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lthough the growing public outcry surrounding antibiotic resistance has only recently propelled sepsis back into the international spotlight, in reality, the sepsis marketplace has been one of high unmet medical need for decades. The condition, which currently lacks specific therapies beyond antimicrobials and basic supportive care, has quietly evolved into one of the most urgent medical issues facing our healthcare system today
Although the growing public outcry surrounding antibiotic resistance has only recently propelled sepsis back into the international spotlight, in reality, the sepsis marketplace has been one of high unmet medical need for decades. The condition, which currently lacks specific therapies beyond antimicrobials and basic supportive care, has quietly evolved into one of the most urgent medical issues facing our healthcare system today. According to the Centers for Disease Control and Prevention, sepsis rates doubled between 2000 and 2008.1Sepsis was the 11th leading cause of death in the United States in 2010, and was the single most expensive condition treated in hospitals in 2011.2,3 Severe sepsis cases involving multiple organ dysfunctions are associated with especially high morbidity and mortality, and consume a vast amount of healthcare resources.4 Not surprisingly, the scarcity of effective treatment options for these patients also places a major financial burden on national healthcare systems. In 2011 alone, the treatment of hospitalized sepsis patients cost $20.3 billion, accounting for a staggering 5.2% of all hospitalization costs and making it the most expensive condition treated in US hospitals.3 This figure does not account for the costs related to treatment following hospital discharge, as sepsis patients who survive often experience lifelong complications. Therefore, total sepsis-related healthcare costs in the United States are likely substantially higher.
With the need for novel therapies abundantly clear, the sepsis marketplace should represent an untapped commercial opportunity for big pharma. The current sepsis pipeline, however, features no drug candidates in late-stage clinical development by the large pharmaceutical companies. The discontinuation of Eli Lilly’s once-marketed sepsis drug Xigris (drotrecogin alfa [activated]), a recombinant human activated protein C, followed by a parade of late-stage failures such as Eisai’s Eritoran (eritoran tetrasodium), AstraZeneca and BTG’s CytoFab (formerly AZD-9773), and Agennix’s talactoferrin alfa (recombinant human talactoferrin) explains big pharma’s reluctance to enter this marketplace and appears to paint a bleak picture for future drug developers. These failures, however, highlight the need for a paradigm shift in how late-stage sepsis clinical studies are conducted. The lack of a universal clinical phenotype-one that can easily be targeted by a one-size-fits-all drug-represents a formidable clinical and commercial barrier to improving the treatment options for sepsis patients. Key opinion leaders (KOLs) interviewed by GlobalData stressed that companies seeking to enter the sepsis marketplace must focus their efforts on demonstrating efficacy in smaller, homogeneous patient populations, or they risk suffering the same fate as Xigris and its counterparts. Therapies targeting coagulopathy, endotoxemia, acute kidney injury (AKI), acute respiratory distress syndrome, and/or immunosuppression were cited as some of the more clinically relevant indications.
Two products in late-stage clinical development-Asahi Kasei Pharma America’s ART-123 (recombinant human soluble thrombomodulin alpha) and Spectral Diagnostics’ Toraymyxin (polymyxin B extracorporeal hemoperfusion column)-exemplify this trend toward targeted therapies. ART-123 is being investigated specifically in severe sepsis patients with coagulopathy and sepsis-associated cardiovascular dysfunction or respiratory failure. Coagulopathy is specifically characterized by an international normalized ratio (INR, also known as prothrombin time) greater than 1.40. Although ART-123 functions through a similar mechanism as the now-defunct Xigris, GlobalData believes that leveraging quantitative measures in specific patient populations to recruit individuals who will most likely benefit from drug treatment is a marked improvement for sepsis clinical trial design. ART-123 is currently being investigated in a pivotal phase 3 study that is using 28-day all-cause mortality as its primary efficacy outcome measure, with an estimated primary completion date of March 2015.5
Leveraging a similar strategy, Spectral Diagnostics is evaluating Toraymyxin specifically in sepsis patients who present with bacterial endotoxemia. Although the product has been approved and marketed in Japan and Europe since 1994 and 2002, respectively, the company has initiated the first large-scale, properly controlled clinical study of Toraymyxin in a well-defined sepsis patient population (the EUPHRATES trial), which is using 28-day all-cause mortality as its primary efficacy outcome measure, with a primary completion date of July 2016.6 Importantly, the company has paired its column, which is highly effective at removing endotoxin from the bloodstream, with its proprietary, FDA-approved endotoxin activity assay (EAA) to specifically target patients with an EAA of 0.60 EAA units or more. GlobalData expects this strategy will allow Spectral to efficiently select patients who are best suited for treatment with Toraymyxin, thereby maximizing its chance of demonstrating efficacy in the EUPHRATES trial.
