Safety Assurance Awaits Further Data for New Psoriasis Drugs

LAS VEGAS – New agents for treating psoriasis have shown great promise in terms of efficacy, but assurances of safety await further data from larger studies.

Thus far, phase II data show impressive efficacy and no worrisome safety signals for the anti-interleukin-17 agents AMG 827 and secukinumab and the small molecules apremilast and tofacitinib. However, the studies have been too small and of insufficient duration to definitively rule out cardiovascular, infectious, and cancer risks, said Dr. Kenneth B. Gordon at the Las Vegas Dermatology Seminar, sponsored by Skin Disease Education Foundation (SDEF).

"It is my hope that these drugs are going to be fantastic. We just have to maintain a level of concern and vigilance for both biologics and small molecules ... We just desperately need large trials," said Dr. Gordon, head of the division of dermatology at NorthShore University HealthSystem, Chicago.

The discovery of IL-17 as a key player in psoriatic plaque formation has led to a new understanding of psoriasis pathophysiology and has become a new target for drug development. However, experience with one agent that blocks IL-12/23 – which induces activated IL-17 – gives pause.

Briakinumab, an extremely effective anti-psoriatic agent that blocks IL 12/23, was withdrawn from development after phase III studies showed a signal – albeit statistically insignificant – for serious infections including cellulitis and pneumonia, MACE events (cardiac arrest, myocardial infarction, and stroke), and malignancies (nonmelanoma skin cancer and squamous cell carcinoma of the lung and nasopharynx).

The absolute MACE event numbers were small, but were counter to what would be expected from a systemic anti-inflammatory agent, which should reduce cardiovascular disease, Dr. Craig L. Leonardi, a clinical professor of dermatology at St. Louis University, said in a separate presentation.

According to Dr. Gordon, "It’s really an exciting time for new psoriatic therapies based on a better understanding of psoriasis pathophysiology. However, we are less excited about phase II data because of what happened to briakinumab in phase III."

It will be essential to determine the etiology of the adverse effects, he said. "If the effects are not related to how well the agent controls psoriasis but to mechanisms like IL-12 blockade that may not have relevance to IL-17, they may not show up [with the new agents in development]. That’s what the phase II studies suggest, but it’s too early to really make a final statement," Dr. Gordon said in an interview.

Phase II data on the anti-IL17 and small molecules were presented earlier this year at the European Academy of Dermatology and Venereology meeting in Lisbon and at the World Congress of Dermatology in Seoul. Among the findings:

• AMG 827: This fully-human monoclonal antibody binds to and blocks the IL-17 receptor. In a phase II, double-blind, randomized, placebo-controlled trial of 198 patients who were randomized to subcutaneous AMG 827 at 280 mg monthly; to 70, 140, or 210 mg every 2 weeks; or to placebo. The primary end point, PASI 75 response rate at week 12, was highest (83%) in patients who received 210 mg every 2 weeks. Moreover, at that dose, the proportion achieving a PASI 100 score, indicating no psoriasis activity, was 63%.

"This is an extraordinarily high-responding drug, similar only to briakinumab," Dr. Gordon commented.

Changes in neutrophil counts were seen, as to be expected from IL-17 and IL-12 blockade. "Some of the changes were significant. We need to keep an eye on this," he said.

• Secukinumab: This novel, fully human antibody to IL-17A was investigated in three separate phase II trials of patients with moderate to severe plaque psoriasis. An intravenous induction dose-ranging study of 100 patients yielded PASI 75 response rates at 12 weeks of 40%-83%. A subcutaneous dose-ranging study of 125 patients produced PASI 75 response rates of 19%-81%, and a subcutaneous regimen-finding trial involving 404 patients determined that a regimen of 150 mg at weeks 0, 1, 2, and 4 produced the best PASI 75 response at week 12, of 55%.

While the safety analysis showed no significant differences from placebo, there were two cases of cardiac disorders – one angina pectoris and one coronary artery disease – in the intravenous dose-ranging study and two cases listed as "cardiac disorders" in the regimen-finding study. "We don’t know if these are significant. We have to look at phase III trials," Dr. Gordon said.

• Apremilast: This small molecule, taken orally, works by inhibiting type 4 phosphodiesterase. In a randomized, placebo-controlled phase II trial of 352 patients with moderate to severe plaque psoriasis, the PASI 75 response rate at 16 weeks was 41% with a 30-mg twice-daily dose.

