A Multicenter Pharmacogenomic Biomarker Study in Matched Patients With Severe Sepsis Treated With or Without Recombinant Human Activated Protein C [Xigris®, Drotrecogin Alfa (Activated)]

The overall purpose of the study is to determine whether either of the Improved Response Polymorphisms (IRPs) individually predicts a differential DrotAA treatment effect in patients with severe sepsis and high risk of death. This will be an international, multicenter, "prospective-retrospective", nonrandomized, controlled, outcome-blinded, genotype-blinded, matched-patients study. No prospective enrollment or treatment of patients will occur under this protocol. Retrospectively collected clinical data and DNA samples will be analyzed for existing cohorts of patients with severe sepsis who were previously treated with DrotAA (treatment group) or not (control group) as part of their standard care in an ICU.

Start Date01 Oct 2011

Sponsor / Collaborator

Sirius Genomics, Inc.

NCT01227187

/ CompletedPhase 2IIT

Safety and Dose Finding Study of Xigris (Drotrecogin Alfa Activated) as an Anti-coagulant in End Stage Renal Disease (ESRD) Patients Treated With Hemodialysis (HD)

The purpose of the study is to assess the safety of Xigris (Drotrecogin alfa) as an anticoagulant at different dose levels during dialysis treatment in patients with End Stage Renal Disease (ESRD).

Start Date01 Oct 2008

Sponsor / Collaborator

Eli Lilly & Co.

100 Clinical Results associated with Drotrecogin alfa (activated)

100 Translational Medicine associated with Drotrecogin alfa (activated)

100 Patents (Medical) associated with Drotrecogin alfa (activated)

665

Literatures (Medical) associated with Drotrecogin alfa (activated)

01 Feb 2026·SEMINARS IN THROMBOSIS AND HEMOSTASIS

Evolution of Clinical Trials in Anticoagulation for Sepsis: Bridging Past to Future

Review

Author: Ferrer, Ricard ; Iba, Toshiaki ; Levy, Jerrold H. ; Helms, Julie ; Maier, Cheryl L.

Abstract:

Demonstrating the efficacy of new treatments in any condition may be a challenging endeavor, and is particularly the case in sepsis. In the early 21st century, recombinant activated protein C showed a survival benefit in severe sepsis; however, subsequent studies could not replicate these results, leading to the discontinuation of this agent. Several potential reasons have been proposed for the unfavorable results of trials, including choosing an inappropriate outcome target. Concerning anticoagulant therapies, some studies have targeted sepsis with disseminated intravascular coagulation (DIC) and demonstrated clinical benefits, while other studies have focused on severe sepsis or septic shock independent of whether patients had DIC. The timing for treatment initiation, dosage, and duration of anticoagulant agents could be significant factors contributing to the limitations faced in these trials. Moreover, relying solely on 28-day mortality as the primary endpoint for sepsis trials may not be appropriate, as it can be influenced by various factors beyond anticoagulant therapies, and discernment in a shorter period might be more pertinent. Success in clinical trials is more likely if these issues are addressed and improvements are made. Recent clinical trials concentrating on anticoagulants are increasingly targeting sepsis or septic shock with coagulopathy, and adopting composite endpoints, including DIC resolution, is anticipated to overcome some of these challenges.

01 May 2024·The Lancet. Respiratory medicine

Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial

Article

BACKGROUND:

Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock.

METHODS:

APROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 μg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The trial was registered at ClinicalTrials.gov (NCT00625209).

FINDINGS:

Of 1241 patients included in the APROCCHSS trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio [OR] 0·60, 95% CI 0·43-0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70-1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53-0·98) in patients with ARDS and 0·85 (0·61-1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46-0·89) in the CAP subgroup and 1·02 (0·75-1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction).

INTERPRETATION:

In a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup.

FUNDING:

Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004.

01 Nov 2023·The Lancet. Respiratory medicine

Identifying molecular phenotypes in sepsis: an analysis of two prospective observational cohorts and secondary analysis of two randomised controlled trials

Article

Author: Kerchberger, V Eric ; Abbott, Jason ; Liu, Kathleen D ; Gomez, Antonio D ; Neyton, Lucile ; Delucchi, Kevin L ; Kangelaris, Kirsten N ; Zhuo, Hanjing ; Walley, Keith R ; Churpek, Matthew M ; He, June ; Mick, Eran ; Russell, James A ; Sarma, Aartik ; Jauregui, Alejandra ; Calfee, Carolyn S ; Wickersham, Nancy ; Ware, Lorraine B ; Hendrickson, Carolyn M ; Leligdowicz, Aleksandra ; Willmore, Andrew ; Chambers, Julia ; Wu, Nelson ; Jones, Chayse ; Langelier, Charles R ; Sinha, Pratik ; Matthay, Michael A

BACKGROUND:

In sepsis and acute respiratory distress syndrome (ARDS), heterogeneity has contributed to difficulty identifying effective pharmacotherapies. In ARDS, two molecular phenotypes (hypoinflammatory and hyperinflammatory) have consistently been identified, with divergent outcomes and treatment responses. In this study, we sought to derive molecular phenotypes in critically ill adults with sepsis, determine their overlap with previous ARDS phenotypes, and evaluate whether they respond differently to treatment in completed sepsis trials.

