Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of Intravenous Varespladib Followed by Oral Varespladib in Addition to Standard of Care in Subjects Bitten by Venomous Snakes

This is a multicenter,randomized,double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability and efficacy of a continuous rate infusion (CRI) of IV varespladib followed by transition to the oral dosage form, varespladib-methyl, concurrently with SOC, in participants bitten by venomous snakes.
Note: Funding Source - FDA-OOPD

Start Date30 May 2023

Sponsor / Collaborator

Ophirex, Inc.Startup

CTRI/2021/11/037901 / CompletedPhase 2

Randomized, Double-Blinded, Placebo-Controlled Add-On Therapy Study to Evaluate the Safety, Tolerability, and Efficacy of a Multi-Dose Regimen of Oral Varespladib-Methyl in Subjects Bitten by Venomous Snakes - BRAVO

Start Date01 Feb 2022

Sponsor / Collaborator

Ophirex, Inc.Startup

NCT04996264 / CompletedPhase 2

Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of a Multi-Dose Regimen of Oral Varespladib-Methyl in Subjects Bitten by Venomous Snakes

This is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability and efficacy of varespladib-methyl, concurrently with standard of care (SOC), in subjects bitten by venomous snakes.

Start Date15 Aug 2021

Sponsor / Collaborator

Ophirex, Inc.Startup

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100 Clinical Results associated with Varespladib

100 Translational Medicine associated with Varespladib

100 Patents (Medical) associated with Varespladib

Literatures (Medical) associated with Varespladib

19 Sep 2024·Toxins

Isolation and Pharmacological Characterisation of Pre-Synaptic Neurotoxins from Thai and Javanese Russell's Viper (Daboia siamensis) Venoms.

Article

Author: Hodgson, Wayne C ; Lay, Mimi

The widespread geographical distribution of Russell's vipers (Daboia spp.) is associated with marked variations in the clinical outcomes of envenoming by species from different countries. This is likely to be due to differences in the quantity and potency of key toxins and, potentially, the presence or absence of some toxins in venoms across the geographical spectrum. In this study, we aimed to isolate and pharmacologically characterise the major neurotoxic components of D. siamensis venoms from Thailand and Java (Indonesia) and explore the efficacy of antivenom and a PLA₂ inhibitor, Varespladib, against the neuromuscular activity. These data will provide insights into the link between venom components and likely clinical outcomes, as well as potential treatment strategies. Venoms were fractionated using RP-HPLC and the in vitro activity of isolated toxins assessed using the chick biventer cervicis nerve-muscle preparation. Two major PLA₂ fractions (i.e., fractions 8 and 10) were isolated from each venom. Fraction 8 from both venoms produced pre-synaptic neurotoxicity and myotoxicity, whereas fraction 10 from both venoms was weakly neurotoxic. The removal of the two fractions from each venom abolished the in vitro neurotoxicity, and partially abolished myotoxicity, of the whole venom. A combination of the two fractions from each venom produced neurotoxic activity that was equivalent to the respective whole venom (10 µg/mL), but the myotoxic effects were not additive. The in vitro neurotoxicity of fraction 8 (100 nM) from each venom was prevented by the pre-administration of Thai Russell's viper monovalent antivenom (2× recommended concentration) or preincubation with Varespladib (100 nM). Additionally, the neurotoxicity produced by a combination of the two fractions was partially reversed by the addition of Varespladib (100-300 nM) 60 min after the fractions. The present study demonstrates that the in vitro skeletal muscle effects of Thai and Javanese D. siamensis venoms are primarily due to key PLA₂ toxins in each venom.

01 Jul 2024·CLINICAL NUTRITION

Inhibiting arachidonic acid generation mitigates aging-induced hyperinsulinemia and insulin resistance in mice

Article

Author: Zhu, Yunxia ; Han, Xiao ; Xiao, Lei ; Chang, Xiaoai ; Xiao, Xiao ; Li, Yating ; Tang, Wei ; Yang, Longxuan

BACKGROUND:

Aging-related type 2 diabetes (T2DM) is characterized by hyperinsulinemia, insulin resistance, and β-cell dysfunction. However, the underlying molecular mechanisms remain to be unclear.

