Investigational JAK inhibitor reduced PASI scores

PRAGUE – The major role that the Janus kinases play in the pathogenesis of psoriasis is confirmed, based on the results of a phase II study of the investigational oral agent ASP015K, according to Dr. Bernhardt Zeiher.

ASP015K inhibits Janus kinase (JAK) 1 and 3, with relative sparing of JAK 2. In a 6-week dose-ranging study of 124 patients with moderate to severe psoriasis, all tested doses – 10, 25, 60, and 100 mg twice daily as well as 50 mg once daily – significantly outperformed placebo in terms of improvement in Psoriasis Area and Severity Index (PASI) scores.

Moreover, immunohistochemistry of skin biopsies gathered at baseline and at days 14 and 42 after initiation of ASP015K showed the drug reduced epidermal thickness, epidermal proliferation as measured by Ki67, and infiltration of CD3 T cells and CD11c dendritic cells. The greatest changes at the cellular level were seen at the highest dose, 100 mg twice daily.

"Although treatment was only for 6 weeks, the defining pathology of psoriasis was reversed in 62% of patients in the 100-mg b.i.d. cohort. In these patients, epidermal thickness was normalized and was comparable with nonlesional skin after treatment, parakeratosis was eliminated, and a granular layer was restored. Keratinocyte proliferation, judged by Ki67 staining, was reversed to levels of nonlesional skin. Major reductions in the number of T cells and inflammatory CD11c-positive dendritic cells were also measured in day 42 biopsies, along with elimination of organized lymphoid structures," according to Dr. Zeiher of Astellas Pharma, Deerfield, Ill., which is developing the JAK 1/3 inhibitor.

Improvements in cellular findings and PASI scores were largely dose-dependent.

Mean PASI scores fell by 12 points over a 6-week period in patients assigned to ASP015K at 100 mg b.i.d.; a 4-point drop in mean PASI scores was seen in placebo-treated controls.

Yet histologic improvements associated with the 50-mg once-daily dose were second in magnitude only to those seen with the 100-mg b.i.d. dose.

"When you look at the kinetics of the drug, you have more JAK inhibition holiday with once-a-day dosing," Dr. Zeiher explained. The notion that a daily JAK inhibition holiday provides added therapeutic benefit is both interesting and readily testable. A planned phase IIb study will evaluate once-daily oral dosing of ASP015K at a range of doses, with 150 mg as the maximum.

The JAK 1/3 inhibitor was well tolerated overall. Three subjects dropped out of the study because of drug-related side effects: two with decreased neutrophil counts but not frank neutropenia on doses of 60 and 100 mg b.i.d., and one as a result of GI upset while on 100 mg b.i.d.

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PRAGUE – The major role that the Janus kinases play in the pathogenesis of psoriasis is confirmed, based on the results of a phase II study of the investigational oral agent ASP015K, according to Dr. Bernhardt Zeiher.

ASP015K inhibits Janus kinase (JAK) 1 and 3, with relative sparing of JAK 2. In a 6-week dose-ranging study of 124 patients with moderate to severe psoriasis, all tested doses – 10, 25, 60, and 100 mg twice daily as well as 50 mg once daily – significantly outperformed placebo in terms of improvement in Psoriasis Area and Severity Index (PASI) scores.

Moreover, immunohistochemistry of skin biopsies gathered at baseline and at days 14 and 42 after initiation of ASP015K showed the drug reduced epidermal thickness, epidermal proliferation as measured by Ki67, and infiltration of CD3 T cells and CD11c dendritic cells. The greatest changes at the cellular level were seen at the highest dose, 100 mg twice daily.

"Although treatment was only for 6 weeks, the defining pathology of psoriasis was reversed in 62% of patients in the 100-mg b.i.d. cohort. In these patients, epidermal thickness was normalized and was comparable with nonlesional skin after treatment, parakeratosis was eliminated, and a granular layer was restored. Keratinocyte proliferation, judged by Ki67 staining, was reversed to levels of nonlesional skin. Major reductions in the number of T cells and inflammatory CD11c-positive dendritic cells were also measured in day 42 biopsies, along with elimination of organized lymphoid structures," according to Dr. Zeiher of Astellas Pharma, Deerfield, Ill., which is developing the JAK 1/3 inhibitor.