METHODS:

We used clinical data and plasma biomarkers from two prospective sepsis cohorts, the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study (N=1140) and the Early Assessment of Renal and Lung Injury (EARLI) study (N=818), in latent class analysis (LCA) to identify the optimal number of classes in each cohort independently. We used validated models trained to classify ARDS phenotypes to evaluate concordance of sepsis and ARDS phenotypes. We applied these models retrospectively to the previously published Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock (PROWESS-SHOCK) trial and Vasopressin and Septic Shock Trial (VASST) to assign phenotypes and evaluate heterogeneity of treatment effect.

FINDINGS:

A two-class model best fit both VALID and EARLI (p<0·0001). In VALID, 804 (70·5%) of the 1140 patients were classified as hypoinflammatory and 336 (29·5%) as hyperinflammatory; in EARLI, 530 (64·8%) of 818 were hypoinflammatory and 288 (35·2%) hyperinflammatory. We observed higher plasma pro-inflammatory cytokines, more vasopressor use, more bacteraemia, lower protein C, and higher mortality in the hyperinflammatory than in the hypoinflammatory phenotype (p<0·0001 for all). Classifier models indicated strong concordance between sepsis phenotypes and previously identified ARDS phenotypes (area under the curve 0·87-0·96, depending on the model). Findings were similar excluding participants with both sepsis and ARDS. In PROWESS-SHOCK, 1142 (68·0%) of 1680 patients had the hypoinflammatory phenotype and 538 (32·0%) had the hyperinflammatory phenotype, and response to activated protein C differed by phenotype (p=0·0043). In VASST, phenotype proportions were similar to other cohorts; however, no treatment interaction with the type of vasopressor was observed (p=0·72).

INTERPRETATION:

Molecular phenotypes previously identified in ARDS are also identifiable in multiple sepsis cohorts and respond differently to activated protein C. Molecular phenotypes could represent a treatable trait in critical illness beyond the patient's syndromic diagnosis.

FUNDING:

US National Institutes of Health.

News (Medical) associated with Drotrecogin alfa (activated)

15 May 2025

·www.prnewswire.com

Abzena Announces Establishment of Scientific Advisory Board to Support Innovation Strategy

