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Navigen, Inc. and University of Utah | Date: 2017-04-05

Disclosed herein are compounds and methods for inhibiting Arf6. Pharmaceutical compositions and methods for treating a subject with an inhibitor of Arf6 are also disclosed herein.


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: 3.00M | Year: 2013

DESCRIPTION provided by applicant With million people living with HIV AIDS including million in the US and million AIDS related deaths annually HIV AIDS remains a formidable global epidemic UNAIDS CDC Modern HIV therapy combines drugs from different classes to form andquot cocktailandquot therapies that have significantly prolonged the lives of many HIV patients However side effects and drug resistance remain serious concerns Thus there is an enduring need for novel HIV inhibitors with new mechanisms of action and stronger barriers to resistance Navigen is a pharmaceutical development company targeting infectious diseases Through an innovative discovery and design process we have identified a novel HIV entry inhibitor protease resistant D peptide that targets HIVandapos s conserved entry machinery and overcomes the current limitations of this inhibitor class Our lead candidate chol PIE trimer inhibits diverse strains from all major subtypes of HIV with high potency and possesses an unprecedented barrier to resistance Further chol PIE trimer appears from our Phase I SBIR preclinical studies to possess pharmacokinetic PK and physicochemical properties that would support development of a once weekly and perhaps once monthly with depot formulation subcutaneous injectable In this three year grant application we propose the following specific aims to advance chol PIE trimer towards IND filing as well as continue to explore potential backup candidates including PIE trimer should problems with chol PIE trimer arise advance the manufacturing and formulation of chol PIE trimer investigate the ADME properties of chol PIE trimer hold a pre IND meeting with the FDA to discuss our nonclinical and early clinical plans evaluate the in vivo proof of concept efficacy of chol PIE trimer in a standard nonhuman primate NHP model of HIV infection and further characterize the safety of chol PIE trimer in toxicology and safety pharmacology studies in rats and NHPs These data will be used to select a final candidate for advancement to IND and ultimately to the clinic as a marketable entry inhibitor This proposal will also provide valuable toxicology data that will advance D peptides as a therapeutic platform against diverse viral infections and other diseases PUBLIC HEALTH RELEVANCE Navigen is developing a novel D peptide inhibitor of HIV entry with remarkable potency breadth and an unparalleled barrier to resistance The goal of this proposal is to establish the in vivo efficacy of our lead candidate chol PIE trimer and advance it towards IND filing and human clinical trials Chol PIE trimer has the potential to offer an exciting new therapeutic option to HIV AIDS patients


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 597.34K | Year: 2015

DESCRIPTION provided by applicant Shiga toxins and Stx are the primary virulence factors of Shiga toxin producing E coli STEC which are major food and waterborne pathogens afflicting both developed and developing countries An estimated STEC infections occur annually in the US In addition to severe and often bloody diarrhea the life threatening complication hemolytic uremic syndrome HUS occurs in of victims primarily children No STEC vaccines or therapies beyond supportive care are available Antibiotics are not used since they can increase toxin production and risk of HUS The severity of STEC infection propensity for outbreaks and lack of effective treatments make STEC concerning potential bioterror agents and a public health priority Here we describe an innovative strategy to discover D peptide inhibitors of Stx to combat STEC infection 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 low immunogenicity They can readily disrupt protein interfaces with high potency and specificity compared to small molecules and are much less expensive to produce than antibodies D peptides are ideal candidates for Stx neutralization in the gut and or systemic circulation Navigenandapos s drug discovery platform employs an enantiomeric screening technology mirror image phage display coupled with protein design We have successfully validated this platform technology by identifying D peptide inhibitors of HIV RSV and Ebola Our anti HIV D peptide was the first potent and specific D peptide inhibitor to be discovered and is in advanced preclinical trials It binds a functionally critical and conserved hydrophobic andquot pocketandquot on HIVandapos s trimeric surface glycoprotein gp A trimeric version of this D peptide binds to all three gp pockets providing a strong avidity boost Stx is each composed of a single enzymatically active A subunit and five receptor binding B subunits that form a pentameric ring Each of the B pentamer subunits contains a vulnerable pocket analogous to those of our viral targets The Stx B subunit pockets are excellent targets for us to next apply our expertise in D peptide drug design given our success in targeting analogous pockets at functionally critical interfaces the pentameric Stx target which inspires design of pentameric D peptides with strong avidity and the likelihood of D peptide stability and activity in the gut without disturbing native flora Furthermore the B subunits of Stx and Stx from Shigella dysenteriae are identical enabling dual therapeutic use for an anti Stx B D peptide These benefits have generated strong enthusiasm for this project from GI infectious disease clinicians who understand the dramatic potential impact an anti Stx D peptide would have in the clinic In this two year grant we propose to discover structurally characterize and optimize pentameric D peptide inhibitors that will neutralize Stx with high potency Success in this project will launch a new class of inhibitors against pathogenic bacteria important to global health PUBLIC HEALTH RELEVANCE Shiga toxin producing E coli STEC are dangerous pathogens that contaminate our food and water causing infections annually in the US Shiga toxins Stx and Stx Stx are the main virulence factors in STEC and can cause painful hemorrhagic colitis bloody diarrhea and life threatening hemolytic uremic syndrome HUS the leading cause of acute childhood renal failure Navigen is developing a novel protease stable Stx inhibitor since no STEC vaccines or treatments beyond supportive care are available


