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Moss R.B.,Nexbio, Inc. | Sanders R.L.,Nexbio, Inc. | Fang F.,Nexbio, Inc.
Advances in Virology | Year: 2011

Influenza, respiratory synctial virus, and parainfluenza are common respiratory infections in immunocompromised transplant recipients, causing significant morbidity and mortality in this patient population. This paper focuses on influenza and parainfluenza virus infections in transplant patients with emphasis on the pandemic 2009 H1N1 influenza infection. Current antiviral treatment recommendations for influenza and parainfluenza in immunocompromised patients as well as novel investigational therapeutic approaches currently being tested in the clinic are discussed. In addition to the morbidity and mortality caused by these viruses, the development of multidrug resistance leading to transmission of resistant viruses is of great public health concern. The development of effective new therapies for influenza and parainfluenza in these high-risk patients is needed with randomized placebo-controlled studies to assess their clinical utility. © 2011 Ronald B. Moss et al.


Moss R.B.,Nexbio, Inc. | Davey R.T.,National Institute of Allergy and Infectious Diseases | Fang F.,Nexbio, Inc.
Journal of Antimicrobial Chemotherapy | Year: 2010

The emergence of the 2009 H1N1 pandemic influenza A virus, as well as constant antigenic drift of seasonal influenza, underscores the remarkable versatility of this virus in adapting to the human population. While vaccines are the principal public health defence against influenza, rapid vaccine development can be a daunting task. Antiviral drugs offer the promise of inhibiting influenza regardless of its genetic variations. However, the rapid rise of resistance to several antivirals has highlighted the need for developing novel therapeutics with reduced drug resistance potential. In this review, we will summarize the effects of the currently licensed anti-influenza drugs as well as the candidates in development against the seasonal and the 2009 H1N1 pandemic influenza A virus with an emphasis on drug resistance. © The Author 2010. Published by Oxford University Press.


Moss R.B.,Nexbio, Inc. | Hansen C.,Nexbio, Inc. | Sanders R.L.,Nexbio, Inc. | Hawley S.,Nexbio, Inc. | And 2 more authors.
Journal of Infectious Diseases | Year: 2012

Background DAS181, a novel host-directed antiviral in development for influenza treatment, was assessed in this phase II clinical trial.Methods This study was a double-blind, placebo-controlled phase II clinical trial assessing influenza viral load and patient safety in otherwise healthy influenza-infected participants. Participants were randomized to a single-dose, multiple-dose, or placebo group and were followed for safety and virologic outcomes.Results A total of 177 laboratory-confirmed influenza-infected participants were enrolled in the trial, which encompassed 3 influenza seasons from 2009-2011 in both the Northern and Southern Hemispheres. Thirty-seven percent of participants had confirmed infection with influenza B, 33% with seasonal H3N2, 29% with pandemic 2009 H1N1, and 1 participant was positive for both influenza B and pandemic 2009 H1N1. Significant effects were observed in regard to decreased change from baseline viral load and viral shedding in the multiple-dose group compared with placebo as measured by quantitative polymerase chain reaction (P <. 05). No instances of H274Y were observed among viral isolates from this trial. Overall, the drug was generally well tolerated.Conclusions DAS181 significantly reduced viral load in participants infected with influenza, thus warranting future clinical development of this novel host-directed therapy.Clinical Trials.gov Identifier. NCT01037205 © 2012 The Author.


Hedlund M.,Nexbio, Inc. | Aschenbrenner L.M.,Nexbio, Inc. | Jensen K.,Nexbio, Inc. | Larson J.L.,Nexbio, Inc. | Fang F.,Nexbio, Inc.
Journal of Infectious Diseases | Year: 2010

