Medical Scientist researching blood samples

OrbeShield® for Acute Radiation Syndrome

Disease Area

GI Acute Radiation Syndrome

Proof-of-ConceptINDPhase 1Phase 2/3Market
Proof-of-Concept
IND
Phase 1
Phase 2/3
Market

Orphan and/or Fast Track Designation

Denotes funding in whole or in part by NIH, BARDA and/or FDA.

Addressing Mass Casualty Events

Acute radiation syndrome, as a result of an accidental or planned nuclear incident, has the potential to impact a large proportion of the population, causing widespread mortality as well as significant long term injury. Lower radiation dose levels, which cause damage to the red and white blood cells of the body, can be mitigated. Higher radiation dose levels, which cause damage to the gastrointestinal tract as well, are more lethal and have no available treatment options. OrbeShield® is an oral, topical anti-inflammatory steroid for the treatment of the gut, which may address both the short-term exacerbation of damage caused by the inflammatory response as well as aiding in re-establishing the normal repair process in the gut over the longer term.  

Background on Acute Radiation Syndrome

A nuclear disaster, whether deliberate or accidental, has the potential to cause mass casualties. Acute Radiation Syndrome (ARS) occurs when there is substantial exposure to a high dose of radiation over a short period of time. Increasing doses of radiation are associated with both increasing organ damage and earlier and higher mortality levels.  

ARS is usually divided into four subcategories:

  • Hematopoietic ARS (H ARS) occurs from damage to the blood cells resulting in loss of immune fighting cells, red blood cells (causing anemia) and consequently severe infections can take hold. Symptoms are seen with exposure as low as 0.3 Gy. Exposure to 2.5 Gy radiation is expected to result in approximately 50% mortality within months without additional hematopoietic directed treatment.
  • Gastrointestinal ARS (GI ARS) occurs at higher dose levels. In addition to the hematopoietic damage, there is also damage to the cells lining the mouth, stomach and intestines, which results in dehydration and additional infection. Symptoms are seen with exposure as low as 6 Gy. Exposure to 10 Gy radiation is expected to result in 100% mortality within 2 weeks.
  • Cardiovascular / Central nervous system ARS (CNS ARS) occurs at even higher radiation exposure. Damage to the cells of the central nervous and cardiovascular systems  happens in parallel with the hematopoietic and gastrointestinal damage at these very high radiation levels. Symptoms are seen with exposure as low as 20 Gy. Exposure to >50 Gy radiation is expected to result in 100% mortality within 3 days.
  • Delayed effects of acute radiation exposure (DEARE) occurs with exposure across the radiation dose range and is caused by incorrect body repair processes yielding long term injury.

Exposure to high radiation dose levels are expected to decrease rapidly as distance from the epicenter of the nuclear incident is achieved. This means that more people will be exposed to H ARS than GI ARS and more people exposed to GI ARS than CNS ARS.

While in all cases of radiation damage, the initial damage is caused by cell death, often subsequent damage is caused by the repair processes of the body which are driven by inflammation and may be “over driven” by these inflammatory processes. As the hematopoietic system recovers, this “overdrive” scenario may become worse.

Current Treatments

Currently there is an approved therapeutic for H ARS but no treatments for GI ARS or CNS ARS related damage.

Filgrastim is approved for use in a mass casualty event to support the re-induction of hematopoietic immune cells which are damaged in the initial radiation exposure. This also reduces the infection rate, which then reduces the mortality rate. However, there is no impact on damage to the gastrointestinal or CNS systems.

There are NO FDA- approved treatments for GI ARS or for damage to the CNS.

Treatments for GI ARS may substantially improve both survival and long term damage from nuclear mass casualty events. GI ARS is expected to occur in a large proportion of the population in a nuclear mass casualty event, making treatments for GI ARS a clear unmet medical need.

Our Approach: OrbeShield®

OrbeShield® is a topical anti-inflammatory treatment for the stomach and intestines. OrbeShield® is the same formulation as SGX203 for Pediatric Crohn’s Disease. The active ingredient is beclomethasone 17,21-dipropionate (BDP).

BDP is a steroid which can reduce local inflammation but has limited ability to penetrate the body.

By providing a formulation of BDP which coats the inside of the gut with steroid, but isn’t absorbed into the bloodstream, the systemic side effects of steroid treatment (including increased risk of infection) are reduced.

OrbeShield® may mitigate the “inflammatory overdrive” occurring in GI ARS, allowing the recovering intestinal cells to structure themselves correctly with reduced long term side effects.

How is OrbeShield® delivered?

OrbeShield® is a combination of two pills, both containing the active ingredient BDP.  One of the pills is designed to dissolve in the stomach, releasing BDP to coat the upper gastrointestinal tract. The other pill is designed to dissolve in the intestine, coating the bottom half of the gastrointestinal tract.

Crohn's disease video image

As an oral drug with good room temperature stability, OrbeShield® can be delivered rapidly and easily in a mass casualty context.

What is known about BDP?

