Biologics

A TLR5 agonist in clinical development — where innate immunity matters most.

Entolimod is a clinical-stage immunotherapeutic designed to activate a well-characterized pathway in the innate immune system. Preclinical and clinical studies are evaluating its potential to modulate immune responses and support tissue recovery across high unmet-need indications.

Mechanism

Entolimod is a Toll-like Receptor 5 (TLR5) agonist. TLR5 is a pattern-recognition receptor on the surface of immune and epithelial cells that, when activated, triggers NF-kB signaling — a central pathway in the body’s innate immune response.

Activation of this pathway has been shown in nonclinical models to influence multiple biological processes associated with the response to radiation exposure, including modulation of cell survival pathways, support of progenitor cell recovery in affected tissues, and effects on immune cell activity, including NK and T cells.

Entolimod is being investigated across multiple indications where activation of this pathway may support cellular and tissue responses. Each indication will require its own clinical development program and regulatory submissions.

Lead indication: Acute Radiation Syndrome

High-dose radiation exposure — whether from a nuclear incident, a radiological weapon, or an accident at an industrial or medical facility — causes Acute Radiation Syndrome (ARS): a cascade of bone marrow failure, gastrointestinal complications, and epithelial damage.

Entolimod is being developed as a medical countermeasure for ARS under the FDA’s Animal Rule — a regulatory framework designed for treatments where human efficacy trials are not ethical or feasible. The program has received Fast Track and Orphan Drug designations from the FDA. The development program includes nonclinical efficacy studies, clinical safety data, and translational work to support dose selection, and continues to advance toward potential regulatory submission.

In a post-hoc pooled analysis of the RS-23 animal study conducted under the FDA Animal Rule, Entolimod was associated with an odds ratio of 7.9. A 25-hour post-exposure treatment window has been observed in nonclinical models. Note: RS-23 was not accepted by FDA as a pivotal study.

Expanded Indications

Neutropenia.

Neutropenia is a life-threatening drop in white blood cells that affects a significant proportion of patients undergoing chemotherapy or radiation therapy. Currently approved agents include G-CSF products such as Neupogen and Neulasta, which address multiple clinical contexts including chemotherapy-induced neutropenia, stem cell mobilization, severe chronic neutropenia, and mitigation of damage from ARS.

Entolimod is being investigated for its potential to activate innate immune pathways and support tissue responses to injury. In nonclinical models, this activity has been associated with effects in both hematopoietic and gastrointestinal tissues. The program is in early-stage development for oncology supportive care. The global market for oncology supportive-care therapies is estimated at more than $22 billion.

Lymphocyte exhaustion.

Chronic infections and cancers can drive T-cells and other lymphocytes into a state of functional exhaustion — reduced cytokine production, reduced proliferative capacity, and loss of effector function. Entolimod’s ability to activate innate immune signaling offers a mechanistic rationale for restoring immune function in these states.

Immune function in older adults.

As people age, immune responses may become less robust and less predictable, which can contribute to increased vulnerability to infection and reduced vaccine responsiveness. Entolimod has been evaluated in a Phase 2 study at Mayo Clinic in healthy older adults receiving influenza vaccination. These data support continued exploratory research into the potential effects of TLR5 activation on age-related immune function.

Chronic Radiation Syndrome.

Chronic Radiation Syndrome results from prolonged, lower-dose radiation exposure — a clinical condition distinct from ARS and without effective treatment. Entolasta, a second-generation follow-on to Entolimod, is being advanced through IND-enabling studies for chronic indications including Chronic Radiation Syndrome.

Development history

Entolimod has been evaluated in nonclinical studies conducted under the framework of the FDA Animal Rule, as well as in human safety studies. In a post-hoc pooled analysis of the RS-23 nonclinical study, observations from animal models have included:

An observed survival advantage over placebo
Associated reductions in radiation-induced apoptosis in nonclinical models
Observed effects on regeneration of progenitor cells in radiation-damaged tissues
Observed effects on gastrointestinal tissue recovery in animal models
Observed improvements in hematopoietic outcomes and peripheral blood recovery in animal models

Note: RS-23 was not accepted by FDA as a pivotal study. Further regulatory discussions and additional studies are contemplated as part of the ongoing development program. Outcomes described reflect observations from animal models and do not establish clinical efficacy in humans.