Astegolimab or Efmarodocokin Alfa in Patients With Severe COVID-19 Pneumonia

A Randomized, Phase 2 Trial

Michael Waters, MD; James A. McKinnell, MD; Andre C. Kalil, MD, MPH; Greg S. Martin, MD, MSc; Timothy G. Buchman, PhD, MD; Wiebke Theess, PhD; Xiaoying Yang, PhD; Annemarie N. Lekkerkerker, PhD, MSc; Tracy Staton, PhD; Carrie M. Rosenberger, PhD; Rajita Pappu, PhD; Yehong Wang, PhD; Wenhui Zhang, PhD; Logan Brooks, MS; Dorothy Cheung, MD; Joshua Galanter, MD, MAS; Hubert Chen, MD; Divya Mohan, MB BChir, PhD; Melicent C. Peck, MD, PhD

Disclosures

Crit Care Med. 2023;51(1):103-116.

Abstract and Introduction

Abstract

Objectives: Severe cases of COVID-19 pneumonia can lead to acute respiratory distress syndrome (ARDS). Release of interleukin (IL)-33, an epithelial-derived alarmin, and IL-33/ST2 pathway activation are linked with ARDS development in other viral infections. IL-22, a cytokine that modulates innate immunity through multiple regenerative and protective mechanisms in lung epithelial cells, is reduced in patients with ARDS. This study aimed to evaluate safety and efficacy of astegolimab, a human immunoglobulin G2 monoclonal antibody that selectively inhibits the IL-33 receptor, ST2, or efmarodocokin alfa, a human IL-22 fusion protein that activates IL-22 signaling, for treatment of severe COVID-19 pneumonia.

Design: Phase 2, double-blind, placebo-controlled study (COVID-astegolimab-IL).

Setting: Hospitals.

Patients: Hospitalized adults with severe COVID-19 pneumonia.

Interventions: Patients were randomized to receive IV astegolimab, efmarodocokin alfa, or placebo, plus standard of care. The primary endpoint was time to recovery, defined as time to a score of 1 or 2 on a 7-category ordinal scale by day 28.

Measurements and Main Results: The study randomized 396 patients. Median time to recovery was 11 days (hazard ratio [HR], 1.01 d; p = 0.93) and 10 days (HR, 1.15 d; p = 0.38) for astegolimab and efmarodocokin alfa, respectively, versus 10 days for placebo. Key secondary endpoints (improved recovery, mortality, or prevention of worsening) showed no treatment benefits. No new safety signals were observed and adverse events were similar across treatment arms. Biomarkers demonstrated that both drugs were pharmacologically active.

Conclusions: Treatment with astegolimab or efmarodocokin alfa did not improve time to recovery in patients with severe COVID-19 pneumonia.

Introduction

In 2020, COVID-19 was the third leading cause of death in the United States. Most COVID-19–associated deaths are due to severe interstitial pneumonia, which progresses to acute respiratory distress syndrome (ARDS) and hypoxemic respiratory failure. ARDS, characterized by increased epithelial and endothelial permeability leading to alveolar edema, has been observed in 16–42% of patients with severe COVID-19.^[1–5] Hyperinflammatory responses, including elevated pro-inflammatory cytokines, are associated with increased mortality in patients with COVID-19.^[4] COVID-19 treatment includes direct antiviral therapeutics and anti-inflammatory agents.

Interleukin (IL)-33, an alarmin released upon epithelial injury in response to allergens, irritants, and infections in the lung,^[6] binds the suppression of tumorigenicity 2 (ST2) (IL-1 receptor-like 1) receptor on multiple immune cell types driving pulmonary inflammation, which triggers downstream cytokine release. Patients with ARDS have elevated serum IL-33.^[7] IL-33 production increases with disease severity^[8,9] and independently predicts poor outcomes in COVID-19.^[10] We hypothesized that astegolimab (MSTT1041A), a fully human immunoglobulin (Ig) G2 monoclonal antibody that binds ST2, blocks IL-33 signaling, and significantly reduces asthma exacerbations in patients with severe asthma,^[11] may reduce hyperinflammation during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

