.9% vs. 17.7% in overall population, 65.2% vs. 10.1% in fenofibrate sub-analysis) and LDL-C (70.8% vs. 16.3% and 71.9% vs. 17.5%, respectively) goals at week 24.

Alirocumab also significantly reduced levels of Apo B, total cholesterol, and Lp(a) versus the overall usual care group and also versus the fenofibrate usual care group, Dr. Del Prato said.

Taking the two studies together, he concluded: “These data support alirocumab as a treatment option in people with diabetes mellitus and hypercholesterolemia despite maximally tolerated statins,” Dr. Del Prato said.
 

Will the lipid-benefits translate into improved cardiovascular outcomes?

The question now is whether the lipid-lowering effects of alirocumab in patients with diabetes will translate into improved cardiovascular outcomes in patients with diabetes.

The results of the ODYSSEY OUTCOMES trial, which is evaluating cardiovascular outcomes during treatment with alirocumab after an acute coronary syndrome, are expected next year. While the trial is not being conducted specifically in patients with diabetes, it is expected that there will be subpopulations of T1DM and T2DM patients included.

Cardiovascular outcomes data on the PCSK9 inhibitor, evolocumab (Repatha, Amgen) in the FOURIER trial were published in March (N Engl J Med 2017;376:1713-22) and provide some evidence that a reduction in major cardiovascular events may be possible with these agents.

Providing independent comment on the study, Angelo Avogaro, MD, of the University of Padova, Italy, said that the additional LDL-C lowering effect of alirocumab on top of statins could theoretically halve the projected 10-year risk of cardiovascular disease using data from the two ODYSSEY studies and the UKPDS Risk Engine. Using a baseline 10-year cardiovascular risk of around 26%-28%, this could be reduced to 11%-13%, he suggested.

Of note, Dr. Avogaro said, was that, at baseline, not all patients were on high intensity statins, the majority received moderate doses, with a good number of patients taking none or who were intolerant to statins included. “This, I like,” he observed.

A reassuring point was that there was no signal of having a detrimental effect on neurocognitive dysfunction, Dr. Avogaro observed, which concurs with recent data published on evolocumab (N Engl J Med 2017; 377:633-43).

Nevertheless, longer-follow-up is needed to examine adverse effects, “especially in those insulin-treated patients experiencing severe hypoglycemic reactions.”

The ODYSSEY DM studies were funded by Sanofi and Regeneron Pharmaceuticals.

Dr. Colhoun has received research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Pfizer, Regeneron Pharmaceuticals, Roche Pharmaceuticals, and Sanofi. She has also been a consultant for Eli Lilly, Regeneron Pharmaceuticals, and Sanofi.

Dr. Del Prato has received research funding from AstraZeneca, Boehringer Ingelheim, Novartis, Merck Sharpe & Dohme, and Novo Nordisk. He is a consultant for or has received honoraria from the preceding companies, as well as from Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, Laboratoires Servier, Sanofi-Aventis, and Takeda Pharmaceuticals.

LISBON – Patients with type 2 diabetes mellitus who also have moderate-to-severe chronic kidney disease (CKD) may be as effectively treated with the glucagonlike peptide–1 receptor agonist dulaglutide (Trulicity) as insulin glargine, the results of an international study showed.

Although comparable effects on glycemic control were seen, patients who received dulaglutide rather than insulin glargine in conjunction with prandial insulin lispro (Humalog) exhibited greater weight loss, had fewer episodes of hypoglycemia, and experienced beneficial effects on two important renal parameters.

Sara Freeman/Frontline Medical News

This article was updated September 28, 2017.

LISBON – Patients with type 2 diabetes mellitus who also have moderate-to-severe chronic kidney disease (CKD) may be as effectively treated with the glucagonlike peptide–1 receptor agonist dulaglutide (Trulicity) as insulin glargine, the results of an international study showed.

Although comparable effects on glycemic control were seen, patients who received dulaglutide rather than insulin glargine in conjunction with prandial insulin lispro (Humalog) exhibited greater weight loss, had fewer episodes of hypoglycemia, and experienced beneficial effects on two important renal parameters.

Sara Freeman/Frontline Medical News

This article was updated September 28, 2017.

LISBON – Patients with type 2 diabetes mellitus who also have moderate-to-severe chronic kidney disease (CKD) may be as effectively treated with the glucagonlike peptide–1 receptor agonist dulaglutide (Trulicity) as insulin glargine, the results of an international study showed.

Although comparable effects on glycemic control were seen, patients who received dulaglutide rather than insulin glargine in conjunction with prandial insulin lispro (Humalog) exhibited greater weight loss, had fewer episodes of hypoglycemia, and experienced beneficial effects on two important renal parameters.

Sara Freeman/Frontline Medical News

This article was updated September 28, 2017.

MADRID – Catastrophic antiphospholipid syndrome (CAPS) is associated with a high mortality rate, but new research presented at the European Congress of Rheumatology shows that patient survival can be significantly improved by a triple therapy treatment approach.

Researchers at the Congress also presented clinical practice guidelines for the diagnosis and management of the rare disease, which accounts for just 1% of patients with antiphospholipid syndrome (APS).

CAPS is characterized by a fast onset of widespread thrombosis, mainly in the small vessels, and, often, microangiopathic hemolytic anemia is seen in the laboratory. If undiagnosed or left untreated, patients may present with multiorgan failure needing intensive care treatment, which can be fatal in up to 50% of cases.

At the Congress, Ignasi Rodríguez-Pintó, MD, presented new data from the CAPS Registry that looks at the combined effect of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins on the survival of patients with CAPS as well as the new clinical practice guidelines.

CAPS Registry study

The aim of the study Dr. Rodríguez-Pintó presented on behalf of the CAPS Registry Project Group was to determine what, if any, survival benefit would be incurred from a triple therapy approach when compared with other different combinations of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins, or none of these treatments.

Although the triple therapy treatment approach is already being used in practice, its use is largely empirical, Dr. Rodríguez-Pintó of the department of autoimmune disease at the Hospital Clinic, Barcelona, explained in a video interview.

The investigators derived their data from episodes of CAPS occurring in patients in the CAPS Registry from the European Forum on Antiphospholipid Antibodies. This international registry was set up in 2000 and has been assembling the clinical, laboratory, and therapeutic findings of patients with CAPS for almost 20 years.

“We observed 525 episodes of CAPS in 502 patients. That means that some patients had two to three episodes of CAPS,” Dr. Rodríguez-Pintó said. Data on 38 episodes of CAPS had to be excluded from the analysis because of missing information, which left 487 episodes occurring in 471 patients.

The mean age of the 471 patients included in the analysis was 38 years. The majority (67.9%) were female and had primary (68.8%) APS. Triple therapy was given to about 40% of patients who experienced CAPS, with about 57% receiving other combinations of drugs and 2.5% receiving no treatment for CAPS.

