A D V E R T I S E R R E TA I N S S O L E R E S P O N S I B I L I T Y F O R C O N T E N T

A D V E R T I S E M E N T F E A T U R E

Adrenomed AGwww.adrenomed.com

The key to treating sepsis and septic shock:matching treatment to causal pathophysiologyAdrenomed AG is translating the concept of precision medicine to acute care witha biomarker-guided antibody therapy for sepsis and septic shock.

With a mortality rate of 20–30% in developedcountries, sepsis represents an enormous publichealth burden. Many survivors experience long-term morbidity and loss of quality of life. In theUS, sepsis accounts for 30–50% of deaths amonghospitalized patients, making it the number onecause of death in hospitals. The annual cost oftreating septic patients in the US alone amountsto $24 billion. The burden of sepsis, on patientsand healthcare providers, has become even morepronounced during the COVID-19 pandemic, assevere cases of COVID-19 present as viral sepsis.

Despite improvements in identifying and manag-ing sepsis over the past 30 years, mortality remainstroublingly high, and new approaches to improvingpatient outcomes are desperately needed. Previousattempts to develop new therapies for sepsis showthat one-size-fits-all approaches are not success-ful. Sepsis is a multi-complex disease with dif-ferent underlying pathophysiologies comparableto cancer, for which targeted biomarker- guidedtreatments have led to therapeutic breakthroughs.

Adrenomed AG, based in Hennigsdorf, Germany,is bringing precision medicine to the acute care set-ting with a pioneering biomarker-guided approachto sepsis. One of the hallmarks of sepsis is loss ofintegrity of the endothelial barrier separating thebloodstream from surrounding tissues, allowingfluid to leak into tissues and eventually leading toorgan failure, shock and death1. To date, dysfunc-tion of the endothelial barrier has been untreat-able. Adrenomed has developed Adrecizumab(HAM8101; enibarcimab), a first-in-class non-blocking monoclonal antibody that binds to andfunctionally stabilizes the peptide hormone adre-nomedullin (ADM), which has a crucial role inmaintaining the endothelial barrier and its function.

Adrenomed is utilizing ADM as a biomarker toguide Adrecizumab treatment to patients withdeteriorating endothelial barrier, while at the sametime using another biomarker, dipeptidyl pepti-dase-3 (DDP3), to exclude patients whose causeof septic shock has a different pathophysiology.With this approach, Adrenomed is shifting sepsistreatment towards precision medicine, ensuringthat patients get the right drug for their underlyingdisease mechanism.

Adrecizumab has completed clinical phase 1 and2 trials, demonstrating a favorable safety profile2

and the ability to systemically improve organ func-tion and reduce mortality rates in septic shockpatients, and is now poised for pivotal phase 2b/3trials in septic shock. Beyond sepsis and septicshock, Adrecizumab has the potential to become

a platform therapy applicable to a wide range ofconditions, in which loss of endothelial barrierintegrity plays a role, such as acute heart failure.

The complexity of sepsisSepsis is a complex disorder or syndrome thatpresents as a cluster of symptoms and biologicalchanges driven by diverse underlying processes,rather than a single disease with a clear-cut aetiol-ogy. Sepsis begins with an infection—bacterial,viral or fungal—that initiates a systemic inflam-matory response. This, in turn, drives loss ofvascular integrity that causes vascular leakage,which results in a drop in blood pressure (and insevere cases septic shock) and reduced organperfusion that can cause organs to fail. Whenmultiple organs fail at once, the patient is at highrisk of dying3 (Fig. 1 (a)).

Contemporary treatment of sepsis followsthis patient journey. The first step is usually totry to control the infection with anti-infectivesor surgery, followed by symptom managementthrough fluid and vasopressor administration torestore blood pressure. If and when organs beginto fail, patients receive supportive care, includingmechanical ventilation, renal replacement therapyand extracorporeal membrane oxygenation4

(Fig. 1 (a)).Missing from this treatment package is any inter-

vention that targets the underlying pathophysi-ological processes driving sepsis. These includethe loss of endothelial barrier function causedby the dysregulated inflammatory response andindicated by elevated blood ADM levels, as wellas disturbance of the renin-angiotensin systems(RAS) caused by elevated levels of DDP3.

