Pipeline

Immunology

Enanta is developing highly potent and selective, oral small molecules for the treatment of inflammatory disease, with an initial focus on diseases driven by an overactive type 2 immune response. Type 2 immune responses are characterized by the overproduction of interleukin-4 (IL-4), IL-5, IL-13, and Immunoglobulin E (IgE), through the activation of TH2 cells, CD4+ T cells, B cells, and innate cellular responses consisting of mast cells, ILC2s, eosinophils, basophils, and macrophages. An overactive response is the primary driver of several inflammatory diseases, including atopic dermatitis (AD), urticarias, asthma, eosinophilic esophagitis (EoE), prurigo nodularis (PN), chronic rhinosinusitis with nasal polyps (CRSwNP), as well as some forms of chronic obstructive pulmonary disease (COPD) and other conditions. 

KIT Inhibition

Our initial immunology program is targeting mast cells by inhibiting the receptor tyrosine kinase known as KIT, a central regulator of mast cell development and activation. Mast cells are tissue-resident immune cells (e.g., skin, lung or GI) that can be activated through various cell surface receptors, resulting in a signaling cascade that leads to degranulation and release of tryptase, histamine and other inflammatory mediators. This release of inflammatory mediators from mast cells and subsequent propagation of a type 2 inflammatory response has been implicated in multiple inflammatory diseases.

Current therapies modulate only a subset of either mast cell stimulants or the downstream mediators of inflammation that mast cells produce (e.g., antihistamines), but do not address the underlying cause of disease, as they do not directly affect mast cells themselves. As a tyrosine kinase receptor, KIT provides pro-survival signals critical to mast cell survival and, therefore, the inhibition of KIT signaling leads to rapid mast cell inactivation and depletion through apoptosis, thereby directly reducing the quantity of mast cells available to drive pathology. Clinical proof of concept for this approach has been demonstrated with positive Phase 2 data for an anti-KIT monoclonal antibody in urticaria and data suggest the potential for best-in-disease efficacy, and a reasonable safety profile.

About Chronic Spontaneous Urticaria

Our initial indication for KIT is chronic spontaneous urticaria, or CSU, a severely debilitating, chronic inflammatory skin disease with no identified triggers.¹ Clinical manifestations of CSU include hives, angioedema, or both.¹ Hives are variable in size and shape and are characterized by swelling, itchiness, and/or a burning sensation¹. Angioedema is characterized by pronounced deep tissue swelling along with tingling, burning, tightness and sometimes pain¹. Patients with CSU also experience symptoms beyond the skin manifestations, including sleep disturbances, fatigue, irritability, anxiety, and depression.² 

CSU can persist for 2–5 years² although some reports estimate that more than half of patients suffer for more than 5 years³. CSU may also recur after months or years of full remission.¹ CSU can be severely disabling, significantly impair quality of life, and affect performance at work or school.¹ CSU impacts twice as many women as men, with an estimated global prevalence between 0.5% – 1% of the population.^1,4 This means that at any given time in the U.S. alone approximately 1.75-3.5 million people are experiencing this condition. The peak age of diagnosis is during the core years of working age (20 – 40 years old).⁴ Standard of care treatment for CSU is antihistamines, however in approximately half the patients, symptom alleviation is not adequate.¹ There is a substantial unmet need for an efficacious oral agent as only a minority of these uncontrolled cases are treated with one indicated biologic (<28%).⁵

Enanta’s Approach to Treating CSU

Enanta has discovered novel, potent and selective oral inhibitors of KIT and selected our lead development candidate, EPS-1421 to enter IND enabling studies. This candidate demonstrates potent nanomolar activity in both binding and cellular assays and is highly selective (>400x) for KIT versus other kinases. This inhibitor also demonstrates strong in vitro and in vivo ADME properties, with a good pharmacokinetic, or PK, profile across multiple preclinical species, and a low potential for drug-drug interactions. The company expects to conduct scale-up activities and IND enabling studies in 2025.

STAT6 Inhibition

Enanta’s second immunology program is targeting STAT6, the transcription factor responsible for IL-4/IL-13 signaling, which drives a Th2 dominant phenotype. Dysregulation of the Th2 immune response drives many allergic and autoimmune diseases, including atopic dermatitis and asthma. STAT6 is a key driver of disease as STAT6 gain-of-function variants result in severe AD and STAT6 loss-of-function variants protect against type 2 high asthma. Furthermore, clinical validation of this pathway exists in several immunology indications from anti-IL-4/13 monoclonal antibodies and JAK inhibitors, which block the IL-4/13 signaling pathway. Our STAT6 inhibitor program offers the potential for an “oral dupilumab” as it directly blocks IL-4/IL-13 signaling, and no oral therapies selectively targeting this pathway are currently available.

