Apremilast improves psoriasis, shows strong safety profile

The oral phosphodiesterase-4 inhibitor apremilast significantly improves moderate to severe psoriasis with minimal side effects, according to data from a phase III, randomized controlled trial of 844 patients.

The drug had an excellent safety profile and resulted in significantly greater improvement in moderate to severe psoriasis than placebo after 16 weeks of treatment in the ESTEEM 1 trial.

The results were reported in a late-breaker session at the annual meeting of the American Academy of Dermatology.

Apremilast is "one of the new small molecules being developed for treatment of psoriasis," said Dr. Kristian Reich of SCIderm Research Institute and Dermatologikum, Hamburg, Germany.

"We believe it has anti-inflammatory properties, because by increasing the intracellular level of cyclic AMP (adenosine monophosphate), it actually activates protein kinase A to modulate the balance between proinflammatory and anti-inflammatory mediators released by a cell in a way that pro-inflammatory mediators are down-regulated and anti-inflammatory mediators are upregulated," he said.

Of 562 patients randomized to receive 30 mg of apremilast twice daily for 16 weeks, 33.1% achieved 75% improvement on the Psoriasis Area Severity Index (PASI-75) scale score, compared with only 5.3% of 282 patients who received placebo. Patients in the treatment group also showed significant improvement compared with the placebo group for secondary endpoints including physician global assessment (PGA) score, change in body surface area affected, and pruritus.

Improvements also were noted in difficult to treat areas such as the scalp and nails. For example, about 50% of affected patients achieved a 50% reduction in nail psoriasis severity, Dr. Reich said.

The study participants were adults with moderate to severe chronic plaque psoriasis, surface area involvement greater than 10%, and a PGA score of 3 or higher. All were candidates for phototherapy or systemic therapy, half had been treated previously with other systemic therapies, including biologics, and nearly 1 in 5 patients had been treated with tumor necrosis factor (TNF) blockers.

Patients initially receiving placebo switched over to active treatment after the first 16 weeks, and treatment in all patients continued at the 30-mg twice-daily dose for an additional 16 weeks, followed by a randomized withdrawal phase through week 52.

The treatment effects seen with apremilast at 16 weeks were slightly greater in patients who had not previously received conventional systemic or biologic therapy compared with the total patient population, but even those with prior failed TNF treatment achieved a PASI-75 response.

Onset of action occurred within 2-4 weeks, and clinically relevant improvement continued beyond 16 weeks. The mean percent change from baseline in PASI score was 54.9% at 16 weeks, and 61.9% at 32 weeks, Dr. Reich said. "It will be interesting to see, long-term, what happens beyond the 16-week endpoint," he added.

The 16-week outcomes in the apremilast group represent "significant moderate efficacy," but the safety profile of the drug is the real story of the data, Dr. Reich said.

"Safety is a major issue when it comes to systemic therapies for psoriasis," he emphasized.

A slightly higher rate of withdrawals in the apremilast group may have been due to gastrointestinal effects, a well-known side effect of TNF inhibitors.

Gastrointestinal side effects included diarrhea and nausea, but most cases were transient, and mild to moderate. Most side effects occurred and resolved within the first 15 days of treatment. In fact, more than 96% of patients reported experiencing either no adverse events or only mild to moderate adverse events. Reports of serious adverse events were similar in the treatment and placebo groups (2.1% v. 2.8%, respectively), as were reports of severe adverse events (3.6% vs. 3.2%, respectively).

No problems were noted with respect to lipid levels, liver enzymes, opportunistic infections, or cardiac abnormalities, and no cases of tuberculosis or lymphoma occurred during the study period.

"What stands out so far is an extremely good safety profile," Dr. Reich said.

ESTEEM 1 is the first of two phase III studies of apremilast for chronic plaque psoriasis. Statistical significance for the primary and major secondary endpoints of both ESTEEM 1 and ESTEEM 2 was announced previously by Celgene, the maker of apremilast.

"A NDA (New Drug Application) submission to the U.S. Food and Drug Administration, based on the combined ESTEEM 1 and 2 studies for psoriasis, is expected in the second half of 2013," according to a Celgene press release.

Celgene previously announced it would file a separate NDA for psoriatic arthritis in the first quarter of 2013, based on data from three other trials (PALACE-1, 2, and 3), which were released in 2012. Another phase III trial (POSTURE) began enrolling patients in April 2012 to evaluate apremilast in patients with ankylosing spondylitis.

Participants in the ESTEEM 1 trial will be enrolled in a 5-year extension study so researchers can collect long-term safety and efficacy data. However, based on the current findings, including data from psoriatic arthritis patients, the drug looks quite promising for the treatment of psoriasis, Dr. Reich said.

"I see this as a prime candidate for future management of psoriasis that allows us to treat a range of patients, including more moderate cases earlier on," he said. Such a treatment is needed, particularly in light of new disease concepts that characterize psoriasis as involving systemic inflammation that requires early control, he explained.