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Fig. 1 | Adrecizumab modifying an important causal pathophysiology of sepsis. a. Standard of care forsepsis and septic shock does not address key pathophysiological process: the loss of vascular integrity.b. The patient journey in sepsis proceeds through a series of progressively more severe stages. c. Molecularpathophysiology in sepsis: i) Loss of vascular integrity, countermeasure increased ADM blood level;ii) ADM enters extravascular space; iii) leaked ADM causes vasodilation. d. Mechanism of action ofAdrecizumab. ADM-Adrecizumab complexes remain in blood, and ADM retains the ability to restorevascular integrity. e. Adrecizumab restores vascular integrity, and improves downstream outcomes forpatients. ADM, adrenomedullin; ECMO, extracorporeal membrane oxygenation; RTT, Renal ReplacementTherapy; VE, vascular endothelial; VSMC, vascular smooth muscle cells.

B28 | September 2021 | www.nature.com/biopharmdeal

A D V E R T I S E R R E TA I N S S O L E R E S P O N S I B I L I T Y F O R C O N T E N T

A D V E R T I S E M E N T F E A T U R E

ADM: key regulator of theendothelial barrierAdrenomed’s goal is to fill the gap in patient treat-ment further downstream of inflammation withAdrecizumab, the first sepsis therapy candidate totarget an important causal pathophysiology of thecondition—loss of vascular integrity and endothe-lial barrier function—rather than merely offeringsymptomatic or supportive relief.

ADM is a free-circulating 52-amino-acid peptidebelonging to the calcitonin gene-related peptidefamily. Originally thought to function principally asa vasodilator, ADM has since been found to have avariety of biological effects, and is a key regulatorof the endothelial barrier and vascular tone. ADMhas also emerged as an important player in thesepsis response. Many of the known mediatorsimplicated in the pathophysiology of sepsis, such ascytokines and hypoxia, increase ADM production.In addition, levels of circulating ADM are elevatedin sepsis, reflecting the body’s repair response toloss of vascular integrity and reduced endothelialbarrier function. Elevated ADM levels also correlatewith disease severity, need for vasopressors, onsetof shock and mortality5,6.

These findings might suggest that ADM is badnews for sepsis, and that blocking its effectsmight prove therapeutic. The biology of ADM has,however, proved more complicated, with differenteffects that simultaneously exacerbate and amelio-rate sepsis. It all depends on where ADM is acting.

As a small peptide, ADM can easily leave thebloodstream by crossing the endothelial barrier andentering the extravascular space, where it affectsvascular smooth muscle cells and regulates vasculartone by promoting vasodilation—an unwelcomeeffect in the context of sepsis as it contributes toincreased hypotension and organ damage. ADMthat remains in the bloodstream, however, has adifferent effect, one that helps mitigate sepsis:promoting stability of the endothelial barrier byrestoring the tight junctions between endothelialcells that ordinarily regulate molecule transportand leakage.

In health, levels of ADM in the bloodstream andextravascular space are in equilibrium so thatendothelial barrier integrity is maintained and bloodpressure remains normal. In sepsis, more ADM isproduced to counteract loss of endothelial barrierfunction, but as the endothelial barrier becomesmore permeable as a result of systemic immunedysregulation, more ADM enters the extravascularspace in a dangerous cycle that can contribute toshock and organ failure (Fig. 1 (c)).

Adrecizumab: precision medicinefor acute careAdrecizumab binds to ADM inside of the bloodvessel, but does not block its action. Instead,Adrecizumab sequesters ADM in the blood-stream, as the ADM-antibody complex is too largeto cross the endothelial barrier. In addition, thecomplex with Adrecizumab increases the half-lifeof ADM, which ordinarily is about 20 minutes, in adose-dependent manner. The half-life extendingbenefits of Adrecizumab are thought to resultfrom the antibody binding to the N-terminalpart of ADM, where proteolytic degradationoccurs. This specific binding of ADM through itsN-terminal domain, which is not required for ADM

to bind to its receptor, is also key to maintainingthe functionality of ADM signalling once ADM isin a complex with Adrecizumab7,8.

By preventing ADM from leaving the blood-stream and enhancing its half-life, Adrecizumabincreases the concentration of functional ADMwithin the lumen of blood vessels where it has theeffect of promoting stability of the endothelialbarrier (Fig. 1 (d)).

