Psoriasis drug pipeline extrudes progress

PRAGUE – Two biologic agents addressing novel therapeutic targets in psoriasis continue to advance in the developmental pipeline, as highlighted in studies presented at the annual congress of the European Academy of Dermatology and Venereology.

Merck’s MK-3222 is a monoclonal antibody directed against the interleukin-23 p19 subunit. MK-3222 specifically binds and neutralizes IL23, and thereby inhibits IL23-dependent Th17 cells, which mediate inflammatory injury in psoriasis.

Dr. Tamara Kopp of the Medical University of Vienna presented a proof-of-concept study which suggested that targeting IL23p19 via MK-3222 could be an important new form of therapy for moderate to severe psoriasis. But there was a potential red flag: Eighteen percent of patients treated with just three doses of the antibody over the course of up to 12 weeks developed antidrug antibodies. The clinical significance of these antibodies will require additional study.

Separately, Dr. Richard Langley presented a secondary analysis of data from a phase II, 125-patient, double-blind, placebo-controlled, dose-ranging study of secukinumab, a fully human monoclonal antibody directed against the proinflammatory cytokine IL17A (Br. J. Dermatol. 2012 Oct. 27 [doi: 10.1111/bjd.12110]). The objective was to determine how long it takes for psoriasis symptoms to return after 8 weeks of therapy.

The answer is that relapse takes a very long time.

At the most effective dose tested in the trial, which was 150 mg of secukinumab given subcutaneously at weeks 0, 4, and 8, a Psoriasis Area and Severity Index (PASI) 75 response was seen at week 12 in 82% of patients assigned to the monoclonal antibody, compared with 9% of placebo-treated controls. A PASI 90 response – that is, at least a 90% reduction in the PASI score compared with baseline – was documented at week 12 in 52% of patients on secukinumab and 5% of controls.

At week 32, fully 24 weeks since the final 150-mg dose, only half of PASI 75 responders to secukinumab had relapsed as defined by loss of at least 50% of the maximum PASI improvement seen at week 12. Median time to relapse was 174 days, reported Dr. Langley, director of research in the division of clinical dermatology and cutaneous science at Dalhousie University in Halifax, N.S.

Secukinumab was quite well tolerated. Indeed, the overall adverse events and serious adverse events were generally similar in nature to placebo, but less frequent.

Based upon the phase II time-to-relapse analysis, it’s likely that two maintenance therapy schedules will be tested in larger studies: one involving retreatment at 4-week intervals, and another in which retreatment is held in abeyance until relapse commences, according to Dr. Langley.

Dr. Kopp reported that the MK-3222 study involved 77 enrollees, 66 of whom completed the 16-week dose-ranging study. Only 2 of the 11 dropouts did so because of adverse events.

All 11 patients who received intravenous MK-3222 at either 3 or 10 mg/kg on days 1, 56, and 84 had a PASI 75 response at week 16. So did 10 of 15 who received 3 mg/kg and 13 of 14 who received 10 mg/kg on days 1, 28, and 56.

The anti-IL23p19 antibody was generally well tolerated, with no dose-related increase in adverse events and no ECG or laboratory abnormalities.

Of the nine patients who developed antidrug antibodies during the study, five had serum drug concentrations that were significantly lower than those of subjects without antidrug antibodies; two of these five patients – those with the most pronounced reduction in drug concentrations – also had neutralizing antidrug antibodies to MK-3222. However, patients with antidrug antibodies did not differ from the others in terms of their clinical response to treatment as reflected in PASI improvement, and their adverse event profile was not outstanding.

Dr. Kopp serves as a consultant to Merck, which is developing MK-3222. The secukinumab study was funded by Novartis. Dr. Langley is a consultant to the company.

b.jancin@elsevier.com

PRAGUE – Two biologic agents addressing novel therapeutic targets in psoriasis continue to advance in the developmental pipeline, as highlighted in studies presented at the annual congress of the European Academy of Dermatology and Venereology.

Merck’s MK-3222 is a monoclonal antibody directed against the interleukin-23 p19 subunit. MK-3222 specifically binds and neutralizes IL23, and thereby inhibits IL23-dependent Th17 cells, which mediate inflammatory injury in psoriasis.

Dr. Tamara Kopp of the Medical University of Vienna presented a proof-of-concept study which suggested that targeting IL23p19 via MK-3222 could be an important new form of therapy for moderate to severe psoriasis. But there was a potential red flag: Eighteen percent of patients treated with just three doses of the antibody over the course of up to 12 weeks developed antidrug antibodies. The clinical significance of these antibodies will require additional study.

Separately, Dr. Richard Langley presented a secondary analysis of data from a phase II, 125-patient, double-blind, placebo-controlled, dose-ranging study of secukinumab, a fully human monoclonal antibody directed against the proinflammatory cytokine IL17A (Br. J. Dermatol. 2012 Oct. 27 [doi: 10.1111/bjd.12110]). The objective was to determine how long it takes for psoriasis symptoms to return after 8 weeks of therapy.

The answer is that relapse takes a very long time.

At the most effective dose tested in the trial, which was 150 mg of secukinumab given subcutaneously at weeks 0, 4, and 8, a Psoriasis Area and Severity Index (PASI) 75 response was seen at week 12 in 82% of patients assigned to the monoclonal antibody, compared with 9% of placebo-treated controls. A PASI 90 response – that is, at least a 90% reduction in the PASI score compared with baseline – was documented at week 12 in 52% of patients on secukinumab and 5% of controls.

