Strong preclinical data, recently published in the International Journal of Molecular Sciences, from eight U.S government-funded in-vivo opaganib studies, supports opaganib’s potential as a nuclear radiation injury therapeutic for homeland security material threat medical countermeasures (MCM) and for antitumor radiotherapy

As an oral, small molecule pill that is highly stable with a more than five-year shelf-life, opaganib is easy to administer and distribute, supporting, if approved, potential central stockpiling by governments for possible use in mass casualty nuclear radiation incidents

Unlike current approved options such as iodine pills, opaganib’s suggested protective effect in radiation injury is not thought to be limited to specific radioactive materials or individual parts of the body. Rather, opaganib’s mechanism of action is believed to suppress ionizing radiation toxicity and inflammatory damage to normal tissue, and promote the robustness of hematopoietic stem cells from radiation damage, potentially supporting increased survival and decreased morbidity

Observations from multiple GI-focused in-vivo models indicate that opaganib may protect normal tissue from damage due to ionizing radiation exposure or cancer radiotherapy, improve antitumor activity and response to chemoradiation and enhance tolerability and survival

Independent external in-vivo studies of the radioprotective capacity of opaganib in bone marrow also show enhanced survival against both lethal and half-lethal whole-body irradiation

Another study has been initiated recently, by RedHill and its partner Apogee Biotechnology Corporation, to assess protective effects of opaganib against radiation-induced hematologic and renal toxicity

Based on FDA guidance specific to opaganib, and subject to a recently scheduled follow-on meeting with FDA, RedHill expects development of opaganib as a homeland security nuclear medical countermeasure to follow the Animal Rule, under which pivotal animal model efficacy studies are applicable when human clinical trials are not ethical or feasible; Discussions regarding further support, funding and development pathway to approval have been initiated with US and other governments

Sponsors of approved medical countermeasures product applications are eligible for a medical countermeasure Priority Review Voucher

Opaganib’s development continues for COVID-19, other pandemic preparedness antiviral indications and oncology, strongly positioning opaganib as a major pipeline-in-a-product intended for multiple indications

TEL AVIV, Israel and RALEIGH, NC, Nov. 14, 2022 /PRNewswire/ — RedHill Biopharma Ltd. (Nasdaq: RDHL) (“RedHill” or the “Company”), a specialty biopharmaceutical company, today announced acceleration of opaganib’s development program for protection against radiation injury and cancer radiotherapy. A recent publication in the International Journal of Molecular Sciences, entitled “Opaganib Protects against Radiation Toxicity: Implications for Homeland Security and Antitumor Radiotherapy”, describes the collective results of eight U.S. government-funded in vivo studies by RedHill and Apogee Biotechnology Corporation (“Apogee”), as well as additional experiments, establishing opaganib’s[1] potential nuclear radiation protection capabilities[2].

The publication highlights observations from numerous studies undertaken in both protection against radiation toxicity and cancer radiotherapy settings. In the relevant study models, opaganib was associated with protection of normal tissue, including gastrointestinal, from radiation damage due to ionizing radiation exposure or cancer radiotherapy, as well as improvement of antitumor activity, response to chemoradiation, and enhancement of tolerability and survival. Additional independent studies demonstrate the radioprotective capacity of opaganib in bone marrow, with opaganib showing enhanced survival in mice which were irradiated with both lethal and half-lethal whole-body radiation[3].

“Subject to further alignment with FDA, we intend to follow the Animal Rule path to approval for opaganib, based on prior FDA guidance specific to opaganib for the intended indication. Development for medical countermeasures may follow the Animal Rule, with pivotal animal model studies of efficacy applicable when human clinical trials are not ethical or feasible. In addition, we intend to seek an expedited development timeframe and eligibility for a Medical Counter Measure Priority Review Voucher. Amid the growing awareness of the need for material threat medical countermeasures and the positive observations seen in these in vivo gastrointestinal focused radiation toxicity and cancer radiotherapy studies, along with external data indicating potential radioprotective capacity of opaganib in bone marrow, we have accelerated our development plans to further test opaganib as a protective agent against nuclear radiation toxicity. We have recently initiated a new study to assess protective effects of opaganib on radiation-induced hematologic and renal toxicity, with our partner Apogee. Another meeting with the FDA is scheduled to seek further guidance on the path to homeland security medical countermeasure approval. Discussions with multiple government agencies in the U.S. and internationally, regarding funding and other governmental support, have been initiated,” said Gilead Raday, Chief Operating Officer and Head of R&D at RedHill. “Importantly, opaganib has demonstrated its safety and tolerability profile in more than 470 people in studies in other indications as well as expanded access use. As an oral, small molecule pill that is highly stable with a greater than five-year shelf-life, opaganib is easy to administer and distribute, supporting potential central countermeasures stockpiling by governments.”

