A First-in-Class Approach to Treating Inflammation
A novel, potent, and orally available covalent STING inhibitor with demonstrated proof-of-mechanism and broad potential to treat autoinflammatory and rare monogenic diseases.
FRTX-10, our lead Stimulator of Interferon Genes (STING) inhibitor candidate, is a new chemical entity that blocks the palmitoylation site of STING within the cGAS-STING pathway, which is required for STING activation. Inhibiting the palmitoylation step within this pathway dampens downstream signaling through IRF3 and NF-κB, ultimately suppressing inflammation, specifically type I interferons.
How is FRTX-10 differentiated?
FRTX-10 has established proof-of-mechanism and a promising profile in initial pharmacokinetics, toxicology, and safety pharmacology studies. It is differentiated by its palmitoylation-focused mechanism, which allows FRTX-10 to inhibit both wild-type STING and gain-of-function hyperactive STING mutants without competitive cGAMP binding. In addition, in vitro studies show that FRTX-10 more potently blocks the STING pathway than other known STING palmitoylation inhibitors. Further, mice treated with FRTX-10 demonstrate significant decreases in pro-inflammatory cytokine production following stimulation of STING. Taken together, FRTX-10 may present a unique and differentiated approach to treat chronic autoinflammatory diseases.
How does FRTX-10 work?
STING is a component of the cGAS-STING pathway, which plays an essential role in activating innate immunity. Cyclic GMP-AMP synthase (cGAS) acts as a DNA sensor, detecting DNA from sources such as invading bacteria, viruses, and cellular debris that can arise from aging and tissue damage. Upon DNA binding, cGAS produces the secondary messenger molecule cyclic GMP-AMP (cGAMP), which binds to STING. STING then undergoes the post-translational modification called palmitoylation, which activates the recruitment of kinases that phosphorylate IRF3 and IκBα. Phosphorylated IRF3 leads to activation of the type I interferon (IFN) response, while phosphorylated IκBα activates NF-κB and increases the secretion of pro-inflammatory cytokines, such as IL-6 and TNFα. Both type I IFNs and pro-inflammatory cytokines drive inflammation.
FRTX-10 inhibits STING palmitoylation, thereby inhibiting the activation of STING and resulting in an efficient shutdown of the STING downstream pathway. Upon in vivo stimulation of mice with a STING agonist, oral administration of FRTX-10 was observed to reduce serum cytokine levels of IL-6 and IFN-β.
Where could FRTX-10 work?
While the innate immune response is an important defense mechanism, excessive signaling through STING is linked to a multitude of high unmet need diseases, ranging from general inflammatory conditions, like systemic lupus erythematosus, to interferonopathies, which are a set of rare genetic disorders characterized by IFN overproduction. STING inhibition presents a targeted first-in-class therapeutic approach for autoimmune and inflammatory diseases driven by a dysregulated type I IFN response.
FRTX-10 in Systemic Lupus Erythematosus
Systemic Lupus Erythematosus (SLE) is a chronic, occasionally life-threatening, multisystem immune-mediated disorder that affects over 1 million individuals in the U.S. A substantial percentage of these patients show elevated cGAS-STING levels, which correlates to increased disease activity. Patients present with variable clinical features ranging from mild joint and skin involvement to life-threatening renal, hematologic, or CNS involvement. The clinical heterogeneity of SLE presentation and the lack of pathognomonic tests pose both a diagnostic and therapeutic challenge for clinicians. Importantly, it has been shown that ~15% of patients display elevated levels of cGAMP in the serum — a strong indicator of the presence of STING pathway overactivation in these patients. Moreover, serum collected from patients with SLE was shown to amplify type I IFN induction. These observations provide a strong rationale for the development of FRTX-10 in SLE, while offering a unique opportunity to specifically select and target patients that will most likely benefit from a STING inhibitor therapy.
