RELEASE: RedHill Accelerates Opaganib Nuclear Radiation Protection Program - Positive Data Released (1)

Robust preclinical data, recently published in the International Journal of Molecular Sciences, from eight US government-funded in vivo studies with opaganib support the potential of opaganib as a therapeutic against nuclear radiation injury for medical countermeasures against the threat of materials for national security (MCM) and for antitumor radiotherapy.

RELEASE: RedHill Accelerates Opaganib Nuclear Radiation Protection Program - Positive Data Released (1)

Robust preclinical data, recently published in the International Journal of Molecular Sciences, from eight US government-funded in vivo studies with opaganib support the potential of opaganib as a therapeutic against nuclear radiation injury for medical countermeasures against the threat of materials for national security (MCM) and for antitumor radiotherapy

As a highly stable, small-molecule oral pill with a shelf life of more than five years, opaganib is easy to administer and distribute, allowing, if approved, its potential centralized storage by governments for possible use in nuclear radiation incidents with mass casualties.

Unlike currently approved options, such as iodine pills, it is believed that the suggested protective effect of opaganib in radiation injury is not limited to specific radioactive materials or individual parts of the body. Rather, opaganib's mechanism of action is thought to suppress ionizing radiation toxicity and inflammatory damage in normal tissue, and promote the robustness of hematopoietic stem cells to 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 increase tolerability and survival

External and independent in vivo studies on the radioprotective capacity of opaganib in bone marrow also show increased survival against lethal and semi-lethal whole-body irradiation

RedHill and its partner Apogee Biotechnology Corporation have recently initiated another study to evaluate the protective effects of opaganib against radiation-induced haematological and renal toxicity.

Based on the FDA guidance specific to opaganib, and subject to a recently scheduled follow-up meeting with the FDA, RedHill expects that the development of opaganib as a nuclear medical countermeasure for national security will follow the Animal Rule, under which studies of efficacy in central animal models are applicable when human clinical trials are not ethical or feasible; Discussions have begun with the US and other governments regarding additional support, funding, and the development pathway for approval.

Sponsors of approved Medical Countermeasures product applications are eligible for a Medical Countermeasures Priority Review Voucher

Opaganib development continues for COVID-19, other pandemic-preparedness antiviral indications, and oncology, strongly positioning opaganib as an important pipeline for multiple indications

TEL AVIV, Israel and RALEIGH, NC, Nov. 17, 2022 /PRNewswire/ -- RedHill Biopharma Ltd. (Nasdaq: RDHL) ("RedHill" or the "Company"), a specialty biopharmaceutical company, today announced the acceleration of opaganib development program for protection against radiation injury and cancer radiotherapy. A recent publication at the link describes the collective results of eight US government-funded in vivo studies conducted by RedHill and Apogee Biotechnology Corporation ("Apogee"), as well as additional experiments, establishing the potential protective capabilities of opaganib[1] against nuclear radiation [2].

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

"Subject to further alignment with the FDA, we intend to follow the Animal Rule path for opaganib approval, based on previous FDA guidance specific to opaganib for the intended indication. Development of medical countermeasures may continue. the Animal Rule, with core studies in animal models of efficacy applicable where human clinical trials are unethical or feasible, In addition, we intend to pursue an accelerated development schedule and eligibility for a priority medical countermeasure review voucher. In view of the growing awareness of the need for medical countermeasures to material threats and the positive observations observed in these in vivo studies of targeted radiation toxicity in the digestive tract and in cancer radiotherapy, together with external data indicating potential radioprotective capacity of opaganib in the bone marrow, we have accelerated our development plans llo to further test opaganib as a protective agent against nuclear radiation toxicity. We have recently initiated a new study to evaluate the protective effects of opaganib on radiation-induced haematological and renal toxicity, with our partner Apogee. Another meeting with the FDA is scheduled to seek further guidance on the path toward approval of national security medical countermeasures. Discussions have been initiated with multiple government agencies in the United States and internationally regarding funding and other government support," said Gilead Raday, Chief Operating Officer and Director of R&D at RedHill. "Importantly, opaganib has demonstrated Safety and tolerability profile in more than 470 people in studies in other indications, as well as in the use of expanded access. As a highly stable, small molecule oral tablet with a shelf life of more than five years, opaganib is easy to administer and distribute, favoring potential stockpiling by governments of central countermeasures."

Mitigation of radiation toxicity is an area of ​​government concern. One of the top priorities of the US government's research efforts is focused on finding drugs that are long-acting and easy to distribute and administer for possible inclusion in the Strategic National Stockpile. For use in mass casualty nuclear radiation incidents involving improvised nuclear or radiological dispersal devices, these drugs must have broad protective capabilities, be able to be administered 24 hours or more after radiation exposure, be safe, and be easy to distribute to a large number of people who need treatment for the acute effects of high-dose radiation exposure throughout the body.

