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

RedHill Biopharma Ltd. [https://www.redhillbio.com/RedHill/ ] (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" [https://www.mdpi.com/1422-0067/23/21/13191/htm ], 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<0.001) 
with this difference between treatments nearly resolving by Day 10.

Effect of opaganib on the lethality of partially shielded irradiation in 
C57BL/6 mice
In multiple scenarios, utilizing partial bone marrow shielding, involving 
different levels of irradiation and with different dosing regimens, opaganib 
was observed to reduce mortality, with the greatest improvement seen when 
opaganib was given both before and after irradiation, reducing mortality from 
82% down to 4% (p<0.001) in the mice given the highest dose of radiation, 16 
Gray (Gy).

Cancer radiotherapy studies with opaganib funded by U.S. government – summary 
of results:
In vitro effects of opaganib on cell radiosensitivity

Opaganib appeared to provide protection from IR-induced cell death, with 
observations showing the level of radiation need to kill 50% and 90% of 
intestinal epithelial cells increasing from 5.56 and 12.16 Gy respectively up 
to 6.46 and 13.2 Gy, respectively. Furthermore, opaganib was observed to 
increase the killing of transformed pancreatic cancer cells by radiation, 
particularly at the high dose of 15 Gy (p<0.05).

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

Pancreatic cancer model: Treatment with either TBI alone or opaganib alone 
substantially reduced tumor growth (p<0.05 and p<0.001, respectively). 
Treatment with opaganib in combination with TBI was associated with 
significantly reduced tumor growth compared to the control group or to the TBI 
alone group (p<0.01 for each comparison) but was not significantly different 
from opaganib alone because of the strong antitumor activity of the drug in 
this model. Importantly, treatment with opaganib did not protect tumors from 
radiation treatment.
Melanoma and E0771 breast cancer model: Opaganib plus TBI was observed to have 
equal or better antitumor activity than TBI alone. Again, opaganib was not 
associated with a diminished tumor response to fractionated radiation treatment 
and increased weight loss from radiation treatment was not observed.

Head & neck cancer model: Treatment with opaganib alone was observed to 
slightly reduce tumor growth, while TBI + cisplatin was observed to 
substantially reduce tumor growth as compared to the control (vehicle) group 
(p<0.001). Treatment with opaganib in combination with TBI + cisplatin was 
associated with the greatest reduction in tumor growth and such treatment group 
had significantly better observations than TBI + cisplatin on Day 21 and after 
(p<0.02). Again, opaganib was not associated with diminished tumor response or 
increased weight loss.

About Opaganib (ABC294640) 

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

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

In an oncology & radiological setting, opaganib has been observed to elevate 
ceramide and reduces sphingosine 1-phosphate (S1P) in cells, conditions that 
increase the antitumor efficacy of radiation while concomitantly suppressing 
inflammatory damage to normal tissue, leading to the potential to suppress 
toxicity from unintended ionizing radiation (IR) exposure and improve patient 
response to chemoradiation. Opaganib has received Orphan Drug designation from 
the U.S. FDA for the treatment of cholangiocarcinoma and is being evaluated in 
a Phase 2a study in advanced cholangiocarcinoma. Patient accrual, treatment and 
analysis in a prostate cancer study is 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, multiple variants, and several other viruses, such as 
Influenza A. Being host-targeted, and based on data accumulated to date, 
opaganib is expected to maintain effect against emerging viral variants. In 
prespecified analyses 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 significant mortality reduction in key 
patient subpopulations versus placebo on top of standard of care. Data from the 
opaganib global Phase 2/3 study has been submitted for peer review and recently 
published in medRxiv 
[https://www.medrxiv.org/content/10.1101/2022.06.12.22276088v1 ].

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

About RedHill Biopharma

RedHill Biopharma Ltd. (Nasdaq: RDHL) is a specialty biopharmaceutical company 
primarily focused on gastrointestinal and infectious diseases. RedHill promotes 
the gastrointestinal drugs, 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 travelers' diarrhea 
in adults[6]. RedHill's key clinical late-stage development programs include: 
(i) RHB-204, with an ongoing Phase 3 study for pulmonary nontuberculous 
mycobacteria (NTM) disease; (ii) opaganib (ABC294640), a first-in-class oral 
broad-acting, host-directed, SK2 selective inhibitor targeting multiple 
indications, including for pandemic preparedness, with a Phase 2/3 program for 
hospitalized COVID-19 and a Phase 2 program in oncology and a radiation 
protection program ongoing; (iii) RHB-107 (upamostat), an oral broad-acting, 
host-directed serine protease inhibitor with potential for pandemic 
preparedness and is in Phase 3-stage development as treatment for 
non-hospitalized symptomatic COVID-19, and targeting multiple other cancer 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 
results from a Phase 3 study for acute gastroenteritis and gastritis and 
positive results from a Phase 2 study for IBS-D. More information about the 
Company is available at www.redhillbio.com/ twitter.com/RedHillBio.

