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Unlocking the Potential of D-Peptide Therapeutics

  • D-peptides have the potential to become an important new class of drugs. Navigen has assembled a team of outstanding scientists with extensive experience in D-peptide discovery and optimization. Our team is committed to establishing Navigen as the industry leader in bringing important new D-peptide therapies forward. We have validated the benefits of D-peptides as drugs with our novel viral entry inhibitor for the treatment and prevention of HIV. This compound, CPT31, has been shown to be safe, potent, and efficacious in non-human primates. Navigen plans to initiate Phase 1 human studies for CPT31 in 2018. We also have strong pre-clinical programs for D-peptides for respiratory syncytial virus (RSV) as well as TNFα for treatment of inflammatory diseases.

  • CPT31 for Treatment and Prevention of HIV

    Navigen’s clinical candidate, the viral entry inhibitor CPT31, is a D-peptide designed to both treat patients with HIV infection and prevent contraction of the disease in healthy individuals. Based on the unique properties of D-peptides and extensive pre-clinical data in non-human primates, CPT31 is expected to have:

    • Efficacy as both a preventative and therapeutic;
    • High potency against all major circulating HIV clades;
    • Strong barrier to resistance resulting from an exceptionally high binding affinity to a highly conserved region of HIV;
    • Low immunogenicity;
    • Minimal side effects due to highly selective targeting of an HIV-specific binding site; and,
    • A pharmacokinetic profile that allows convenient long-acting dosing to support improved patient compliance.
  • Press play to see how CPT31 blocks HIV. Animation by Janet Iwasa, University of Utah http://scienceofHIV.org

    In collaboration with the National Institutes of Health (NIH), we have generated strong efficacy data for CPT31 in a non-human primate (NHP) HIV model. In this model, CPT31 monotherapy was shown to both prevent infection and maintain virus levels below levels of detection in infected NHPs with controlled virus.

     

    CPT31 prevents HIV from entering cells by targeting gp41, a protein essential for viral entry. Gp41 has long been recognized as a promising target for HIV treatment and prevention. An L-peptide drug that binds gp41, Fuzeon®, was approved for HIV treatment. However, as an L-peptide, Fuzeon is rapidly degraded by the body, thus it requires large and frequent dosing (twice daily injection). Furthermore, development of drug resistance is a significant problem for Fuzeon. These factors limit its commercial viability.

     

    A region of gp41 known as “the pocket” is highly conserved (i.e. mutates less frequently than other regions of HIV). Thus, it takes much longer for the virus to develop resistance to drugs targeting the pocket (Fuzeon does not bind the pocket). Many attempts have been made to develop pocket-binding small molecules and antibodies that would be more effective therapies than Fuzeon. However, small molecules were not potent enough to block the large protein-protein interface partly formed by the pocket during HIV entry. Antibodies are too large to access the space in which the pocket resides. Navigen’s CPT31 binds the pocket with extraordinarily high affinity and has succeeded against this target when all other types of molecules have failed. As expected by specifically targeting the conserved pocket, CPT31 is much less susceptible to drug resistance than Fuzeon.

  • CPT31 Addresses Many Unmet Needs in the Treatment and Prevention of HIV

    While recent advances in the treatment of HIV have led to significant improvements in health and quality of life for millions of people around the world, there are still unmet needs in both treatment and prevention. Approximately 25-30% of patients on treatment are not achieving viral suppression. Three critical factors contribute to the challenge of suppressing the virus in treated patients: 1) serious side effects of current therapies; 2) lack of compliance driven by side effects and inconvenient daily dosing schedules; and 3) development of drug-resistant virus. Most HIV drugs on the market today are known to present a risk of long-term toxicity as well as unpleasant side effects including GI discomfort, insomnia, and depression, among others. These factors contribute to high rates of treatment non-compliance that in turn contributes to development of drug resistance. Many patients have developed resistance to one or more of the currently used classes of HIV drugs. A safe and effective therapy with more convenient dosing and high barriers to resistance would represent a major advance in HIV patient care. We believe CPT31 will be that major advance.

     

    Navigen has received significant funding support for the CPT31 development program from the National Institutes of Health (NIH), including a $300K Phase I SBIR, a $3MM, three-year Phase II SBIR, and a $500K R56 award, with additional applications for grant funding pending.

  • D-Peptides for Treatment and Prevention of Human Respiratory Syncytial Virus (RSV)

    Crystal structure of an anti-RSV D-peptide (orange) bound to its target

    RSV is a leading cause of severe respiratory tract infections primarily affecting infants, young children, and seniors. RSV infection leads to over 250,000 hospitalizations and 14,000 deaths each year in the U.S. Worldwide, each year RSV is responsible for 200,000 deaths of children under five years old.

