Ebola virus disease
RedHill Announces New Opaganib Chinese Patent Against Ebola Virus Valid Through 2035
The new Chinese patent for opaganib as a therapy for inhibition of single-stranded RNA virus replication (notably Ebola Disease Virus) is valid through 2035 and adds to opaganib's strong global intellectual property portfolio across multiple indications
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U.S. Army studies suggest that opaganib may be the first host-directed molecule to show activity in vivo in Ebola virus disease, delivering a statistically significant increase in survival; separately, opaganib demonstrated robust synergistic effect in vitro when combined with remdesivir (Veklury®; Gilead Sciences, Inc.), improving viral inhibition while maintaining cell viability
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A host-directed and potentially broad acting twice-daily oral, small molecule, opaganib is in development for multiple indications, including COVID-19, acute respiratory distress syndrome, oncology and two U.S. Government-sponsored countermeasures programs for Acute Radiation Syndrome and Sulfur Mustard exposure. It has a demonstrated safety and efficacy profile, and is well-suited to counter nuclear / chemical exposure and viral pandemic scenarios, being viral mutation-resistant, and easy to administer and distribute
TEL-AVIV, Israel and RALEIGH, N.C., May 6, 2024 /PRNewswire/ -- RedHill Biopharma Ltd. (NASDAQ: RDHL) ("RedHill" or the "Company"), a specialty biopharmaceutical company, today announced the issue of a new Chinese patent Notice of Allowance covering opaganib[1] as a therapyg for inhibition of single-stranded RNA virus replication (notably Ebola Disease Virus) from the Chinese National Intellectual Property Administration (CNIPA), valid through 2035 (Chinese Patent Application No.: 202110229970.9 issued April 29, 2024).
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"This new patent adds to the existing intellectual property portfolio protecting opaganib across multiple indications and represents the first China patent in the Ebola patent family," said Guy Goldberg, RedHill's Chief Business Officer. "U.S. Army studies suggest that opaganib may be the first host-directed molecule to show activity in vivo in Ebola virus disease, delivering a statistically significant increase in survival. Targeting multiple indications, including selection by two U.S. Government countermeasures programs for Acute Radiation Syndrome and Sulfur Mustard exposure, oral opaganib, has a demonstrated safety and efficacy profile and is well-suited to viral pandemic scenarios, being viral mutation-resistant, and easy to administer and distribute."
About Ebola virus disease:
According to the Centers for Disease Control and Prevention (CDC), Ebola disease is a rare and often deadly illness, caused by infection by one of a group of four viruses, known as ebolaviruses, that are found primarily in sub-Saharan Africa and are known as: Zaire, Sudan, Taï Forest (formerly Côte d'Ivoire) and Bundibugyo. Transmission of the disease is mostly through contact with an infected animal (bat or nonhuman primate) or a sick or dead person infected with an ebolavirus. The course of the illness typically progresses from "dry" symptoms initially (such as fever, aches and pains, and fatigue), and then progresses to "wet" symptoms (such as diarrhea, vomiting and unexplained hemorrhaging, bleeding or bruising) as the person becomes sicker. There are currently only two FDA-approved therapies to treat EVD caused by the Ebola virus, species Zaire ebolavirus, in adults and children; Inmazeb™ (atoltivimab/maftivimab/odesivimab, Regeneron Pharmaceuticals, Inc), a combination of three monoclonal antibodies and Ebanga™ (ansuvimab-zykl, Ridgeback Biotherapeutics, LP), a single monoclonal antibody. Both are intravenously infused direct acting monoclonal antibody antivirals that bind to glycoproteins on the Ebola virus's surface to prevent the virus from entering a person's cells. There is an urgent need for host-directed small molecule therapies that may be effective against multiple strains of ebolavirus, less likely to be impacted by viral mutation, and that are easy to store, distribute and administer, especially in areas where healthcare services and infrastructures may be sub-optimal.
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About Opaganib (ABC294640)
Opaganib, a proprietary investigational host-directed and potentially broad-acting drug, is a first-in-class, orally administered sphingosine kinase-2 (SPHK2) selective inhibitor with anticancer, anti-inflammatory and antiviral activity, targeting multiple potential diseases, including gastrointestinal acute radiation syndrome (GI-ARS), COVID-19, other viruses as part of pandemic preparedness, and cholangiocarcinoma (bile duct cancer).
