Briakinumab, Ustekinumab Trials Point to Future Psoriasis Treatment

Increased insight into the pathogenesis of psoriasis has led to the development of new drugs with novel mechanisms of action, as well as safer and more effective approaches to treatment with conventional drugs

As a result, treatment options for the management of patients with moderate to severe psoriasis in particular – nearly 25% of all patients with psoriasis, according to the National Psoriasis Foundation – have broadened substantially, and research reported during the past year suggests they are on track for continued expansion.

Among the most notable trials of the year were establishing the "unsurpassed efficacy" of Abbott’s investigational monoclonal antibody briakinumab, according to Dr. Craig Leonardi, a dermatologist and psoriasis specialist at St. Louis University. Like the recently approved psoriatic drug ustekinumab (Stelara), briakinumab is an injectable biologic agent that targets the interleukin-12 and -23 (IL-12/23) proteins, which are believed to promote the inflammation associated with psoriasis.

IL-12/23 Inhibition

Four phase III clinical studies of briakinumab were presented at the annual meeting of the European Academy of Dermatology and Venereology (EADV) in Gothenburg, Sweden.

– M06-890. In this trial, comparing the efficacy and safety of briakinumab to placebo, 80.7% of the 981 patients randomized to receive briakinumab every 4 weeks following an induction phase experienced a 75% improvement in psoriasis symptoms (PASI 75) at week 12, compared with 4.5% of the 484 patients randomized to placebo. Additionally, 61.6% and 32.2% of patients, respectively, saw 90% and 100% symptom clearance. And at week 52, 82.4% of patients who had achieved PASI 75 maintained at least that level of clearance.

– M10-315 and M10-114. In each of two 12-week trials comparing briakinumab to etanercept, significantly more patients randomized to briakinumab achieved Physician Global Assessment (PGA) scores of 0 or 1 and PASI 75 clearance. In the 350-patient M10-315 and the 347-patient M10-114 studies, respectively, 72.7% and 71% of patients randomized to briakinumab treatment achieved PGA 0 or 1, compared with 29.5% and 39.7% of patients randomized to etanercept therapy and 4.2% and 2.9% of those randomized to placebo.

Additionally, in the respective studies, 80.6% and 81.9% of the briakinumab-treated patients achieved PASI 75, compared with 39.6% and 56% of the etanercept patents, and 6.9% and 7.4% of the placebo groups.

– M10-255. The fourth trial of 317 patients was a head-to-head comparison with methotrexate in which 81.8% of briakinumab patients achieved PASI 75 clearance at 24 weeks, compared with 39.9% of those taking methotrexate. At 52 weeks, the PASI 75 clearance rates were 66.2% in the briakinumab group and 23.9% in the methotrexate group.

The most common adverse events observed across all four studies and in an ongoing open-label extension were upper respiratory infection, nasopharyngitis, headache, arthralgia, hypertension, and back pain. The incidence of infection and malignancy with briakinumab were higher than those with placebo, but were similar to those in patients treated with etanercept or methotrexate, according to a press release issued by Abbott.

Of particular note is the incidence of major adverse cardiovascular events (MACE) associated with briakinumab, Dr. Leonardi said in an interview. In the M06-890 trial, for example, seven briakinumab patients – all of whom had identifiable underlying cardiovascular risk factors, according to Abbott – experienced a MACE. A similar number of major cardiovascular events were observed in phase III trials of ustekinumab (Stelara), the IL 12/23 antagonist that received Food and Drug Administration approval for psoriasis treatment, he said. "Both drugs share the same mechanism of action, so it’s important to be cautious," he said. "Briakinumab has been submitted for FDA approval. We are awaiting review and comment."

Ustekinumab

Positive ustekinumab results were also presented last year. A pooled analysis of safety data reported at the summer academy meeting of the American Academy of Dermatology in Chicago demonstrated a favorable risk/benefit profile for up to 3 years of treatment.

Based on integrated data for 3,117 patients from the pivotal phase III PHOENIX 1 and PHOENIX 2 trials and the phase III ACCEPT trial, the investigators reported that the overall rates of adverse and serious adverse events were comparable in the 45-mg and 90-mg ustekinumab patient groups.

For the 45-mg and 90-mg patient groups, respectively, the per-hundred-patient-year rates were 0.82 and 1.50 for serious infections, 0.69 and 0.46 for noncutaneous malignancies, and 0.41 and 0.35 for MACE.

