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SALT LAKE CITY, UT, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 145.27K | Year: 2013

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) affects approximately 1.3 million adults in the United States and up to 1.5% of the population worldwide. In its progressive form the disease has debilitating effects including painful inflammation and destruction of the joints. This affliction leads to considerable lost work and disability. A hallmark of the RA inflammatory response is vascular instability. The vascular endothelium is continuously balancing the requirement to maintain a stable network with a capacity to regenerate. It is continuously challenged by destabilizing factors in response to inflammatory stress. An increase in vascular permeability in RA leads to infiltration of the synovial endothelium by leukocytes. Indeed, this may be a critical first step in initiation of RA, as well a its progression. We have shown that inhibition of a non-canonical ARNO/Arf6 pathway, independent of the canonical NF-kB pathway and immune system regulation is involved in maintaining vascular stability and provides consistent therapeutic benefit in a mouse model of RA. Current therapeutics for RA fall into a number of categories: cytokine inhibitors, B cell and T cel depleting or blocking agents, inhibitors of purine and pyrimidine synthesis, NSAIDs, and corticosteroids. While their direct mechanisms of action are varied, the central strategy of these therapies is to dampen the immune response via inhibition of the NF-kB pathway. The dominant market players are costly anti-TNF injectable therapies that carry a considerable risk of increased infection. The goal of this project is to identify clinically and commercially viable structural classes of ARNO/Arf6 small molecule inhibitors that may be effective at preventing the advancement of RA. Atcompletion of this Phase I grant, we will have identified a series of structural classes and hit compounds that reduce endothelial permeability. In Phase II our efforts will focus on optimizing hit compounds for solubility, permeability, metabolic stability, and specificity, while minimizing potential safety concerns. The resulting lead compounds must be novel chemical entities that can be patent protected. Following this optimization step, lead compounds will be tested in in vivo RA models, and their pharmacokinetic, ADME, and safety profiles will be established. By the end of Phase II, we will have a set of prioritized leads and will be well-positioned to begin IND-enabling preclinical studies. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis affects approximately 1.3 million adults in the United States, 1.5% of the population worldwide, and has debilitating effects including painful inflammation and destructions of the joints. The dominant market competitors are costly anti-TNFinjectable therapies that function by dampening the immune response, and therefore carry a considerable risk of infection. The proposed project in this Phase I SBIR will discover small molecules that inhibit a newly discovered ARNO/Arf6 pathway involved in increased vascular permeability while having minimal or no effect on immune system function.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 150.64K | Year: 2013

DESCRIPTION (provided by applicant): Age-Related Macular Degeneration is the most common cause of legal blindness in people over 60, affecting an estimated 1.6 million patients. Additionally, over 400,000 diabetic Americans are diagnosed each year with vision-threatening retinal edema and/or neovascularization. The main therapeutic strategies that have been successful to date have focused on reducing the signals from the destabilizing pathways. This is the basis of anti-VEGF therapies which are costly biologics administered by intraocular injection, typically once monthly. Navigen seeks to explore an alternative and innovative approach to treating the pathologic angiogenesis and endothelial hyperpermeability of the retinal and choroidal vascular beds. Our approach restores the balance toward vascular homeostasis by stimulating vascular stabilization signals. Through its work on guidance cues, the laboratory of Navigen's scientific co-founder, Dr. Dean Li, identified a novel endothelial- specific receptor, Robo4, that when activated by its cognate ligand, Slit2, stabilizes the endothelium and inhibits pathologic cytokine- and growth factor-induced angiogenesis and vascular leak by inhibiting the activation of ADP-ribosylation factor-6 (Arf6). These findings suggest that Robo4 activation, and specifically inhibition of Arf6, provides vascular stabilization signals that actively instruct the endothelium to maintain cell- cell junctions and limit vascular leak and invasion. Our preliminary data and the published literature support the relevance of Arf6 in vascular eye disease. This proposal outlines a strategy to identify novel small molecule inhibitors of Arf6 and to test these in in vitro models of vascular eye disease. By adopting an approach based on identifying small molecule inhibitors of Arf6, we anticipate that potential market advantages include: a small molecule for which topical or oral administration are feasible; a broad based approach to blocking VEGF and other cytokine mediated leak and angiogenesis,and a distinct biochemical pathway that may either replace or augment current anti-VEGF centric therapies. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Age-Related Macular Degeneration is the most common cause of legal blindness in people over 60, affecting an estimated 1.6 million patients. Additionally, over 400,000 diabetic Americans are diagnosed each year with vision threatening retinal edema and/or neovascularization. There is abundant evidence that small G protein ADP ribosylation factor 6 (Arf6) is of therapeutic interest in vascular eye disease; however, no small molecule inhibitors exist to this highly relevant target. The goal of this Phase I SBIR project is o identify clinically and commercially viable structural classes of Arf6 inhibitors that are effectiv at reducing the pathologic angiogenesis and hyperpermeability associated with vascular eye diseases.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 2.00M | Year: 2015

