Brodalumab, Ixekizumab Rapidly Improve Psoriasis

Two monoclonal antibodies targeting interleukin-17 proved effective and safe for moderate to severe plaque psoriasis, according to the results of two phase II clinical trials reported in the March 29 issue of the New England Journal of Medicine.

Both agents had a rapid onset of action and improved scores on the psoriasis area and severity (PASI) index, as well as on measures of dermatology-related quality of life and overall well-being, compared with placebo. Both agents also showed increasing efficacy at higher doses, indicating a dose-response effect, according to the industry-sponsored studies.

Brodalumab

In the first study, researchers assessed brodalumab (AMG 827), a human anti-interleukin-17RA monoclonal antibody that antagonizes the interleukin-17 pathway, in 198 patients at 23 international sites.

The study patients were randomly assigned to receive 70 mg, 140 mg, or 210 mg of brodalumab (at weeks 1, 2, 4, 6, 8, and 10), 280 mg of brodalumab monthly, or placebo injections. A subgroup of 20 patients also underwent skin biopsy at baseline and at week 12, reported Dr. Kim A. Papp of Probity Medical Research, Waterloo, Ont., and his associates.

The mean patient age was 43 years, and the mean duration of psoriasis was 19 years. Most patients had previously received topical and systemic treatments, including phototherapy, and 35% had previously received biologic therapy.

The primary efficacy outcome – percentage improvement in PASI score at week 12 – was significantly greater in every brodalumab group than in the placebo group. Mean improvements were 45% with 70 mg, 85.9% with 140 mg, 86.3% with 210 mg, and 76% with 280 mg, and 16% with placebo.

"Similarly, a significantly higher percentage of patients in the brodalumab groups than in the placebo group [was] assessed as being clear of psoriasis (score of 0 on the physician’s global assessment) or as having minimal disease (score of 1) at week 12," Dr. Papp and his colleagues wrote (N. Engl. J. Med. 2012;366:1181-9)

In addition, the extent of the affected body-surface area was significantly smaller with active treatment than with placebo. Scores on the Dermatology Life Quality Index (DLQI) were significantly lower in the brodalumab groups, indicating that psoriasis had less of an impact on health-related quality of life. And scores on both physical and mental components of the SF-36 were significantly higher, indicating improved well-being, with brodalumab.

Among study patients who underwent skin biopsy, keratin 16 staining of the upper epidermis was reduced, and epidermal thickness and CD3 counts were decreased, at all doses of brodalumab except 70 mg. "This finding indicates a reversal of regenerative epidermal maturation, which is the essential pathological characteristic of psoriasis that causes epidermal hyperplasia and abnormal differentiation, with scaling and thickness as the clinical correlates," Dr. Papp and his associates noted.

At 16-week follow-up, which was 6-8 weeks after the final dose of brodalumab, PASI scores showed a diminished drug effect but were still better than those at baseline.

There were three serious adverse events, only one of which was related to the study drug. This was an asymptomatic case of grade 3 neutropenia, which resolved when the study drug was discontinued. A less serious case of neutropenia developed in another patient.

Ixekizumab

The second study assessed ixekizumab (LY2439821), a humanized IgG4 monoclonal antibody that neutralizes interleukin-17, in 142 patients with moderate to severe plaque psoriasis. The study patients were randomly assigned to receive subcutaneous injections of placebo or 10 mg, 25 mg, 75 mg, or 150 mg of ixekizumab at baseline and at 2, 4, 8, 12, and 16 weeks, reported Dr. Craig Leonardi of the department of dermatology, St. Louis University, and his associates.

The primary efficacy end point was the proportion of patients who achieved at least a 75% improvement in PASI score at 12 weeks. Significantly more patients at all ixekizumab doses except 10 mg achieved this benchmark (76.7%-82.8%), compared with placebo (7.7%).

In addition, significantly more patients (approximately 40%) in the higher-dose groups achieved a 100% improvement in PASI scores, indicating complete clearance of psoriasis, than in the placebo group. And significantly more patients receiving active treatment received physician’s global assessment scores of 0, indicating complete clearance, or 1, indicating minimal disease.

As with brodalumab, the beneficial effect of ixekizumab was evident as early as 1 week into treatment. The drug also significantly improved DLQI scores and decreased the severity of itching, Dr. Leonardi and his colleagues reported (New Engl. J. Med. 2012;366:1190-9).

Of note, ixekizumab was significantly more effective than placebo in patients who had psoriasis in difficult to treat areas such as the scalp and nails.

