Identification of HIF1A as a therapeutic target during SARS-CoV-2–associated lung injury
Bentley Bobrow, Samuel D. Luber, Paul Potnuru, Katherine Figarella, Jieun Kim, Yanyu Wang, In Hyuk Bang, David Robinson, Paulina B. Sergot, Steven K. Burke, Tingting Mills, Constanza de Dios, Robert Suchting, George W. Williams, Adit A. Ginde, Yafen Liang, Hongfang Liu, Charles Green, Marie-Francoise Doursout, Alparslan Turan, Daniel I. Sessler, Xiaoyi Yuan, Holger K. Eltzschig
Bentley Bobrow, Samuel D. Luber, Paul Potnuru, Katherine Figarella, Jieun Kim, Yanyu Wang, In Hyuk Bang, David Robinson, Paulina B. Sergot, Steven K. Burke, Tingting Mills, Constanza de Dios, Robert Suchting, George W. Williams, Adit A. Ginde, Yafen Liang, Hongfang Liu, Charles Green, Marie-Francoise Doursout, Alparslan Turan, Daniel I. Sessler, Xiaoyi Yuan, Holger K. Eltzschig
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Research Article Inflammation Therapeutics

Identification of HIF1A as a therapeutic target during SARS-CoV-2–associated lung injury

Abstract

Hypoxia-inducible factors (HIFs) promote lung protection and pathogen eradication during acute lung injury. We, therefore, tested the theory that pharmacologic stabilization of HIFs dampens lung injury during SARS-CoV-2 pneumonia. Initial studies in murine SARS-CoV-2 models showed improved outcomes after treatment with the FDA-approved HIF stabilizer vadadustat. Subsequent studies in genetic models implicated alveolus-expressed Hif1a in mediating lung protection. Therefore, we performed a randomized, double-blinded, multicenter phase II trial in patients admitted for SARS-CoV-2 infection and concomitant hypoxia (SpO2 ≤ 94%). Patients (n = 448) were randomized to oral vadadustat (900 mg/day) or placebo for up to 14 days. Safety events were similar between the 2 groups. Vadadustat treatment induced surrogate HIF target genes. The primary outcome of severe lung injury requiring high oxygen support on day 14 occurred in 43 patients in the vadadustat group and 53 patients in the placebo group (estimated probability, 13.3% vs. 16.9%). Among patients with baseline fraction of inspired oxygen of 80% or higher (n = 106), the estimated probability of the primary outcome was 12.1% (vadadustat) versus 79.1% (placebo), indicating an even greater benefit in patients with more severe baseline hypoxia. HIF1A is a likely therapeutic target during SARS-CoV-2–associated lung injury. Robust clinical trials of HIF stabilizers during pathogen-associated lung injury are warranted.

Authors

Bentley Bobrow, Samuel D. Luber, Paul Potnuru, Katherine Figarella, Jieun Kim, Yanyu Wang, In Hyuk Bang, David Robinson, Paulina B. Sergot, Steven K. Burke, Tingting Mills, Constanza de Dios, Robert Suchting, George W. Williams, Adit A. Ginde, Yafen Liang, Hongfang Liu, Charles Green, Marie-Francoise Doursout, Alparslan Turan, Daniel I. Sessler, Xiaoyi Yuan, Holger K. Eltzschig

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Figure 5

Efficacy of vadadustat in hospitalized patients with SARS-CoV-2 infection and concomitant hypoxia.

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Efficacy of vadadustat in hospitalized patients with SARS-CoV-2 infectio...
(A) Erythropoietin level in the plasma measured by ELISA showing changes over 14 days. Mean slopes with 95% Bayesian credible intervals (CrIs) are shown, highlighting a 3-fold increase in erythropoietin levels in the vadadustat group (β = 3, 95% CrI = 1.94 to 4.03) compared with placebo (β = 0.85, 95% CrI = 0.61 to 1.08) with a >99% posterior probability (PP) of treatment and time interaction. (B) Proportion of patients with severe lung injury requiring high oxygen support (NIAID-OS score ≥ 6) on day 14 (primary outcome). The vadadustat group showed a reduced absolute probability (13.3%) compared with placebo (16.9%), with an absolute risk difference (ARD) of –3.6% (95% CrI = –8.4% to 0.9%). PPs of benefit for ARD < 0% and ARD ≤ –2.5% are 94% and 69%, respectively. (C) Proportion of patients with NIAID-OS score ≥ 6 on day 7 (key secondary outcome). Vadadustat treatment demonstrated a higher likelihood of clinical improvement compared with placebo, with an ARD of –4.2% (95% CrI = –9.0% to –0.1%) and a PP of benefit (ARD < 0%) of 97%. (D) Inflammatory mediators in the plasma measured by MILLIPLEX Multiplex Assays (IL-17E, IP-10, M-CSF, and TNF-α) between day 0 and day 7. Vadadustat treatment resulted in greater reductions in systemic inflammation compared with placebo, with significant differences noted for each marker. P values were obtained by Mann-Whitney U test. In the bar-and-whisker plots, the bounds of the boxes represent the 25%–75% interquartile range, the lines within the boxes represent the median, the whiskers represent data min/max, and there are no outlying values. (E) Subgroup analysis by FiO2 levels upon hospital admission. PPs of clinical benefit for vadadustat (relative to placebo) were highest in patients with baseline FiO2 ≥ 80% (PP > 99%), followed by lower probabilities for FiO2 60%–79% (PP = 92%), 40%–59% (PP = 95%), and <40% (PP = 66%).