METHODS:

We conducted non-targeted metabolomics to compare human serum samples from young adults (YA), elderly adults (EA), and elderly adults with diabetes (EA + DM) of Chinese population. Adult mice and aged mice were intragastrically administered with varespladib every day for two weeks and metabolic characteristics were monitored. Serum levels of arachidonic acid, insulin, and C-peptide, as well as serum activity of secretory phospholipase A2 (sPLA2) were detected in mice. Mouse islet perfusion assays were used to assess insulin secretion ability. Phosphorylated AKT levels were measured to evaluate insulin sensitivities of peripheral tissues in mice.

RESULTS:

Non-targeted metabolomics analysis of human serum samples revealed differential metabolic signatures among the YA, EA, and EA + DM groups. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed significant enhancement of arachidonic acid metabolism and glycerophospholipid metabolism in the EA group compared with the YA group. Further analysis identified two metabolic fluxes that favored the accumulation of arachidonic acid in the elderly. Increased levels of arachidonic acid were also confirmed in aged mice with hyperinsulinemia and insulin resistance, together with subsequent glucose intolerance. Conversely, inhibiting the generation of arachidonic acid with varespladib, an inhibitor of sPLA2, reduced aging-associated diabetes by improving hyperinsulinemia and hepatic insulin resistance in aged mice but not in adult mice. Islet perfusion assays also showed that varespladib treatment suppressed the enhanced insulin secretion observed in aged islets.

CONCLUSIONS:

Collectively, our findings uncover that arachidonic acid serves as a metabolic hub in Chinese elderly population. Our results also suggest that arachidonic acid plays a fundamental role in regulating β-cell function during aging and point to a novel therapy for aging-associated diabetes.

01 Apr 2023·Prostaglandins, leukotrienes, and essential fatty acids

Phospholipase A2 enzymes differently impact PUFA release and oxylipin formation ex vivo in rat hearts

Article

Author: Winter, Tanja ; Aukema, Harold M ; Manson, Anne

Phospholipase A₂ (PLA₂) enzymes cleave cell membrane phospholipids and release polyunsaturated fatty acids (PUFA), which can be converted into oxylipins. However, little is known about PLA₂ preference for PUFA, and even less is known about how this further impacts oxylipin formation. Therefore, we investigated the role of different PLA₂ groups in PUFA release and oxylipin formation in rat hearts. Sprague-Dawley rat heart homogenates were incubated without or with varespladib (VAR), methyl arachidonyl fluorophosphonate (MAFP) or EDTA. Free PUFA and oxylipins were determined by HPLC-MS/MS, and isoform expressions by RT-qPCR. Inhibition of sPLA₂ IIA and/or V by VAR reduced the release of ARA and DHA, but only DHA oxylipins were inhibited. MAFP reduced the release of ARA, DHA, ALA, and EPA, and the formation of ARA, LA, DGLA, DHA, ALA, and EPA oxylipins. Interestingly, cyclooxygenase and 12-lipoxygenase oxylipins were not inhibited. mRNA expression levels of sPLA₂ and iPLA₂ isoforms were highest whereas levels of cPLA₂ were low, consistent with activity. In conclusion, sPLA₂ enzymes lead to the formation of DHA oxylipins, while iPLA₂ is likely responsible for the formation of most other oxylipins in healthy rat hearts. Oxylipin formation cannot be implied from PUFA release, thus, both should be evaluated in PLA₂ activity studies.

News (Medical) associated with Varespladib

23 Oct 2024

·www.biospace.com

Ophirex Publishes Phase 2 Data in BMJ Global Health from the First Use of Varespladib to Treat Venomous Snakebite Victims