These rates were consistent with expectations for both general and psoriasis populations, and they remained stable over time, according to Dr. Leonardi, one of the study investigators. The maintenance of the favorable safety profile in patients who have been treated for several years is "encouraging," he said, noting that ongoing 5-year follow-up studies will enable continued monitoring of the drug’s safety.

Other important developments that may bode well for the treatment of psoriasis include data on IL-17 inhibitors, oral and topical janus kinase (JAK) inhibitors, an oral phosphodiesterase inhibitor, several IL-23 blockers, and topical niacin/calcipotriene, according to Dr. Leonardi and Dr. Alice B. Gottlieb of Tufts Medical Center in Boston.

Targeting IL-17

Recent studies have suggested that IL-17A–producing T cells have a crucial role in the pathogenesis of psoriasis, making them a potential treatment target.

In a phase II trial, a fully human IL-17 antibody AIN457 (Novartis) produced clinically meaningful reductions of disease activity at 4 and 12 weeks in 13 of 18 psoriasis patients who were randomized to receive a single 3-mg/kg intravenous infusion of the drug. At study weeks 4 and 12, respectively, the mean PASI score decreased by 58% and 63% in the AIN457 patients, compared with 4% and 9% in placebo patients, the authors wrote (Sci. Transl. Med. 2010;52:52ra72).

The results of a phase I study of another IL-17 drug – Amgen’s AMG 827, which binds to and blocks signaling via the IL-17 receptor – were reported at the EADV meeting. Most of the 16 patients who received a single dose of the fully human monoclonal antibody experienced substantial improvements in psoriasis symptoms. Based on the favorable findings, a phase II study is currently underway.

JAK 3 Inhibitors

The JAK pathways are also believed to have roles in the psoriasis disease cascade and as such have emerged as a treatment target. The four known JAK enzymes – JAK1, JAK2, JAK3, and tyrosine kinase (TYK) 2 – are components of signaling mechanisms used by multiple cytokines and growth factors that trigger dysregulated inflammatory pathways, according to Dr. Gottlieb. Oral and topical inhibitors of JAK are in phase II and III trials and have had promising results so far, she said in an interview.

In a 197-patient, phase II efficacy and safety study, Pfizer’s investigational oral JAK3 inhibitor, tentatively named tasocitinib (CP-690550), produced statistically significant responses at 12 weeks, compared with placebo in adults with moderate to severe psoriasis. The PASI 75 responses for patients randomized to twice daily tasocitinib at 2-mg, 5-mg, and 15-mg doses, respectively, were 25%, 40.8%, and 66.7%, compared with 2.0% for placebo, according to a company-issued statement. Additionally, as early as study week 4, "treatment with 5 and 15 mg twice daily of tasocitinib significantly improved patient-reported health-related quality of life outcomes."

Regarding safety, three patients randomized to tasocitinib treatment experienced a total of five serious adverse events during the study. Additionally, the investigators observed dose dependent decreases in mean neutrophil counts and hemoglobin values and increases in mean LDL, HDL, and total cholesterol levels. A large-scale, phase III trial program, called Oral Psoriasis Treatment (OPT) trials, is currently underway.

Topical JAK inhibitors are also under development, which presumably will avoid some of the complications associated with systemic therapy, according to Dr. Gottlieb, who is involved with investigations of Incyte’s topical JAK1/JAK2 inhibitor, INCB18424, which has demonstrated robust activity and safety in placebo-controlled, multidose, phase IIb trials in patients with mild to moderate psoriasis.

In studies reported by Dr. Gottlieb at last year’s annual meeting of the American Academy of Dermatology, topical application of INCB18424 cream led to significant improvement in the psoriatic lesions of treated patients at day 28, with the total lesion scores decreasing twofold, compared with placebo. "The effects were seen as early as 2 weeks, and they extended through" the study period," she said, noting that immunohistochemical staining and microarray gene analysis data confirmed the improvement in skin histology and the reduction in the psoriatic molecular signature.

Apremilast May Break Ground

Poised to be "the first oral medication with a new mechanism of action for psoriasis in almost 20 years," the phosphodiesterase 4 (PDE4) enzyme inhibitor apremilast (Celgene) demonstrated favorable results in a phase IIb study reported in December 2009 and has recently begun phase III trials, according to Dr. Leonardi.

In the phase IIb trial, 352 patients with moderate to severe plaque-type psoriasis were randomized to receive 10 mg, 20 mg or 30 mg of apremilast twice per day or placebo. Of the apremilast patients, 41% of the 30-mg group, 29% of the 20-mg group, and 11% of the 10-mg group achieved a PASI 75 after 16 weeks, compared with 6% of the placebo group, according a company statement.

