A Single-blind, Randomized, Placebo-Controlled 3-Part Study in Healthy Volunteers and Patients With Mild Asthma to Investigate the Safety, Tolerability and Pharmacokinetics of Inhaled AZD0449 Following Single and Multiple Ascending Doses and to Investigate the Anti-Inflammatory Effect of Inhaled AZD0449

This will be a Phase I, first in human (FIH) study consisting of the following parts: Part 1a (SAD), Part 1b (IV Cohort), Part 2 (Multiple ascending dose (MAD), and Part 3 dry-powder inhalation (DPI)/ Proof of mechanism (PoM). Part 1a of the study will be a randomized, single-blind, placebo-controlled, SAD, sequential group design study performed at a single study center. Part 1b, will be an open-label, single-dose, single-cohort study. It will follow a 2-stage design in the way that participants from Part 1a will be selected for the IV Cohort in Part 1b. Part 2 of the study will be a randomized, single-blind, placebo-controlled, MAD, sequential group design and study performed at 3 study centers. Part 3a/b will be a randomized, single-blind, placebo-controlled, DPI/PoM study. The expected duration of each subject in Part 1a of the study is up to 36 days and up to 53 days for subjects participating in Part 1b. The expected duration of each participant in Part 2 is up to 52 days and Part 3 is up to 55 days.

Start Date30 Nov 2018

Sponsor / Collaborator

AstraZeneca PLC

100 Clinical Results associated with AZD-0449

100 Translational Medicine associated with AZD-0449

100 Patents (Medical) associated with AZD-0449

Literatures (Medical) associated with AZD-0449

01 Apr 2014·The Journal of allergy and clinical immunologyQ1 · MEDICINE

Janus kinase 1/3 signaling pathways are key initiators of TH2 differentiation and lung allergic responses

Q1 · MEDICINE

Article

Author: Takeda, Katsuyuki ; Li, Hui ; Ashino, Shigeru ; Joetham, Anthony ; Gelfand, Erwin W ; Taylor, Vanessa ; Pine, Polly R

BACKGROUND:

Janus kinases (JAKs) are regulators of signaling through cytokine receptors. The importance of JAK1/3 signaling on TH2 differentiation and development of lung allergic responses has not been investigated.

OBJECTIVE:

We sought to examine a selective JAK1/3 inhibitor (R256) on differentiation of TH subsets in vitro and on development of ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) and inflammation in an experimental model of asthma.

METHODS:

A selective JAK1/3 inhibitor was used to assay the importance of this pathway on induction of TH1, TH2, and TH17 differentiation in vitro. In vivo, the effects of inhibiting JAK1/3 signaling were examined by administering the inhibitor during the sensitization or allergen challenge phases in the primary challenge model or just before provocative challenge in the secondary challenge model. Airway inflammation and AHR were examined after the last airway challenge.

RESULTS:

In vitro, R256 inhibited differentiation of TH2 but not TH1 or TH17 cells, which was associated with downregulation of signal transducer and activator of transcription (STAT) 6 and STAT5 phosphorylation. However, once polarized, TH2 cells were unaffected by the inhibitor. In vivo, R256 administered during the OVA sensitization phase prevented the development of AHR, airway eosinophilia, mucus hypersecretion, and TH2 cytokine production without changes in TH1 and TH17 cytokine levels, indicating that selective blockade of TH2 differentiation was critical. Inhibitor administration after OVA sensitization but during the challenge phases in the primary or secondary challenge models similarly suppressed AHR, airway eosinophilia, and mucus hypersecretion without any reduction in TH2 cytokine production, suggesting the inhibitory effects were downstream of TH2 cytokine receptor signaling pathways.

CONCLUSIONS:

Targeting the TH2-dependent JAK/STAT activation pathway represents a novel therapeutic approach for the treatment of asthma.

01 Mar 2001·Acta pharmacologica Sinica

Accumulation of ofloxacin and tosufloxacin in fluoroquinolone-resistant E coli.