The study was sponsored by Celgene.

The oral phosphodiesterase-4 inhibitor apremilast significantly improves moderate to severe psoriasis with minimal side effects, according to data from a phase III, randomized controlled trial of 844 patients.

The drug had an excellent safety profile and resulted in significantly greater improvement in moderate to severe psoriasis than placebo after 16 weeks of treatment in the ESTEEM 1 trial.

The results were reported in a late-breaker session at the annual meeting of the American Academy of Dermatology.

Apremilast is "one of the new small molecules being developed for treatment of psoriasis," said Dr. Kristian Reich of SCIderm Research Institute and Dermatologikum, Hamburg, Germany.

"We believe it has anti-inflammatory properties, because by increasing the intracellular level of cyclic AMP (adenosine monophosphate), it actually activates protein kinase A to modulate the balance between proinflammatory and anti-inflammatory mediators released by a cell in a way that pro-inflammatory mediators are down-regulated and anti-inflammatory mediators are upregulated," he said.

Of 562 patients randomized to receive 30 mg of apremilast twice daily for 16 weeks, 33.1% achieved 75% improvement on the Psoriasis Area Severity Index (PASI-75) scale score, compared with only 5.3% of 282 patients who received placebo. Patients in the treatment group also showed significant improvement compared with the placebo group for secondary endpoints including physician global assessment (PGA) score, change in body surface area affected, and pruritus.

Improvements also were noted in difficult to treat areas such as the scalp and nails. For example, about 50% of affected patients achieved a 50% reduction in nail psoriasis severity, Dr. Reich said.

The study participants were adults with moderate to severe chronic plaque psoriasis, surface area involvement greater than 10%, and a PGA score of 3 or higher. All were candidates for phototherapy or systemic therapy, half had been treated previously with other systemic therapies, including biologics, and nearly 1 in 5 patients had been treated with tumor necrosis factor (TNF) blockers.

Patients initially receiving placebo switched over to active treatment after the first 16 weeks, and treatment in all patients continued at the 30-mg twice-daily dose for an additional 16 weeks, followed by a randomized withdrawal phase through week 52.

The treatment effects seen with apremilast at 16 weeks were slightly greater in patients who had not previously received conventional systemic or biologic therapy compared with the total patient population, but even those with prior failed TNF treatment achieved a PASI-75 response.

Onset of action occurred within 2-4 weeks, and clinically relevant improvement continued beyond 16 weeks. The mean percent change from baseline in PASI score was 54.9% at 16 weeks, and 61.9% at 32 weeks, Dr. Reich said. "It will be interesting to see, long-term, what happens beyond the 16-week endpoint," he added.

The 16-week outcomes in the apremilast group represent "significant moderate efficacy," but the safety profile of the drug is the real story of the data, Dr. Reich said.

"Safety is a major issue when it comes to systemic therapies for psoriasis," he emphasized.

A slightly higher rate of withdrawals in the apremilast group may have been due to gastrointestinal effects, a well-known side effect of TNF inhibitors.

Gastrointestinal side effects included diarrhea and nausea, but most cases were transient, and mild to moderate. Most side effects occurred and resolved within the first 15 days of treatment. In fact, more than 96% of patients reported experiencing either no adverse events or only mild to moderate adverse events. Reports of serious adverse events were similar in the treatment and placebo groups (2.1% v. 2.8%, respectively), as were reports of severe adverse events (3.6% vs. 3.2%, respectively).

No problems were noted with respect to lipid levels, liver enzymes, opportunistic infections, or cardiac abnormalities, and no cases of tuberculosis or lymphoma occurred during the study period.

"What stands out so far is an extremely good safety profile," Dr. Reich said.

ESTEEM 1 is the first of two phase III studies of apremilast for chronic plaque psoriasis. Statistical significance for the primary and major secondary endpoints of both ESTEEM 1 and ESTEEM 2 was announced previously by Celgene, the maker of apremilast.

"A NDA (New Drug Application) submission to the U.S. Food and Drug Administration, based on the combined ESTEEM 1 and 2 studies for psoriasis, is expected in the second half of 2013," according to a Celgene press release.

Celgene previously announced it would file a separate NDA for psoriatic arthritis in the first quarter of 2013, based on data from three other trials (PALACE-1, 2, and 3), which were released in 2012. Another phase III trial (POSTURE) began enrolling patients in April 2012 to evaluate apremilast in patients with ankylosing spondylitis.

Participants in the ESTEEM 1 trial will be enrolled in a 5-year extension study so researchers can collect long-term safety and efficacy data. However, based on the current findings, including data from psoriatic arthritis patients, the drug looks quite promising for the treatment of psoriasis, Dr. Reich said.

"I see this as a prime candidate for future management of psoriasis that allows us to treat a range of patients, including more moderate cases earlier on," he said. Such a treatment is needed, particularly in light of new disease concepts that characterize psoriasis as involving systemic inflammation that requires early control, he explained.

