Health Boards
Thu-01-03-2012, 11:41 AM
Researchers have found that ustekinumab (Stelara, Janssen Biotech, Inc.), a novel interleukin 12 (IL-12) and IL-23 antagonist, has a favorable benefit–risk profile for up to 3 years of treatment for moderate to severe psoriasis.
Because many patients with psoriasis require decades of treatment, researchers are particularly concerned with finding therapies that will retain their efficacy without causing serious adverse effects. "Chronic use of conventional systemic therapies has been associated with a hazard of cumulative end-organ toxicities (e.g., hepatotoxicity with methotrexate and nephrotoxicity with cyclosporine)," the authors write.
Ustekinumab is a fully human monoclonal antibody that works by binding to the shared p40 subunit of IL-12 and IL-23. The current report is a long-term extension of the Psoriasis Followed by Long-Term Extension (PHOENIX) 1 study, a phase 3, randomized, double-blind, placebo-controlled trial that initially evaluated ustekinumab through 76 weeks of treatment. The report focuses on efficacy through 3 years because 4 other trials have reported detailed information on the drug's safety during that period.
The researchers performed analyses of clinical efficacy in the following groups:
# the overall study population,
# early responders who maintained dosing every 12 weeks through 3 years,
# responders who were withdrawn from therapy and who were subsequently retreated, and
# partial responders who had the dosing interval changed from every 12 weeks to every 8 weeks.
The First 76 Weeks
The PHOENIX 1 study included 766 patients with moderate-to-severe psoriasis who were randomly assigned to receive placebo or ustekinumab 45 mg or 90 mg at week 0, week 4, and every 12 weeks after that (period 1: week 0 - week 12). At week 12, patients in the placebo group crossed over to receive ustekinumab 45 mg or 90 mg at week 12, week 16, and every 12 weeks after that (period 2: week 12 - week 40). Starting at week 28, treatment was based on treatment response:
Responders were participants whose scores on the Psoriasis Area and Severity Index (PASI) improved by at least 75% (PASI75) at both week 28 and week 40.
Partial responders were patients whose PASI scores improved by from 50% to 74% (PASI50-74) at week 28, or by less than 75% (< PASI75) at week 40.
Nonresponders were patients with less than 50% PASI (< PASI50) improvement at week 28.
At week 40, responders who were randomly assigned to receive ustekinumab at baseline were rerandomized either to keep receiving ustekinumab every 12 weeks or to withdraw from treatment (period 3: week 40 - week 76), with follow-up through 3 years (period 4: week 76 - year 3).
Responders who were randomly assigned to receive placebo at baseline were withdrawn from treatment at week 40, with follow-up through 3 years.
At the time of psoriasis recurrence (loss of ≥50% of PASI improvement achieved at week 40), patients who had been withdrawn from therapy were retreated with 2 doses of ustekinumab 4 weeks apart, followed by administration every 12 weeks thereafter.
The dosing interval was shortened to every 8 weeks in partial responders, and treatment was withdrawn in nonresponders.
Weeks 77 Through Year 3
Of the 766 patients enrolled in the study, 753 received at least 1 dose of ustekinumab, and 601 (79.8%) of those continued in the study through year 3.
At week 76, PASI75 response was achieved by 61.2% (45 mg) and 72.4% (90 mg), and these results remained consistent through year 3.
In the overall population, PASI90 responses remained stable through year 3 with stable maintenance dosing and no evidence of decreasing response (45 mg: 33.9% at week 76 and 36.1% at year 3; 90 mg: 44.9% and 45.5%, respectively). Similarly, the median PASI improvement was relatively stable (45 mg: 82.4% at week 76 and 83.6% at year 3; 90 mg: 87.2% and 88.4%, respectively), and PGA response of 0 or 1 remained consistent as well (cleared or minimal; 45 mg: 43.6% and 42.6%; 90 mg: 54.9% and 52.5%).
