Navigen has interests in new pharmaceutical and device technologies. We do not target any specific size or stage of project. Rather, we seek the best technologies and most passionate inventors. Each project retains a great deal of autonomy, which provides the opportunity for an unusually high level of participation by inventors. The end result is a unique blending of the positive aspects of a focused start-up with the multi-faceted capabilities of a larger, established company.

Representative Current Technologies:

HIV and D-peptides. HIV entry is mediated by the trimeric HIV Envelope (Env) protein. The gp41 subunit of Env directly catalyzes fusion between the viral and target cell membranes. gp41 has a highly conserved hydrophobic pocket region that is essential for viral entry. This pocket is a promising inhibitory target, but has proven "undruggable" for traditional small molecule inhibitors. Peptides, such as the HIV entry inhibitor Fuzeon, can block these types of large protein-protein interaction surfaces, but their poor pharmacokinetic properties have hampered their widespread adoption. For example, Fuzeon requires twice daily 90 mg injections and costs ~$30,000/year.

To overcome these challenges, we have developed non-degradable D-peptides that bind the gp41 pocket and inhibit HIV entry. D-peptides are mirror-images of naturally occurring L-peptides and are highly resistant to proteolysis. Our lead candidate, PIE12-trimer, is a trimeric D-peptide that potently blocks all major HIV strains and demonstrates low toxicity in human explants and cell lines. It has a best-in-class resistance profile and shows no cross resistance with other inhibitors (including Fuzeon). PIE12-trimer is a promising candidate for both prevention (topical microbicide) and treatment of HIV. Our D-peptide discovery strategy is broadly applicable to other enveloped viruses (e.g., Ebola, Respiratory Syncytial Virus, and Influenza).

This technology arose out of the laboratory of Michael Kay, MD, PhD, Department of Biochemistry at the University of Utah. Navigen has exclusively licensed this technology from the University.

References:

Welch, BD, Francis, JN, Redman, JS, Paul, S, Weinstock, MT, Reeves, JD, Lie, YS, Whitby FG, Eckert, DM, Hill, CP, Root, MJ, and Kay, MS. Design of a Potent D-peptide HIV-1 Entry Inhibitor with a Strong Barrier to Resistance (2010). Journal of Virology 84: 11235-44.

Welch, BW, VanDemark, AP, Hill, CP, and Kay, MS. Potent D-peptide Inhibitors of HIV-1 Entry (2007). PNAS 104: 16828-33.

Eckert, DM, Malashkevich, VN, Hong, LH, Carr, PA, and Kim, PS. Inhibiting HIV-1 Entry: Discovery of D-Peptide Inhibitors that Target the gp41 Coiled-Coil Pocket (1999). Cell 99: 103-115.

Slit/Robo Pathway and Vascular Stabilization. Capillary leak, tissue edema, organ failure, and death are common endpoints in patients exposed to serious infections, and evidence is growing that these common endpoints are the direct result of the response of the vascular endothelium to cytokine storm, the massive release of cytokines as part of the innate immune system response to infection. Slit proteins, acting through their Robo (Roundabout) receptors, have a well known role in axonal guidance during neural development. The laboratory of Dr. Dean Li, Navigen's Chief Scientific Officer and co-founder, identified an endothelial-specific Robo, Robo4, and determined its role in maintaining vascular integrity. One of the first effects of angiogenic factors and inflammatory cytokines on endothelial cells is to trigger the dissociation of cell-cell contacts, leading to increased vascular permeability. Dr. Li and colleagues have illustrated in in vitro models that activation of Robo4 receptors with Slit2N can substantially reduce vascular permeability induced by lipopolysaccharide (LPS), tumor necrosis factor-a (TNF-a), and interleukin-1ß (IL-1ß), all important mediators of inflammation.

Because the Slit-Robo4 pathway tempers the effects of such a broad range of angiogenic and inflammatory cytokines on the endothelium, Dr. Li and colleagues examined whether Slit2N promotes vascular stability by directly enhancing the mechanisms responsible for cell-cell interactions. In the endothelium, critical stabilizing interactions are mediated by the adherens junction protein, vascular endothelial cadherin (VE-cadherin). IL-1ß reduced VE-cadherin levels at the cell surface and Slit2N negated this effect. Further, IL-1ß stimulation decreased p120-catenin (a critical stabilizer of VE-cadherin) at the cell surface and Slit2N reversed this effect as well.

