Cystic Fibrosis Foundation Therapeutics
Cystic Fibrosis Foundation Therapeutics
News Article | November 10, 2016
Topline data for Phase 2 study of systemic sclerosis on track to be reported in fourth quarter of 2016; Topline data for Phase 2 study of cystic fibrosis on track to be reported in first quarter of 2017 NORWOOD, MA--(Marketwired - November 10, 2016) - Corbus Pharmaceuticals Holdings, Inc. ( : CRBP) ("Corbus" or the "Company"), a clinical stage drug development company targeting rare, chronic, serious inflammatory and fibrotic diseases, announced today its financial results for the three months ended September 30, 2016. The Company also provided an update to its corporate progress and the clinical status and anticipated milestones for Resunab, its novel synthetic oral endocannabinoid-mimetic drug that is designed to resolve chronic inflammation and halt fibrosis. Resunab is currently being evaluated in three separate Phase 2 clinical studies in diffuse cutaneous systemic sclerosis ("systemic sclerosis"), cystic fibrosis ("CF") and skin-predominant dermatomyositis. A fourth NIH-sponsored clinical study of Resunab in systemic lupus erythematosus ("SLE") is planned to begin during the first half of 2017. "We are pleased with the progress we have made over the course of 2016 and our ability to execute a complex clinical development program. We look forward to clinical data from our three current Phase 2 studies," stated Yuval Cohen, Ph.D., Chief Executive Officer of the Company. "Moving forward, we continue our commitment to clinically advance Resunab as a potential therapy for individuals with serious inflammatory and fibrotic diseases," concluded Dr. Cohen. Summary of Financial Results for Third Quarter 2016 For the three months ended September 30, 2016, the Company reported a net loss of approximately $5,347,000, or a net loss per diluted share of $0.12, compared to a net loss of approximately $2,254,000, or a net loss per diluted share of $0.06 for the three months ended September 30, 2015. For the nine months ended September 30, 2016, the Company reported a net loss of approximately $12,428,000, or a net loss per diluted share of $0.31, compared to a net loss of approximately $6,352,000, or a net loss per diluted share of $0.22 for the nine months ended September 30, 2015. The increases in the net losses for the three and the nine months ended September 30, 2016 are attributable to increased spending on clinical studies for systemic sclerosis and CF and increased compensation related to increased staffing, bonuses, and stock-based compensation expense. The Company ended the quarter with approximately $18.9 million of cash and cash equivalents. The Company expects the cash on hand together with the remaining milestone payments of $1,500,000 from the Cystic Fibrosis Foundation Therapeutics, Inc., which the Company expects to receive in the first quarter of 2017, to be sufficient to meet its operating and capital requirements into the fourth quarter of 2017 based on current planned expenditures. About Resunab Resunab is a novel synthetic oral endocannabinoid-mimetic drug that preferentially binds to the CB2 receptor expressed on activated immune cells and fibroblasts. CB2 activation triggers endogenous pathways that resolve inflammation and halt fibrosis. Preclinical and Phase 1 studies have shown Resunab to have a favorable safety, tolerability and pharmacokinetic profile. It has also demonstrated promising potency in preclinical models of inflammation and fibrosis. Resunab is designed to trigger the production of "Specialized Pro-resolving Lipid Mediators" that activate an endogenous cascade responsible for the resolution of inflammation and fibrosis, while reducing production of multiple inflammatory mediators. Resunab has direct effects on fibroblasts to halt tissue scarring. In effect, Resunab triggers endogenous pathways to turn "off" chronic inflammation and fibrotic processes, without causing immunosuppression. About Corbus Corbus Pharmaceuticals Holdings, Inc. is a clinical stage pharmaceutical company focused on the development and commercialization of novel therapeutics to treat rare, chronic, and serious inflammatory and fibrotic diseases. Our lead product candidate, Resunab, is a novel synthetic oral endocannabinoid-mimetic drug designed to resolve chronic inflammation, and fibrotic processes. Resunab is currently in Phase 2 clinical studies for the treatment of cystic fibrosis, diffuse cutaneous systemic sclerosis and skin-predominant dermatomyositis, with a fourth Phase 2 trial in systemic lupus erythematosus planned