Efficacy signal observed in subgroup of victims treated within five hours of bite reinforces critical importance of timely treatment and need for a field therapy that could improve patient outcomes Globally, 75% of deaths from venomous snakebites occur before the victim can reach appropriately-equipped medical care CORTE MADERA, Calif.--(BUSINESS WIRE)--Ophirex, Inc., a Public Benefit Corporation developing an oral treatment to address the unmet medical needs of snakebite victims globally, today announced that BMJ Global Health has published data from the company’s BRAVO trial evaluating oral varespladib. Varespladib is a small synthetic molecule that directly inhibits secretory phospholipase A2 (sPLA2), an enzyme that is present in more than 95% of all snake venoms. The oral form is being developed as an early intervention treatment for patients and has potential to be the first-ever field therapy for snakebite envenoming, providing treatment at “time-of-bite.” The article in BMJ Global Health details results from BRAVO (Broad-spectrum Rapid Antidote: Varespladib Oral for snakebite), a multi-center, randomized, double-blind, placebo-controlled, Phase 2 study designed to evaluate the safety, tolerability and efficacy of oral varespladib. It enrolled 95 patients in the U.S. and India who were administered either varespladib or placebo in conjunction with the standard of care, which included antivenom in 93 of the 95 patients. “The BRAVO trial set out to do something no one has done before. In addition to being the first study to evaluate a direct toxin inhibitor for the treatment of snakebites, BRAVO was the first clinical trial to enroll patients bitten by any species of snake across two continents, including some of the world’s deadliest species,” said Timothy Platts-Mills, M.D., MSc, Chief Medical Officer of Ophirex. “While this Phase 2 study did not meet its primary endpoint, a promising signal of benefit was seen in the group of patients receiving treatment within five hours of a bite, reinforcing varespladib’s potential as an early treatment option and suggesting initial utility as a field treatment.” For the early treatment subgroup, clinically important differences were observed across important outcomes, such as lower illness severity over the first week, higher rates of complete recovery, and improved patient-reported function in patients receiving varespladib. Results from the BRAVO trial also suggest that varespladib is safe and well tolerated for the treatment of snakebite, adding to a robust body of safety data for this therapeutic candidate. “Antivenom, the current standard of care for snakebites, has several limitations, including the need to match antivenom to specific snake types, the risk of anaphylaxis, and the need to be administered intravenously in a medical setting. Yet we know that 75% of deaths due to venomous snakebites occur before the victim ever reaches the hospital. Even in those patients who survive, early treatment leads to better outcomes,” said Charles J. Gerardo, M.D., Professor and Chair for the Department of Emergency Medicine at Duke University and BRAVO trial investigator. “These data represent an encouraging advancement for patients bitten by snakes with the potential to fill a significant unmet need as a real world, early treatment before a patient reaches a healthcare facility.” “India has the greatest snakebite burden in the world, and 97% of snakebite deaths in the country occur in rural areas far from medical care and current treatments. A novel therapeutic molecule such as oral varespladib in addition to standard of care has the potential to enable treatment at the time of bite or en route to a more advanced facility and could be an important improvement in care for patients and medical systems alike,” said Dr. Suneetha D.K., Professor and Head of Internal Medicine, Mysore Medical College and Research Institute, Mysuru and a BRAVO trial investigator. “These findings support Ophirex’s vision to advance varespladib initially as an oral field treatment available at the time of the bite. We look forward to applying key learnings from this clinical trial to ongoing studies that address the long unmet need for a field treatment,” said Matthew R. Lewin, MD, PhD, Chief Scientific Officer and Founder of Ophirex, who first published the concept of this molecule as a field treatment in snakebite in 2016. The manuscript, titled “Oral Varespladib for the Treatment of Snakebite Envenoming in India and the United States (BRAVO): A Phase 2 Randomised Clinical Trial,” is available online here . About Ophirex Ophirex is a Delaware Public Benefit Corporation developing a first-of-its-kind oral treatment to address the global unmet need of venomous snakebites. Worldwide, there are approximately 500,000 cases of snakebite envenoming resulting in death or permanent disability each year. While antivenom has been the standard of care to treat these bites for more than 100 years, it can only be administered in a hospital setting. This poses a significant challenge as 75% of deaths from venomous snakebites occur before the victim can reach appropriately equipped medical care. Ophirex is advancing its investigational treatment, varespladib, as a broad-spectrum treatment for snakebite in both oral and intravenous formulations with human and veterinary applications. Ideally taken immediately following a bite, it is intended to provide a bridge to survival between bite and arrival to the hospital. If successful, this early intervention is anticipated to result in improved overall outcomes for patients at risk of death and long-term disability from snakebite. The company has presented some of the BRAVO data at scientific conferences. Ophirex is concluding a separate Phase 2 study to evaluate IV-to-oral dosing of varespladib for snakebite envenoming based on learnings from BRAVO. For more information, visit . Contacts Media Contact: Emma Yang Health+Commerce emma@healthandcommerce.com 908-391-7197