Mitigation of radiation toxicity is an area of governmental concern. A key priority for US government research efforts is focused on finding long shelf-life and easy to distribute and administer drugs for potential inclusion in the Strategic National Stockpile. Such drugs, to be used in mass casualty nuclear radiation incidents involving improvised nuclear or radiological dispersal devices, should have broad-acting protective capability, be able to be administered 24 hours or later after radiation exposure, be safe and be easy to distribute to large numbers of people needing treatment for the acute effects of high dose, whole-body radiation exposure.

Currently, to the best of the Company’s knowledge, only four FDA-approved medical countermeasure therapies are available. Three of these options are limited to effects caused by a small number of specific radioactive materials or to specific parts of the body. Potassium iodide (iodine pills) is intended to be used to protect against thyroid damage from the release of radioiodine. It works by preventing the thyroid from taking up radioactive iodine but seems to offer no protection to the rest of the body from irradiation and is of limited benefit unless given immediately upon exposure. The other two, Prussian Blue and DTPA (diethylenetriamine pentaacetate) provide protection by limiting the half-life in the body of specific materials: radioactive cesium and thallium, in the case of Prussian Blue, and radioactive plutonium, americium, and curium, in the case of DTPA. The fourth option, filgrastim, is intended for acute radiation syndrome resulting from high-dose radiation. Filgrastim does not seem to protect the body against the radiation itself and works by stimulating the creation of new white blood cells to protect the body from infections, which the body can no longer do in the presence of radiation-induced bone marrow destruction – as long as there are viable stem cells to stimulate.

We believe that opaganib’s protection would not be limited to specific radioactive materials or individual parts of the body. Much of the damage caused by radiation exposure is caused by inflammation secondary to the effects of ionizing radiation itself – known as Acute Radiation Syndrome. Opaganib, a sphingosine kinase-2 (SK2) inhibitor, is thought to exert its protective effects via an anti-inflammatory mechanism of action involving ceramide elevation and reduction of sphingosine 1-phosphate (S1P) in human cells – suppressing inflammatory damage to normal tissue and thus suppressing toxicity from unintended ionizing radiation exposure. It has also been reported in the literature that inhibition of sphingosine kinase 2 promotes the viability and robustness of hematopoietic stem cells, even in the face of radiation damage, supporting increased survival.

Protection against radiation toxicity studies with opaganib funded by U.S. government – summary of results:

Effect of opaganib on the lethality of TBI (Total Body Irradiation) in C57BL/6 mice

Vehicle-treated mice had pronounced symptoms indicative of severe GI damage, and all animals had to be euthanized within 14 days of radiation exposure. In contrast, protection was observed in the opaganib-treated group, in which 71% of the mice survived indefinitely.

Accumulation and pharmacodynamics of opaganib in mouse small intestine

In vehicle-treated mice, TNFα expression in the small intestines was observed to be up-regulated as early as 1 hour after Total Body Irradiation (TBI) and remained highly elevated for at least 26 hours. In contrast, pretreatment with opaganib was observed to not only block the induction of TNFα by TBI but also to reduce tissue TNFα levels below the baseline level indicating prolonged biodistribution of opaganib into the small intestine at sufficient levels to inhibit SK2 and suppress radiation-induced inflammation.

Effects of opaganib on GI damage following TBI

Post-radiation decreases in villus height (villi are a critical component of the intestines ability to absorb nutrients and indicative of intestinal health) were observed in the vehicle-treated animals compared with non-irradiated controls. In contrast, villus height was maintained in the opaganib-treated mice. Additionally, while there was evidence of cell depletion after 10 days in all groups, there were significantly more cells present at 4 days after irradiation in the opaganib-treated mice compared to vehicle controls (p

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