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 298.73K | Year: 2015

DESCRIPTION provided by applicant Activating mutations in G proteins are the drivers of oncogenesis in numerous cancers Therefore identifying drugs that block the signaling pathways controlled by these mutations could have enormous therapeutic consequences Uveal melanoma is a prototypical G driven cancer in which about of tumors have activating mutations in one of two G encoding genes GNAQ and GNA Although progress has been made in the treatment of primary uveal melanoma tumors metastasis occurs in approximately of patients and once the tumor has spread to other tissues and organs usually the liver no current treatments are effective and the disease is invariably fatal Therefore finding a treatment that reduces metastasis or can reduce tumor establishment or growth of metastatic uveal melanomas is of utmost importance especially if the treatment also has therapeutic potential for several other cancers Activating mutations in GNAQ and GNA control at least two major signaling pathways that are important for melanocyte transformation and uveal melanoma growth These signaling pathways activate mitogen activated protein kinase extracellular signal regulated kinases MAPK ERK and YAP to control AP and YAP TEAD mediated transcription that leads to transformation and tumor growth We and our collaborators at the University of Utah have identified the small GTPase ADP ribosylation factor ARF as a primary immediate effector of constitutively activated GNAQ Knocking down ARF expression or inhibiting its activation with the small molecule compound SecinH has the same effect as knocking down constitutively activated GNAQ We have demonstrated that ARF knockdown inhibits the establishment and growth of tumors in an orthotopic xenograft mouse model of uveal melanoma and have preliminary data suggesting that small molecule inhibition of ARF likewise reduces tumor formation and growth These results suggest that ARF inhibition may be an effective method for treating both primary and metastatic uveal melanoma In this Phase I study we will test our hypothesis by pursuing two aims In Aim we will determine whether novel ARF inhibitors can inhibit proliferation anchorage independent colony growth and invasion of uveal melanoma cells In Aim we will test the efficacy of our inhibitors in our orthotopic xenograft model of human uveal melanoma As noted above G proteins play important roles in many cancers Therefore results from this Phase I study may have much broader implications for the treatment of multiple cancers Success will place us in an ideal position to proceed to a Phase II study in which we will continue to examine the efficacy of these compounds in other animal models of uveal melanoma to show general applicability while also performing pharmacokinetic and detailed toxicity studies These Phase II studies will be necessary to obtain IND approval and allow for future clinical trials PUBLIC HEALTH RELEVANCE Uveal melanoma is the most common adult primary tumor of the eyeball and often has a propensity to spread to other parts of the body especially the liver where it establishes secondary tumors that are invariably fatal We have identified a protein that plays an important role in the molecular signaling pathways that control the establishment and growth of uveal melanomas and have synthesized small molecule compounds that can inhibit the activity of this required protein In this Phase I study we will determine whether these small molecule inhibitors are appropriate for further drug development by testing whether they can inhibit the establishment and growth of tumors in an animal model of human uveal melanoma