There were no serious adverse events. Two patients developed grade 2 neutropenia. Two patients showed elevations in liver enzymes that subsided when the drug was discontinued.

Both groups of investigators said their findings demonstrate that interleukin-17 is an appropriate target for psoriasis treatment. They also noted that the phase-II studies were too small and too brief to assess these agents’ effects on the risk of infection and cardiovascular events, and noted that further, longer-term studies of safety and efficacy are needed.

Even though there were few adverse effects in these two clinical trials and few patients withdrew from the studies, "a 12-week follow-up period is too short to assess the safety of treatments targeting interleukin-17," said Ari Waisman, Ph.D., in remarks taken from his editorial accompanying the reports on brodalumab and ixekizumab (N. Engl. J. Med. 2012;366:1251-2).

Despite the patients’ marked improvements with both brodalumab and ixekizumab, "future trials involving larger numbers of patients treated and followed for a much longer period of time will be needed," Dr. Waisman of the Institute for Molecular Medicine at Johannes-Gutenberg University of Mainz (Germany) said.

Dr. Papp’s study was funded by Amgen; Dr. Papp and his associates reported ties to numerous industry sources. Dr. Leonardi’s study was funded by Eli Lilly; Dr. Leonardi reported ties to Abbott, Amgen, Celgene, Centocor, Eli Lilly, Pfizer, Galderma, Incyte, Maruho, Schering-Plough, Sirtris, Stiefel, Novartis, Novo Nordisk, Vascular Biogenics, and Wyeth. Dr. Waisman reported ties to Teva, Phenex, and GlaxoSmithKline.

Two monoclonal antibodies targeting interleukin-17 proved effective and safe for moderate to severe plaque psoriasis, according to the results of two phase II clinical trials reported in the March 29 issue of the New England Journal of Medicine.

Both agents had a rapid onset of action and improved scores on the psoriasis area and severity (PASI) index, as well as on measures of dermatology-related quality of life and overall well-being, compared with placebo. Both agents also showed increasing efficacy at higher doses, indicating a dose-response effect, according to the industry-sponsored studies.

Brodalumab

In the first study, researchers assessed brodalumab (AMG 827), a human anti-interleukin-17RA monoclonal antibody that antagonizes the interleukin-17 pathway, in 198 patients at 23 international sites.

The study patients were randomly assigned to receive 70 mg, 140 mg, or 210 mg of brodalumab (at weeks 1, 2, 4, 6, 8, and 10), 280 mg of brodalumab monthly, or placebo injections. A subgroup of 20 patients also underwent skin biopsy at baseline and at week 12, reported Dr. Kim A. Papp of Probity Medical Research, Waterloo, Ont., and his associates.

The mean patient age was 43 years, and the mean duration of psoriasis was 19 years. Most patients had previously received topical and systemic treatments, including phototherapy, and 35% had previously received biologic therapy.

The primary efficacy outcome – percentage improvement in PASI score at week 12 – was significantly greater in every brodalumab group than in the placebo group. Mean improvements were 45% with 70 mg, 85.9% with 140 mg, 86.3% with 210 mg, and 76% with 280 mg, and 16% with placebo.

"Similarly, a significantly higher percentage of patients in the brodalumab groups than in the placebo group [was] assessed as being clear of psoriasis (score of 0 on the physician’s global assessment) or as having minimal disease (score of 1) at week 12," Dr. Papp and his colleagues wrote (N. Engl. J. Med. 2012;366:1181-9)

In addition, the extent of the affected body-surface area was significantly smaller with active treatment than with placebo. Scores on the Dermatology Life Quality Index (DLQI) were significantly lower in the brodalumab groups, indicating that psoriasis had less of an impact on health-related quality of life. And scores on both physical and mental components of the SF-36 were significantly higher, indicating improved well-being, with brodalumab.

Among study patients who underwent skin biopsy, keratin 16 staining of the upper epidermis was reduced, and epidermal thickness and CD3 counts were decreased, at all doses of brodalumab except 70 mg. "This finding indicates a reversal of regenerative epidermal maturation, which is the essential pathological characteristic of psoriasis that causes epidermal hyperplasia and abnormal differentiation, with scaling and thickness as the clinical correlates," Dr. Papp and his associates noted.

At 16-week follow-up, which was 6-8 weeks after the final dose of brodalumab, PASI scores showed a diminished drug effect but were still better than those at baseline.

There were three serious adverse events, only one of which was related to the study drug. This was an asymptomatic case of grade 3 neutropenia, which resolved when the study drug was discontinued. A less serious case of neutropenia developed in another patient.

