Enlivex Therapeutics Ltd. (NASDAQ: 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 (NYSE: MRK) bezlotoxumab or Aridis Pharmaceuticals Inc.’s (NASDAQ: 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.

As part of a new generation of companies representing the future of cell therapy – off-the-shelf, highly scalable and low COGS “beyond CAR-T” cell therapies – Enlivex is focused on a highly differentiated novel immunotherapeutic mechanism – macrophage homeostasis. Macrophage homeostasis is severely disrupted by certain diseases states, and such imbalance is critical to the progression of the diseases. Allocetra has the potential to introduce highly-effective, low-cost allogeneic cell therapies for life-threatening clinical indications that are defined as “unmet medical needs”, including sepsis – one of the leading causes of mortality, and oncology, through restoration of macrophage homeostasis. Enlivex is led by a seasoned management team who founded PROLOR Biotech and led it to a successful $560 financial exit and a partnership with Pfizer. PROLOR’s lead product, now named NGenla® by Pfizer, recently received marketing approval in Australia, Canada, Japan and the EU.

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Safe Harbor Statement: This press release contains forward-looking statements, which may be identified by words such as “expects,” “plans,” “projects,” “will,” “may,” “anticipates,” “believes,” “should,” “would”, “could,” “intends,” “estimates,” “suggests,” “has the potential to” and other words of similar meaning, including statements regarding expected cash balances, market opportunities for the results of current clinical studies and preclinical experiments, the effectiveness of, and market opportunities for, ALLOCETRATM programs. All such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Investors are cautioned that forward-looking statements involve risks and uncertainties that may affect Enlivex’s business and prospects, including the risks that Enlivex may not succeed in generating any revenues or developing any commercial products; that the products in development may fail, may not achieve the expected results or effectiveness and/or may not generate data that would support the approval or marketing of these products for the indications being studied or for other indications; that ongoing studies may not continue to show substantial or any activity; and other risks and uncertainties that may cause results to differ materially from those set forth in the forward-looking statements. The results of clinical trials in humans may produce results that differ significantly from the results of clinical and other trials in animals. The results of early-stage trials may differ significantly from the results of more developed, later-stage trials. The development of any products using the ALLOCETRATM product line could also be affected by a number of other factors, including unexpected safety, efficacy or manufacturing issues, additional time requirements for data analyses and decision making, the impact of pharmaceutical industry regulation, the impact of competitive products and pricing and the impact of patents and other proprietary rights held by competitors and other third parties. In addition to the risk factors described above, investors should consider the economic, competitive, governmental, technological and other factors discussed in Enlivex’s filings with the Securities and Exchange Commission, including in the Company’s most recent Annual Report on Form 20-F filed with the Securities and Exchange Commission. The forward-looking statements contained in this press release speak only as of the date the statements were made, and we do not undertake any obligation to update forward-looking statements, except as required under applicable law.

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