Novel therapeutics target ‘fickle, unpredictable’ lupus
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The recent approval of anifrolumab highlights what may be a new wave of therapeutic advances made in lupus, according to a presenter at the 2021 Congress of Clinical Rheumatology-East.
For Richard Furie, MD, chief of the division of rheumatology at Northwell Health and professor of medicine at Hofstra/Northwell School of Medicine in New York, these advances cannot come soon enough. “Even now, in the modern era, we are losing about 15% to 20% of our patients at 15 years,” he said. “Lupus ranks No. 1 in mortality rate in chronic inflammatory diseases.”
Some of the major unmet needs in the field include treatments for lupus nephritis, severe renal disease, flare prevention without using steroids or immunosuppressive drugs and a reliable method of inducing remission in a large proportion of patients. “We also must think about quality of life,” Furie said.
The main stumbling block is that lupus disease can take a number of forms, according to Furie. “Lupus is fickle,” he said. “Lupus is unpredictable.”
Furie lauded efforts by the research community to look at specific targets, starting with interferon. He noted that patients may exhibit high activity of one or more of the five subtypes of type 1 interferon or also have high type 2 or type 3 interferon activity.
Anifrolumab (Saphnelo, AstraZeneca) is a monoclonal antibody to the type 1 interferon receptor and blocks all five subtypes, according to Furie. “This is a very important strategy,” he said.
Furie noted that when he submitted the slides, the FDA had not yet approved anifrolumab. He acknowledged that there are still questions about the way it will be used in the real world. “How will we position it?” he said. “Time will tell.”
Keeping on the theme of interferons, Furie discussed BIIB059 (Biogen), a monoclonal antibody to BDCA2. “When BDCA2 is ligated, it is internalized, and cytokine interferon synthesis is shut down,” he said.
Phase 2 data showed that Cutaneous LE Disease Area and Score Index (CLASI) score improved by some 40 percentage points in patients treated with “various doses” of BIIB059, according to Furie. “This program has moved to phase 3,” he said.
Turning to B-cell directed therapies, Furie next discussed iberdomide (Celgene), a small molecule that binds cereblon and promotes proteasomal degradation of ikaros (IKZF1) and aiolos (IKZF3). He described IKZF1 and IKZF3 as transcription factors involved in immune cell development and homeostasis. Iberdomide yielded encouraging phase 2 results as assessed by SLE Responder Index (SRI).
The next batch of targets that may bear fruit in lupus treatment are cytokines such as interleukin-10, IL-6, IL-21, IL-2 restoration, IL-12/23 and the janus kinase (JAK)/ signal transducer and activator of transcription (STAT) signaling pathway. “There are a lot of potential cytokines to target,” Furie said.
Furie showed particular interest in IL-2. “Patients with lupus are relatively deficient in IL-2 production,” he said.
Upstream from the JAK/STAT pathway is TYK2, which is targeted by baricitinib, according to Furie. “There is a lot of excitement about TYK2 inhibitors,” he said.
Dapirolizumab (Biogen/UCB), an antibody to the CD40 ligand, has yielded encouraging BILAG-Based Composite Lupus Assessment (BICLA) responses.
As for “burning questions” that remain in the specialty, Furie noted that lupus nephritis is still associated with poor outcomes and continues to challenge clinicians. Another question is whether patients with class III, IV or V disease should receive combination therapy.
A growing body of data is showing that voclosporin or belimumab (Benlysta, GlaxoSmithKline), in addition to background cyclophosphamide or mycophenolate mofetil, can lead to better results. However, these approaches have yet to take widespread root in the rheumatology community. “People do not want to change their ways,” he said.
Regarding patients with class V disease, Furie urged patience, noting that immediate improvement may be an unrealistic goal. “Maybe class V patients need more time to get better,” he said.
As for lupus patients in general, there may be one more key puzzle piece that is still necessary for developing even better targeted therapies. “We need predictive biomarkers for sure,” Furie said.
Despite these issues, the approval of anifrolumab is certainly reason for hope, according to Furie. “I am very optimistic about the future,” he said. “We are kind of on a roll.”
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Furie R. New and Emerging Therapies in SLE. Presented at: Congress of Clinical Rheumatology-East annual symposium; August 12-15, 2021 (hybrid meeting).
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