Efzofitimod for the Treatment of Pulmonary Sarcoidosis

Abstract

BackgroundPulmonary sarcoidosis is characterized by the accumulation of immune cells that form granulomas affecting the lungs. Efzofitimod (ATYR1923), a novel immunomodulator, selectively binds neuropilin 2, which is upregulated on immune cells in response to lung inflammation.Research QuestionWhat is the tolerability, safety, and effect on outcomes of efzofitimod in pulmonary sarcoidosis?Study Design And MethodsIn this randomized, double-blind, placebo-controlled study evaluating multiple ascending doses of efzofitimod administered intravenously every 4 weeks for 24 weeks, randomized patients (2:1) underwent a steroid taper to 5 mg/d by week 8 or < 5 mg/d after week 16. The primary end point was the incidence of adverse events (AEs); secondary end points included steroid reduction, change in lung function, and patient-reported outcomes on health-related quality-of-life scales.ResultsThirty-seven patients received at least one dose of study medication. Efzofitimod was well tolerated at all doses, with no new or unexpected AEs and no dose-dependent AE incidence. Average daily steroid doses through end of study were 6.8 mg, 6.5 mg, and 5.6 mg for the 1 mg/kg, 3 mg/kg, and 5 mg/kg groups compared with 7.2 mg for placebo, resulting in a baseline-adjusted relative steroid reduction of 5%, 9%, and 22%, respectively. Clinically meaningful improvements were achieved across several patient-reported outcomes, several of which reached statistical significance in the 5 mg/kg dose arm. A dose-dependent but nonsignificant trend toward improved lung function also was observed for 3 and 5 mg/kg.InterpretationEfzofitimod was safe and well tolerated and was associated with dose-dependent improvements of several clinically relevant end points compared with placebo. The results of this study support further evaluation of efzofitimod in pulmonary sarcoidosis.Trial RegistryClinicalTrials.gov; No.: NCT03824392; URL: www.clinicaltrials.gov Pulmonary sarcoidosis is characterized by the accumulation of immune cells that form granulomas affecting the lungs. Efzofitimod (ATYR1923), a novel immunomodulator, selectively binds neuropilin 2, which is upregulated on immune cells in response to lung inflammation. What is the tolerability, safety, and effect on outcomes of efzofitimod in pulmonary sarcoidosis? In this randomized, double-blind, placebo-controlled study evaluating multiple ascending doses of efzofitimod administered intravenously every 4 weeks for 24 weeks, randomized patients (2:1) underwent a steroid taper to 5 mg/d by week 8 or < 5 mg/d after week 16. The primary end point was the incidence of adverse events (AEs); secondary end points included steroid reduction, change in lung function, and patient-reported outcomes on health-related quality-of-life scales. Thirty-seven patients received at least one dose of study medication. Efzofitimod was well tolerated at all doses, with no new or unexpected AEs and no dose-dependent AE incidence. Average daily steroid doses through end of study were 6.8 mg, 6.5 mg, and 5.6 mg for the 1 mg/kg, 3 mg/kg, and 5 mg/kg groups compared with 7.2 mg for placebo, resulting in a baseline-adjusted relative steroid reduction of 5%, 9%, and 22%, respectively. Clinically meaningful improvements were achieved across several patient-reported outcomes, several of which reached statistical significance in the 5 mg/kg dose arm. A dose-dependent but nonsignificant trend toward improved lung function also was observed for 3 and 5 mg/kg. Efzofitimod was safe and well tolerated and was associated with dose-dependent improvements of several clinically relevant end points compared with placebo. The results of this study support further evaluation of efzofitimod in pulmonary sarcoidosis. ClinicalTrials.gov; No.: NCT03824392; URL: www.clinicaltrials.gov Take-home PointsResearch Question: What is the tolerability of efzofitimod for pulmonary sarcoidosis, and can we discern any evidence of clinical efficacy to support a larger trial?Results: No differences were found in adverse effects or tolerability between participants randomized to efzofitimod