IL-22, an IL-10 family cytokine, acts directly on epithelial tissue. By working through regenerative and protective mechanisms, IL-22 may protect and repair lung epithelial tissue from ventilation-induced damage^[12] and acute lung injury^[13] following viral infections.^[14,15] Patients with ARDS show reduced IL-22 levels in bronchoalveolar lavage fluid compared with mechanically ventilated patients without lung injury.^[14] Based on this, we hypothesized that efmarodocokin alfa (UTTR1147A), a fusion of human IL-22 and the IgG4 crystallizable fragment,^[16] may promote lung recovery in SARS-CoV-2 infection. The COVID-astegolimab-interleukin (COVASTIL) trial independently investigated the reduction in hyperinflammation via IL-33 blockade with astegolimab and prevention/repair of lung damage by IL-22 pathway activation with efmarodocokin alfa in patients with severe COVID-19 pneumonia.

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Table 1. Baseline Demographic and Clinical Characteristics
Characteristic	Placebo^a (n = 134)	Astegolimab (n = 130)	Efmarodocokin Alfa (n = 132)	All Patients (n = 396)
Age
Median (range), yr	57 (26–89)	58 (29–94)	57 (27–86)	57 (26–94)
Sex, n (%)
Female	45 (34)	56 (43)	52 (39)	153 (39)
Male	89 (66)	74 (57)	80 (61)	243 (61)
Clinical status^b, n (%)
2	3 (2)	4 (3.08)	1 (0.76)	8 (2.02)
3	47 (35)	49 (38)	57 (43)	153 (39)
4	71 (53)	64 (49)	63 (48)	198 (50)
5	10 (7)	8 (6)	8 (6)	26 (7)
6	3 (2)	4 (3)	2 (2)	9 (2)
Not available	0	1 (1)	1 (1)	2 (1)
Baseline mechanical ventilation, n (%)
No	122 (91)	117 (90)	121 (92)	360 (91)
Yes	12 (9)	13 (10)	11 (8)	36 (9)
Duration of hospitalization at randomization
Mean (range), d	4.14 (1–15)	4.47 (1–16)	4.55 (1–20)	4.38 (1–20)
ICU admission, n (%)
Admitted to ICU at randomization	63 (47)	58 (45)	47 (36)	168 (42)
Not admitted to ICU at randomization	71 (53)	72 (55)	85 (64)	228 (58)
Duration of COVID-19 diagnosis at randomization
n	133	130	132	395
Mean (range), d	5.33 (1–16)	5.89 (1–15)	5.9 (1–19)	5.71 (1–19)
Duration of COVID-19 symptoms at randomization
n	133	129	132	394
Mean (range), d	11.59 (1–42)	11.38 (1–24)	11.58 (1–26)	11.52 (1–42)
C-reactive protein
n	122	120	126	368
mg/L, mean ± SD	79.9 ± 64.8	77.3 ± 90.1	81.7 ± 71.7	79.7 ± 76.0
Remdesivir treatment on study, n (%)	78 (58.2)	74 (56.9)	75 (56.8)	227 (57.3)
Tocilizumab treatment on study, n (%)	16 (11.9)	18 (13.8)	13 (9.8)	47 (11.9)
Steroid use on study, n (%)	126 (94.0)	129 (99.2)	126 (95.5)	381 (96.2)

^aMatching placebo groups for astegolimab and efmarodocokin alfa were pooled for all analyses.
^bClinical status was defined by the 7-category ordinal scale: 1, discharged (or "ready for discharge" as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or ≤ 2 L supplemental oxygen); 2, non-ICU hospital ward (or "ready for hospital ward") not requiring supplemental oxygen; 3, non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen; 4, ICU or non-ICU hospital ward, requiring noninvasive ventilation or high-flow oxygen; 5, ICU, requiring intubation and mechanical ventilation; 6, ICU, requiring extracorporeal membrane oxygenation or mechanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy); 7, death.