Adverse effects were dose-dependent. Adverse events that occurred in 5% or more of patients included headache, nausea, diarrhea, and upper respiratory tract infections. These typically occurred early in the course of treatment.

Serious adverse events included one myocardial infarction and one case of prostate cancer in the 30-mg BID group. But there was also a prostate cancer and a sudden death among the placebo recipients. "We really don’t have enough patients to look at adverse effects," Dr. Gordon said.

• Tofacitinib: This oral Janus kinase inhibitor demonstrated dose-dependent efficacy, with 67% of patients randomized at 15 mg twice a day achieving PASI 75 and "clear" or "almost clear." The phase II, 12-week, double-blind, placebo-controlled trial enrolled 197 patients with moderate to severe plaque psoriasis.

Concomitant overall decreases in hemoglobin and neutrophil counts from baseline were also dose-dependent. The finding did not specify the proportion of patients who had the decreases or the individual degree of change. "If everyone had a small change, it’s not going to bother me too much. But, if 10% of patients had a big change, it’s a really important finding. Those are the questions we need to ask," Dr. Gordon said.

Dr. Gordon said that so far the phase II safety data for the agents are encouraging, but enthusiasm should still be tempered. "When multiple drugs with the same mechanism have [similar] results, you start to feel more confident. But still, we need to see larger studies."

"It’s really an exciting time for new psoriatic therapies based on a better understanding of psoriasis pathophysiology."

Dr. Leonardi’s presentation focused on anti-IL 12/23 inhibitor treatment; he noted that the recently-approved monoclonal antibody ustekinumab binds to the same shared p40 subunit of IL-12 and IL-23 as briakinumab, the agent that was withdrawn from development in phase III. "There are more similarities than differences" between the two agents, he commented.

He and his colleagues recently conducted a meta-analysis of 22 randomized controlled clinical trials of biologic therapies comprising 10,183 patients with chronic plaque psoriasis, in which 10 of 3,179 patients receiving either ustekinumab or briakinumab experienced a MACE, compared with 0 events in 1,474 patients receiving placebo, for a MACE rate of 1.33 per 100 patient-years.

In contrast, no difference was seen among patients in the anti-TNF-alpha trials, with only 1 of 3,858 patients receiving anti-TNF-alpha agents experiencing a MACE, compared with 1 of 1,812 patients receiving placebo (JAMA 2011;306:864-71).

Although the difference for the anti-IL 12/23 agents was not statistically significant, the data set was not large enough to detect rare events. "This is a class effect in my mind," Dr. Leonardi said, adding that he uses ustekinumab as a second-line agent, after the TNF antagonists.

"It’s important to remember that all new drugs are ‘new’ ... We will learn more and more about these drugs as time goes on," he said.

Dr. Gordon disclosed that he has received research support or honoraria as a consultant from Abbott, Amgen, Centocor, Eli Lilly, Merck, Novartis, and Pfizer. Dr. Leonardi disclosed that he has had financial relationships with 23 companies that are involved in psoriasis treatment development, including Abbott and Centocor.

SDEF and this news organization are owned by Elsevier.

LAS VEGAS – New agents for treating psoriasis have shown great promise in terms of efficacy, but assurances of safety await further data from larger studies.

Thus far, phase II data show impressive efficacy and no worrisome safety signals for the anti-interleukin-17 agents AMG 827 and secukinumab and the small molecules apremilast and tofacitinib. However, the studies have been too small and of insufficient duration to definitively rule out cardiovascular, infectious, and cancer risks, said Dr. Kenneth B. Gordon at the Las Vegas Dermatology Seminar, sponsored by Skin Disease Education Foundation (SDEF).

"It is my hope that these drugs are going to be fantastic. We just have to maintain a level of concern and vigilance for both biologics and small molecules ... We just desperately need large trials," said Dr. Gordon, head of the division of dermatology at NorthShore University HealthSystem, Chicago.

The discovery of IL-17 as a key player in psoriatic plaque formation has led to a new understanding of psoriasis pathophysiology and has become a new target for drug development. However, experience with one agent that blocks IL-12/23 – which induces activated IL-17 – gives pause.

Briakinumab, an extremely effective anti-psoriatic agent that blocks IL 12/23, was withdrawn from development after phase III studies showed a signal – albeit statistically insignificant – for serious infections including cellulitis and pneumonia, MACE events (cardiac arrest, myocardial infarction, and stroke), and malignancies (nonmelanoma skin cancer and squamous cell carcinoma of the lung and nasopharynx).