     

    Currently, there are no vaccines to prevent RSV and no safe and effective RSV therapeutics available for all RSV patients. A partially effective RSV preventative, Synagis®, is available but only for high-risk premature infants and young children with chronic heart and lung disease.

     

    Navigen is developing anti-RSV D-peptides that have the potential to both prevent and treat RSV infection. Like our anti-HIV drug candidate, these D-peptides target a region of RSV essential for entry into host cells. We have shown via structural biology that our lead, CR32T, forms a highly specific interaction with its RSV target, and we have demonstrated it has potent anti-viral activity (mid nM IC50) in vitro.

     

    The RSV program has benefited from a $600K, two-year NIH Phase I SBIR award and a $3MM, three-year NIH Phase II SBIR grant awarded in 2016.

  • Targeting Inflammatory Diseases: Anti-TNF D-peptides

    TNF Trimer in Complex with TNF Receptor

    Navigen is developing a D-peptide antagonist of tumor necrosis factor (TNF) for inflammatory diseases including inflammatory bowel disease and rheumatoid arthritis. Currently available anti-TNF antibodies are widely used but have high rates of non-response among patients. For example, up to 50% of inflammatory bowel disease and rheumatoid arthritis patients develop antibodies that render these drugs ineffective. D-peptides are minimally immunogenic, reducing or eliminating the risk of a significant anti-drug antibody response.

     

    In addition, anti-TNF antibodies are systemically delivered to patients, resulting in a risk of immunosuppression. D-peptides are stable in the gut when taken orally, but they are not systemically absorbed. Therefore, they can potentially treat inflammatory bowel disease locally without immunocompromising patients.

ARF-6 Inhibitors

  • ARF-6 is an intracellular convergence point for many inflammatory agents (e.g., lipopolysaccharides) and cytokines (e.g., IL-6), which, alone or together, can cause increased leakiness of blood vessels and more release of inflammatory agents, potentially creating the “cytokine storm” that leads to systemic inflammatory response syndrome, end organ failure, and death.

     

    Four well-known inflammatory pathways, IL-1R, IL-6R, TLR4, and VEGFR, have ARF6 as a common mediator. Activation of ARF6 leads to cadherin internalization, inducing vascular leak.

    Researchers at the University of Utah led by Dr. Dean Li, together with Navigen, have shown that inhibiting ARF-6 effectively blocks a number of pro-inflammatory signalling pathways from inducing vascular leak. Importantly, ARF-6 inhibition does not appear to dampen the ability of the immune system. A variety of conditions can cause ARF-6-mediated vascular leak, including acute lung injury, serious viral infections, sepsis, and retinopathies. Due to high mortality and lack of available therapy for acute lung injury, Navigen’s development efforts have focused on developing our lead ARF-6 inhibitor, NAV-5093, for this condition.

     

    ALI, also known in its more severe form as acute respiratory distress syndrome (ARDS), is a life-threatening lung condition that prevents sufficient oxygenation of blood. Causes of ALI include aspiration, inhalation injury, bacterial and viral pneumonias, trauma, and sepsis. These can trigger an overwhelming inflammatory response (cytokine storm) that increases endothelial and epithelial permeability and efflux of inflammatory cells, protein, and water from the vascular system into the lung alveoli (air sacs). In many patients, this inflammatory response results in hypoxemia, multi-organ failure, cardiovascular collapse, shock, and death. There are approximately 200,000 cases of ALI in the U.S. each year. The mortality rate of patients with ALI/ARDS is approximately 40%, and those who survive often have lasting lung damage and other disabilities associated with lack of oxygen to the brain.

     

    Reduction in LPS-induced bronchoalveolar lavage fluid (BALF) cell count by NAV-5093. Pooled data from several experiments. Each data point represents one mouse. *, p < 0.05, ****, p < 0.0001

    Navigen has identified proprietary small molecules that block ARF-6 activation. In animal models of disease, Navigen’s ARF-6 inhibitors have been shown to:

    • Reduce the effects of LPS in a model of acute lung injury;
    • Improve survival in animal models of endotoxemia/sepsis;
    • Improve survival in animals infected with antibiotic resistant bacteria;
    • Improve survival in animals infected with cerebral malaria;
    • Reduce retinal permeability in animal models of age-related macular degeneration and diabetic retinopathy; and,
    • Significantly reduce inflammation in an animal model of rheumatoid arthritis.

    Navigen is currently conducting IND-enabling studies with its clinical candidate for ALI/ARDS, NAV-5093 and expects to file an IND in late 2018.