Document text
Principal Investigator: Siddhartha De
Organization: 7 HILLS PHARMA, LLC
Fiscal Year: 2024
Award: $953,477
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Americans aged ≥65 years accounted for 57% and 75% of all influenza-related hospitalizations and deaths,
respectively, in the 2019-20 season, despite a vaccination rate of ~68%. Flu vaccine effectiveness is lower in
the elderly than in younger adults, requiring either a high-dose (Fluzone® HD) or an adjuvanted (FluAd®) vaccine.
Antigen mismatch in vaccine vs. circulating strains results in insufficient protection, and poor responses in the
elderly remain major public health concerns. Cell-mediated immunity may correlate better than humoral
immunity for vaccine protection in the elderly. Adjuvants used to enhance vaccine efficacy, such as MPLA, CpG
and alum, trigger either innate or antibody responses, but not a T cell response. While existing adjuvants or
increased antigen load may partially improve seroconversion, overall vaccine effectiveness and T cell responses
may be suboptimal in at-risk populations. New adjuvants are needed that induce robust T cell responses for
pathogen clearance. A key factor for suboptimal vaccine effectiveness in the elderly is immunosenescence, a
gradual age-related immune decline. Prolonged cell adhesion mediated by integrins α4β1 and αLβ2 and their
cognate ligands, VCAM-1 and ICAM-1, is essential for effective antigen presentation and T cell priming at the
immune synapse between antigen presenting cells (APCs) and naïve T cells, as well as for T cell memory and
effector functions. Deficient APC-T cell adhesion attenuates T cell activation and memory. Age-related defects
in ICAM-1 induction on activated dendritic cells may decrease T cell priming, resulting in suboptimal vaccine
effectiveness in the elderly. 7HP349 is a first-in-concept, oral, small-molecule, allosteric α4β1/αLβ2 activator that
may promote APC-T cell adhesion, and improve T helper function and the effectiveness of geriatric influenza
vaccination. In mice, 7HP349 significantly improved the effectiveness of influenza, Chagas disease, SARS-CoV-
2 and tuberculosis vaccines, not only via humoral responses but also cell-mediated immunity, which differentiates
it from current or emerging competition. A first-in-human Phase I clinical study to evaluate the safety, tolerability
and PK of 7HP349 in healthy male subjects was completed in 4Q 2021. 7HP349 was shown to be safe and orally
bioavailable, with no treatment-related serious adverse events. Additionally, the optimal pharmacokinetic dose
was identified. In this application, we propose to evaluate 7HP349 as an oral adjuvant to influenza vaccination
in aging mice with pre-existing immunity, that would be representative of vaccination in the elderly. Additionally,
to activate a supplemental IND for geriatric influenza, we plan to complete additional required Chemistry,
Manufacturing and Control activities that will include development of a 100 mg strength to enable once daily,
one pill dosing to improve patient compliance, and manufacture of cGMP 7HP349 Drug Product to support the
IND and build inventory for a future Phase I/IIa clinical study in elderly subjects to assess the safety of 7HP349
and to evaluate its immunogenicity in combination with Fluzone® HD, which will also lay the foundation for its
potential use in enhancing the effectiveness of other infectious disease vaccines in vulnerable sub-populations.
Terms: <19S Gamma Globulin><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><7S Gamma Globulin><> 65 years><Acylneuraminyl hydrolase><Adjuvant><Aged 65 and Over><Aging><Agreement><Alum Adjuvant><American><American Trypanosomiasis><Animal Model><Animal Models and Related Studies><Antibody Response><Antigen Presentation><Antigen-Presenting Cells><Antigens><Assay><Attenuated><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bioassay><Bioavailability><Biological Assay><Biological Availability><Blood Serum><CD106><CD106 Antigens><CD49d-CD29><CD54 Antigens><COVID-19 virus><COVID19 virus><Cell Adhesion><Cell Locomotion><Cell Mediated Immunology><Cell Migration><Cell Movement><Cell-Mediated Immunity><Cellular Adhesion><Cellular Immunity><Cellular Migration><Cellular Motility><Cessation of life><Chagas Disease><Chemistry><Clinical><Clinical Research><Clinical Study><Clinical Trials><CoV-2><CoV2><Communicable Diseases><Control Groups><Cross Reactions><Cyclic GMP><Data><Death><Defect><Dendritic Cells><Development><Disease><Disorder><Dosage Forms><Dose><Drug Kinetics><Drugs><ELISA><ELISPOT><Effectiveness><Elderly><Enzyme-Linked Immunosorbent Assay><Equipment and supply inventories><Exposure to><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Flu vaccination><Fluzone><Formulation><Foundations><Future><Grippe><Groups