Biologics Up Cardiovascular Risk, New Analysis Finds

LAS VEGAS – Increased risk for major cardiovascular events may be a "class effect" associated with two monoclonal antibody therapies for psoriasis, Dr. Craig Leonardi said.

"I used to give them a pass on this, but no more. I'm going to point out a few things that bother me," he said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

Ustekinumab, which is approved to treat adults with moderate to severe plaque psoriasis, and the investigational psoriasis drug briakinumab inhibit interleukin 12 (IL-12) and IL-23 proteins linked to inflammation. Conventional thought holds that reducing systemic inflammation should decrease cardiovascular risk, but ustekinumab and briakinumab have been associated with an increase in major cardiovascular events in clinical trials, said Dr. Leonardi, a dermatologist and psoriasis specialist at St. Louis University.

(Abbott Laboratories pulled briakinumab from the drug approval process in the United States and Europe in a financial filing on Jan. 14.)

He recently conducted a meta-analysis summarizing major cardiovascular events during the placebo-controlled portions of 19 trials encompassing all the biologic therapies for psoriasis. Only one patient on placebo developed a major cardiovascular event in a study of etanercept. Five patients on ustekinumab, five on briakinumab, and one on adalimumab developed major cardiovascular events.

In a separate look at Phase III trials data on ustekinumab, adverse events included chest pain in one patient on placebo, a case of angina, and a case of stroke in patients on low-dose therapy (45 mg). On high-dose therapy (90 mg) one patient developed congestive cardiomyopathy and died and another required a coronary artery bypass graft, he noted.

"I think there's a bit of an imbalance when I look at these data" in major cardiovascular events, he said.

In data on 3,117 patients followed for 3 years or less, the risk for major cardiovascular events (MI, stroke, or death from cardiovascular causes) seemed to be higher on ustekinumab during the initial 12-week placebo-controlled portions of the study but the risk leveled out between groups over time, Dr. Leonardi said.

During the controlled period, the incidence of major cardiovascular events was 0 per 100 patient-years in the placebo group, 0.98/100 patient-years on low-dose ustekinumab, and 1.47/100 patient-years on high-dose ustekinumab. Over the 3-year period, the incidence was 0.55, 0.41, and 0.35 per 100 patient-years, respectively.

Even in Phase II trial data on ustekinumab there was a potential "signal" of increased risk for major cardiovascular events, Dr. Leonardi added. Looking at data from all trials of ustekinumab for any indication (not just psoriasis), there's a "flurry" of major cardiovascular events early in treatment that then settles down and becomes comparable to the placebo group over time.

"The statisticians will say that there's no statistically significant difference between the treated versus the placebo" in major cardiovascular events, "but I don't think we have to be a rocket scientist to see that there’s something very different going on" between groups, Dr. Leonardi said.

Safety data from the placebo-controlled periods in phase III data on briakinumab suggest even greater problems. "The news here, quite frankly, is not good," he said.

There were three MIs, one cardiac arrest, and a stroke in 981 patients on briakinumab, compared with none in 484 patients on placebo. In addition, five patients on briakinumab and one on placebo developed serious infections requiring hospitalization and IV antibiotics. Six patients on briakinumab and none on placebo developed malignancies, all of them squamous cell carcinomas of the skin, lung, or nasopharynx.

"Cancers usually take months or years to show up, and yet these showed up in the first 12 weeks" on treatment," he noted.

The combination of increased risks for major cardiovascular events, malignancies, and infections with briakinumab is "unprecedented," he said. "We should pay close attention to this data."

Both drugs can boast "impressive" efficacy in treating plaque psoriasis, but the potential risks need to be carefully considered, Dr. Leonardi said.

He recommends considering all options when selecting a biologic treatment for psoriasis, even if patients request the treatment they only have to get every 3 months. Remember that patients with psoriasis typically have multiple cardiac risk factors. If ustekinumab is used, start with a low dose regardless of the patient’s weight, Dr. Leonardi advised.

"Consider adding low-dose aspirin, 81 mg per day," he added. "That's what I’m doing."

Analyses underway by the Food and Drug Administration and the drug companies should provide further insights into the potential risks and benefits of these drugs.

"Remember that all new drugs are new," Dr. Leonardi cautioned. "We don't know everything we need to know about new drugs, especially when there's a new mechanism of action."

He speculated that the monoclonal antibody therapies increase major cardiovascular events by increasing delivery of IL-12 and IL-23 to atherosclerotic plaques, or perhaps the p40 subunits of IL-12 and IL-23 form dimers that become bioactive. Or, some unknown biologic activity could be at play.

SDEF and this news organization are owned by Elsevier. Dr. Leonardi declared having potential conflicts of interest with Abbott and Centocor, which manufacture briakinumab and ustekinumab, and with Abgenix, Allergan, Alza, Amgen, Biogen-IDEC, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Connetics, Corixa, Fujisawa, Galderma, Genentech, Genzyme, GSK, Incyte, Isis, Lilly, Medimmune, Miravant, Pfizer, Schering Plough, Serono, Synta, Wyeth, and Xoma.

