A Phase I study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of GDC-0214 conducted in three parts: a single ascending dose study in healthy volunteers, a multiple-ascending dose study in healthy volunteers, and a proof of activity study in patients with mild asthma.

Start Date11 Dec 2017

Sponsor / Collaborator

Genentech, Inc.

100 Clinical Results associated with GDC-0214

100 Translational Medicine associated with GDC-0214

100 Patents (Medical) associated with GDC-0214

Literatures (Medical) associated with GDC-0214

03 Jun 2024·Molecular pharmaceutics

Correction to “Inhaled JAK Inhibitor GDC-0214 Nanoaggregate Powder Exhibits Improved Pharmacokinetic Profile in Rats Compared to the Micronized Form: Benefits of Thin Film Freezing”

Author: Manandhar, Rachana ; Narang, Ajit ; Sahakijpijarn, Sawittree ; Nagapudi, Karthik ; Shetty, Nivedita ; Taft, David R. ; Jara, Miguel O. ; Lubach, Joseph ; Moon, Chaeho ; Williams, Robert O. ; Maier, Esther Y. ; Praphawatvet, Tuangrat

ADVERTISEMENT RETURN TO ARTICLES ASAPPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to "Inhaled JAK Inhibitor GDC-0214 Nanoaggregate Powder Exhibits Improved Pharmacokinetic Profile in Rats Compared to the Micronized Form: Benefits of Thin Film Freezing"Chaeho Moon*Chaeho MoonMore by Chaeho Moonhttps://orcid.org/0000-0001-6986-5158, Sawittree SahakijpijarnSawittree SahakijpijarnMore by Sawittree Sahakijpijarn, Esther Y. MaierEsther Y. MaierMore by Esther Y. Maier, David R. TaftDavid R. TaftMore by David R. Taft, Miguel O. JaraMiguel O. JaraMore by Miguel O. Jarahttps://orcid.org/0000-0002-2568-8660, Tuangrat PraphawatvetTuangrat PraphawatvetMore by Tuangrat Praphawatvet, Rachana ManandharRachana ManandharMore by Rachana Manandhar, Nivedita ShettyNivedita ShettyMore by Nivedita Shetty, Joseph LubachJoseph LubachMore by Joseph Lubachhttps://orcid.org/0000-0002-5806-0204, Ajit NarangAjit NarangMore by Ajit Naranghttps://orcid.org/0000-0002-9417-1307, Karthik NagapudiKarthik NagapudiMore by Karthik Nagapudi, and Robert O. Williams III*Robert O. Williams, IIIMore by Robert O. Williams, IIIhttps://orcid.org/0000-0003-4993-6427Cite this: Mol. Pharmaceutics 2024, XXXX, XXX, XXX-XXXPublication Date (Web):April 25, 2024Publication History Received9 April 2024Published online25 April 2024https://doi.org/10.1021/acs.molpharmaceut.4c00382© 2024 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views-Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (556 KB) Get e-Alertsclose Get e-Alerts

05 Feb 2024·Molecular pharmaceutics

Inhaled JAK Inhibitor GDC-0214 Nanoaggregate Powder Exhibits Improved Pharmacokinetic Profile in Rats Compared to the Micronized Form: Benefits of Thin Film Freezing

Article

Asthma is a common chronic disease affecting the airways in the lungs. The receptors of allergic cytokines, including interleukin (IL)-4, IL-5, and IL-13, trigger the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, which involves the pathogenesis of asthma. GDC-0214 is a JAK inhibitor that was developed as a potent and selective target for the treatment of asthma, specifically targeting the lungs. While inhaled GDC-0214 is a promising novel treatment option against asthma, improvement is still needed to achieve increased potency of the powder formulation and a reduced number of capsules containing powder to be inhaled. In this study, high-potency amorphous powder formulations containing GDC-0214 nanoaggregates for dry powder inhalation were developed using particle engineering technology, thin film freezing (TFF). A high dose per capsule was successfully achieved by enhancing the solubility of GDC-0214 and powder conditioning. Lactose and/or leucine as excipients exhibited optimum stability and aerosolization of GDC-0214 nanoaggregates, and aerosolization of the dose was independent of air flow through the device between 2 and 6 kPa pressure drops. In the rat PK study, formulation F20, which contains 80% GDC-0214 and 20% lactose, resulted in the highest AUC_0-24h in the lungs with the lowest AUC_0-24h in the plasma that corresponds to a 4.8-fold higher ratio of the lung-to-plasma exposures compared to micronized crystalline GDC-0214 powder administered by dry powder inhalation. Therefore, GDC-0214 nanoaggregates produced by TFF provided an improved dry powder for inhalation that can lead to enhanced therapeutic efficacy with a lower risk of systemic toxicity.

01 Aug 2022·Pulmonary pharmacology & therapeutics

Effects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation

Article

Author: Kunder, Rebecca ; Sparks, Jenny ; Gugelmann, Hallam ; Galanter, Joshua ; Zou, Yixuan ; Oldfield, Karen ; Chang, Joanna K ; Grimbaldeston, Michele A ; Wilson, Mark S ; Eliahu, Avi ; Durk, Matthew R ; Kung, Stacey ; Zhu, Rui ; Braithwaite, Irene ; Doppen, Marjan ; Wilson, Maria ; Beasley, Richard ; Chen, Hubert ; Black, Melissa ; Choy, David F ; Owen, Ryan ; Staton, Tracy

BACKGROUND:

Janus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations.

AIM:

To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation.

METHODS:

This study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18-65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEV₁)> 70% predicted, FeNO >40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed.

RESULTS:

Of 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41-222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: -6 (-43, 32) at 10 mg QD, -26 (-53, 2) at 30 mg QD, -55 (-78, -32) at 40 mg BID and -52 (-72, -32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful.

CONCLUSIONS:

In patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns.

AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY:

ACTRN12619000227190.

100 Deals associated with GDC-0214

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 1	New Zealand	Genentech, Inc.	-

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