Opaganib's host-directed action 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 (SPHK2, DES1 and GCS).
Opaganib was selected by the U.S. Government's Radiation and Nuclear Countermeasures Program (RNCP), led by the National Institute of Allergy and Infectious Diseases, part of the HHS National Institutes of Health, for the nuclear medical countermeasures product development pipeline as a potential treatment for Acute Radiation Syndrome (ARS).
Opaganib has demonstrated antiviral activity against SARS-CoV-2, multiple variants, and several other viruses, such as Influenza A and Ebola. Opaganib delivered a statistically significant increase in survival time when given at 150 mg/kg twice a day (BID) in a United States Army Medical Research Institute of Infectious Diseases (USAMRIID) in vivo Ebola virus study, making it the first host-directed molecule to show activity in Ebola virus disease. Opaganib also recently demonstrated a distinct synergistic effect when combined individually with remdesivir (Veklury®, Gilead Sciences Inc.), significantly improving potency while maintaining cell viability, in a U.S. Army-funded and conducted in vitro Ebola virus study.
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. Opaganib has demonstrated its safety and tolerability profile in more than 470 people in multiple clinical studies and expanded access use. Data from the opaganib global Phase 2/3 study was published in medRxiv.
Opaganib has received Orphan Drug designation from the FDA for the treatment of cholangiocarcinoma and has undergone studies in advanced cholangiocarcinoma (Phase 2a) and prostate cancer. Opaganib also has a Phase 1 chemoradiotherapy study protocol ready for FDA-IND submission.
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 Talicia®, for the treatment of Helicobacter pylori (H. Pylori) infection in adults[2], and Aemcolo®, for the treatment of travelers' diarrhea in adults[3]. RedHill's key clinical late-stage development programs include: (i) opaganib (ABC294640), a first-in-class oral broad-acting, host-directed SPHK2 selective inhibitor with potential for pandemic preparedness, targeting multiple indications with a U.S. Government collaboration for development for Acute Radiation Syndrome (ARS), a Phase 2/3 program for hospitalized COVID-19, and a Phase 2 program in oncology; (ii) RHB-107 (upamostat), an oral broad-acting, host-directed, serine protease inhibitor with potential for pandemic preparedness is in late-stage development as a treatment for non-hospitalized symptomatic COVID-19, with non-dilutive external funding covering the entirety of the RHB-107 arm of the 300-patient Phase 2 adaptive platform trial, and is also targeting multiple other cancer and inflammatory gastrointestinal diseases; (iii) RHB-102, with potential UK submission for chemotherapy and radiotherapy induced nausea and vomiting, positive results from a Phase 3 study for acute gastroenteritis and gastritis and positive results from a Phase 2 study for IBS-D; (iv) RHB-104, with positive results from a first Phase 3 study for Crohn's disease; and (v) RHB-204, a Phase 3-stage program for pulmonary nontuberculous mycobacteria (NTM) disease.
More information about the Company is available at www.Redhillbio.Com / twitter.Com/RedHillBio.
[1] Opaganib is an investigational new drug, not available for commercial distribution.[2] 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.[3] 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.
