Enlivex Therapeutics Stock

Enlivex Therapeutics Ltd. operates as a clinical-stage macrophage reprogramming immunotherapy company.

The company develops Allocetra, a universal, off-the-shelf cell therapy designed to reprogram macrophages into their homeostatic state. By restoring macrophage homeostasis, Allocetra has the potential to provide a novel immunotherapeutic mechanism of action for life-threatening clinical indications that are defined as 'unmet medical needs', as a stand-alone therapy or in combination with leading therapeutic agents.

The company's primary innovative immunotherapy, Allocetra, represents a paradigm shift in macrophage reprogramming, moving from targeting a specific subset of macrophages or a specific pathway effecting macrophages activity, to a fundamental view of macrophage homeostasis. Restoring macrophage homeostasis may induce the immune system to rebalance itself to normal levels of operation, thereby promoting disease resolution.

The company focuses on two main clinical verticals: sepsis and solid tumors (the Indications).

Frozen Formulation of Allocetra

The company completed the development of frozen formulation Allocetra, in the first quarter of 2022, which was twelve months ahead of schedule. While the liquid formulation of Allocetra has a shelf life of 96 hours, the frozen formulation is expected to have a shelf life spanning multiple years. Due to the early completion of the development of frozen formulation Allocetra, the company utilizes it in its ongoing Phase II sepsis trial going forward], rather than introducing it only at the start of a Phase III study, as previously planned. The company initiated the utilization of frozen formulation Allocetra in its ongoing solid tumor Phase I/II trials, and plan to solely use the frozen formulation Allocetra in all subsequent clinical studies.

Sepsis

The company is developing Allocetra as an adjunctive immunomodulating cell therapy for avoiding organ failure caused by sepsis. The drug would be administered intravenously to the patient following the diagnosis of sepsis in addition to standard of care treatment.

Preclinical Data, Sepsis

In its preclinical study, the company utilized a murine cecal ligation puncture (CLP) sepsis model. The CLP model has been proposed to more closely replicate the nature and course of clinical sepsis, as compared to other models.

The company evaluated the effect of Allocetra in mice, given 4 hours after the end of a CLP procedure, in combination with Ertapenem a highly effective antibiotic commonly used for the treatment of severe or high-risk bacterial infections.

Allocetra downregulated pro-inflammatory cytokines/chemokines. In the preclinical study, Allocetra delayed and prevented mortality in animal models with sepsis by rebalancing the immune system.

Allocetra for the Treatment of Organ Dysfunction and Failure Associated with Sepsis

In late 2019, the company completed its Phase Ib clinical trial of Allocetran in patients with severe sepsis. The company has designed Allocetra to eliminate the need to find matched donors as the source of the therapeutic cells. Following regulatory approval, if obtained, Allocetra would allow the company to manufacture therapeutic product inventory that could be used for additional clinical indications that require swift infusion of the product to patients. The first such indication Enlivex is targeting is prevention of cytokine storms and organ dysfunction associated with sepsis. The aim of the Phase Ib clinical trial was to determine the safety and efficacy profile and tolerability of Allocetra, in subjects admitted to the emergency room with sepsis. On March 18, 2020, the company announced the final safety and efficacy data from its completed Phase Ib.

In 2021, the company initiated a placebo-controlled, randomized, dose-finding, multi-center, Phase II trial evaluating liquid Allocetra in patients with pneumonia-associated sepsis. During 2022, the company amended the protocol of this clinical trial to treat newly recruited patients with frozen formulation Allocetra and expand the study population to include patients whose septic condition stems from biliary, urinary tract, or peritoneal infections. The company is planning to file another protocol amendment and submit the proposed changes to regulators in the second quarter of 2023. The amendment will include an increase in the patients' SOFA score range, effectively allowing recruitment of patients with higher levels of sepsis severity, and a change to two cohorts (treatment and placebo) in lieu of the four-cohort structure. The company does not expect a material timeline delay for top-line data readouts, which are expected in Q1 2024.

