Efzofitimod: a novel anti-inflammatory agent for sarcoidosis

Main Article Content

Robert P. Baughman
Vis Niranjan
Gennyne Walker
Christoph Burkart
Suzanne Paz
Yeeting Chong
David Siefker
Eileen Sun
Leslie Nangle
Sarah Forster
Michael Muders
Carol Farver
Elyse Lower
Sanjay Shukla
Daniel A Culver

Keywords

sarcoidosis, NRP-2, treatment, mechanism of action

Abstract

Efzofitimod is a first-in-class biologic based on a naturally occurring splice variant of histidyl-tRNA synthetase (HARS) that downregulates immune responses via selective modulation of neuropilin-2 (NRP2). Preclinical data found high expression of NRP2 in sarcoidosis granulomas. Treatment with efzofitimod reduced the granulomatous inflammation induced by P. acnes in an animal model of sarcoidosis. A dose escalating trial of efzofitimod in sarcoidosis with chronic symptomatic pulmonary disease found that treatment with efzofitimod was associated with improved quality of life with a trend towards reduced glucocorticoid use and stable to improved pulmonary function. These studies have led to a large Phase 3 trial of efzofitimod in symptomatic pulmonary sarcoidosis.

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References

(1) Freist W, Verhey JF, Rahlmann A et al. Histidyl-tRNA synthetase. Biol Chem 1999; 380(6):623-646.
(2) Rajendran V, Kalita P, Shukla H et al. Aminoacyl-tRNA synthetases: Structure, function, and drug discovery. Int J Biol Macromol 2018; 111:400-414. doi: 10.1016/j.ijbiomac.2017.12.157. Epub;%2018 Jan 3.:400-414.
(3) Galindo-Feria AS, Notarnicola A, Lundberg IE et al. Aminoacyl-tRNA Synthetases: On Anti-Synthetase Syndrome and Beyond. Front Immunol 2022; 13:866087. doi: 10.3389/fimmu.2022.866087. eCollection;%2022.:866087.
(4) Rubio Gomez MA, Ibba M. Aminoacyl-tRNA synthetases. RNA 2020; 26(8):910-936.
(5) Lo WS, Gardiner E, Xu Z et al. Human tRNA synthetase catalytic nulls with diverse functions. Science 2014; 345(6194):328-332.
(6) Wang R, Zhao Y, Qi F et al. Analysis of the clinical features of antisynthetase syndrome: a retrospective cohort study in China. Clin Rheumatol 2022;10-06404.
(7) Cavagna L, Nuño L, Scirè CA et al. Clinical Spectrum Time Course in Anti Jo-1 Positive Antisynthetase Syndrome: Results From an International Retrospective Multicenter Study. Medicine (Baltimore) 2015; 94(32):e1144.
(8) Adams RA, Fernandes-Cerqueira C, Notarnicola A et al. Serum-circulating His-tRNA synthetase inhibits organ-targeted immune responses. Cell Mol Immunol 2021; 18(6):1463-1475.
(9) Roy S, Bag AK, Singh RK et al. Multifaceted Role of Neuropilins in the Immune System: Potential Targets for Immunotherapy. Front Immunol 2017; 8:1228. doi: 10.3389/fimmu.2017.01228. eCollection;%2017.:1228.
(10) Immormino RM, Lauzier DC, Nakano H et al. Neuropilin-2 regulates airway inflammatory responses to inhaled lipopolysaccharide. Am J Physiol Lung Cell Mol Physiol 2018; 315(2):L202-L211.
(11) Paz S, Julian MW, Siefker D et al. Immunomodulatory protein ATYR1923 disrupts an in vitro model of sarcoid granuloma formation. 2021: OA3968.
(12) Paz S, Chu D, Ferrer M et al. Neuropilin-2, the Specific Binding Partner to ATYR1923, Is Expressed in Sarcoid Granulomas and Key Immune Cells. 2020: A3099.
(13) Paz S, Polizzi C, Chu D et al. ATYR 1923 reduces neutrophil infiltration in an acute lipopolysaccharide (LPS) lung injurty model. 2019.
(14) Kishi J, Nishioka Y, Kuwahara T et al. Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice. Eur Respir J 2011; 38(2):415-424.
(15) Eishi Y, Suga M, Ishige I et al. Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol 2002; 40(1):198-204.
(16) Burkart C, Seikkula L, Eide L et al. ATYR1923 Modulates the Inflammatory Response in Experimental Models of Interstitial Lung Disease. 2019: A2421.
(17) Crouser ED, Maier LA, Wilson KC et al. Diagnosis and Detection of Sarcoidosis. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med 2020; 201(8):e26-e51.
(18) Baughman RP, Valeyre D, Korsten P et al. ERS clinical practice guidelines on treatment of sarcoidosis. Eur Respir J 2021; 58(6):2004079-2020.
(19) Kirkil G, Lower EE, Baughman RP. Predictors of Mortality in Pulmonary Sarcoidosis. Chest 2018; 153(1):105-113.
(20) Mostard RL, Voo S, van Kroonenburgh MJ et al. Inflammatory activity assessment by F18 FDG-PET/CT in persistent symptomatic sarcoidosis. Respir Med 2011; 105(12):1917-1924.
(21) Xu L, Kligerman S, Burke A. End-stage sarcoid lung disease is distinct from usual interstitial pneumonia. Am J Surg Pathol 2013; 37(4):593-600.
(22) Obi ON, Lower EE, Baughman RP. Biologic and advanced immunomodulating therapeutic options for sarcoidosis: a clinical update. Expert Rev Clin Pharmacol 2021; 14(2):179-210.
(23) Khan NA, Donatelli CV, Tonelli AR et al. Toxicity risk from glucocorticoids in sarcoidosis patients. Respir Med 2017; 132:9-14. doi: 10.1016/j.rmed.2017.09.003. Epub;%2017 Sep 8.:9-14.
(24) Judson MA, Chaudhry H, Louis A et al. The effect of corticosteroids on quality of life in a sarcoidosis clinic: the results of a propensity analysis. Respir Med 2015; 109(4):526-531.
(25) Culver DA, Aryal S, Barney J et al. Efzofitimod for the treatment of pulmonary sarcoidosis. Chest 2022;(22):10.
(26) Baughman RP, Judson MA, Beaumont JL et al. Evaluating the Minimal Clinically Important Difference of the King's Sarcoidosis Questionnaire in a Multicenter Prospective Study. Ann Am Thorac Soc 2021; 18(3):477-485.
(27) Baughman RP, Winget DB, Lower EE. Prospective, randomized, double blind trial of methotrexate as a steroid sparing agent for sarcoidosis: analysis of first 25 patients. Am J Respir Crit Care Med 1997; 155:A944.
(28) Baughman RP, Iannuzzi MC, Lower EE et al. Use of fluticasone for acute symptomatic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19:198-204.
(29) Park MK, Fontana JR, Babaali H et al. Steroid sparing effects of pentoxifylline in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2009; 26:121-131.
(30) Judson MA, Baughman RP, Costabel U et al. Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis. Eur Respir J 2014; 44:1296-1307.
(31) Culver DA, Aryal S, Barney J et al. Efzofitimod for the treatment of pulmonary sarcoidosis. Chest 2022;(22):10.
(32) Obi ON, Saketkoo LA, Russell AM et al. Sarcoidosis: Updates on therapeutic drug trials and novel treatment approaches. Front Med (Lausanne) 2022; 9:991783. doi: 10.3389/fmed.2022.991783. eCollection;%2022.:991783.

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