ACR: Investigational lupus drugs test new or reworked approaches to treatment

SAN FRANCISCO – A variety of new, repurposed, and reformulated compounds have made their way into clinical trials for systemic lupus erythematosus, as evidenced by an abstracts session devoted to them at the annual meeting of the American College of Rheumatology. The drugs undergoing testing include a subcutaneous formulation of belimumab, anifrolumab, dapirolizumab pegol, arsenic trioxide, and low-dose interleukin-2.

Some of the approaches have a longer track record, and are at the phase III stage of evaluation. One such molecule is belimumab (Benlysta), a recombinant human monoclonal antibody targeted to B-lymphocyte stimulator. It is approved as an intravenous formulation for treating adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy, but is being tested as a self-administered subcutaneous injection.

“Self-administration of subcutaneous (SC) belimumab will enhance treatment options for patients with SLE,” commented Dr. William Stohl of the University of Southern California, Los Angeles. He and his colleagues explored the potential of SC belimumab in a double-blind, placebo-controlled, 52-week BLISSFUL trial in which all SLE patients received standard of care and were randomized to weekly placebo SC injections (n = 280) or belimumab 200 mg SC weekly (n = 556) across 177 sites in 30 countries. The trial is sponsored by GlaxoSmithKline, which markets belimumab. Belimumab achieved the trial’s primary endpoint, the rate of response on the SLE Responder Index 4 (SRI-4) at week 52 (odds ratio, 1.64; 95% confidence interval, 1.22-2.20; P = .0011) and the key secondary endpoint of time to first severe flare (OR, 0.50; 95% CI, 0.34-0.73; P = .0003). Belimumab treatment reduced steroid use but not to a statistically significant extent (OR, 1.65; 95% CI, 0.95-2.84; P = .0732). The approach was well tolerated.

Another monoclonal antibody of note, anifrolumab, blocks the receptor for type 1 interferon, which has been implicated in SLE pathology. A phase IIb trial funded by MedImmune that involved 305 seropositive patients with moderate to severe SLE who had not responded to prior therapy randomized the patients to intravenous placebo (n = 102) or intravenous anifrolumab at 300 mg (n = 99) or 1,000 mg (n = 104) every 4 weeks for 48 weeks. Significant alterations of serum biomarkers were apparent, which were reflected by the clinical benefits observed. The study arms were comparable at baseline demographically and in SLE clinical characteristics. The primary efficacy endpoint of SRI-4 at day 169 was achieved by 300 mg and 1,000 mg anifrolumab in 34.3% and 28.8% of patients, respectively, compared with 17.6% of those in the placebo arm (P = .014 and .063, respectively). Both doses also achieved the secondary endpoint of SRI-4 at day 365 (51.5% for 300 mg and 38.5% for 1,000 mg), compared with 25.5% in the placebo arm (P less than .001 and P = .048, respectively). Organ-specific measures, the frequency and severity of flares, and disease activity were all beneficially affected by both doses. The adverse event profile and frequency were similar in the study arms. “Patients with active SLE became less active,” commented the study’s principal investigator, Dr. Richard A. Furie of the North Shore–LIJ Health System, New York. “Targeting the [interferon alpha/beta receptor] is a promising therapeutic approach for patients with SLE who do not respond to currently available therapies.”

Other approaches to SLE treatment are more exploratory or represent a repurposing of established drugs. A UCB- and Biogen-sponsored, phase I, double-blind, placebo-controlled study explored the effect of repeated doses of dapirolizumab pegol over 10 weeks, with 28 weeks of follow-up. Dapirolizumab pegol consists of a pegylated, humanized anti-CD40 ligand Fab fragment that lacks the Fc region that has produced thromboembolic complications in earlier studies of monoclonal antibodies to CD40 ligand. In the study, the drug produced no serious treatment-emergent adverse events and no deaths in 14 patients, and showed some initial signs of activity in several measures of clinical response, compared with 7 placebo-treated patients.

