Strong preclinical knowledge, not too long ago revealed within the International Journal of Molecular Sciences, from eight U.S authorities-funded in-vivo opaganib research, helps opaganib’s potential as a nuclear radiation harm therapeutic for homeland safety materials risk medical countermeasures (MCM) and for antitumor radiotherapy
As an oral, small molecule tablet that’s extremely secure with a greater than 5-12 months shelf-life, opaganib is simple to manage and distribute, supporting, if authorized, potential central stockpiling by governments for attainable use in mass casualty nuclear radiation incidents
Unlike present authorized choices corresponding to iodine capsules, opaganib’s advised protecting impact in radiation harm will not be considered restricted to particular radioactive supplies or particular person components of the physique. Rather, opaganib’s mechanism of motion is believed to suppress ionizing radiation toxicity and inflammatory injury to regular tissue, and promote the robustness of hematopoietic stem cells from radiation injury, doubtlessly supporting elevated survival and decreased morbidity
Observations from a number of GI-targeted in-vivo fashions point out that opaganib could defend regular tissue from injury attributable to ionizing radiation publicity or most cancers radiotherapy, enhance antitumor exercise and response to chemoradiation and improve tolerability and survival
Independent exterior in-vivo research of the radioprotective capability of opaganib in bone marrow additionally present enhanced survival towards each deadly and half-deadly complete-physique irradiation
Another examine has been initiated not too long ago, by RedHill and its accomplice Apogee Biotechnology Corporation, to evaluate protecting results of opaganib towards radiation-induced hematologic and renal toxicity
Based on FDA steerage particular to opaganib, and topic to a not too long ago scheduled comply with-on assembly with FDA, RedHill expects growth of opaganib as a homeland safety nuclear medical countermeasure to comply with the Animal Rule, underneath which pivotal animal mannequin efficacy research are relevant when human scientific trials should not moral or possible; Discussions relating to additional help, funding and growth pathway to approval have been initiated with US and different governments
Sponsors of authorized medical countermeasures product purposes are eligible for a medical countermeasure Priority Review Voucher
Opaganib’s growth continues for COVID-19, different pandemic preparedness antiviral indications and oncology, strongly positioning opaganib as a significant pipeline-in-a-product supposed for a number of indications
TEL AVIV, Israel and RALEIGH, NC, Nov. 14, 2022 /PRNewswire/ — RedHill Biopharma Ltd. (Nasdaq: RDHL) (“RedHill” or the “Company”), a specialty biopharmaceutical firm, right now introduced acceleration of opaganib’s growth program for defense towards radiation harm and most cancers radiotherapy. A current publication within the International Journal of Molecular Sciences, entitled “Opaganib Protects against Radiation Toxicity: Implications for Homeland Security and Antitumor Radiotherapy”, describes the collective outcomes of eight U.S. authorities-funded in vivo research by RedHill and Apogee Biotechnology Corporation (“Apogee”), in addition to further experiments, establishing opaganib’s[1] potential nuclear radiation safety capabilities[2].
The publication highlights observations from quite a few research undertaken in each safety towards radiation toxicity and most cancers radiotherapy settings. In the related examine fashions, opaganib was related to safety of regular tissue, together with gastrointestinal, from radiation injury attributable to ionizing radiation publicity or most cancers radiotherapy, in addition to enchancment of antitumor exercise, response to chemoradiation, and enhancement of tolerability and survival. Additional unbiased research display the radioprotective capability of opaganib in bone marrow, with opaganib displaying enhanced survival in mice which have been irradiated with each deadly and half-deadly complete-physique 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,” stated 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 space of governmental concern. A key precedence for US authorities analysis efforts is targeted on discovering lengthy shelf-life and straightforward to distribute and administer medication for potential inclusion within the Strategic National Stockpile. Such medication, for use in mass casualty nuclear radiation incidents involving improvised nuclear or radiological dispersal units, ought to have broad-appearing protecting functionality, be capable of be administered 24 hours or later after radiation publicity, be secure and be simple to distribute to massive numbers of individuals needing remedy for the acute results of excessive dose, complete-physique radiation publicity.