to commence during the first half of 2017. For more information, please visit www.CorbusPharma.com and connect with the Company on Twitter, LinkedIn, Google+ and Facebook. Forward-Looking Statements This press release contains certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934 and Private Securities Litigation Reform Act, as amended, including those relating to the Company's product development, clinical and regulatory timelines, market opportunity, competitive position, possible or assumed future results of operations, business strategies, potential growth opportunities and other statement that are predictive in nature. These forward-looking statements are based on current expectations, estimates, forecasts and projections about the industry and markets in which we operate and management's current beliefs and assumptions. These statements may be identified by the use of forward-looking expressions, including, but not limited to, "expect," "anticipate," "intend," "plan," "believe," "estimate," "potential," "predict," "project," "should," "would" and similar expressions and the negatives of those terms. These statements relate to future events or our financial performance and involve known and unknown risks, uncertainties, and other factors which may cause actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Such factors include those set forth in the Company's filings with the Securities and Exchange Commission. Prospective investors are cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date of this press release. The Company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.
News Article | December 8, 2016
BEDMINSTER, N.J., Dec. 08, 2016 (GLOBE NEWSWIRE) -- Matinas BioPharma Holdings, Inc. (OTCQB:MTNB), a clinical-stage biopharmaceutical company focused on identifying and developing safe and effective broad spectrum therapeutics for the treatment of serious and life-threatening infections, announced today that it has received a research contract award from Cystic Fibrosis Foundation Therapeutics Inc. (CFFT), the non-profit drug discovery and development affiliate of the Cystic Fibrosis Foundation, to study its lead antibiotic product candidate MAT2501, for the treatment of pre-clinical nontuberculous mycobacterium infection (NTM) in models of cystic fibrosis (CF). The award provided by CFFT will support a collaborative research program between Matinas BioPharma and Colorado State University (CSU) to study the efficacy of MAT2501 in the treatment of NTM infection by a range of mycobacterium species, including mycobacterium abscessus, in a CF lung infection model developed by CSU. NTM infections have emerged in recent years as an increasing problem to individuals with cystic fibrosis and other lung diseases. NTM infections are or have become increasingly resistant to most available antibiotics, making them extremely difficult to treat. Currently available treatments have limited efficacy for treating these life-threatening infections in people with CF and have also been shown to be highly toxic to patients. MAT2501 is Matinas BioPharma’s orally-administered, encochleated formulation of the broad spectrum IV-only aminoglycoside antibiotic agent amikacin, which utilizes the Company’s proprietary lipid-crystal nano-particle delivery technology. Amikacin is currently used to treat different types of chronic and acute bacterial infections, including NTM infections and various multidrug-resistant gram negative bacterial infections. IV-administered amikacin is associated with major side effects including nephrotoxicity and ototoxicity (permanent loss of hearing) with long-term use. “We are honored to receive the support of Cystic Fibrosis Foundation Therapeutics for this important research program, and our hope is that this is the beginning of what promises to be a long-term relationship as we advance the clinical development of MAT2501. Mycobacterium infections in people with cystic fibrosis are very difficult to treat, to a significant degree, because of the unique complications associated with CF. In earlier pre-clinical work, we demonstrated the efficacy of MAT2501 against several mycobacterium species. Anti-infectives formulated in our cochleate technology are uniquely targeted toward the site of infection while significantly reducing toxicities. We are looking forward to working with CFFT and CSU with the goal to expand the treatment options for CF patients battling these multi-drug resistant mycobacterium infections,” said Raphael Mannino, Ph.D., Chief Scientific Officer of Matinas BioPharma and Principal Investigator