In conducted clinical studies a single intravenousadministration of Adrecizumab led to a dose-dependent increase in plasma ADM concentrationwithin minutes, an effect that has been seen in allspecies investigated to date. Adrecizumab’s half-lifeof approximately 15 days in healthy subjects allowsfor administration of a single dose in treating sepsisand septic shock2, covering the critical first weekafter onset of the disease.

Dysregulation of endothelial barrier integrity,which Adrecizumab counteracts, is at the core ofmany cases of sepsis and septic shock, but not all; insome, plasma elevation of DDP3 also is a driver formortality. Previous clinical trials of sepsis therapieshave typically recruited patients with diverse aeti-ologies for sepsis, and did not distinguish betweenthose experiencing dysregulation of endothelial bar-rier function and DPP3 pathways, which may maskbenefits that accrue only to a subset of patientsexhibiting particular pathological processes.

Adrenomed’s biomarker-guided, precision medi-cine approach means that treatment is matchedto underlying pathophysiology to be diseasemodifying: patients with sepsis/septic shock whoshow elevated levels of plasma ADM can receiveAdrecizumab, while those whose show high levelsof DDP3, and who are therefore less likely to benefitfrom Adrecizumab, will not. To rapidly identify thesegroups of patients, the biomarkers bio-ADM andDPP3 can be tested with SphingoTec’s commerciallyavailable Nexus IB10 point-of-care platform within20 minutes.

The phase 2 AdrenOSS-2 trial has demonstratedthe benefits of this biomarker-guided approach. InAdrenOSS-2, which recruited 301 patients across24 active European sites, septic shock patients withelevated ADM (>70 pg/ml) received Adrecizumabat either 4 mg/kg or 2 mg/kg, or placebo. The anti-body was well tolerated and showed a favorable

safety profile, thereby reaching its primary objec-tive. Analyses of both Adrecizumab dose groupswere combined, and AdrenOSS-2 included aprespecified analysis by exclusion of patients withelevated DPP3 (>70 ng/ml), which removed 32patients from the final analysis.

For patients with ADM >70 pg/ml and DPP3<70ng/ml, Adrecizumab led to rapid and sustainedimprovement in organ function measured by theclinical-validated SOFA (Sequential Organ FailureAssessment) score, and reduced mortality at 28days from 26% to 18% (Fig. 2 (b)).

Building on the lessons learned in the AdrenOSS-2trial, Adrenomed is now planning a pivotal phase2b/3 trial program, ENCOURAGE, which will userefined inclusion/exclusion criteria and explore thebenefits of earlier intervention, with separate trialsfor sepsis and septic shock. The ENCOURAGE tri-als will form the basis for marketing applicationsfor the treatment of sepsis and septic shock. Morethan 50% of septic shock patients treated withinthe intensive care unit would be eligible for thebiomarker-guided treatment with Adrecizumab.

Backed by decades of experience in sepsis diag-nostics, Adrenomed is dedicated to pioneeringprecision medicine for acute care. Adrenomedwelcomes discussions with potential investors orpartners who are interested in joining in the develop-ment and commercialization of Adrecizumab in sep-sis and septic shock to benefit millions of patients.1. Lee, W. L., Slutsky, A. S. New Engl. J. Med. 363, 689–691 (2010).

2. Geven, C. et al. Br. J. Clin. Pharmacol. 84, 2129–2141 (2018).

3. Shankar-Hari, M. et al. JAMA 315, 775–787 (2016).

4. Rhodes, A. et al. Intens. Care Med. 43, 304–377 (2017).

5. Mebazaa, A. et al. Crit. Care 22, 354 (2018).

6. Caironi, P. et al. Chest 152, 312–320 (2017).

7. Geven, C. et al. Shock 50, 132–140 (2018).

8. Struck, J. et al. Intens. Care Med. Exp. 1, 3 (2013).

Frauke Hein, Chief Business OfficerAdrenomed AGHennigsdorf, GermanyTel: +49 3302 20 77 8 0Email: fhein@adrenomed.com

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Fig. 2 | Results from the AdrenOSS-2 trial. a. SOFA scores 24h post-treatment showed that organfunction in patients receiving placebo worsened, but significantly improved in patients receivingAdrecizumab (p<0.05). b. Survival 28 days post-treatment is improved by Adrecizumab treatmentcompared with placebo. (Shown is the prespecified subset of intention-to-treat with DPP3 <70ng/ml;Hazard Ratio=0.65 [0.39–1.1].)

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