Solid Tumors, Macrophage Programming, and Solid Cancer Treatments

The company is also developing Allocetra as a next-generation solid cancer immunotherapy. While first-generation immuno-oncology therapies, such as checkpoint inhibitors, are a significant therapeutic advancement, most patients do not achieve durable clinical benefit.

The data from the company's extensive preclinical studies shows that the Allocetra cells, which have demonstrated robust safety profile in sepsis and COVID-19 clinical trials, have reprogrammed macrophage populations in the tumor microenvironment and surrounding tissues, resulting in a major increase in complete remission for preclinical subjects and survival duration.

The company has initiated a Phase I/II trial evaluating Allocetra in combination with chemotherapy in solid peritoneal tumors in the third quarter of 2022 and a Phase I/II trial evaluating Allocetra in combination with an immune checkpoint inhibitor in the fourth quarter of 2022. The company received a positive Data and Safety Monitoring Board (DSMB) recommendation and Israeli Ministry of Health (IMOH) clearance to continue its Phase I/II clinical trial of Allocetra combined with chemotherapy in patients with peritoneal metastases arising from solid cancers. The recruitment of patients has been on-track, and the company expects to complete enrollment and announce data readouts by Q2 2024.

The company also received a positive DSMB recommendation and IMOH clearance to continue its second Phase I/II clinical trial, which is evaluating Allocetra as monotherapy and in combination with anti-PD1 checkpoint inhibitors in patients with advanced-stage solid tumors. The recruitment of patients has been on-track, and the company expects to complete enrollment in the intravenous-infusion monotherapy and low-dose combination cohorts by the end of Q2 2023. This study also received the U.S. Food & Drug Administration (FDA) clearance for an Investigational New Drug (IND) application at the end of 2022, as well as clearance in February 2023 from the Spanish Agency of Medicines and Medical Devices to open the study in Spain. The company recently announced a clinical collaboration with BeiGene to evaluate the safety and efficacy of Allocetra in combination with tislelizumab, an anti-PD-1 immune checkpoint inhibitor, for the treatment of patients with advanced-stage solid tumors, a part of the company's ongoing Phase I/II clinical trial in patients with advanced-stage solid tumors.

COVID-19, Severe and Critical Patient Population

The company had previously included treatment of COVID-19 as a clinical vertical and conducted certain trials in respect of the treatment of COVID-19; however, it has determined to focus its resources on the Indications.

On February 3, 2021, the company reported positive top-line results from Phase II clinical trial that evaluated Allocetra in severe and critical COVID-19 patients and provided a program update.

In light of the encouraging results of the Phase Ib and Phase II clinical trials of Allocetra in severe and critical COVID-19 patients, the company initiated during 2021 a randomized, controlled Phase IIb clinical trial of Allocetra in severe and critical COVID-19 patients hospitalized in medical centers in Israel and certain European countries.

License Agreements

Tolaren Ltd.

In April 2008, Tolaren Ltd. (Tolaren) granted to the company an exclusive, irrevocable, worldwide, royalty free, and sublicensable license to research, develop, commercialize, manufacture, market, sell, distribute, and otherwise use and exploit a certain patent, patent rights and pending patent applications relating to the method for using apoptotic cells as a treatment for various autoimmune and inflammatory disorders and the production processes with respect to the same. Pursuant to the license, the company has agreed to manage, maintain, and defend the licensed patents, including managing the registration of such patents in different countries.

Hadasit Medical Research Services and Development Ltd. and Yissum Research and Development Company Ltd.

In March 2006, the institutes jointly granted the company an exclusive, worldwide, royalty free, and sublicensable license to research, develop, commercialize, manufacture, market, sell, distribute, and otherwise use and exploit a certain patent and patent rights relating to the therapeutic use of dead or dying cells, including apoptotic or necrotic cells, as well as any associated materials, methods or technology, as well as a method of using the heparin-binding domain of TSP thrombospondin-1, or TSP-1, which it may develop in the future as a molecular-based therapy for the treatment of inflammatory bowel disease.

