PR98796

 

TEL AVIV, Israel and RALEIGH, NC, November 14, 2022 /PRNewswire=KYODO JBN/ --

 

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, TNFa 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

TNFa by TBI but also to reduce tissue TNFa 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(R) for opioid-induced constipation in

adults[4], Talicia(R) for the treatment of Helicobacter pylori (H. pylori)

infection in adults[5], and Aemcolo(R) 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(R); (v) the Company's ability

to successfully commercialize and promote Movantik(R), Talicia(R) and Aemcolo(R);

(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(R) (naloxegol) is indicated for opioid-induced constipation (OIC).

Full prescribing information see: www.movantik.com

[5] Talicia(R) (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(R) (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