The phase I/II proof of concept LUPSENIC trial assessed the safety and efficacy (as a secondary endpoint) of arsenic trioxide as potential treatment for moderate to severe SLE. Arsenic trioxide is approved for the treatment of acute promyelocytic leukemia. The regimen comprised 10 fixed-dose intravenous infusions over 24 days and a 20-week follow-up. “With only 4 weeks of treatment, arsenic trioxide demonstrated an acceptable safety and tolerability profile at 24 weeks with promising short-term clinical efficacy,” said Dr. Mohamed Hamidou of Nantes (France) University Hospital, which sponsored the study along with Medsenic. The results warrant further study, Dr. Hamidou said, with a focus on long-term safety and the value of the approach as a maintenance therapy.

The first trial to examine low-dose interleukin-2 (IL-2) in SLE indicated the value of IL-2 in reestablishing immune homeostasis. A total of 40 SLE patients in the open-label, uncontrolled, prospective study received three courses of SC injections of 1 million IU of IL-2, with a 2-week break between courses. Response to IL-2 was swift and robust as determined by a variety of lab and renal function parameters, and improved clinical characteristics. The immunologic basis for the improvements appears to be an immune modulation involving the selective expansion of regulatory T cells, and selective suppression of follicular and IL-17–producing helper T cells. The Peking University People’s Hospital and Monash University sponsored the study.

Dr. Stohl reported consulting fees from Akros Pharma, Janssen, and GlaxoSmithKline. Dr. Furie has received research grants from MedImmune. Dr. Hamidou had no disclosures.

SAN FRANCISCO – A variety of new, repurposed, and reformulated compounds have made their way into clinical trials for systemic lupus erythematosus, as evidenced by an abstracts session devoted to them at the annual meeting of the American College of Rheumatology. The drugs undergoing testing include a subcutaneous formulation of belimumab, anifrolumab, dapirolizumab pegol, arsenic trioxide, and low-dose interleukin-2.

Some of the approaches have a longer track record, and are at the phase III stage of evaluation. One such molecule is belimumab (Benlysta), a recombinant human monoclonal antibody targeted to B-lymphocyte stimulator. It is approved as an intravenous formulation for treating adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy, but is being tested as a self-administered subcutaneous injection.

“Self-administration of subcutaneous (SC) belimumab will enhance treatment options for patients with SLE,” commented Dr. William Stohl of the University of Southern California, Los Angeles. He and his colleagues explored the potential of SC belimumab in a double-blind, placebo-controlled, 52-week BLISSFUL trial in which all SLE patients received standard of care and were randomized to weekly placebo SC injections (n = 280) or belimumab 200 mg SC weekly (n = 556) across 177 sites in 30 countries. The trial is sponsored by GlaxoSmithKline, which markets belimumab. Belimumab achieved the trial’s primary endpoint, the rate of response on the SLE Responder Index 4 (SRI-4) at week 52 (odds ratio, 1.64; 95% confidence interval, 1.22-2.20; P = .0011) and the key secondary endpoint of time to first severe flare (OR, 0.50; 95% CI, 0.34-0.73; P = .0003). Belimumab treatment reduced steroid use but not to a statistically significant extent (OR, 1.65; 95% CI, 0.95-2.84; P = .0732). The approach was well tolerated.

Another monoclonal antibody of note, anifrolumab, blocks the receptor for type 1 interferon, which has been implicated in SLE pathology. A phase IIb trial funded by MedImmune that involved 305 seropositive patients with moderate to severe SLE who had not responded to prior therapy randomized the patients to intravenous placebo (n = 102) or intravenous anifrolumab at 300 mg (n = 99) or 1,000 mg (n = 104) every 4 weeks for 48 weeks. Significant alterations of serum biomarkers were apparent, which were reflected by the clinical benefits observed. The study arms were comparable at baseline demographically and in SLE clinical characteristics. The primary efficacy endpoint of SRI-4 at day 169 was achieved by 300 mg and 1,000 mg anifrolumab in 34.3% and 28.8% of patients, respectively, compared with 17.6% of those in the placebo arm (P = .014 and .063, respectively). Both doses also achieved the secondary endpoint of SRI-4 at day 365 (51.5% for 300 mg and 38.5% for 1,000 mg), compared with 25.5% in the placebo arm (P less than .001 and P = .048, respectively). Organ-specific measures, the frequency and severity of flares, and disease activity were all beneficially affected by both doses. The adverse event profile and frequency were similar in the study arms. “Patients with active SLE became less active,” commented the study’s principal investigator, Dr. Richard A. Furie of the North Shore–LIJ Health System, New York. “Targeting the [interferon alpha/beta receptor] is a promising therapeutic approach for patients with SLE who do not respond to currently available therapies.”