A comparison of infection rates showed that infections occurred in 48% of the 30 mg apremilast patients and 33% of the placebo patients. No serious adverse events related to apremilast were reported.

The positive results have led to the initiation of two pivotal phase III trials: the multicenter ESTEEM 1 and ESTEEM 2 safety and efficacy studies comprising, respectively, 825 patients and 405 patients with moderate to severe plaque psoriasis. Primary outcome data from both studies will be available in the summer of 2011.

Topical Niacin/Calcipotriene

The nonsteroidal topical options for psoriasis will likely be expanded further by the addition of topical niacin (nicotinamide) to standard treatment with the synthetic vitamin D derivative calcipotriene, according to Dr. Gottlieb.

A recent 168-patient multicenter, double-blind, randomized trial reported that 50% of patients randomized to combination therapy with 0.005% calcipotriene and 1.4% nicotinamide achieved symptom clearance or near clearance, compared with 18.8% of patients randomized to placebo, 25% of patients treated with nicotinamide alone, and 31.5% of patients treated with calcipotriene alone.

The findings suggest that the combination therapy "may prove effective as an alternative therapeutic option to calcipotriene monotherapy and may provide an attractive option for patients seeking an effective corticosteroid-sparing topical psoriatic agent," the investigators wrote (J. Am. Acad. Dermatol. 2010;63:775-81).

In the midst of all of the new developments, it is important to note that tumor necrosis factor (TNF) antagonists continue to perform well, Dr. Leonardi stressed. "Given that the class is now 12 years old and includes 2 million patients, we are unlikely to learn of major safety risks at this point, and registry data support the notion that TNF blockade is cardioprotective in [rheumatoid arthritis], in distinction to the IL 12/23 blockers, where the MACE issue is unresolved," he said. "At this point, it is important for dermatologists to remember that the IL-12/23 drugs, in particular, are new, and since they are psoriasis specific, there are no other disease states where they were previously used."

Until the new drugs are in widespread use, "they should be used with caution," Dr. Leonardi continued. "The last psoriasis-specific biologic we used was Raptiva, which was voluntarily removed from the market by Genentech after 3 patients were identified with a rare and fatal central nervous system infection. At the time these patients were identified, the drug had been on the market for 5 years and had been used in 23,000 patients."

What this means in clinical practice is that ustekinumab or briakinumab may be reasonable options for patients with a history of failure of TNF antagonists or a history of central or peripheral demyelination, but until longer-term safety data are available, it should not be the first choice in the majority of treatment-naive patients, said Dr. Leonardi.

Dr. Leonardi is a consultant, investigator, and/or on the speakers bureau of Amgen, Abbott, Celgene, Centocor, Genentech, Incyte, Novartis Pfizer, and several other pharmaceutical companies.

Dr. Gottlieb has current consulting/advisory board agreements with Abbott, Amgen, Celgene, Incyte, and numerous other pharmaceutical companies.

Increased insight into the pathogenesis of psoriasis has led to the development of new drugs with novel mechanisms of action, as well as safer and more effective approaches to treatment with conventional drugs

As a result, treatment options for the management of patients with moderate to severe psoriasis in particular – nearly 25% of all patients with psoriasis, according to the National Psoriasis Foundation – have broadened substantially, and research reported during the past year suggests they are on track for continued expansion.

Among the most notable trials of the year were establishing the "unsurpassed efficacy" of Abbott’s investigational monoclonal antibody briakinumab, according to Dr. Craig Leonardi, a dermatologist and psoriasis specialist at St. Louis University. Like the recently approved psoriatic drug ustekinumab (Stelara), briakinumab is an injectable biologic agent that targets the interleukin-12 and -23 (IL-12/23) proteins, which are believed to promote the inflammation associated with psoriasis.

IL-12/23 Inhibition

Four phase III clinical studies of briakinumab were presented at the annual meeting of the European Academy of Dermatology and Venereology (EADV) in Gothenburg, Sweden.

– M06-890. In this trial, comparing the efficacy and safety of briakinumab to placebo, 80.7% of the 981 patients randomized to receive briakinumab every 4 weeks following an induction phase experienced a 75% improvement in psoriasis symptoms (PASI 75) at week 12, compared with 4.5% of the 484 patients randomized to placebo. Additionally, 61.6% and 32.2% of patients, respectively, saw 90% and 100% symptom clearance. And at week 52, 82.4% of patients who had achieved PASI 75 maintained at least that level of clearance.