The Slit-Robo4 pathway offers a potential means of controlling the endothelial response to cytokine storm, thereby limiting breakdown of the vascular endothelium. Indeed, Dr. Li and colleagues have demonstrated convincing evidence of efficacy of Slit2N in mouse models of acute lung injury (ALI), influenza and sepsis. In these studies, Slit2N reduced vascular leak as measured by extravasation of Evans blue dye from the vascular space into organs such as lung (ALI, influenza) and spleen and liver (sepsis). Importantly, Slit2N also significantly reduced mortality in animal models of influenza and sepsis. These findings have been the subject of recent expert commentaries in high profile scientific journals.

References:

Park KW, Morrison CM, Sorensen LK, Jones CA, Rao Y, Chien C-B, Wu JY, Urness LD and Li DY. Robo4 Is a Vascular-Specific Receptor that Inhibits Endothelial Migration (2003). Developmental Biology 261: 251-67.

Jones CA, London NR, Chen H, Park KW, Sauvaget D, Stockton RA, Wythe JD, Suh W, Larrieu-Lahargue F, Mukouyama Y-s, Lindblom P, Seth P, Frias A, Nishiya N, Ginsberg MH, Gerhardt H, Zhang K, and Li DY. Robo Stabilizes the Vascular Network by Inhibiting Pathologic Angiogenesis and Endothelial Hyperpermeability (2008). Nature Medicine 14:448-53.

Jones CA, Nishiya N, London NR, Zhu W, Sorensen LK, Chan AC, Lim CJ, Chen H, Zhang Q, Schultz PG, Hayallah AM, Thomas KR, Famulok M, Zhang K, Ginsberg MH, and Li DY. Slit2-Robo4 Signalling  Promotes Vascular Stability by Blocking Arf6 Activity (2009). Nature Cell Biology X: 1325-33.

London NR, Zhu W, Bozza FA, Smith MCP, Greif DM, Sorensen LK, Chen L, Kaminoh Y, Chan AC, Passi SF, Day CW, Barnard DL, Zimmerman GA, Krasnow MA, and Li DY. Targeting Robo4-Dependent Slit Signaling to Survive the Cytokine Storm in Sepsis and Influenza (2010). Science Translational Medicine 2:23ra19.

Lee WL and Slutsky AS. Sepsis and Endothelial Permeability (2010). New England Journal of Medicine 363:689-91.

Goldenberg NM, Steinberg BE, Slutsky AS, and Lee WL. Broken Barriers: A New Take on Sepsis Pathogenesis (2011). Science Translational Medicine 3:88ps25.

The Veritract SmartTube™ for Enteral Feeding. Veritract, Inc., is developing a steerable feeding tube with integrated optics. The SmartTube™ will enable healthcare providers to efficiently and routinely place nasoenteral feeding tubes at the bedside while minimizing patient exposure to radiation and risk of misplacement. The device was conceived by John Fang, MD, Medical Director, Department of Gastroenterology at the University of Utah Medical Center and offers clear advantages over the current technology for placement of feeding tubes.

Feeding tube placement is one of the most common procedures performed in the hospital ICU. Each year, in the U.S. alone, more than 1.2 million small bore feeding tubes are placed. Current practices for placement vary widely from highly technical, very expensive procedures such as endoscopy to what is known as "blind placement" at the bedside. The latter is inexpensive but results in thousands of deaths each year from misplacement of the tube into the lungs. Veritract's SmartTube™ combines the safety and accuracy of the more expensive methods of feeding tube placement (i.e., endoscopy and fluoroscopy) with the convenience and efficiency of bedside placement.

Navigen has entered into an agreement to provide management services to Veritract. These services include corporate management, market analysis, financing, business development, and project management. Hunter Jackson has been appointed by the Veritract Board of Directors as CEO and director of Veritract, and Brandi Simpson as Chief Business Officer. They join John Fang, MD, the Chief Scientific Officer of Veritract and Tim Nieman, Chief Operating Officer, in driving this valuable new technology through the regulatory process and into the marketplace.