Overall, 177 of the 487 (36.3%) episodes of CAPS were fatal.

“Triple therapy was associated with a higher chance of survival when compared to other combinations or to none of these treatments,” Dr. Rodríguez-Pintó said.

While 28% of patients with CAPS died in the triple therapy group, mortality was 41% with other combinations of treatments and 75% with none of these treatments.

All-cause mortality was reduced by 47% with triple therapy, compared with none of these treatments. The adjusted odds ratio (aOR) when comparing survival between triple therapy and no treatment was 7.7, with a 95% confidence interval of 2.0 to 29.7. The aOR comparing other drug combinations versus none of these treatments was 6.8 (95% CI, 1.7-29.6).

“For a long time, we have been saying that triple therapy would probably be the best approach, but we had no firm evidence,” Dr. Rodríguez-Pintó said.

“So, this is the first time that we have clear clinical evidence of the benefit of these approaches, and I think that these results are important because they will give us more confidence in how we treat patients and help develop guidance on [the treatment’s] use in the future.”

Guidelines

A steering committee composed of representatives from the European Commission–funded RARE-BestPractices project and McMaster University in Hamilton, Ont., used GRADE methodology to develop the guidelines for CAPS diagnosis and management. The committee answered three diagnostic and seven treatment questions that originated from a panel of 19 international stakeholders, including Dr. Rodríguez-Pintó, through systematic reviews of the literature that used Cochrane criteria.

Although the review of studies did not include the study of CAPS Registry data that Dr. Rodríguez-Pintó and his colleagues conducted, he said that the recommendations still confirm the value of using a triple therapy approach to treatment.

The panel created three diagnostic recommendations for patients suspected of having CAPS, all of which were conditional and based on very low certainty of evidence: use preliminary CAPS classification criteria to diagnose CAPS; use or nonuse of biopsy, depending on the circumstances, because of its high specificity but possibly low sensitivity for thrombotic microangiopathy; and test for antiphospholipid antibodies, which should not delay initiation of treatment.

All seven first-line treatment recommendations that the panel developed relied on a very low certainty of evidence, and most were conditional:

• Triple therapy combination treatment with corticosteroids, heparin, and plasma exchange or intravenous immunoglobulins instead of a single agent or other combination treatments.
• Therapeutic dose anticoagulation was one of only two treatment recommendations to be considered “strong,” but use of direct oral anticoagulants is not advised.
• Therapeutic plasma exchange is recommended for use with other therapies and should be strongly considered for patients with microangiopathic hemolytic anemia.
• Intravenous immunoglobulin is advised for use in conjunction with other therapies and should be given special consideration for patients with immune thrombocytopenia or renal insufficiency.
• Antiplatelet agents are conditionally recommended as an add-on therapy, but their potential mortality benefit is tempered by increased risk of bleeding when used with anticoagulants. Strong consideration should be given to their use as an alternative therapy to anticoagulation when anticoagulation is contraindicated for a reason other than bleeding.
• Rituximab (Rituxan) should not be used because of little available data on its use, uncertainty regarding long-term consequences, and its expense – except for refractory cases where other therapies have been insufficient.
• Corticosteroids should not be used because of their lack of efficacy in CAPS when used alone and potential for adverse effects, except for certain circumstances where they may be indicated.

The authors of the guidelines emphasized that these recommendations are not meant to apply to every CAPS patient. They also noted that the available evidence did not allow for temporal analysis of treatments and that conclusions could not be drawn regarding “first-line” versus “second-line” therapies.

None of the authors of the registry study or the guidelines had relevant conflicts of interest to declare.

[email protected]

MADRID – Catastrophic antiphospholipid syndrome (CAPS) is associated with a high mortality rate, but new research presented at the European Congress of Rheumatology shows that patient survival can be significantly improved by a triple therapy treatment approach.

Researchers at the Congress also presented clinical practice guidelines for the diagnosis and management of the rare disease, which accounts for just 1% of patients with antiphospholipid syndrome (APS).

CAPS is characterized by a fast onset of widespread thrombosis, mainly in the small vessels, and, often, microangiopathic hemolytic anemia is seen in the laboratory. If undiagnosed or left untreated, patients may present with multiorgan failure needing intensive care treatment, which can be fatal in up to 50% of cases.

At the Congress, Ignasi Rodríguez-Pintó, MD, presented new data from the CAPS Registry that looks at the combined effect of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins on the survival of patients with CAPS as well as the new clinical practice guidelines.

CAPS Registry study

The aim of the study Dr. Rodríguez-Pintó presented on behalf of the CAPS Registry Project Group was to determine what, if any, survival benefit would be incurred from a triple therapy approach when compared with other different combinations of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins, or none of these treatments.

Although the triple therapy treatment approach is already being used in practice, its use is largely empirical, Dr. Rodríguez-Pintó of the department of autoimmune disease at the Hospital Clinic, Barcelona, explained in a video interview.

The investigators derived their data from episodes of CAPS occurring in patients in the CAPS Registry from the European Forum on Antiphospholipid Antibodies. This international registry was set up in 2000 and has been assembling the clinical, laboratory, and therapeutic findings of patients with CAPS for almost 20 years.

“We observed 525 episodes of CAPS in 502 patients. That means that some patients had two to three episodes of CAPS,” Dr. Rodríguez-Pintó said. Data on 38 episodes of CAPS had to be excluded from the analysis because of missing information, which left 487 episodes occurring in 471 patients.

The mean age of the 471 patients included in the analysis was 38 years. The majority (67.9%) were female and had primary (68.8%) APS. Triple therapy was given to about 40% of patients who experienced CAPS, with about 57% receiving other combinations of drugs and 2.5% receiving no treatment for CAPS.

Overall, 177 of the 487 (36.3%) episodes of CAPS were fatal.

“Triple therapy was associated with a higher chance of survival when compared to other combinations or to none of these treatments,” Dr. Rodríguez-Pintó said.

While 28% of patients with CAPS died in the triple therapy group, mortality was 41% with other combinations of treatments and 75% with none of these treatments.

All-cause mortality was reduced by 47% with triple therapy, compared with none of these treatments. The adjusted odds ratio (aOR) when comparing survival between triple therapy and no treatment was 7.7, with a 95% confidence interval of 2.0 to 29.7. The aOR comparing other drug combinations versus none of these treatments was 6.8 (95% CI, 1.7-29.6).

“For a long time, we have been saying that triple therapy would probably be the best approach, but we had no firm evidence,” Dr. Rodríguez-Pintó said.

“So, this is the first time that we have clear clinical evidence of the benefit of these approaches, and I think that these results are important because they will give us more confidence in how we treat patients and help develop guidance on [the treatment’s] use in the future.”

