Shifting the Balance through DYRK1A Inhibition
A potent, highly selective, and orally bioavailable potential first-in-class DYRK1A inhibitor with strong preclinical validation and broad potential to treat debilitating autoimmune and inflammatory conditions.
Our lead development-stage program, FRTX-02, is a new chemical entity that is currently being studied in a first-in-human Phase 1 trial to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamics in both healthy volunteers and subjects with atopic dermatitis. FRTX-02 is the first oral DYRK1A inhibitor intended for patients with autoimmune diseases to be administered in humans. Topline SAD and MAD results from the ongoing Phase 1 study are anticipated to be announced by early 2023.
How is FRTX-02 differentiated?
FRTX-02 inhibits DYRK1A, representing a novel mechanism of action that aims to restore immune homeostasis in patients whose immune system is imbalanced due to an underlying autoimmune condition. FRTX-02 acts by supporting the function of anti-inflammatory regulatory T cells while simultaneously inhibiting pro-inflammatory pathways. This contrasts with many current standard of care treatments for autoimmune diseases, such as JAK inhibitors, that broadly suppress the immune system, leading to increased risk of serious infections that can result in hospitalization and may even be life-threatening. Oral administration of FRTX-02 in preclinical proof-of-concept studies has yielded promising efficacy and significant cytokine reduction in several preclinical models of autoimmune diseases, suggesting that its treatment may present a new and differentiated approach across many high unmet need diseases.
How does FRTX-02 work?
FRTX-02’s dual mode of action targeting both adaptive and innate immune responses presents a unique opportunity to treat a wide array of immune-inflammatory conditions, including atopic dermatitis, type 1 diabetes, and rheumatoid arthritis, amongst others.
On the adaptive immunity axis, FRTX-02 supports the differentiation of regulatory T cells (Tregs) while also limiting pro-inflammatory helper T cells (Th). Tregs curb overactive immune reactions and inflammation to maintain self-tolerance. Functional impairment of Tregs with concomitant hyperactivation of autoreactive Th cells, such as Th1, Th2 and Th17, results in dysregulation of immune homeostasis and can lead to development of autoimmune diseases. FRTX-02 may shift the adaptive immune system balance towards equilibrium, therefore presenting a promising and novel approach to treating these diseases.
On the innate immunity axis, FRTX-02 has successfully demonstrated inhibition of IRAK4 phosphorylation and its respective downstream signaling pathway. This is achieved through induction of alternative splicing of MyD88, a central hub in inflammatory responses involved in the downstream signaling of TLRs and other cytokine receptors of the IL-1 family that relay signals through MyD88, to activate pro-inflammatory NF-kB. Specifically, the MyD88 gene produces two alternatively spliced isoforms, MyD88-L (long) and MyD88-S (short). MyD88-L drives inflammatory NF-kB signaling, whereas MyD88-S acts as a dominant negative inhibitor of inflammation. In chronic inflammatory conditions, the regulation of MyD88 alternative splicing may be impaired, leading to exacerbation of inflammation through prominence of MyD88-L and consequent overactivation of MyD88-dependent receptor signaling with substantial cytokine and chemokine secretion. FRTX-02 promotes MyD88 splicing into the MyD88-S isoform, thus limiting pro-inflammatory signaling and restoring regulation of this pathway.
Where could FRTX-02 work?
FRTX-02’s dual mode of action targeting both adaptive and innate immune responses presents a unique opportunity to treat a wide array of immune-inflammatory conditions, including atopic dermatitis, type 1 diabetes, and rheumatoid arthritis, amongst others.
FRTX-02 in Atopic Dermatitis
Atopic dermatitis (AD), or atopic eczema, is the most common chronic inflammatory skin disease worldwide. More than 29 million adults in the U.S. are affected by AD. Up to 2/3 of patients have moderate or severe symptoms, leading to a substantial decrease in the quality of life associated with chronic skin inflammation, skin barrier defects, and persistent itch.
Dysregulated Th2 signaling is a cornerstone in the pathogenesis of AD. Moreover, innate immune mechanisms contribute to chronic skin inflammation. There remains a need for effective, safe, and orally available treatment options for patients with moderate and severe AD who do not respond to current standard of care treatments. Given FRTX-02’s potential to modulate both adaptive and innate immunity, it could present a new and meaningful therapeutic option for AD patients, if approved.