ART-123 and Toraymyxin represent a step in the right direction, but a developer of an earlier-stage pipeline product for sepsis is more drastically rethinking their clinical trial design. AM-Pharma is investigating the use of recombinant human alkaline phosphatase (recAP) in sepsis patients with AKI, a condition cited by KOLs as being a major cause of mortality in sepsis patients. In the latest study they have selected creatinine clearance as the primary efficacy outcome measure, rather than 28-day all-cause mortality, which has been used historically to evaluate sepsis drugs. This subtle difference is important because the outcome is directly related to the drug’s mechanism of action. The firm had previously demonstrated early efficacy with a bovine-based molecule in two small phase 2 trials. Development of the anti-inflammatory was halted, however, due to a short half-life and safety concerns associated with its bovine origins.7,8 Positive phase 1 results of the human-based recAP were announced this past March, and the company will begin a phase 2 study (ALPINE) this October.9 According to experts interviewed by GlobalData, AM-Pharma’s strategy of highlighting recAP’s ability to halt the progression of renal dysfunction or eliminate the need for hemodialysis represents a novel trial design approach that will help minimize risk while still positioning recAP as a welcomed addition to the sepsis treatment arsenal, even if it does not necessarily demonstrate a mortality benefit.
Targeting narrow segments of the sepsis patient population in clinical trials will certainly better position a pipeline candidate for approval, but this approach also guarantees a smaller pool of patients once a novel therapy reaches the market. GlobalData expects that developers, in an attempt to ensure a favorable return on investment, will likely seek premium pricing for these novel sepsis-specific therapies. This pricing strategy should be justifiable by drug developers, considering that the current price tag for sepsis treatments comes in at more than $20 billion a year in the United States.3 Moreover, setting high prices for medicines when they serve smaller patient populations in areas of high unmet need is not unprecedented, as it has occurred in the context of both antibiotics and orphan diseases.10 Therefore, extending this concept toward sepsis-specific therapies would not be a stretch, and would actually incentivize companies to move forward with development in this high-risk area.
Treating sepsis patients has been a problem for decades, and regardless of whether antibiotic resistance continues to increase, physicians need sepsis-specific and host-directed therapies to treat the most critically ill patients. With firms beginning to acknowledge the heterogeneity of the sepsis patient population and exploring innovative clinical trial enrollment criteria and endpoint selection, these needs may soon be addressed-albeit with specialized, high-cost products.
Dr Hansel is an analyst on the infectious diseases team at GlobalData in Boston, Massachusetts, where he is currently working on an in-depth report covering the marketed and pipeline therapies for sepsis.
Disclosure information: The author reports no financial disclosures as related to products discussed in this article.
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Asahi Kasei Pharma America Corporation. Phase 3 safety and efficacy study of ART-123 in subjects with severe sepsis and coagulopathy, NCT01598831. http://clinicaltrials.gov/ct2/show/study/NCT01598831. Accessed September 17, 2014.
Spectral Diagnostics. Safety and efficacy of Polymyxin B hemoperfusion (PMX) for septic shock (EUPHRATES), NCT01046669. http://www.clinicaltrials.gov/ct2/show/NCT01046669. Accessed September 17, 2014.
Heemskerk S, Masereeuw R, Moesker O, et al; APSEP Study Group. Alkaline phosphatase treatment improves renal function in severe sepsis or septic shock patients. Crit Care Med. 2009;37(2):417–423, e1.
Pickkers P, Heemskerk S, Schouten J, et al. Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial. Crit Care. 2012;16(1):R14.
AM-Pharma. A safety, tolerability, efficacy, and QoL study of human recAP in the treatment of patients with SA-AKI (ALPINE), NCT02182440. http://www.clinicaltrials.gov/ct2/show/NCT02182440. Accessed September 17, 2014.
Infectious Diseases Society of America (IDSA). IDSA Statement on Limited Population Antibacterial Drug (LPAD) Approval Mechanism. 2013. http://www.idsociety.org/uploadedFiles/IDSA/Policy_and_Advocacy/Current_Topics_and_Issues/Advancing_Product_Research_and_Development/Bad_Bugs_No_Drugs/Statements/IDSA%20LPAD%20Statement%20to%20FDA.March%201%202013.pdf. Accessed September 17, 2014.