Acute Flaccid Myelitis

A single-RNA-based vaccine against enterovirus-D68, a respiratory virus and causative agent of severe paralytic disease in children, by the Erasmus group shows great promise in generating broadly cross-neutralizing antibodies in mice and macaque models of infection. Enterovirus-D68 (EV-D68; see Glossary), a member of the Picornaviridae positive-sense RNA virus family, is of increased public health concern due to its association with both severe respiratory disease and acute flaccid myelitis (AFM), a paralytic disease with similarities to poliomyelitis [1,2]. The rise in both prevalence and severity of disease associated with EV-D68 makes the need for an effective vaccine more necessary than ever. While enveloped viruses like coronaviruses have a viral This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) grants R01141359 and R01104928. N.P. is supported by NIH/NIAID training grant AI095190. W.T.J. had a role in a prior grant application led by members of the HDT Bio team who were part of the published study. Glossary Acute flaccid myelitis (AFM) a paralytic disease, primarily in young children, associated with viral infection, with global outbreaks in 2012, 2014, 2016, and 2018. Clade a group of viruses within a species thought to have evolved from a common ancestor and displaying common characteristics, often but not always with regards to immune responses. Enterovirus-A71 (EV-71) a respiratory virus, first isolated in 1969, which is extremely similar to EV-D68 in genome organization and capsid structure and is Acute flaccid myelitis (AFM) a paralytic disease, primarily in young children, associated with viral infection, with global outbreaks in 2012, 2014, 2016, and 2018. Clade a group of viruses within a species thought to have evolved from a common ancestor and displaying common characteristics, often but not always with regards to immune responses. Enterovirus-A71 (EV-71) a respiratory virus, first isolated in 1969, which is extremely similar to EV-D68 in genome organization and capsid structure and is

SEATTLE, WA, USA I August 7, 2024 I HDT Bio Corp., a developer of immunotherapies for oncology and infectious diseases, today announced the publication demonstrating the potential for self-amplifying RNA vaccines to be used as tools in our pandemic preparedness toolbox against non-enveloped viruses, a unique group of pathogens. RNA vaccines have revolutionized our ability to respond to pandemics in a timely manner, however, to date, a roadmap for such a response has only been developed and executed for certain enveloped viruses, “a relatively easy target for the technology”, says Dr. Jesse Erasmus, Director of Virology at HDT Bio and senior author. “Both enveloped viruses and RNA vaccines share at least one thing in common; each convert their host cells into bioreactors. In contrast, non-enveloped virusesdepend on complex processes to release their progeny from infected cells, and co-opting those mechanisms to release vaccine antigens from RNA messages is less straightforward.” Non-enveloped viruses, belonging to the same family of viruses that cause Polio, were recently identified as having pandemic potential by the National Institutes of Allergy and Infectious Disease (NIAID). To date, no mRNA vaccines have been described for this group. To develop a roadmap, the authors focused on a prototype member, enterovirus D68 (EV-D68), which spreads via the respiratory route and is implicated in a neuroinvasive disease of children, called acute flaccid myelitis. The study, funded by National Institutes of Health (NIH) and led by researchers at HDT Bio in collaboration with the Rocky Mountain Laboratories (NIAID/NIH), The Institute for Quantitative Biomedicine at Rutgers, and University of Chapel Hill School of Medicine, investigated the efficacy of HDT Bio’s self-amplifying repRNA/LION™ technology for vaccination against EV-D68 respiratory infection and resulting disease. The researchers characterized the antigenic landscape of EV-D68 variants to inform vaccine composition requirements related to circulating strains. Additionally, they demonstrated robust neutralizing antibody responses after vaccination. Given the poor ability of current mRNA vaccines to protect the upper respiratory tract and therefore reduce transmission of the respiratory virus that causes COVID-19, the authors also evaluated whether HDT’s platform could offer any improvements compared to conventional lipid nanoparticle technology in mouse models of EV-D68 respiratory infection. In this model, the RNA vaccine was similar to COVID-19 vaccines, which provided great protection of the lower respiratory tract but poor control of virus in the nose. In contrast, HDT’s vaccine formulated with LION™ was able to control virus in both the nose and the lungs, despite being delivered into the muscle. “Mucosal vaccination by spraying vaccine in the nose or delivery to other mucosal surfaces, is thought to be required for protection of those surfaces”, said Dr. Nikki Warner, first author, “so this is a significant finding, especially if replicated in larger animal models or in humans”. Previously, HDT published studies demonstrating robust control of the virus that causes COVID-19 in the noses of LION™/repRNA-vaccinated hamsters and nonhuman primates. The publication can be found on the Science Translational Medicine website and on the Publications page of the HDT Bio website . More information, including a copy of the paper, can be found online at the Science Translational Medicine press package at https://www.eurekalert.org/press/medpak/ . About HDT Bio HDT Bio is a Seattle-based, clinical-stage biopharmaceutical development company. With core technology and expertise in nucleic acid formulation, the company develops products that seek to harness host-directed immune responses. HDT Bio’s work focuses on infectious disease and oncology vaccines and therapeutics through early-stage collaborations with partners worldwide. The company’s vaccine platforms combine formulation and adjuvant ingredients to stabilize and deliver RNA to the immune system to stimulate responses. HDT Bio’s repRNA/LION™ was the first self-amplifying RNA vaccine platform to ever receive a regulatory authorization. SOURCE: HDT Bio