– M10-315 and M10-114. In each of two 12-week trials comparing briakinumab to etanercept, significantly more patients randomized to briakinumab achieved Physician Global Assessment (PGA) scores of 0 or 1 and PASI 75 clearance. In the 350-patient M10-315 and the 347-patient M10-114 studies, respectively, 72.7% and 71% of patients randomized to briakinumab treatment achieved PGA 0 or 1, compared with 29.5% and 39.7% of patients randomized to etanercept therapy and 4.2% and 2.9% of those randomized to placebo.

Additionally, in the respective studies, 80.6% and 81.9% of the briakinumab-treated patients achieved PASI 75, compared with 39.6% and 56% of the etanercept patents, and 6.9% and 7.4% of the placebo groups.

– M10-255. The fourth trial of 317 patients was a head-to-head comparison with methotrexate in which 81.8% of briakinumab patients achieved PASI 75 clearance at 24 weeks, compared with 39.9% of those taking methotrexate. At 52 weeks, the PASI 75 clearance rates were 66.2% in the briakinumab group and 23.9% in the methotrexate group.

The most common adverse events observed across all four studies and in an ongoing open-label extension were upper respiratory infection, nasopharyngitis, headache, arthralgia, hypertension, and back pain. The incidence of infection and malignancy with briakinumab were higher than those with placebo, but were similar to those in patients treated with etanercept or methotrexate, according to a press release issued by Abbott.

Of particular note is the incidence of major adverse cardiovascular events (MACE) associated with briakinumab, Dr. Leonardi said in an interview. In the M06-890 trial, for example, seven briakinumab patients – all of whom had identifiable underlying cardiovascular risk factors, according to Abbott – experienced a MACE. A similar number of major cardiovascular events were observed in phase III trials of ustekinumab (Stelara), the IL 12/23 antagonist that received Food and Drug Administration approval for psoriasis treatment, he said. "Both drugs share the same mechanism of action, so it’s important to be cautious," he said. "Briakinumab has been submitted for FDA approval. We are awaiting review and comment."

Ustekinumab

Positive ustekinumab results were also presented last year. A pooled analysis of safety data reported at the summer academy meeting of the American Academy of Dermatology in Chicago demonstrated a favorable risk/benefit profile for up to 3 years of treatment.

Based on integrated data for 3,117 patients from the pivotal phase III PHOENIX 1 and PHOENIX 2 trials and the phase III ACCEPT trial, the investigators reported that the overall rates of adverse and serious adverse events were comparable in the 45-mg and 90-mg ustekinumab patient groups.

For the 45-mg and 90-mg patient groups, respectively, the per-hundred-patient-year rates were 0.82 and 1.50 for serious infections, 0.69 and 0.46 for noncutaneous malignancies, and 0.41 and 0.35 for MACE.

These rates were consistent with expectations for both general and psoriasis populations, and they remained stable over time, according to Dr. Leonardi, one of the study investigators. The maintenance of the favorable safety profile in patients who have been treated for several years is "encouraging," he said, noting that ongoing 5-year follow-up studies will enable continued monitoring of the drug’s safety.

Other important developments that may bode well for the treatment of psoriasis include data on IL-17 inhibitors, oral and topical janus kinase (JAK) inhibitors, an oral phosphodiesterase inhibitor, several IL-23 blockers, and topical niacin/calcipotriene, according to Dr. Leonardi and Dr. Alice B. Gottlieb of Tufts Medical Center in Boston.

Targeting IL-17

Recent studies have suggested that IL-17A–producing T cells have a crucial role in the pathogenesis of psoriasis, making them a potential treatment target.

In a phase II trial, a fully human IL-17 antibody AIN457 (Novartis) produced clinically meaningful reductions of disease activity at 4 and 12 weeks in 13 of 18 psoriasis patients who were randomized to receive a single 3-mg/kg intravenous infusion of the drug. At study weeks 4 and 12, respectively, the mean PASI score decreased by 58% and 63% in the AIN457 patients, compared with 4% and 9% in placebo patients, the authors wrote (Sci. Transl. Med. 2010;52:52ra72).

The results of a phase I study of another IL-17 drug – Amgen’s AMG 827, which binds to and blocks signaling via the IL-17 receptor – were reported at the EADV meeting. Most of the 16 patients who received a single dose of the fully human monoclonal antibody experienced substantial improvements in psoriasis symptoms. Based on the favorable findings, a phase II study is currently underway.