The absolute MACE event numbers were small, but were counter to what would be expected from a systemic anti-inflammatory agent, which should reduce cardiovascular disease, Dr. Craig L. Leonardi, a clinical professor of dermatology at St. Louis University, said in a separate presentation.

According to Dr. Gordon, "It’s really an exciting time for new psoriatic therapies based on a better understanding of psoriasis pathophysiology. However, we are less excited about phase II data because of what happened to briakinumab in phase III."

It will be essential to determine the etiology of the adverse effects, he said. "If the effects are not related to how well the agent controls psoriasis but to mechanisms like IL-12 blockade that may not have relevance to IL-17, they may not show up [with the new agents in development]. That’s what the phase II studies suggest, but it’s too early to really make a final statement," Dr. Gordon said in an interview.

Phase II data on the anti-IL17 and small molecules were presented earlier this year at the European Academy of Dermatology and Venereology meeting in Lisbon and at the World Congress of Dermatology in Seoul. Among the findings:

• AMG 827: This fully-human monoclonal antibody binds to and blocks the IL-17 receptor. In a phase II, double-blind, randomized, placebo-controlled trial of 198 patients who were randomized to subcutaneous AMG 827 at 280 mg monthly; to 70, 140, or 210 mg every 2 weeks; or to placebo. The primary end point, PASI 75 response rate at week 12, was highest (83%) in patients who received 210 mg every 2 weeks. Moreover, at that dose, the proportion achieving a PASI 100 score, indicating no psoriasis activity, was 63%.

"This is an extraordinarily high-responding drug, similar only to briakinumab," Dr. Gordon commented.

Changes in neutrophil counts were seen, as to be expected from IL-17 and IL-12 blockade. "Some of the changes were significant. We need to keep an eye on this," he said.

• Secukinumab: This novel, fully human antibody to IL-17A was investigated in three separate phase II trials of patients with moderate to severe plaque psoriasis. An intravenous induction dose-ranging study of 100 patients yielded PASI 75 response rates at 12 weeks of 40%-83%. A subcutaneous dose-ranging study of 125 patients produced PASI 75 response rates of 19%-81%, and a subcutaneous regimen-finding trial involving 404 patients determined that a regimen of 150 mg at weeks 0, 1, 2, and 4 produced the best PASI 75 response at week 12, of 55%.

While the safety analysis showed no significant differences from placebo, there were two cases of cardiac disorders – one angina pectoris and one coronary artery disease – in the intravenous dose-ranging study and two cases listed as "cardiac disorders" in the regimen-finding study. "We don’t know if these are significant. We have to look at phase III trials," Dr. Gordon said.

• Apremilast: This small molecule, taken orally, works by inhibiting type 4 phosphodiesterase. In a randomized, placebo-controlled phase II trial of 352 patients with moderate to severe plaque psoriasis, the PASI 75 response rate at 16 weeks was 41% with a 30-mg twice-daily dose.

Adverse effects were dose-dependent. Adverse events that occurred in 5% or more of patients included headache, nausea, diarrhea, and upper respiratory tract infections. These typically occurred early in the course of treatment.

Serious adverse events included one myocardial infarction and one case of prostate cancer in the 30-mg BID group. But there was also a prostate cancer and a sudden death among the placebo recipients. "We really don’t have enough patients to look at adverse effects," Dr. Gordon said.

• Tofacitinib: This oral Janus kinase inhibitor demonstrated dose-dependent efficacy, with 67% of patients randomized at 15 mg twice a day achieving PASI 75 and "clear" or "almost clear." The phase II, 12-week, double-blind, placebo-controlled trial enrolled 197 patients with moderate to severe plaque psoriasis.

Concomitant overall decreases in hemoglobin and neutrophil counts from baseline were also dose-dependent. The finding did not specify the proportion of patients who had the decreases or the individual degree of change. "If everyone had a small change, it’s not going to bother me too much. But, if 10% of patients had a big change, it’s a really important finding. Those are the questions we need to ask," Dr. Gordon said.

Dr. Gordon said that so far the phase II safety data for the agents are encouraging, but enthusiasm should still be tempered. "When multiple drugs with the same mechanism have [similar] results, you start to feel more confident. But still, we need to see larger studies."

"It’s really an exciting time for new psoriatic therapies based on a better understanding of psoriasis pathophysiology."