Forward Looking Statements
This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 and may discuss investment opportunities, stock analysis, financial performance, investor relations, and market trends. Such statements, including, but not limited to, statements regarding the intended use of net proceeds from the offering, may be preceded by the words "intends," "may," "will," "plans," "expects," "anticipates," "projects," "predicts," "estimates," "aims," "believes," "hopes," "potential" or similar words and include statements regarding the risk that the Company will not comply with the listing requirements of the Nasdaq Capital Market ("Nasdaq") to remain listed for trading on Nasdaq, the addition of new revenue generating products, out-licensing of the Company's development pipeline assets, timing of opaganib's development for Acute Radiation Syndrome, non-dilutive development funding from RHB-107 and its inclusion in a key platform study. 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, without limitation, market and other conditions, the risk that the addition of new revenue generating products or out-licensing transactions will not occur; the risk that acceptance onto the RNCP Product Development Pipeline will not guarantee ongoing development or that any such development will not be completed or successful; 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 the FDA pre-study requirements will not be met and/or that the Phase 3 study of RHB-107 in COVID-19 outpatients will not be approved to commence or if approved, will not be completed or, should that be the case, that we will not be successful in obtaining alternative non-dilutive development funding for RHB-107, the risk that HB-107's late-stage development for non-hospitalized COVID-19 will not benefit from the resources redirected from the terminated RHB-204 Phase 3 study, that the Phase 2/3 COVID-19 study for RHB-107 may not be successful and, even if successful, such studies and results may not be sufficient for regulatory applications, including emergency use or marketing applications, and that additional COVID-19 studies for opaganib and RHB-107 are likely to be required, as well as risks and uncertainties associated with the risk that the Company will not successfully commercialize its products; as well as risks and uncertainties associated with (i) the initiation, timing, progress and results of the Company's research, manufacturing, pre-clinical 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 pre-clinical studies or clinical trials or the development of a commercial companion diagnostic for the detection of MAP; (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 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 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, pre-clinical 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 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 experiences using investigative drugs under the Company's Expanded Access Program; (xiv) competition from other companies and technologies within the Company's industry; and (xv) the hiring and employment commencement date of executive managers. 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 April 8, 2024. 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
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How Ugandan Tobacco Farming Inadvertently Threatens Spread Of Bat-Borne Viruses
April 23, 2024
4 min read
How Ugandan Tobacco Farming Inadvertently Threatens Spread of Bat-Borne Viruses
By cutting trees in response to international demand for tobacco, farmers induced wildlife to start eating virus-laden bat guano
Black and white colobus monkeys in Uganda have been seen eating bat guano loaded with viruses.
Ondrej Prosicky/Alamy Stock Photo
Zoonotic diseases, or illnesses transmitted from animals to humans, account for about three quarters of new infectious diseases around the world, including some that could lead to pandemics. The risk of a pathogen jumping from an animal to a human increases when people encroach on ecosystems and cause relationships to be disrupted between species—but how that risk actually becomes a reality can be unpredictable and difficult to untangle.
A new paper published this week in Communications Biology shines rare light on one such case study: an example showing how international demand for tobacco led to habitat alterations in Uganda that seemingly drove chimpanzees and other species to begin consuming bat guano for mineral nutrients. In that process, the animals might have been exposed to more than two dozen viruses, including a novel cousin of the COVID-causing pathogen SARS-CoV-2.
"This is the butterfly effect of infectious disease ecology," says senior study author Tony Goldberg, a wildlife epidemiologist at the University of Wisconsin–Madison. "Far-flung events like demand for tobacco can have crazy, unintended consequences for disease emergence that follow pathways that we rarely see and can't predict."
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Goldberg and his colleagues' study focuses on human and ecological interactions in the Budongo Forest Reserve in western Uganda. The first hint the team had that something strange was going on was when their collaborators in Uganda noticed chimpanzees gathering at a large, hollow tree and eating something from within it. Upon closer inspection, the field researchers realized the chimps were consuming bat guano, which had been deposited by a colony of Noack's roundleaf bats that were roosting in the hollowed-out tree.
Although researchers had been observing chimpanzees in Budongo for decades, none had ever seen or heard of anything like this before. So Goldberg and his colleagues set up field cameras by the tree. Videos they collected between 2017 and 2019 revealed 839 instances of guano consumption, not only by chimpanzees but also by black-and-white colobus monkeys and red duikers, a type of forest antelope.
Bat guano isn't the only seemingly odd thing that field staff and scientists at Budongo have observed chimpanzees and other wildlife eating. Chimps will also sometimes eat clay, for example, or termite mounds. The reason, researchers have found, is that animals living in Budongo, like those in many tropical ecosystems, face a scarcity of dietary minerals.
So when the bat guano observations came to light, Goldberg and others immediately thought it must be connected to diet. Because animals had never been observed eating guano before, however, the researchers figured that something in the environment must have changed. The story that emerged was more complex than they imagined—and hinged on the disappearance of a specific palm tree, Raphia farinifera.
In years past chimpanzees and other animals were often observed eating the decaying wood of fallen R. Farinifera palms, which they sought out for minerals. But between 2006 and 2012 tobacco farming increased in the area. Local farmers began cutting down R. Farinifera to use the tree's tough, peelable fronds to make strings on which to hang tobacco leaves to dry. Demand was so high that R. Farinifera nearly disappeared from Budongo altogether.