This press release contains "forward-looking statements" within the meaning of 
the Private Securities Litigation Reform Act of 1995. Such statements may be 
preceded by the words "intends," "may," "will," "plans," "expects," 
"anticipates," "projects," "predicts," "estimates," "aims," "believes," 
"hopes," "potential" or similar words. Forward-looking statements are based on 
certain assumptions and are subject to various known and unknown risks and 
uncertainties, many of which are beyond the Company's control and cannot be 
predicted or quantified, and consequently, actual results may differ materially 
from those expressed or implied by such forward-looking statements. Such risks 
and uncertainties include the risk that opaganib will not be shown to elevate 
ceramide and reduce sphingosine 1-phosphate (S1P) in cells, increasing the 
antitumor efficacy of radiation while concomitantly suppressing inflammatory 
damage to normal tissue, leading to the potential to suppress toxicity from 
unintended ionizing radiation (IR) exposure and improve patient response to 
chemoradiation in an oncology & radiological setting, the risk that the FDA 
does not agree with the Company's proposed development plans for opaganib for 
any indication, the risk that observations from preclinical studies are not 
indicative or predictive of results in clinical trials, the risk that opaganib 
will not be shown to be broad acting, host-directed candidate therapies for 
pandemic preparedness, the risk that a pivotal Phase 3 trial for opaganib will 
not be initiated or that such trial be successful and, even if successful, such 
study and results may not be sufficient for regulatory applications, including 
emergency use or marketing applications, and that additional COVID-19 studies 
for opaganib are required by regulatory authorities to support such potential 
applications and the use or marketing of opaganib for COVID-19 patients, that 
opaganib will not be effective against emerging viral variants, as well as 
risks and uncertainties associated with (i) the initiation, timing, progress 
and results of the Company's research, manufacturing, preclinical studies, 
clinical trials, and other therapeutic candidate development efforts, and the 
timing of the commercial launch of its commercial products and ones it may 
acquire or develop in the future; (ii) the Company's ability to advance its 
therapeutic candidates into clinical trials or to successfully complete its 
preclinical studies or clinical trials (iii) the extent and number and type of 
additional studies that the Company may be required to conduct and the 
Company's receipt of regulatory approvals for its therapeutic candidates, and 
the timing of other regulatory filings, approvals and feedback; (iv) the 
manufacturing, clinical development, commercialization, and market acceptance 
of the Company's therapeutic candidates and Talicia®; (v) the Company's ability 
to successfully commercialize and promote Movantik®, Talicia® and Aemcolo®; 
(vi) the Company's ability to establish and maintain corporate collaborations; 
(vii) the Company's ability to acquire products approved for marketing in the 
U.S. that achieve commercial success and build and sustain its own marketing 
and commercialization capabilities; (viii) the interpretation of the properties 
and characteristics of the Company's therapeutic candidates and the results 
obtained with its therapeutic candidates in research, preclinical studies or 
clinical trials; (ix) the implementation of the Company's business model, 
strategic plans for its business and therapeutic candidates; (x) the scope of 
protection the Company is able to establish and maintain for intellectual 
property rights covering its therapeutic candidates and commercial products and 
its ability to operate its business without infringing the intellectual 
property rights of others; (xi) parties from whom the Company licenses its 
intellectual property defaulting in their obligations to the Company; (xii) 
estimates of the Company's expenses, future revenues, capital requirements and 
needs for additional financing; (xiii) the effect of patients suffering adverse 
events using investigative drugs under the Company's Expanded Access Program; 
and (xiv) competition from other companies and technologies within the 
Company's industry. More detailed information about the Company and the risk 
factors that may affect the realization of forward-looking statements is set 
forth in the Company's filings with the Securities and Exchange Commission 
(SEC), including the Company's Annual Report on Form 20-F filed with the SEC on 
March 17, 2022, and the Company's Report on Form 6-K filed with the SEC on 
November 10, 2022. All forward-looking statements included in this press 
release are made only as of the date of this press release. The Company assumes 
no obligation to update any written or oral forward-looking statement, whether 
as a result of new information, future events or otherwise unless required by 
law.

Company contact:

Adi Frish
Chief Corporate & Business Development Officer
RedHill Biopharma
+972-54-6543-112
adi@redhillbio.com

Category: R&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. October 
2022;140(15):1686-1701.
[4] Movantik® (naloxegol) is indicated for opioid-induced constipation (OIC). 
Full prescribing information see: 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 travelers' diarrhea 
caused by noninvasive strains of Escherichia coli in adults. For full 
prescribing information see: www.aemcolo.com.

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SOURCE: RedHill Biopharma Ltd