Ixekizumab

The second study assessed ixekizumab (LY2439821), a humanized IgG4 monoclonal antibody that neutralizes interleukin-17, in 142 patients with moderate to severe plaque psoriasis. The study patients were randomly assigned to receive subcutaneous injections of placebo or 10 mg, 25 mg, 75 mg, or 150 mg of ixekizumab at baseline and at 2, 4, 8, 12, and 16 weeks, reported Dr. Craig Leonardi of the department of dermatology, St. Louis University, and his associates.

The primary efficacy end point was the proportion of patients who achieved at least a 75% improvement in PASI score at 12 weeks. Significantly more patients at all ixekizumab doses except 10 mg achieved this benchmark (76.7%-82.8%), compared with placebo (7.7%).

In addition, significantly more patients (approximately 40%) in the higher-dose groups achieved a 100% improvement in PASI scores, indicating complete clearance of psoriasis, than in the placebo group. And significantly more patients receiving active treatment received physician’s global assessment scores of 0, indicating complete clearance, or 1, indicating minimal disease.

As with brodalumab, the beneficial effect of ixekizumab was evident as early as 1 week into treatment. The drug also significantly improved DLQI scores and decreased the severity of itching, Dr. Leonardi and his colleagues reported (New Engl. J. Med. 2012;366:1190-9).

Of note, ixekizumab was significantly more effective than placebo in patients who had psoriasis in difficult to treat areas such as the scalp and nails.

There were no serious adverse events. Two patients developed grade 2 neutropenia. Two patients showed elevations in liver enzymes that subsided when the drug was discontinued.

Both groups of investigators said their findings demonstrate that interleukin-17 is an appropriate target for psoriasis treatment. They also noted that the phase-II studies were too small and too brief to assess these agents’ effects on the risk of infection and cardiovascular events, and noted that further, longer-term studies of safety and efficacy are needed.

Even though there were few adverse effects in these two clinical trials and few patients withdrew from the studies, "a 12-week follow-up period is too short to assess the safety of treatments targeting interleukin-17," said Ari Waisman, Ph.D., in remarks taken from his editorial accompanying the reports on brodalumab and ixekizumab (N. Engl. J. Med. 2012;366:1251-2).

Despite the patients’ marked improvements with both brodalumab and ixekizumab, "future trials involving larger numbers of patients treated and followed for a much longer period of time will be needed," Dr. Waisman of the Institute for Molecular Medicine at Johannes-Gutenberg University of Mainz (Germany) said.

Dr. Papp’s study was funded by Amgen; Dr. Papp and his associates reported ties to numerous industry sources. Dr. Leonardi’s study was funded by Eli Lilly; Dr. Leonardi reported ties to Abbott, Amgen, Celgene, Centocor, Eli Lilly, Pfizer, Galderma, Incyte, Maruho, Schering-Plough, Sirtris, Stiefel, Novartis, Novo Nordisk, Vascular Biogenics, and Wyeth. Dr. Waisman reported ties to Teva, Phenex, and GlaxoSmithKline.

Two monoclonal antibodies targeting interleukin-17 proved effective and safe for moderate to severe plaque psoriasis, according to the results of two phase II clinical trials reported in the March 29 issue of the New England Journal of Medicine.

Both agents had a rapid onset of action and improved scores on the psoriasis area and severity (PASI) index, as well as on measures of dermatology-related quality of life and overall well-being, compared with placebo. Both agents also showed increasing efficacy at higher doses, indicating a dose-response effect, according to the industry-sponsored studies.

Brodalumab

In the first study, researchers assessed brodalumab (AMG 827), a human anti-interleukin-17RA monoclonal antibody that antagonizes the interleukin-17 pathway, in 198 patients at 23 international sites.

The study patients were randomly assigned to receive 70 mg, 140 mg, or 210 mg of brodalumab (at weeks 1, 2, 4, 6, 8, and 10), 280 mg of brodalumab monthly, or placebo injections. A subgroup of 20 patients also underwent skin biopsy at baseline and at week 12, reported Dr. Kim A. Papp of Probity Medical Research, Waterloo, Ont., and his associates.

The mean patient age was 43 years, and the mean duration of psoriasis was 19 years. Most patients had previously received topical and systemic treatments, including phototherapy, and 35% had previously received biologic therapy.

The primary efficacy outcome – percentage improvement in PASI score at week 12 – was significantly greater in every brodalumab group than in the placebo group. Mean improvements were 45% with 70 mg, 85.9% with 140 mg, 86.3% with 210 mg, and 76% with 280 mg, and 16% with placebo.