Currently, to one of the best of the Company’s data, solely 4 FDA-authorized medical countermeasure therapies can be found. Three of those choices are restricted to results brought on by a small variety of particular radioactive supplies or to particular components of the physique. Potassium iodide (iodine capsules) is meant for use to guard towards thyroid injury from the discharge of radioiodine. It works by stopping the thyroid from taking on radioactive iodine however appears to supply no safety to the remainder of the physique from irradiation and is of restricted profit except given instantly upon publicity. The different two, Prussian Blue and DTPA (diethylenetriamine pentaacetate) present safety by limiting the half-life within the physique of particular supplies: radioactive cesium and thallium, within the case of Prussian Blue, and radioactive plutonium, americium, and curium, within the case of DTPA. The fourth choice, filgrastim, is meant for acute radiation syndrome ensuing from excessive-dose radiation. Filgrastim doesn’t appear to guard the physique towards the radiation itself and works by stimulating the creation of recent white blood cells to guard the physique from infections, which the physique can not do within the presence of radiation-induced bone marrow destruction – so long as there are viable stem cells to stimulate.
We imagine that opaganib’s safety wouldn’t be restricted to particular radioactive supplies or particular person components of the physique. Much of the injury brought on by radiation publicity is brought on by irritation secondary to the results of ionizing radiation itself – referred to as Acute Radiation Syndrome. Opaganib, a sphingosine kinase-2 (SK2) inhibitor, is believed to exert its protecting results by way of an anti-inflammatory mechanism of motion involving ceramide elevation and discount of sphingosine 1-phosphate (S1P) in human cells – suppressing inflammatory injury to regular tissue and thus suppressing toxicity from unintended ionizing radiation publicity. It has additionally been reported within the literature that inhibition of sphingosine kinase 2 promotes the viability and robustness of hematopoietic stem cells, even within the face of radiation injury, supporting elevated survival.
Protection towards radiation toxicity research with opaganib funded by U.S. authorities – abstract of outcomes:
Effect of opaganib on the lethality of TBI (Total Body Irradiation) in C57BL/6 mice
Vehicle-treated mice had pronounced signs indicative of extreme GI injury, and all animals needed to be euthanized inside 14 days of radiation publicity. In distinction, safety was noticed within the opaganib-handled group, by which 71% of the mice survived indefinitely.
Accumulation and pharmacodynamics of opaganib in mouse small gut
In car-handled mice, TNFα expression within the small intestines was noticed to be up-regulated as early as 1 hour after Total Body Irradiation (TBI) and remained extremely elevated for not less than 26 hours. In distinction, pretreatment with opaganib was noticed to not solely block the induction of TNFα by TBI but additionally to scale back tissue TNFα ranges under the baseline stage indicating extended biodistribution of opaganib into the small gut at adequate ranges to inhibit SK2 and suppress radiation-induced irritation.
Effects of opaganib on GI injury following TBI
Post-radiation decreases in villus top (villi are a crucial element of the intestines means to soak up vitamins and indicative of intestinal well being) have been noticed within the car-handled animals in contrast with non-irradiated controls. In distinction, villus top was maintained within the opaganib-handled mice. Additionally, whereas there was proof of cell depletion after 10 days in all teams, there have been considerably extra cells current at 4 days after irradiation within the opaganib-handled mice in comparison with car controls (p<0.001) with this distinction between therapies almost resolving by Day 10.
Effect of opaganib on the lethality of partially shielded irradiation in C57BL/6 mice
In a number of situations, using partial bone marrow shielding, involving completely different ranges of irradiation and with completely different dosing regimens, opaganib was noticed to scale back mortality, with the best enchancment seen when opaganib was given each earlier than and after irradiation, decreasing mortality from 82% all the way down to 4% (p<0.001) within the mice given the best dose of radiation, 16 Gray (Gy).
Cancer radiotherapy research with opaganib funded by U.S. authorities – abstract of outcomes:
In vitro results of opaganib on cell radiosensitivity
Opaganib appeared to offer safety from IR-induced cell dying, with observations displaying the extent of radiation must kill 50% and 90% of intestinal epithelial cells growing from 5.56 and 12.16 Gy respectively as much as 6.46 and 13.2 Gy, respectively. Furthermore, opaganib was noticed to extend the killing of reworked pancreatic most cancers cells by radiation, significantly on the excessive dose of 15 Gy (p<0.05).
In vivo results of mixture of opaganib with radiation on tumor progress (a number of most cancers-sorts):
Pancreatic most cancers mannequin: Treatment with both TBI alone or opaganib alone considerably decreased tumor progress (p<0.05 and p<0.001, respectively). Treatment with opaganib together with TBI was related to considerably decreased tumor progress in comparison with the management group or to the TBI alone group (p<0.01 for every comparability) however was not considerably completely different from opaganib alone due to the robust antitumor exercise of the drug on this mannequin. Importantly, remedy with opaganib didn’t defend tumors from radiation remedy.