Background. DAS181 (Fludase) is a sialidase fusion protein in clinical development as a broad-spectrum antiinfluenza virus (IFV) therapeutic agent. Previous reports by other investigators have raised the concern that desialylation of airway epithelium might increase susceptibility to Streptococcus pneumoniae infection. Methods. To address whether DAS 181 would lead to an increased risk of pneumococcal infection, we tested S. pneumoniae colonization after DAS 181 treatment of human A549 cells, healthy mice, and mice challenged with a lethal dose of IFV A/PR/8/34 (H1N1) or A/Victoria/3/75 (H3N2), followed by 104 cfu of S. pneumoniae (D39) on day 3 or day 7. DAS181 treatment was given 24-48 h after IFV challenge. Results. DAS181 treatment did not increase S. pneumoniae colonization in vitro or in vivo in healthy animals. In IFV-infected mice, DAS181 prevented pneumonia and significantly prolonged survival and inhibited the IFV titer by 3≥3 logs. None of the treated animals showed enhanced S. pneumoniae colonization of the lung. In addition, opportunistic infections with Citrobacter species or Klebsiella species occurred only in mice receiving vehicle, not in animals treated with DAS181. Conclusions. These data indicate that DAS181 treatment does not exacerbate secondary bacterial infection in mice. DAS181 may reduce the risk of secondary bacterial infection by inhibiting IFV. © 2010 by the Infectious Diseases Society of America. All rights reserved.


Hedlund M.,Nexbio, Inc. | Larson J.L.,Nexbio, Inc. | Fang F.,Nexbio, Inc.
Viruses | Year: 2010

While vaccines are the primary public health response to seasonal and pandemic flu, short of a universal vaccine there are inherent limitations to this approach. Antiviral drugs provide valuable alternative options for treatment and prophylaxis of influenza. Here, we will review drugs and drug candidates against influenza with an emphasis on the recent progress of a host-targeting entry-blocker drug candidate, DAS181, a sialidase fusion protein. © 2010 by the authors.


Triana-Baltzer G.B.,Nexbio, Inc. | Sanders R.L.,Nexbio, Inc. | Hedlund M.,Nexbio, Inc. | Jensen K.A.,Nexbio, Inc. | And 3 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2011

Background: Influenza viruses (IFVs) frequently achieve resistance to antiviral drugs, necessitating the development of compounds with novel mechanisms of action. DAS181 (Fludase®), a sialidase fusion protein, may have a reduced potential for generating drug resistance due to its novel host-targeting mechanism of action. Methods: IFV strains B/Maryland/1/59 and A/Victoria/3/75 (H3N2) were subjected to >30 passages under increasing selective pressure with DAS181. The DAS181-selected IFV isolates were characterized in vitro and in mice. Results: Despite extensive passaging, DAS181-selected viruses exhibited a very low level of resistance to DAS181, which ranged between 3- and 18-fold increase in EC50. DAS181-selected viruses displayed an attenuated phenotype in vitro, as exhibited by slower growth, smaller plaque size and increased particle to pfu ratios relative to wild-type virus. Further, the DAS181 resistance phenotype was unstable and was substantially reversed over time upon DAS181 withdrawal. In mice, the DAS181-selected viruses exhibited no greater virulence than their wild-type counterparts. Genotypic and phenotypic analysis of DAS181-selected viruses revealed mutations in the haemagglutinin (HA) and neuraminidase (NA) molecules and also changes in HA and NA function. Conclusions: Results indicate that resistance to DAS181 is minimal and unstable. The DAS181-selected IFV isolates exhibit reduced fitness in vitro, likely due to altered HA and NA functions. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


The present invention provides a method of reducing the quanitity of mucus in the respiratory tract of a subject with elevated levels of mucus in said respiratory tract. The method includes administering to the subject a compound or composition containing a therapeutically effective amount of a fusion protein comprising a sialidase or an active portion thereof and an anchoring domain. The therapeutically effective amount comprises an amount of the fusion protein that results in a reduction of the quanitity of mucus in the respiratory tract after administration of the compound or composition when compared to the quantity of mucus present prior to administration of the compound or composition.