or placebo. Patient-reported outcomes improved in the higher-dose arms and positive trends for other end points were found.Interpretation: Efzofitimod may be useful for pulmonary sarcoidosis. Larger studies are needed to confirm and extend these findings. Research Question: What is the tolerability of efzofitimod for pulmonary sarcoidosis, and can we discern any evidence of clinical efficacy to support a larger trial? Results: No differences were found in adverse effects or tolerability between participants randomized to efzofitimod or placebo. Patient-reported outcomes improved in the higher-dose arms and positive trends for other end points were found. Interpretation: Efzofitimod may be useful for pulmonary sarcoidosis. Larger studies are needed to confirm and extend these findings. Sarcoidosis is a multisystem, granulomatous disorder that most commonly affects the lungs.1Culver D.A. Judson M.A. New advances in the management of pulmonary sarcoidosis.BMJ. 2019; 367: l5553Crossref PubMed Scopus (43) Google Scholar Patients often demonstrate organ-specific symptoms such as dyspnea and cough, but also show a range of other disabling nonspecific symptoms (eg, fatigue) that have a major impact on quality of life (QOL). For patients with pulmonary sarcoidosis, the goal of treatment is to reduce the risk of death or permanent disability (danger) or to improve the patient’s QOL,2Baughman R.P. Valeyre D. Korsten P. et al.ERS clinical practice guidelines on treatment of sarcoidosis.Eur Respir J. 2021; 5820040709Crossref PubMed Scopus (185) Google Scholar while secondarily managing the inflammation that may lead to pulmonary fibrosis and irreversible loss of lung function.3Drent M. Costabel U. Crouser E.D. Grunewald J. Bonella F. Misconceptions regarding symptoms of sarcoidosis.Lancet Respir Med. 2021; 9: 816-818Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar,4Faverio P. De Giacomi F. Bonaiti G. et al.Management of chronic respiratory failure in interstitial lung diseases: overview and clinical insights.Int J Med. 2019; 16: 967-980Google Scholar The consensus standard of care includes oral corticosteroids that act mainly by suppressing inflammatory genes.1Culver D.A. Judson M.A. New advances in the management of pulmonary sarcoidosis.BMJ. 2019; 367: l5553Crossref PubMed Scopus (43) Google Scholar,5Schutt A.C. Bullington W.M. Judson M.A. Pharmacotherapy for pulmonary sarcoidosis: a Delphi consensus study.Respir Med. 2010; 104: 717-723Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar Although corticosteroid therapy has been shown to stabilize or improve the disease, long-term corticosteroid use is associated with significant side effects, including substantial weight gain, development of insulin resistance, risk of infection,6Khan N.A. Donatelli C.V. Tonelli A.R. et al.Toxicity risk from glucocorticoids in sarcoidosis patients.Respir Med. 2017; 132: 9-14Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar and impaired QOL.7Cox S.E. Donohue J.F. Brown C.D. Kataria Y.P. Judson M.A. Health-related quality of life in persons with sarcoidosis.Chest. 2004; 125: 997-1004Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar Alternatives, such as immunosuppressive and cytotoxic agents (eg, methotrexate), can be used; however, these therapies also have significant side effects and toxicities.8Judson M.A. The treatment of pulmonary sarcoidosis.Respir Med. 2012; 106: 1351-1361Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Hence, a need exists to find new and effective treatments for pulmonary sarcoidosis with fewer side effects and a positive impact on QOL. Efzofitimod (ATYR1923) is a novel IV biological immunomodulator composed of a splice variant of histidyl-tRNA synthetase9Zhou J.J. Wang F. Xu Z. et al.Secreted histidyl-tRNA synthetase splice variants elaborate major epitopes for autoantibodies in inflammatory myositis.J Biol Chem. 2014; 289: 19269-19275Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar,10Lo W.S. Gardiner E. Xu Z. et al.Human tRNA synthetase catalytic nulls with diverse functions.Science. 