Eric Devroe, founder, CEO and – for now – the only full-time employee of Opsonix Inc., is well aware of multiple failed efforts by drug developers to thwart the often deadly effects of sepsis. Many of those shortfalls, he maintained, focused on approaches that attempted to temper the immune response, which occurs downstream in the sepsis cascade.

The approach of Cambridge, Mass.-based Opsonix is distinct "in that we are providing a means to rapidly extract the wide range of sepsis-causing pathogens – and, importantly, immunogenic debris and toxins released from killed pathogens – from circulating blood," Devroe told BioWorld Today.

The core technology at Opsonix is based on pathogen-capture proteins, which are engineered versions of human blood opsonins – molecular components of the innate immune system that help to clear pathogens and the toxins they release. The company – whose name "pays homage to opsonins," Devroe said – is seeking to develop therapeutic products by applying recombinant protein engineering to harness the binding properties of opsonins that enable them to clear a broad range of infectious microbes and toxic components from blood and prevent the inflammatory cascade that leads to sepsis.

The company's lead molecule is a recombinant human protein derived from mannose binding lectin (MBL) fused to the Fc region of human immunoglobulin (FcMBL). When attached to the membrane of a dialyzer-type device, the FcMBL can remove a broad range of bacteria, fungi, parasites, viruses and toxins responsible for initiating the sepsis cascade, including antibiotic-resistant organisms.

The scientific premise is that the company's FcMBL-based pathogen-extracting therapy will enable broad-spectrum treatment of blood-borne infectious diseases at an early stage, when treatment is most effective, without the need to wait for identification of a specific disease-causing pathogen.

Some of the sepsis candidates that failed in the clinic over the past five years also sought to attack all-cause mortality. Eisai Inc., a unit of Tokyo-based Eisai Co. Ltd., halted efforts to advance eritoran (E5564) after the Toll-like receptor 4 antagonist failed to meet the efficacy endpoint in the phase III ACCESS (A Controlled Comparison of Eritoran and Placebo in Patients with Severe Sepsis) study. (See BioWorld Today, Jan. 26, 2011.)

A year later, sepsis claimed another victim when AZD9773 (Cytofab), which London-based Astrazeneca plc was developing with BTG plc, failed to separate from placebo in a phase IIb trial in 300 patients with severe sepsis or septic shock. The potential for the anti-TNF-alpha polyclonal antibody fragment to succeed in sepsis was a major factor in the merger between London-based BTG and Biocompatibles plc. (See BioWorld Today, Nov. 22, 2010, and Aug. 9, 2012.)

Also in 2012, sepsis confounded another potential treatment with the curtailment of the phase II/III trial of talactoferrin, developed by Agennix AG, of Planegg, Germany. The company was later forced to liquidate when the candidate also failed to move the needle in a phase III trial in lung cancer. (See BioWorld Today, Feb. 3, 2012, and May 25, 2013.)

Other clinical failures in sepsis included Centocor Inc., now Janssen Biotech Inc., a unit of Johnson & Johnson, of New Brunswick, N.J.; Immunex Corp., of Seattle, a unit of Amgen Inc., of Thousand Oaks, Calif.; Xoma Ltd., of Berkeley, Calif.; and Icos Corp., subsequently acquired by development partner Eli Lilly and Co., of Indianapolis.

ALONE OR IN COMBINATION WITH ANTIBIOTICS

Opsonix obviously is confident that history won't repeat itself with its candidate. In preclinical rodent studies published by the company's scientific founders, Donald Ingber and Michael Super, the FcMBL-based pathogen-extracting therapy reduced pathogen load, corresponding inflammatory cell infiltrate and levels of multiple pro-inflammatory cytokines that play a role in the sepsis cascade. Ingber is founding director and Super is senior staff scientist at Harvard University's Wyss Institute for Biologically Inspired Engineering.

Their studies, published in Nature Medicine and Biomaterials, showed that the FcMBL pathogen-extracting therapy removed more than 90 percent of pathogen load from flowing blood, attenuated production of cytokines that drive the sepsis inflammatory cascade and increased survival in animals with lethal endotoxemia.

The pathogen-extracting therapy was designed to work in synergy with conventional antibiotic treatments. Thus, the company's sepsis therapy offers the potential to be used alone or in combination with existing treatments.

Devroe, a scientist and entrepreneur who most recently served as executive director of strategic alliances at the University of Texas MD Anderson Cancer Center, joined Wyss last year as an entrepreneur in residence and worked with Ingber and Super for about a year to refine and validate the technology while raising money for the start-up. Devroe credited the Institute's technology transfer model, which de-risks high-value technologies from a technical and business perspective to increase their likelihood of commercial success, with enabling a quick transition of the intellectual property to Opsonix. The company holds an exclusive global license to the technology covering the use of engineered opsonin proteins in pathogen-extracting devices and companion diagnostics.

In October, Opsonix was officially launched with an $8 million series A round led by Baxter Ventures, with participation by private investor Hansjörg Wyss. The round represented a true initial raise for Opsonix, but while the research program was housed at Wyss, the technology was supported by more than $22 million in grant funding from the Defense Advanced Research Projects Agency, or DARPA, under its dialysis-like therapeutics program.

Proceeds from the initial round will fund additional preclinical studies with the goal of advancing the lead candidate into the clinic, though Devroe declined to predict a timetable for the start of human studies.

A separate step required to deliver the pathogen-extracting therapy is to attach FcMBL to the membrane of a dialyzer-type device. Devroe declined to say whether Opsonix will seek to develop the device internally or through a partnership and whether the company will seek to advance the therapy as a drug or device.

"As we develop additional preclinical and clinical data with our pathogen-extracting therapy, Opsonix will explore a range of different business and commercial opportunities, including potential partnerships," he said.

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