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Receives New Designation for Treatment of Platelet-Activating Anti-Platelet Factor 4 (PF4) Disorders Complements FDA Orphan Drug Designation and Fast Track Designation for VLX-1005 Aug. 14, 2024 -- Veralox Therapeutics, a clinical-stage biotechnology company developing first-in-class therapies targeting the 12-lipoxygenase (12-LOX) pathway, announced that the European Medicines Agency (EMA) has granted Orphan Drug Designation (ODD) to VLX-1005, a small molecule 12-LOX inhibitor for the treatment of platelet-activating anti-platelet factor 4 (PF4) disorders. VLX-1005 previously secured ODD from the U.S. Food and Drug Administration for prophylaxis of thrombosis in patients with heparin-induced thrombocytopenia (HIT) as well as FDA Fast Track Designation. This latest decision in Europe represents another regulatory achievement and builds on the successful development of VLX-1005 that has progressed through completed Phase 1 clinical studies, and into the ongoing Phase 2 trial ALATHEA (“A study of VLX-1005 to evaluate thrombocyte change in HEpArin-induced thrombocytopenia”). “This EMA designation is an important step forward in the development of VLX-1005 in addressing serious diseases caused by platelet-activating anti-PF4 disorders such as HIT,” said Michael Hanna, M.D., Chief Medical Officer of Veralox Therapeutics. “This is a significant regulatory milestone for Veralox and is an important acknowledgement of the potential of VLX-1005 as treatment for HIT.” HIT is a serious, potentially life-threatening platelet disorder that can arise after taking the blood thinner heparin, which by American Heart Association and European Society of Cardiology guidelines is the standard-of-care anticoagulant for many cardiovascular procedures. Heparin is commonly used to prevent blood clots following heart surgeries, cardiopulmonary bypass and many other procedures such as kidney dialysis. In rare cases, heparin triggers a reaction that activates platelets, consuming them in a process that lowers platelet counts (thrombocytopenia) to unsafe levels while promoting clot formation, which then increases the risk for potentially fatal or life-threatening thromboembolic events. Between one quarter and one third of those who develop HIT die from the condition and a significant proportion of patients develop new blood clots, which could result in deep vein thrombosis, pulmonary embolism, heart attack or stroke. VLX-1005 has successfully completed Phase 1 clinical trials and has demonstrated a favorable safety and tolerability profile and preferred pharmacokinetics in healthy participants and is currently enrolling patients in the Phase 2 clinical study. ODD is a designation that provides incentives to advance the development of therapeutics for rare diseases, including reduced fees for multiple steps in the development process such as protocol assistance, marketing authorization applications, and 10 years of market exclusivity. In addition to the above-mentioned benefits within the European Union, member states may also offer specific stimuli for the development of orphan drugs. HIT is a rare but serious complication of heparin exposure during heart, orthopedic, vascular and other surgeries and during kidney dialysis, where heparin is commonly used to prevent blood clotting. Due to the high utilization of heparin, there are more than 300,000 suspected cases of HIT each year in the United States. Approximately 50,000 cases are confirmed each year and these patients have a high risk of developing severe consequences including death (25-30 percent); amputation (10 percent); new thrombosis including deep vein thrombosis (DVT), stroke, myocardial (MI) infarction (20 percent) and major bleeding (20 percent). The diagnosis and management of HIT is complex and a large unmet need remains for new therapies due to the limited available therapeutic options. VLX-1005 is a novel, small molecule inhibitor of 12-lipoxygenase (12-LOX) intended for the treatment or prevention of thrombosis in adults with heparin-induced thrombocytopenia (HIT). A potent and selective inhibitor of 12-LOX, VLX-1005 inhibits platelet 12-HETE production. In vivo inhibition of 12-HETE synthesis and efficacy of VLX-1005 have been shown in animal models of thrombosis and HIT and the efficacy in preventing or treating thrombosis was not accompanied by increases in bleeding. Two Phase 1 studies completed in 96 healthy participants showed favorable safety and tolerability with no deaths, no serious adverse events and no trend in AE reporting with increased dosing of VLX-1005. A Phase 2 study (VLX-1005-003) to evaluate VLX-1005 in patients with suspected HIT is currently enrolling patients across 12 clinical sites. Additional information is available at clinicaltrials.gov, identifier NCT05785819. Veralox Therapeutics Inc. is developing first-in-class therapeutics targeting 12-lipoxygenase, pioneering a new class of therapies that treat the underlying pathologies of serious immune-inflammatory diseases. The company’s lead candidate, VLX-1005, is in development for the treatment of patients with heparin-induced thrombocytopenia. VLX-1005 has previously been awarded Orphan Drug and Fast Track Designations by the U.S. Food and Drug Administration. The company has second-generation orally bioavailable 12-LOX antagonists under development for type 1 diabetes and other immune-mediated and inflammatory diseases. The content above comes from the network. if any infringement, please contact us to modify.