2014; 345: 328-332Crossref PubMed Scopus (92) Google Scholar that encodes the immunomodulatory domain that binds to the neuropilin 2 receptor protein.11Xu Z. Chong Y. Crampton S. et al.ATYR1923 specifically binds to neuropilin-2, a novel therapeutic target for the treatment of immune-mediated diseases [abstract].Am J Respir Crit Care Med. 2020; 201: A3074Google Scholar Neuropilin 2 is a pleiotropic receptor12Immormino R.M. Lauzier D.C. Nakano H. et al.Neuropilin-2 regulates airway inflammatory responses to inhaled lipopolysaccharide.Am J Physiol Lung Cell Mol Physiol. 2018; 315: L202-L211Crossref PubMed Scopus (15) Google Scholar that is upregulated on the surface of activated immune cells responsible for inflammation and granuloma formation in the lungs of patients with pulmonary sarcoidosis.13Paz S. Chu S. Ferrer M. et al.Neuropilin-2, the specific binding partner to ATYR1923, is expressed in sarcoid granulomas and key immune cells [abstract].Am J Respir Crit Care Med. 2020; 201: A3099Google Scholar Preclinical studies have shown that efzofitimod regulates immune responses14Burkett C. Seikkula M. Eide L. et al.ATYR1923 modulates the inflammatory response in experimental models of interstitial lung disease [abstract].Am J Respir Crit Care Med. 2019; 199: A2421Google Scholar, 15Adams R.A. Fernandes-Cerqueira C. Notarnicola A. et al.Serum-circulating his-tRNA synthetase inhibits organ-targeted immune responses.Cell Mol Immunol. 2021; 18: 1463-1475Crossref PubMed Scopus (17) Google Scholar, 16Paz S. Polizzi C. Chu D. et al.ATYR1923 reduces neutrophil Infiltration in an acute lipopolysaccharide (LPS) lung injury model.Keystone Symposia Conference. 2019; B7 ([abstract])Google Scholar and significantly reduces lung fibrosis and inflammation.17Nangle L.A. Tong Y. Crampton S.P. et al.The resokine pathway is implicated in the pathology of interstitial lung disease [abstract].Am J Respir Crit Care Med. 2017; 195: A7068Google Scholar,18Ogilvie K. Xu Q. Do M.H. et al.Pre-clinical characterization of iMod. Fc, an immune-modulatory therapeutic with potentially broad application in interstitial lung diseases.Am J Respir Crit Care Med. 2018; 197 ([abstract]): A1064Google Scholar Thus, efzofitimod may leverage a naturally occurring human immunomodulatory function to control or balance the human immune system therapeutically. In healthy volunteers, single doses of efzofitimod (0.03-5 mg/kg) are well tolerated, with no significant safety concerns.19aTyr Pharma, Inc.aTyr Pharma announces positive phase 1 data for ATYR1923 therapeutic candidate [online press release]. June 26, 2018. aTyr Pharma, Inc..https://investors.atyrpharma.com/news-releases/news-release-details/atyr-pharma-announces-positive-phase-1-data-atyr1923-therapeuticDate accessed: January 3, 2022Google Scholar Efzofitimod pharmacokinetics are dose proportional over the range of 0.03 to 5.0 mg/kg, with a mean half-life ranging from 167 to 242 h (7-10 days), supporting once every 4 weeks dosing.19aTyr Pharma, Inc.aTyr Pharma announces positive phase 1 data for ATYR1923 therapeutic candidate [online press release]. June 26, 2018. aTyr Pharma, Inc..https://investors.atyrpharma.com/news-releases/news-release-details/atyr-pharma-announces-positive-phase-1-data-atyr1923-therapeuticDate accessed: January 3, 2022Google Scholar Herein, we present the primary clinical data from the first investigation of efzofitimod in patients with pulmonary sarcoidosis designed to evaluate the safety, tolerability, and preliminary efficacy in this patient population. Patients were 18 to 75 years of age, had a diagnosis of pulmonary sarcoidosis for ≥ 6 months according to the 1999 American Thoracic Society standards,20Hunninghake G.W. Costabel U. Ando M. et al.ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders.Sarcoidosis Vasc Diffuse Lung Dis. 1999; 16: 149-173PubMed Google Scholar and showed evidence of parenchymal involvement. The full inclusion and exclusion criteria are provided in e-Appendix 1. This was a randomized, double-blind, placebo-controlled multiple ascending dose study with three sequential dose cohorts with a 2:1 randomization (efzofitimod to placebo) in the study was patients Patients from of the three cohorts were safety and efficacy between and The treatment of IV of study (efzofitimod or placebo) once every 4 weeks for a of weeks 1 and weeks and with the study at week and tolerability of evaluation of adverse events and and clinical of daily corticosteroid dose over the study and the of patients achieved the dose of 5 through week 24 also were Pulmonary function including the and of the lungs for were also Patient-reported was by the Sarcoidosis the Sarcoidosis the the and the and The of is in 1. on patients a taper of corticosteroid from the dose of to mg/d of to a target dose of 5 which was to be on or The corticosteroid dose was to be every 1 to 2 weeks, on the with the as as the patient reached the goal dose by Patients were at the target corticosteroid dose of 5 mg/d through week in the corticosteroid dose < 5 mg/d after week the further to be Patients acute of sarcoidosis symptoms or were to the taper were to treatment with corticosteroid doses the clinical on of the taper be the The primary end point was to evaluate the safety and tolerability of efzofitimod in patients with pulmonary sarcoidosis. events were from the of and the for were as any AE or of an after of the study through after the The of AE was by the the for to e-Appendix 1 for of The were by of of patients the to study and Patients were study and any AEs that or 24 h after study were as For the secondary of effect of the included the the from to week 24 for patient and a the for the through end of The the the daily corticosteroid dose patient over the The development of and that histidyl-tRNA was to outcomes the change from in lung function through week The change in from to week 24 also were as patient-reported outcomes of impact of disease and response to M.A. M. and differences for the Sarcoidosis A new patient-reported J Respir Crit Care Med. PubMed Scopus Google to and lung D. et al.The development and of the Sarcoidosis for the of PubMed Scopus Google of chronic of a specific for patients with chronic PubMed Scopus Google of ≥ are to substantial J. H. M. in sarcoidosis: the J 2004; 9: PubMed Scopus Google and of in the of dyspnea at and at the the is the the of D. of the in a clinical Respir J. PubMed Scopus Google The primary all patients received any of study and was on the treatment The primary efficacy was the as all randomized patients received at least one of study were in an to the phase of the were mean and were with the and of patients for were the of or a for with the results as the between groups and in the least mean A of patients were randomized and received at least one dose of study received and and patients received the 1 mg/kg, 3 mg/kg, and 5 mg/kg efzofitimod doses, respectively. patients of (eg, and of and one of patients the study were well across the treatment The mean was with and disease including pulmonary function, were across treatment corticosteroid use was across treatment of patients in the were compared with the efzofitimod treatment all patients were received with a mean daily steroid dose of and patients to < mg/d of and by treatment are in and and randomized patients received at least one of study mg/kg mg/kg mg/kg of disease, lung function dyspnea to steroid use were to dose to < to < immunomodulator use are as or mean were as the on or the first dose multiple were on 1 (eg, the the first dose was as dyspnea of lungs for Research randomized patients received at least one of study were to dose in a new are as or mean were as the on or the first dose multiple were on 1 (eg, the the first dose was as dyspnea of lungs for Research No or AEs were observed in the the of patients with an AE was between the and efzofitimod treatment with no between AE and efzofitimod dose AEs the respiratory system system were most and included cough, and respiratory events were dose to be in and treatment The incidence of respiratory events across all treatment groups is in this patient and with the and to mg/kg mg/kg mg/kg respiratory are as adverse in a new are as adverse the treatment patients in the and patients efzofitimod 3 For these events included and of pulmonary sarcoidosis. The between sarcoidosis and study was as was to the study