Guidelines

A steering committee composed of representatives from the European Commission–funded RARE-BestPractices project and McMaster University in Hamilton, Ont., used GRADE methodology to develop the guidelines for CAPS diagnosis and management. The committee answered three diagnostic and seven treatment questions that originated from a panel of 19 international stakeholders, including Dr. Rodríguez-Pintó, through systematic reviews of the literature that used Cochrane criteria.

Although the review of studies did not include the study of CAPS Registry data that Dr. Rodríguez-Pintó and his colleagues conducted, he said that the recommendations still confirm the value of using a triple therapy approach to treatment.

The panel created three diagnostic recommendations for patients suspected of having CAPS, all of which were conditional and based on very low certainty of evidence: use preliminary CAPS classification criteria to diagnose CAPS; use or nonuse of biopsy, depending on the circumstances, because of its high specificity but possibly low sensitivity for thrombotic microangiopathy; and test for antiphospholipid antibodies, which should not delay initiation of treatment.

All seven first-line treatment recommendations that the panel developed relied on a very low certainty of evidence, and most were conditional:

• Triple therapy combination treatment with corticosteroids, heparin, and plasma exchange or intravenous immunoglobulins instead of a single agent or other combination treatments.
• Therapeutic dose anticoagulation was one of only two treatment recommendations to be considered “strong,” but use of direct oral anticoagulants is not advised.
• Therapeutic plasma exchange is recommended for use with other therapies and should be strongly considered for patients with microangiopathic hemolytic anemia.
• Intravenous immunoglobulin is advised for use in conjunction with other therapies and should be given special consideration for patients with immune thrombocytopenia or renal insufficiency.
• Antiplatelet agents are conditionally recommended as an add-on therapy, but their potential mortality benefit is tempered by increased risk of bleeding when used with anticoagulants. Strong consideration should be given to their use as an alternative therapy to anticoagulation when anticoagulation is contraindicated for a reason other than bleeding.
• Rituximab (Rituxan) should not be used because of little available data on its use, uncertainty regarding long-term consequences, and its expense – except for refractory cases where other therapies have been insufficient.
• Corticosteroids should not be used because of their lack of efficacy in CAPS when used alone and potential for adverse effects, except for certain circumstances where they may be indicated.

The authors of the guidelines emphasized that these recommendations are not meant to apply to every CAPS patient. They also noted that the available evidence did not allow for temporal analysis of treatments and that conclusions could not be drawn regarding “first-line” versus “second-line” therapies.

None of the authors of the registry study or the guidelines had relevant conflicts of interest to declare.

[email protected]

MADRID – Catastrophic antiphospholipid syndrome (CAPS) is associated with a high mortality rate, but new research presented at the European Congress of Rheumatology shows that patient survival can be significantly improved by a triple therapy treatment approach.

Researchers at the Congress also presented clinical practice guidelines for the diagnosis and management of the rare disease, which accounts for just 1% of patients with antiphospholipid syndrome (APS).

CAPS is characterized by a fast onset of widespread thrombosis, mainly in the small vessels, and, often, microangiopathic hemolytic anemia is seen in the laboratory. If undiagnosed or left untreated, patients may present with multiorgan failure needing intensive care treatment, which can be fatal in up to 50% of cases.

At the Congress, Ignasi Rodríguez-Pintó, MD, presented new data from the CAPS Registry that looks at the combined effect of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins on the survival of patients with CAPS as well as the new clinical practice guidelines.

CAPS Registry study

The aim of the study Dr. Rodríguez-Pintó presented on behalf of the CAPS Registry Project Group was to determine what, if any, survival benefit would be incurred from a triple therapy approach when compared with other different combinations of anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins, or none of these treatments.

Although the triple therapy treatment approach is already being used in practice, its use is largely empirical, Dr. Rodríguez-Pintó of the department of autoimmune disease at the Hospital Clinic, Barcelona, explained in a video interview.

The investigators derived their data from episodes of CAPS occurring in patients in the CAPS Registry from the European Forum on Antiphospholipid Antibodies. This international registry was set up in 2000 and has been assembling the clinical, laboratory, and therapeutic findings of patients with CAPS for almost 20 years.

“We observed 525 episodes of CAPS in 502 patients. That means that some patients had two to three episodes of CAPS,” Dr. Rodríguez-Pintó said. Data on 38 episodes of CAPS had to be excluded from the analysis because of missing information, which left 487 episodes occurring in 471 patients.

The mean age of the 471 patients included in the analysis was 38 years. The majority (67.9%) were female and had primary (68.8%) APS. Triple therapy was given to about 40% of patients who experienced CAPS, with about 57% receiving other combinations of drugs and 2.5% receiving no treatment for CAPS.

Overall, 177 of the 487 (36.3%) episodes of CAPS were fatal.

“Triple therapy was associated with a higher chance of survival when compared to other combinations or to none of these treatments,” Dr. Rodríguez-Pintó said.

While 28% of patients with CAPS died in the triple therapy group, mortality was 41% with other combinations of treatments and 75% with none of these treatments.

All-cause mortality was reduced by 47% with triple therapy, compared with none of these treatments. The adjusted odds ratio (aOR) when comparing survival between triple therapy and no treatment was 7.7, with a 95% confidence interval of 2.0 to 29.7. The aOR comparing other drug combinations versus none of these treatments was 6.8 (95% CI, 1.7-29.6).

“For a long time, we have been saying that triple therapy would probably be the best approach, but we had no firm evidence,” Dr. Rodríguez-Pintó said.

“So, this is the first time that we have clear clinical evidence of the benefit of these approaches, and I think that these results are important because they will give us more confidence in how we treat patients and help develop guidance on [the treatment’s] use in the future.”

Guidelines

A steering committee composed of representatives from the European Commission–funded RARE-BestPractices project and McMaster University in Hamilton, Ont., used GRADE methodology to develop the guidelines for CAPS diagnosis and management. The committee answered three diagnostic and seven treatment questions that originated from a panel of 19 international stakeholders, including Dr. Rodríguez-Pintó, through systematic reviews of the literature that used Cochrane criteria.

Although the review of studies did not include the study of CAPS Registry data that Dr. Rodríguez-Pintó and his colleagues conducted, he said that the recommendations still confirm the value of using a triple therapy approach to treatment.

The panel created three diagnostic recommendations for patients suspected of having CAPS, all of which were conditional and based on very low certainty of evidence: use preliminary CAPS classification criteria to diagnose CAPS; use or nonuse of biopsy, depending on the circumstances, because of its high specificity but possibly low sensitivity for thrombotic microangiopathy; and test for antiphospholipid antibodies, which should not delay initiation of treatment.