at risk><Guanosine Cyclic Monophosphate><Guidelines><H1N1><H1N1 Virus><H5N1><H5N1 virus><Hemagglutinin><Hospital Admission><Hospitalization><Human><Humoral Immunities><ICAM-1><INCAM-110><IgA><IgG><IgM><Immune><Immune response><Immune system><Immunes><Immunity><Immunoglobulin A><Immunoglobulin G><Immunoglobulin M><Immunological response><Individual><Inducible Cell Adhesion Molecule 110><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza><Influenza A H5N1><Influenza A Virus, H1N1 Subtype><Influenza A Virus, H5N1 Subtype><Influenza Vaccines><Influenza Virus><Influenza immunization><Influenza vaccination><Integrin Heterodimer alpha4beta1><Integrin alpha(4)beta(1)><Integrin alpha4beta1><Integrin α4β1><Integrin-mediated Cell Adhesion><Integrin-mediated Cell Adhesion Pathway><Integrins><Integrins Extracellular Matrix><Intercellular adhesion molecule 1><Inventory><Life><Ligands><MF59><MTB vaccine><Measures><Medication><Memory><Mice><Mice Mammals><Modern Man><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><N-Acylneuraminate Glycohydrolases><Neuraminidase><New Caledonia><Oligosaccharide Sialidase><Oral><Patient Compliance><People at risk><Persons at risk><Pharmaceutical Preparations><Pharmacokinetics><Phase><Physiologic Availability><Play><Populations at Risk><Pre IND FDA meeting><Pre-IND mtg><Prophylactic vaccination against influenza><Public Health><Recommendation><Risk><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Safety><Schedule><Seasons><Serious Adverse Event><Serum><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe Adverse Event><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Shapes><Sialidase><South American Trypanosomiasis><Speed><Surrogate Markers><T cell response><T memory cell><T-Cell Activation><T-Cells><T-Lymphocyte><TB vaccine><Testing><Time><Tuberculosis Vaccines><VCAM><VCAM-1><VLA-4><Vaccinated><Vaccination><Vaccine for TB><Vaccine for Tuberculosis><Vaccines><Vascular Cell Adhesion Molecule><Vascular Cell Adhesion Molecule-1><Veiled Cells><Very Late Activation Antigen-4><Very Late Antigen-4><Viral><Viral Antigens><Virus><Work><Wuhan coronavirus><above age 65><access to vaccination><access to vaccines><accessory cell><activate T cells><adaptive immunity><adult youth><advanced age><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age associated><age correlated><age dependent><age linked><age of 65 years onward><age related><age specific><aged><aged 65 and greater><aged 65+><aged mice><aged mouse><aged ≥65><alum><aluminum sulfate><anti-TB vaccine><antibody-based immunity><attenuate><attenuates><avian influenza H5N1><avian influenza H5N1 virus><cGMP><cell motility><coronavirus disease 2019 virus><coronavirus disease-19 virus><cross reactivity><developmental><drug/agent><elderly mice><enzyme linked immunoassay><enzyme linked immunospot assay><exo alpha sialidase><first in man><first-in-human><flow cytophotometry><flu immunisation><flu infection><flu serotype><flu strain><flu subtype><flu vaccine><flu viral strain><flu virus infection><flu virus strain><flu virus vaccine><geriatric><hCoV19><host response><human old age (65+)><immune senescence><immune system response><immunogen><immunogenicity><immunological synapse><immunoresponse><immunosenescence><improved><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza serotype><influenza strain><influenza subtype><influenza viral strain><influenza virus infection><influenza virus strain><influenza virus vaccination><influenza virus vaccine><influenzavirus><male><manufacture><memory T lymphocyte><model of animal><mortality><mouse model><murine model><nCoV2><old age><old mice><over 65 years><pandemic><pandemic disease><pathogen><patient adherence><patient cooperation><pill><pre-IND consultation><pre-IND discussion><pre-IND meeting><pre-Investigational New Drug meeting><pre-clinical><pre-clinical study><preclinical><preclinical study><programs><residence><residential building><residential site><response><safety assessment><safety testing><senior citizen><serious adverse experience><serious adverse reaction><seroconversion><small molecule><social role><surrogate bio-markers><surrogate biomarkers><thymus derived lymphocyte><vaccination access><vaccination against influenza><vaccination availability><vaccination study><vaccination trial><vaccine access><vaccine against M. tuberculosis><vaccine against Mtb><vaccine against Mycobacterium tuberculosis><vaccine against TB><vaccine against flu><vaccine against influenza><vaccine against tuberculosis><vaccine availability><vaccine candidates against tuberculosis><vaccine effectiveness><vaccine efficacy><vaccine response><vaccine responsiveness><vaccine study><vaccine trial><vaccine-induced response><virus antigen><young adult><young adulthood><≥65 years>