LAS VEGAS – Increased risk for major cardiovascular events may be a "class effect" associated with two monoclonal antibody therapies for psoriasis, Dr. Craig Leonardi said.

"I used to give them a pass on this, but no more. I'm going to point out a few things that bother me," he said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

Ustekinumab, which is approved to treat adults with moderate to severe plaque psoriasis, and the investigational psoriasis drug briakinumab inhibit interleukin 12 (IL-12) and IL-23 proteins linked to inflammation. Conventional thought holds that reducing systemic inflammation should decrease cardiovascular risk, but ustekinumab and briakinumab have been associated with an increase in major cardiovascular events in clinical trials, said Dr. Leonardi, a dermatologist and psoriasis specialist at St. Louis University.

(Abbott Laboratories pulled briakinumab from the drug approval process in the United States and Europe in a financial filing on Jan. 14.)

He recently conducted a meta-analysis summarizing major cardiovascular events during the placebo-controlled portions of 19 trials encompassing all the biologic therapies for psoriasis. Only one patient on placebo developed a major cardiovascular event in a study of etanercept. Five patients on ustekinumab, five on briakinumab, and one on adalimumab developed major cardiovascular events.

In a separate look at Phase III trials data on ustekinumab, adverse events included chest pain in one patient on placebo, a case of angina, and a case of stroke in patients on low-dose therapy (45 mg). On high-dose therapy (90 mg) one patient developed congestive cardiomyopathy and died and another required a coronary artery bypass graft, he noted.

"I think there's a bit of an imbalance when I look at these data" in major cardiovascular events, he said.

In data on 3,117 patients followed for 3 years or less, the risk for major cardiovascular events (MI, stroke, or death from cardiovascular causes) seemed to be higher on ustekinumab during the initial 12-week placebo-controlled portions of the study but the risk leveled out between groups over time, Dr. Leonardi said.

During the controlled period, the incidence of major cardiovascular events was 0 per 100 patient-years in the placebo group, 0.98/100 patient-years on low-dose ustekinumab, and 1.47/100 patient-years on high-dose ustekinumab. Over the 3-year period, the incidence was 0.55, 0.41, and 0.35 per 100 patient-years, respectively.

Even in Phase II trial data on ustekinumab there was a potential "signal" of increased risk for major cardiovascular events, Dr. Leonardi added. Looking at data from all trials of ustekinumab for any indication (not just psoriasis), there's a "flurry" of major cardiovascular events early in treatment that then settles down and becomes comparable to the placebo group over time.

"The statisticians will say that there's no statistically significant difference between the treated versus the placebo" in major cardiovascular events, "but I don't think we have to be a rocket scientist to see that there’s something very different going on" between groups, Dr. Leonardi said.

Safety data from the placebo-controlled periods in phase III data on briakinumab suggest even greater problems. "The news here, quite frankly, is not good," he said.

There were three MIs, one cardiac arrest, and a stroke in 981 patients on briakinumab, compared with none in 484 patients on placebo. In addition, five patients on briakinumab and one on placebo developed serious infections requiring hospitalization and IV antibiotics. Six patients on briakinumab and none on placebo developed malignancies, all of them squamous cell carcinomas of the skin, lung, or nasopharynx.

"Cancers usually take months or years to show up, and yet these showed up in the first 12 weeks" on treatment," he noted.

The combination of increased risks for major cardiovascular events, malignancies, and infections with briakinumab is "unprecedented," he said. "We should pay close attention to this data."

Both drugs can boast "impressive" efficacy in treating plaque psoriasis, but the potential risks need to be carefully considered, Dr. Leonardi said.

He recommends considering all options when selecting a biologic treatment for psoriasis, even if patients request the treatment they only have to get every 3 months. Remember that patients with psoriasis typically have multiple cardiac risk factors. If ustekinumab is used, start with a low dose regardless of the patient’s weight, Dr. Leonardi advised.

"Consider adding low-dose aspirin, 81 mg per day," he added. "That's what I’m doing."

Analyses underway by the Food and Drug Administration and the drug companies should provide further insights into the potential risks and benefits of these drugs.

"Remember that all new drugs are new," Dr. Leonardi cautioned. "We don't know everything we need to know about new drugs, especially when there's a new mechanism of action."

He speculated that the monoclonal antibody therapies increase major cardiovascular events by increasing delivery of IL-12 and IL-23 to atherosclerotic plaques, or perhaps the p40 subunits of IL-12 and IL-23 form dimers that become bioactive. Or, some unknown biologic activity could be at play.

SDEF and this news organization are owned by Elsevier. Dr. Leonardi declared having potential conflicts of interest with Abbott and Centocor, which manufacture briakinumab and ustekinumab, and with Abgenix, Allergan, Alza, Amgen, Biogen-IDEC, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Connetics, Corixa, Fujisawa, Galderma, Genentech, Genzyme, GSK, Incyte, Isis, Lilly, Medimmune, Miravant, Pfizer, Schering Plough, Serono, Synta, Wyeth, and Xoma.

