Emerging and Antibiotic Resistant Infectious Disease
Orphan and/or Fast Track Designation
Denotes funding by NIH, BARDA, DTRA and/or FDA.
Novel Broad Spectrum Treatment for Bacterial Infection
The current treatment for bacterial infection is antibiotics. While antibiotics have been “miracle drugs”, their Achilles heel is the generation of antibiotic resistance. Currently 23,000 people in the US die due to antibiotic resistant infections and the rate of resistance continues to grow rapidly. Emerging infectious diseases are infections which we don’t yet know about, caused by pathogens that have not been well characterized. Some of these infections can be caused by bacteria. However, antibiotics only work on specific types of bacteria, and there is no guarantee that current antibiotics can address every new bacterial infection. Dusquetide, an Innate Defense Regulator and the active ingredient in SGX943, modulates the innate immune response to infection. Because it doesn’t target the bacteria directly, it is effective irrespective of the type of bacteria. This means it can be used before the specific bacteria has been identified, or when the bacteria is resistant to antibiotics and it can be used in conjunction with all major classes of antibiotics.
Background on Bacterial Infectious Disease
Before the advent of antibiotics, bacteria killed many people. Many diseases, which are today considered trivial, killed thousands:
Before antibiotics, 90% of children with bacterial meningitis died. Survivors faced long term consequences, including deafness and mental disability
Strep throat could be a fatal disease, and ear infections sometimes spread from the ear to the brain, causing severe problems
Other serious infections, from tuberculosis to pneumonia to whooping cough, were caused by aggressive bacteria that reproduced with extraordinary speed and led to serious illness and sometimes death
Before antibiotics, cancer treatment and many routine surgeries would have caused serious infections leading to death
The current treatment for acute bacterial infection is antibiotics.
Antibiotic usage is dictated by a number of considerations:
Location of the infection. Because the antibiotic is only effective if it can target the bacteria at high enough concentrations, treatment is dictated by whether enough antibiotic can be delivered to the site of infection.
Type of bacteria. Choosing the wrong antibiotic means the bacteria will continue to grow. Bacteria are classified in a number of ways:
At the crudest level, they are classified as intracellular or extracellular. Generally extracellular bacteria are easier to kill while intracellular bacteria hide within cells where it is more difficult to deliver the antibiotics
Different bacteria also have different types of cell walls and are classified as being either “Gram-positive” or “Gram-negative”
There are also substrains of bacteria that have developed resistance to antibiotic treatment. This is a case of evolution in action. And different bacteria have come up with different solutions. Unfortunately they can also share these solutions with other bacteria, meaning that the problem of antibiotic resistance is an ever-spreading and ever-growing one
Side effects of the antibiotics. For instance, antibiotics which affect the good gut bacteria will increase the chances of other types of infection in future.
Our Approach: SGX943
The treatment of bacterial infection has to date involved trying to kill the bacteria or prevent their replication through the use of antibiotic. This is akin to the use of chemotherapy to kill tumor cells. However, as in cancer treatment, there are other potential approaches.
SGX943 represents a complementary approach to infection control. Instead of killing the bacteria directly, dusquetide modulates the innate immune response, increasing the immune response to both control the infection and dampen the inflammation.
The SGX943 approach has a number of advantages:
Because the bacteria aren’t directly targeted, bacteria are unlikely to gain resistance.
Because the bacteria aren’t directly targeted, it doesn’t matter if the bacteria are antibiotic resistant.
Because the bacteria aren’t directly targeted, it doesn’t matter where or how they infect. In a Phase 2 clinical trial, Dusquetide has been shown to defend against gram-positive, gram-negative, intracellular and extracellular bacteria.
Because the bacteria aren’t directly targeted, dusquetide can be used in combination with antibiotics.
Because dusquetide targets and modulates the innate immune system, dusquetide doesn’t need to be delivered directly to the site of infection.
SGX943 is a rapid 4-minute injection that may be administered upon suspicion of bacterial-origin infection, prior to any confirmatory testing, and may be given in combination with antibiotics. Treatment is continued every 2-3 days until resolution of infection.
What is SGX943?
SGX943 is an investigational, intravenous formulation of the Innate Defense Regulator, dusquetide, for the treatment of infectious disease.
What are Innate Defense Regulators?
