Genomics and pharmacogenomics of sepsis: so close and yet so far

Sapru et al. show in this issue of Critical Care that variants of thrombomodulin and the endothelial protein C receptor, but not protein C, are associated with mortality and organ dysfunction (ventilation-free and organ failure-free days) in ARDS. Hundreds of gene variants have been found prognostic in sepsis. However, none of these prognostic genomic biomarkers are used clinically. Predictive biomarker discovery (pharmacogenomics) usually follows a candidate gene approach, utilizing knowledge of drug pathways. Pharmacogenomics could be applied to enhance efficacy and safety of drugs used for treatment of sepsis (e.g., norepinephrine, epinephrine, vasopressin, and corticosteroids). Pharmacogenomics can enhance drug development in sepsis, which is very important because there is no approved drug for sepsis. Pharmacogenomics biomarkers must pass three milestones: scientific, regulatory, and commercial. Huge challenges remain but great opportunities for pharmacogenomics of sepsis are on the horizon.

reliance on literature for biological plausibility of the "significant" variants. These innovative insights could lead to "predictive biomarkers" for response to recombinant human TM and even activated protein C (APC) in sepsis.
Predictive biomarker discovery often follows a candidate gene approach, utilizing knowledge of drug receptors, transporters, enzymes that metabolize a drug, and drug target pathways. Predictive biomarkers often have high clinical utility. FDA-approved drug labels have a hierarchy of recommendations for companion diagnostics: (1) for information (i.e., descriptions of published studies of PGx related to the drug); (2) recommended-physicians are encouraged to measure the biomarker; and (3) required-physicians MUST use the companion diagnostic to prescribe the drug. The required companion diagnostic relates to trastuzumab: HER2 must test positive for identifying good responders to order trastuzumab.
The PGx biomarker discovery pathway is arduous, timeconsuming, and expensive. A successful PGx biomarker must pass three milestones: scientific, regulatory, and commercial. Scientific steps include: a decision regarding a nonhypothesis-driven (genome-wide) vs a candidate gene approach, RCTs, significant drug/PGx biomarker interaction, validation often in a separate RCT, and validation of a rapid turnaround time (TAT) kit in real time. The regulatory node includes many submissions and visits to regulators before and after each study. Regulators have approved PGx biomarkers in cancer that were assessed at the end of pivotal RCTs provided that the biomarker hypothesis was logged before locking the RCT dataset. Thus, selection of PGx biomarkers may occur in parallel with RCT execution. Finally, the commercial node includes costs of kits, reimbursement methods and amounts, FDA-approved and EMEA-approved manufacturing, and distribution of a rapid TAT kit (and sometimes a unique "box" for measuring the biomarker) to hospitals (laboratories and/or ICUs or EDs).
PGx could be applied to enhance efficacy and safety of drugs in use for sepsis and septic shock including norepinephrine, epinephrine, vasopressin, and corticosteroids (CS) ( Table 1); known genomic variants intersect with these drugs. Genomics of the CS and vasopressin (AVP) axes have been well studied for prediction of response to CS (and less so vasopressin), because CS and AVP variants are widely studied in many conditions and because CS are used in so many conditions (Table 1).
PGx can also enhance drug development, very important since there is no approved drug for sepsis. PGx could increase chances of drug development success in sepsis; that is, precision medicine to enrich the heterogeneous sepsis cohorts [2,6]. Potential predictive biomarkers/companion diagnostics could be used with recombinant human TM, selepressin, angiotensin II, PCSK9 inhibitor, IL-7, and esmolol ( Table 1). Studies of PGx of ACE inhibitors in cardiovascular disease and IL-7 in cancer could inform angiotensin II and IL-7 PGx in sepsis (Table 1). Several drugs used clinically in sepsis have proven companion diagnostics (Table 1).
Finally, PGx could resurrect "dead" drugs by increasing efficacy. APC could be resurrected by using genetic variants such as those discovered by Sapru et al. [1] that might mark patients who have an enhanced response to APC to enrich patient selection in a future RCT (Table 1).
In summary, there remain huge challenges but great opportunities for genomics, and I think more importantly for PGx of sepsis. We are close-but yet so far because there are many complex steps and milestones to bring a novel PGx biomarker to septic patients and their caregivers. I remain very optimistic that researchers such as Sapru et al. [1] and other scientists in the field are up to the challenge! Abbreviations APC, activated protein C; CS, corticosteroids; EPCR, endothelial protein C receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; PGx, pharmacogenomics; RCT, randomized controlled trial; TAT, turnaround time; TM, thrombomodulin Authors' contributions JAR conceived, designed, researched, and wrote the submission. The author read and approved the final manuscript.
Competing interests JAR reports patents owned by the University of British Columbia (UBC) that are related to PCSK9 inhibitor(s) and sepsis and related to the use of vasopressin in septic shock. JAR is an inventor on these patents. JAR is a founder, director, and shareholder in Cyon Therapeutics Inc. (developing a sepsis therapy); has share options in Leading Biosciences Inc.; and is a shareholder in Molecular You Corp. JAR reports receiving consulting fees from Cubist Pharmaceuticals (now owned by Merck, formerly was Trius Pharmaceuticals; developing antibiotics), Leading Biosciences (developing a sepsis therapeutic), Ferring Pharmaceuticals (manufacturing vasopressin and developing selepressin), Grifols (selling albumin), and La Jolla Pharmaceuticals (developing angiotensin II); chairs the DSMB of a trial of angiotensin II), CytoVale Inc. (developing a sepsis diagnostic), and Asahi Kesai Pharmaceuticals of America (AKPA; developing recombinant thrombomodulin); and reports having received grant support from Ferring Pharmaceuticals and from Grifols that was provided to and administered by UBC.