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.63K | Year: 2015

DESCRIPTION provided by applicant Acute lung injury ALI and acute respiratory distress syndrome ARDS result from a common pathogenic process pulmonary injury or infection triggers an overwhelming inflammatory response andquot cytokine stormandquot that results in increased endothelial and epithelial permeability and efflux of inflammatory cells protein and water from the vascular system into the alveolar space The incidence of ALI is estimated to be approximately cases per person years The treatment for those afflicted remains largely supportive with a mortality rate of approximately We have demonstrated that the small GTPase Arf is a convergence point in the signaling pathways of several inflammatory mediators and cytokines with demonstrated involvement in ALI ARDS Activation of Arf into its GTP bound state induces vascular leak and edema which play major roles in the pathophysiology of ALI ARDS Thus we hypothesize that pharmacological inhibition of Arf provides an opportunity to combat actions of multiple cytokines in ALI ARDS an approach which may be more effective than targeting single pathways with highly specific inhibitors This rationale is supported by the encouraging preliminary in vivo data generated with our small molecule inhibitor of Arf NAV in a murine model of lipopolysaccharide LPS induced ALI This phase SBIR will improve upon our current NAV series of Arf inhibitors through an in silico molecular modeling effort to identify compounds with improved potency and hydrophilicity We will determine potency in a biochemical nucleotide exchange assay and verify activity in a mechanism based cellular Arf pulldown assay Compounds with an optimal mix of potency and hydrophilicity will be screened in vivo to determine pharmacokinetic PK parameters We will then demonstrate proof of concept efficacy in the murine LPS induced ALI model Successful completion of these activities will accomplish two very important goals First it will provide proof of concept that inhibiting Arf is a promising novel approach for treating ALI ARDS Second it will position us to continue medicinal chemistry optimization of Arf inhibitors in Lead Optimization activities in phase optimization of potency selectivity solubility ADMET properties patentability Successful completion of this development program may result in a therapy effective for treating humans with ALI ARDS PUBLIC HEALTH RELEVANCE Acute lung injury ALI and the more severe acute respiratory distress syndrome ARDS result from a common pathogenic process pulmonary injury or infection triggers an overwhelming inflammatory response andquot cytokine stormandquot that results in increased endothelial and epithelial permeability and efflux of inflammatory cells protein and water from the vascular system into the alveolar space The incidence of ALI is estimated to be approximately cases per person years Treatment for ALI ARDS is primarily supportive care and though there have been improvements in outcomes over the past decade due to improved strategies of mechanical ventilation and advances in general supportive measures the mortality rate of patients with ALI ARDS is approximately


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: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 290.92K | Year: 2015