Patent
Nexbio, Inc. | Date: 2010-08-23

The present invention provides new compositions and methods for preventing and treating pathogen infection. In particular, the present invention provides compounds having an anchoring domain that anchors the compound to the surface of a target cell, and a therapeutic domain that can act extracellularly to prevent infection of a target cell by a pathogen, such as a virus. The present invention also comprises therapeutic compositions having sialidase activity, including protein-based compounds having sialidase catalytic domains. Compounds of the invention can be used for treating or preventing pathogen infection, and for treating and reducing allergic and inflammatory responses. The invention also provides compositions and methods for enhancing transduction of target cells by recombinant viruses. Such compositions and methods can be used in gene therapy.


Trademark
Nexbio, Inc. | Date: 2010-01-28

Pharmaceutical preparations for the prevention, prophylaxis, containment, and treatment of infectious disease and viral illness, namely, Influenza, Parainfluenza, Respiratory Syncitial Virus, Filovirus, Ebola Virus, Marburg Virus, and Viral Hemorrhagic Fever, immunological disorders, inflammation, inflammatory diseases, Respiratory diseases, Black Lung, Chronic Obstructive Pulmonary Disease (COPD), Emphysema, Cystic Fibrosis, Hepatitis, High Blood Pressure, Systemic Inflammatory Response Syndrome (SIRS), Severe Acute Respiratory Syndrome (SARS), Sepsis, Septic Shock, Toxic Shock Syndrome.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2010

DESCRIPTION (provided by applicant): Broad-spectrum prophylaxis and therapeutics for respiratory viral infections are highly desirable due to the immense socioeconomic burden imposed by the respiratory viruses. Human parainfluenza viruses (HPIV) represent a significant portion of respiratory viral disease. There are currently no approved treatments for the prevention or treatment of HPIV. The aims of this proposal are the first steps in a clinical development program to address this unmet medical need. The long-term objective of this project is to bring DAS181 into clinical trials in an HPIV indication. DAS181 is a recombinant fusion protein composed of a sialidase catalytic domain fused with an epithelium-anchoring sequence which functions by eliminating sialic acids on the airway epithelium. DAS181 is currently in clinical development for treatment of influenza virus (IFV) infection. IFVs and HPIVs share a common pathway of virus binding to sialic acids on the surface of cells as the initial step in infection. Since DAS181 works by inactivating sialic acid, the drug potentially confers very broad protection against any virus utilizing binding to sialic acid to gain entry into the cell. There are two specific aims of this proposal: first, to demonstrate the in vitro efficacy and pharmacodynamics of DAS181 against clinical isolates of HPIV and second, to demonstrate the in vivo efficacy of DAS181 against HPIV using a cotton rat model with DAS181 prophlyaxis and treatment. To establish the proof-of-principle in vitro, clinical isolates confirmed to be HPIV1, 2 or 3 will be obtained. At least 20 different clinical isolates will be established for testing sensitivity to DAS181. The ability of DAS181 to inhibit HPIV infection in LLC-MK cells will be evaluated. The susceptibility of various HPIV isolates to DAS181 will be compared by EC50 and EC90 values at an equal level of viral challenge. The potential anti- HPIV effect of DAS181 against clinical HPIV isolates will also be evaluated using the well-differentiated human airway epithelium culture (HAE). This model will allow the assessment of time of DAS181 exposure on the infection of HPIV. The cotton rat model of HPIV will be used to determine in vivo efficacy. Following the establishment of the model to determine the optimum infection of HPIV isolates, the efficacy of DAS181 will be evaluated in the prophylaxis, pre-HPIV inoculation model. Subsequent in vivo studies in cotton rats will define the time course of DAS181 treatment for existing HPIV infection. Accomplishing these two aims of defining pharmacological efficacy of DAS181 in HPIV infection will provide the rationale for engaging in pre-INS development, IND submission, and eventually the conduct of clinical trials in this indication. As DAS181 is already in a Phase I clinical trial for an influenza indication, the development path forward into an HPIV indication could be quite rapid upon this demonstration of potent activity against HPIV. PUBLIC HEALTH RELEVANCE: There is currently no treatment for human parainfluenza viral (HPIV) infection and no vaccine for prevention of infection. Yet HPIV represents a significant disease burden, especially for children, and represents a large unmet medical need. The proposed studies will establish Fludase(R), a novel recombinant fusion protein, as a potential drug for HPIV infections.

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