• The United States Food and Drug Administration (FDA) has cleared the investigational new drug (IND) application for EV68-228-N, a human monoclonal IgG1 against the capsid of enterovirus D68 (EV-D68) designed as an intravenous therapeutic for the treatment of acute flaccid myelitis (AFM) • The Phase 1 study is ongoing, and the first patient has been dosed at the Vanderbilt University Medical Center (VUMC) LONDON, UK I June 28, 2024 I KBio, one of the leading developers of new biological treatments derived from a plant-based production system, today announced that the United States Food and Drug Administration (FDA) has cleared the investigational new drug (IND) application for EV68-228-N, a human monoclonal IgG1 against the capsid of enterovirus D68 (EV-D68) designed as an intravenous therapeutic for the treatment of acute flaccid myelitis (AFM). EV68-228-N is being manufactured by KBio using its proprietary Rapid Protein Production Platform (RP3), which allows for the production of biologics using Nicotiana benthamiana . KBio’s Drug Master File (DMF) was reviewed by the FDA as part of this IND submission. The Phase 1 placebo-controlled double-blinded study is evaluating the safety and pharmacokinetics of single ascending doses of EV68-228-N following intravenous administration in healthy adult volunteers. The first patient has been dosed at the Vanderbilt University Medical Center (VUMC). Dr. Matthew Vogt discovered EV68-228 as a postdoctoral fellow in the Crowe laboratory at the Vanderbilt University Medical Center. In partnership with Dr. Vogt and Dr. C. Buddy Creech, the study’s principal investigator and director of the Vanderbilt Vaccine Research Program, KBio and ZabBio successfully transitioned the antibody from research and discovery into this first-in-human study by leveraging the RP3 platform and the combined decades of regulatory expertise in developing plant-produced biopharmaceuticals at KBio and ZabBio. “We’re pleased that the FDA has granted IND clearance for EV68-228-N in AFM, which is a rare and serious neurologic condition that can cause symptoms such as muscle weakness and progressive paralysis. AFM cases have been rising since 2014, and there are no approved disease-specific treatments,” said Patrick Doyle, chief executive officer at KBio. “Using our proprietary plant-based RP3 platform, we’re able to manufacture a monoclonal antibody that is directed against enterovirus, the most common cause of AFM. This novel platform was developed to produce high-quality biologics in an unprecedented 8-10 weeks, which allows for cost-effective and efficient production. We’re looking forward to continued enrollment in the study and providing a sense of renewed hope for these patients.” The trial will include 36 healthy volunteers ages 18 to 49. Six will receive a placebo (control group) and 30 (in groups of 10) will receive either a 3, 10 or 30 mg/kg dose of EV68-228-N intravenously. As part of the safety evaluation, scientists will monitor the first two participants in each group receiving the experimental treatment for at least 72 hours before others receive the infusion. Researchers will then monitor and evaluate participants during nine subsequent in-person examinations during the next 120 days. The trial is being sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the National Institutes of Health (NIH). It is being conducted in collaboration with multiple academic centers through the NIAID-funded Infectious Diseases Clinical Research Consortium (IDCRC), which encompasses the Institute’s long-standing Vaccine and Treatment Evaluation Units (VTEU). Monoclonal antibodies have expansive applications across diverse therapeutic areas. However, limitations exist in manufacturing these potentially life-saving medicines. Leveraging an eco-friendly production system that offers unprecedented speed and scalability, KBio develops monoclonal antibody therapeutics and vaccines with the potential to address a broad range of indications and public health challenges. About KBio KBio aims to create a new generation of biologics using its plant-based platform, Rapid Protein Production Platform (RP3), which has demonstrated the ability to create drug candidates at a fraction of the time and cost of conventional platforms. The Company is focused on discovering and developing monoclonal antibodies targeting validated pathways for immunological diseases and due to the speed and accuracy of its antibody production system, is positioned well to develop fast follower therapies against validated drug targets. KBio’s plant-based platform also has unique capabilities for addressing public health challenges where rapid development and large-scale production of vaccines and other bioactives are critical. Through a third-party partner, the Company is working with several health organizations that are funding its public health-specific pipeline. Formed in December 2021, KBio is a subsidiary of BAT with operations in the UK and U.S. For more information, please visit www.kbio.com . About Infectious Disease Clinical Research Consortium (IDCRC) The IDCRC , consisting of the Vaccine Treatment and Evaluation Units (VTEUs) and the IDCRC Leadership Group (UM1AI148684), was formed in 2019 to support the planning and implementation of infectious diseases clinical research that efficiently addresses the scientific priorities of NIAID. The consortium includes infectious diseases leaders and clinical researchers from Emory University, University of Maryland School of Medicine, Baylor College of Medicine, Cincinnati Children’s Medical Center and University of Cincinnati, FHI360, Fred Hutchinson Cancer Research Center, Johns Hopkins University, Kaiser Permanente Washington Health Research Institute, New York University, Saint Louis University, Vanderbilt University Medical Center, University of Alabama at Birmingham, University of Rochester, University of Washington, and NIAID. View other IDCRC studies . SOURCE: KBio