DESCRIPTION provided by applicant The development of non opioid analgesics for the control of postsurgical pain is widely acknowledged as an important goal The side effects of opioids most notably respiratory depression but also including sedation nausea constipation and sleep impairment make their use challenging and even potentially life threatening Of course the difficulties posed by opioid use are magnified tremendously by the potential for addiction and abuse In large part because of the need to limit the use of opioids the moderate severe or extreme pain experienced by about of patients after surgery is often undertreated Adjuvant agents such as gabapentin magnesium and ketamine are used in the perioperative setting andquot multimodal therapyandquot to reduce acute postoperative pain and the development of persistent pain as well as to reduce use of opioids Unfortunately however many of the most efficacious andquot add onandquot therapies also carry negative side effects related to the central nervous system CNS There remains a need for new classes of potent and effective analgesics for treatment of postoperative pain that do not have CNS related side effects and high abuse potential We believe that metabolically stable peripherally restricted galanin analogs have the potential to replace or reduce the use of opioids in treatment of acute postoperative pain However there is confusion in literature about the galanin receptor subtype that would be more effective in mediating antinociception We will evaluate two analogs in this proposal with the goal of selecting a lead candidate for phase efforts focused on drug development activities One of these analogs is somewhat selective for the galanin type receptor the other being somewhat galanin type receptor preferring Both have shown good efficacy in various rodent models of pain and no evidence of major side effects like those associated with opioids In this phase application we will evaluate our two analogs in mice to determine pharmacokinetic PK parameters potency and efficacy in the plantar incision model of postsurgical pain and toxicity over the course of a day study Completion of these aims will allow us to better define the PK efficacy and short term toxicity of our two analogs allowing us to select one compound as the lead for subsequent phase studies This phase project is the starting point for exploring the efficacy of galanin analogs for multiple pain states information gained in this project will supplement efforts to develop a galanin analog for other forms of pain beyond postoperative Metabolically stable peripherally restricted galanin analogs represent novel first in class pharmacologic therapies to replace or reduce use of opioids and other CNS active therapies in treatment of postoperative pain PUBLIC HEALTH RELEVANCE The development of non opioid analgesics for the control of postsurgical pain is widely acknowledged as an important goal Side effects of opioids include respiratory depression sedation nausea constipation sleep impairment and a high potential for abuse and addiction Navigen is developing novel metabolically stable peripherally restricted galanin analogs to replace or reduce the use of opioids in treatment of postoperative pain


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 992.26K | Year: 2016

PROJECT SUMMARY Respiratory syncytial virus RSV is the major cause of severe lower respiratory tract infections in children and infants affecting an estimated million people and causing up to deaths worldwide per year WHO In the US young children and adults are hospitalized annually due to RSV infection High risk adults the elderly and patients with chronic heart or lung disease experience the highest RSV attributed mortality in the US deaths year commensurate with the mortality rates of seasonal influenza RSV costs the US healthcare system billions of dollars annually No vaccines or safe and effective therapeutics for RSV are available although several products are in clinical trials Currently RSV treatment is mostly limited to supportive care however for the most acute cases in children ribavirin a broad range antiviral with questionable RSV efficacy and significant safety issues can be used Use of Synagis palivizumab a monoclonal antibody that inhibits RSV infection in the lower respiratory tract is limited to the highest risk children Furthermore Synagis is very expensive $ $ for a standard course of therapy for a premature infant and it only reduces RSV related hospitalizations by There is an urgent need for new and more cost effective anti RSV prophylactics and therapies that can be applied to both children and adults During Phase I of this award Navigen employed an innovative strategy to identify a novel protease resistant D peptide drug lead CR T which targets the RSV entry machinery Our drug discovery platform employs an enantiomeric screening technology mirror image phage display coupled with protein design to identify D peptides that bind to a conserved and functionally critical site on the virusandapos s F fusion protein CR T binds F with pM affinity and prevents it from completing a conformational change required for RSV to enter permissive cells As such it is a potent inhibitor of RSV in vitro We have successfully validated this platform technology by identifying promising inhibitors for several viruses that share a conserved entry mechanism Our analogous anti HIV D peptide CPT inhibits all major circulating HIV strains possesses an extremely high barrier to resistance and has minimal immunogenicity CPT has demonstrated great potential in preclinical testing including initial safety and efficacy studies in rodents and non human primates Our experience with CPT will facilitate rapid advancement of CR T In this three year Phase II application we will determine the breadth of CR T against multiple primary RSV isolates A and B strains determine its potency in a gold standard animal model of RSV infection using both preventative and therapeutic dosing regimens and complete IND enabling studies Our ultimate goal is to advance this promising drug candidate to the clinic where it will have a significant worldwide impact as a safe and effective preventative and therapeutic for RSV infection in children and adults PROJECT NARRATIVE Human respiratory syncytial virus RSV is the most common cause of hospitalization for infants and young children reinfections can occur throughout life and it is a major cause of morbidity and mortality in the elderly comparable to flu A partially effective antibody can reduce serious complications when administered prophylactically however it is costly and only available to the highest risk infants and children andlt months old Because no vaccine or safe and effective treatment is available Navigen is advancing its potent anti RSV compound that has the potential to address the considerable unmet need to prevent and treat RSV infections in children and adults

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