Article

Author: Lei, B J ; Feng, P ; Zhong, L ; Xia, P Y ; Lv, X J

AIM:

To make sure whether there is a difference in mechanism existed in the resistant E coli strains accumulated hydrophilic fluoroquinolone ofloxacin and hydrophobic fluoroquinoline tosufloxacin.

METHODS:

Fluoroquinolone accumulation in bacteria and effect of active efflux were measured by fluorescence method. Analysis of outer membrane proteins was made by SDS-PAGE. E coli strains included JF701 and JF703 that are OmpC- or OmpF-deficient mutants of E coli K-12 respectively, and the susceptible strain Ecs and its in-vitro selected resistant strains R2, R256, and clinical resistant isolates R5, R6.

RESULTS:

Ecs accumulated ofloxacin almost at the same concentration as JF701, but JF703 did about 1/2 of that lower than JF701. However, four resistant strains accumulated ofloxacin about 5 to 7-fold lower than those susceptible strains. On the other hand, there was no significant difference for the accumulation of tosufloxacin between fluoroquinolone-resistant and -susceptible strains. After addition of proton ionophore DNP for 5 min and 10 min, the accumulation of tosufloxacin slowly decreased in E coli strains, whereas the accumulation of ofloxacin was increased, especially in the resistant strains. A good relevance exists between the accumulation increment of ofloxacin and its MIC for each E coli strain after addition of DNP for 5 min and 10 min (r=0.9623 and 0.8006 respectively). Furthermore, both OmpF and OmpC in Ecs, OmpF-deficiency in R2, R256 and OmpC-deficiency in R5, R6 were observed.

CONCLUSION:

The accumulation of ofloxacin other than tosufloxacin could be reduced by OmpF-deficiency and active efflux, and the latter may be an important factor in the development of resistance to hydrophilic fluoroquinolone in E coli.

01 Aug 1989·Oncogene

Characterization of monoclonal antibody R256, specific for activated ras p21 with arginine at 12, and analysis of breast carcinoma of v-Harvey-ras transgenic mouse.

Article

Author: Sinn, E ; Carney, W P ; Pullano, T G

The ras family of proto-oncogenes can be activated into transforming genes by single point mutations resulting in p21 products with amino acid substitutions at positions 12, 13 and 61. Here we describe a monoclonal antibody designated R256 which reacts specifically with a synthetic peptide corresponding to amino acids 5 to 16 of ras p21 activated by the substitution of arginine for glycine at position 12. It does not react with peptides representing other activating substitutions at position 12. Western blot studies showed that R256 reacts specifically with recombinant ras p21 containing an arginine-12 substitution but is unreactive with the normal glycine-12 recombinant p21. R256 binds the activated Kirsten p21 in human lung tumor cell line A2182, which contains an activated arginine-12 p21. R256 is also specific for arginine-12 p21 extracted from NIH3T3 cells transformed by the viral Harvey-ras p21, containing arginine at 12, and is not reactive with transformants containing activated p21s with valine, serine, aspartic acid, glutamic acid, cysteine or normal glycine at position 12. When R256 was used to test for expression of arginine-12 p21 in tissues of transgenic mice containing an MMTV/v-Harvey-ras transgene, the monoclonal antibody was able to determine that the arginine-12 p21 transgene product was present in breast tumors but not in normal tissues. The ability of R256 to react specifically with arginine-12 p21 may prove to be valuable in the study of ras oncogenesis in model systems and in determining the presence of arginine-12 p21 in human tumors.