SAN DIEGO, May 15, 2025 /PRNewswire/ -- Abzena, the leading end-to-end integrated CDMO + CRO for complex biologics and bioconjugates, has announced today the formation of its Scientific Advisory Board (SAB) comprised of biopharma industry experts with diversified expertise in Discovery Research & Development (R&D) and Chemistry, Manufacturing, and Controls (CMC). The new advisory board will work closely with Abzena's scientific and commercial leadership to provide strategic guidance and expert insights that support Abzena's continued commitment to growth and innovation. Matt Stober, CEO of Abzena, said, "The establishment of the Scientific Advisory Board was a strategic decision to help guide the future of Abzena. We have seen considerable momentum over the past few years in supporting complex and innovative modalities, such as Antibody-drug conjugates (ADCs), Antibody-oligonucleotide conjugates (AOCs), and bispecifics. We aim to continue building upon this by offering the most state-of-the-art technologies and capabilities to support our customers' programs. These experts will be instrumental in assisting us with this mission by evaluating our strategies and providing recommendations that will further enhance our ability to move medicines forward to patients faster." Joe Principe, CCO of Abzena, said, "We are honored to welcome these distinguished individuals to our Scientific Advisory Board. These founding members are recognized leaders in our industry, bringing a wealth of expertise that will help guide us as we continue through this significant phase of our growth. We look forward to their contributions and the positive impact that they will have on our organization." Founding members of Abzena's Scientific Advisory Board are: John Knight, Ph.D., is the founder of JKONSULT, a UK-based consulting firm, where he provides process chemistry and CMC consulting services for early-stage chemical development and transfer-to-plant projects, with a primary focus on material supplies for toxicological studies, Phase I, and Phase II clinical trials. Dr Knight has 38 years of pharmaceutical industry experience, with prior roles at GSK, Vernalis, and Evotec. Kamal Egodage, Ph.D., MBA, is the President of Lasanth® Consulting, where he provides consultation services for biologics that span from discovery through commercialization, including CMC development, regulatory strategy, interactions with health authorities, and corporate development strategy. Prior to establishing his consultancy in 2017, Dr. Egodage accumulated over 20 years of industry experience at Eli Lilly, Pharmacia, Monsanto, Symic Bio, and Novartis (Switzerland), where he was the Head of Strategy and Business Development for Biologics. Morris Rosenberg, D.Sc., is an independent consultant with over 25 years of experience in the development of therapeutic agents to treat a variety of human diseases. As a consultant, he provides advisory services to early research and clinical-stage companies on product development strategies for biologics, biosimilars, and ADC therapies. Prior to this, Dr Rosenberg played a key role in the development and commercialization of ADC-based therapies at Seattle Genetics and Immunomedics and participated in the development and launch of Trodelvy®, Adcetris®, Avonex®, Angiomax®, Xigris®, and Forteo®. Scott Rudge, Ph.D., co-founded RMC Pharmaceutical Solutions in 2004, which was acquired by Syner-G BioPharma Group in January 2023. He is a Principal Consultant with Syner-G, and leads its Commercial and Scientific Advisory Boards, and is a member of the Syner-G Board. He also currently serves as SVP of Product Development at Margaux Biologics, Head of CMC for Antidote Therapeutics and Optigo Biotherapeutics, is a Key Advisor to Jurata, and is an Adjunct Professor of Chemical Engineering at the University of Colorado. Dr Rudge has over 33 years of experience directing Process Engineering, Process Development, Product Development, and overall Pharmaceutical Operations, and has built and led several organizations in the biopharmaceutical industry. Steven Sandoval is the founder and serves as the CEO/ Operations Head of Pharmaceutical Technical Solutions, Inc. (PTSI). Providing technical oversight and client representative support to the Biotechnology, Gene Therapy, Viral Vector, Cell Therapy, T-CELL, CAR T, mRNA, 503a/ 503b Compounding, and Vaccine Pharmaceutical Industries since 2010. Prior to this, he held senior leadership roles at Pfenex Inc., Parsons (BMS), and Amgen. He has over 30 years of experience in biopharmaceutical manufacturing, operations, CMC tech transfer, engineering, facilities, and quality leadership services. Tatyana Touzova is the Chief Pharmaceutical Development & Manufacturing Officer at SERA Medicines, where she oversees CMC, regulatory, and nonclinical development from drug discovery through clinical stages. Prior to this, she held the position of Chief Operating Officer at AstralBio, AlmataBio, and ValenzaBio, where she directed CMC, manufacturing, and regulatory operations for multiple clinical-stage programs. She has over 35 years of experience in drug development, regulatory affairs, and commercial manufacturing of biologics and complex therapeutics and is recognized as an expert in CMC strategy, GMP compliance, and global regulatory submissions. About Abzena Abzena is the leading end-to-end bioconjugate and complex biologics CDMO + CRO. From discovery through commercial launch, we support customers with fully integrated programs or individual services designed to de-risk and streamline the development of new treatments for patients in need. With the ability to tailor its strategy and customer experience to each project, Abzena develops and implements innovative solutions that enable biotech and biopharma companies to realize the full potential of their molecule and move medicines forward faster. The company has research, development, and cGMP facilities across locations in San Diego, CA, Bristol, PA, and Cambridge, UK. Abzena is owned by Welsh, Carson, Anderson & Stowe, one of the world's leading private equity investors. Learn more at abzena.com. SOURCE Abzena WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

AcquisitionPhase 2Executive Change

25 Feb 2009

·www.biospace.com

MedWatch: FDA Early Communication about an Ongoing Safety Review Xigris

FDA is aware of a retrospective study (Gentry et al.: Adverse outcomes associated with the use of drotrecogin alfa (activated) in patients with severe sepsis and baseline bleeding precaution, Crit Care Med 2009),1 which reported an increased risk of serious bleeding events and of death in patients with sepsis (a severe illness related to a bloodstream infection) and baseline bleeding risk factors who received drotrecogin alfa (activated). Drotrecogin alfa (activated), marketed as Xigris, is a recombinant human activated protein C indicated for the reduction of mortality in adult patients with severe sepsis who have a high risk of death.3 The baseline bleeding risk factors as defined by this study are the same as those described in the Xigris prescribing information, under the Contraindications and the Warnings and Precautions sections of the package insert.