DESCRIPTION provided by applicant Ebola virus causes highly lethal hemorrhagic fever in humans and non human primates Since the first outbreak in there have been over natural human outbreaks with an average mortality rate near There are no approved agents to prevent or treat Ebola infection Due to ease of dissemination high lethality and ability to cause widespread panic the CDC defines Ebola as a Category A bioterror agent their category of highest concern There is great need for an effective Ebola preventative and or treatment to combat both natural outbreaks and potential bioterror attacks Using an innovative mirror image design strategy Navigen has identified a novel D peptide drug lead to combat Ebola D peptides the mirror images of natural L peptides cannot be digested by proteases and therefore have the potential for long in vivo half lives and reduced immunogenicity As peptides they can readily disrupt andquot undruggableandquot large protein protein interfaces with high potency and specificity a rare trait for small molecule drugs Navigenandapos s drug discovery platform employs an enantiomeric screening technology mirror image phage display coupled with protein design to identify and then affinity mature D peptides that block viruses as they attempt to enter cells This platform technology has been successfully validated by Navigenandapos s optimized anti HIV drug currently in advanced preclinical development which binds to a highly conserved region on the HIV envelope protein and blocks entry in all major circulating HIV strains Ebola has a similarly conserved target on its surface protein GP Navigenandapos s anti Ebola drug lead binds to this conserved region and specifically inhibits pseudotyped Ebola entry into target cells with nanomolar potency In this three year SBIR grant Navigen proposes to affinity mature our lead candidate through innovative phage display techniques coupled with structure guided peptide design demonstrate efficacy against multiple Ebola strains in tissue culture perform preclinical pharmacokinetic PK studies and basic toxicology to support animal efficacy experiments and demonstrate efficacy in gatekeeper mouse and gold standard non human primate models of Ebola infection Upon completion of the proposed studies Navigen will be well positioned to execute studies that will lead to new drug approval via the Animal Rule PUBLIC HEALTH RELEVANCE Ebola virus causes a highly lethal hemorrhagic fever for which there are no approved therapeutics or vaccines More than natural Ebola virus outbreaks have occurred with four since the summer of and the virus poses a serious risk as a potential bioterror agent Category A CDC Navigen is developing a novel broad spectrum inhibitor of Ebola virus infection to help protect and or treat individuals during natural outbreak or a bioterror attack


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 557.53K | Year: 2011

DESCRIPTION (provided by applicant): In the United States alone, sepsis affects approximately 700,000 patients and leads to death of over 210,000 people per year. Sepsis is a clinical syndrome that results from a complex interaction between host and infectious agents, and is characterized by systemic activation of inflammatory and coagulation cascades. Hemodynamic changes, widespread microcirculatory disturbances and cellular alterations, leading to an uncoupling between blood flow and metabolic requirements, are implicated in the development of multiple organ dysfunction, responsible for most of deaths. Navigen believes that it has a unique means of preventing the hemodynamic changes and microcirculatory disturbances - the vascular leak - associated with sepsis. Our scientific co-founder, Dr. Dean Li, identified a novel receptor, Robo4, that is expressed in mature vessels and is upregulated following endothelial injury. Robo4, when activated by its protein ligand, Slit2, reduces vascular leak in vitro and invivo. Our work has further illustrated that activation of the Robo4 receptor interferes with the downstream signaling cascades from multiple permeability factors including TNF-alpha, interleukins, and thrombin. We have cloned an active fragment of Slit2,Slit2N, which appears to have identical efficacy to Slit2, and is more easily produced than the native protein. Navigen has demonstrated that Slit2N is effective in reducing mortality in the animal model of sepsis induced by cecal ligation and puncture. Due to the challenges associated with protein therapeutics, Dr. Li sought to identify a small molecule that could affect the Robo4 pathway in a manner similar to Slit2N. Dr. Li and collaborators determined that a critical downstream step in Robo4 activationis the inhibition of a small GTPase, ADP ribosylation factor 6 (ARF6). Dr. Li and colleagues further determined that ARF6 can be blocked through inhibition of its ARF-GEF, cytohesin2/ARNO, using a small molecule inhibitor, NAV838. Dr. Li's laboratory, in collaboration with Navigen, has shown that inhibition of ARF6, either by blocking its ARF-GEF or through the inhibitory activation of Robo4 by Slit2N, produced similar phenotypes: inhibition of VEGF-induced migration in endothelial cells. Navigen is seekingfunding under this application to confirm the efficacy of Slit2N in the treatment of sepsis and to determine whether NAV838, as a small molecule, may be an even more viable approach to treating sepsis than Slit2N. Navigen would anticipate advancing the superior compound forward to IND for eventual commercialization. The proposed research is intended to accomplish 3 goals: 1) develop animal models of sepsis induced by pseudomonas pneumonia (PAP) in which antibiotic therapy dose and timing are titrated to achieve seven-day mortality of approximately 50%, 2) test efficacy and indentify most efficacious dose of Slit2N combined with antibiotic therapy in models of CLP and PAP (PAP established in Aim 1), 3) determine whether NAV838 combined with antibiotics may have greater efficacy than Slit2N plus antibiotics by testing in animal models of CLP and PAP. PUBLIC HEALTH RELEVANCE: Sepsis is a clinical syndrome that results from a complex interaction between host and infectious agents, and is characterized bysystemic activation of multiple inflammatory pathways, including cytokine network and coagulation. Mortality associated with severe sepsis ranges between 30 to 50 percent and sepsis is the leading cause of morbidity and mortality in surgical patients and trauma victims. Currently, there are no effective therapies for the treatment of Sepsis.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 592.07K | Year: 2012