All seven first-line treatment recommendations that the panel developed relied on a very low certainty of evidence, and most were conditional:

• Triple therapy combination treatment with corticosteroids, heparin, and plasma exchange or intravenous immunoglobulins instead of a single agent or other combination treatments.
• Therapeutic dose anticoagulation was one of only two treatment recommendations to be considered “strong,” but use of direct oral anticoagulants is not advised.
• Therapeutic plasma exchange is recommended for use with other therapies and should be strongly considered for patients with microangiopathic hemolytic anemia.
• Intravenous immunoglobulin is advised for use in conjunction with other therapies and should be given special consideration for patients with immune thrombocytopenia or renal insufficiency.
• Antiplatelet agents are conditionally recommended as an add-on therapy, but their potential mortality benefit is tempered by increased risk of bleeding when used with anticoagulants. Strong consideration should be given to their use as an alternative therapy to anticoagulation when anticoagulation is contraindicated for a reason other than bleeding.
• Rituximab (Rituxan) should not be used because of little available data on its use, uncertainty regarding long-term consequences, and its expense – except for refractory cases where other therapies have been insufficient.
• Corticosteroids should not be used because of their lack of efficacy in CAPS when used alone and potential for adverse effects, except for certain circumstances where they may be indicated.

The authors of the guidelines emphasized that these recommendations are not meant to apply to every CAPS patient. They also noted that the available evidence did not allow for temporal analysis of treatments and that conclusions could not be drawn regarding “first-line” versus “second-line” therapies.

None of the authors of the registry study or the guidelines had relevant conflicts of interest to declare.

[email protected]

MADRID – Negative beliefs and uncertainty regarding treatment with methotrexate, as well as dislike for the drug, contribute the most to rheumatoid arthritis patients’ nonadherence to the therapy, with one study finding that about one-third were nonadherent at the time they were eligible to start biologic therapy.

The French cross-sectional survey of 244 patients who were not responding to methotrexate found that 34% actually had poor adherence, including 54% who skipped doses and 38% who temporarily stopped treatment without their doctors’ recommendation. In comparison, patients who were deemed adherent had a lower rate of skipping doses (15%) or temporarily stopped treatment without their doctors’ recommendation (4%), both of which were statistically significant differences, Catherine Beauvais, MD, reported at the European Congress of Rheumatology. Nonadherence was defined as taking less than 80% of doses, according to the CQR19 (Compliance Questionnaire for Rheumatology).

“We have identified profiles of adherence,” Dr. Beauvais of Saint-Antoine Hospital in Paris commented in an interview.

“Among nonadherent patients, there are two profiles,” she added. “We have patients who are not responding to methotrexate but they also have negative beliefs, low levels of support, and they have professional impairment. [Then,] there are patients who do not like their treatment [although it is being well tolerated].”

The other profiles identified were of patients with good adherence to methotrexate with a higher or lower impact on patient outcomes.

In a poster presentation, Dr. Beauvais and her coauthors suggested that the “detection of patients’ profiles may allow targeted strategies to improve or maintain adherence.”

The FORGET survey was conducted over a 3-month period starting in July 2016. A total of 78 rheumatologists recruited patients who were inadequately responding to methotrexate and, thus, eligible to start biologic treatment for rheumatoid arthritis. Both the rheumatologists and the patients completed questionnaires, with 200 questionnaires being completed by patients and their rheumatologist.

As might be suspected for an RA population, 72% of respondents were women, with a mean age of 54 years. Over half (58%) had at least one comorbidity, and the mean disease activity score in 28 joints at the time of the survey was 4.07.

Significant factors for nonadherence were feeling constrained about taking treatment, cited by 29% of respondents; feeling “less good” with a change in dosage (31%); and feeling that treatment was “doing me more harm than good” (19% of respondents).

Surprisingly, most rheumatologists seemed to be unaware of their patients’ lack of adherence to their medication, despite saying that they asked about adherence in more than 80% of their patients.

Rheumatologists proposed the addition of a biologic to methotrexate more often if patients were nonadherent than if patients showed good compliance (91% vs. 68%; P less than .01).

Effect of patient attitudes on compliance

A team of U.K. researchers evaluated how attitudes toward treatment with methotrexate affected patients’ compliance in a separate poster presentation at the meeting.

MADRID – Negative beliefs and uncertainty regarding treatment with methotrexate, as well as dislike for the drug, contribute the most to rheumatoid arthritis patients’ nonadherence to the therapy, with one study finding that about one-third were nonadherent at the time they were eligible to start biologic therapy.

The French cross-sectional survey of 244 patients who were not responding to methotrexate found that 34% actually had poor adherence, including 54% who skipped doses and 38% who temporarily stopped treatment without their doctors’ recommendation. In comparison, patients who were deemed adherent had a lower rate of skipping doses (15%) or temporarily stopped treatment without their doctors’ recommendation (4%), both of which were statistically significant differences, Catherine Beauvais, MD, reported at the European Congress of Rheumatology. Nonadherence was defined as taking less than 80% of doses, according to the CQR19 (Compliance Questionnaire for Rheumatology).

“We have identified profiles of adherence,” Dr. Beauvais of Saint-Antoine Hospital in Paris commented in an interview.

“Among nonadherent patients, there are two profiles,” she added. “We have patients who are not responding to methotrexate but they also have negative beliefs, low levels of support, and they have professional impairment. [Then,] there are patients who do not like their treatment [although it is being well tolerated].”

The other profiles identified were of patients with good adherence to methotrexate with a higher or lower impact on patient outcomes.

In a poster presentation, Dr. Beauvais and her coauthors suggested that the “detection of patients’ profiles may allow targeted strategies to improve or maintain adherence.”

The FORGET survey was conducted over a 3-month period starting in July 2016. A total of 78 rheumatologists recruited patients who were inadequately responding to methotrexate and, thus, eligible to start biologic treatment for rheumatoid arthritis. Both the rheumatologists and the patients completed questionnaires, with 200 questionnaires being completed by patients and their rheumatologist.

As might be suspected for an RA population, 72% of respondents were women, with a mean age of 54 years. Over half (58%) had at least one comorbidity, and the mean disease activity score in 28 joints at the time of the survey was 4.07.

Significant factors for nonadherence were feeling constrained about taking treatment, cited by 29% of respondents; feeling “less good” with a change in dosage (31%); and feeling that treatment was “doing me more harm than good” (19% of respondents).

Surprisingly, most rheumatologists seemed to be unaware of their patients’ lack of adherence to their medication, despite saying that they asked about adherence in more than 80% of their patients.

Rheumatologists proposed the addition of a biologic to methotrexate more often if patients were nonadherent than if patients showed good compliance (91% vs. 68%; P less than .01).

Effect of patient attitudes on compliance

A team of U.K. researchers evaluated how attitudes toward treatment with methotrexate affected patients’ compliance in a separate poster presentation at the meeting.

MADRID – Negative beliefs and uncertainty regarding treatment with methotrexate, as well as dislike for the drug, contribute the most to rheumatoid arthritis patients’ nonadherence to the therapy, with one study finding that about one-third were nonadherent at the time they were eligible to start biologic therapy.

