SGX943 is an Innate Defense Regulator (IDR), containing the same active ingredient as SGX942 (dusquetide). Dusquetide is a fully synthetic, 5-amino acid peptide with high aqueous solubility and stability. Extensive in vivo preclinical studies have demonstrated enhanced clearance of bacterial infection with SGX943 administration. SGX943 has shown efficacy against both gram-negative and gram-positive bacterial infections in preclinical models, independent of whether the bacteria is antibiotic resistant or antibiotic sensitive.
The innate immune system is responsible for rapid and non-specific responses to combat bacterial infection. Augmenting these responses represents an alternative approach to treating bacterial infections. In animal models, IDRs are efficacious against both antibiotic-sensitive and antibiotic-resistant infections, both gram-positive and gram-negative bacteria, and are active irrespective of whether the bacteria occupies a primarily extracellular or intracellular niche. IDRs are also effective as stand-alone agents or in conjunction with antibiotics. An IDR for the treatment of serious bacterial infections encompasses a number of clinical advantages including:
- Treatment when antibiotics are contraindicated, such as:
- before the infectious organism and/or its antibiotic susceptibility is known; or
- in at-risk populations prior to infection.
- An ability to be used as an additive, complementary treatment with antibiotics, thereby:
- enhancing efficacy of sub-optimal antibiotic regimens (e.g., partially antibiotic-resistant infections);
- enhancing clearance of infection, thereby minimizing the generation of antibiotic resistance; and
- reducing the required antibiotic dose, again potentially minimizing the generation of antibiotic resistance.
- An ability to modulate the deleterious consequences of inflammation in response to the infection, including the inflammation caused by antibiotic-driven bacterial lysis; and
- Being unlikely to generate bacterial resistance since the IDR acts on the host, and not the pathogen.
Importantly, systemic inflammation and multi-organ failure is the ultimate common outcome of not only emerging and/or antibiotic-resistant infectious diseases, but also of most biothreat agents (e.g., Burkholderia pseudomallei), indicating that dusquetide would be applicable not only to antibiotic-resistant infection, but also to biothreat agents, especially where the pathogen is not known and/or has been engineered for enhanced antibiotic resistance.
IDRs such as dusquetide can change the downstream balance between anti-infective/tissue-healing activities and inflammatory activities of the innate immune system. Dusquetide increases host anti-infective responses, including increased macrophage recruitment to the site of infection, enhanced bacterial clearance and survival in acute animal infection models. Because dusquetide is a host-directed therapeutic, it is not susceptible to mechanisms of antibiotic resistance, is agnostic to the causative agent and is complementary to (and even synergistic with) antibiotics. Unlike antibiotics, IDRs also modulate the inflammatory response, decreasing the often deleterious consequences of excessive inflammation. The IDR mechanism and activity has been extensively tested in animals, including both antibiotic resistant infection and biothreat agents (e.g., B. pseudomallei) and published.
In addition, pursuit of the lead clinical IDR, dusquetide, in both Phase 1 and Phase 2 clinical studies in oral mucositis has demonstrated complete concordance between non-clinical and clinical activities. Dusquetide has been demonstrated to be safe and exhibit anti-inflammatory properties in an 84-patient single and multiple ascending dose Phase 1 study and it has shown to be efficacious and well tolerated in a 111-patient Phase 2 study in oral mucositis in head and neck cancer patients. The pathogenesis of oral mucositis results in a dysregulated innate immune response, including an over-exuberant inflammatory response, which serves to exacerbate the underlying tissue damage caused by chemoradiation therapy. Dusquetide has been shown to modulate this inflammatory response to chemoradiation damage, resulting in a 50% overall decrease in the duration of severe oral mucositis in head and neck cancer patients receiving CRT, as well as a 67% decrease in severe oral mucositis in patients most at risk for severe oral mucositis. In addition to experiencing oral mucositis, these patients are also at significant risk for infection, and treatment with dusquetide was shown to significantly reduce the rate of infection as a recorded AE. These results were completely consistent with nonclinical results, indicating that all the findings in animals (including anti-infective activity), translated to humans.
The IDR technology platform (also referred to by its research name SGX94) represents a novel and innovative approach to therapeutically modulating immune defenses by targeting the innate immune system. Preclinical data indicate that SGX94 (dusquetide) is active in models of a wide range of therapeutic indications including severe side-effects of chemo- and/or radiation-therapy and life-threatening bacterial infections. Please refer to the SGX94 (Dusquetide) Executive Summary (pdf) for more detailed information.
Soligenix has a strong worldwide intellectual property position on dusquetide and related analogs including composition of matter.
About Innate Defense Regulators (IDRs)
Innate Defense Regulators are a family of short, synthetic, proprietary peptide and peptide-like analogs with a dual-mode of efficacy, modulating the innate immune response to both damage and pathogen-associated signals, enhancing resolution of infection and tissue damage while suppressing harmful inflammation. IDRs do not impact the adaptive immune system and do not interfere with chemotherapy, radiation therapy or antibiotic treatments. Soligenix has demonstrated the preclinical efficacy of IDRs in diseases associated with dysregulated innate immune responses and tissue damage, such as oral mucositis subsequent to chemotherapy or radiation therapy. Moreover, IDRs are also efficacious in other diseases associated with both Gram-positive and Gram-negative bacterial infections, as well as infections with antibiotic resistant organisms like methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE).
IDRs bind to a pivotal regulatory protein in the innate defense system, known as p62 or sequestosome-1. IDRs bind specifically to the ZZ domain of p62 and a co-crystal structure of the IDR binding site with SGX94 has been obtained.
About Innate Immunity
The immune system is constantly exposed to pathogenic microorganisms (bacteria, virus, fungi, and parasites) but has evolved a powerful response to deal with these threats to our health. This response has been divided into two general types of reactions: reactions of innate immunity and reactions of adaptive immunity. Innate immunity is the “first responder” component of the immune system that is immediately activated to destroy invading microorganisms and trigger inflammation that contributes to blocking their assault. If microorganisms breach the innate immune system, adaptive immunity is activated. Adaptive immunity uses T and B cells to produce antibodies and killer cells to destroy infected cells. The two components of the immune system provide excellent protection against infections but they also pose a risk. If the activation threshold of either component is too low, or if activation is excessive, inflammatory disease may follow.
The innate immune system is a highly integrated system of cells involving both circulating blood cells and cells in tissues protecting us from pathogens at all body surfaces that interface with the external environment: skin, mouth, gastro-intestinal tract and lung. Innate immunity is dependent on rapidly sensing infection or damage and responding quickly with both inflammation and host repair or anti infective functions. When excessive activation of innate immunity causes inflammation, modulation of the activated innate immune system can re-direct the system to decrease inflammatory responses and increase the anti-infection or healing responses. The innate immune system responds quickly by sensing non-specific molecules released by the process of infection and damage through its Toll-like receptors and associated receptors. The p62 molecule integrates and regulates the signals sensed by these receptors and can re-direct the response of the innate immune system in a benign way without perturbing the function of the adaptive immune system.