JAK 3 Inhibitors

The JAK pathways are also believed to have roles in the psoriasis disease cascade and as such have emerged as a treatment target. The four known JAK enzymes – JAK1, JAK2, JAK3, and tyrosine kinase (TYK) 2 – are components of signaling mechanisms used by multiple cytokines and growth factors that trigger dysregulated inflammatory pathways, according to Dr. Gottlieb. Oral and topical inhibitors of JAK are in phase II and III trials and have had promising results so far, she said in an interview.

In a 197-patient, phase II efficacy and safety study, Pfizer’s investigational oral JAK3 inhibitor, tentatively named tasocitinib (CP-690550), produced statistically significant responses at 12 weeks, compared with placebo in adults with moderate to severe psoriasis. The PASI 75 responses for patients randomized to twice daily tasocitinib at 2-mg, 5-mg, and 15-mg doses, respectively, were 25%, 40.8%, and 66.7%, compared with 2.0% for placebo, according to a company-issued statement. Additionally, as early as study week 4, "treatment with 5 and 15 mg twice daily of tasocitinib significantly improved patient-reported health-related quality of life outcomes."

Regarding safety, three patients randomized to tasocitinib treatment experienced a total of five serious adverse events during the study. Additionally, the investigators observed dose dependent decreases in mean neutrophil counts and hemoglobin values and increases in mean LDL, HDL, and total cholesterol levels. A large-scale, phase III trial program, called Oral Psoriasis Treatment (OPT) trials, is currently underway.

Topical JAK inhibitors are also under development, which presumably will avoid some of the complications associated with systemic therapy, according to Dr. Gottlieb, who is involved with investigations of Incyte’s topical JAK1/JAK2 inhibitor, INCB18424, which has demonstrated robust activity and safety in placebo-controlled, multidose, phase IIb trials in patients with mild to moderate psoriasis.

In studies reported by Dr. Gottlieb at last year’s annual meeting of the American Academy of Dermatology, topical application of INCB18424 cream led to significant improvement in the psoriatic lesions of treated patients at day 28, with the total lesion scores decreasing twofold, compared with placebo. "The effects were seen as early as 2 weeks, and they extended through" the study period," she said, noting that immunohistochemical staining and microarray gene analysis data confirmed the improvement in skin histology and the reduction in the psoriatic molecular signature.

Apremilast May Break Ground

Poised to be "the first oral medication with a new mechanism of action for psoriasis in almost 20 years," the phosphodiesterase 4 (PDE4) enzyme inhibitor apremilast (Celgene) demonstrated favorable results in a phase IIb study reported in December 2009 and has recently begun phase III trials, according to Dr. Leonardi.

In the phase IIb trial, 352 patients with moderate to severe plaque-type psoriasis were randomized to receive 10 mg, 20 mg or 30 mg of apremilast twice per day or placebo. Of the apremilast patients, 41% of the 30-mg group, 29% of the 20-mg group, and 11% of the 10-mg group achieved a PASI 75 after 16 weeks, compared with 6% of the placebo group, according a company statement.

A comparison of infection rates showed that infections occurred in 48% of the 30 mg apremilast patients and 33% of the placebo patients. No serious adverse events related to apremilast were reported.

The positive results have led to the initiation of two pivotal phase III trials: the multicenter ESTEEM 1 and ESTEEM 2 safety and efficacy studies comprising, respectively, 825 patients and 405 patients with moderate to severe plaque psoriasis. Primary outcome data from both studies will be available in the summer of 2011.

Topical Niacin/Calcipotriene

The nonsteroidal topical options for psoriasis will likely be expanded further by the addition of topical niacin (nicotinamide) to standard treatment with the synthetic vitamin D derivative calcipotriene, according to Dr. Gottlieb.

A recent 168-patient multicenter, double-blind, randomized trial reported that 50% of patients randomized to combination therapy with 0.005% calcipotriene and 1.4% nicotinamide achieved symptom clearance or near clearance, compared with 18.8% of patients randomized to placebo, 25% of patients treated with nicotinamide alone, and 31.5% of patients treated with calcipotriene alone.

The findings suggest that the combination therapy "may prove effective as an alternative therapeutic option to calcipotriene monotherapy and may provide an attractive option for patients seeking an effective corticosteroid-sparing topical psoriatic agent," the investigators wrote (J. Am. Acad. Dermatol. 2010;63:775-81).