Melanoma and E0771 breast most cancers mannequin: Opaganib plus TBI was noticed to have equal or higher antitumor exercise than TBI alone. Again, opaganib was not related to a diminished tumor response to fractionated radiation remedy and elevated weight reduction from radiation remedy was not noticed.
Head & neck most cancers mannequin: Treatment with opaganib alone was noticed to barely scale back tumor progress, whereas TBI + cisplatin was noticed to considerably scale back tumor progress as in comparison with the management (car) group (p<0.001). Treatment with opaganib together with TBI + cisplatin was related to the best discount in tumor progress and such remedy group had considerably higher observations than TBI + cisplatin on Day 21 and after (p<0.02). Again, opaganib was not related to diminished tumor response or elevated weight reduction.
About Opaganib (ABC294640)
Opaganib a brand new chemical entity, is an orally administered, first-in-class proprietary selective inhibitor of sphingosine kinase-2 (SK2) with advised anti-inflammatory, anticancer, radioprotective and antiviral exercise.
Opaganib is believed to work by means of the inhibition of a number of pathways, the induction of autophagy and apoptosis, and disruption of viral replication, by means of simultaneous inhibition of three sphingolipid-metabolizing enzymes in human cells (SK2, DES1 and GCS).
In an oncology & radiological setting, opaganib has been noticed to raise ceramide and reduces sphingosine 1-phosphate (S1P) in cells, circumstances that enhance the antitumor efficacy of radiation whereas concomitantly suppressing inflammatory injury to regular tissue, resulting in the potential to suppress toxicity from unintended ionizing radiation (IR) publicity and enhance affected person response to chemoradiation. Opaganib has acquired Orphan Drug designation from the U.S. FDA for the remedy of cholangiocarcinoma and is being evaluated in a Phase 2a examine in superior cholangiocarcinoma. Patient accrual, remedy and evaluation in a prostate most cancers examine is ongoing. Opaganib has a Phase 1 chemoradiotherapy examine protocol prepared for IND submission.
Opaganib has demonstrated broad-appearing, host-directed, antiviral exercise towards SARS-CoV-2, a number of variants, and several other different viruses, corresponding to Influenza A. Being host-focused, and primarily based on knowledge amassed up to now, opaganib is predicted to keep up impact towards rising viral variants. In prespecified analyses of Phase 2/3 scientific knowledge in hospitalized sufferers with average to extreme COVID-19, oral opaganib demonstrated improved viral RNA clearance, quicker time to restoration and vital mortality discount in key affected person subpopulations versus placebo on high of ordinary of care. Data from the opaganib international Phase 2/3 examine has been submitted for peer assessment and not too long ago revealed in medRxiv.
Opaganib has additionally proven optimistic preclinical leads to renal fibrosis, and has the potential to focus on a number of oncology, radioprotection, viral, inflammatory, and gastrointestinal indications.
About RedHill Biopharma
RedHill Biopharma Ltd. (Nasdaq: RDHL) is a specialty biopharmaceutical firm primarily targeted on gastrointestinal and infectious illnesses. RedHill promotes the gastrointestinal medication, Movantik® for opioid-induced constipation in adults[4], Talicia® for the remedy of Helicobacter pylori (H. pylori) an infection in adults[5], and Aemcolo® for the remedy of vacationers’ diarrhea in adults[6]. RedHill’s key scientific late-stage growth applications embrace: (i) RHB-204, with an ongoing Phase 3 examine for pulmonary nontuberculous mycobacteria (NTM) illness; (ii) opaganib (ABC294640), a primary–in–class oral broad-appearing, host-directed, SK2 selective inhibitor focusing on a number of indications, together with for pandemic preparedness, with a Phase 2/3 program for hospitalized COVID-19 and a Phase 2 program in oncology and a radiation safety program ongoing; (iii) RHB-107 (upamostat), an oral broad-appearing, host-directed serine protease inhibitor with potential for pandemic preparedness and is in Phase 3-stage growth as remedy for non-hospitalized symptomatic COVID-19, and focusing on a number of different most cancers and inflammatory gastrointestinal illnesses; (iv) RHB-104, with optimistic outcomes from a primary Phase 3 examine for Crohn’s illness; and (v) RHB-102, with optimistic outcomes from a Phase 3 examine for acute gastroenteritis and gastritis and optimistic outcomes from a Phase 2 examine for IBS-D. More details about the Company is on the market at www.redhillbio.com/ twitter.com/RedHillBio.
