RedHill accelerates Opaganib nuclear radiation protection

Specialty biopharmaceuticals company RedHill Biopharma Ltd.
(NASDAQ: RDHL) ("RedHill" or the "Company") today announced the acceleration of Opaganib's radiation injury protection and cancer radiation therapy development programs
。 The International Journal of Molecular Sciences recently published an article titled "Opaganib Protects against Radiation Toxicity: Implications for Homeland Security and Antitumor Radiotherapy," which describes U.
S.
government-funded The aggregate results of eight in vivo studies conducted by RedHill and Apogee Biotechnology Corporation ("Apogee"), as well as other experiments, determined the radiation protection potential of Opaganib [^{1] [2].}

This article highlights observations from numerous studies conducted in radiation toxicity protection and radiation therapy settings for cancer
.
In relevant research models, Opaganib was associated with normal tissue protection, including gastrointestinal tract, such as radiation damage due to ionizing radiation or radiation therapy to cancer, improvement in antitumor activity, coping with radiotherapy, and enhanced tolerability and survival
.
Other independent studies have shown the radiation protection ability of Opaganib in bone marrow, and Opaganib has shown higher survival rates in mice exposed to lethal and semi-lethal systemic radiation ^[3].

"To further cooperate with FDA, we plan to follow the path of the Law of Animal Efficacy to obtain Opaganib approval
, based on FDA's previous specific guidance for the intended indication of Opaganib.
" The development of medical countermeasures can follow the Law of Animal Efficacy, which states that key animal models can be used to study
the efficacy of key animal models when human clinical trials are unethical or unfeasible.
In addition, we plan to seek a faster development timeline and qualification
for the Medical Countermeasure Priority Review Voucher.
As the growing recognition of the need for medical countermeasures against material threats and the positive observations seen in these studies of radiation toxicity and cancer radiation therapy in the gastrointestinal tract in the body, coupled with external data indicating Opaganib's potential radiation protection in bone marrow, we accelerated our development program to further test
Opaganib as a protective agent against nuclear radiation toxicity.
We recently conducted a new study with our partner Apogee to evaluate the protective effect
of Opaganib against radiation-induced blood and kidney toxicity.
We have scheduled another meeting with the FDA to seek further guidance
on the path to approval for Homeland Security medical countermeasures.
We have begun discussions
with various government agencies in the United States and internationally regarding funding and other government support.
said Gilead Raday, Chief Operating Officer and Head of Research and Development at RedHill
.
Importantly, Opaganib has demonstrated its safety and tolerability
in more than 470 subjects in studies of other indications and expanded use.
Opaganib is a highly stable oral small molecule tablet with a shelf life of over 5 years, easy to take and distribute, and supports the government's potential central countermeasure stockpile
.
"

Reducing radiation toxicity is an area
of concern for governments.
A key focus of the U.
S.
government's research efforts is to find drugs with long shelf life that are easy to distribute and take in order to be included in the national strategic reserve
.
Such drugs will be used in mass casualty nuclear radiation incidents involving improvised nuclear proliferation or radiodiffusion devices, should have a broad protective capacity, be able to be taken 24 hours or later after radiation, and be easily and safely distributed to large numbers of people
who require treatment for the acute consequences of high doses of systemic radiation.

Currently, to the company's knowledge, only four FDA-approved medical countermeasure therapies are available
.
Three of these options are limited to a few specific radioactive substances or specific parts of
the body.
Potassium iodide (iodine tablets) is designed to prevent the release of radioactive iodine from causing damage
to the thyroid gland.
It works by preventing the thyroid gland from absorbing radioactive iodine, but it does not appear to protect the rest of the body from radiation and needs to be taken immediately after exposure or it has limited
effectiveness.
The other two, Prussian Blue and DTPA (diethylenetriamine pentaacetate), provide protection by limiting the half-life of specific materials in the body: Prussian Blue is for the treatment of radioactive cesium and thallium, and in DTPA is for the treatment of radioactive plutonium, americium and curium
.
The fourth option is filgrastim and is intended for acute radiation syndrome
caused by high doses of radiation.
Filgrastim does not appear to protect the body from radiation by itself, but rather protects the body from infection by stimulating the production of new white blood cells (as long as there are living stem cells that can be stimulated), which the body cannot do in the case of
radiation-induced bone marrow destruction.

We believe that Opaganib's protection is not limited to certain radioactive substances or individual parts of the body
.
Most of the damage caused by radiation is caused by secondary inflammation produced by ionizing radiation itself, which is called acute radiation syndrome
.
Opaganib is a sphingoglycine kinase-2 (SK2) inhibitor that is thought to exert its protective effects through an anti-inflammatory mechanism, including inhibition of inflammatory damage to normal tissues by inhibiting accidental ionizing radiation exposure toxicity by involving elevated ceramides and reducing the effects of sphingoglycin 1-phosphate (S1P) in human cells
.
It has also been reported in the literature that inhibition of sphingosine kinase 2 can promote the activity and robustness of hematopoietic stem cells, improving survival even in the face of radiation damage
.

U.
S.
Government Funded Opaganib Radiation Protection Study - Summary of Results:

Efficacy of Opaganib on the lethality of TBI (total body irradiation) in C57BL/6 mice

Excipients-treated mice developed severe gastrointestinal impairment and all animals had to be
euthanized within 14 days of exposure.
In contrast, protective effects were observed in the Opaganib-treated group, where 71 percent of mice survived
indefinitely.