News (Medical) associated with AZD-0449

23 Feb 2015

·www.biospace.com

Rigel Lands $339 Million+ Cancer Deal With Bristol-Myers Squibb

February 23, 2015 By Riley McDermid , BioSpace.com Breaking News Sr. Editor South San Francisco, Calif.-based Rigel Pharmaceuticals, Inc. announced Monday that it has entered into a collaboration agreement with Bristol-Myers Squibb Company that will develop cancer drugs based on Rigel ’s portfolio of small molecule TGF beta receptor kinase inhibitors.“So far, Rigel has identified a large number of orally bioavailable, potent and selective small molecule inhibitors of TGF beta receptor kinases that have demonstrated in vivo efficacy, in preclinical animal models of cancer, consistent with an immune-mediated mechanism of action,” said the company The company currently has multiple drugs in mid- or late-stage clinical trials. Those include fostamatinib, an oral spleen tyrosine kinase (SYK) inhibitor, which is in Phase III clinical trials for immune thrombocytopenic purpura (ITP) and initiating a Phase II clinical trial for IgA nephropathy (IgAN); R348, a topical JAK/SYK inhibitor, in a Phase III clinical trial for dry eye in ocular graft-versus-host disease (GvHD). It also has two oncology product candidates in Phase I development with partners BerGenBio AG and Daiichi Sankyo, Inc. ; and two preclinical programs with AstraZeneca for R256 in asthma and Bristol-Myers Squibb for TGF beta inhibitors in immuno-oncology. Under the terms of the deal, Bristol-Myers Squibb will pay Rigel $30 million upfront with developmental and regulatory milestones that could add up to more than $309 million. Bristol-Myers Squibb gets exclusive, worldwide rights to develop and commercialize any drugs that come from the collaboration, while Rigel will also be eligible to receive tiered royalties on the net sales of any products from the collaboration. “As a company dedicated to leading scientific advances in immuno-oncology, we are committed to exploring the utility of TGF beta inhibition as a potential therapeutic to fight certain cancers,” said Carl Decicco, head of Discovery and Research and Development at Bristol-Myers Squibb in a statement. “Working with Rigel and having access to their TGF beta receptor kinase inhibitors extends our existing portfolio of immunotherapeutic approaches to include this key mediator of immunosuppression in the tumor microenvironment.” The partnership is gaining notice because recent research has suggest that TGF beta can act as an immunosuppressant for effector cell proliferation, while simultaneously promoting differentiation of certain suppressive T-cells. Those can significantly dampen anti-tumor host immune responses, which can hinder or even stop tumor growth. “This collaboration places our TGF beta receptor kinase inhibitor program into the hands of Bristol-Myers Squibb , a premier immuno-oncology company. Together, we believe TGF beta inhibition may offer novel therapeutic opportunities in oncology treatments,” said Raul Rodriguez , president and chief executive officer of Rigel . “ Rigel has focused on immunology, and oncology via numerous partnerships. This collaboration is Rigel ‘s first in immuno-oncology and is one of the Company’s several programs in this area.” BioSpace Temperature Poll Analyst Mark Schoenebaum , a biotech and pharmaceuticals analyst and medical doctor for ISI Group Evercore , has been running a Best Hair in Biopharma contest for several months now. So far, the candidates are Bristol-Myers Squibb Company ‘s John Elicker , Receptos ’ Chief Executive Officer Faheem Hasnain , Celgene ‘s Vice President of Investor Relations Patrick Flanigan and Acorda Therapeutics ’ Ron Cohen . We want to know what our BioSpace community thinks: Who do you believe actually has the Best Hair in BioPharma? var _polldaddy = [] || _polldaddy; _polldaddy.push( { type: "iframe", auto: "1", domain: "biospace.polldaddy.com/s/", id: "will-hiring-heat-up-in-2018", placeholder: "pd_1424676772" } ); (function(d,c,j){if(!document.getElementById(j)){var pd=d.createElement(c),s;pd.id=j;pd.src=(' '==document.location.protocol)?' ':' ';s=document.getElementsByTagName(c)[0];s.parentNode.insertBefore(pd,s);}}(document,'script','pd-embed')); Read at BioSpace.com

Phase 2License out/inImmunotherapyPhase 3Phase 1

100 Deals associated with AZD-0449

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 1	Germany	AstraZeneca PLC	30 Nov 2018
Asthma	Phase 1	New Zealand	AstraZeneca PLC	30 Nov 2018
Asthma	Phase 1	United Kingdom	AstraZeneca PLC	30 Nov 2018

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