The French cross-sectional survey of 244 patients who were not responding to methotrexate found that 34% actually had poor adherence, including 54% who skipped doses and 38% who temporarily stopped treatment without their doctors’ recommendation. In comparison, patients who were deemed adherent had a lower rate of skipping doses (15%) or temporarily stopped treatment without their doctors’ recommendation (4%), both of which were statistically significant differences, Catherine Beauvais, MD, reported at the European Congress of Rheumatology. Nonadherence was defined as taking less than 80% of doses, according to the CQR19 (Compliance Questionnaire for Rheumatology).

“We have identified profiles of adherence,” Dr. Beauvais of Saint-Antoine Hospital in Paris commented in an interview.

“Among nonadherent patients, there are two profiles,” she added. “We have patients who are not responding to methotrexate but they also have negative beliefs, low levels of support, and they have professional impairment. [Then,] there are patients who do not like their treatment [although it is being well tolerated].”

The other profiles identified were of patients with good adherence to methotrexate with a higher or lower impact on patient outcomes.

In a poster presentation, Dr. Beauvais and her coauthors suggested that the “detection of patients’ profiles may allow targeted strategies to improve or maintain adherence.”

The FORGET survey was conducted over a 3-month period starting in July 2016. A total of 78 rheumatologists recruited patients who were inadequately responding to methotrexate and, thus, eligible to start biologic treatment for rheumatoid arthritis. Both the rheumatologists and the patients completed questionnaires, with 200 questionnaires being completed by patients and their rheumatologist.

As might be suspected for an RA population, 72% of respondents were women, with a mean age of 54 years. Over half (58%) had at least one comorbidity, and the mean disease activity score in 28 joints at the time of the survey was 4.07.

Significant factors for nonadherence were feeling constrained about taking treatment, cited by 29% of respondents; feeling “less good” with a change in dosage (31%); and feeling that treatment was “doing me more harm than good” (19% of respondents).

Surprisingly, most rheumatologists seemed to be unaware of their patients’ lack of adherence to their medication, despite saying that they asked about adherence in more than 80% of their patients.

Rheumatologists proposed the addition of a biologic to methotrexate more often if patients were nonadherent than if patients showed good compliance (91% vs. 68%; P less than .01).

Effect of patient attitudes on compliance

A team of U.K. researchers evaluated how attitudes toward treatment with methotrexate affected patients’ compliance in a separate poster presentation at the meeting.

MADRID – Two independently conducted, randomized, phase 2 trials of novel agents for moderate to severe knee osteoarthritis have produced promising results, as reported at the European Congress of Rheumatology.

In the 24-week, dose-ranging TRIUMPH trial involving 175 patients, treatment with the synthetic trans-capsaicin CNTX-4975 was associated with improvements in several clinical parameters, such as pain when walking, knee stiffness, and physical function, as well as being generally well tolerated.

copyright Nandyphotos/Thinkstock

Synthetic trans-capsaicin CNTX-4975

“Few effective pharmacologic therapies are available to manage the chronic pain of OA,” said Randall Stevens, MD, chief medical officer for Centrexion Therapeutics (Boston), the company developing CNTX-4975. Both NSAIDs and corticosteroids are associated with substantial toxicities, he argued, and opioid analgesics are not ideal to use long term because of the risk of side effects and addiction.

CNTX-4975 is a nonopioid analgesic that acts directly on the pain fibers in the knee, Dr. Stevens explained. Specifically, after a single injection, it targets the capsaicin receptor (transient receptor potential vanilloid 1, TRPV1) to inactivate only the local fibers transmitting pain signals to the brain. It does not affect other sensory fibers involved in sensation to touch or pressure, he said.

The aim of the phase 2b TRIUMPH trial was to examine the efficacy and safety of two doses (0.5 mg and 1.0 mg) of the synthetic trans-capsaicin versus placebo in patients with chronic, stable, moderate to severe knee OA who had been experiencing knee pain for at least 2 months or more. For inclusion, patients could be aged between 45 and 80 years, have a body mass index of up to 45 kg/m², and had to have failed treatment or not be able to tolerate oral or intra-articular analgesics. Patients who had undergone recent knee surgery were excluded.

The primary endpoint was the change in pain with walking from baseline to week 12 measured as the area under the curve (AUC) for daily Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 score. Significant improvements were seen, with a least squares mean difference (LSMD) of –0.8 (P = .07) and –1.6 (P less than .0001) with the 0.5 mg and 1.0 mg doses of CNTX-4975, respectively, versus placebo.

The effects of CNTX-4975 were maintained to 24 weeks, Dr. Stevens reported, with significant improvements in pain with walking, comparing the 1.0-mg dose with placebo (LSMD, –1.35; P = .0002).

“These are the largest effect sizes I’ve seen with osteoarthritis knee pain,” Dr. Stevens said.

The investigators saw improvements in other efficacy endpoints, such as the weekly pain with walking (WOMAC A1) score and the change in weekly average joint stiffness (WOMAC B subscale, LSMD: −2.5; P = .0013) and physical function (WOMAC C subscale, LSMD: −18.3; P = .004) versus placebo at week 12. Numerically greater improvements occurred at week 24.

A similar percentage of patients experienced any treatment-emergent adverse events in the 1.0-mg (29.6%) CNTX-4975 treated and placebo groups (30%). Although a higher percentage of patients given the lower CNTX-4975 dose reported side effects (47.1%), most were mild to moderate and were considered unrelated to study treatment. Arthralgia was the most common side effect with CNTX-4975 1.0 mg versus placebo (7% vs. 5.7%).

“With these findings, we are moving in to phase 3 with the 1.0-mg dose,” Dr. Stevens said.

Wnt inhibitor SM04690

Promising data from the phase 2 trial of the Wnt inhibitor SM04690 also suggest that it, too, could soon be heading into phase 3 trials.

Several early clinical studies have been completed already, noted Yusuf Yazici, MD, chief medical officer of Samumed (San Diego), the California-based company that is developing SMO4690.

SM04690 is a small molecule inhibitor of the Wnt pathway, which is involved in increased bone formation and turnover, he explained. The hypothesis is that by blocking this pathway, the joint can be protected and cartilage could perhaps be regenerated.

Dr. Yazici presented radiographic outcomes at 26 weeks from a 52-week trial that “demonstrated SM04690 treatment maintained or increased medial joint space width compared to placebo.” This is important, as “joint space narrowing is indicative of OA progression and is predictive of knee surgery,” and radiographic progression remains a “gold standard” for assessing potential disease modification in OA, said Dr. Yazici, who is also clinical associate professor and director of the Seligman Center for Advanced Therapeutics at New York University.

In the phase 2 trial he presented, three doses of SM04690 (0.03 mg, 0.07 mg, and 0.23 mg), given as one 2-mL intra-articular injection into a single target knee, were tested and compared against placebo. The target knee was the knee designated as causing the patient the most pain, according to the study investigator.