of the CF research program. MAT2501 is specifically designed to provide targeted delivery of the potent antibiotic amikacin while providing a significantly improved safety and tolerability profile, in order to allow for chronic dosing of this potent antibiotic agent. In preclinical studies MAT2501 demonstrated oral bioavailability and targeted delivery of amikacin directly to the site of infection in both pulmonary (lung) and disseminated NTM infections. American Thoracic Society (ATS)/Infectious Disease Society of America (IDSA) guidance for the treatment of patients with NTM infections refractory to guideline therapy includes a treatment duration of 12 months or longer. The profile of MAT2501 was designed to allow for safe and tolerable use of amikacin during such long-term treatment. MAT2501 is designated as a Qualified Infectious Disease Product (QIDP) and as an Orphan Drug for the treatment of NTM by the U.S. Food and Drug Administration (FDA). Orphan Drug designation of MAT2501 provides for a seven-year marketing exclusivity period against competition in the United States upon FDA approval, as well as other incentives and exemptions, including waiver of Prescription Drug User Fee Act (PDUFA) filing fees and tax credits for the cost of the clinical research. If MAT2501 is ultimately approved by the FDA, the seven-year period of marketing exclusivity from orphan designation combined with the additional five years of marketing exclusivity provided by the QIDP designation, provides for a potential total of 12 years of marketing exclusivity. The Company also intends to explore the development of MAT2501 for the treatment of a variety of multi-drug resistant, gram negative bacterial infections. Nontuberculous mycobacteria (NTM) are naturally occurring organisms found in water, soil, plants and animals. NTM causes many serious and life-threatening diseases, including pulmonary disease, skin and soft tissue disease, joint infections and, in immunocompromised individuals, disseminated infection. The most common clinical manifestation of NTM disease is pulmonary, or lung, disease. NTM lung infection occurs when a person inhales the organism from their environment. While most people do not become ill, some individuals develop a slow, progressive and destructive disease when NTM infects the airways and lung tissue leading to inflammation in the respiratory system. Individuals susceptible to the infection often have an unknown defect in their lung structure or immune system, lung damage from a pre-existing chronic obstructive pulmonary disease (COPD), such as emphysema and bronchiectasis, cystic fibrosis, or an immune deficiency disorder, such as HIV or AIDS. There are about 50,000 to 90,000 people with NTM pulmonary disease in the United States, with a much higher frequency in older adults, and these numbers appear to be increasing. However, NTM can affect any age group. Without treatment, the progressive lung infection caused by NTM results in severe cough, fatigue, and often weight loss. In some people NTM infections can become chronic and require ongoing treatment. Treatment may be difficult because NTM bacteria may be resistant to many common types of antibiotics. Severe NTM lung disease can have a significant impact on quality of life and can be life-threatening. MAT2501 is an orally-administered, encochleated formulation of the broad spectrum IV-only aminoglycoside antibiotic agent amikacin, which utilizes the Company’s proprietary, lipid-crystal, nanoparticle delivery technology. Amikacin is currently used to treat different types of chronic and acute bacterial infections, including NTM infections and various multidrug-resistant gram negative bacterial infections. IV-administered amikacin is associated with major side effects including nephrotoxicity and ototoxicity (permanent loss of hearing) with long-term use. MAT2501 is specifically designed to provide targeted delivery of the potent antibiotic amikacin while providing a significantly improved safety and tolerability profile. In preclinical studies MAT2501 demonstrated oral bioavailability and targeted delivery of amikacin directly to the site of infection in both pulmonary (lung) and disseminated NTM infections. Matinas recently received FDA clearance to initiate a Phase 1 clinical study of MAT2501 under the open IND for the treatment of non-tuberculous mycobacterium infections. The FDA has also designated MAT2501 as a QIDP and an Orphan Drug for the treatment of NTM infections. The Company intends to initially develop MAT2501 for the treatment of NTM infections and will also