Among initial responders who received treatment every 12 weeks, more than 80% maintained PASI75 response through week 76 (45 mg: 81.8%; 90mg: 86.6%). This response rate was sustained through year 3 (45 mg: 80.9%; 90 mg: 82.7%). Most (93.3%) of these patients had PASI50 improvement or greater through year 3. Significant proportions of patients experienced PASI90 (45 mg: 42.6%; 90 mg: 58.0%) and PASI100 (45 mg: 22.1%; 90 mg: 38.3%) responses through year 3.
Approximately 50% of the patients withdrawn from treatment lost PASI75 response within approximately 16 weeks of their last treatment.
Scores on the Dermatology Life Quality Index paralleled clinical improvements for the most part.
Initial partial responders had their dosing interval shortened from every 12 weeks to every 8 weeks, and about half of those achieved and maintained (45 mg: 50.9%) or improved (90 mg: 52.0%) PASI 75 response through year 3.
"Ustekinumab was generally well-tolerated through up to 3 years of follow-up, as most [adverse events] were mild, non-serious, and did not require treatment discontinuation," the authors write.
"The safety profile of ustekinumab through up to 3 years of treatment appears generally favorable, is consistent with previous observations through week 76 and compares favorably with other biologics," they add.
"Importantly, no evidence of cumulative organ toxicities that may limit the long-term utility of conventional systemic agents was observed."
"These results continue to support the favorable benefit-risk profile of ustekinumab in the treatment of moderate-to-severe psoriasis with continuous, stable maintenance dosing through 3 years of therapy. High level efficacy and a consistent safety profile were sustained over time," write the authors.
Jeffrey Weinberg, MD, director of clinical research in the Department of Dermatology at Beth Israel Medical Center in New York City, commented on the study in a telephone interview with Medscape Medical News. He explained that the biggest question dermatologists have is whether a drug is safe to use long-term, and that although this is a small cohort of people, it is "a good thing to see is that there are no new side effects, and no increase in side effects that are noted as time goes on."
"This is what we need with a new drug. We need to observe a new drug as it continues to be used in individuals and as it's used in practice, and be very observant for long-term safety," Dr. Weinberg said.
"What they have provided so far is very encouraging. It just needs longer-term follow-up and analysis of how the drug does as it's used in more and more people," concluded Dr. Weinberg.
Source: medscape.com
Because many patients with psoriasis require decades of treatment, researchers are particularly concerned with finding therapies that will retain their efficacy without causing serious adverse effects. "Chronic use of conventional systemic therapies has been associated with a hazard of cumulative end-organ toxicities (e.g., hepatotoxicity with methotrexate and nephrotoxicity with cyclosporine)," the authors write.
Ustekinumab is a fully human monoclonal antibody that works by binding to the shared p40 subunit of IL-12 and IL-23. The current report is a long-term extension of the Psoriasis Followed by Long-Term Extension (PHOENIX) 1 study, a phase 3, randomized, double-blind, placebo-controlled trial that initially evaluated ustekinumab through 76 weeks of treatment. The report focuses on efficacy through 3 years because 4 other trials have reported detailed information on the drug's safety during that period.
The researchers performed analyses of clinical efficacy in the following groups:
# the overall study population,
# early responders who maintained dosing every 12 weeks through 3 years,
# responders who were withdrawn from therapy and who were subsequently retreated, and
# partial responders who had the dosing interval changed from every 12 weeks to every 8 weeks.
The First 76 Weeks
The PHOENIX 1 study included 766 patients with moderate-to-severe psoriasis who were randomly assigned to receive placebo or ustekinumab 45 mg or 90 mg at week 0, week 4, and every 12 weeks after that (period 1: week 0 - week 12). At week 12, patients in the placebo group crossed over to receive ustekinumab 45 mg or 90 mg at week 12, week 16, and every 12 weeks after that (period 2: week 12 - week 40). Starting at week 28, treatment was based on treatment response:
Responders were participants whose scores on the Psoriasis Area and Severity Index (PASI) improved by at least 75% (PASI75) at both week 28 and week 40.
Partial responders were patients whose PASI scores improved by from 50% to 74% (PASI50-74) at week 28, or by less than 75% (< PASI75) at week 40.