Radiographs of both knees were taken at the start of treatment, at week 26, and again at week 52, with the change in medial joint space width analyzed. Clinical assessments included changes in WOMAC total, function, and pain subscale scores, and patients’ and physicians’ global assessments.

A total of 455 subjects, mean age 60 years, were randomized into the trial.

Considering all patients, the mean increase in medial joint space width from baseline to 26-week assessment versus placebo was –0.07 mm in the SM04690 0.03-mg group, –0.16 mm in the SM04690 0.07-mg group, and –0.03 mm in the SM04690 0.23-mg group.

An improvement in mean medial joint space narrowing was observed in 47.6% with SM04690 0.03 mg, 40.5% with 0.07 mg, 39.6% with 0.23 mg, and 30.5% with placebo. There was no change in a respective 7.6%, 9%, 17.8%, and 11.4%, and narrowing in the remainder (44.8%, 50.5%, 42,6%, and 58.1%) in this intent-to-treat population.

The investigators conducted prespecified subanalyses in a “unilateral symptomatic” population of 164 patients, and this showed slightly better results, with a higher probability of improved medial joint space width with SM04690 than with placebo (odds ratio, 5.2; 95% confidence interval, 2.1-12.8; P less than .001).

However, an important limitation of the study is that it was not formerly powered to look at radiographic progression, Dr. Yazici said. Nevertheless, radiographs were centrally read and high intra- and inter-observer reproducibility was observed.

Safety and clinical outcomes from the trial, which were reported separately in a poster at the meeting, showed no undue concerns and clinically meaningful improvements in both patients’ and physicians’ global assessments of pain with SM04690 versus placebo.

“Radiographic and clinical outcomes from this 26-week interim analysis of a 52-week trial suggest that SM04690 has potential as a disease-modifying osteoarthritis drug (DMOAD) for knee OA,” Dr. Yazici concluded.

The studies were supported by Samumed and by Centrexion Therapeutics. Dr. Yazici is an employee and shareholder of Samumed. Dr. Stevens is an employee and shareholder of Centrexion Therapeutics.

MADRID – Two independently conducted, randomized, phase 2 trials of novel agents for moderate to severe knee osteoarthritis have produced promising results, as reported at the European Congress of Rheumatology.

In the 24-week, dose-ranging TRIUMPH trial involving 175 patients, treatment with the synthetic trans-capsaicin CNTX-4975 was associated with improvements in several clinical parameters, such as pain when walking, knee stiffness, and physical function, as well as being generally well tolerated.

copyright Nandyphotos/Thinkstock

Synthetic trans-capsaicin CNTX-4975

“Few effective pharmacologic therapies are available to manage the chronic pain of OA,” said Randall Stevens, MD, chief medical officer for Centrexion Therapeutics (Boston), the company developing CNTX-4975. Both NSAIDs and corticosteroids are associated with substantial toxicities, he argued, and opioid analgesics are not ideal to use long term because of the risk of side effects and addiction.

CNTX-4975 is a nonopioid analgesic that acts directly on the pain fibers in the knee, Dr. Stevens explained. Specifically, after a single injection, it targets the capsaicin receptor (transient receptor potential vanilloid 1, TRPV1) to inactivate only the local fibers transmitting pain signals to the brain. It does not affect other sensory fibers involved in sensation to touch or pressure, he said.

The aim of the phase 2b TRIUMPH trial was to examine the efficacy and safety of two doses (0.5 mg and 1.0 mg) of the synthetic trans-capsaicin versus placebo in patients with chronic, stable, moderate to severe knee OA who had been experiencing knee pain for at least 2 months or more. For inclusion, patients could be aged between 45 and 80 years, have a body mass index of up to 45 kg/m², and had to have failed treatment or not be able to tolerate oral or intra-articular analgesics. Patients who had undergone recent knee surgery were excluded.

The primary endpoint was the change in pain with walking from baseline to week 12 measured as the area under the curve (AUC) for daily Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 score. Significant improvements were seen, with a least squares mean difference (LSMD) of –0.8 (P = .07) and –1.6 (P less than .0001) with the 0.5 mg and 1.0 mg doses of CNTX-4975, respectively, versus placebo.

The effects of CNTX-4975 were maintained to 24 weeks, Dr. Stevens reported, with significant improvements in pain with walking, comparing the 1.0-mg dose with placebo (LSMD, –1.35; P = .0002).

“These are the largest effect sizes I’ve seen with osteoarthritis knee pain,” Dr. Stevens said.

The investigators saw improvements in other efficacy endpoints, such as the weekly pain with walking (WOMAC A1) score and the change in weekly average joint stiffness (WOMAC B subscale, LSMD: −2.5; P = .0013) and physical function (WOMAC C subscale, LSMD: −18.3; P = .004) versus placebo at week 12. Numerically greater improvements occurred at week 24.

A similar percentage of patients experienced any treatment-emergent adverse events in the 1.0-mg (29.6%) CNTX-4975 treated and placebo groups (30%). Although a higher percentage of patients given the lower CNTX-4975 dose reported side effects (47.1%), most were mild to moderate and were considered unrelated to study treatment. Arthralgia was the most common side effect with CNTX-4975 1.0 mg versus placebo (7% vs. 5.7%).

“With these findings, we are moving in to phase 3 with the 1.0-mg dose,” Dr. Stevens said.

Wnt inhibitor SM04690

Promising data from the phase 2 trial of the Wnt inhibitor SM04690 also suggest that it, too, could soon be heading into phase 3 trials.

Several early clinical studies have been completed already, noted Yusuf Yazici, MD, chief medical officer of Samumed (San Diego), the California-based company that is developing SMO4690.

SM04690 is a small molecule inhibitor of the Wnt pathway, which is involved in increased bone formation and turnover, he explained. The hypothesis is that by blocking this pathway, the joint can be protected and cartilage could perhaps be regenerated.

Dr. Yazici presented radiographic outcomes at 26 weeks from a 52-week trial that “demonstrated SM04690 treatment maintained or increased medial joint space width compared to placebo.” This is important, as “joint space narrowing is indicative of OA progression and is predictive of knee surgery,” and radiographic progression remains a “gold standard” for assessing potential disease modification in OA, said Dr. Yazici, who is also clinical associate professor and director of the Seligman Center for Advanced Therapeutics at New York University.

In the phase 2 trial he presented, three doses of SM04690 (0.03 mg, 0.07 mg, and 0.23 mg), given as one 2-mL intra-articular injection into a single target knee, were tested and compared against placebo. The target knee was the knee designated as causing the patient the most pain, according to the study investigator.

Radiographs of both knees were taken at the start of treatment, at week 26, and again at week 52, with the change in medial joint space width analyzed. Clinical assessments included changes in WOMAC total, function, and pain subscale scores, and patients’ and physicians’ global assessments.