"That eliminated the primary source of minerals for animals, so they had to fall back on other sources," Goldberg says. Bat guano, it turned out, was a great alternative. The researchers do not know how the chimpanzees and other animals knew to seek out guano, yet tests they ran confirmed the material is high in sodium, potassium, magnesium and phosphorus.
Because this was bat guano, though, Goldberg and his colleagues also wanted to test for viruses. "Bats are wonderful creatures; we love them. But they do carry viruses," Goldberg says. "We wanted to know what else the chimpanzees might be getting from this bat guano."
Tests of 11 guano samples collected from the hollow tree over eight months in 2018 and 2019 revealed 27 different viruses, including a novel coronavirus that's the equivalent of "a first cousin" to SARS-CoV-2, Goldberg says. Analyses the researchers ran to try to predict whether the novel coronavirus might be able to infect people came back as inconclusive because the new pathogen appears to latch on to cells in a different way than SARS-CoV-2 does. "We don't know enough about this flavor of coronavirus to predict what it could infect," Goldberg says.
"The overarching theme of anthropogenic drivers causing ecological changes that could result in pathogenic viral spillover is very real, and this paper highlights an additional, intriguing way through which this might happen," says Rebekah Kading, a microbiologist at Colorado State University, who was not involved in the research. "While this potential spillover pathway is still hypothetical, it is important to recognize situations such as this one in which the public health consequences could be significant, while the potential solution to mitigating this threat could be as simple as offering farmers materials for binding tobacco leaves to reduce the pressure on the R. Farinifera tree."
The new study raises additional questions, including how widespread the phenomenon of chimpanzees and other species eating bat guano might be. All of the observations came from the single tree, but Goldberg guesses that there are likely other instances of the behavior that are happening elsewhere in Budongo and other mineral-poor ecosystems around the world. He also wonders whether guano consumption might eventually be shown to be tied to the mystery of Ebola viruses' origins.
Many scientists suspect that bats might serve as the natural host for Ebola viruses, and chimpanzees, red duikers and black-and-white colobus monkeys are all species that have been implicated in various Ebola outbreaks after humans have come into contact with them. "This paper could help lift the veil over a mystery that's plagued disease ecology for decades: How do wild animals like chimpanzees contract Ebola viruses, probably from bats, in the wild?" Goldberg says. "It's a lucky example of pulling back the curtain and seeing a series of hidden events that could be preceding outbreaks."
Creating The Next Wave Of Antibody Therapies Requires Innovative Collaboration
Next-generation broadly neutralizing antibodies (bnAbs) have the potential to transform the fight against global health threats like HIV, malaria, and Ebola. The commercialization of these innovative antibody therapies could save millions of lives annually. But turning promise into reality requires foresight and commitment.
Broadly neutralizing antibodies are a type of protein that can recognize and neutralize a wide range of pathogens, including multiple strains of viruses such as HIV. This versatility makes them highly valuable in medicine, promising effective treatments and preventive measures against infectious diseases. New discoveries are improving the potency and durability of antibodies in general.
But significant roadblocks, particularly concerning manufacturing investments, impede the path of antibody therapies from the lab to the clinic. The cost of producing bnAbs far exceeds that of small-molecule drugs, making their production financially unfeasible without the promise of substantial returns. Compared to other biologics, bnAbs could cost more than the new weight loss drugs to produce, though less than CAR-T cell therapy. This cost structure is particularly prohibitive when considering the economic constraints in the low-income countries where these treatments are most urgently needed.
Think about using a biannual regimen of bnAbs for HIV, which could dramatically reduce transmission rates. The HIV Vaccine Trials Network is currently identifying bnAbs for a Phase 2B trial to fill unmet need. Yet, the cost of producing such a regimen is prohibitive, according to estimates made by Infectious Economics, the company I founded. Our data, which I'm presenting at the HIV Vaccine Trials Network Full Group Meeting on May 1 in Washington, D.C., place the U.S. Market potential at more than $1.3 billion. But in a country like Malawi, which has high HIV transmission rates and low per-capita income, the price per dose must be as low as $8 — far below the production cost — to be economically viable.