Nonresponders were patients with less than 50% PASI (< PASI50) improvement at week 28.
At week 40, responders who were randomly assigned to receive ustekinumab at baseline were rerandomized either to keep receiving ustekinumab every 12 weeks or to withdraw from treatment (period 3: week 40 - week 76), with follow-up through 3 years (period 4: week 76 - year 3).
Responders who were randomly assigned to receive placebo at baseline were withdrawn from treatment at week 40, with follow-up through 3 years.
At the time of psoriasis recurrence (loss of ≥50% of PASI improvement achieved at week 40), patients who had been withdrawn from therapy were retreated with 2 doses of ustekinumab 4 weeks apart, followed by administration every 12 weeks thereafter.
The dosing interval was shortened to every 8 weeks in partial responders, and treatment was withdrawn in nonresponders.
Weeks 77 Through Year 3
Of the 766 patients enrolled in the study, 753 received at least 1 dose of ustekinumab, and 601 (79.8%) of those continued in the study through year 3.
At week 76, PASI75 response was achieved by 61.2% (45 mg) and 72.4% (90 mg), and these results remained consistent through year 3.
In the overall population, PASI90 responses remained stable through year 3 with stable maintenance dosing and no evidence of decreasing response (45 mg: 33.9% at week 76 and 36.1% at year 3; 90 mg: 44.9% and 45.5%, respectively). Similarly, the median PASI improvement was relatively stable (45 mg: 82.4% at week 76 and 83.6% at year 3; 90 mg: 87.2% and 88.4%, respectively), and PGA response of 0 or 1 remained consistent as well (cleared or minimal; 45 mg: 43.6% and 42.6%; 90 mg: 54.9% and 52.5%).
Among initial responders who received treatment every 12 weeks, more than 80% maintained PASI75 response through week 76 (45 mg: 81.8%; 90mg: 86.6%). This response rate was sustained through year 3 (45 mg: 80.9%; 90 mg: 82.7%). Most (93.3%) of these patients had PASI50 improvement or greater through year 3. Significant proportions of patients experienced PASI90 (45 mg: 42.6%; 90 mg: 58.0%) and PASI100 (45 mg: 22.1%; 90 mg: 38.3%) responses through year 3.
Approximately 50% of the patients withdrawn from treatment lost PASI75 response within approximately 16 weeks of their last treatment.
Scores on the Dermatology Life Quality Index paralleled clinical improvements for the most part.
Initial partial responders had their dosing interval shortened from every 12 weeks to every 8 weeks, and about half of those achieved and maintained (45 mg: 50.9%) or improved (90 mg: 52.0%) PASI 75 response through year 3.
"Ustekinumab was generally well-tolerated through up to 3 years of follow-up, as most [adverse events] were mild, non-serious, and did not require treatment discontinuation," the authors write.
"The safety profile of ustekinumab through up to 3 years of treatment appears generally favorable, is consistent with previous observations through week 76 and compares favorably with other biologics," they add.
"Importantly, no evidence of cumulative organ toxicities that may limit the long-term utility of conventional systemic agents was observed."
"These results continue to support the favorable benefit-risk profile of ustekinumab in the treatment of moderate-to-severe psoriasis with continuous, stable maintenance dosing through 3 years of therapy. High level efficacy and a consistent safety profile were sustained over time," write the authors.
Jeffrey Weinberg, MD, director of clinical research in the Department of Dermatology at Beth Israel Medical Center in New York City, commented on the study in a telephone interview with Medscape Medical News. He explained that the biggest question dermatologists have is whether a drug is safe to use long-term, and that although this is a small cohort of people, it is "a good thing to see is that there are no new side effects, and no increase in side effects that are noted as time goes on."
"This is what we need with a new drug. We need to observe a new drug as it continues to be used in individuals and as it's used in practice, and be very observant for long-term safety," Dr. Weinberg said.
"What they have provided so far is very encouraging. It just needs longer-term follow-up and analysis of how the drug does as it's used in more and more people," concluded Dr. Weinberg.
Source: medscape.com