explore the development of MAT2501 for the treatment of a variety of multi-drug resistant, gram negative bacterial infections. If approved, we believe MAT2501 would become the first orally bioavailable aminoglycoside and represent a significant improvement over existing therapies from a treatment and health economic perspective. Matinas BioPharma is a clinical-stage biopharmaceutical company focused on identifying and developing safe and effective broad spectrum therapeutics for the treatment of serious and life-threatening infections. The Company's proprietary, disruptive technology utilizes lipid-crystal nano-particle cochleates to nano-encapsulate existing drugs, making them safer, more tolerable, less toxic and orally bioavailable. The Company's lead drug candidate is MAT2203, an orally-administered, encochleated formulation of amphotericin B (a broad spectrum fungicidal agent). The Company has an open Investigational New Drug (IND) application for MAT2501, which is an orally-administered, encochleated formulation of amikacin (a broad spectrum aminoglycoside antibiotic agent) for acute bacterial infections, including non-tuberculous mycobacterium (NTM) and multi-drug resistant gram negative bacterial infections. The Company's lead anti-infective product candidates, MAT2203 and MAT2501, position Matinas BioPharma to become a leader in the safe and effective delivery of anti-infective therapies utilizing its proprietary lipid-crystal nano-particle cochleate formulation technology. For more information, please visit www.matinasbiopharma.com and connect with the Company on Twitter, LinkedIn, Facebook, and Google+. Forward Looking Statements: This release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including those relating to the Company's strategic focus and the future development of its product candidates, including MAT2203 and MAT2501, the anticipated timing of regulatory submissions, the anticipated timing of clinical studies, the Company’s ability to identify and pursue development and partnership opportunities for its products or platform delivery technology on favorable terms, if at all, and the ability to obtain required regulatory approval and other statements that are predictive in nature, that depend upon or refer to future events or conditions. All statements other than statements of historical fact are statements that could be forward-looking statements. Forward-looking statements include words such as "expects," "anticipates," "intends," "plans," "could," "believes," "estimates" and similar expressions. These statements involve known and unknown risks, uncertainties and other factors which may cause actual results to be materially different from any future results expressed or implied by the forward-looking statements. Forward-looking statements are subject to a number of risks and uncertainties, including, but not limited to, our ability to obtain additional capital to meet our liquidity needs on acceptable terms, or at all, including the additional capital which will be necessary to complete the clinical trials of our product candidates; our ability to successfully complete research and further development and commercialization of our product candidates; the uncertainties inherent in clinical testing; the timing, cost and uncertainty of obtaining regulatory approvals; our ability to maintain and derive benefit from the Qualified Infectious Disease Product (QIDP), Orphan and/or Fast Track designations for MAT2203 and MAT2501, which does not change the standards for regulatory approval or guarantee regulatory approval on an expedited basis, or at all; our ability to protect the Company's intellectual property; the loss of any executive officers or key personnel or consultants; competition; changes in the regulatory landscape or the imposition of regulations that affect the Company's products; and the other factors listed under "Risk Factors" in our filings with the SEC, including Forms 10-K, 10-Q and 8-K. Investors are cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date of this release. Except as may be required by law, the Company does not undertake any obligation to release publicly any revisions to such forward-looking statements to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events. Matinas BioPharma's product candidates are all in a development stage and are not available for sale or use.
Kim S.J.,Oregon Health And Science University |
Yoon J.S.,Oregon Health And Science University |
Shishido H.,Oregon Health And Science University |
Yang Z.,Oregon Health And Science University |
And 4 more authors.