This press launch accommodates “forward-looking statements” throughout the that means of the Private Securities Litigation Reform Act of 1995. Such statements could also be preceded by the phrases “intends,” “may,” “will,” “plans,” “expects,” “anticipates,” “projects,” “predicts,” “estimates,” “aims,” “believes,” “hopes,” “potential” or comparable phrases. Forward-looking statements are primarily based on sure assumptions and are topic to varied recognized and unknown dangers and uncertainties, lots of that are past the Company’s management and can’t be predicted or quantified, and consequently, precise outcomes could differ materially from these expressed or implied by such ahead-wanting statements. Such dangers and uncertainties embrace the danger that opaganib is not going to be proven to raise ceramide and scale back sphingosine 1-phosphate (S1P) in cells, growing the antitumor efficacy of radiation whereas concomitantly suppressing inflammatory injury to regular tissue, resulting in the potential to suppress toxicity from unintended ionizing radiation (IR) publicity and enhance affected person response to chemoradiation in an oncology & radiological setting, the danger that the FDA doesn’t agree with the Company’s proposed growth plans for opaganib for any indication, the danger that observations from preclinical research should not indicative or predictive of leads to scientific trials, the danger that opaganib is not going to be proven to be broad appearing, host-directed candidate therapies for pandemic preparedness, the danger {that a} pivotal Phase 3 trial for opaganib is not going to be initiated or that such trial achieve success and, even when profitable, such examine and outcomes is probably not adequate for regulatory purposes, together with emergency use or advertising purposes, and that further COVID-19 research for opaganib are required by regulatory authorities to help such potential purposes and the use or advertising of opaganib for COVID-19 sufferers, that opaganib is not going to be efficient towards rising viral variants, in addition to dangers and uncertainties related to (i) the initiation, timing, progress and outcomes of the Company’s analysis, manufacturing, preclinical research, scientific trials, and different therapeutic candidate growth efforts, and the timing of the industrial launch of its industrial merchandise and ones it might purchase or develop sooner or later; (ii) the Company’s means to advance its therapeutic candidates into scientific trials or to efficiently full its preclinical research or scientific trials (iii) the extent and quantity and kind of further research that the Company could also be required to conduct and the Company’s receipt of regulatory approvals for its therapeutic candidates, and the timing of different regulatory filings, approvals and suggestions; (iv) the manufacturing, scientific growth, commercialization, and market acceptance of the Company’s therapeutic candidates and Talicia®; (v) the Company’s means to efficiently commercialize and promote Movantik®, Talicia® and Aemcolo®; (vi) the Company’s means to determine and preserve company collaborations; (vii) the Company’s means to accumulate merchandise authorized for advertising within the U.S. that obtain industrial success and construct and maintain its personal advertising and commercialization capabilities; (viii) the interpretation of the properties and traits of the Company’s therapeutic candidates and the outcomes obtained with its therapeutic candidates in analysis, preclinical research or scientific trials; (ix) the implementation of the Company’s business mannequin, strategic plans for its business and therapeutic candidates; (x) the scope of safety the Company is ready to set up and preserve for mental property rights protecting its therapeutic candidates and industrial merchandise and its means to function its business with out infringing the mental property rights of others; (xi) events from whom the Company licenses its mental property defaulting of their obligations to the Company; (xii) estimates of the Company’s bills, future revenues, capital necessities and desires for extra financing; (xiii) the impact of sufferers struggling opposed occasions utilizing investigative medication underneath the Company’s Expanded Access Program; and (xiv) competitors from different corporations and applied sciences throughout the Company’s business. More detailed details about the Company and the danger components that will have an effect on the belief of ahead-wanting statements is about forth within the Company’s filings with the Securities and Exchange Commission (SEC), together with 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-Ok filed with the SEC on November 10, 2022. All ahead-wanting statements included on this press launch are made solely as of the date of this press launch. The Company assumes no obligation to replace any written or oral ahead-wanting assertion, whether or not because of new info, future occasions or in any other case except required by regulation.
Company contact:
Adi Frish
Chief Corporate & Business Development Officer
RedHill Biopharma
+972-54-6543-112
[email protected]
Category: R&D
[1] Opaganib is an investigational new drug, not obtainable for industrial distribution.
[2] Maines LW, Schrecengost RS, Zhuang Y, Keller SN, Smith RA, Green CL, Smith CD. Opaganib Protects towards 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 info see: www.movantik.com
[5] Talicia® (omeprazole magnesium, amoxicillin and rifabutin) is indicated for the remedy of H. pylori an infection in adults. For full prescribing info see: www.Talicia.com.
[6] Aemcolo® (rifamycin) is indicated for the remedy of vacationers’ diarrhea brought on by noninvasive strains of Escherichia coli in adults. For full prescribing info see: www.aemcolo.com.
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