Resetting The Immune System For Lasting Remission
By Iain Kilty
Despite decades of therapeutic advances, a stark reality faces the millions of patients living with an autoimmune or inflammatory disease: moving beyond symptom management remains frustratingly difficult to achieve with the current treatment options available. In inflammatory bowel disease, up to 80% of patients fail to achieve a sustained remission. Similar patterns are evident in rheumatoid arthritis and atopic dermatitis, where approximately 70% of patients using existing therapies also do not reach remission. These statistics underscore a critical question: How do we move beyond alleviating the signs and symptoms of disease to achieve lasting, functional cures and address the large unmet medical need that persists for these patient populations?
The Evolving Landscape Of Autoimmune Treatment
The treatment landscape for autoimmune and inflammatory diseases has evolved through three distinct phases. The first era, dating back as far as the 1960s, relied on broad immunosuppressants such as chemotherapies and steroids, powerful but indiscriminate treatments that carried significant side effects. The second era in the early 2000s introduced biologics and targeted therapies, such as JAK inhibitors, which provided improved efficacy but with limited remission rates and remaining safety concerns. Today, we stand at the threshold of a third era, one focused on pursuing novel targets and improved modalities, offering the potential to not only alleviate symptoms but to modify disease to deliver lasting remission. With autoimmune and inflammatory diseases affecting millions of patients worldwide, this shift beyond symptom management is an important step forward and has become a critical area of research for our industry, given the pace of scientific progress underway and the global market opportunity.
Emerging therapeutic approaches offer hope of safer, scalable, and more effective solutions for patients. Recent advances in immunology have catalyzed a transition toward therapies aimed at resetting the immune system, rather suppressing it. The potential of T-cell engagers and CAR-T therapies, which have demonstrated efficacy in oncology and are now being explored for autoimmune and inflammatory conditions, are generating significant interest. By selectively targeting immune cells, these therapies seek to restore immune balance rather than relying on broad immunosuppression.
However, these novel modalities are not without their challenges. CAR-T therapies, for example, require complex manufacturing processes and may not be commercially viable for widespread autoimmune applications. Additionally, T-cell engagers have been associated with neurological side effects and cytokine storm responses. Alternative approaches are still needed, and one that is gaining traction is the development of small molecular protein degraders. Unlike biologics, these therapies can be orally administered, making them more accessible and convenient for patients. As the protein is being degraded, as opposed to its activity being inhibited, this increases the range of druggable targets, offering the potential for greater efficacy and safety. For example, transcription factors have historically been challenging small molecule targets, but therapies are now being advanced to degrade these important regulators of inflammation. Kymera Therapeutics' KT-621, a first-in-class oral STAT6 degrader, exemplifies this approach for TH2-driven allergic and atopic diseases. Preclinical data demonstrated that KT-621 achieves potent degradation of STAT6, an essential transcription factor driving TH2 inflammation, with the potential to provide dupilumab-like efficacy but in an oral formulation for conditions like atopic dermatitis.
Case Study: Atopic Dermatitis
A prime example of the evolution underway in the treatment of inflammatory disease can be seen in the treatment of atopic dermatitis, the most common chronic inflammatory skin disease. More than five million people in the U.S. and Europe are living with a moderate to severe form of the disease, which is characterized by skin barrier dysfunction, persistent inflammation, and severe itching, significantly impacting quality of life. The development of JAK inhibitors, such as Pfizer’s abrocitinib, which I was proud to work on, marked a significant step forward in treating inflammatory skin diseases. These therapies provided superior efficacy compared to traditional treatments, but their broader adoption was hindered by class safety concerns, most notably, cardiovascular risks that were only fully recognized post-approval. While these setbacks limit uptake of the drug, they underscore the importance of refining current therapeutic approaches.
