2013 Publications

European Respiratory Society Annual Congress 2013

Abstract P735:
Thematic Poster Session : Novel drugs and biomarkers in respiratory medicine, Sunday 8th September 2013, HALL 1-12, Session 84, Convention Centre de Gran Via, Barcelona. Viewing Time: 12:50-14:40
The In Vitro Profile Of ADC3680, A Potent And Selective CRTh2 Antagonist For The Treatment Of Inadequately Controlled Asthma.
M.F. Fitzgerald1, M. Whitmarsh2, J. Prosser1, A. Banyard 3, P. Lockey4

1Pulmagen Therapeutics (Asthma) Ltd - Slough/UK, 2Argenta - Slough/UK, 3The Medicines Evaluation Unit - Manchester/UK, 4Argenta - Harlow/UK

PGD2 levels are increased in the BAL fluid of asthmatic patients irrespective of inhaled corticosteroid (ICS) treatment. Recent data have shown that antagonists of the PGD2 receptor CRTh2 improve lung function in patients with uncontrolled asthma.

ADC3680 is a potent and selective antagonist of human CRTh2 receptors with an affinity (Ki) of 1.6 nM, which is significantly greater than for other prostanoid receptors; DP1 (Ki >5000 nM) and EP1 – EP4 (Ki > 4100 nM). Limited TP receptor binding activity was observed at high concentrations (Ki >300 nM) but no functional TP activity was observed at physiologically relevant concentrations in a platelet aggregation response assay. Whilst highly plasma protein-bound (> 99%), addition of plasma protein (2.5%) had only a small effect on ADC3680 potency with affinity reduced ~4-fold.

In functional assays measuring PGD2-stimulated phosphorylation of intracellular Akt, ADC3680 was a potent and competitive antagonist (Ki 0.48 nM). Increasing PGD2 concentrations (up to 300 nM) had little effect on ADC3680 potency consistent with its relatively slow rate of receptor dissociation (t1/2 = 19.8 min). Addition of PGD2 (30 nM) to blood from healthy volunteers stimulated eosinophil shape change (ESC), which was inhibited by ADC3680 (IC50=10 nM, IC90=35 nM) with similar data observed in atopic asthmatics.

For optimal efficacy in asthma, a low 6 mg oral dose is predicted to give plasma ADC3680 levels > ESC IC90 for 24 hrs. ADC3680 has an excellent non-clinical safety profile and 6 month toxicology studies show a significant margin (~400) at the NOAEL. The efficacy of ADC3680 is currently being evaluated in asthma subjects not controlled on ICS.

Abstract P3401:
Poster Discussion : New clinical trials of asthma and COPD drugs, Tuesday 10th September 2013, Room 3.5, Session 346, Convention Centre de Gran Via, Barcelona. Viewing Time: 08:30-10:30
The safety, PK and PD profile of ADC3680, a potent and selective CRTh2 antagonist, in healthy volunteers and partly controlled atopic asthmatic subjects.
M.F. Fitzgerald1, S. Snape1, S. Febbraro2, D. Singh3, C. Pattwell3, B. Ruparelia1, N. Snell1

1Pulmagen Therapeutics (Asthma) Ltd - Slough/UK, 2Simbec Research Ltd - Merthyr Tydfil/UK, 3The Medicines Evaluation Unit - Manchester/UK

ADC3680 is a potent and selective CRTh2 antagonist whose efficacy is currently being evaluated in subjects with uncontrolled asthma on ICS.

In Phase I, 88 healthy volunteers were exposed to ≥1 dose of ADC3680 (1 – 200 mg as single doses; 10, 30 and 90 mg once daily for 7 days; and 10 mg daily for 14 days). 24 further subjects with partly controlled asthma on ICS, received 22.73 mg ADC3680 once daily for 28 days.

ADC3680 is relatively rapidly absorbed (tmax 2.5 hrs) and suitable for once-daily oral dosing (t1/2 11 – 15 hrs). Total plasma clearance of ADC3680 is low with little evidence of accumulation on repeat dosing.

ADC3680 was safe and well tolerated at single doses up to 200 mg, at doses up to 90 mg administered once daily for 7 days and in post-menopausal female volunteers at a single dose of 25 mg. ADC3680 was also well-tolerated in atopic asthmatics (22.73 mg once daily for 28 days). Most adverse events reported were mild or moderate and were considered to be unrelated to treatment and there were no clinically significant changes in laboratory safety parameters.

ADC3680 blocked the PGD2 mediated eosinophil shape change response (ESC) ex vivo in blood from healthy and asthmatic subjects. >90% inhibition of ESC was observed with ADC3680 at single (1 to 200 mg) and multiple ADC3680 doses (10, 30, and 90 mg once daily for 7 days). In asthmatic subjects, ADC3680 (22.73 mg daily) blocked ESC by >95% 24 hours post-dose on Day 1, and at 24 and 48 hours post-dose after 28 days' treatment.

The overall PK, safety and PD profile of ADC3680 support its further development as a low dose (<10 mg), once daily oral therapy for asthma.


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