Type I interferon (IFN) has long been recognized as a key component in systemic lupus erythematosus (SLE), but the role it plays has not always been clear. At different stages in research, IFN has been identified as a causal factor in lupus, a biomarker, and a potential therapeutic target. IFN can play all three roles, but recently there has been much debate about whether IFN is a therapeutic target.
Anifrolumab, an anti-IFN monoclonal antibody, has completed two Phase 3 trials. The first trial, TULIP (Treatment of Uncontrolled Lupus via the interferon Pathway) 1, failed to meet its endpoints in 2018. A slightly different companion trial, TULIP 2, showed a greater reduction in disease activity compared to placebo when top line results were unveiled earlier this year.
“There has been a case building for many years about the importance of interferons in the pathogenesis of lupus,” said Timothy Niewold, MD, Judith and Stewart Colton Professor of Medicine and Pathology and Director of the Colton Center for Autoimmunity at the New York University School of Medicine. “One of the most exciting recent developments is that drug companies have created agents to target the interferon pathway. It’s been a rocky road, but there have been some positive results.”
Dr. Niewold will discuss the current state of clinical trials in IFN and lupus during this year’s Immunology Update: Type I Interferon in SLE: Causal Factor, Biomarker, or Therapeutic Agent? on Tuesday from 4:30 – 5:30 pm in Room B304-B305, Building B of the Georgia World Congress Center. Also during the session, Virginia Pascual, MD, Director of the Gale and Ira Drukier Institute for Children’s Health and Ronay Menschel Professor of Pediatrics at Weill Cornell Medicine will discuss the latest findings in clinical correlations and pathogenic potential for type I IFN in lupus.
IFN promotes, or primes, the immune system and plays a critical role in the pathogenesis of lupus and possibly other autoimmune diseases. In lupus, control over the type I IFN system malfunctions, leading to an overproduction of IFN.
The problem for clinicians and patients, Dr. Niewold noted, is that there are no type 1 IFN inhibitors approved for clinical use. The only biologic agent currently approved for lupus, belimumab, is a B-cell activating factor inhibitor. Belimumab’s approval in 2011 ended a 50-year drought in new lupus treatments, but no new agents have appeared in the past eight years.
Multiple agents in recent clinical trials target different components of the type I IFN pathway in lupus, Dr. Niewold said. The first Phase 2 trials of antibodies targeting interferon alpha did not meet endpoints, and these agents were not taken forward for further development. Anifrolumab showed strong Phase 2 results, raising hopes for the two TULIP Phase 3 trials.
Anifrolumab binds to the type I IFN receptor, blocking the activity of all type I IFNs, including IFN-α, IFN-β and I FN-ω. TULIP 1 failed to meet its primary endpoint of reducing disease activity as measured by the SLE Responder Index 4 in August 2018. TULIP 2 met its primary endpoint of reducing disease activity as measured by the British Isles Lupus Assessment Group Based Composite Lupus Assessment.
Where anifrolumab goes from here is an open question.
“One trial made the endpoint, and the other one did not, so clearly we are interested in the differences in the trial designs between the two studies.” Dr. Niewold said. “If they go to the FDA for approval, it will be more difficult than if both trials had succeeded. But they could go forward for approval, especially in lupus, where there aren’t a lot of other agents available and a huge unmet need. This symposium will offer the state of the art as we know it today in targeting interferons in lupus.”