References:

de Aguilar-Nascimento JE, Kudsk KA. Clinical costs of feeding tube placement. JPEN J Parenter Enteral Nutr. 2007; 31(4): 269-73.

Halloran O, Grecu B, Sinha A. Methods and complications of nasoenteral intubation. JPEN Journal of parenteral and enteral nutrition. 2011; 35(1): 61-6.

Krenitsky J. Blind bedside placement of feeding tubes: treatment or threat? Practical Gastroenterology. 2011; XXXV(3): 32-42.

Powers J, Chance R, Bortenschlager L, Hottenstein J, Bobel K, Gervasio J, et al. Bedside Placement of Small-Bowel Feeding Tubes: In the Intensive Care Unit. Critical Care Nurse. 2003; 23(1): 16-24.

Burns SM, Carpenter R, Blevins C, Bragg S, Marshall M, Browne L, et al. Detection of inadvertent airway intubation during gastric tube insertion: Capnography versus a colorimetric carbon dioxide detector. Am J Crit Care. 2006; 15(2): 188-95.

Trujillo EB, Robinson MK, Jacobs DO. Feeding critically ill patients: current concepts. Critical Care Nurse. 2001; 21(4): 60-9; quiz 70-1.

The Cowley Snare. The use of intravascular snares to retrieve or reposition medical devices or materials is a common practice with an estimated 300,000 procedures performed in the U.S. each year.  However, successful device retrieval often requires the use of multiple snares and prolonged attempts adding radiation exposure and a cumulative risk of additional complications.  When clinicians fail to successfully retrieve medical devices via use of a snare, they must decide whether to leave the object in the patient or resort to open surgical retrieval; an expensive and more dangerous alternative.

Despite various designs in commercially available retrieval devices and the use of "hand-made" snares when commercially available snares fail, limitations remain that contribute to prolonged procedure times, added risk, and in some cases simple failure to retrieve devices.  Reported rates of complete failure to retrieve embolized devices range from 7% to 11%.  Prolonged retrieval procedures also add to the amount of radiation to which patients are exposed, with reported exposures as high as 3770 mGy.  Since complication rates and overall costs increase with cumulative procedure time, there is clear benefit to the patient and hospital if retrieval of devices can be accomplished rapidly and efficiently.

Navigen has partnered with interventional radiologist Dr. Collin Cowley and medical device engineer Tim Nieman to develop a novel snare device, the Cowley Snare, which overcomes the major limitations of commercially available snares.  The Cowley Snare is capable of both 90 degree deflection and torque translation through the length of the device.  This design incorporates the basic elements required to capture and retrieve an object in 3-dimensional space around the tip of the guide catheter.  The Cowley Snare will facilitate retrieval of foreign objects resulting in fewer retrieval failures, lower complication rates, reduced radiation exposure, cost savings, and overall improved outcomes for patients.

We expect to be in postion for 510k filing by January 2013.

References:

Onal B, Coskun B, Karabulut R, Ilgit ET, Turkyilmaz Z, Sonmez K. Interventional radiological retrieval of embolized vascular access device fragments. Diagn Interv Radiol. 2011.

Sheth R, Someshwar V, Warawdekar G. Percutaneous retrieval of misplaced intravascular foreign objects with the Dormia basket: an effective solution. Cardiovasc Intervent Radiol. 2007; 30(1): 48-53.

Yen HJ, Hwang B, Lee PC, Meng CC. Transcatheter retrieval of different types of central venous catheter fragment: experience in 13 cases. Angiology. 2006; 57(3): 347-53.

Rimon U, Bensaid P, Golan G, Garniek A, Khaitovich B, Dotan Z, et al. Optease vena cava filter optimal indwelling time and retrievability. Cardiovasc Intervent Radiol. 2011; 34(3): 532-5.

Gabelmann A, Kramer S, Gorich J. Percutaneous retrieval of lost or misplaced intravascular objects. AJR Am J Roentgenol. 2001; 176(6): 1509-13.