Other approaches to SLE treatment are more exploratory or represent a repurposing of established drugs. A UCB- and Biogen-sponsored, phase I, double-blind, placebo-controlled study explored the effect of repeated doses of dapirolizumab pegol over 10 weeks, with 28 weeks of follow-up. Dapirolizumab pegol consists of a pegylated, humanized anti-CD40 ligand Fab fragment that lacks the Fc region that has produced thromboembolic complications in earlier studies of monoclonal antibodies to CD40 ligand. In the study, the drug produced no serious treatment-emergent adverse events and no deaths in 14 patients, and showed some initial signs of activity in several measures of clinical response, compared with 7 placebo-treated patients.

The phase I/II proof of concept LUPSENIC trial assessed the safety and efficacy (as a secondary endpoint) of arsenic trioxide as potential treatment for moderate to severe SLE. Arsenic trioxide is approved for the treatment of acute promyelocytic leukemia. The regimen comprised 10 fixed-dose intravenous infusions over 24 days and a 20-week follow-up. “With only 4 weeks of treatment, arsenic trioxide demonstrated an acceptable safety and tolerability profile at 24 weeks with promising short-term clinical efficacy,” said Dr. Mohamed Hamidou of Nantes (France) University Hospital, which sponsored the study along with Medsenic. The results warrant further study, Dr. Hamidou said, with a focus on long-term safety and the value of the approach as a maintenance therapy.

The first trial to examine low-dose interleukin-2 (IL-2) in SLE indicated the value of IL-2 in reestablishing immune homeostasis. A total of 40 SLE patients in the open-label, uncontrolled, prospective study received three courses of SC injections of 1 million IU of IL-2, with a 2-week break between courses. Response to IL-2 was swift and robust as determined by a variety of lab and renal function parameters, and improved clinical characteristics. The immunologic basis for the improvements appears to be an immune modulation involving the selective expansion of regulatory T cells, and selective suppression of follicular and IL-17–producing helper T cells. The Peking University People’s Hospital and Monash University sponsored the study.

Dr. Stohl reported consulting fees from Akros Pharma, Janssen, and GlaxoSmithKline. Dr. Furie has received research grants from MedImmune. Dr. Hamidou had no disclosures.

SAN FRANCISCO – A variety of new, repurposed, and reformulated compounds have made their way into clinical trials for systemic lupus erythematosus, as evidenced by an abstracts session devoted to them at the annual meeting of the American College of Rheumatology. The drugs undergoing testing include a subcutaneous formulation of belimumab, anifrolumab, dapirolizumab pegol, arsenic trioxide, and low-dose interleukin-2.

Some of the approaches have a longer track record, and are at the phase III stage of evaluation. One such molecule is belimumab (Benlysta), a recombinant human monoclonal antibody targeted to B-lymphocyte stimulator. It is approved as an intravenous formulation for treating adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy, but is being tested as a self-administered subcutaneous injection.

“Self-administration of subcutaneous (SC) belimumab will enhance treatment options for patients with SLE,” commented Dr. William Stohl of the University of Southern California, Los Angeles. He and his colleagues explored the potential of SC belimumab in a double-blind, placebo-controlled, 52-week BLISSFUL trial in which all SLE patients received standard of care and were randomized to weekly placebo SC injections (n = 280) or belimumab 200 mg SC weekly (n = 556) across 177 sites in 30 countries. The trial is sponsored by GlaxoSmithKline, which markets belimumab. Belimumab achieved the trial’s primary endpoint, the rate of response on the SLE Responder Index 4 (SRI-4) at week 52 (odds ratio, 1.64; 95% confidence interval, 1.22-2.20; P = .0011) and the key secondary endpoint of time to first severe flare (OR, 0.50; 95% CI, 0.34-0.73; P = .0003). Belimumab treatment reduced steroid use but not to a statistically significant extent (OR, 1.65; 95% CI, 0.95-2.84; P = .0732). The approach was well tolerated.