Intellectual Property and Patents and Proprietary Rights

The company owns and in-licenses issued patents and pending patent applications in various jurisdictions worldwide, including three issued patents and several pending patent application in the United States, one issued patent in Israel, two issued patents and several pending patent application in the EU and several international patent application filed with the World Intellectual Property Organization under the PCT. The company has sought patent protection for certain methods of producing and using autologous and allogeneic Allocetra. The company also intends to seek patent protection for its discovery programs, and any other inventions to which it has rights, where available and when appropriate.

The company has multiple patent families in which certain patents have been granted and there are other pending patent applications covering products under development and the uses thereof. The first patent family, titled 'Disease Therapy Using Dying or Dead Cells' has IP granted by the U.S. Patent and Trademark Office (USPTO; Patent No. 9,567,568), the European Patent Office (EPO; Patent No. EP1879601), and Israel Patent Office (IPO; Patent No. IL187122) with patent terms of 04-May-2025 (the U.S.) and 04-May-2026 (Israel and Europe - DE, FR, IE, GB), respectively. The second patent family, titled 'Therapeutic Apoptotic Cell Preparations, Method for Producing Same and Uses Thereof' has patents granted in the U.S. (Patent Nos. 10,077,426 and 10,927,343) with term dates in 2033 and 2034, respectively. Patents in this family have also been granted in Australia, Canada, China, Europe, Israel, and Japan, which have a term date of December 5, 2033.

A third patent family, titled 'THERAPEUTIC POOLED BLOOD APOPTOTIC CELL PREPARATIONS AND USES THEREOF' has granted patents in the U.S. (Patent No. 10,857,181), Australia, China, Europe, Israel, and Japan, having a term date of April 21, 2036 (July 15, 2036 for the U.S. patent). Pending applications in this patent family include those filed in Australia, Canada, China, Europe, Hong Kong, Israel, Japan, South Korea, and the U.S., many of which have entered prosecution. A fourth patent family, titled 'COMBINATION IMMUNE THERAPY AND CYTOKINE CONTROL THERAPY FOR CANCER TREATMENT,' for combination therapies with CAR T-cells, has granted patents in the U.S. (Patent Nos. 11,000,548 and 11,000,548), Australia, Europe, Israel, and Japan, having a term date of February 18, 2036. Pending applications in prosecution in this family include those filed in the U.S., Australia, Canada, China, Europe, Israel, Japan, and South Korea. A fifth patent family, titled 'EARLY APOPTOTIC CELLS FOR USE TREATING SEPSIS' has granted patents in the U.S. (Patent Nos. 11,304,976; 11,497,767; and 11,318,163) having a term date of February 18, 2036. Pending application sin this patent family include those filed in the U.S. (allowed), Australia, Canada, China, Europe, Israel, Japan, and South Korea. A sixth patent family, titled 'THERAPEUTIC APOPTOTIC CELLS FOR CANCER THERAPY' has pending applications in the U.S., Australia, Canada, China, Europe, Israel, Japan, and South Korea.

A seventh patent family, titled 'THERAPEUTIC APOPTOTIC CELLS FOR TREATMENT OF OSTEOARTHRITIS' has pending applications in the U.S., Australia, Canada, China, Europe, Israel, Japan, and South Korea. An eighth patent family, titled 'USE OF EARLY APOPTOTIC CELLS FOR TREATING COVID-19' has pending applications in the U.S., Australia, Canada, China, Europe, Israel, Japan, and South Korea. Various additional patent families with pending applications in the U.S. and in other countries are under prosecution or are in the preliminary stages and have been filed as provisional U.S. patents or International (PCT) applications.

Research and Development

For the year ended December 31, 2022, the company incurred research and development expenses in the aggregate of $18,693,000.