Currently, to the company's knowledge, there are only four FDA-approved medical countermeasure therapies. 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 used to protect the thyroid from damage caused by the release of radioactive iodine. It works by preventing the thyroid from absorbing radioactive iodine, but it does not appear to offer any protection to the rest of the body from radiation and is of limited benefit if not given immediately after 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 plutonium, americium, and curium. radioactive, in the case of DTPA. The fourth option, filgrastim, is intended for acute radiation syndrome resulting from high doses of radiation. Filgrastim does not appear to protect the body against radiation itself and works by stimulating the creation of new white blood cells to protect the body from infection, something 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 due to inflammation secondary to the effects of the ionizing radiation itself, which is known as Acute Radiation Syndrome. Opaganib, a sphingosine kinase-2 (SK2) inhibitor, is thought to exert its protective effects through an anti-inflammatory mechanism of action involving elevation of ceramide and reduction of sphingosine 1-phosphate (S1P) in the human cells, suppressing inflammatory damage in normal tissue and thus the toxicity of unintentional 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.

US government-funded radiation toxicity protection studies with opaganib - summary of results:

Effect of opaganib on TBI (total body irradiation) lethality in C57BL/6 mice

Vehicle-treated mice exhibited pronounced symptoms indicative of severe gastrointestinal 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.

Opaganib accumulation and pharmacodynamics in the small intestine of mice

In vehicle-treated mice, TNFα expression in the small intestine was observed to be upregulated from 1 hour after total body irradiation (TBI) and remained highly elevated for at least 26 hours. In contrast, opaganib pretreatment was found not only to block TBI induction of TNFα, but also to reduce TNFα levels in tissues below baseline, indicating prolonged biodistribution of opaganib in the small intestine. at levels sufficient to inhibit SK2 and suppress radiation-induced inflammation.

Effects of opaganib on GI damage after TBI

Post-irradiation, decreased villous height (the villi are a critical component of the intestine's ability to absorb nutrients and indicative of intestinal health) was observed in vehicle-treated animals compared to non-irradiated controls. . In contrast, the villus height was maintained in the opaganib-treated mice. Furthermore, while there was evidence of cell depletion after 10 days in all groups, significantly more cells were present at 4 days post-irradiation in opaganib-treated mice compared to vehicle controls (p<0.001). and this difference between treatments was almost resolved by day 10.

Effect of opaganib on the lethality of partially shielded irradiation in C57BL/6 mice

In multiple scenarios, using partial bone marrow shielding, with different levels of irradiation, and with different dosing regimens, opaganib was shown to reduce mortality, with the greatest improvement seen when opaganib was given both before and after irradiation. reducing mortality from 82% to 4% (p<0.001) in mice given the highest dose of radiation, 16 Gray (Gy).

US government-funded cancer radiation therapy studies with opaganib - summary of results:

In vitro effects of opaganib on cellular radiosensitivity

Opaganib appeared to provide protection against IR-induced cell death, and observations showed that the level of radiation required to kill 50% and 90% of intestinal epithelial cells was increased by 5.56 and 12.16 Gy, respectively. , up to 6.46 and 13.2 Gy, respectively. In addition, opaganib was shown to increase the clearance of radiation-transformed pancreatic cancer cells, especially at the high dose of 15 Gy (p<0.05).

In vivo effects of the combination of opaganib with radiation on tumor growth (multiple cancer types):

Pancreatic cancer model: Treatment with TBI alone or with opaganib alone substantially reduced tumor growth (p<0.05 and p<0.001, respectively). Treatment with opaganib in combination with TBI was associated with a significant reduction in tumor growth compared to the control group or the TBI group alone (p<0.01 for each comparison), but was not significantly different from opaganib alone. due to the strong antitumor activity of the drug in this model. Importantly, opaganib treatment did not protect tumors from radiation therapy.

Melanoma and breast cancer model E0771: Opaganib plus TBI was shown to have antitumor activity equal to or better than TBI alone. Again, opaganib was not associated with decreased tumor response to fractionated radiation treatment, and no increased weight loss from radiation treatment was observed.

Head and neck cancer model: Treatment with opaganib alone was observed to slightly reduce tumor growth, whereas TBI cisplatin was observed to substantially reduce tumor growth compared to the control group (vehicle) (p<0.001 ). Opaganib treatment in combination with cisplatin TBI was associated with the greatest reduction in tumor growth, with that treatment group having significantly better observations than cisplatin TBI at day 21 and beyond (p<0.02). Again, opaganib was not associated with decreased tumor response or increased weight loss.