Science | Year: 2015
In cells, biosynthetic machinery coordinates protein synthesis and folding to optimize efficiency and minimize off-pathway outcomes. However, it has been difficult to delineate experimentally the mechanisms responsible. Using fluorescence resonance energy transfer, we studied cotranslational folding of the first nucleotide-binding domain from the cystic fibrosis transmembrane conductance regulator. During synthesis, folding occurred discretely via sequential compaction of N-terminal, α-helical, and α/β-core subdomains. Moreover, the timing of these events was critical; premature α-subdomain folding prevented subsequent core formation. This process was facilitated by modulating intrinsic folding propensity in three distinct ways: delaying a-subdomain compaction, facilitating β-strand intercalation, and optimizing translation kinetics via codon usage. Thus, de novo folding is translationally tuned by an integrated cellular response that shapes the cotranslational folding landscape at critical stages of synthesis. © 2015, American Association for the Advancement of Science. All rights reserved.
News Article | October 28, 2016
ATLANTA, GA--(Marketwired - October 28, 2016) - Celtaxsys, Inc., a clinical stage drug development company focused on advancing therapies for patients with rare inflammatory diseases, announced today the publication of the first in a series of papers detailing the results from the Phase 1 clinical trials for its flagship drug, acebilustat. Acebilustat is a novel once-daily oral anti-inflammatory drug in development for treatment of cystic fibrosis (CF) and other rare inflammatory diseases. This first paper details pharmacokinetics (PK), pharmacodynamics (PD) and drug-drug interaction results, as well as initial safety and tolerability, from three Phase 1 studies of acebilustat in healthy volunteers and patients with CF. Acebilustat was observed to be safe and well tolerated in the Phase 1 studies. The PK and PD support Phase 2 development of oral acebilustat in once-daily doses of 50 mg and 100 mg, demonstrating a rapid and sustained effect on modulating leukotriene B4, the pharmacologic target of this first-in-class leukotriene A4 hydrolase inhibitor. Importantly, no difference was observed in drug exposures between healthy volunteers and CF patients, and there was no difference in exposure when given under fasting conditions or after consuming a high fat meal. Finally, acebilustat did not induce CYP3A4, indicating that it may be suitable for use in combination with marketed CFTR modulators (Kalydeco® and Orkambi®). The article will be published online in the peer-reviewed journal Clinical and Translational Science (CTS), a publication of the American Society for Clinical Pharmacology and Therapeutics (ASCPT). Follow this link to visit the CTS homepage: http://ascpt.onlinelibrary.wiley.com/hub/journal/10.1111/(ISSN)1752-8062. A Phase 2 study in CF patients (EMPIRE-CF) is currently enrolling in North America and Europe to test the ability of once-daily oral doses of 50 mg and 100 mg acebilustat to stem the decline in lung function, and potentially improve airway clearance, over 48 weeks of treatment in these patients. This program is supported by a research grant from Cystic Fibrosis Foundation Therapeutics. For more information about this Phase 2 study, please visit: https://clinicaltrials.gov/ct2/show/NCT02443688. About Cystic Fibrosis: Cystic fibrosis (CF) is a life-threatening disease that affects the lung and digestive system of 70,000 patients worldwide. CF is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene leading to abnormal CFTR protein functioning, causing the body to accumulate excessive levels of unusually thick mucus in the lungs, causing severe infections that can require hospitalization. CFTR protein dysfunction also results in malabsorption of nutrients and sometimes intestinal blockage. Respiratory distress in CF, defined as acute difficulty in breathing, infection and/or hospitalization, is most commonly related to lung infection and inflammation induced lung tissue damage resulting from an overwhelming and dysfunctional response by dysregulated neutrophils. Treatment of this lung inflammation is, therefore, thought to be key to improving CF patients' lung health and wellbeing. For more information on CF, visit: www.cff.org. About acebilustat (formerly CTX-4430): Acebilustat is a once-daily oral drug candidate being tested for the treatment of inflammatory diseases. It is a novel small molecule inhibitor of Leukotriene A4 Hydrolase (LTA4H), the key enzyme in the production of the potent inflammatory mediator Leukotriene B4 (LTB4). LTA4H and LTB4 have been strongly implicated in the pathogenesis of many diseases involving inflammation, including cystic fibrosis. About Celtaxsys: Celtaxsys, Inc. is a privately-held pharmaceutical discovery and development company focused on advancing medicine to treat patients suffering from rare inflammatory diseases. The company is developing a sustainable pipeline of first-in-class immune-modulators, including its flagship compound acebilustat (formerly CTX-4430). Our follow-on molecules enable new intellectual property and exhibit differentiated properties that allow optimization for alternate routes of administration. For more information, please visit: www.celtaxsys.com.