At Sitryx, we are building on advances made in the field, leveraging new scientific insights and understanding of biology to develop novel oral therapies to restore immune balance in autoimmune and inflammatory disease. Our lead candidate, SYX-5219, an oral, disease-modifying anti-inflammatory therapy, targets a critical enzyme that regulates cell metabolism called pyruvate kinase M2 (PKM2). Modulation of PKM2 alters B and T lymphocyte function and represents a novel therapeutic target with the potential to rebalance the immune system, normalize immune cell function and drive sustained disease remission.
Orally administered treatments are particularly attractive in dermatology and immunology for several reasons. Beyond patient convenience, oral therapies can enable earlier intervention and provide greater opportunity to integrate with existing treatments, including biologics. Their attractiveness is exemplified by Gilead’s recent strategic partnership with LEO Pharma to accelerate the development and commercialization of their oral STAT6 programs for the potential treatment of patients with inflammatory diseases. STAT6 is a specific transcription factor required for IL-4 and IL-13 cytokine signaling in Th2-mediated inflammatory conditions. While this focused cytokine approach represents one strategy, at Sitryx we are pursuing broader precision immunology approaches through immunometabolism, where metabolic pathways are targeted to modulate multiple immune cell functions simultaneously. The industry's increasing investment in both targeted cytokine pathways and novel immunometabolic approaches signals an evolution in how companies are approaching oral therapeutics for inflammatory conditions.
From CSO To CEO: A New Perspective
My transition from Chief Scientific Officer to CEO at Sitryx has provided me with new insights into how scientific innovation and investment strategies intersect in the biotech sector. While my scientific background remains invaluable to me, inevitably my focus turns to maintaining the growth of our company, raising capital, and building investor relationships. Interestingly — and perhaps kismet — this evolution in my career has coincided with a surge of interest in the autoimmune and inflammatory disease space. Just look at Johnson & Johnson’s recent deals. In May 2024, they committed nearly $2.1 billion to expand their atopic dermatitis portfolio through two major acquisitions. First, they purchased Proteologix for $850 million to secure its bispecific antibody portfolio, then followed with a $1.25 billion investment in Numab Therapeutics to acquire rights to NM26, a Phase 2-ready bispecific antibody. At industry gatherings — the J.P. Morgan Healthcare Conference at the start of the year was one — investors gravitate toward scalable solutions that tie scientific innovation with commercial viability. This has manifested in growing enthusiasm for small molecule therapeutics, driven by their oral delivery and broader market potential, considerations that align with both investor interests and the overarching goal to develop widely accessible solutions for patients who remain underserved despite existing therapies.
The convergence of scientific innovation, strategic investment and scalable therapeutic approaches is welcoming in a new era for autoimmune and inflammatory disease treatment. The shift from biologics to oral, small molecule therapies, coupled with precision immunology approaches, positions us to address the significant unmet need in this space. As we’ve seen through recent industry developments and substantial investments, the future of immunology lies not only in suppressing symptoms, but in resetting and rebalancing the immune system for lasting patient benefit.
About The Author:
Iain Kilty was appointed CEO of Sitryx in July 2024. He joined the Company as CSO in May 2021, with 25 years of global biopharmaceutical industry experience leading programs from idea through to clinical development across a range of indications and therapeutic modalities. He developed as a drug discoverer through a 22-year tenure at Pfizer, starting as an internal industrial postdoc and taking on roles of increasing responsibility working across the drug discovery paradigm from target identification to leading the early clinical cluster in Rheumatology and Dermatology. Ultimately Iain served as Vice President Preclinical Sciences in the Inflammation and Immunology Research Unit, where he was responsible for a portfolio of both small and large molecule programs targeted across rheumatology, dermatology and gastroenterology. Iain left Pfizer at the end of 2018 to join Atlas Venture where he was the Chief Scientific Officer of Quench Bio, responsible for the company’s scientific strategy and execution, whilst also working as an Entrepreneur in Residence across the Atlas portfolio. Iain graduated with a BA and MA Cantab in Biochemistry from Jesus College, University of Cambridge, UK, before completing his Ph.D in the Breast Cancer Research Laboratories at the University of Liverpool, UK.