About Atopic Dermatitis

Our initial indication for STAT6 is atopic dermatitis (AD), a chronic dermatological disease characterized by dry, red, inflamed, irritated and itchy skin that can appear anywhere on the body. Scratching leads to further redness, swelling, cracking, “weeping” clear fluid, crusting, and scaling. AD is long lasting or chronic there can be periods of time when the disease is worse, called flares, followed by periods when the skin improves or clears up entirely, called remissions.⁶ The disease can significantly impact quality of life by leading a limited lifestyle, avoiding social interactions and impacting activities.⁷

AD usually appears during childhood and can continue through adulthood, although it can occur at any age.⁸  Globally, 206 million people have AD.⁸ In the U.S., the disease affects more than 9.6 million children and 19 million adults.^7,9 Approximately 40% of adults have moderate to severe disease.⁹ The majority of moderate to severe patients are treated with an IL-4/IL-13 monoclonal antibody (e.g., dupilumab) despite modest efficacy, while only a minority are treated with oral JAK inhibitors (e.g., upadacitinib) which have a box warning for serious infections, mortality, malignancy, major adverse cardiac events, and thrombosis.^10,11 Thus, there is a significant need for an efficacious and safe oral agent.

Enanta’s Approach to Treating AD

Enanta has a discovery stage program to develop oral STAT6 inhibitors to treat AD and potentially other indications by blocking the IL-4/IL-13 signaling pathway. We have discovered novel, potent and selective oral inhibitors of STAT6, which are being optimized in the discovery stage. Our prototype inhibitors have potent activity and high selectivity for STAT6 over other STATs in both biochemical and cellular assays and demonstrate systemic in vivo target engagement after ex vivo IL-4 stimulation. We are continuing to evaluate multiple compounds in preclinical studies and expect to conduct lead optimization for this program in 2025.

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1. Kaplan A et al. Chronic Spontaneous Urticaria: Focus on Pathophysiology to Unlock Treatment Advances. Allergy. 2023; 78(2): 389–401.
2. Yosipovitch et al. Current and Emerging Therapies for Chronic Spontaneous Urticaria: A Narrative Review. Dermatol Ther (Heidelb). 2023; 13(8): 1647–1660. 
3. Balp M-M et al. Clinical Remission of Chronic Spontaneous Urticaria (CSU): A Targeted Literature Review. Dermatol Ther (Heidelb). 2022; 12(1): 15–27.
4. Maurer M et al. Unmet Clinical Needs in Chronic Spontaneous Urticaria. A GA²LEN Task Force Report. Allergy 2011; 66(3): 317–330.
5. Clarivate Treatment Algorithms: Claims Data Analysis – Chronic spontaneous urticaria, February 2023. ©2023 DR/Decision Resources, LLC. All rights reserved. Reproduction, distribution, transmission or publication is prohibited. Reprinted with permission. Clarivate makes no representation or warranty as to the accuracy or completeness of the data (“Clarivate Materials”) set forth herein and shall have, and accept, no liability of any kind, whether in contract, tort (including negligence) or otherwise, to any third party arising from or related to use of the Clarivate Materials by Enanta Pharmaceuticals Inc (“Enanta Pharmaceuticals Inc”). Any use which Enanta Pharmaceuticals Inc or a third party makes of the Clarivate Materials, or any reliance on it, or decisions to be made based on it, are the sole responsibilities of Client and such third party. In no way shall any data appearing in the Clarivate Materials amount to any form of prediction of future events or circumstances and no such reliance may be inferred or implied.
6. National Institute of Arthritis and Musculoskeletal and Skin Diseases – Atopic Dermatitis. Last Accessed: November 2024. 
7. Silverberg, Jonathan I et al. “Patient burden and quality of life in atopic dermatitis in US adults: A population-based cross-sectional study.” Annals of Allergy, Asthma & Immunology: Official Publication of the American College of Allergy, Asthma, & Immunology vol. 121,3 (2018): 340-347. doi:10.1016/j.anai.2018.07.006
8. Tian, Jingru et al. “Global epidemiology of atopic dermatitis: a comprehensive systematic analysis and modelling study.” The British Journal of Dermatology vol. 190,1 (2023): 55-61. doi:10.1093/bjd/ljad339
9. Asthma and Allergy Foundation of America: https://aafa.org/asthma-allergy-research/our-research/atopic-dermatitis-in-america/. Last accessed: November 2024.
10. Market share ($) from Evaluate Pharma, © Evaluate Ltd, 9/2024, www.evaluate.com
11. Prescribing Information for upadacitinib. Last accessed: November 2024.