Momentum builds in lupus R&D
by Elizabeth Bolitho
Lupus is an autoimmune disease which affects about 1 in 1000 people, which commonly causes joint pain, skin rashes and tiredness. Treatment options are improving for patients with lupus, and the target discovery landscape is heating up. Although largely considered a systemic disease, the unpredictability of lupus makes both diagnosis and drug development challenging, with significant unmet need.
Over the past 5 years, more than 800 new proteins and genes involved in lupus have been uncovered that could act as potential drug targets for the disease, according to Causaly. 2021 was particularly prolific, with over 200 targets identified. These were overwhelmingly enzymes, reflecting the leading role of these catalytic proteins across the wider drug target landscape. But they also included a growing share of non-coding RNA and transcription factors. Indeed, in 2022, transport protein, receptors and signaling protein targets together narrowly outnumbered new enzyme targets in lupus, (‘new targets’ are defined as molecules with target potential, but which are not necessarily validated or druggable.) That year, interferons (a family of signaling proteins) generated almost three times as much evidence as the next-most published targets, interleukin-6 and TNFSF13b, a B-cell stimulator. Interferon type 1 and TNFSF13b, also known as B lymphocyte stimulator, are both the targets of approved lupus drugs.
Although the lupus target discovery growth rate of 18% between 2021 and 2022 was below that seen in other autoimmune diseases, such as psoriasis, multiple sclerosis, rheumatoid arthritis or Crohn’s disease, 2022 brought an exciting advance in scientists’ understanding of the genetics of lupus. A rare mutation in the gene encoding toll-like receptor 7 (TLR-7), an intracellular RNA sensor, was found to play a causative role in the early onset of lupus in one young patient, providing a reassuringly concrete link between lupus and TLR7. This receptor, whose potential as a target began to fully emerge back in the 2000s, is involved in the innate immune response to viral infections.
The discovery of the TLR7 gene mutation, along with recent lupus product launches, prompted a July 2022 editorial in The Lancet, titled: “2022: a banner year for systemic lupus erythematosus?”
Despite the optimism, there is a long way to go. Multiple environmental, hormonal, genetic and epigenetic factors often trigger lupus flares. The condition causes a wide range of symptoms, including skin rashes, mouth sores, joint pain, fatigue, and organ damage. These may differ significantly from one individual to another, can vary over time, and their precise causes remain poorly understood. This complexity explains the long history of failed clinical trials in the field.
Until about a decade ago, therapy options were limited to aspirin, corticosteroids, and the anti-malarial drug hydroxychloroquine to alleviate symptoms. In 2011, GlaxoSmithKline’s Benylsta (belimumab) became the first targeted treatment to gain approval; it blocks the B-lymphocyte stimulator, involved in the production of “auto-antibodies”. A decade later, AstraZeneca’s Saphnelo (anifrolumab) arrived as an add-on therapy for the most common form of the lupus, systemic lupus erythematosus (SLE). Saphnelo targets a receptor for type 1 interferon and is also being investigated in lupus nephritis , cutaneous lupus (skin rashes) and myositis,. Another drug, Aurinia’s Lupkynis (voclosporin) was approved in 2021 for lupus nephritis.
None of these treatments provide a cure for lupus, but they help reduce symptoms and their approval validates the target pathways, helping scientists build a fuller understanding of disease mechanisms – and informing further drug R&D. The current clinical pipeline includes compounds targeting blood dendritic cell antigen 2 (BDCA2), a protein found on the (plasmacytoid dendritic) cells, and a CD-40 targeting antibody that, so far, hasn’t shown the thrombosis risk associated with others in the class. Another mid-stage clinical compound, with FDA breakthrough status, binds to heat shock protein 8 (HSPA8) and modulates T cells upstream of existing therapies.
Several drugs already approved for other autoimmune conditions are also being assessed in lupus, including Novartis’ interleukin-17 (IL-17) inhibitor secukinumab, approved as Cosentyx for psoriatic arthritis and Bristol Myers Squibb’s TYK-2 inhibitor deucravacitinib, approved for plaque psoriasis as Sotyktu. Some cancer drugs, like Roche’s CD-20 targeting obinutuzumab (Gazyva) are also being investigated in lupus.
Lupus’ divergent symptoms make drug discovery and development challenging. As with many other diseases, multiple treatment options will likely be required. That requires continued progress in lupus target discovery and validation.
To find out more about lupus target discovery, including annual totals and breakdowns by target type, and for a deep dive into the most promising potential targets, download the 2023 Target Discovery Spotlight: Lupus and Autoimmune Diseases report.