News Article | November 3, 2016
Acebilustat clinical trial results are especially encouraging given lung inflammation continues to be the leading cause of morbidity and premature mortality associated with CF ATLANTA, GA--(Marketwired - November 03, 2016) - Celtaxsys, Inc., a clinical stage drug development company advancing therapies for patients with rare inflammatory diseases, announced today the publication of the second paper detailing the results from Phase 1 clinical trials for its flagship drug, acebilustat. Acebilustat is a novel once-daily oral anti-inflammatory drug in development for treatment of cystic fibrosis (CF) and other rare inflammatory diseases. This second paper details the effect of acebilustat on lung and systemic inflammatory biomarkers in a Phase 1B study in adult CF patients. Acebilustat doses of 50 mg and 100 mg demonstrated reductions in markers of lung and systemic inflammation after 15 days of treatment in patients with CF. Sputum neutrophil count was reduced by 65% from baseline values in patients treated with 100 mg acebilustat, suggesting the potential for acebilustat treatment to enhance airway clearance. Notably, the combined treated group demonstrated a 58% reduction in sputum neutrophil elastase versus the placebo group. Neutrophil elastase is the most predictive biomarker for future decline in lung function in patients with CF. Reductions in serum C-reactive protein and sputum neutrophil DNA, two additional biomarkers strongly associated with CF lung inflammation, were also observed in acebilustat-treated patients. Both dose levels were observed to be safe and well-tolerated and no negative trends were observed in lung function. Importantly, even in the presence of reduced sputum neutrophil counts, bacterial colonization of the lung, as measured by sputum bacterial load, remained unchanged. A Phase 2 study in CF patients (EMPIRE-CF) is currently enrolling in North America and Europe to test the ability of once-daily oral doses of 50 mg and 100 mg acebilustat to stem the decline in lung function and, potentially improve airway clearance, over 48 weeks of treatment in these patients. The ongoing Phase 2 study allows CF patients with any underlying genetic mutation to receive anti-inflammatory treatment with acebilustat in conjunction with their usual treatment which could include CFTR modulators (Kalydeco® and Orkambi®). This program is supported by a research grant from Cystic Fibrosis Foundation Therapeutics. For more information about this Phase 2 study, please visit: https://clinicaltrials.gov/ct2/show/NCT02443688. The article is published online in the peer-reviewed journal Clinical and Translational Science (CTS), a publication of the American Society for Clinical Pharmacology and Therapeutics (ASCPT). The full article can be downloaded from CTS via the following link: http://onlinelibrary.wiley.com/doi/10.1111/cts.12428/full. About Cystic Fibrosis: Cystic fibrosis (CF) is a life-threatening disease that affects the lung and digestive system of 70,000 patients worldwide. CF is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene leading to abnormal CFTR protein functioning, causing the body to accumulate excessive levels of unusually thick mucus in the lungs, leading to inflammation and severe infections that can reduce lung function and require hospitalization. CFTR protein dysfunction also results in malabsorption of nutrients and sometimes intestinal blockage. Respiratory distress in CF, defined as acute difficulty in breathing and infection with or without hospitalization, is most commonly related to lung infection and inflammation induced lung tissue damage resulting from an overwhelming and dysfunctional response by dysregulated neutrophils. Treatment of this lung inflammation is, therefore, thought to be key to improving CF patients' lung health and wellbeing. For more information on CF, visit: www.cff.org. About acebilustat (formerly CTX-4430): Acebilustat is a once-daily oral drug candidate being tested for the treatment of inflammatory diseases. It is a novel small molecule inhibitor of Leukotriene A4 Hydrolase (LTA4H), the key enzyme in the production of the potent inflammatory mediator Leukotriene B4 (LTB4). LTA4H and LTB4 have been strongly implicated in the pathogenesis of many diseases involving inflammation, including cystic fibrosis. About Celtaxsys: Celtaxsys, Inc. is a privately-held pharmaceutical discovery and development company focused on advancing medicine to treat patients suffering from rare inflammatory diseases. The company is developing a sustainable pipeline of first-in-class immune-modulators, including its flagship compound acebilustat (formerly CTX-4430). Our follow-on molecules enable new intellectual property and exhibit differentiated properties that allow optimization for alternate routes of administration. For more information, please visit: www.celtaxsys.com.