At week 32, fully 24 weeks since the final 150-mg dose, only half of PASI 75 responders to secukinumab had relapsed as defined by loss of at least 50% of the maximum PASI improvement seen at week 12. Median time to relapse was 174 days, reported Dr. Langley, director of research in the division of clinical dermatology and cutaneous science at Dalhousie University in Halifax, N.S.

Secukinumab was quite well tolerated. Indeed, the overall adverse events and serious adverse events were generally similar in nature to placebo, but less frequent.

Based upon the phase II time-to-relapse analysis, it’s likely that two maintenance therapy schedules will be tested in larger studies: one involving retreatment at 4-week intervals, and another in which retreatment is held in abeyance until relapse commences, according to Dr. Langley.

Dr. Kopp reported that the MK-3222 study involved 77 enrollees, 66 of whom completed the 16-week dose-ranging study. Only 2 of the 11 dropouts did so because of adverse events.

All 11 patients who received intravenous MK-3222 at either 3 or 10 mg/kg on days 1, 56, and 84 had a PASI 75 response at week 16. So did 10 of 15 who received 3 mg/kg and 13 of 14 who received 10 mg/kg on days 1, 28, and 56.

The anti-IL23p19 antibody was generally well tolerated, with no dose-related increase in adverse events and no ECG or laboratory abnormalities.

Of the nine patients who developed antidrug antibodies during the study, five had serum drug concentrations that were significantly lower than those of subjects without antidrug antibodies; two of these five patients – those with the most pronounced reduction in drug concentrations – also had neutralizing antidrug antibodies to MK-3222. However, patients with antidrug antibodies did not differ from the others in terms of their clinical response to treatment as reflected in PASI improvement, and their adverse event profile was not outstanding.

Dr. Kopp serves as a consultant to Merck, which is developing MK-3222. The secukinumab study was funded by Novartis. Dr. Langley is a consultant to the company.

b.jancin@elsevier.com

PRAGUE – Two biologic agents addressing novel therapeutic targets in psoriasis continue to advance in the developmental pipeline, as highlighted in studies presented at the annual congress of the European Academy of Dermatology and Venereology.

Merck’s MK-3222 is a monoclonal antibody directed against the interleukin-23 p19 subunit. MK-3222 specifically binds and neutralizes IL23, and thereby inhibits IL23-dependent Th17 cells, which mediate inflammatory injury in psoriasis.

Dr. Tamara Kopp of the Medical University of Vienna presented a proof-of-concept study which suggested that targeting IL23p19 via MK-3222 could be an important new form of therapy for moderate to severe psoriasis. But there was a potential red flag: Eighteen percent of patients treated with just three doses of the antibody over the course of up to 12 weeks developed antidrug antibodies. The clinical significance of these antibodies will require additional study.

Separately, Dr. Richard Langley presented a secondary analysis of data from a phase II, 125-patient, double-blind, placebo-controlled, dose-ranging study of secukinumab, a fully human monoclonal antibody directed against the proinflammatory cytokine IL17A (Br. J. Dermatol. 2012 Oct. 27 [doi: 10.1111/bjd.12110]). The objective was to determine how long it takes for psoriasis symptoms to return after 8 weeks of therapy.

The answer is that relapse takes a very long time.

At the most effective dose tested in the trial, which was 150 mg of secukinumab given subcutaneously at weeks 0, 4, and 8, a Psoriasis Area and Severity Index (PASI) 75 response was seen at week 12 in 82% of patients assigned to the monoclonal antibody, compared with 9% of placebo-treated controls. A PASI 90 response – that is, at least a 90% reduction in the PASI score compared with baseline – was documented at week 12 in 52% of patients on secukinumab and 5% of controls.

At week 32, fully 24 weeks since the final 150-mg dose, only half of PASI 75 responders to secukinumab had relapsed as defined by loss of at least 50% of the maximum PASI improvement seen at week 12. Median time to relapse was 174 days, reported Dr. Langley, director of research in the division of clinical dermatology and cutaneous science at Dalhousie University in Halifax, N.S.

Secukinumab was quite well tolerated. Indeed, the overall adverse events and serious adverse events were generally similar in nature to placebo, but less frequent.

Based upon the phase II time-to-relapse analysis, it’s likely that two maintenance therapy schedules will be tested in larger studies: one involving retreatment at 4-week intervals, and another in which retreatment is held in abeyance until relapse commences, according to Dr. Langley.

Dr. Kopp reported that the MK-3222 study involved 77 enrollees, 66 of whom completed the 16-week dose-ranging study. Only 2 of the 11 dropouts did so because of adverse events.

All 11 patients who received intravenous MK-3222 at either 3 or 10 mg/kg on days 1, 56, and 84 had a PASI 75 response at week 16. So did 10 of 15 who received 3 mg/kg and 13 of 14 who received 10 mg/kg on days 1, 28, and 56.

The anti-IL23p19 antibody was generally well tolerated, with no dose-related increase in adverse events and no ECG or laboratory abnormalities.

Of the nine patients who developed antidrug antibodies during the study, five had serum drug concentrations that were significantly lower than those of subjects without antidrug antibodies; two of these five patients – those with the most pronounced reduction in drug concentrations – also had neutralizing antidrug antibodies to MK-3222. However, patients with antidrug antibodies did not differ from the others in terms of their clinical response to treatment as reflected in PASI improvement, and their adverse event profile was not outstanding.

Dr. Kopp serves as a consultant to Merck, which is developing MK-3222. The secukinumab study was funded by Novartis. Dr. Langley is a consultant to the company.

b.jancin@elsevier.com