With regards to the AstraZeneca and Johnson & Johnson vaccines, the findings concretely implicate the adenovirus as the culprit behind rare cases of vaccine-induced immune thrombocytopenia and thrombosis. The rare, deadly blood clots triggered by an autoimmune response to the COVID-19 vaccines from Johnson & Johnson and AstraZeneca seem to be caused by a gene that’s also responsible for an unusual but almost identical reaction to the virus that causes the common cold. The findings could have implications for future vaccines.  In a letter published May 15 in The New England Journal of Medicine, an international team of scientists explained that people who carry certain variants of a gene called IGLV3-21*02 are predisposed to developing both vaccine-induced immune thrombocytopenia and thrombosis (VITT) and the same type of reaction after infection with the adenovirus. Both the J&J and AstraZeneca vaccines are delivered to the body in adenovirus vectors, which explains why the etiology of the conditions is the same.  “Our findings have the important clinical implication that lessons learned from VITT are applicable to rare cases of blood clotting after adenovirus infections, as well as having implications for vaccine development," Tom Gordon, M.D., Ph.D., of Flinders University, who led the co-study, said in a press release. Theodore Warkentin, M.D. from McMaster University in Canada and Andreas Greinacher, M.D., from Greifswald University in Germany also led the work.  AstraZeneca’s vaccine, Vaxzevria, was dogged by reports of VITT not long after the shot rolled out in Europe. Soon after, news of VITT in six U.S. patients who took the J&J vaccine emerged as well, prompting officials to pause it to investigate and later restrict its use. It was removed from the market entirely two years later. AstraZeneca’s shot remained available in some parts of Europe until May 2024, when the company requested its marketing approval be revoked due to a decline in demand.  As of May 2023, the same month J&J’s vaccine was pulled, there had been 60 cases of VITT reported in the U.S., including nine deaths. The last count for VITT cases related to AstraZeneca’s vaccine in the U.K. before it was taken off the market was 455, with 81 deaths, according to the U.K.'s healthcare watchdog the Medicines and Healthcare products Regulatory Agency.  The reactions are caused by antibodies against the protein platelet factor 4, or PF4, a protein involved in blood clotting. In 2022, Gordon and his colleagues used a screening method called antibody proteomics to show that antibodies expressed by a variant of IGLV3-21*02 targeted PF4. Genetic analysis of five patients who developed VITT after getting the AstraZeneca vaccine showed that all of them had this gene variant.  Then, in 2023, another research team reported that adenovirus infection led to the same anti-PF4 antibodies and immune thrombocytopenia and thrombosis. The pathogenesis was identical to VITT; this was the first signal of an “anti-PF4 disorder,” as the researchers called it, that might share its etiology.  The two groups teamed up to validate their hypotheses. When they analyzed the structure of the anti-PF4 antibodies from patients in each group and superimposed them, they found they were “extremely similar,” as they wrote in the NEJM letter.  “Such an extraordinary level of autoantibody fingerprint identity between two disorders—at the level of patient-derived antibodies—strongly indicates that VITT and the anti-PF4 disorder that is associated with adenoviral infection are a distinct class of adverse immune responses associated with viral (presumably, adenoviral) structures,” the researchers wrote.  With regards to the AstraZeneca and J&J vaccines, the findings concretely implicate the adenovirus as the cause of VITT rather than other ingredients. But while the researchers know that the immune response to the virus triggers the creation of antibodies to PF4, they still need to identify the antigen, or the proteins or sugars on the virus, that stimulates their creation. This would potentially enable them to genetically engineer the adenovirus vector so it doesn’t have the antigen and, thus, makes adenovirus-based vaccines safer. The team behind the new NEJM paper is currently investigating the antigenic epitope, or the part of the antigen the immune system recognizes, Gordon confirmed to Fierce Biotech Research in an email.  Previously, the Flinders scientists said it may be possible to create a genetic test that can identify patients at risk of VITT as well as to come up with a therapy that neutralizes the anti-PF4 antibodies.  In a statement to Bloomberg earlier this week, an AstraZeneca spokesperson said the company “welcomes any further examination of the possible underlying mechanism of thrombosis with thrombocytopenia syndrome.” J&J told the outlet in an email that it supports the research as well and that “more data are needed to fully understand potential factors that may be associated with this rare event.” 