A total of 455 subjects, mean age 60 years, were randomized into the trial.

Considering all patients, the mean increase in medial joint space width from baseline to 26-week assessment versus placebo was –0.07 mm in the SM04690 0.03-mg group, –0.16 mm in the SM04690 0.07-mg group, and –0.03 mm in the SM04690 0.23-mg group.

An improvement in mean medial joint space narrowing was observed in 47.6% with SM04690 0.03 mg, 40.5% with 0.07 mg, 39.6% with 0.23 mg, and 30.5% with placebo. There was no change in a respective 7.6%, 9%, 17.8%, and 11.4%, and narrowing in the remainder (44.8%, 50.5%, 42,6%, and 58.1%) in this intent-to-treat population.

The investigators conducted prespecified subanalyses in a “unilateral symptomatic” population of 164 patients, and this showed slightly better results, with a higher probability of improved medial joint space width with SM04690 than with placebo (odds ratio, 5.2; 95% confidence interval, 2.1-12.8; P less than .001).

However, an important limitation of the study is that it was not formerly powered to look at radiographic progression, Dr. Yazici said. Nevertheless, radiographs were centrally read and high intra- and inter-observer reproducibility was observed.

Safety and clinical outcomes from the trial, which were reported separately in a poster at the meeting, showed no undue concerns and clinically meaningful improvements in both patients’ and physicians’ global assessments of pain with SM04690 versus placebo.

“Radiographic and clinical outcomes from this 26-week interim analysis of a 52-week trial suggest that SM04690 has potential as a disease-modifying osteoarthritis drug (DMOAD) for knee OA,” Dr. Yazici concluded.

The studies were supported by Samumed and by Centrexion Therapeutics. Dr. Yazici is an employee and shareholder of Samumed. Dr. Stevens is an employee and shareholder of Centrexion Therapeutics.

MADRID – Two independently conducted, randomized, phase 2 trials of novel agents for moderate to severe knee osteoarthritis have produced promising results, as reported at the European Congress of Rheumatology.

In the 24-week, dose-ranging TRIUMPH trial involving 175 patients, treatment with the synthetic trans-capsaicin CNTX-4975 was associated with improvements in several clinical parameters, such as pain when walking, knee stiffness, and physical function, as well as being generally well tolerated.

copyright Nandyphotos/Thinkstock

Synthetic trans-capsaicin CNTX-4975

“Few effective pharmacologic therapies are available to manage the chronic pain of OA,” said Randall Stevens, MD, chief medical officer for Centrexion Therapeutics (Boston), the company developing CNTX-4975. Both NSAIDs and corticosteroids are associated with substantial toxicities, he argued, and opioid analgesics are not ideal to use long term because of the risk of side effects and addiction.

CNTX-4975 is a nonopioid analgesic that acts directly on the pain fibers in the knee, Dr. Stevens explained. Specifically, after a single injection, it targets the capsaicin receptor (transient receptor potential vanilloid 1, TRPV1) to inactivate only the local fibers transmitting pain signals to the brain. It does not affect other sensory fibers involved in sensation to touch or pressure, he said.

The aim of the phase 2b TRIUMPH trial was to examine the efficacy and safety of two doses (0.5 mg and 1.0 mg) of the synthetic trans-capsaicin versus placebo in patients with chronic, stable, moderate to severe knee OA who had been experiencing knee pain for at least 2 months or more. For inclusion, patients could be aged between 45 and 80 years, have a body mass index of up to 45 kg/m², and had to have failed treatment or not be able to tolerate oral or intra-articular analgesics. Patients who had undergone recent knee surgery were excluded.

The primary endpoint was the change in pain with walking from baseline to week 12 measured as the area under the curve (AUC) for daily Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 score. Significant improvements were seen, with a least squares mean difference (LSMD) of –0.8 (P = .07) and –1.6 (P less than .0001) with the 0.5 mg and 1.0 mg doses of CNTX-4975, respectively, versus placebo.

The effects of CNTX-4975 were maintained to 24 weeks, Dr. Stevens reported, with significant improvements in pain with walking, comparing the 1.0-mg dose with placebo (LSMD, –1.35; P = .0002).

“These are the largest effect sizes I’ve seen with osteoarthritis knee pain,” Dr. Stevens said.

The investigators saw improvements in other efficacy endpoints, such as the weekly pain with walking (WOMAC A1) score and the change in weekly average joint stiffness (WOMAC B subscale, LSMD: −2.5; P = .0013) and physical function (WOMAC C subscale, LSMD: −18.3; P = .004) versus placebo at week 12. Numerically greater improvements occurred at week 24.

A similar percentage of patients experienced any treatment-emergent adverse events in the 1.0-mg (29.6%) CNTX-4975 treated and placebo groups (30%). Although a higher percentage of patients given the lower CNTX-4975 dose reported side effects (47.1%), most were mild to moderate and were considered unrelated to study treatment. Arthralgia was the most common side effect with CNTX-4975 1.0 mg versus placebo (7% vs. 5.7%).

“With these findings, we are moving in to phase 3 with the 1.0-mg dose,” Dr. Stevens said.

Wnt inhibitor SM04690

Promising data from the phase 2 trial of the Wnt inhibitor SM04690 also suggest that it, too, could soon be heading into phase 3 trials.

Several early clinical studies have been completed already, noted Yusuf Yazici, MD, chief medical officer of Samumed (San Diego), the California-based company that is developing SMO4690.

SM04690 is a small molecule inhibitor of the Wnt pathway, which is involved in increased bone formation and turnover, he explained. The hypothesis is that by blocking this pathway, the joint can be protected and cartilage could perhaps be regenerated.

Dr. Yazici presented radiographic outcomes at 26 weeks from a 52-week trial that “demonstrated SM04690 treatment maintained or increased medial joint space width compared to placebo.” This is important, as “joint space narrowing is indicative of OA progression and is predictive of knee surgery,” and radiographic progression remains a “gold standard” for assessing potential disease modification in OA, said Dr. Yazici, who is also clinical associate professor and director of the Seligman Center for Advanced Therapeutics at New York University.

In the phase 2 trial he presented, three doses of SM04690 (0.03 mg, 0.07 mg, and 0.23 mg), given as one 2-mL intra-articular injection into a single target knee, were tested and compared against placebo. The target knee was the knee designated as causing the patient the most pain, according to the study investigator.

Radiographs of both knees were taken at the start of treatment, at week 26, and again at week 52, with the change in medial joint space width analyzed. Clinical assessments included changes in WOMAC total, function, and pain subscale scores, and patients’ and physicians’ global assessments.

A total of 455 subjects, mean age 60 years, were randomized into the trial.

Considering all patients, the mean increase in medial joint space width from baseline to 26-week assessment versus placebo was –0.07 mm in the SM04690 0.03-mg group, –0.16 mm in the SM04690 0.07-mg group, and –0.03 mm in the SM04690 0.23-mg group.