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is the major cause of severe lower respiratory tract infections in children and infants, affecting an estimated 64 million people and causing 160,000 deaths worldwide per year (WHO). Each year in the United States, ~100,000 infants and ~170,000 adults are hospitalized due to RSV infection. High-risk adults (elderly and patients with chronic heart or lung disease) experience the highest RSV-attributed mortality in the US (~14,000 deaths/year), similar to the rates of seasonal influenza. The annual cost of RSV on the US healthcare system is ~ 2 billion. Currently, no vaccines or disease-specific therapeutics are available to combat RSV, and treatment is mostly limited to supportive care. For the most acute cases, ribavirin, a broad-range antiviral with questionable efficacy and significant safety issues can be used, though it is not indicated for adults. Only one preventative is available, Synagis (Palivizumab), a monoclonal antibody that inhibits RSV infection, but its use is limited to high-risk infants. Synagis is very expensive (~ 5000 for a course of therapy) and reduces RSV-related hospitalizations of high-risk infants by only 55%. There is an urgent need for new anti-RSV prophylacticsand therapies that can be applied to a broad patient population. In this project we will apply an innovative strategy to identify novel, protease-resistant D-peptide drug candidates for the critically underserved RSV patient population. Our drug discoveryplatform employs an enantiomeric screening technology (mirror-image phage display) coupled with protein design, to identify D- peptides that stop the virus as it attempts to enter a cell. We have successfully validated this platform technology by identifying a promising anti-HIV preclinical candidate, which is the most specific and potent D- peptide inhibitor known. Our anti-HIV D-peptide targets a conserved pocket found on a region of the HIV envelope protein, the N-trimer, which is transiently exposed during viral entry. It inhibits all maor circulating HIV-1 strains and, by design, possesses an extremely high barrier to resistance. RSV uses a highly similar mechanism of viral entry, and an analogous vulnerable pocket on the N-trimer has been identifiedon the RSV viral surface. This pocket will be the target for our discovery efforts. In this two-year Phase I SBIR, we propose to identify and structurally characterize 1st generation D-peptide RSV entry inhibitors. In Phase II we will rapidly apply all ofthe optimization techniques used in our HIV discovery efforts, which improved the potency of our HIV-specific drug by over six orders of magnitude and gave it an extraordinary resistance barrier. Once we have fully optimized the potency, specificity and resistance profile of our D-peptide RSV entry inhibitor, we will explore its utility as an anti-RSV therapeutic and preventative. PUBLIC HEALTH RELEVANCE: Respiratory syncytial virus (RSV) infection causes hospitalization of an estimated 270,000 infants and high-risk adults in the US each year, leading to 2 billion in medical costs. No therapies exist to treat infected patients, and the only availabe preventative therapy is very expensive, modestly effective, and limited to use in high-risk infants.Navigen Pharmaceuticals is developing a potent and novel inhibitor of RSV infection, which, if successful, will address the considerable unmet need for new anti-RSV prophylactics and therapies that can be applied to a broad patient population.

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