Inflammation is a critical way that the body fights off infectious agents, but when that inflammation gets out of control — as is the case in the autoimmune conditions rheumatoid arthritis (RA) and psoriasis — it causes a problem. In recent years, scientists have developed ways to treat both of these conditions; their efforts have greatly improved the quality of life for patients.

“We've been in this really blessed era where a huge swath of innovations have happened. … [They have] really transformed something that had been once sort of like a death sentence to now really having good therapeutic options,” said Elizabeth Laws, the Vice President and Department Head of Immunology and Inflammation at Sanofi. But, she added, “There's still a lot of room for a safe, oral efficacious drug in this space.”
Laws and her team are developing therapies for chronic inflammatory diseases, including rheumatoid arthritis (RA) and psoriasis (1,2). In particular, Law oversees the clinical trials for a new oral tumor necrosis factor receptor 1 (TNFR1) inhibitor: SAR441566.
TNFR1 inhibitors block the activity of TNFR1, a receptor that plays a crucial role in the inflammatory response. When the pro-inflammatory cytokine TNF-alpha binds to TNFR1, it triggers a signaling cascade that leads to inflammation and tissue damage. By inhibiting TNFR1, these drugs interrupt this pathway, reducing inflammation and its associated symptoms.
Currently, monoclonal antibodies that target TNF-alpha are used to treat various inflammatory diseases like RA and psoriasis. However, these biologics have limitations, such as the need for multiple injections and potential side effects including increased risk of infections and heart problems.
Sanofi recently completed a Phase 1 proof-of-mechanism clinical trial for SAR441566 to treat psoriasis. The novel TNFR1 inhibitor was well-tolerated and clinically effective in patients with mild to moderate psoriasis. The company is now recruiting patients for a Phase 2 dose-finding study in patients with moderate to severe RA. Laws and her team hope that this oral medication may offer an alternative to existing medications that are less effective and require multiple injections.
How did Sanofi begin developing inflammatory therapeutics?
At Sanofi, our mission is to improve patient lives for chronic, debilitating inflammatory diseases. Over the past 20 years, we have unlocked the biology of these different diseases, for example the role that different cytokines play in the inflammatory pathway and their interdependencies. What we have tried to do as a company is to pursue and build a robust pipeline around these targeted therapies.
This was the “Holy Grail” we were chasing — the first oral formulation of a TNFR1 inhibitor.
- Elizabeth Laws, Sanofi
Why are TNFR1 inhibitors an attractive drug target?
Every company is looking for a safe oral TNFR1 small molecule inhibitor. These drugs can also modulate T regulatory cells and keep the brakes on the inflammatory system. Historically, this has been done with immunosuppressants, but this systemically downregulates inflammation. Glucocorticosteroids are an example of these, but they have adverse side effects, so people can’t take them long term. The pharmaceutical industry is now going after TNFR1 inhibitors for more specificity to treat these conditions.
What has the development process been like for this compound?
Developing an oral drug is always complicated, and it's been in development for many years. We have had a large number of initial candidates that have undergone preclinical testing. Then, we must refine the formulation to ensure efficient manufacturing and that people can take it as a pill. We're excited for this one because it's actually met that high bar. It's really difficult to get something through all of that criteria. It's been many years in the works and lots of blood, sweat, and tears to get to this moment.
How did you feel when you saw positive results both from RA and psoriasis Phase I clinical trials?
When our team first saw the results, we were very excited. This was the “Holy Grail'' we were chasing — the first oral formulation of a TNFR1 inhibitor. Ten years ago, we were still unsure of this technology. Now, we are close to solving this puzzle. Results from our Phase 1 trials show that the formulation is safe and well tolerated in small patient cohorts.
How else could this technology be used?
Oral medications are easy to combine with other therapies, which makes them easier for people to take compared to having multiple injections. People wouldn’t need to go to a medical office for repeated visits. We have some ideas, such as combining oral TNFR1 inhibitors with other advanced therapies that can boost their anti-inflammatory effect. A lot of inflammatory diseases are comorbid, so by treating both comorbidities at one time, we could boost overall outcomes.
This interview has been condensed and edited for clarity.
References
- Vugler, A. et al. An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis. Front Pharmacol 13, 1037983 (2022).
- Fishbein, A. et al. The Potential of an Oral TNFα Inhibitor with TNFR1 Specificity: Results of a Phase 1b Proof-of-mechanism Trial in Psoriasis. CR Convergence 2023, Abstract 0443. https://acrabstracts.org/abstract/the-potential-of-an-oral-tnfα-inhibitor-with-tnfr1-specificity-results-of-a-phase-1b-proof-of-mechanism-trial-in-psoriasis/