TLR6

Advances a new formulation with improved stability in the clinicSingle ascending dose phase successfully completed, multiple ascending dose phase underway MELBOURNE, Australia, Aug. 27, 2024 (GLOBE NEWSWIRE) -- ENA Respiratory, a clinical-stage pharmaceutical company developing innate immune modulators for the prevention of complications associated with respiratory viral infections in at-risk populations, announces today that it has advanced its Phase Ib study of its dry powder formulation of INNA-051 to enable clinical progression of an improved drug product with an anticipated shelf life of over two years at room temperature. The study is designed to test the safety, tolerability, pharmacodynamics, and pharmacokinetics of INNA-051 administered intra-nasally as a new dry powder formulation to individuals aged 60 and over. The study is to recruit up to 40 participants and is being conducted at Scientia Clinical Research facility in Sydney, Australia. The first two cohorts have successfully been dosed with single ascending doses with safety in line with expectations for INNA-51’s mode of action and the multiple ascending dose phase of weekly dosing is underway. Results are expected in Q4 of this year. ENA Respiratory’s CEO, Christophe Demaison, PhD, said: “Despite advances in vaccines and antiviral treatments, serious viral respiratory infections remain a major cause of hospitalisation and mortality for older adults with comorbiditiesi, a population of over 34 million people in the US alone. INNA-051 is designed to boost the body’s innate immune response – the natural first line of defence – directly at the site of infection and prevent complications relating to viral infections whether caused by a common respiratory virus or an emerging new strain. This Phase Ib is a further important step in our clinical development plan as we aim to bring this potentially impactful new approach to patients at risk of significant harm from respiratory viral infections.” A virus-agnostic intranasal antiviral host defence immunomodulator, INNA-051, is a potent first-in-class agonist of toll-like receptor 2/6 (TLR2/6), which plays a key role in recognizing pathogens and triggering the innate immune response. Having demonstrated accelerated viral clearance and local stimulation of antiviral host defences in a Phase IIa proof-of-principle study using a liquid formulation in an influenza-challenge model, ENA Respiratory has developed an improved dry powder formulation which extends product shelf life to more than 24 months at room temperature with no requirement for cold-chain storage and distribution. ENA is preparing for an international Phase IIb study to assess the safety and potential efficacy of INNA-051 in decreasing the duration and severity of illness related to community-acquired respiratory viral infections in older adults in assisted living facilities at risk due to comorbidities including COPD, asthma cardiovascular disease and diabetes. About ENA Respiratory ENA Respiratory is a clinical-stage pharmaceutical company tackling serious respiratory viral infections through the development of host defence immune modulators which locally prime and boost the body’s innate immune response – the natural first line of defence. Being virus-agnostic, immune modulators are complementary to often virus-specific vaccines and existing direct-acting antivirals. The company’s lead product, INNA-051, is a potent agonist of toll-like receptor 2/6 (TLR2/6) which plays a key role in recognising pathogens and triggering the innate immune response. With a safe profile supporting prophylaxis use, it has demonstrated accelerated viral clearance and stimulation of antiviral host defences, including IFN Type I & III responses, in a Phase IIa proof-of-principle study using an influenza-challenge model. INNA-051 is being developed as a convenient, once-a-week nasal dry powder product to prevent complications associated with respiratory viral infections in at-risk populations, including the elderly, those with an underlying medical condition (including chronic lung conditions, diabetes, kidney disease, and cardiovascular disease) and individuals with occupational risk (e.g. first responders, military or essential services personnel). Headquartered in Melbourne, Australia, the company has raised