In several preclinical models of AD, orally administered FRTX-02 led to significant decreases in pro-inflammatory cytokines and chemokines and significant amelioration of disease severity. These robust preclinical data demonstrated efficacy either on par or superior to current treatments. The ongoing first-in-human Phase 1 trial with FRTX-02 is initially enrolling healthy volunteers and is expected to enroll AD patients in Part 2 of the study. (NCT05382819).
FRTX-02 in Type 1 Diabetes
Type 1 Diabetes (T1D) is an autoimmune condition causing insulin deficiency due to the elimination of insulin-producing pancreatic beta cells by the body’s own immune system. Insulin is a hormone regulating glucose consumption by all cells in the organism. Low insulin levels result in high blood glucose that leads to typical symptoms, including extreme thirst, fatigue, weight loss, and blurred vision. Over time, high blood glucose levels can lead to life-threatening complications in all the major organ systems.
T1D remains the most common form of diabetes in children, accounting for approximately 80% of new diabetes diagnoses in patients ≤19 years in the U.S. There are currently no curative treatments available for T1D, and the key therapeutic focus remains the control of blood glucose levels. However, up to 80% of patients do not achieve glycemic control.
DYRK1A kinase inhibition has been implicated in beta cell proliferation in several preclinical models of T1D. In addition, lack of immune regulation by Tregs has been proposed as one of the mechanisms driving beta cell destruction. These findings uniquely position FRTX-02 to address the autoimmune aspect of T1D and beta cell biology, which could serve as a first-of-kind, disease-modifying treatment for this lifelong condition.
FRTX-02 in Rheumatoid Arthritis
Rheumatoid Arthritis (RA) is a chronic inflammatory joint disease that can cause cartilage and bone damage, as well as disability. RA affects approximately 1.5 million adults in the U.S. and there are currently no curative therapies. While existing therapies provide large benefit to patients by slowing disease progression, up to 20% become refractory to standard therapy and are in need of novel treatment options to prevent rapid disease progression and debilitating joint destruction.
DYRK1A has shown to be upregulated in synovial tissue of patients suffering from RA and increasing abundance of pro-inflammatory Th17 cells correlates with disease severity. Furthermore, several preclinical models of FRTX-02 have demonstrated promising efficacy compared to current standard of care treatments, including JAK inhibitors and biologics, as well as encouraging data demonstrating reduction in swollen limbs and modulation of key pathogenic cytokines. Based on this, FRTX-02’s mechanism provides a promising scientific rationale to clinically benefit RA patients.
Sources:
- Khor, B. et al. The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells. Elife 4, 1–27 (2015).
- Talk by Dr. Bernard Khor, Benaroya Research Institute
- De Arras, L. & Alper, S. Limiting of the Innate Immune Response by SF3A-Dependent Control of MyD88 Alternative mRNA Splicing. PLOS Genet. 9, e1003855 (2013).
- Burns, K. et al. Inhibition of Interleukin 1 Receptor/Toll-like Receptor Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4. J. Exp. Med. 197, 263 (2003).
- Seo, D. H. et al. P001 The novel DYRK1a inhibitor VRN024219 alleviates disease severity on the IBD mouse models by modulating T-cell differentiation. J. Crohn’s Colitis 14, S129–S129 (2020).
- 25 th Annual Meeting of the RNA Society 2020: Lee F et al. Signal-dependent Regulation of Alternative Splicing in Innate Immunity
- Kaplan, M. J. Targeting the myddosome in systemic autoimmunity‐ ready for prime time? Arthritis Rheumatol. Art. 41951 (2021).
- Liu Y.A. et al. Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133. J. Med. Chem. 63, 2958–2973 (2020).
- Langan, S. M., Irvine, A. D. & Weidinger, S. Atopic dermatitis. Lancet 396, 345–360 (2020).
- DiMeglio, L. A., Evans-Molina, C. & Oram, R. A. Type 1 diabetes. Lancet 391, 2449–2462 (2018).
- Guo, X. et al. Dyrk1A promotes the proliferation, migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis via down-regulating Spry2 and activating the ERK MAPK pathway. Tissue Cell 55, 63–70 (2018).