Clinical Result

100 Deals associated with Drotrecogin alfa (activated)

External Link

KEGG	Wiki	ATC	Drug Bank
D03918	Drotrecogin alfa (activated)	B01AD10	DB00055

R&D Status

Approved

10 top approved records.

to view more data

Indication	Country/Location	Organization	Date
Multiple Organ Failure	European Union	Eli Lilly Nederland BV	22 Aug 2002
Multiple Organ Failure	Iceland	Eli Lilly Nederland BV	22 Aug 2002
Multiple Organ Failure	Liechtenstein	Eli Lilly Nederland BV	22 Aug 2002
Multiple Organ Failure	Norway	Eli Lilly Nederland BV	22 Aug 2002
Sepsis	United States	Eli Lilly & Co.	21 Nov 2001

Developing

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Shock, Septic	Phase 3	Germany	Eli Lilly & Co.	19 Dec 2007
Hypotension	Phase 3	United States	Eli Lilly & Co.	01 Jun 2004
Hypotension	Phase 3	France	Eli Lilly & Co.	01 Jun 2004
Kidney Failure, Chronic	Phase 2	United States	Eli Lilly & Co.	01 Oct 2008
Organ dysfunction syndrome	Phase 2	Germany	Eli Lilly & Co.	04 Jul 2006
Pulmonary Embolism	Phase 2	Germany	Eli Lilly & Co.	01 Sep 2004

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01227187 (Xigris1003, CTgov)	Phase 2	Kidney Failure, Chronic	12	APC (APC Initiation Dose 12 μg/kg/h)	xqgpxqdvgg(ytlvtymulr) = tafzfibuvg lwwbuakrxw (dvdahhsfez, NA) View more	-	03 Feb 2022
				APC (APC Initiation Dose 18 μg/kg/h)	xqgpxqdvgg(ytlvtymulr) = ymhaaexkbz lwwbuakrxw (dvdahhsfez, 4.6) View more
NCT00741013 (CTgov)	Early Phase 1	airway disease \| Pneumonia	22	Placebo (Placebo Pill and Intravenous (i.v.) Placebo)	kjbsavpylz(mfbfrouebv) = zacmiubctz ixtdbgyriz (vymjpossup, 9.2) View more	-	26 May 2014
				Lovastatin (Lovastatin Pill and i.v. Placebo)	kjbsavpylz(mfbfrouebv) = dfatqpmoch ixtdbgyriz (vymjpossup, 4.3) View more
NCT00604214 (PROWESS-SHOCK, CTgov)	Phase 3	Shock, Septic	1,696	Drotrecogin alfa (activated) (Drotrecogin Alfa (Activated))	oavkckljwo = vlpcwyikcg ixbkhjvqbo (kximdgwfpk, xgwuwmntyq - mgactyftrj) View more	-	18 Sep 2012
				Placebo (Placebo)	oavkckljwo = fjajsqhnva ixbkhjvqbo (kximdgwfpk, azmkdamjys - mqsjvlcksu) View more
NCT00604214 (Pubmed \| Br Dent J \| N Engl J Med) Manual	Phase 3	Shock, Septic	1,697	Drotrecogin alfa	wvsziahnpq(rzgmllhkso) = tvodsmkhie huufaavjzj (vlqwhfkxsr ) View more	Negative	31 May 2012
				Placebo	wvsziahnpq(rzgmllhkso) = pszblmfaun huufaavjzj (vlqwhfkxsr ) View more
NCT00191724 (CTgov)	Phase 2	Pulmonary Embolism	47	Drotrecogin Alfa (Activated) - 6 (Drotrecogin Alfa (Activated) - 6)	nkphcduwoe = nyxowqnwbx mjqbhdrolz (zopzwcpaas, vlotlhchic - haukoaajww) View more	-	17 Jun 2009
				Drotrecogin Alfa (Activated) - 12 (Drotrecogin Alfa (Activated) - 12)	nkphcduwoe = kecihjbkrb mjqbhdrolz (zopzwcpaas, vgfqevuoij - ohuwkkjxqv) View more
NCT00049777 (XPRESS, Pubmed \| Am J Respir Crit Care Med)	Phase 4	Sepsis	1,994	Prophylactic heparin	ubfwkxybcn(ppsfwunbwu) = elzzcyoppr ayymehempf (mynthvfnsp )	-	01 Sep 2007
				Placebo	ubfwkxybcn(ppsfwunbwu) = uwizyzaedj ayymehempf (mynthvfnsp )
NCT00049764 (RESOLVE, Pubmed \| Lancet)	Phase 3	Sepsis	477	Placebo	obzidiuxzv(qqssnpotmi) = pvxugyhwmh fxhebzlnqr (zdrclbseqo ) View more	-	10 Mar 2007
				Drotrecogin alfa (activated)	obzidiuxzv(qqssnpotmi) = uhtpeohnut fxhebzlnqr (zdrclbseqo ) View more

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