Table 2. Primary and Key Secondary Efficacy Endpoints
Endpoints	Placebo^a (n = 134)	Astegolimab (n = 130)	Efmarodocokin Alfa (n = 132)
Primary efficacy endpoint
Time to recovery, d (median)^b	10.0	11.0	10.0
HR (95% CI)		1.01 (0.75–1.36)	1.15 (0.86–1.54)
p		0.93	0.36
Secondary efficacy endpoints
Time to hospital discharge or "ready for discharge," d (median)	10.0	11.0	10.0
HR (95% CI)		1.11 (0.83–1.49)	1.16 (0.87–1.56)
p		0.47	0.31
Proportion of patients alive and free of respiratory failure, n (%)^c	51 (38.1)	51 (39.2)	53 (40.2)
Difference in rate (95% CI)		1.17 (–11.34 to 13.68)	2.09 (–10.39 to 14.57)
OR (95% CI; p)		1.05 (0.64–1.72; 0.85)	1.09 (0.67–1.79; 0.73)
Rate of invasive mechanical ventilation or extracorporeal membrane oxygenation, n (%)	33 (24.6)	37 (28.5)	32 (24.2)
Difference in rate (95% CI)		3.83 (–7.57 to 15.24)	–0.38 (–11.46 to 10.70)
OR (95% CI; p)		1.22 (0.70–2.10; 0.48)	0.98 (0.56–1.71; 0.94)
Ventilator-free days to day 28 (time to extubation), d (median)	28	28	28
Difference in medians		0.0	0.0
p (van Elteren test)		0.80	0.86
Rate of ICU stay, n (%)	78 (58.2)	71 (54.6)	61 (46.2)
Difference in rate (95% CI)		–3.59 (–16.31 to 9.12)	–12.00 (–24.67 to 0.67)
OR (95% CI; p)		0.85 (0.53–1.41; 0.56)	0.62 (0.38–1.00; 0.050)
Duration of ICU stay (time to ICU discharge), d (median)	3.10	2.62	0.00
Difference in medians		–0.48	–3.10
p (van Elteren test)		0.48	0.057
Mortality rate at day 14, n (%)	8 (6.0)	11 (8.5)	11 (8.3)
Difference in rate (95% CI)		2.49 (–4.51 to 9.49)	2.36 (–4.58 to 9.31)
OR (95% CI; p)		1.46 (0.57–3.74; 0.43)	1.42 (0.56–3.68; 0.45)
Mortality rate at day 28 (n patients), n (%)	15 (11.2)	19 (14.6)	17 (12.9)
Difference in rate (95% CI)		3.42 (–5.42 to 12.26)	1.68 (–6.89 to 10.26)
OR (95% CI; p)		1.36 (0.66–2.80; 0.41)	1.17 (0.56–2.46; 0.67)

HR = hazard ratio, OR = odds ratio.
^aMatching placebo groups for astegolimab and efmarodocokin alfa were pooled for all analyses.
^bDefined as time (d) to score of 1 or 2 on the 7-category ordinal scale (whichever occurred first).
^cRequiring noninvasive ventilation, high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation at day 28.

Table 3. Overview of Adverse Events
Safety Outcomes	Placebo^a (n = 134)	Astegolimab (n = 130)	Efmarodocokin Alfa (n = 132)	All Patients (n = 396)
Number of patients with ≥ 1 AE, n (%)	87 (65)	85 (65)	95 (72)	267 (67)
Number of AEs	344	376	377	1,097
Number of deaths, n (%)	23 (17)	23 (17)	21 (16)	67 (17)
Number of patients withdrawn from study due to an AE, n (%)	1 (1)	1 (1)	0	2 (1)
Number of patients with ≥ 1 of the following events, n (%)
Serious AE	38 (28)	38 (29)	34 (26)	110 (28)
Serious AE leading to withdrawal from treatment	2 (2)	2 (2)	1 (1)	5 (1)
Related serious AE	0	2 (2)	3 (2)	5 (1)
AE leading to withdrawal from treatment	4 (3)	3 (2)	3 (2)	10 (3)
Related AE	15 (11)	12 (9)	25 (19)	52 (13)
Grade 3–5 AE	43 (32)	46 (35)	41 (31)	130 (33)

AE = adverse event.
^aMatching placebo groups for astegolimab and efmarodocokin alfa were pooled for all analyses.