Beclomethasone dipropionate (BDP) is a very well-known steroid that has been used in inhaled products for asthma, in nasal sprays for rhinitis and in skin creams for rashes. It has been used in children and adults for over 40 years. There is a lot of information known about the safety and efficacy of BDP.

Mechanism of Action

As with all corticosteroids, BDP binds to the corticosteroid receptor and has anti-inflammatory action, suppressing the infiltration of inflammatory cells to the local site of action.

The distinguishing feature of BDP is that it does not travel throughout the body easily, meaning that it has a local action without inducing as many side effects throughout the body. This also means that the BDP must be delivered directly to where it is needed – which is reflected in the unique oral formulation that is used in OrbeShield®.

In the context of radiation damage, systemic steroid use would be dangerous as it would also suppress the activity of the immune system (which is also trying to recover). However, topical application of steroids to the GI tract may both stop ongoing inflammatory damage (which may be increasing cell death in addition to the initial radiation damage) and can stop the longer term process of fibrosis (which may yield long term irreversible damage to the intestines in any survivors).  

More details on the mechanism of action of OrbeShield® can be found in our Reference Literature.

Clinical Studies & Commercialization

Clinical studies with the OrbeShield® product candidate are being pursued in the context of our SGX203 program for Pediatric Crohn’s Disease. Pending government funding, we plan to continue development under the FDA Animal Rule, including conducting a pivotal animal efficacy study.

Commercialization of the OrbeShield® product candidate will be in concert with US government stockpiling requirements.

Previous Nonclinical Studies with OrbeShield®

Previous nonclinical studies with OrbeShield® have demonstrated delayed mortality in mini-pigs after total body irradiation mimicking a mass casualty event. Related studies in other animals have also suggested a significant reduction in long term fibrosis of the GI tract with OrbeShield® treatment.

Previous Clinical Studies with OrbeShield®

The safety and efficacy of OrbeShield® was assessed in a Phase 1 study in 24 male and female healthy adolescents and young adults. It was found to be safe, to have no effect on bone metabolism (a common problem with systemic steroids) and to have limited systemic availability.

OrbeShield® has also been investigated previously in approximately 300 adults with Graft versus Host disease, so significant safety information with this formulation has been collected.

Other Potential Uses for OrbeShield®

A topical oral anti-inflammatory with action limited to the gastrointestinal tract may be useful in a number of other inflammatory conditions, including inflammatory conditions of the intestines.

Pediatric Crohn’s Disease

The OrbeShield® formulation is also being explored in the context of Pediatric Crohn’s Disease, an inflammatory bowel disease which in children involves all parts of the intestine.

Radiation Enteritis (SGX201)

Inflammation of the gut after radiation therapy is also a common occurrence in the context of cancer treatment. In particular, radiation enteritis is a known side-effect of cancer treatment of bladder, uterus, cervix, rectum, prostate and vagina and in all cases, anti-inflammatory treatment of the gut lining may reduce the damage to the gut.

Symptoms of acute radiation enteritis include nausea, vomiting, abdominal pain and rectal bleeding. While the symptoms of most patients may fade a few weeks or months after radiation treatment, 20% of patients may go on to develop chronic radiation enteritis. There are over 100,000 patients annually in the US receiving abdominal or pelvic radiation treatment for cancer who are at risk of developing acute and chronic radiation enteritis. SGX201 consists of the delayed release tablet containing BDP, specifically targeting the lower gastrointestinal tract.

Regulatory Status

OrbeShield® has been granted Orphan Drug designation for the prevention of death following a potentially lethal dose of total body irradiation (TBI) during or after a radiation disaster by the US FDA.

OrbeShield® has been granted Fast Track designation for the reduction of mortality associated with GI ARS by the US FDA.

Development of OrbeShield® for Acute Radiation Syndrome requires the use of the Animal Rule.

What is the Animal Rule?

Because acute radiation exposure is an unpredictable event and because exposing humans to radiation is unethical, approval of a GI ARS therapeutic will utilize the FDA “Animal Rule” (21 CFR 601.90 through 601.95).

The Animal Rule represents a different regulatory pathway from normal clinical development. Whereas normal clinical development depends on clinical trials – including safety (Phase 1), proof of concept efficacy and safety (Phase 2) and definitive efficacy and safety (Phase 3) trials, the Animal Rule instead utilizes a combination of human and animal testing. There are 3 key components to using the Animal Rule:

  1. Safety is demonstrated in humans (Phase 1 and Phase 2 studies)
  2. Efficacy is demonstrated in animals in pivotal animal studies (replacing the traditional Phase 3 studies)
  3. Both the response to disease and the response to treatment must be demonstrated to be similar between the animal models and humans.

This additional requirement for increased agreement between animal and human disease and treatment response is unique to the Animal Rule.

Intellectual Property

Soligenix has a strong worldwide intellectual property position on the proprietary formulation of BDP as an oral topical treatment for the gastrointestinal tract in Acute Radiation Syndrome and related inflammatory conditions of the gut.

In addition, orphan drug designation gives 7 years of marketing exclusivity for OrbeShield® in the US, if approved.

Our pipeline focuses on orphan and unmet medical need across a range of indications