Dr. Leonardi’s presentation focused on anti-IL 12/23 inhibitor treatment; he noted that the recently-approved monoclonal antibody ustekinumab binds to the same shared p40 subunit of IL-12 and IL-23 as briakinumab, the agent that was withdrawn from development in phase III. "There are more similarities than differences" between the two agents, he commented.

He and his colleagues recently conducted a meta-analysis of 22 randomized controlled clinical trials of biologic therapies comprising 10,183 patients with chronic plaque psoriasis, in which 10 of 3,179 patients receiving either ustekinumab or briakinumab experienced a MACE, compared with 0 events in 1,474 patients receiving placebo, for a MACE rate of 1.33 per 100 patient-years.

In contrast, no difference was seen among patients in the anti-TNF-alpha trials, with only 1 of 3,858 patients receiving anti-TNF-alpha agents experiencing a MACE, compared with 1 of 1,812 patients receiving placebo (JAMA 2011;306:864-71).

Although the difference for the anti-IL 12/23 agents was not statistically significant, the data set was not large enough to detect rare events. "This is a class effect in my mind," Dr. Leonardi said, adding that he uses ustekinumab as a second-line agent, after the TNF antagonists.

"It’s important to remember that all new drugs are ‘new’ ... We will learn more and more about these drugs as time goes on," he said.

Dr. Gordon disclosed that he has received research support or honoraria as a consultant from Abbott, Amgen, Centocor, Eli Lilly, Merck, Novartis, and Pfizer. Dr. Leonardi disclosed that he has had financial relationships with 23 companies that are involved in psoriasis treatment development, including Abbott and Centocor.

SDEF and this news organization are owned by Elsevier.

LAS VEGAS – New agents for treating psoriasis have shown great promise in terms of efficacy, but assurances of safety await further data from larger studies.

Thus far, phase II data show impressive efficacy and no worrisome safety signals for the anti-interleukin-17 agents AMG 827 and secukinumab and the small molecules apremilast and tofacitinib. However, the studies have been too small and of insufficient duration to definitively rule out cardiovascular, infectious, and cancer risks, said Dr. Kenneth B. Gordon at the Las Vegas Dermatology Seminar, sponsored by Skin Disease Education Foundation (SDEF).

"It is my hope that these drugs are going to be fantastic. We just have to maintain a level of concern and vigilance for both biologics and small molecules ... We just desperately need large trials," said Dr. Gordon, head of the division of dermatology at NorthShore University HealthSystem, Chicago.

The discovery of IL-17 as a key player in psoriatic plaque formation has led to a new understanding of psoriasis pathophysiology and has become a new target for drug development. However, experience with one agent that blocks IL-12/23 – which induces activated IL-17 – gives pause.

Briakinumab, an extremely effective anti-psoriatic agent that blocks IL 12/23, was withdrawn from development after phase III studies showed a signal – albeit statistically insignificant – for serious infections including cellulitis and pneumonia, MACE events (cardiac arrest, myocardial infarction, and stroke), and malignancies (nonmelanoma skin cancer and squamous cell carcinoma of the lung and nasopharynx).

The absolute MACE event numbers were small, but were counter to what would be expected from a systemic anti-inflammatory agent, which should reduce cardiovascular disease, Dr. Craig L. Leonardi, a clinical professor of dermatology at St. Louis University, said in a separate presentation.

According to Dr. Gordon, "It’s really an exciting time for new psoriatic therapies based on a better understanding of psoriasis pathophysiology. However, we are less excited about phase II data because of what happened to briakinumab in phase III."

It will be essential to determine the etiology of the adverse effects, he said. "If the effects are not related to how well the agent controls psoriasis but to mechanisms like IL-12 blockade that may not have relevance to IL-17, they may not show up [with the new agents in development]. That’s what the phase II studies suggest, but it’s too early to really make a final statement," Dr. Gordon said in an interview.

Phase II data on the anti-IL17 and small molecules were presented earlier this year at the European Academy of Dermatology and Venereology meeting in Lisbon and at the World Congress of Dermatology in Seoul. Among the findings:

• AMG 827: This fully-human monoclonal antibody binds to and blocks the IL-17 receptor. In a phase II, double-blind, randomized, placebo-controlled trial of 198 patients who were randomized to subcutaneous AMG 827 at 280 mg monthly; to 70, 140, or 210 mg every 2 weeks; or to placebo. The primary end point, PASI 75 response rate at week 12, was highest (83%) in patients who received 210 mg every 2 weeks. Moreover, at that dose, the proportion achieving a PASI 100 score, indicating no psoriasis activity, was 63%.