Another monoclonal antibody of note, anifrolumab, blocks the receptor for type 1 interferon, which has been implicated in SLE pathology. A phase IIb trial funded by MedImmune that involved 305 seropositive patients with moderate to severe SLE who had not responded to prior therapy randomized the patients to intravenous placebo (n = 102) or intravenous anifrolumab at 300 mg (n = 99) or 1,000 mg (n = 104) every 4 weeks for 48 weeks. Significant alterations of serum biomarkers were apparent, which were reflected by the clinical benefits observed. The study arms were comparable at baseline demographically and in SLE clinical characteristics. The primary efficacy endpoint of SRI-4 at day 169 was achieved by 300 mg and 1,000 mg anifrolumab in 34.3% and 28.8% of patients, respectively, compared with 17.6% of those in the placebo arm (P = .014 and .063, respectively). Both doses also achieved the secondary endpoint of SRI-4 at day 365 (51.5% for 300 mg and 38.5% for 1,000 mg), compared with 25.5% in the placebo arm (P less than .001 and P = .048, respectively). Organ-specific measures, the frequency and severity of flares, and disease activity were all beneficially affected by both doses. The adverse event profile and frequency were similar in the study arms. “Patients with active SLE became less active,” commented the study’s principal investigator, Dr. Richard A. Furie of the North Shore–LIJ Health System, New York. “Targeting the [interferon alpha/beta receptor] is a promising therapeutic approach for patients with SLE who do not respond to currently available therapies.”

Other approaches to SLE treatment are more exploratory or represent a repurposing of established drugs. A UCB- and Biogen-sponsored, phase I, double-blind, placebo-controlled study explored the effect of repeated doses of dapirolizumab pegol over 10 weeks, with 28 weeks of follow-up. Dapirolizumab pegol consists of a pegylated, humanized anti-CD40 ligand Fab fragment that lacks the Fc region that has produced thromboembolic complications in earlier studies of monoclonal antibodies to CD40 ligand. In the study, the drug produced no serious treatment-emergent adverse events and no deaths in 14 patients, and showed some initial signs of activity in several measures of clinical response, compared with 7 placebo-treated patients.

The phase I/II proof of concept LUPSENIC trial assessed the safety and efficacy (as a secondary endpoint) of arsenic trioxide as potential treatment for moderate to severe SLE. Arsenic trioxide is approved for the treatment of acute promyelocytic leukemia. The regimen comprised 10 fixed-dose intravenous infusions over 24 days and a 20-week follow-up. “With only 4 weeks of treatment, arsenic trioxide demonstrated an acceptable safety and tolerability profile at 24 weeks with promising short-term clinical efficacy,” said Dr. Mohamed Hamidou of Nantes (France) University Hospital, which sponsored the study along with Medsenic. The results warrant further study, Dr. Hamidou said, with a focus on long-term safety and the value of the approach as a maintenance therapy.

The first trial to examine low-dose interleukin-2 (IL-2) in SLE indicated the value of IL-2 in reestablishing immune homeostasis. A total of 40 SLE patients in the open-label, uncontrolled, prospective study received three courses of SC injections of 1 million IU of IL-2, with a 2-week break between courses. Response to IL-2 was swift and robust as determined by a variety of lab and renal function parameters, and improved clinical characteristics. The immunologic basis for the improvements appears to be an immune modulation involving the selective expansion of regulatory T cells, and selective suppression of follicular and IL-17–producing helper T cells. The Peking University People’s Hospital and Monash University sponsored the study.

Dr. Stohl reported consulting fees from Akros Pharma, Janssen, and GlaxoSmithKline. Dr. Furie has received research grants from MedImmune. Dr. Hamidou had no disclosures.