US$26M (AU$44million) in equity financing from Brandon Capital, The Minderoo Foundation and Uniseed. It is partnered with the COPD Foundation to support the clinical development of INNA-051 in COPD and has been awarded a US$8.18million contract from the U.S. Department of Defence. It is a member BLUE KNIGHT™, a joint initiative between Johnson & Johnson Innovation and BARDA designed to accelerate next-gen potential solutions for future pandemics. For more information, please visit https://enarespiratory.com Follow us on LinkedIn: https://www.linkedin.com/company/enarespiratory-pty-ltd/ For further information please contact:Media – AustraliaKirrily Davis, E: kdavis@bcpvc.com M: +61 (0)401 220228 Media – InternationalCharles ConsultantsSue Charles, E: sue.charles@charles-consultants.com M: +44 (0)7968 726585Chris Gardner, E: Chris@CGComms.onmicrosoft.com M: +44 (0)7956 031077 ____________________ i https://archive-cdc-gov.libproxy1.nus.edu.sg/#/details?url=https://www-cdc-gov.libproxy1.nus.edu.sg/ncird/surveillance/respiratory-illnesses/index.html

MELBOURNE, Australia, April 29, 2024 (GLOBE NEWSWIRE) -- ENA Respiratory, a clinical-stage pharmaceutical company developing innate immune modulators for the prevention of complications associated with respiratory viral infections in at-risk populations, announces today that the U.S. Food and Drug Administration (‘FDA’) has issued a ‘safe to proceed’ notice for its investigational new drug (‘IND’) application for a Phase 1b study of its novel dry powder formulation of INNA-051. A virus-agnostic intranasal antiviral host defence immunomodulator, INNA-051 is a potent first-in-class agonist of toll-like receptor 2/6 (TLR2/6) which plays a key role in recognizing pathogens and triggering the innate immune response. Having demonstrated accelerated viral clearance and local stimulation of antiviral host defences in a Phase IIa proof-of-principle study using a liquid formulation in an influenza-challenge model, ENA Respiratory has developed an improved dry powder formulation to take into further clinical development. ENA Respiratory’s CEO, Christophe Demaison, PhD said: “We are pleased that the FDA has cleared our IND for our dry powder formulation of INNA-051, which is expected to provide extended shelf life at room temperature. FDA clearance is a significant milestone for the company as it supports late-stage clinical development of INNA-051.” In parallel with the IND application, ENA has submitted ethics approval for a Phase 1b study in Australia. This study is expected to be initiated in mid-2024 with the aim to assess the safety, tolerability, pharmacodynamics, and pharmacokinetics of the dry powder formulation of INNA-051 in older adults. ENA Respiratory’s Medicine Development Leader Ruth Tal-Singer, PhD said: “The study is an essential step in supporting our planned international seasonal prophylaxis Phase 2b study in older adults at risk of severe complications from viral respiratory diseases due to conditions including diabetes, cardiovascular or lung diseases. By targeting the innate immune system at the primary site of most viral respiratory infections, INNA-051 has the potential to address an unmet need in this most vulnerable population as a complementary virus-agnostic approach to available vaccines and direct-acting antivirals, which are often virus-specific.” About ENA Respiratory ENA Respiratory is a clinical-stage pharmaceutical company tackling serious respiratory viral infections through the development of host defence immune modulators which locally prime and boost the body’s innate immune response – the natural first line of defence. Being virus-agnostic, immune modulators are complementary to often virus-specific vaccines and existing direct-acting antivirals. The company’s lead product, INNA-051, is a potent agonist of toll-like receptor 2/6 (TLR2/6) which plays a key role in recognising pathogens and triggering the innate immune response. With a safe profile supporting prophylaxis use, it has demonstrated accelerated viral clearance and stimulation of antiviral host defences, including IFN Type I & III responses, in a Phase IIa proof-of-principle study using an influenza-challenge model. INNA-051 is being developed as a convenient, once-a-week nasal dry powder product to prevent complications