In a monumental stride toward combating Systemic Sclerosis-Interstitial Lung Disease (SSC-ILD), aTyr Pharma, Inc. unveiled the data related to its first-in-class drug, Efzofitimod, at the European Respiratory Society (ERS) International Congress 2023. This congress, renowned for its critical role in advancing respiratory research and innovation, provided the ideal platform for aTyr Pharma to showcase a pivotal poster titled: “Efzofitimod: A Novel Therapeutic Candidate for SSc-ILD,” outlining the promising potential of Efzofitimod in the realm of Systemic Sclerosis-Interstitial Lung Disease (SSC-ILD) treatment.

Systemic Sclerosis (SSc), also known as scleroderma, is a rare autoimmune disease characterized by the overproduction of collagen, leading to fibrosis and hardening of the skin and internal organs. One of the most severe complications of SSc is Interstitial Lung Disease (ILD), which affects a significant proportion of SSc patients. In 2022, it was estimated that approximately 200,000 individuals were living with Systemic Sclerosis (SSc), and an estimated 65,000 cases were identified as Systemic Sclerosis-associated Interstitial Lung Disease (SSc-ILD) within the 7MM (the United States, Germany, France, Italy, Spain, the United Kingdom, and Japan), based on the assessment from DelveInsight’s Systemic Sclerosis-associated Interstitial Lung Disease (SSc-ILD) Epidemiology and Market Report. Among these cases, nearly 55,000 SSc-ILD cases were diagnosed across the 7MM countries during the same year. Projections suggest that these case numbers will likely increase during the forecast period (2019–2023).

As Systemic Sclerosis-Interstitial Lung Disease (SSc-ILD) exhibits significant dissimilarity among patients, the approach to its management varies based on individual profiles. While traditional immunosuppressive agents like cyclophosphamide and mycophenolate mofetil (MMF) remain fundamental in treating SSc-ILD, they have shown only modest effects in improving Forced Vital Capacity (FVC).

Recent developments have introduced two other medications: nintedanib (OFEV), a tyrosine kinase inhibitor, and tocilizumab (ACTEMRA), the first biologic agent designed to target the interleukin-6 pathway in SSc-ILD. Both of these therapies have received approval from the FDA and are indicated for slowing the rate of decline in pulmonary function among patients diagnosed with SSc-ILD. Despite these FDA approvals, the optimal therapeutic strategy for managing patients with SSc-ILD is yet to be determined, especially given the heterogeneity of the disease.

Efzofitimod is an immunomodulator demonstrating clinical proof-of-concept (POC) in pulmonary sarcoidosis, a related ILD. In animal models of ILD, including SSc-ILD, efzofitimod reduced inflammation and fibrosis. The key lies in its mechanism of action; Efzofitimod binds to neuropilin-2 (NRP2), a membrane protein upregulated at sites of inflammation, particularly on myeloid cells involved in the pathology of both sarcoidosis and SSc-ILD. NRP2 has previously been shown to be highly expressed in myeloid cells within sarcoidosis granulomas. aTyr Pharma aimed to explore the therapeutic potential of efzofitimod in SSc-ILD by evaluating myeloid cells from SSc-ILD patients. NRP2 was highly expressed on macrophages in the skin of scleroderma patients. Similar to sarcoidosis, circulating monocytes from SSc-ILD patients expressed higher levels of NRP2 than healthy donors, exhibited a dysregulated CCR2/CCL2 signaling axis, secreted high levels of pro-inflammatory cytokines at baseline, and responded abnormally to LPS compared to healthy donors. Efzofitimod downregulated inflammatory cytokines and receptors on primary monocyte-derived macrophages, including CD14, a membrane protein associated with the progression of Systemic Sclerosis (SSC) disease.

Given the similarities observed between myeloid responses of SSc-ILD and sarcoidosis and the anti-inflammatory effect of efzofitimod on myeloid cells, together with its anti-inflammatory and anti-fibrotic effects in animals and clinical POC in sarcoidosis, efzofitimod is a promising therapeutic candidate for SSc-ILD with a novel mechanism of action.

SSc-ILD pathology is driven by the same immune cells central to sarcoidosis pathology, and NRP2 is upregulated on these cells, particularly on macrophages. What sets Efzofitimod apart is its demonstrated ability to reduce lung and skin fibrosis in animal models of SSc and idiopathic pulmonary fibrosis, where it matched or outperformed known anti-fibrotic agents, including nintedanib (OFEV, Boehringer Ingelheim) and pirfenidone (ESBRIET, Genentech), according to aTyr.

A Phase II, randomized, double-blind, placebo-controlled, proof-of-concept study, EFZO-CONNECT (NCT05892614), is scheduled to begin in September 2023, which will evaluate the efficacy, safety, and tolerability of efzofitimod in patients with systemic sclerosis (SSc)-related interstitial lung disease (SSc-ILD). The drug has already received orphan drug and fast-track designation by the US FDA, further strengthening the likelihood of its approval. These designations reflect the potential of efzofitimod to address a significant unmet need for patients with SSc-ILD.

Efzofitimod's emergence as a promising therapeutic candidate for Systemic Sclerosis-Interstitial Lung Disease (SSC-ILD) offers newfound hope for those living with this challenging condition. With its novel mechanism of action and demonstrated effectiveness in preclinical and clinical settings, Efzofitimod represents optimism in the quest to enhance the quality of life and prognosis for individuals affected by SSc-ILD. As the journey unfolds, the unveiling of this ground-breaking drug at ERS 2023 marks a significant milestone in the pursuit of better treatment options and brighter tomorrows for SSc-ILD patients worldwide, contributing to an increasing market size for Systemic Sclerosis-Interstitial Lung Disease (SSC-ILD) by 2032 across the 7MM.