Phase 2Clinical Result

07 May 2024

·www.sciencedaily.com

First effective treatment found for spitting cobra snakebite

Scientists have discovered a new snakebite treatment to prevent the devastating tissue damage caused by African spitting cobra venom. Spitting cobra venom is incredibly potent and causes dermonecrosis, which presents as rapid destruction of skin, muscle and bone around the site of the snakebite, and can lead to permanent injuries and disfigurements, including limb loss and amputations in extreme cases. Using the repurposed small molecule drug varespladib to block one of the two major dermonecrosis-causing toxins in spitting cobra venom prevents skin and muscle damage. Each year, it is estimated that snakebite causes long term detrimental effects in around 400,000 people across the world, with a substantial proportion of those in Africa the result of spitting cobra bites. Scientists have discovered a groundbreaking new snakebite treatment to prevent the devastating tissue damage caused by African spitting cobra venom. Spitting cobra venom is incredibly potent and causes dermonecrosis, which presents as rapid destruction of skin, muscle and bone around the site of the snakebite, and can lead to permanent injuries and disfigurements, including limb loss and amputations in extreme cases. Professor Nicholas Casewell and Liverpool School of Tropical Medicine colleagues including Dr Steven Hall -- who is now at Lancaster University- discovered that using the repurposed small molecule drug varespladib to block one of the two major dermonecrosis-causing toxins in spitting cobra venom prevents skin and muscle damage. Each year, it is estimated that snakebite causes long term detrimental effects in around 400,000 people across the world, with a substantial proportion of those in Africa the result of spitting cobra bites. Currently, there is no effective treatment for tackling severe local envenoming caused by spitting cobra venom. Existing antivenoms only work on bites by other snake species and are often ineffective for treating local envenoming because antivenom antibodies are too large to effectively penetrate into the region around the bite site. Professor Nicholas Casewell of LSTM said: "Our findings hold much promise to improve the treatment of tropical snakebite. Current treatments for spitting cobra bites are widely regarded as being ineffective, meaning that rates of disability and amputation have remained high across much of Africa. Our data shows that blocking just one of the main toxin families in spitting cobra venom will likely prevent the debilitating tissue damage seen in thousands of snakebite patients each year." Professor Casewell's team, led by PhD student Keirah Bartlett and Dr Steven Hall, then of LSTM and now at Lancaster University, and also involving researchers from Canada, Denmark, Costa Rica and the USA, first analysed spitting cobra venom to identify the toxins responsible for causing venom-induced dermonecrosis. The results showed that cytotoxic three-finger toxins (CTx) are largely responsible but that phospholipases A2 (PLA2) toxins play a critical role in the process. Local injection of the PLA2-inhibiting drug varespladib reduced the extent of dermonecrosis, even when delivered up to an hour after the venom, and the protection conferred by the drug also extended to venom-induced muscle toxicity. According to the authors, the findings suggest that varespladib could become an invaluable treatment against the tissue-damaging effects of black-necked and red spitting cobra venoms, which cause extensive morbidity in snakebite victims across the African continent. Lead author Keirah Bartlett said: "These findings are extremely promising, not only does this offer up a new mode of treatment where previously nothing effective existed, but because varespladib has already gone through testing in human clinical trials, including for snakebite, it could be available for use in real world patients very soon." Dr Hall added: "Snakebite is a devastating neglected tropical disease, with tissue destruction caused by necrotic snake venoms permanently injuring hundreds of thousands of victims every year. Our work shows that the repurposed drug, Varespladib, is incredibly effective at inhibiting such necrosis caused by African spitting cobras; an exciting finding as their venoms are particularly fast-acting and destructive. We hope this work helps pave the way to future snakebite therapies that can save the lives and limbs of victims worldwide." Professor Casewell's team are already looking for viable treatments that effectively block the venom CTx. Having treatments available against both toxins has the potential to enhance the potency of varespladib, and could significantly reduce the long-term morbidity associated with spitting cobra bites in Africa and beyond.

Clinical Result

06 Dec 2011

·www.biospace.com

Anthera Pharmaceuticals, Inc. Promotes Dr. Debra Odink to Chief Technology Officer