Rowe S.M.,University of Alabama at Birmingham |
Heltshe S.L.,University of Washington |
Heltshe S.L.,Seattle Childrens Research Institute |
Gonska T.,University of Toronto |
And 11 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2014
Rationale: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation. Objectives: To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers. Methods: We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, b-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P , 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m2; P , 0.001). Sweat chloride decreased from baseline to 6 months (mean change, 253.8 mmol/L; 95% confidence interval, 257.7 to 249.9; P , 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P , 0.001) and Pseudomonas aeruginosa burden (P , 0.01). Significant improvements in mucociliary clearance (P,0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor. Conclusions: Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology. Copyright © 2014 by the American Thoracic Society.
Accurso F.J.,University of Colorado at Denver |
Rowe S.M.,University of Alabama at Birmingham |
Clancy J.P.,University of Alabama at Birmingham |
Boyle M.P.,Johns Hopkins Medical Institutions |
And 24 more authors.
New England Journal of Medicine | Year: 2010
BACKGROUND: A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cellsurface CFTR in vitro. METHODS: We randomly assigned 39 adults with cystic fibrosis and at least one G551D-CFTR allele to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study). RESULTS: At day 28, in the group of subjects who received 150 mg of VX-770, the median change in the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) from baseline was -3.5 mV (range, -8.3 to 0.5; P = 0.02 for the within-subject comparison, P = 0.13 vs. placebo), and the median change in the level of sweat chloride was -59.5 mmol per liter (range, -66.0 to -19.0; P = 0.008 within-subject, P = 0.02 vs. placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P = 0.008 for the within-subject comparison, P = 0.56 vs. placebo). None of the subjects withdrew from the study. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770. CONCLUSIONS: This study to evaluate the safety and adverse-event profile of VX-770 showed that VX-770 was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis. (Funded by Vertex Pharmaceuticals and others; ClinicalTrials.gov number, NCT00457821.) Copyright © 2010 Massachusetts Medical Society.
Protasevich I.,University of Alabama at Birmingham |
Yang Z.,University of Alabama at Birmingham |
Wang C.,Columbia University |
Atwell S.,Eli Lilly and Company |
And 5 more authors.
Protein Science | Year: 2010
Misfolding and degradation of CFTR is the cause of disease in patients with the most prevalent CFTR mutation, an in-frame deletion of phenylalanine (F508del), located in the first nucleotide-binding domain of human CFTR (hNBD1). Studies of (F508del)CFTR cellular folding suggest that both intra- and inter-domain folding is impaired. (F508del)CFTR is a temperature-sensitive mutant, that is, lowering growth temperature, improves both export, and plasma membrane residence times. Yet, paradoxically, F508del does not alter the fold of isolated hNBD1 nor did it seem to perturb its unfolding transition in previous isothermal chemical denaturation studies. We therefore studied the in vitro thermal unfolding of matched hNBD1 constructs ±F508del to shed light on the defective folding mechanism and the basis for the thermal instability of (F508del)CFTR. Using primarily differential scanning calorimetry (DSC) and circular dichroism, we show for all hNBD1 pairs studied, that F508del lowers the unfolding transition temperature (Tm) by 6-7°C and that unfolding occurs via a kinetically-controlled, irreversible transition in isolated monomers. A thermal unfolding mechanism is derived from nonlinear least squares fitting of comprehensive DSC data sets. All data are consistent with a simple three-state thermal unfolding mechanism for hNBD1 ± F508del: N(±MgATP) ⇆ IT(±MgATP) → AT → (AT)n. The equilibrium unfolding to intermediate, IT, is followed by the rate-determining, irreversible formation of a partially folded, aggregation-prone, monomeric state, AT, forwhich aggregation to (AT)n and further unfolding occur with no detectable heat change. Fitted parameters indicate that F508del thermodynamically destabilizes the native state, N, and accelerates the formation of AT. © 2010 The Protein Society.