In the midst of all of the new developments, it is important to note that tumor necrosis factor (TNF) antagonists continue to perform well, Dr. Leonardi stressed. "Given that the class is now 12 years old and includes 2 million patients, we are unlikely to learn of major safety risks at this point, and registry data support the notion that TNF blockade is cardioprotective in [rheumatoid arthritis], in distinction to the IL 12/23 blockers, where the MACE issue is unresolved," he said. "At this point, it is important for dermatologists to remember that the IL-12/23 drugs, in particular, are new, and since they are psoriasis specific, there are no other disease states where they were previously used."

Until the new drugs are in widespread use, "they should be used with caution," Dr. Leonardi continued. "The last psoriasis-specific biologic we used was Raptiva, which was voluntarily removed from the market by Genentech after 3 patients were identified with a rare and fatal central nervous system infection. At the time these patients were identified, the drug had been on the market for 5 years and had been used in 23,000 patients."

What this means in clinical practice is that ustekinumab or briakinumab may be reasonable options for patients with a history of failure of TNF antagonists or a history of central or peripheral demyelination, but until longer-term safety data are available, it should not be the first choice in the majority of treatment-naive patients, said Dr. Leonardi.

Dr. Leonardi is a consultant, investigator, and/or on the speakers bureau of Amgen, Abbott, Celgene, Centocor, Genentech, Incyte, Novartis Pfizer, and several other pharmaceutical companies.

Dr. Gottlieb has current consulting/advisory board agreements with Abbott, Amgen, Celgene, Incyte, and numerous other pharmaceutical companies.

Increased insight into the pathogenesis of psoriasis has led to the development of new drugs with novel mechanisms of action, as well as safer and more effective approaches to treatment with conventional drugs

As a result, treatment options for the management of patients with moderate to severe psoriasis in particular – nearly 25% of all patients with psoriasis, according to the National Psoriasis Foundation – have broadened substantially, and research reported during the past year suggests they are on track for continued expansion.

Among the most notable trials of the year were establishing the "unsurpassed efficacy" of Abbott’s investigational monoclonal antibody briakinumab, according to Dr. Craig Leonardi, a dermatologist and psoriasis specialist at St. Louis University. Like the recently approved psoriatic drug ustekinumab (Stelara), briakinumab is an injectable biologic agent that targets the interleukin-12 and -23 (IL-12/23) proteins, which are believed to promote the inflammation associated with psoriasis.

IL-12/23 Inhibition

Four phase III clinical studies of briakinumab were presented at the annual meeting of the European Academy of Dermatology and Venereology (EADV) in Gothenburg, Sweden.

– M06-890. In this trial, comparing the efficacy and safety of briakinumab to placebo, 80.7% of the 981 patients randomized to receive briakinumab every 4 weeks following an induction phase experienced a 75% improvement in psoriasis symptoms (PASI 75) at week 12, compared with 4.5% of the 484 patients randomized to placebo. Additionally, 61.6% and 32.2% of patients, respectively, saw 90% and 100% symptom clearance. And at week 52, 82.4% of patients who had achieved PASI 75 maintained at least that level of clearance.

– M10-315 and M10-114. In each of two 12-week trials comparing briakinumab to etanercept, significantly more patients randomized to briakinumab achieved Physician Global Assessment (PGA) scores of 0 or 1 and PASI 75 clearance. In the 350-patient M10-315 and the 347-patient M10-114 studies, respectively, 72.7% and 71% of patients randomized to briakinumab treatment achieved PGA 0 or 1, compared with 29.5% and 39.7% of patients randomized to etanercept therapy and 4.2% and 2.9% of those randomized to placebo.

Additionally, in the respective studies, 80.6% and 81.9% of the briakinumab-treated patients achieved PASI 75, compared with 39.6% and 56% of the etanercept patents, and 6.9% and 7.4% of the placebo groups.

– M10-255. The fourth trial of 317 patients was a head-to-head comparison with methotrexate in which 81.8% of briakinumab patients achieved PASI 75 clearance at 24 weeks, compared with 39.9% of those taking methotrexate. At 52 weeks, the PASI 75 clearance rates were 66.2% in the briakinumab group and 23.9% in the methotrexate group.

The most common adverse events observed across all four studies and in an ongoing open-label extension were upper respiratory infection, nasopharyngitis, headache, arthralgia, hypertension, and back pain. The incidence of infection and malignancy with briakinumab were higher than those with placebo, but were similar to those in patients treated with etanercept or methotrexate, according to a press release issued by Abbott.