Accumulation and pharmacodynamics of Opaganib in mouse small intestine

In excipient-treated mice, up-regulation of TNFα expression in the small intestine was observed as early as 1 h after total body irradiation (TBI) and remained high for
at least 26 hours.
In contrast, pretreatment with Opaganib not only blocked the induction of TNFα by TBI, but also reduced tissue TNFα levels below baseline levels, suggesting that the biodistribution of Opaganib into the small intestine was extended enough to inhibit SK2 and inhibit
radiation-induced inflammation.

Efficacy of Opaganib on gastrointestinal injury after TBI

A decrease in villi height after radiation was observed in excipient-treated animals compared to non-radiated control (villi are a key component of the gut's ability to absorb nutrients and a marker of gut health).

In contrast, the villi height of Opaganib-treated mice remained constant
.
Furthermore, while all groups had evidence of cell depletion after 10 days, the number of cells in Opaganib-treated mice increased significantly at 4 days after radiation compared to the excipient control group (p<0.
001), and the difference between the two groups was almost eliminated
on day 10.

Efficacy of Opaganib on the lethality of partially shielded radiation in C57BL/6 mice

In a variety of cases, using partial bone marrow shielding, involving different radiation levels and different dosage regimens, Opaganib was observed to reduce mortality; In mice given the highest dose of 16 Gray (Gy), Opaganib was given before and after radiation, and mortality decreased from 82% to 4% (p<0.
001), with the greatest improvement
in mortality.

U.
S.
Government Funded Opaganib Cancer Radiation Therapy Study - Summary of Results:

In vitro efficacy of Opaganib on cellular radiosensitivity

Opaganib appears to provide protection against radiation-induced cell death, with observations showing that the radiation levels required to kill 50% and 90% of intestinal epithelial cells increased from 5.
56 and 12.
16 Gy to 6.
46 and 13.
2 Gy
, respectively.
In addition, Opaganib was observed to increase the killing effect of radiation on transforming pancreatic cancer cells, especially at
high doses of 15 Gy (p<0.
05).

In vivo efficacy of opaganib combined with radiotherapy for tumor growth (multiple cancer types):

Pancreatic carcinoma model: TBI alone or Opaganib alone significantly reduced tumor growth (p<0.
05 and p<0.
001, respectively).

Treatment with Opaganib in combination with TBI significantly reduced tumor growth compared with control or TBI alone (p<0.
01 per comparison), but was not significantly different from Opaganib alone, as the drug had strong antitumor activity
in this model.
Importantly, treatment with Opaganib does not protect tumors from radiation therapy
.

Melanoma and E0771 Breast Cancer Model: Antitumor activity with Opaganib plus TBI was observed to be the same or better
than TBI alone.
Similarly, Opaganib was not associated with a weakened tumor response to graded radiotherapy, nor was an increase
in radiotherapy-induced weight loss observed.

Head and neck cancer models: It was observed that treatment with Opaganib alone slightly reduced tumor growth, while TBI+ cisplatin treatment significantly reduced tumor growth (p<0.
001)
compared to the control (excipients) group.
Opaganib combined with TBI+ cisplatin had the greatest inhibitory effect on tumor growth, and this treatment group was observed to significantly outperform TBI+ cisplatin treatment at day 21 and beyond (p<0.
02
).
Similarly, Opaganib was not
associated with reduced tumor response or increased weight loss.

About Opaganib (ABC294640)

Opaganib, a novel drug, is a best-in-class proprietary selective inhibitor of oral sphingosine kinase 2 (SK2) with recommended anti-inflammatory, anticancer, anti-radiation and antiviral activities
.

Opaganib is thought to be effective
by simultaneously inhibiting three sphingolipid-metabolizing enzymes (SK2, DES1, and GCS) in human cells, thereby inhibiting multiple pathways, inducing autophagy and apoptosis, and disrupting viral replication.

In oncological and radiological settings, Opaganib has been observed to increase ceramides in cells and reduce sphingosine 1-phosphate (S1P), a condition that increases the anti-tumor efficacy of radiation while inhibiting inflammatory damage to normal tissues, making it possible to inhibit accidental ionizing radiation (IR) toxicity and improve patient response
to radiotherapy.
Opaganib for the treatment of cholangiocarcinoma has also received rare drug designation from the U.
S.
Food and Drug Administration and is currently being evaluated
in a Phase 2a study for advanced cholangiocarcinoma.
Patient accumulation, treatment, and analysis of prostate cancer research are ongoing
.
Opaganib has prepared a Phase 1 radiotherapy protocol for submission to IND
.

Opaganib has demonstrated broad-playing, host-oriented antiviral activity
against SARS-CoV-2, multiple variants, and several other viruses such as influenza A viruses.
Opaganib targets hosts and, based on data accumulated to date, is expected to maintain its effect
on emerging virus variants.
In a pre-specified analysis of Phase 2/3 clinical data from moderately severe COVID-hospitalized patients, oral Opaganib showed improved viral RNA clearance, faster recovery time, and significantly lower
mortality in key patient subsets compared to the placebo group receiving standard care.
Data from the Opaganib Global Phase 2/3 study has been submitted for peer review and was recently published in
medRxiv.

Opaganib has also shown positive preclinical results for renal fibrosis and has the potential to be used to treat multiple oncology, radioprotection, viral, inflammatory and gastrointestinal indications
.

[1] Opaganib is a new drug for investigational use and is not commercially available
.

[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.
In 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.