patient in the 3 AEs and pulmonary which were to be to the study In events at 1 mg/kg and and events at 5 mg/kg and of the 3 events with efzofitimod were or were in one patients received and one patient received and acute mg/kg patients study treatment of an of which were as to the study one patient in the of and one patient in the 1 mg/kg efzofitimod of patient in the 1 mg/kg efzofitimod an acute of pulmonary sarcoidosis that was to study but in treatment on the incidence of patients was with one patient in the 3 mg/kg efzofitimod to on three that were by the to be to study but of the No patients received efzofitimod showed positive results for or synthetase (eg, and no trends were or across treatment groups for or The daily dose of corticosteroid at was across treatment efzofitimod groups showed a corticosteroid use through week 24 compared with the to be dose with the reduction observed in the 5 mg/kg treatment with a from compared with a in placebo, a of Average daily steroid doses through end of study were 6.8 mg, 6.5 mg, and 5.6 mg for the 1 mg/kg, 3 mg/kg, and 5 mg/kg compared with 7.2 mg for the resulting in a baseline-adjusted relative steroid reduction of 5%, 9%, and 22%, respectively. A of between and efzofitimod that the efzofitimod treatment groups showed a from in corticosteroid use the study for 3 mg/kg and for 5 mg/kg) compared with placebo. these trends in corticosteroid reduction, three patients at the dose mg/kg) were to taper corticosteroid and this through the end of the corticosteroid that was was to end points use the to end of mg/kg mg/kg mg/kg daily from of for steroid from in the of change from to to to to mg and are as mean or the corticosteroid that was was to end points use the to end of from of for steroid the of change from in a new are as mean or the the doses of efzofitimod in improvements in key lung function at week 24 from compared with placebo, with a dose-dependent effect to placebo, the effects of 5 mg/kg efzofitimod were observed (eg, week 4 for and week for and were across all points through week over the study with and 1 mg/kg efzofitimod and with the doses of efzofitimod Although the improvements in and statistical significance at the 5 mg/kg dose in of the the trend we observed the of biological further investigation in a larger population. observed with the support the that the 5 mg/kg dose may a with trends that were significant improvements in the mean change from to week 24 for and compared with trends in week 24 5 mg/kg significant improvements were observed week 24 as statistical observed by week statistical observed by week 8 statistical observed by week 4 and through week 24 and trends toward in observed at week 8 The in other or were in at 24 from in the from for for mg/kg mg/kg mg/kg lung in lung in in in significance < Sarcoidosis patient-reported Sarcoidosis from for for in a new significance < Sarcoidosis patient-reported Sarcoidosis The results from the present study that efzofitimod is safe and well tolerated in patients with pulmonary sarcoidosis, with no dose regarding the incidence of no trends or across efzofitimod treatment were regarding change from in clinical and no differences from were No and or of AEs in a of or AEs were with no dose-dependent between AE and The 3 AEs after efzofitimod treatment and were by the to be to be to the study and in or of No was as by the incidence of patients with and the of after efzofitimod treatment groups showed a corticosteroid use at week 24 compared with the which to be dose with the observed in the 5 mg/kg treatment patients were to taper patient in the and three patients 5 the patient be for 8 weeks of sarcoidosis and of to corticosteroid was in all with data that patients with sarcoidosis in clinical can taper corticosteroid over a of several M.A. R.P. Costabel U. et and efficacy of or in patients with chronic sarcoidosis.Eur Respir J. 2014; PubMed Scopus Google Scholar to of patients with occurring 6 months of R.M. J. H. in sarcoidosis: the of to corticosteroid Full Text Full Text PDF PubMed Scopus Google G. L. P. The of chronic sarcoid patients with Vasc Diffuse Lung Dis. Google Scholar the of this