HAYWARD, Calif., Dec. 5, 2011 /PRNewswire/ -- Anthera Pharmaceuticals, Inc. (Nasdaq: ANTH), a biopharmaceutical company developing therapeutics to treat serious diseases associated with inflammation and autoimmune disorders, today announced Dr. Debra Odink has been promoted to the role of Chief Technology Officer and Senior Vice President. "Over the past several years, Debra's increasing roles, responsibility and scientific leadership has been critical to the success of Anthera's development programs," said Paul F. Truex, President and Chief Executive Officer. "As Chief Technology Officer, Debra's strong oversight will continue to drive the advancement and execution of our corporate strategy." Dr. Odink joined Anthera in 2005 and has been serving as the Senior Vice President of Pharmaceutical Research and Development since that date. She has over eighteen years of global pharmaceutical chemistry and product development experience. Prior to joining Anthera, she served as the Vice President of Product and Process Development at Peninsula Pharmaceuticals where she was responsible for the company's manufacturing and product development strategies for assets licensed to the company. Additionally, she has held various positions at Elan Pharmaceuticals and Roche where she contributed to development efforts for multiple new drug candidates. Dr. Odink holds various patents for novel drug formulations and is author of multiple publications. She obtained her Bachelor of Science in Chemistry at California State University Stanislaus and her Ph.D. in Inorganic Chemistry at the University of California Davis. About Anthera Pharmaceuticals Anthera Pharmaceuticals is a biopharmaceutical company focused on developing and commercializing products to treat serious diseases associated with inflammation, including cardiovascular and autoimmune diseases. Anthera has one Phase 3 clinical program, A-002, and two Phase 2 clinical programs, A-623 and A-001. A-002 and A-001 inhibit a novel enzyme target known as secretory phospholipase A2, or sPLA2. Elevated levels of sPLA2 have been implicated in a variety of acute inflammatory conditions, including acute coronary syndrome and acute chest syndrome, as well as chronic diseases such as stable coronary artery disease, or CAD. Anthera's Phase 2 product candidate, A-623, targets elevated levels of B-lymphocyte stimulator, or BLyS, which has been associated with a variety of B-cell mediated autoimmune diseases, including systemic lupus erythematosus, or lupus. For more information, please visit . Safe Harbor Statement Any statements contained in this press release that refer to future events or other non-historical matters, including statements that are preceded by, followed by, or that include such words as "estimate," "intend," "anticipate," "believe," "plan," "goal," "expect," "project," or similar statements, are forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements are based on Anthera's expectations as of the date of this press release and are subject to certain risks and uncertainties that could cause actual results to differ materially as set forth in Anthera's public filings with the SEC, including Anthera's Annual Report on Form 10-K for the year ended December 31, 2010 and Quarterly Report on Form 10-Q for the quarter ended September 30, 2011. Anthera disclaims any intent or obligation to update any forward-looking statements, whether because of new information, future events or otherwise, except as required by applicable law. CONTACT: Bianca Nery of Anthera Pharmaceuticals, Inc., bnery@anthera.com or 510.856.5586. SOURCE Anthera Pharmaceuticals, Inc.

100 Deals associated with Varespladib

External Link

KEGG	Wiki	ATC	Drug Bank
D08221	Varespladib	-	DB05737

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Coronary Syndrome	Phase 3	US	Anthera Pharmaceuticals, Inc.	01 May 2010
Acute Coronary Syndrome	Phase 3	AU	Anthera Pharmaceuticals, Inc.	01 May 2010
Acute Coronary Syndrome	Phase 3	CA	Anthera Pharmaceuticals, Inc.	01 May 2010
Acute Coronary Syndrome	Phase 3	CZ	Anthera Pharmaceuticals, Inc.	01 May 2010
Acute Coronary Syndrome	Phase 3	GE	Anthera Pharmaceuticals, Inc.	01 May 2010
Acute Coronary Syndrome	Phase 3	DE	Anthera Pharmaceuticals, Inc.	01 May 2010
Acute Coronary Syndrome	Phase 3	HU	Anthera Pharmaceuticals, Inc.	01 May 2010
Acute Coronary Syndrome	Phase 3	IN	Anthera Pharmaceuticals, Inc.	01 May 2010
Acute Coronary Syndrome	Phase 3	IT	Anthera Pharmaceuticals, Inc.	01 May 2010
Acute Coronary Syndrome	Phase 3	LB	Anthera Pharmaceuticals, Inc.	01 May 2010

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01130246 (VISTA-16, Pubmed \| JAMA)	Phase 3	Acute Coronary Syndrome	5,145	Varespladib	(lsrsuxzxdp) = symhpjzybj zbpyzbydge (alwuwdvjhs ) View more	Negative	15 Jan 2014
				Placebo	(lsrsuxzxdp) = knwpvwklts zbpyzbydge (alwuwdvjhs ) View more
NCT00743925 (FRANCIS-ACS, Pubmed \| J Am Coll Cardiol)	Phase 2	Acute Coronary Syndrome	625	Varespladib 500 mg	(gqijrxibem) = rrshsgarqi dxmdwvwlpd (uhtuajfhzo ) View more	Positive	28 Sep 2010
				Placebo	(gqijrxibem) = txkdpbfggd dxmdwvwlpd (uhtuajfhzo ) View more

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