timapiprant (OC000459) / Chiesi - LARVOL DELTA

Six promising drug repurposing candidates for Alzheimer's disease and their sex-specific mechanisms and efficacy. (PubMed, Neural Regen Res) - "These included ibudilast, timapiprant, RG2833, diazoxide/ dibenzoylmethane (combined), and BT-11, which targeted key Alzheimer's disease-related molecular pathways such as amyloid-beta plaques, Tau tangles, and neuroinflammation. These drugs, at various stages of development, offer hope for not only managing symptoms but also addressing the underlying mechanisms of Alzheimer's disease. This review underscores the need for a multifaceted approach to Alzheimer's disease treatment, combining symptom relief with disease modification."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation

Novel aryl hydrocarbon receptor agonists as potential anti-inflammatory therapeutics: Identification and validation through drug repurposing. (PubMed, Biochem Pharmacol) - "While Febuxostat, Nitazoxanide, Rabeprazole, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester, 3-Indolepropionic acid, and Indirubin, were already known as AhR agonists, Nabumetone, Teriflunomide, Timapiprant/OC000459, and Caffeic acid phenylethyl ester have not yet been directly described in this context. Five candidates restored the epithelial barrier, as evidenced by increased transepithelial electrical resistance and induction of the tight junction proteins claudin-1/-2 and occludin, while exhibiting anti-inflammatory effects, i.e., decreased expression of toll-like receptor 4. Out of these, one compound was selected for future in vivo preclinical studies."

IO biomarker • Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • CLDN1 • CYP1A1 • IL1B • OCLN • TLR4

The Effects of OC000459 on Nasal Mediators (clinicaltrials.gov) - P1/2 | N=12 | Completed | Sponsor: Trevor Hansel | Phase classification: P1 ➔ P1/2 | N=20 ➔ 12

Enrollment change • Phase classification • Allergic Rhinitis • Immunology • Inflammation • IL13 • IL4 • IL5

Attenuation of Laser-Induced Choroidal Neovascularization by Blockade of Prostaglandin D2 Receptor 2. (PubMed, Transl Vis Sci Technol) - "Using a laser-induced CNV model, the CNV size of wild-type (WT) mice treated with DP2 antagonist (CAY10471 or OC000459) was compared with that of untreated mice...DP2 blockade attenuated choroidal neovascularization. Drugs targeting DP2 are potentially a novel treatment for age-related macular degeneration."

Journal • Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders • PTGDR • PTGDR2

Investigation on the use of fused deposition modeling for the production of IR dosage forms containing Timapiprant. (PubMed, Int J Pharm X) - "Formulations based on different polymeric carriers were screened, leading to the identification of a polyvinyl alcohol-based one, which turned out acceptable for versatility in terms of active ingredient content, printability and dissolution performance (i.e. capability to meet the dissolution specification set, envisaging >80% of the drug dissolved within 30 min). Following an in-depth evaluation on the influence of TMP solid state and of the voids volume resulting from printing on dissolution, few prototypes with shapes especially devised for therapy customization were successfully printed and were compliant with the dissolution specification set."

Journal • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Timapiprant, a prostaglandin D2 receptor antagonist, ameliorates pathology in a rat Alzheimer's model. (PubMed, Life Sci Alliance) - "Timapiprant significantly mitigated Alzheimer's disease pathology and cognitive deficits in TgF344-AD males. Thus, selective DP2 antagonists have potential as therapeutics to treat Alzheimer's disease."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Immunology • Inflammation • PTGDR

Effect of CRTH2 antagonism on the response to experimental rhinovirus infection in asthma: a pilot randomised controlled trial. (PubMed, Thorax) - "Timapiprant treatment had little impact on the clinicopathological changes induced by RV-A16 infection in partially controlled asthma."

Clinical • Journal • Asthma • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases

The impact of CRTH2 antagonist OC 000459 on pulmonary function of asthma patients: a meta-analysis of randomized controlled trials. (PubMed, Postepy Dermatol Alergol) - "Overall, compared with the control intervention for asthma patients, CRTH2 antagonist OC 000459 could significantly improve FEV (SMD = 0.22; 95% CI: 0.02-0.42; p = 0.03), peak expiratory flow (SMD = 0.22; 95% CI: 0.01-0.42; p = 0.04) and reduce the respiratory tract infection (RR = 0.47; 95% CI: 0.26-0.85; p = 0.01), but revealed no remarkable effect on predicted FEV (SMD = 0.14; 95% CI: -0.18 to 0.45; p = 0.39), or treatment-related adverse events (RR = 0.84; 95% CI: 0.52-1.36; p = 0.48). CRTH2 antagonist OC 000459 might be effective and safe to improve pulmonary function in asthma patients."

Journal • Retrospective data • Review • Asthma • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases

PERSEA: Efficacy and Safety of CHF 6532 in Patients With Uncontrolled Severe Eosinophilic Asthma (clinicaltrials.gov) - P3; N=810; Terminated; Sponsor: Chiesi Farmaceutici S.p.A.; The DMC recommended to stop the study for futility. The Sponsor issued a notification of early study termination.