About Opaganib (ABC294640) Opaganib, a new chemical entity, is a first-in-class, orally administered, selective inhibitor of sphingosine kinase-2 (SK2) with anti-inflammatory, anticancer, radioprotective, and antiviral activity.

Opaganib is thought to work by inhibiting multiple pathways, inducing autophagy and apoptosis, and disrupting viral replication, through simultaneous inhibition of three sphingolipid-metabolizing enzymes in human cells (SK2, DES1, and GCS).

In an oncology and radiological setting, opaganib has been shown to elevate ceramide and reduce sphingosine 1-phosphate (S1P) in cells, conditions that increase the antitumor efficacy of radiation while suppressing inflammatory damage in normal tissue, leading to the potential to suppress the toxicity of unintentional ionizing radiation (IR) exposure and improve patient response to chemoradiation. Opaganib has received orphan drug designation from the US FDA for the treatment of cholangiocarcinoma and is being evaluated in a phase 2a study in advanced cholangiocarcinoma. Patient enrollment, treatment, and analysis in a prostate cancer study are ongoing. Opaganib has a Phase 1 chemoradiotherapy study protocol ready for IND submission.

Opaganib has demonstrated broad-acting, host-directed antiviral activity against SARS-CoV-2, its multiple variants, and several other viruses, including influenza A. Being host-directed, and based on cumulative data to date, To date, opaganib is expected to maintain its effect against emerging viral variants. In prespecified analyzes of phase 2/3 clinical data in hospitalized patients with moderate to severe COVID-19, oral opaganib demonstrated improved viral RNA clearance, faster time to recovery, and significantly reduced mortality in subpopulations number of patients versus placebo, in addition to standard treatment. Data from the global phase 2/3 study of opaganib have been peer-reviewed and recently published on medRxiv.

Opaganib has also shown positive preclinical results in renal fibrosis, and has the potential to target multiple oncologic, radiation protection, viral, inflammatory, and gastrointestinal indications.

About RedHill Biopharma RedHill Biopharma Ltd. (Nasdaq: RDHL) is a biopharmaceutical company specializing in gastrointestinal and infectious diseases. RedHill promotes the gastrointestinal medications Movantik® for opioid-induced constipation in adults[4], Talicia® for the treatment of Helicobacter pylori (H. pylori) infection in adults[5] and Aemcolo® for the treatment of diarrhea traveler in adults[6]. RedHill's major late-stage clinical development programs are (i) RHB-204, with an ongoing Phase 3 study for non-tuberculous mycobacterial (NTM) lung disease; (ii) opaganib (ABC294640), a first-in-class, host-targeted, broad-acting, selective SK2 inhibitor targeting multiple indications, including pandemic preparedness, with a Phase 2 program /3 for hospitalized COVID-19 and a Phase 2 program in oncology and an ongoing radiation protection program; (iii) RHB-107 (upamostat), a broad-acting, host-directed, oral serine protease inhibitor with potential for pandemic preparedness and is in phase 3 development as a treatment for non-symptomatic COVID-19 hospitalized, and directed to multiple other cancers and inflammatory gastrointestinal diseases; (iv) RHB-104, with positive results from a first phase 3 study for Crohn's disease; and (v) RHB-102, with positive Phase 3 study results for acute gastroenteritis and gastritis and positive Phase 2 study results for IBS-D. Learn more about the company at www.redhillbio.com/twitter.com/RedHillBio.

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Contact: Adi Frish Director of Business and Corporate Development RedHill Biopharma 972-54-6543-112 adi@redhillbio.com

Category: I D

[1] Opaganib is an investigational new drug, not available for commercial distribution. [2] Maines LW, Schrecengost RS, Zhuang Y, Keller SN, Smith RA, Green CL, Smith CD. Opaganib Protects against Radiation Toxicity: Implications for Homeland Security and Antitumor Radiotherapy. International Journal of Molecular Sciences. 2022; 23(21):13191. https://doi.org/10.3390/ijms232113191.[3] Li C. et al., Loss of Sphingosine Kinase 2 Promotes the Expansion of Hematopoietic Stem Cells by Improving Their Metabolic Fitness. Blood. Oct 2022;140(15):1686-1701.[4] Movantik® (naloxegol) is indicated for opioid-induced constipation (OIC). Full prescribing information at: www.movantik.com[5] Talicia® (omeprazole magnesium, amoxicillin, and rifabutin) is indicated for the treatment of H. pylori infection in adults. For full prescribing information, see: www.Talicia.com.[6] Aemcolo® (rifamycin) is indicated for the treatment of traveler's diarrhea caused by non-invasive strains of Escherichia coli in adults. For full prescribing information, see: www.aemcolo.com.

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