Improvements in cellular findings and PASI scores were largely dose-dependent.

Mean PASI scores fell by 12 points over a 6-week period in patients assigned to ASP015K at 100 mg b.i.d.; a 4-point drop in mean PASI scores was seen in placebo-treated controls.

Yet histologic improvements associated with the 50-mg once-daily dose were second in magnitude only to those seen with the 100-mg b.i.d. dose.

"When you look at the kinetics of the drug, you have more JAK inhibition holiday with once-a-day dosing," Dr. Zeiher explained. The notion that a daily JAK inhibition holiday provides added therapeutic benefit is both interesting and readily testable. A planned phase IIb study will evaluate once-daily oral dosing of ASP015K at a range of doses, with 150 mg as the maximum.

The JAK 1/3 inhibitor was well tolerated overall. Three subjects dropped out of the study because of drug-related side effects: two with decreased neutrophil counts but not frank neutropenia on doses of 60 and 100 mg b.i.d., and one as a result of GI upset while on 100 mg b.i.d.

[email protected]

PRAGUE – The major role that the Janus kinases play in the pathogenesis of psoriasis is confirmed, based on the results of a phase II study of the investigational oral agent ASP015K, according to Dr. Bernhardt Zeiher.

ASP015K inhibits Janus kinase (JAK) 1 and 3, with relative sparing of JAK 2. In a 6-week dose-ranging study of 124 patients with moderate to severe psoriasis, all tested doses – 10, 25, 60, and 100 mg twice daily as well as 50 mg once daily – significantly outperformed placebo in terms of improvement in Psoriasis Area and Severity Index (PASI) scores.

Moreover, immunohistochemistry of skin biopsies gathered at baseline and at days 14 and 42 after initiation of ASP015K showed the drug reduced epidermal thickness, epidermal proliferation as measured by Ki67, and infiltration of CD3 T cells and CD11c dendritic cells. The greatest changes at the cellular level were seen at the highest dose, 100 mg twice daily.

"Although treatment was only for 6 weeks, the defining pathology of psoriasis was reversed in 62% of patients in the 100-mg b.i.d. cohort. In these patients, epidermal thickness was normalized and was comparable with nonlesional skin after treatment, parakeratosis was eliminated, and a granular layer was restored. Keratinocyte proliferation, judged by Ki67 staining, was reversed to levels of nonlesional skin. Major reductions in the number of T cells and inflammatory CD11c-positive dendritic cells were also measured in day 42 biopsies, along with elimination of organized lymphoid structures," according to Dr. Zeiher of Astellas Pharma, Deerfield, Ill., which is developing the JAK 1/3 inhibitor.

Improvements in cellular findings and PASI scores were largely dose-dependent.

Mean PASI scores fell by 12 points over a 6-week period in patients assigned to ASP015K at 100 mg b.i.d.; a 4-point drop in mean PASI scores was seen in placebo-treated controls.

Yet histologic improvements associated with the 50-mg once-daily dose were second in magnitude only to those seen with the 100-mg b.i.d. dose.

"When you look at the kinetics of the drug, you have more JAK inhibition holiday with once-a-day dosing," Dr. Zeiher explained. The notion that a daily JAK inhibition holiday provides added therapeutic benefit is both interesting and readily testable. A planned phase IIb study will evaluate once-daily oral dosing of ASP015K at a range of doses, with 150 mg as the maximum.

The JAK 1/3 inhibitor was well tolerated overall. Three subjects dropped out of the study because of drug-related side effects: two with decreased neutrophil counts but not frank neutropenia on doses of 60 and 100 mg b.i.d., and one as a result of GI upset while on 100 mg b.i.d.

[email protected]