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Effect of OC459 on the Response to Rhinovirus Challenge in Asthma (clinicaltrials.gov) - P2; N=44; Completed; Sponsor: Imperial College London; Recruiting ➔ Completed; N=28 ➔ 44

Enrollment change • Trial completion • Asthma • Immunology • Respiratory Diseases

[VIRTUAL] The CRTH2 Antagonist Timapiprant Does Not Alter the Response Rhinovirus Infection in Asthma: A Randomized, Placebo-Controlled Trial (ATS-I 2020) - "Timapiprant failed to attenuate RV-induced asthma exacerbations in subjects with moderately severe partially-controlled asthma, other than to suppress a small increase in CRTH2 + cells in the bronchial wall. Three weeks pre-treatment with timapiprant may have been insufficient, and/or timpapiprant may only be effective in subjects with more severe/less controlled eosinophilic asthma."

Clinical • Asthma • Immunology • Respiratory Diseases • IL13 • IL4 • IL5

Ocular allergy: update on clinical trials. (PubMed, Curr Opin Allergy Clin Immunol) - "Currently, the primary advances in treatment for allergic conjunctivitis has shifted from new ophthalmic agents to immunotherapy and improvement of drug delivery. This includes the classic subcutaneous and sublingual and the novel epicutaneous and intralymphatic immunotherapy delivery systems as well as an edible rice vaccine. New targets for treatment have spurred research into new antagonist drugs such as (OC000459), a prostaglandin D2 antagonist. The Marinosolv formulation using tacrolimus shows promise and may be considered for other ophthalmic agents in the future. Other nonpharmacological treatments such as stenting and mechanical barrier gel have demonstrated their usefulness in treating ocular symptoms."

Clinical • Journal • Allergy • Conjunctivitis • Immunology • Ocular Infections • Ocular Inflammation • Ophthalmology

Atopix Therapeutics announces positive phase IIb results for once daily OC459 in asthma (Fort Mill Times) - P2b, N=480; NCT00890877; "OC459, at a dose of 25mg once a day, showed a statistically significant improvement in lung function compared to placebo....Treatment with OC459 led to a statistically-significant reduction in the incidence of respiratory tract infections, an effect believed to be due to dampening the harmful Th2 immune response detrimental to the outcome of asthma patients infected with rhinovirus."

P2b data • Asthma

Proof of concept study of OC000459 in eosinophilic esophagitis (clinicaltrials.gov) - P2, N=26; Active, not recruiting -> Completed

Trial completion

A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma (Clin Exp Allergy) - P2, N=132; In Full Analysis (FA) population, mean change in forced expiratory volume in 1s (FEV1) was 7.1% on OC000459 vs. 4.3% on PBO (not significant); in Per Protocol (PP) population, mean changes were 9.2% & 1.8%, respectively (p=0.037); Improvement in quality of life was apparent in both FA & PP populations [p=0.0113 & p=0.0022, respectively]; OC000459 shows promise as novel oral treatment for asthma & related disorders

P2 data • Asthma • Immunology

The CRTH2 Antagonist Timapiprant Does Not Alter the Response Rhinovirus Infection in Asthma: A Randomized, Placebo-Controlled Trial (ATS 2020) - "Timapiprant failed to attenuate RV-induced asthma exacerbations in subjects with moderately severe partially-controlled asthma, other than to suppress a small increase in CRTH2+ cells in the bronchial wall. Three weeks pre-treatment with timapiprant may have been insufficient, and/or timpapiprant may only be effective in subjects with more severe/less controlled eosinophilic asthma."

Clinical • IL13 • IL4 • IL5

Late Breaking Abstract - Effect of timapiprant, a DP2 antagonist, on airway inflammation in severe eosinophilic asthma (ERS 2019) - "Treatment for 12 weeks with timapiprant in severe eosinophilic asthma patients was associated with an evident reduction of airway eosinophilic inflammation and an increase in FEV1 (although not statistically significant due to the limited sample size). Studies in larger population are needed to confirm these effects."

Late-breaking abstract

Late Breaking Abstract - An assessment of potential predictive biomarkers for the treatment of severe eosinophilic asthma with CRTH2 antagonists (ERS 2019) - "Baseline blood total CRTH2+ cells (r=0.75; p<0.001), eosinophils (r=0.76; p<0.001), basophils (r=0.53; p=<0.05), Type-2 cytotoxic T (Tc2) cells (r=0.52; p=<0.05), and sputum eosinophils (r=0.82; p<0.0001) were correlated significantly with the reduction in the sputum eosinophil count with timapiprant treatment. Conclusion High levels of blood total CRTH2+ cells, eosinophils, basophils, Tc2 cells, and sputum eosinophils are associated with the anti-inflammatory effect of timapiprant treatment and could be potential predictive biomarkers of response."

Biomarker • Late-breaking abstract

Effect of OC000459 on Eosinophilic Airway Inflammation in Severe Asthma (clinicaltrials.gov) - P2; N=40; Completed; Sponsor: Atopix Therapeutics, Ltd.; Recruiting ➔ Completed

Clinical • Trial completion