associated with respiratory viral infections in at-risk populations, including the elderly, those with an underlying medical condition (including chronic lung conditions, diabetes, kidney disease, and cardiovascular disease) and individuals with occupational risk (e.g. first responders, military or essential services personnel). Headquartered in Melbourne, Australia, the company has raised US$26M (AU$44million) in equity financing from Brandon Capital, The Minderoo Foundation and Uniseed. It is partnered with the COPD Foundation to support the clinical development of INNA-051 in COPD and has been awarded a US$8.18million contract from the U.S. Department of Defence. It is a member BLUE KNIGHT™, a joint initiative between Johnson & Johnson Innovation and BARDA designed to accelerate next-gen potential solutions for future pandemics. For more information, please visit https://enarespiratory.com Follow us on LinkedIn For further information please contact: Media – Australia Kirrily Davis, E: kdavis@bcpvc.com M: +61 (0)401 220228 Media – International Charles Consultants Sue Charles, E: sue.charles@charles-consultants.com M: +44 (0)7968 726585 Chris Gardner, E: Chris@CGComms.onmicrosoft.com M: +44 (0)7956 031077

The TLR agonists used in vaccine formulations come in various forms, ranging from lipopeptides to single-stranded DNA and RNA. Below, we will introduce the main categories of TLR adjuvants. 👇Please click on the picture link below for free registration or login directly if you have freemium accounts, you can browse the latest research progress on drugs, indications, organizations, clinical trials, clinical results, and drug patents related to this target. TLR2TLR2 is expressed on the surface of various cells, including monocytes, macrophages, endothelial cells, epithelial cells, natural killer cells, dendritic cells, myeloid-derived suppressor cells, platelets, and mast cells. The PAMP library recognized by TLR2 is the most extensive, as it can form heterodimers with TLR1 and TLR6 (and TLR10 in humans). The range of TLR2 adjuvants is extensive, including synthetic lipopeptides (PAM3CSK4 and PAM2CSK4), arabino-mannose lipids, phospholipidic acid, GPI membrane anchors, yeast polysaccharides, and peptidoglycans. Recent trends in TLR2 research include the discovery of small synthetic TLR2 agonists, improvements in the characteristics of traditional TLR2 agonists, and the bio-conjugation of TLR2 with vaccine antigens. For example, XS15 (PAM3CS-GDPKHPKSF) is a new TLR-1/2 agonist based on PAM3CS, where the four lysines (K4) of PAM3CSK4 are replaced with a nonapeptide (GDPKHPKSF) to alter the solubility of the conjugate, promoting uptake and facilitating purification. Constraints of using TLR2 agonists as adjuvants include the size, complexity, and hydrophobicity of most ligands. TLR3TLR3 is an intracellular recognition system that reacts to viral nucleic acids (dsRNA, ssRNA, and ssDNA) and endogenous double-stranded RNA. Many TLR3 agonists have been developed, such as RGC100 and ARNAX, a synthetic DNA-RNA hybrid compound. However, in the past two years, researchers have returned to using traditional dsRNA analog ligands, such as poly IC, focusing on improving their delivery modes and new disease applications. TLR4TLR4 is the most studied member of the TLR family, recognizing lipopolysaccharides (LPS). TLR4 is located on the cell membrane, mainly expressed on myeloid cells, but not on plasmacytoid dendritic cells (pDCs) and immature B cells. TLR4 recognizes LPS through its co-receptors myeloid differentiation factor-2 (MD-2) and CD14. Recent works on TLR4 agonists concentrate on the development and evaluation of modified products, such as monophosphoryl lipid A (MPLA) and Glucopyranosyl lipid A (GLA), which are structurally related to LPS, but have no high pyrogenicity while maintaining strong immunoenhancing characteristics, thus increasing their clinical feasibility. TLR5TLR5 recognizes flagellin protein and is expressed on epithelial cells and immune cells (such as macrophages and immature DC), generating immune responses through the MyD88-dependent signaling pathway. Recent work on TLR5 agonists has mainly focused on enhancing tolerance. Unfortunately, flagellin can induce unnecessary hyperreactivity, as a protein, it can induce antibodies against itself, interfering