Authors and Disclosures

Michael Waters, MD¹, James A. McKinnell, MD^2,3, Andre C. Kalil, MD, MPH⁴, Greg S. Martin, MD, MSc⁵, Timothy G. Buchman, PhD, MD⁶, Wiebke Theess, PhD⁷, Xiaoying Yang, PhD⁸, Annemarie N. Lekkerkerker, PhD, MSc⁹, Tracy Staton, PhD⁹, Carrie M. Rosenberger, PhD¹⁰, Rajita Pappu, PhD¹¹, Yehong Wang, PhD¹², Wenhui Zhang, PhD¹², Logan Brooks, MS¹², Dorothy Cheung, MD⁷, Joshua Galanter, MD, MAS¹³, Hubert Chen, MD⁷, Divya Mohan, MB BChir, PhD⁷ and Melicent C. Peck, MD, PhD⁷ for the COVID-astegolimabinterleukin (IL) (COVASTIL) Study Group

1 Velocity Clinical Research, Chula Vista, CA.
2 David Geffen School of Medicine, Harbor-UCLA Medical Center, Torrance, CA.
3 Milefchik-Rand Medical Group, Torrance Memorial Medical Center, Torrance, CA.
4 Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.
5 Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, and Grady Health System, Atlanta, GA.
6 Department of Surgery, Emory University School of Medicine, Atlanta, GA.
7 Early Clinical Development, Genentech, Inc., South San Francisco, CA.
8 Product Development Data Sciences, Genentech, Inc., South San Francisco, CA.
9 Biomarker Development, Genentech, Inc., South San Francisco, CA.
10 Biomarker Discovery, Genentech, Inc., South San Francisco, CA.
11 Immunology Discovery, Genentech, Inc., South San Francisco, CA.
12 Clinical Pharmacology, Genentech, Inc., South San Francisco, CA.
13 Product Development Safety, Genentech, Inc., South San Francisco, CA.

Drs. Waters and McKinnell contributed equally as co-first authors; Drs. Mohan and Peck contributed equally as co-senior authors.

Dr. Waters has received funding from Genentech paid to his institution for the conduct of this trial. Dr. McKinnell has received funding from Genentech paid to his institution for the conduct of this trial; he reports receiving research funding paid to his institution from Gilead, Eli Lilly and Company, and Duke University; and he received funding from Pfizer and ThermoFisher. Dr. Martin has received compensation for service as a monitor of the COVID-astegolimab-interleukin trial. Dr. Buchman serves as a Senior Advisor to Biomedical Advanced Research and Development Authority (BARDA), U.S. Department of Health and Human Services under an agreement between his employer, Emory University, and that agency; he also serves as Editor-in-Chief of Critical Care Medicine, and Emory University similarly receives payment for that service from the Society of Critical Care Medicine. Drs. McKinnell, Martin, Buchman, Theess, Lekkerkerker, Staton, Rosenberger, Pappu, Wang, Zhang, Brooks, Cheung, Galanter, Chen, Mohan, and Peck disclosed the off-label product use of Astegolimab and Efmarodocokin Alfa. Dr. Theess is currently an employee of F. Hoffmann-La Roche and owns Roche stock. Drs. Staton and Wang are former employees of Genentech and own Roche stock. Dr. Chen is a former employee of Genentech. Drs. Martin, Theess, Yang, Lekkerkerker, Staton, Rosenberger, Pappu, Wang, Zhang, Cheung, Galanter, Chen, Mohan, and Peck received funding from Genentech. Drs. Theess's, Lekkerkerker's, Staton's, Rosenberger's, Wang's, Zhang's, Cheung's, Chen's, Mohan's, and Peck's institutions received funding from the Department of Health and Human Services, the Office of the Assistant Secretary for Preparedness and Response, and the BARDA (OT number: HHSO100201800036C). Drs. Theess, Yang, Lekkerkerker, Staton, Rosenberger, Pappu, Wang, Zhang, Brooks, Cheung, Galanter, Chen, Mohan, and Peck are employees of Genentech, a member of the Roche group, and own Roche stock. Drs. Theess and Brooks disclosed they are employed by F. Hoffman-LaRoche. Drs. Theess, Lekkerkerker, Staton, Rosenberger, Pappu, Wang, Zhang, Brooks, Cheung, Galanter, Chen, Mohan, and Peck disclosed work for hire. Dr. Brooks disclosed that he is a Principal Computational Researcher at Genentech. Dr. Kalil has disclosed that he does not have any potential conflicts of interest.

Current address for Dr. Theess
F. Hoffman-LaRoche, Basel, Switzerland; Dr. Wang: Gilead Sciences, Inc., Foster City, CA; and Dr. Chen: Krystal Biotech, Inc., Pittsburgh, PA.