"Similarly, a significantly higher percentage of patients in the brodalumab groups than in the placebo group [was] assessed as being clear of psoriasis (score of 0 on the physician’s global assessment) or as having minimal disease (score of 1) at week 12," Dr. Papp and his colleagues wrote (N. Engl. J. Med. 2012;366:1181-9)

In addition, the extent of the affected body-surface area was significantly smaller with active treatment than with placebo. Scores on the Dermatology Life Quality Index (DLQI) were significantly lower in the brodalumab groups, indicating that psoriasis had less of an impact on health-related quality of life. And scores on both physical and mental components of the SF-36 were significantly higher, indicating improved well-being, with brodalumab.

Among study patients who underwent skin biopsy, keratin 16 staining of the upper epidermis was reduced, and epidermal thickness and CD3 counts were decreased, at all doses of brodalumab except 70 mg. "This finding indicates a reversal of regenerative epidermal maturation, which is the essential pathological characteristic of psoriasis that causes epidermal hyperplasia and abnormal differentiation, with scaling and thickness as the clinical correlates," Dr. Papp and his associates noted.

At 16-week follow-up, which was 6-8 weeks after the final dose of brodalumab, PASI scores showed a diminished drug effect but were still better than those at baseline.

There were three serious adverse events, only one of which was related to the study drug. This was an asymptomatic case of grade 3 neutropenia, which resolved when the study drug was discontinued. A less serious case of neutropenia developed in another patient.

Ixekizumab

The second study assessed ixekizumab (LY2439821), a humanized IgG4 monoclonal antibody that neutralizes interleukin-17, in 142 patients with moderate to severe plaque psoriasis. The study patients were randomly assigned to receive subcutaneous injections of placebo or 10 mg, 25 mg, 75 mg, or 150 mg of ixekizumab at baseline and at 2, 4, 8, 12, and 16 weeks, reported Dr. Craig Leonardi of the department of dermatology, St. Louis University, and his associates.

The primary efficacy end point was the proportion of patients who achieved at least a 75% improvement in PASI score at 12 weeks. Significantly more patients at all ixekizumab doses except 10 mg achieved this benchmark (76.7%-82.8%), compared with placebo (7.7%).

In addition, significantly more patients (approximately 40%) in the higher-dose groups achieved a 100% improvement in PASI scores, indicating complete clearance of psoriasis, than in the placebo group. And significantly more patients receiving active treatment received physician’s global assessment scores of 0, indicating complete clearance, or 1, indicating minimal disease.

As with brodalumab, the beneficial effect of ixekizumab was evident as early as 1 week into treatment. The drug also significantly improved DLQI scores and decreased the severity of itching, Dr. Leonardi and his colleagues reported (New Engl. J. Med. 2012;366:1190-9).

Of note, ixekizumab was significantly more effective than placebo in patients who had psoriasis in difficult to treat areas such as the scalp and nails.

There were no serious adverse events. Two patients developed grade 2 neutropenia. Two patients showed elevations in liver enzymes that subsided when the drug was discontinued.

Both groups of investigators said their findings demonstrate that interleukin-17 is an appropriate target for psoriasis treatment. They also noted that the phase-II studies were too small and too brief to assess these agents’ effects on the risk of infection and cardiovascular events, and noted that further, longer-term studies of safety and efficacy are needed.

Even though there were few adverse effects in these two clinical trials and few patients withdrew from the studies, "a 12-week follow-up period is too short to assess the safety of treatments targeting interleukin-17," said Ari Waisman, Ph.D., in remarks taken from his editorial accompanying the reports on brodalumab and ixekizumab (N. Engl. J. Med. 2012;366:1251-2).

Despite the patients’ marked improvements with both brodalumab and ixekizumab, "future trials involving larger numbers of patients treated and followed for a much longer period of time will be needed," Dr. Waisman of the Institute for Molecular Medicine at Johannes-Gutenberg University of Mainz (Germany) said.

Dr. Papp’s study was funded by Amgen; Dr. Papp and his associates reported ties to numerous industry sources. Dr. Leonardi’s study was funded by Eli Lilly; Dr. Leonardi reported ties to Abbott, Amgen, Celgene, Centocor, Eli Lilly, Pfizer, Galderma, Incyte, Maruho, Schering-Plough, Sirtris, Stiefel, Novartis, Novo Nordisk, Vascular Biogenics, and Wyeth. Dr. Waisman reported ties to Teva, Phenex, and GlaxoSmithKline.