This disparity raises a critical question: Why would a pharmaceutical firm invest in a product that many of its most desperate customers cannot afford? Our analysis shows that bridging this gap would require targeted financial interventions ranging from $1 million to $20 million per country annually to make such therapies viable in key low- and middle-income markets.
My perspective on the need for accessible antibody therapies is shaped by extensive experience in both the public and private sectors. As an infectious disease epidemiologist and pharmaceutical economist, I've led essential research on the real-world effectiveness and economic value of drugs, vaccines, and diagnostics. Serving in the White House during the early stages of the Covid-19 pandemic, where I helped shape policies that balanced rapid vaccine and therapeutic development with economic considerations, provided me with firsthand insight into the complexities of scaling medical innovations in crisis situations.
The case of Covid-19 antibodies are a good example of this. Rapidly developed and deployed in high-income countries, their utility waned with the advent of mRNA vaccines and the emergence of Omicron variants, illustrating the complex dynamics of pharmaceutical economics, dynamics that are heightened in poorer regions. Evusheld was initially approved in the United Kingdom in March 2022, which then changed course by August. The U.K.'s National Institute for Health and Care Excellence said, "The rapidly evolving nature of Covid-19 means we need to have a way of establishing the cost effectiveness of existing medicines against current variants in an agile way."
One lesson learned from Covid products was the importance of monitoring real-world data to reevaluate how the effectiveness of a medicine may change over time as a disease agent evolves.
The FDA's recent approval of a long-acting antibody for preventing respiratory syncytial virus (RSV) in infants signals a growing recognition of the value of such antibody treatments. Yet without systemic changes, the promise of antibodies for diseases like malaria, Ebola, Zika, Lassa fever, and others remains unfulfilled. The global health community broadly agrees that it must reduce production costs and improve distribution systems to make these therapies accessible where they are most needed. Writing in STAT, physician-scientist Utibe R. Essien coined the term pharmacoequity to portray a health system in which everyone, regardless of race, class, or availability of resources, has access to the highest quality, evidence-based medical therapy indicated for their condition. Unitaid has discussed how this effort will require novel business models and new partnerships among governments, industry leaders, and philanthropic organizations, mirroring successful precedents like the PEPFAR program, which has saved 25 million lives.
I propose a versatile business model wherein a consortium — including pharmaceutical companies and philanthropic organizations — establishes manufacturing capabilities not just in one facility, but potentially in several of them, ideally located in middle-income markets like Brazil. As I described at the HIV Vaccine Trials Network Full Group Meeting, this approach could enable a diversified portfolio of products to reduce financial risks for the manufacturer. In this portfolio, higher-revenue antibodies, such as certain cancer treatments, would provide robust profits due to their higher prices and stable demand. These profits would, in turn, subsidize the production of less-profitable but crucially needed antibodies for infectious diseases like malaria and HIV. The financial risks associated with producing lower-margin products would be mitigated by the guaranteed returns from high-demand drugs.
Licensing fees paid to the intellectual property holders of the high-revenue drugs would ensure that they receive appropriate compensation for them. To maintain market differentiation and protect brands in high-income markets, products would be sold under different brand names. This strategic partitioning would maximize global access while safeguarding profitability and brand integrity.
Immediate steps toward this goal should include securing upfront funding and commitments from governments and private funders to offset the initial risks for manufacturers. Fostering community engagement and building local capacities are also essential for the sustainable adoption of these bnAb innovations.
As the pharmaceutical market stands today, the alignment of economic incentives with global health goals is off track. Aligning them is not only a moral imperative but a practical necessity for economic security. Without decisive action, the next medical breakthrough could languish in development limbo, out of reach for those who need it most.
It is time for a concerted effort to ensure that the next wave of antibody innovations — potentially as transformative as vaccines — reaches all corners of the globe. Only through collaborative innovation and equitable health policies can the power of these groundbreaking therapies be truly harnessed. Waiting for another global health crisis to force action would be disastrous. The time to incentivize sustainable global access to innovation is now.
Blythe Adamson, Ph.D., is a health economist and pharmacoepidemiologist, founder of Infectious Economics, head of international outcomes research and evidence generation at Flatiron Health, and an affiliate professor in The Comparative Health Outcomes, Policy and Economics Institute at the University of Washington.
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