PubMed | Cystic Fibrosis Foundation Therapeutics, Stanford University, University of Alabama at Birmingham, Harvard Stem Cell Institute and 2 more.
Type: Journal Article | Journal: Cell stem cell | Year: 2016
Functional modeling of many adult epithelia is limited by the difficulty in maintaining relevant stem cell populations in culture. Here, we show that dual inhibition of SMAD signaling pathways enables robust expansion of primary epithelial basal cell populations. We find that TGF/BMP/SMAD pathway signaling is strongly activated in luminal and suprabasal cells ofseveral epithelia, but suppressed in p63+ basal cells. In airway epithelium, SMAD signaling promotes differentiation, and its inhibition leads to stem cell hyperplasia. Using dual SMAD signaling inhibition in a feeder-free culture system, we have been able to expand airway basal stem cells from multiple species. Expanded cells can produce functional airway epithelium physiologically responsive to clinically relevant drugs, such as CFTR modulators. This approach is effective for the clonal expansion of single human cells and for basal cell populations from epithelial tissues from all three germ layers and therefore may be broadly applicable for modeling of epithelia.
Lewis H.A.,SGX Pharmaceuticals |
Wang C.,Columbia University |
Zhao X.,SGX Pharmaceuticals |
Hamuro Y.,ExSAR Corporation |
And 10 more authors.
Journal of Molecular Biology | Year: 2010
The ΔF508 mutation in nucleotide-binding domain 1 (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) is the predominant cause of cystic fibrosis. Previous biophysical studies on human F508 and ΔF508 domains showed only local structural changes restricted to residues 509-511 and only minor differences in folding rate and stability. These results were remarkable because ΔF508 was widely assumed to perturb domain folding based on the fact that it prevents trafficking of CFTR out of the endoplasmic reticulum. However, the previously reported crystal structures did not come from matched F508 and ΔF508 constructs, and the ΔF508 structure contained additional mutations that were required to obtain sufficient protein solubility. In this article, we present additional biophysical studies of NBD1 designed to address these ambiguities. Mass spectral measurements of backbone amide 1H/2H exchange rates in matched F508 and ΔF508 constructs reveal that ΔF508 increases backbone dynamics at residues 509-511 and the adjacent protein segments but not elsewhere in NBD1. These measurements also confirm a high level of flexibility in the protein segments exhibiting variable conformations in the crystal structures. We additionally present crystal structures of a broader set of human NBD1 constructs, including one harboring the native F508 residue and others harboring the ΔF508 mutation in the presence of fewer and different solubilizing mutations. The only consistent conformational difference is observed at residues 509-511. The side chain of residue V510 in this loop is mostly buried in all non-ΔF508 structures but completely solvent exposed in all ΔF508 structures. These results reinforce the importance of the perturbation ΔF508 causes in the surface topography of NBD1 in a region likely to mediate contact with the transmembrane domains of CFTR. However, they also suggest that increased exposure of the 509-511 loop and increased dynamics in its vicinity could promote aggregation in vitro and aberrant intermolecular interactions that impede trafficking in vivo. © 2009 Elsevier Ltd.