LONDON, United Kingdom — After years of clinical trial failures, an anti-interferon antibody, anifrolumab, has been shown to dramatically reduce disease activity in extrarenal systemic lupus erythematosus.
In a large phase 2 trial, "we saw consistent, good results with anifrolumab across multiple measures of disease activity," said Richard Furie, MD, chief of rheumatology at Northwell Health in Long Island, New York. "I think these results give us more than hope."
"There has been failure after failure after failure in terms of new clinical trials, not just in extrarenal lupus, but also in lupus nephritis," Dr Furie told Medscape Medical News. "There is a great need for safer therapies, for better therapies, and for targeted therapies. And now we have these phase 2 study results that are very robust."
The findings were presented here at the European League Against Rheumatism Congress 2016.
The 305 study participants were randomized to one of three treatment groups for 48 weeks: 99 received intravenous (IV) anifrolumab 300 mg every 4 weeks; 104 received IV anifrolumab 1000 mg every 4 weeks; and 102 received placebo.
The entry criteria for the trial were rigorous, Dr Furie explained. Patients had to be serologically active and had to have clinical activity, with a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of at least 6, a British Isles Lupus Activity Group 2004 (BILAG-2004) score of 1A or 2B, and a Physician Global Assessment score greater than 1.
Most patients were on a range of background therapies.
Patients were stratified by several factors, including interferon gene expression signature (low or high), prednisone dose, and SLEDAI-2K score.
At baseline, the average SLEDAI-2K score was around 11 and the clinical SLEDAI-2K score minus laboratory elements was around 9, Dr Furie reported.
The primary efficacy measure was a composite of the proportion of patients who achieved a Systemic Lupus Erythematosus Responder Index (SRI) score of 4 at day 169 and a sustained reduction in oral corticosteroid dose to below 10 mg/day from day 85 to day 169.
"At 6 months, about twice as many patients who received the 300 mg dose had achieved an SRI-4 response plus steroid taper as placebo patients," Dr Furie reported.
Responses were not as robust in the 1000 mg group.
Table. Patients Achieving the Primary End Point
| Patients | Anifrolumab 300 mg Group, % | Anifrolumab 1000 mg Group, % | Placebo Group, % |
| All (n = 305) | |||
| Day 169 | 34.3 | 28.8 | 17.6 |
| Day 365 | 51.5 | 38.5 | 25.5 |
| High interferon gene expression (n = 229) | |||
| Day 169 | 36.0 | 28.2 | 13.2 |
| Day 365 | 52.0 | 38.5 | 19.7 |
| Low interferon gene expression (n = 76) | |||
| Day 169 | 29.2 | 30.8 | 30.8 |
| Day 365 | 50.0 | 38.5 | 42.3 |
About three-quarters of the patients had high interferon gene expression and, in this group, "results were even more dramatic," said Dr Furie. Again, results were less robust in the 1000 mg group.
At day 169, all 76 patients with low interferon gene expression responded equally well, regardless of treatment.
At day 169, BILAG-Based Composite Lupus Assessment scores were almost 20% higher in the 300 mg group than in the placebo group; at day 365, scores were 29% higher.
At day 365, disease activity was low in more patients in the 300 mg and 1000 mg groups than in the placebo group (35.4% vs 32.7% vs 17.6%). The same pattern was seen for major clinical response, defined as a BILAG-2004 index score of C or better at day 169 with maintenance of response to day 365 (19.2% vs 17.3% vs 6.9%).
"Dramatic" improvements were seen in patients who had a Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score of at least 10 at baseline, Dr Furie pointed out.
In this subgroup, seven times more patients in the 300 mg group than in the placebo group had achieved an improvement in CLASI activity score of at least 50% at day 169. And at day 365, patients in the 300 mg group were almost 4.5 times more likely than those in the placebo group to have achieved this improvement in CLASI activity score.
At day 169, more than 45% of patients in the 300 mg group had reduced their corticosteroid dose to 7.5 mg/day or less, whereas this reduction was achieved by only about one-third of those in the 1000 mg group and about one-quarter of those in the placebo group. At day 365, this rose to more than 56% in the 300 mg group, but there was little change in either of the other two groups.
The only real disappointment in the trial was the fact that although changes in the FACIT Fatigue Scale score and the SF-36 at day 365 were numerically higher in the anifrolumab groups than in the placebo group, the differences were not significant.
Adverse Events
Anifrolumab inhibits all type 1 interferon receptors, so it was expected that treatment would increase the risk for severe infection, Dr Furie explained.
"The concern here is about viral infections. We did see a dose-dependent increase in shingles from the 300 to 1000 mg groups," he reported. Specifically, 10 patients in the 1000 mg developed a herpes zoster infection, as did five patients in the 300 mg group and two patients in the placebo group.
The same pattern was seen for influenza. There were eight reports of influenza infection in the 1000 mg group, six in the 300 mg group, and two in the placebo group.
"However, overall, the safety and tolerability of anifrolumab was acceptable," said Dr Furie, who explained that the greater efficacy of anifrolumab seen in patients with a high interferon gene expression signature supports the pathobiology of type 1 interferon receptor inhibition.
Anifrolumab is an "important advance," said Ruth Fritsch-Stroke, MD, from Utrecht University in the Netherlands. The data presented by Dr Furie are significantly more encouraging than recent trial data involving other anti-interferon antibodies, such as sifalimumab.
"After a long interval in which we've had nothing apart from belimumab, finally something has come up that we think will help patients with lupus," she told Medscape Medical News.
However, in this study, anifrolumab did not improve quality of life, Marc Bijl, MD, from Martini Hospital in Groningen, the Netherlands, pointed out.
"It seems there is always a discrepancy between what we measure in terms of disease activity and what patients feel," Dr Bijl explained.
This might reflect the fact that the dose of steroids used in the study was being tapered as a requisite part of the primary efficacy measure. "I think patients need more time," Dr Bijl said.
"Each time you taper steroids, patients often feel poorly," he said. "It takes time to get to a stable dose of steroids, but once there, I think patients will feel better."
The study was funded by MedImmune. Dr Furie reports financial relationships with MedImmune, Genentech, Roche, and Neovacs. Dr Fritsch-Stork and Dr Bijl have disclosed no relevant financial relationships.
European League Against Rheumatism (EULAR) Congress 2016: Abstract OP0291. Presented June 11, 2016.
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Cite this: Anti-Interferon Antibody Curbs Lupus Disease Activity - Medscape - Jun 14, 2016.
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