with its function as an adjuvant. This issue has been solved by research through removing the B cell epitope region from flagellin, the deimmunized flagellin retains its TLR5 adjuvant activity. TLR7/8TLR7 and TLR8 are located on the endosomal membrane of immune cells. TLR7 is primarily expressed in pDC and B cells, while TLR8 is expressed in myeloid dendritic cells and monocytes, with lower expression in pDC. TLR7/8 recognizes single-strand ribonucleic acid (ssRNA), and signals through the MyD88-dependent pathway. Among natural ligands, oligonucleotides (ORNs) enriched with adenine and uridine can activate TLR8 without any effect on TLR7. However, ORNs enriched in guanine activate TLR7 and TLR8-dependent signal transduction. TLR7 exists as a monomer and dimerizes in the presence of ligand, while TLR8 exists as weakly dimerized in its natural state and undergoes conformational change when ligand binds. To date, more than15 novel heterocyclic molecules, such as imidazoquinoline, oxazine, pyrimidine, pyridopyrimidine, pyrrolopyrimidine and benzimidazole, have been identified as TLR7/8 agonists. A common drawback of TLR7/8 agonists is their reactogenicity, and in recent years, numerous studies have attempted to overcome these adverse effects. Encapsulating TLR7/8 agonists in nanoparticles based on cationic DOEPC liposome formulations, or covalently linking these small molecules to hyperbranched polymers, can avoid their harmful systemic reactions while preserving their impact on humoral immunity. TLR9TLR9 is located within the endosomal membrane in cells, recognizing the single-stranded unmethylated CpG oligonucleotides of bacteria and virus DNA. TLR9 is expressed on immune cells such as dendritic cells, macrophages, natural killer cells, and other APCs. Synthetic CpG sequences can be used as TLR9 agonists to enhance the immune response of vaccines, and each unique sequence variant combination has been proven to have different structural and biological characteristics. The latest developments in TLR9 agonists in the past two years have mainly focused on the efficient delivery and uptake of CpG to cells. For example, one study introduced a new method of conjugating CpG-ODN to novel cationic liposomes, this compound can induce a strong immune response at low antigen and adjuvant doses. Combined TLR AdjuvantsCombining different TLR agonists in a single vaccine can generate a synergistic effect, driving potent vaccine immune responses. For example, liposomal adjuvants containing 1V270 (TLR7 agonist) and 2B182C (TLR4 agonist) induced balanced anti-HA and anti-NA IgG1 and IgG2a responses against influenza, without the overreactivity commonly associated with Th1 proinflammatory responses. Similarly, one study assessed the co-encapsulation of ovalbumin (OVA) with ten unique combinations of two to three TLR ligands, including Pam3CSK4 (TLR2 agonist), MPLA (TLR4 agonist), imiquimod (TLR7/8 agonist) and CpG (TLR9 agonist), with triple combinations promoting antigen-specific antibody titers through a balanced overall Th1/Th2 response. Therefore, combinations of TLR adjuvants can offer broad customizability of immune responses. Combinations of TLR agonists with other PAMPs such as NOD2 and macrophage-inducible Ca²⁺-dependent lectin receptor (Mincle) ligands are also promising. Covalent linkage of CL239 (TLR7 agonist) and muramyl dipeptide (NOD2 agonist), and incorporation of the dual agonist as nanoparticles with the NP-p24 HIV vaccine, synergistically enhanced protection in mice. SummarizeTLR agonists utilize endogenous innate immune pathways to enhance vaccine adaptive immune responses. Over the past two years, the domain of adjuvants has been primarily governed by research into the COVID-19 vaccine. The driving force of this pandemic has rapidly promoted the development of the adjuvant field, and several novel adjuvants have now been incorporated into licensed vaccines for COVID-19. Beyond COVID-19, the demand for more effective adjuvants continues to grow, particularly in the areas of difficult-to-prevent infectious diseases such as cancer, malaria, tuberculosis, and HIV. Unraveling the mechanisms behind the action of TLR co-adjuvants, coupled with increased safety and efficacy research data, can help drive the development of the next generation of adjuvant platforms.