A Novel Immunotherapy That Could Bring Hope To Millions Of Sepsis Patients Received MultiCountry Clearance For Expanded Clinical Trial

Enlivex Therapeutics Ltd. ENLV announced that Israel, Spain and Greece have cleared amendments to the company’s Phase II trial protocol that will allow the study to enroll more patients. 

The cleared amendments also allow Enlivex to use a newly developed frozen formulation of AllocetraTM — the macrophage reprogramming immunotherapy it’s evaluating as a potential sepsis treatment in the clinical trial. 

The Current Standard Of Care For Sepsis Needs Improvement

Each year, about 1.7 million U.S. adults develop sepsis in response to an infection. Of those, about 350,000 will die from septic shock, according to the Centers for Disease Control (CDC). Despite the risks of sepsis, there is currently no specific treatment for the life-threatening condition. 

That’s because it’s not a pathogen in its own right but an extreme response to an infection the patient already has. That underlying infection can be bacterial, fungal or viral so treating sepsis often starts with identifying the underlying infection and administering the appropriate antibiotic, antimicrobial or antiviral treatment.

This initial treatment, along with intravenous fluids and vasopressors to maintain organ function and blood pressure, forms the current standard of care, but they’re really just a way of keeping the patient alive while their immune system, hopefully, fights the infection causing the sepsis response. 

Even with this standard of care, timing is everything. In a study of New York State Department of Health data, researchers found that for each hour antibiotic treatment was delayed in patients with sepsis, the risk of mortality increased by 4%. In other words, patients need to receive treatment as soon as possible to increase the odds of survival. 

This large unmet need has motivated many pharmaceutical companies to explore new treatment options, but so far, few have shown significant promise. For example, monoclonal antibodies (mAbs), like Merck & Co. Inc.’s MRK bezlotoxumab or Aridis Pharmaceuticals Inc.’s ARDS tosatoxumab, have made some headway, but these are engineered to target specific infections. So doctors would need to identify the specific mAb to use and hope that one exists for that particular infection, which is not a guarantee since mAbs are still relatively new.

Enlivex’s Allocetra Is An Immunotherapy That Could Rebalance The Immune Response

At its core, sepsis is an extreme immune response to an infection in the body. That’s why Enlivex has chosen to explore immunotherapy options for treating the condition. AllocetraTM, it’s leading drug candidate, works by reprogramming macrophages from healthy donor cells to help the patient’s own macrophages return to their homeostatic state of stability. 

Macrophages are a type of immune cell that circulates throughout the body, monitoring for signs of infection. When a pathogen is spotted, they immediately “eat” it and send out an alarm signal to the rest of the immune system. Certain conditions, like sepsis, can disrupt macrophages, triggering an excessive inflammatory response that can end up causing the organ damage and organ failure that make sepsis so life-threatening. 

Allocetra’s formula uses donor macrophages that have been programmed to send out an “eat me” signal to the host’s macrophages. Once engulfed, the donor cells then reprogram those host macrophages to return to their homeostatic state.

In the preclinical and clinical trials Enlivex has completed so far, that return to homeostasis has resulted in reduced mortality and improved sequential organ failure assessment (SOFA) scores, suggesting that the immunotherapy could help moderate the immune response and protect organs from damage and failure. 

While antimicrobials will still be necessary for fighting the underlying infection, Allocetra’s ability to influence the host’s overactive immune response could become an essential tool for preventing long-term damage and reducing mortality rates. 

The Phase II Clinical Trial Will Include An Expanded Patient Population And A More Shelf-Stable Version Of Allocetra

Initially, the Phase II trial was limited to patients with pneumonia-associated sepsis. With the recent amendments cleared by Israel, Spain and Greece, Enlivex is now able to expand the trial to include patients with sepsis related to biliary, urinary tract and peritoneal infections. 

The amendments also clear the way for the clinical-stage immunotherapy company to treat patients in the trial with its newer frozen formulation of Allocetra. In development for the last two years, frozen Allocetra is expected to have a shelf life spanning years rather than the 96-hour shelf life of the liquid version. A longer shelf life means Enlivex can manufacture the novel immunotherapy at scale and hospitals can keep it in stock so that it’s readily available for rapid deployment for the treatment of sepsis patients. 

Enlivex plans to submit these same protocol amendments in other jurisdictions in hopes of further expanding its Phase II research. But with the regulatory clearance achieved so far, the company is optimistic that it can shorten the timeline to potential approval of frozen Allocetra as a sepsis treatment, which could move up the date of a possible commercial launch. 

Featured photo by Alexander Grey on Unsplash

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