A mechanism that led some patients to experience cases of deadly clotting following some types of Covid-19 vaccination has been identified in new research. A mechanism that led some patients to experience cases of deadly clotting following some types of Covid-19 vaccination has been identified in new research. In a paper published in Blood, scientists from the University of Birmingham funded by the National Institute for Health and Care Research and the British Heart Foundation have been able to identify how deadly blood clots, in the disease known as Vaccine-Induced Immune Thrombocytopenia and Thrombosis (VITT), occur. Previous studies have shown that patients with VITT produce antibodies that stick to a protein called Platelet factor 4 (PF4) to create a large cluster of molecules called an immune complex. Following the development of a complex, platelets and cells of the immune system causing clotting and inflammation are activated, but the precise nature of what PF4 does in this event was unknown. In this latest study, the team used blood taken from healthy donors, as well as serum and plasma from patients with VITT, and have been able to learn for the first time how PF4 was directly involved in the activation of platelets and resulted in thrombotic events. By sticking to a receptor called c-Mpl on the surface of platelets, PF4 triggered the production of the small cells known to cause clotting. Dr Pip Nicolson, Associate Clinical Professor in Cardiovascular Medicine at the University of Birmingham and senior author of the study said: "The major advances seen in vaccine development during the global Covid-19 pandemic were thrown into sharp relief following the tragic, rare cases of vaccine-induced immune thrombosis. While there were alternative vaccines available to continue to provide protection against the coronavirus in some countries around the world, understanding the mechanisms behind these cases is critical to ensuring that the technology for delivering vaccines can be used with confidence in the future." Dr Richard Buka, Research Fellow in the Institute of Cardiovascular Sciences and co-lead author "As well as identifying a new way in which platelets are being activated in a potentially deadly manner in VITT, our research has also been able to find how this mechanism may lead to new drugs to protect against blood clots in VITT and blood clots in general." Variations on a drug used to treat bone marrow cancers could be developed to protect VITT patients from deadly clotting, the research also found. The team used ruxolitinib, a drug used to treat some types of blood cancer, to block the receptor being triggered by PF4 following the vaccine-induced event. Although they note that the current form of the drug is unsuitable for use in VITT patients, the team nevertheless identified that blocking the pathway through ruxolitinib slowed down platelet aggregation and demonstrates a potential future way to protect patients from blood clots. Dr Samantha Montague, Research Fellow in the Institute of Cardiovascular Sciences at the University of Birmingham and co-lead author of the paper said: "It is gratifying that we have been able to identify a new, important biological mechanism through trying to thoroughly understand a new disease. This work helps us to understand more fundamental things about how blood clots form and may also be relevant in other related diseases that are more common. "Our ongoing research funded by the British Heart Foundation is looking at how we can identify patients who may develop VITT, with a view that future vaccine programmes around the world can be delivered while understanding and managing the potential risk for those few at greatest risk."