Experimental antibodies target cytokines to calm SLE

BOSTON – Two investigational monoclonal antibodies, each targeting a different cytokine, showed good activity against systemic lupus erythematosus in two separate studies presented at the annual meeting of the American College of Rheumatology.

Sifalimumab, a fully human monoclonal antibody that binds to and neutralizes several different subtypes of interferon-alpha (IFN-alpha), was better than placebo at improving measures of systemic lupus erythematosus (SLE) disease activity in 431 patients enrolled in a phase IIb safety and efficacy study, said Dr. Munther Khamashta of the Graham Hughes Lupus Research Laboratory at King’s College London.

“The primary endpoint, SRI [Systemic Lupus Erythematosus Responder Index] response at 52 weeks, was significant at all doses of sifalimumab, compared with placebo,” he said at the meeting.

There were no major unexpected adverse events with the drug. Investigators have previously documented increased frequency of herpes zoster infections in patients receiving sifalimumab, but the infections respond promptly to antiviral medication, he added.

Sifalimumab is targeted against the type I interferon receptor present on most cells. The specific target is IFN-alpha, the predominant subtype of type I interferons, which have been shown to play a key role in the pathogenesis of SLE.

In the phase II study, 431 adults with moderate to severe active SLE were screened and randomly assigned to receive either sifalimumab in an intravenous infusion every 4 weeks for 1 year at one of three doses – 200 mg, 600 mg, or 1,200 mg – or to placebo on the same schedule. The patients were permitted to receive up to three oral or intramuscular burst and taper steroids up to day 127 of the study.

SRI responses at 52 weeks were seen in 45.4% of patients on placebo, 58.3% of patients on the 200-mg dose (P vs. placebo = .057), 56.5% on the 600-mg dose (P = .094), and 59.8% for the 1,200-mg dose (P = .031).

Dr. Khamashta said that, at the final analysis, the investigators considered a P value less than .098 to be statistically significant because they needed to adjust for a type 1 error rate of 0.1 in the primary endpoint after they performed an interim analysis of the data.

There also were significant improvements in the sifalimumab arms vs. placebo in affected joint counts and in two secondary endpoints at specific doses: improvement in skin rash as measured by CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) and improvement in fatigue.

Anti–interleukin-6 monoclonal antibody tested

An investigational monoclonal antibody targeting a different cytokine, interleukin-6 (IL-6), appeared to reduce the severity of lupus flares, with activity occurring as early as 24 weeks, in a phase II, dose-ranging study of 183 patients with active SLE, said Dr. Daniel J. Wallace, a rheumatologist at Cedars-Sinai Medical Center in Los Angeles.

Although the drug was deemed to be safe at doses of 10 mg and 50 mg given by subcutaneous injection every 8 weeks, there were four deaths attributed to the medication, including two cases of pulmonary embolism and one of cardiorespiratory arrest in patients treated with the 200-mg dose and a suspected pulmonary embolism in a 32-year-old woman treated with the 10-mg dose. The investigators said that Pfizer, the study sponsor, determined that further studies are warranted to better characterize the benefits and risks of the 10-mg and 50-mg doses but will no longer study the 200-mg dose.

The biologic drug, still known only as PF-04236921, is a fully human antibody that binds to and neutralizes the IL-6 ligand rather than the receptor.

Dr. Wallace said that the rationale for targeting IL-6 in lupus is that there are increased IL-6 levels in the disease produced by T and B cells. Hyperactive B cells from SLE patients produce large amounts of immunoglobulins, and blocking IL-6 decreases immunoglobulin and anti-DNA production. A small, open-label study conducted at the National Institutes of Health with an anti-IL-6 receptor showed promising clinical and serologic responses, he noted.

The study reported by Dr. Khamashta was supported by AstraZeneca. He disclosed research grants from Bayer. The study reported by Dr. Wallace was supported by Pfizer. He reported having no relevant disclosures.

BOSTON – Two investigational monoclonal antibodies, each targeting a different cytokine, showed good activity against systemic lupus erythematosus in two separate studies presented at the annual meeting of the American College of Rheumatology.

Sifalimumab, a fully human monoclonal antibody that binds to and neutralizes several different subtypes of interferon-alpha (IFN-alpha), was better than placebo at improving measures of systemic lupus erythematosus (SLE) disease activity in 431 patients enrolled in a phase IIb safety and efficacy study, said Dr. Munther Khamashta of the Graham Hughes Lupus Research Laboratory at King’s College London.

“The primary endpoint, SRI [Systemic Lupus Erythematosus Responder Index] response at 52 weeks, was significant at all doses of sifalimumab, compared with placebo,” he said at the meeting.

There were no major unexpected adverse events with the drug. Investigators have previously documented increased frequency of herpes zoster infections in patients receiving sifalimumab, but the infections respond promptly to antiviral medication, he added.

Sifalimumab is targeted against the type I interferon receptor present on most cells. The specific target is IFN-alpha, the predominant subtype of type I interferons, which have been shown to play a key role in the pathogenesis of SLE.

In the phase II study, 431 adults with moderate to severe active SLE were screened and randomly assigned to receive either sifalimumab in an intravenous infusion every 4 weeks for 1 year at one of three doses – 200 mg, 600 mg, or 1,200 mg – or to placebo on the same schedule. The patients were permitted to receive up to three oral or intramuscular burst and taper steroids up to day 127 of the study.

SRI responses at 52 weeks were seen in 45.4% of patients on placebo, 58.3% of patients on the 200-mg dose (P vs. placebo = .057), 56.5% on the 600-mg dose (P = .094), and 59.8% for the 1,200-mg dose (P = .031).

Dr. Khamashta said that, at the final analysis, the investigators considered a P value less than .098 to be statistically significant because they needed to adjust for a type 1 error rate of 0.1 in the primary endpoint after they performed an interim analysis of the data.