we were to demonstrate differences in to corticosteroid taper the study which may biological of the medication. Although the of steroid reduction be steroid on dose A in the daily dose may in a meaningful in the over 1 the Society steroid reduction a R.P. Valeyre D. Korsten P. et al.ERS clinical practice guidelines on treatment of sarcoidosis.Eur Respir J. 2021; 5820040709Crossref PubMed Scopus (185) Google Scholar with placebo, the doses of efzofitimod in improvements in and through week a dose-dependent effect on lung The of observed in the study was but all patients were therapy for pulmonary sarcoidosis at the of study of chronic pulmonary sarcoidosis have a significant in R.P. Valeyre D. Korsten P. et al.ERS clinical practice guidelines on treatment of sarcoidosis.Eur Respir J. 2021; 5820040709Crossref PubMed Scopus (185) Google R.P. H. and experimental therapy of pulmonary sarcoidosis.Eur Respir J. PubMed Scopus Google Scholar The in were to observed in the treatment of a randomized of in which the mean was R.P. M. M. et therapy in patients with chronic sarcoidosis and pulmonary J Respir Crit Care Med. PubMed Scopus Google Scholar In that corticosteroids were of corticosteroid as therapy for pulmonary sarcoidosis have found improvements in et Thoracic Society sarcoidosis effects of long-term corticosteroid PubMed Scopus Google A. P. Pulmonary Sarcoidosis treatment of sarcoidosis pulmonary Full Text Full Text PDF PubMed Scopus Google Scholar in have been a major for treatment of R.P. K. et patient treatment 2018; PubMed Scopus Google Scholar end points were that were for multiple observed significant improvements at week 24 in such as and in the 5 mg/kg Patients received 5 mg/kg efzofitimod significant improvements in lung at week 8 and significant improvements in as as week of these significance through week The of change in these at 24 weeks the clinically differences For improved by points with 5 mg/kg efzofitimod the of 8 for the 3 mg/kg and 5 mg/kg efzofitimod groups the of 4 the dose was For the lung the change in the 3 mg/kg and 5 mg/kg groups meaningful M.A. M. and differences for the Sarcoidosis A new patient-reported J Respir Crit Care Med. PubMed Scopus Google Scholar The in the also the of 4 De J. M. differences for the in sarcoidosis.Respir Med. Full Text Full Text PDF Scopus (92) Google however, these patients may have The of these in studies evaluating in health-related treatment of pulmonary R.P. Judson M.A. D.A. et to reduce acute pulmonary events in sarcoidosis: a randomized clinical Vasc Diffuse Lung Dis. 2021; R.P. et for chronic pulmonary 2017; 195: PubMed Scopus Google Scholar The major of this study is the and as such the results need to be in a larger by the for most of the of the were present for several of the key end points and the are which to statistical for that the major end points in of a effect of that a larger may the findings. also that statistical for multiple and were of the of the patients in this study were mg of further in was to be the a effect and improved the is the of a corticosteroid on for or in corticosteroid may in the but in this effect to reduce the of positive the patients were corticosteroid is also to improvements in efzofitimod or efzofitimod a reduction of which has been associated with as by the and Respiratory S.E. Donohue J.F. Brown C.D. Kataria Y.P. Judson M.A. Health-related quality of life in persons with sarcoidosis.Chest. 2004; 125: 997-1004Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar The dose response that the a corticosteroid reduction, is to to the observed several patients of the study of the of clinical the In patients with pulmonary sarcoidosis, efzofitimod was safe and well clinically meaningful improvements after 5 mg/kg efzofitimod with corticosteroid use and improvements in lung function and compared with placebo, the risk of side of the of patients in this these be as results support further evaluation in of efzofitimod in patients with pulmonary sarcoidosis. by aTyr Pharma L. A. M. is by the of and P. H. S. S. is by the of and the American Thoracic Society

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