Innate Defense Regulators (IDRs) are a new class of compound that change the response of the innate immune system by decreasing inflammation and increasing anti-infective and tissue healing activities.
IDRs are drugs that modulate the response of the innate immune system to any insult – including infection and tissue damage. Their main modes of action are to control inflammation while enhancing tissue healing and anti-infective action.
Dusquetide is the first IDR to be tested in the clinic.
What is Dusquetide?
Dusquetide is a drug composed of 5 amino acids, naturally occurring molecules which make up the proteins in your body. Therefore metabolism of dusquetide results in additional building blocks for your body and does not interfere with any other drugs you may be taking.
What is Innate Immunity?
The innate immune system is the pre-programmed response arm of the immune system. By two years of age, most people’s innate immune system is fully functional. In order to identify threats, the innate immune system looks for common “response patterns” or signals in different types of tissue damage and infections.
The innate immune system is your rapid response team to deal with immediate threats (infection, wounds, radiation damage, etc.).
How Innate Immunity Works
The innate immune system is characterized by many different “damage detectors” (receptors) that people are born with.
The damage detectors respond immediately (there is no need to wait for the immune system to ‘learn’ anything). This is a primary difference between innate immunity (immediate response) and adaptive immunity (learned response of T-cells and antibodies where the learning process can take days or weeks).
Triggering the damage detectors launches both inflammatory responses as well as tissue healing and anti-infective responses.
Regardless of the damage detectors activated, only a few proteins inside the cell are responsible for dictating the immediate response of the innate immune system.
Mechanism of Action
Unlike other attempts to modulate the innate immune response, IDRs like dusquetide are unique because they target the intracellular control nodes including the protein p62 of the innate immune system – changing the character of the innate immune response. They decrease or control the inflammatory component and increase the tissue healing or anti-infective component. The effect on the innate immune response is immediate (within 30 minutes) and long-lasting (up to 5 days).
Cellular Response to Dusquetide Treatment
Within the cells, dusquetide binds to the protein known as p62 or sequestosome-1. Binding to this protein changes the balance of activation between inflammatory and non-inflammatory pathways.
SGX943 contains the same active ingredient and formulation as SGX942.
We are currently conducting clinical research with SGX942 in oral mucositis in head and neck cancer patients. Oral mucositis is driven by dysfunction of the innate immune system and Innate Defense Regulators reset the innate immune response – mitigating the damaging inflammatory response caused by chemotherapy and radiation. The DOM-INNATE trial (Dusquetide treatment in Oral Mucositis – by modulating INNATE immunity) is a pivotal Phase 3 registration trial enrolling in the United States and Europe. With enrollment ongoing and an interim analysis planned for Q3 2019, we expect to complete enrollment of approximately 190 subjects this year.
The SGX943 program, including trials specific to the infectious disease indication, will be further developed in concert with Government funding. Because SGX942 and SGX943 share the same active ingredient and same formulation, many of the findings in the SGX942 Oral Mucositis program can be used to advance the SGX943 program.
Previous Clinical Studies with Dusquetide
Dusquetide has demonstrated safety in a Phase 1 clinical study in 84 healthy volunteers.
In a Phase 2, placebo-controlled, clinical study in 111 head and neck cancer patients, SGX942 (same active ingredient/formulation as SGX943) was safe, well tolerated, and effective in reducing the duration of severe oral mucositis. Of particular importance, dusquetide was also effective at reducing the rate of infection in these patients. The administration of dusquetide appeared to prevent infections and/or treat the infections before they could be diagnosed. This activity was completely in line with the nonclinical animal results.
Because dusquetide modulates the innate immune results to any insult, including tissue damage caused by chemotherapy and radiation, it is also expected to be effective in oral mucositis, a debilitating side effect of cancer chemotherapy. Dusquetide treatment in oral mucositis is the primary indication for dusquetide and is being pursued in our SGX942 program.
As an Innate Defense Regulator, dusquetide (the active ingredient in SGX942 and SGX943) may also play a role in cancer treatment and acute inflammatory conditions.
SGX943 has Fast Track designation for the treatment of melioidosis in the United States.
Soligenix has a strong worldwide intellectual property position on the composition of matter of dusquetide and related analogs and on therapeutic use in infectious disease, infectious disease in combination with antibiotic treatment and in oral mucositis, as well as other indications.
Our pipeline focuses on orphan and unmet medical need across a range of indications