There also were significant improvements in the sifalimumab arms vs. placebo in affected joint counts and in two secondary endpoints at specific doses: improvement in skin rash as measured by CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) and improvement in fatigue.

Anti–interleukin-6 monoclonal antibody tested

An investigational monoclonal antibody targeting a different cytokine, interleukin-6 (IL-6), appeared to reduce the severity of lupus flares, with activity occurring as early as 24 weeks, in a phase II, dose-ranging study of 183 patients with active SLE, said Dr. Daniel J. Wallace, a rheumatologist at Cedars-Sinai Medical Center in Los Angeles.

Although the drug was deemed to be safe at doses of 10 mg and 50 mg given by subcutaneous injection every 8 weeks, there were four deaths attributed to the medication, including two cases of pulmonary embolism and one of cardiorespiratory arrest in patients treated with the 200-mg dose and a suspected pulmonary embolism in a 32-year-old woman treated with the 10-mg dose. The investigators said that Pfizer, the study sponsor, determined that further studies are warranted to better characterize the benefits and risks of the 10-mg and 50-mg doses but will no longer study the 200-mg dose.

The biologic drug, still known only as PF-04236921, is a fully human antibody that binds to and neutralizes the IL-6 ligand rather than the receptor.

Dr. Wallace said that the rationale for targeting IL-6 in lupus is that there are increased IL-6 levels in the disease produced by T and B cells. Hyperactive B cells from SLE patients produce large amounts of immunoglobulins, and blocking IL-6 decreases immunoglobulin and anti-DNA production. A small, open-label study conducted at the National Institutes of Health with an anti-IL-6 receptor showed promising clinical and serologic responses, he noted.

The study reported by Dr. Khamashta was supported by AstraZeneca. He disclosed research grants from Bayer. The study reported by Dr. Wallace was supported by Pfizer. He reported having no relevant disclosures.

BOSTON – Two investigational monoclonal antibodies, each targeting a different cytokine, showed good activity against systemic lupus erythematosus in two separate studies presented at the annual meeting of the American College of Rheumatology.

Sifalimumab, a fully human monoclonal antibody that binds to and neutralizes several different subtypes of interferon-alpha (IFN-alpha), was better than placebo at improving measures of systemic lupus erythematosus (SLE) disease activity in 431 patients enrolled in a phase IIb safety and efficacy study, said Dr. Munther Khamashta of the Graham Hughes Lupus Research Laboratory at King’s College London.

“The primary endpoint, SRI [Systemic Lupus Erythematosus Responder Index] response at 52 weeks, was significant at all doses of sifalimumab, compared with placebo,” he said at the meeting.

There were no major unexpected adverse events with the drug. Investigators have previously documented increased frequency of herpes zoster infections in patients receiving sifalimumab, but the infections respond promptly to antiviral medication, he added.

Sifalimumab is targeted against the type I interferon receptor present on most cells. The specific target is IFN-alpha, the predominant subtype of type I interferons, which have been shown to play a key role in the pathogenesis of SLE.

In the phase II study, 431 adults with moderate to severe active SLE were screened and randomly assigned to receive either sifalimumab in an intravenous infusion every 4 weeks for 1 year at one of three doses – 200 mg, 600 mg, or 1,200 mg – or to placebo on the same schedule. The patients were permitted to receive up to three oral or intramuscular burst and taper steroids up to day 127 of the study.

SRI responses at 52 weeks were seen in 45.4% of patients on placebo, 58.3% of patients on the 200-mg dose (P vs. placebo = .057), 56.5% on the 600-mg dose (P = .094), and 59.8% for the 1,200-mg dose (P = .031).

Dr. Khamashta said that, at the final analysis, the investigators considered a P value less than .098 to be statistically significant because they needed to adjust for a type 1 error rate of 0.1 in the primary endpoint after they performed an interim analysis of the data.

There also were significant improvements in the sifalimumab arms vs. placebo in affected joint counts and in two secondary endpoints at specific doses: improvement in skin rash as measured by CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) and improvement in fatigue.

Anti–interleukin-6 monoclonal antibody tested

An investigational monoclonal antibody targeting a different cytokine, interleukin-6 (IL-6), appeared to reduce the severity of lupus flares, with activity occurring as early as 24 weeks, in a phase II, dose-ranging study of 183 patients with active SLE, said Dr. Daniel J. Wallace, a rheumatologist at Cedars-Sinai Medical Center in Los Angeles.

Although the drug was deemed to be safe at doses of 10 mg and 50 mg given by subcutaneous injection every 8 weeks, there were four deaths attributed to the medication, including two cases of pulmonary embolism and one of cardiorespiratory arrest in patients treated with the 200-mg dose and a suspected pulmonary embolism in a 32-year-old woman treated with the 10-mg dose. The investigators said that Pfizer, the study sponsor, determined that further studies are warranted to better characterize the benefits and risks of the 10-mg and 50-mg doses but will no longer study the 200-mg dose.

The biologic drug, still known only as PF-04236921, is a fully human antibody that binds to and neutralizes the IL-6 ligand rather than the receptor.

Dr. Wallace said that the rationale for targeting IL-6 in lupus is that there are increased IL-6 levels in the disease produced by T and B cells. Hyperactive B cells from SLE patients produce large amounts of immunoglobulins, and blocking IL-6 decreases immunoglobulin and anti-DNA production. A small, open-label study conducted at the National Institutes of Health with an anti-IL-6 receptor showed promising clinical and serologic responses, he noted.

The study reported by Dr. Khamashta was supported by AstraZeneca. He disclosed research grants from Bayer. The study reported by Dr. Wallace was supported by Pfizer. He reported having no relevant disclosures.