Of particular note is the incidence of major adverse cardiovascular events (MACE) associated with briakinumab, Dr. Leonardi said in an interview. In the M06-890 trial, for example, seven briakinumab patients – all of whom had identifiable underlying cardiovascular risk factors, according to Abbott – experienced a MACE. A similar number of major cardiovascular events were observed in phase III trials of ustekinumab (Stelara), the IL 12/23 antagonist that received Food and Drug Administration approval for psoriasis treatment, he said. "Both drugs share the same mechanism of action, so it’s important to be cautious," he said. "Briakinumab has been submitted for FDA approval. We are awaiting review and comment."

Ustekinumab

Positive ustekinumab results were also presented last year. A pooled analysis of safety data reported at the summer academy meeting of the American Academy of Dermatology in Chicago demonstrated a favorable risk/benefit profile for up to 3 years of treatment.

Based on integrated data for 3,117 patients from the pivotal phase III PHOENIX 1 and PHOENIX 2 trials and the phase III ACCEPT trial, the investigators reported that the overall rates of adverse and serious adverse events were comparable in the 45-mg and 90-mg ustekinumab patient groups.

For the 45-mg and 90-mg patient groups, respectively, the per-hundred-patient-year rates were 0.82 and 1.50 for serious infections, 0.69 and 0.46 for noncutaneous malignancies, and 0.41 and 0.35 for MACE.

These rates were consistent with expectations for both general and psoriasis populations, and they remained stable over time, according to Dr. Leonardi, one of the study investigators. The maintenance of the favorable safety profile in patients who have been treated for several years is "encouraging," he said, noting that ongoing 5-year follow-up studies will enable continued monitoring of the drug’s safety.

Other important developments that may bode well for the treatment of psoriasis include data on IL-17 inhibitors, oral and topical janus kinase (JAK) inhibitors, an oral phosphodiesterase inhibitor, several IL-23 blockers, and topical niacin/calcipotriene, according to Dr. Leonardi and Dr. Alice B. Gottlieb of Tufts Medical Center in Boston.

Targeting IL-17

Recent studies have suggested that IL-17A–producing T cells have a crucial role in the pathogenesis of psoriasis, making them a potential treatment target.

In a phase II trial, a fully human IL-17 antibody AIN457 (Novartis) produced clinically meaningful reductions of disease activity at 4 and 12 weeks in 13 of 18 psoriasis patients who were randomized to receive a single 3-mg/kg intravenous infusion of the drug. At study weeks 4 and 12, respectively, the mean PASI score decreased by 58% and 63% in the AIN457 patients, compared with 4% and 9% in placebo patients, the authors wrote (Sci. Transl. Med. 2010;52:52ra72).

The results of a phase I study of another IL-17 drug – Amgen’s AMG 827, which binds to and blocks signaling via the IL-17 receptor – were reported at the EADV meeting. Most of the 16 patients who received a single dose of the fully human monoclonal antibody experienced substantial improvements in psoriasis symptoms. Based on the favorable findings, a phase II study is currently underway.

JAK 3 Inhibitors

The JAK pathways are also believed to have roles in the psoriasis disease cascade and as such have emerged as a treatment target. The four known JAK enzymes – JAK1, JAK2, JAK3, and tyrosine kinase (TYK) 2 – are components of signaling mechanisms used by multiple cytokines and growth factors that trigger dysregulated inflammatory pathways, according to Dr. Gottlieb. Oral and topical inhibitors of JAK are in phase II and III trials and have had promising results so far, she said in an interview.

In a 197-patient, phase II efficacy and safety study, Pfizer’s investigational oral JAK3 inhibitor, tentatively named tasocitinib (CP-690550), produced statistically significant responses at 12 weeks, compared with placebo in adults with moderate to severe psoriasis. The PASI 75 responses for patients randomized to twice daily tasocitinib at 2-mg, 5-mg, and 15-mg doses, respectively, were 25%, 40.8%, and 66.7%, compared with 2.0% for placebo, according to a company-issued statement. Additionally, as early as study week 4, "treatment with 5 and 15 mg twice daily of tasocitinib significantly improved patient-reported health-related quality of life outcomes."

Regarding safety, three patients randomized to tasocitinib treatment experienced a total of five serious adverse events during the study. Additionally, the investigators observed dose dependent decreases in mean neutrophil counts and hemoglobin values and increases in mean LDL, HDL, and total cholesterol levels. A large-scale, phase III trial program, called Oral Psoriasis Treatment (OPT) trials, is currently underway.