An improvement in mean medial joint space narrowing was observed in 47.6% with SM04690 0.03 mg, 40.5% with 0.07 mg, 39.6% with 0.23 mg, and 30.5% with placebo. There was no change in a respective 7.6%, 9%, 17.8%, and 11.4%, and narrowing in the remainder (44.8%, 50.5%, 42,6%, and 58.1%) in this intent-to-treat population.

The investigators conducted prespecified subanalyses in a “unilateral symptomatic” population of 164 patients, and this showed slightly better results, with a higher probability of improved medial joint space width with SM04690 than with placebo (odds ratio, 5.2; 95% confidence interval, 2.1-12.8; P less than .001).

However, an important limitation of the study is that it was not formerly powered to look at radiographic progression, Dr. Yazici said. Nevertheless, radiographs were centrally read and high intra- and inter-observer reproducibility was observed.

Safety and clinical outcomes from the trial, which were reported separately in a poster at the meeting, showed no undue concerns and clinically meaningful improvements in both patients’ and physicians’ global assessments of pain with SM04690 versus placebo.

“Radiographic and clinical outcomes from this 26-week interim analysis of a 52-week trial suggest that SM04690 has potential as a disease-modifying osteoarthritis drug (DMOAD) for knee OA,” Dr. Yazici concluded.

The studies were supported by Samumed and by Centrexion Therapeutics. Dr. Yazici is an employee and shareholder of Samumed. Dr. Stevens is an employee and shareholder of Centrexion Therapeutics.

MADRID – Treatment with the dual interleukin (IL) 1 blocker ABT-981 did not improve pain scores or erosive joint damage in patients with hand osteoarthritis (OA) in a phase 2a trial reported at the European Congress of Rheumatology.

The disappointing findings suggest that IL-1 may not be an effective target in erosive hand OA, said Margreet Kloppenburg, MD, of Leiden (the Netherlands) University Medical Center, even though the investigators obtained adequate pharmacodynamic results that suggested it was effectively blocking both IL-1 alpha and IL-1 beta.

Sara Freeman/Frontline Medical News

Disappointing results with cytokine targeting

Hand OA affects around 11% of the OA population and erosive hand OA is a very painful phenotype that affects multiple joints, Xavier Chevalier, MD, of Henri-Mondor Hospital, Paris XII University (France), said during a separate session at the congress.

While there is a rationale for using anti-inflammatory drugs for erosive hand OA, so far there just have not been many, if any, real successes. “The effect sizes are small,” Dr. Chevalier said. “There are not a lot of drugs when compared to hip and knee OA,” he observed.

Sara Freeman/Frontline Medical News

[email protected]

On Twitter @rheumnews1

MADRID – Treatment with the dual interleukin (IL) 1 blocker ABT-981 did not improve pain scores or erosive joint damage in patients with hand osteoarthritis (OA) in a phase 2a trial reported at the European Congress of Rheumatology.

The disappointing findings suggest that IL-1 may not be an effective target in erosive hand OA, said Margreet Kloppenburg, MD, of Leiden (the Netherlands) University Medical Center, even though the investigators obtained adequate pharmacodynamic results that suggested it was effectively blocking both IL-1 alpha and IL-1 beta.

Sara Freeman/Frontline Medical News

Disappointing results with cytokine targeting

Hand OA affects around 11% of the OA population and erosive hand OA is a very painful phenotype that affects multiple joints, Xavier Chevalier, MD, of Henri-Mondor Hospital, Paris XII University (France), said during a separate session at the congress.

While there is a rationale for using anti-inflammatory drugs for erosive hand OA, so far there just have not been many, if any, real successes. “The effect sizes are small,” Dr. Chevalier said. “There are not a lot of drugs when compared to hip and knee OA,” he observed.

Sara Freeman/Frontline Medical News

[email protected]

On Twitter @rheumnews1

MADRID – Treatment with the dual interleukin (IL) 1 blocker ABT-981 did not improve pain scores or erosive joint damage in patients with hand osteoarthritis (OA) in a phase 2a trial reported at the European Congress of Rheumatology.

The disappointing findings suggest that IL-1 may not be an effective target in erosive hand OA, said Margreet Kloppenburg, MD, of Leiden (the Netherlands) University Medical Center, even though the investigators obtained adequate pharmacodynamic results that suggested it was effectively blocking both IL-1 alpha and IL-1 beta.

Sara Freeman/Frontline Medical News

Disappointing results with cytokine targeting

Hand OA affects around 11% of the OA population and erosive hand OA is a very painful phenotype that affects multiple joints, Xavier Chevalier, MD, of Henri-Mondor Hospital, Paris XII University (France), said during a separate session at the congress.

While there is a rationale for using anti-inflammatory drugs for erosive hand OA, so far there just have not been many, if any, real successes. “The effect sizes are small,” Dr. Chevalier said. “There are not a lot of drugs when compared to hip and knee OA,” he observed.

Sara Freeman/Frontline Medical News

[email protected]

On Twitter @rheumnews1

MADRID – Two-year results from the Care in early RA (CareRA) trial demonstrated the sustained effectiveness of a treat-to-target approach in patients with early rheumatoid arthritis at high risk for progression.

The percentage of patients who achieved clinical remission with one of three disease-modifying antirheumatic drug (DMARD) and glucocorticoid-containing regimens ranged from 60% to 65% at 1 year, and the percentage of those patients who were able to maintain their remission at all time points in year 2 ranged from 55% to 70%, none of which were significantly different from each other.

Sara Freeman/Frontline Medical News

[email protected]

On Twitter @rheumnews1

MADRID – Two-year results from the Care in early RA (CareRA) trial demonstrated the sustained effectiveness of a treat-to-target approach in patients with early rheumatoid arthritis at high risk for progression.

The percentage of patients who achieved clinical remission with one of three disease-modifying antirheumatic drug (DMARD) and glucocorticoid-containing regimens ranged from 60% to 65% at 1 year, and the percentage of those patients who were able to maintain their remission at all time points in year 2 ranged from 55% to 70%, none of which were significantly different from each other.

Sara Freeman/Frontline Medical News

[email protected]

On Twitter @rheumnews1

MADRID – Two-year results from the Care in early RA (CareRA) trial demonstrated the sustained effectiveness of a treat-to-target approach in patients with early rheumatoid arthritis at high risk for progression.

The percentage of patients who achieved clinical remission with one of three disease-modifying antirheumatic drug (DMARD) and glucocorticoid-containing regimens ranged from 60% to 65% at 1 year, and the percentage of those patients who were able to maintain their remission at all time points in year 2 ranged from 55% to 70%, none of which were significantly different from each other.

Sara Freeman/Frontline Medical News

[email protected]

On Twitter @rheumnews1