FRTX-10 in Dermatomyositis
Dermatomyositis (DM) is a rare inflammatory disorder generally characterized by progressive muscle weakness and degenerative skin changes. DM typically can arise in early childhood (between 5 and 14 years; juvenile form) or in late adulthood (after 50 years of age). Associated organ involvement varies between patients and may include joint inflammation, calcinosis, gastrointestinal disturbances, and cardiovascular and/or pulmonary manifestations. Patients with DM may experience difficulties in performing daily functions due to loss of muscle strength and, in some individuals, impairments in speech, swallowing, and breathing that could be life-threatening. Skin disease in DM is particularly challenging to manage, often associated with persistent itch, and may lead to difficulty sleeping in many patients.
Prevalence in the U.S. is estimated to be between 17 and 43 thousand patients. Current treatments are broadly immunosuppressive, with around 60% of patients not achieving sufficient symptom control. Many patients fail to respond to current therapies, or develop resistance or intolerance. Recent clinical evidence suggests the critical role that overactive type I IFN response may play in DM pathogenesis. Type I IFNs and the genes they regulate are increased in DM patients’ samples and are associated with clinical presentations. Inhibiting type I IFN response downstream of STING could benefit these high unmet need patients.
FRTX-10 in Non-Alcoholic Steatohepatitis
Non-alcoholic steatohepatitis (NASH) is a chronic inflammatory liver disease characterized by fat accumulation in liver cells with concomitant inflammation and fibrosis. NASH patients are often presented with other comorbidities, including obesity, hypertension, and type 2 diabetes. Up to 20% of NASH patients progress to cirrhosis, resulting in increased liver-related mortality. NASH patients also have a higher risk for hepatocellular carcinoma.
It is expected that almost 38 million adults in the U.S. will be diagnosed with NASH in 2022, and these numbers are expected to grow with increasing rates of obesity and diabetes. There are currently no pharmacological treatments that arrest or revert liver fibrosis, which is a key predictor of progression to cirrhosis. Inflammation is a crucial driver of liver fibrosis in NASH. Recent data suggest that patients with NASH have increased cell-free circulating mitochondrial DNA (mtDNA) levels in the serum due to accumulating cell damage. mtDNA can drive cGAS-STING signaling, perpetuating the cascade of inflammation that causes fibrosis.
Sources:
- Motwani M, Pesiridis S, Fitzgerald KA. DNA sensing by the cGAS-STING pathway in health and disease. Nat Rev Genet 2019;20(11):657-674.
- Hansen AL, Mukai K, Schopfer FJ, Taguchi T, Holm CK. STING palmitoylation as a therapeutic target. Cell Mol Immunol 2019;16(3):236-241.
- Crow MK, Olferiev M, Kirou KA. Type I Interferons in Autoimmune Disease. Annu Rev Pathol. 2019;14:369-393.
- d’Angelo DM, Di Filippo P, Breda L, Chiarelli F. Type I Interferonopathies in Children: An Overview. Front Pediatr. 2021;9:631329.
- Decout A, Katz JD, Venkatraman S, Ablasser A. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol 2021;21(9):548-569.
- Prabakaran T, Troldborg A, Kumpunya S, et al. A STING antagonist modulating the interaction with STIM1 blocks ER-to-Golgi trafficking and inhibits lupus pathology. EBioMedicine. 2021;66:103314.
- Sheka, A. C. et al. Nonalcoholic Steatohepatitis: A Review. JAMA – Journal of the American Medical Association, 323(12), 1175–1183 (2020).
- Sanyal, A. J. et al. The Natural History of Advanced Fibrosis Due to Nonalcoholic Steatohepatitis: Data From the Simtuzumab Trials. Hepatology, 70(6), 1913–1927 (2019).
- Kronzer, V. L. et al. Incidence, prevalence, and mortality of dermatomyositis: a population‐based cohort study. Arthritis Care & Research (2021).
- Cobos, G. A., Femia, A., & Vleugels, R. A. Dermatomyositis: An Update on Diagnosis and Treatment. American Journal of Clinical Dermatology, 21(3), 339–353 (2020).