Topical JAK inhibitors are also under development, which presumably will avoid some of the complications associated with systemic therapy, according to Dr. Gottlieb, who is involved with investigations of Incyte’s topical JAK1/JAK2 inhibitor, INCB18424, which has demonstrated robust activity and safety in placebo-controlled, multidose, phase IIb trials in patients with mild to moderate psoriasis.

In studies reported by Dr. Gottlieb at last year’s annual meeting of the American Academy of Dermatology, topical application of INCB18424 cream led to significant improvement in the psoriatic lesions of treated patients at day 28, with the total lesion scores decreasing twofold, compared with placebo. "The effects were seen as early as 2 weeks, and they extended through" the study period," she said, noting that immunohistochemical staining and microarray gene analysis data confirmed the improvement in skin histology and the reduction in the psoriatic molecular signature.

Apremilast May Break Ground

Poised to be "the first oral medication with a new mechanism of action for psoriasis in almost 20 years," the phosphodiesterase 4 (PDE4) enzyme inhibitor apremilast (Celgene) demonstrated favorable results in a phase IIb study reported in December 2009 and has recently begun phase III trials, according to Dr. Leonardi.

In the phase IIb trial, 352 patients with moderate to severe plaque-type psoriasis were randomized to receive 10 mg, 20 mg or 30 mg of apremilast twice per day or placebo. Of the apremilast patients, 41% of the 30-mg group, 29% of the 20-mg group, and 11% of the 10-mg group achieved a PASI 75 after 16 weeks, compared with 6% of the placebo group, according a company statement.

A comparison of infection rates showed that infections occurred in 48% of the 30 mg apremilast patients and 33% of the placebo patients. No serious adverse events related to apremilast were reported.

The positive results have led to the initiation of two pivotal phase III trials: the multicenter ESTEEM 1 and ESTEEM 2 safety and efficacy studies comprising, respectively, 825 patients and 405 patients with moderate to severe plaque psoriasis. Primary outcome data from both studies will be available in the summer of 2011.

Topical Niacin/Calcipotriene

The nonsteroidal topical options for psoriasis will likely be expanded further by the addition of topical niacin (nicotinamide) to standard treatment with the synthetic vitamin D derivative calcipotriene, according to Dr. Gottlieb.

A recent 168-patient multicenter, double-blind, randomized trial reported that 50% of patients randomized to combination therapy with 0.005% calcipotriene and 1.4% nicotinamide achieved symptom clearance or near clearance, compared with 18.8% of patients randomized to placebo, 25% of patients treated with nicotinamide alone, and 31.5% of patients treated with calcipotriene alone.

The findings suggest that the combination therapy "may prove effective as an alternative therapeutic option to calcipotriene monotherapy and may provide an attractive option for patients seeking an effective corticosteroid-sparing topical psoriatic agent," the investigators wrote (J. Am. Acad. Dermatol. 2010;63:775-81).

In the midst of all of the new developments, it is important to note that tumor necrosis factor (TNF) antagonists continue to perform well, Dr. Leonardi stressed. "Given that the class is now 12 years old and includes 2 million patients, we are unlikely to learn of major safety risks at this point, and registry data support the notion that TNF blockade is cardioprotective in [rheumatoid arthritis], in distinction to the IL 12/23 blockers, where the MACE issue is unresolved," he said. "At this point, it is important for dermatologists to remember that the IL-12/23 drugs, in particular, are new, and since they are psoriasis specific, there are no other disease states where they were previously used."

Until the new drugs are in widespread use, "they should be used with caution," Dr. Leonardi continued. "The last psoriasis-specific biologic we used was Raptiva, which was voluntarily removed from the market by Genentech after 3 patients were identified with a rare and fatal central nervous system infection. At the time these patients were identified, the drug had been on the market for 5 years and had been used in 23,000 patients."

What this means in clinical practice is that ustekinumab or briakinumab may be reasonable options for patients with a history of failure of TNF antagonists or a history of central or peripheral demyelination, but until longer-term safety data are available, it should not be the first choice in the majority of treatment-naive patients, said Dr. Leonardi.

Dr. Leonardi is a consultant, investigator, and/or on the speakers bureau of Amgen, Abbott, Celgene, Centocor, Genentech, Incyte, Novartis Pfizer, and several other pharmaceutical companies.

Dr. Gottlieb has current consulting/advisory board agreements with Abbott, Amgen, Celgene, Incyte, and numerous other pharmaceutical companies.