"This is an extraordinarily high-responding drug, similar only to briakinumab," Dr. Gordon commented.

Changes in neutrophil counts were seen, as to be expected from IL-17 and IL-12 blockade. "Some of the changes were significant. We need to keep an eye on this," he said.

• Secukinumab: This novel, fully human antibody to IL-17A was investigated in three separate phase II trials of patients with moderate to severe plaque psoriasis. An intravenous induction dose-ranging study of 100 patients yielded PASI 75 response rates at 12 weeks of 40%-83%. A subcutaneous dose-ranging study of 125 patients produced PASI 75 response rates of 19%-81%, and a subcutaneous regimen-finding trial involving 404 patients determined that a regimen of 150 mg at weeks 0, 1, 2, and 4 produced the best PASI 75 response at week 12, of 55%.

While the safety analysis showed no significant differences from placebo, there were two cases of cardiac disorders – one angina pectoris and one coronary artery disease – in the intravenous dose-ranging study and two cases listed as "cardiac disorders" in the regimen-finding study. "We don’t know if these are significant. We have to look at phase III trials," Dr. Gordon said.

• Apremilast: This small molecule, taken orally, works by inhibiting type 4 phosphodiesterase. In a randomized, placebo-controlled phase II trial of 352 patients with moderate to severe plaque psoriasis, the PASI 75 response rate at 16 weeks was 41% with a 30-mg twice-daily dose.

Adverse effects were dose-dependent. Adverse events that occurred in 5% or more of patients included headache, nausea, diarrhea, and upper respiratory tract infections. These typically occurred early in the course of treatment.

Serious adverse events included one myocardial infarction and one case of prostate cancer in the 30-mg BID group. But there was also a prostate cancer and a sudden death among the placebo recipients. "We really don’t have enough patients to look at adverse effects," Dr. Gordon said.

• Tofacitinib: This oral Janus kinase inhibitor demonstrated dose-dependent efficacy, with 67% of patients randomized at 15 mg twice a day achieving PASI 75 and "clear" or "almost clear." The phase II, 12-week, double-blind, placebo-controlled trial enrolled 197 patients with moderate to severe plaque psoriasis.

Concomitant overall decreases in hemoglobin and neutrophil counts from baseline were also dose-dependent. The finding did not specify the proportion of patients who had the decreases or the individual degree of change. "If everyone had a small change, it’s not going to bother me too much. But, if 10% of patients had a big change, it’s a really important finding. Those are the questions we need to ask," Dr. Gordon said.

Dr. Gordon said that so far the phase II safety data for the agents are encouraging, but enthusiasm should still be tempered. "When multiple drugs with the same mechanism have [similar] results, you start to feel more confident. But still, we need to see larger studies."

"It’s really an exciting time for new psoriatic therapies based on a better understanding of psoriasis pathophysiology."

Dr. Leonardi’s presentation focused on anti-IL 12/23 inhibitor treatment; he noted that the recently-approved monoclonal antibody ustekinumab binds to the same shared p40 subunit of IL-12 and IL-23 as briakinumab, the agent that was withdrawn from development in phase III. "There are more similarities than differences" between the two agents, he commented.

He and his colleagues recently conducted a meta-analysis of 22 randomized controlled clinical trials of biologic therapies comprising 10,183 patients with chronic plaque psoriasis, in which 10 of 3,179 patients receiving either ustekinumab or briakinumab experienced a MACE, compared with 0 events in 1,474 patients receiving placebo, for a MACE rate of 1.33 per 100 patient-years.

In contrast, no difference was seen among patients in the anti-TNF-alpha trials, with only 1 of 3,858 patients receiving anti-TNF-alpha agents experiencing a MACE, compared with 1 of 1,812 patients receiving placebo (JAMA 2011;306:864-71).

Although the difference for the anti-IL 12/23 agents was not statistically significant, the data set was not large enough to detect rare events. "This is a class effect in my mind," Dr. Leonardi said, adding that he uses ustekinumab as a second-line agent, after the TNF antagonists.

"It’s important to remember that all new drugs are ‘new’ ... We will learn more and more about these drugs as time goes on," he said.

Dr. Gordon disclosed that he has received research support or honoraria as a consultant from Abbott, Amgen, Centocor, Eli Lilly, Merck, Novartis, and Pfizer. Dr. Leonardi disclosed that he has had financial relationships with 23 companies that are involved in psoriasis treatment development, including Abbott and Centocor.

SDEF and this news organization are owned by Elsevier.