The study was sponsored by Celgene.

The oral phosphodiesterase-4 inhibitor apremilast significantly improves moderate to severe psoriasis with minimal side effects, according to data from a phase III, randomized controlled trial of 844 patients.

The drug had an excellent safety profile and resulted in significantly greater improvement in moderate to severe psoriasis than placebo after 16 weeks of treatment in the ESTEEM 1 trial.

The results were reported in a late-breaker session at the annual meeting of the American Academy of Dermatology.

Apremilast is "one of the new small molecules being developed for treatment of psoriasis," said Dr. Kristian Reich of SCIderm Research Institute and Dermatologikum, Hamburg, Germany.

"We believe it has anti-inflammatory properties, because by increasing the intracellular level of cyclic AMP (adenosine monophosphate), it actually activates protein kinase A to modulate the balance between proinflammatory and anti-inflammatory mediators released by a cell in a way that pro-inflammatory mediators are down-regulated and anti-inflammatory mediators are upregulated," he said.

Of 562 patients randomized to receive 30 mg of apremilast twice daily for 16 weeks, 33.1% achieved 75% improvement on the Psoriasis Area Severity Index (PASI-75) scale score, compared with only 5.3% of 282 patients who received placebo. Patients in the treatment group also showed significant improvement compared with the placebo group for secondary endpoints including physician global assessment (PGA) score, change in body surface area affected, and pruritus.

Improvements also were noted in difficult to treat areas such as the scalp and nails. For example, about 50% of affected patients achieved a 50% reduction in nail psoriasis severity, Dr. Reich said.

The study participants were adults with moderate to severe chronic plaque psoriasis, surface area involvement greater than 10%, and a PGA score of 3 or higher. All were candidates for phototherapy or systemic therapy, half had been treated previously with other systemic therapies, including biologics, and nearly 1 in 5 patients had been treated with tumor necrosis factor (TNF) blockers.

Patients initially receiving placebo switched over to active treatment after the first 16 weeks, and treatment in all patients continued at the 30-mg twice-daily dose for an additional 16 weeks, followed by a randomized withdrawal phase through week 52.

The treatment effects seen with apremilast at 16 weeks were slightly greater in patients who had not previously received conventional systemic or biologic therapy compared with the total patient population, but even those with prior failed TNF treatment achieved a PASI-75 response.

Onset of action occurred within 2-4 weeks, and clinically relevant improvement continued beyond 16 weeks. The mean percent change from baseline in PASI score was 54.9% at 16 weeks, and 61.9% at 32 weeks, Dr. Reich said. "It will be interesting to see, long-term, what happens beyond the 16-week endpoint," he added.

The 16-week outcomes in the apremilast group represent "significant moderate efficacy," but the safety profile of the drug is the real story of the data, Dr. Reich said.

"Safety is a major issue when it comes to systemic therapies for psoriasis," he emphasized.

A slightly higher rate of withdrawals in the apremilast group may have been due to gastrointestinal effects, a well-known side effect of TNF inhibitors.

Gastrointestinal side effects included diarrhea and nausea, but most cases were transient, and mild to moderate. Most side effects occurred and resolved within the first 15 days of treatment. In fact, more than 96% of patients reported experiencing either no adverse events or only mild to moderate adverse events. Reports of serious adverse events were similar in the treatment and placebo groups (2.1% v. 2.8%, respectively), as were reports of severe adverse events (3.6% vs. 3.2%, respectively).

No problems were noted with respect to lipid levels, liver enzymes, opportunistic infections, or cardiac abnormalities, and no cases of tuberculosis or lymphoma occurred during the study period.

"What stands out so far is an extremely good safety profile," Dr. Reich said.

ESTEEM 1 is the first of two phase III studies of apremilast for chronic plaque psoriasis. Statistical significance for the primary and major secondary endpoints of both ESTEEM 1 and ESTEEM 2 was announced previously by Celgene, the maker of apremilast.

"A NDA (New Drug Application) submission to the U.S. Food and Drug Administration, based on the combined ESTEEM 1 and 2 studies for psoriasis, is expected in the second half of 2013," according to a Celgene press release.

Celgene previously announced it would file a separate NDA for psoriatic arthritis in the first quarter of 2013, based on data from three other trials (PALACE-1, 2, and 3), which were released in 2012. Another phase III trial (POSTURE) began enrolling patients in April 2012 to evaluate apremilast in patients with ankylosing spondylitis.

Participants in the ESTEEM 1 trial will be enrolled in a 5-year extension study so researchers can collect long-term safety and efficacy data. However, based on the current findings, including data from psoriatic arthritis patients, the drug looks quite promising for the treatment of psoriasis, Dr. Reich said.

"I see this as a prime candidate for future management of psoriasis that allows us to treat a range of patients, including more moderate cases earlier on," he said. Such a treatment is needed, particularly in light of new disease concepts that characterize psoriasis as involving systemic inflammation that requires early control, he explained.

The study was sponsored by Celgene.