LAS VEGAS – Increased risk for major cardiovascular events may be a "class effect" associated with two monoclonal antibody therapies for psoriasis, Dr. Craig Leonardi said.

"I used to give them a pass on this, but no more. I'm going to point out a few things that bother me," he said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

Ustekinumab, which is approved to treat adults with moderate to severe plaque psoriasis, and the investigational psoriasis drug briakinumab inhibit interleukin 12 (IL-12) and IL-23 proteins linked to inflammation. Conventional thought holds that reducing systemic inflammation should decrease cardiovascular risk, but ustekinumab and briakinumab have been associated with an increase in major cardiovascular events in clinical trials, said Dr. Leonardi, a dermatologist and psoriasis specialist at St. Louis University.

(Abbott Laboratories pulled briakinumab from the drug approval process in the United States and Europe in a financial filing on Jan. 14.)

He recently conducted a meta-analysis summarizing major cardiovascular events during the placebo-controlled portions of 19 trials encompassing all the biologic therapies for psoriasis. Only one patient on placebo developed a major cardiovascular event in a study of etanercept. Five patients on ustekinumab, five on briakinumab, and one on adalimumab developed major cardiovascular events.

In a separate look at Phase III trials data on ustekinumab, adverse events included chest pain in one patient on placebo, a case of angina, and a case of stroke in patients on low-dose therapy (45 mg). On high-dose therapy (90 mg) one patient developed congestive cardiomyopathy and died and another required a coronary artery bypass graft, he noted.

"I think there's a bit of an imbalance when I look at these data" in major cardiovascular events, he said.

In data on 3,117 patients followed for 3 years or less, the risk for major cardiovascular events (MI, stroke, or death from cardiovascular causes) seemed to be higher on ustekinumab during the initial 12-week placebo-controlled portions of the study but the risk leveled out between groups over time, Dr. Leonardi said.

During the controlled period, the incidence of major cardiovascular events was 0 per 100 patient-years in the placebo group, 0.98/100 patient-years on low-dose ustekinumab, and 1.47/100 patient-years on high-dose ustekinumab. Over the 3-year period, the incidence was 0.55, 0.41, and 0.35 per 100 patient-years, respectively.

Even in Phase II trial data on ustekinumab there was a potential "signal" of increased risk for major cardiovascular events, Dr. Leonardi added. Looking at data from all trials of ustekinumab for any indication (not just psoriasis), there's a "flurry" of major cardiovascular events early in treatment that then settles down and becomes comparable to the placebo group over time.

"The statisticians will say that there's no statistically significant difference between the treated versus the placebo" in major cardiovascular events, "but I don't think we have to be a rocket scientist to see that there’s something very different going on" between groups, Dr. Leonardi said.

Safety data from the placebo-controlled periods in phase III data on briakinumab suggest even greater problems. "The news here, quite frankly, is not good," he said.

There were three MIs, one cardiac arrest, and a stroke in 981 patients on briakinumab, compared with none in 484 patients on placebo. In addition, five patients on briakinumab and one on placebo developed serious infections requiring hospitalization and IV antibiotics. Six patients on briakinumab and none on placebo developed malignancies, all of them squamous cell carcinomas of the skin, lung, or nasopharynx.

"Cancers usually take months or years to show up, and yet these showed up in the first 12 weeks" on treatment," he noted.

The combination of increased risks for major cardiovascular events, malignancies, and infections with briakinumab is "unprecedented," he said. "We should pay close attention to this data."

Both drugs can boast "impressive" efficacy in treating plaque psoriasis, but the potential risks need to be carefully considered, Dr. Leonardi said.

He recommends considering all options when selecting a biologic treatment for psoriasis, even if patients request the treatment they only have to get every 3 months. Remember that patients with psoriasis typically have multiple cardiac risk factors. If ustekinumab is used, start with a low dose regardless of the patient’s weight, Dr. Leonardi advised.

"Consider adding low-dose aspirin, 81 mg per day," he added. "That's what I’m doing."

Analyses underway by the Food and Drug Administration and the drug companies should provide further insights into the potential risks and benefits of these drugs.

"Remember that all new drugs are new," Dr. Leonardi cautioned. "We don't know everything we need to know about new drugs, especially when there's a new mechanism of action."

He speculated that the monoclonal antibody therapies increase major cardiovascular events by increasing delivery of IL-12 and IL-23 to atherosclerotic plaques, or perhaps the p40 subunits of IL-12 and IL-23 form dimers that become bioactive. Or, some unknown biologic activity could be at play.

SDEF and this news organization are owned by Elsevier. Dr. Leonardi declared having potential conflicts of interest with Abbott and Centocor, which manufacture briakinumab and ustekinumab, and with Abgenix, Allergan, Alza, Amgen, Biogen-IDEC, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Connetics, Corixa, Fujisawa, Galderma, Genentech, Genzyme, GSK, Incyte, Isis, Lilly, Medimmune, Miravant, Pfizer, Schering Plough, Serono, Synta, Wyeth, and Xoma.