2013 Publications - continued

American Thoracic Society Annual Conference 2013

Abstract A2617:
B32-ADVANCES IN ASTHMA THERAPY, Monday, May 20, 2013, Area B (Halls C-D, 200 Level) Pennsylvania Convention Center, Poster Board Number: B38, Viewing Time: 10:45-12:30
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, S. Snape1, 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 whether they are treated with inhaled corticosteroids (ICS) or not. In asthma, the key receptor for PGD2 is thought to be CRTh2 and recent clinical data have shown that antagonists of this receptor 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 ADC3680 does not appear to have any functional activity at the TP receptor, exhibiting no activity at physiologically relevant concentrations in a platelet aggregation response assay. Although ADC3680 is highly plasma protein-bound (> 99%), addition of plasma protein (2.5%) had only a small effect on potency; with affinity reduced approximately 4-fold.

In functional assays, measuring PGD2-stimulated phosphorylation of intracellular Akt using CHO cells expressing the human CRTh2 receptor, ADC3680 was shown to be a potent and competitive CRTh2 receptor antagonist (Ki 0.48 nM). Increasing concentrations of PGD2 (up to 300 nM) had little effect on the potency of ADC3680, consistent with its relatively slow rate of receptor dissociation (t1/2 = 19.8 min). The addition of PGD2 (30 nM) to whole citrated blood from healthy volunteers stimulated eosinophil shape change (ESC), which was inhibited by ADC3680 in a concentration-dependent manner with an IC50 of 10 nM and an IC90 of 35 nM. Further studies have indicated that there is no difference in the potency of ADC3680 in the ESC assay when blood from atopic asthmatic subjects was evaluated.

For optimal efficacy in asthma, a dose as low as 6 mg is predicted to achieve plasma ADC3680 levels at or above the ESC IC90 for 24 hrs. ADC3680 has an excellent non-clinical safety profile and the 6 month toxicology studies show that there is a significant margin of approximately 400 at the NOAEL. The efficacy of ADC3680 is currently being evaluated in asthma subjects who are not controlled on low to medium dose ICS.


Abstract A3874:
C23-NOVEL THERAPEUTICS IN ASTHMA, Tuesday, May 21, 2013 Room 113 A (100 Level) Pennsylvania Convention Center, Poster Board Number: 314, Viewing Time: 8:15-9:15, Discussion Time: 9:15-10:45
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, A. Banyard3, C. Pattwell3, B. Ruparelia1, N.J.C. 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 despite low to medium dose ICS.

In Phase I, 88 healthy volunteers have been exposed to at least one dose of ADC3680 capsules (1 – 200 mg as single doses; 10, 30 and 90 mg once daily for 7 days; and 10 mg daily for 14 days). A further 24 subjects with partly controlled atopic asthma, despite ICS therapy, have received a 22.73 mg ADC3680 tablet once daily for 28 days.

ADC3680 is relatively rapidly absorbed (tmax 2.5 hrs), is suitable for once-daily oral dosing (t1/2 11 – 15 hrs), dose adjustments based on gender are not necessary and food does not significantly affect exposure. Total plasma clearance of ADC3680 is low and the apparent volume of distribution indicates distribution out of the plasma. There was little evidence of accumulation on repeat dosing.

ADC3680 was safe and well tolerated in healthy male volunteers 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 male and female subjects with atopic asthma (22.73 mg once daily for 28 days). Most adverse events reported were mild or moderate and were considered to be unrelated to treatment. There were no clinically significant changes in laboratory safety parameters noted. No other safety issues of clinical relevance were identified that were considered likely to be treatment-related.

ADC3680 blocked the PGD2 mediated eosinophil shape change response (ESC) in an ex vivo assay in healthy and asthmatic subjects. >90% inhibition of ESC was observed in blood samples collected from healthy male volunteers dosed with ADC3680 at single (1 to 200 mg) and multiple ADC3680 doses (10, 30, and 90 mg once daily for 7 days). The effect was apparent within 1 hour of dosing, was sustained for the 7 day dosing period and for up to 48 hours after the last dose. 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.

 

Previous Publications

American Thoracic Society Annual Conference 2010
Effects of low dose inhaled theophylline (ADC4022) co-administered with budesonide on inflammatory markers and lung function in patients with COPD.
N. Barnes, MBBS FRCP1, S. Snape, PhD2, J.C. Fox, PhD2, M. Fitzgerald, PhD2, N. Snell, MD 2, I.D. Pavord, MD, PhD3, P. Jeffery, PhD4, Y. Qiu, MD, PhD4, D. Singh, MD5, A. Antczak, MD6, E. Nizankowska-Mogilnicka, MD, PhD7

1London Chest Hospital - London/UK, 2Argenta Discovery - Harlow/UK, 3Glenfield Hospital - Leicester/UK, 4Imperial College - London/UK, 5The University of Manchester - Manchester/UK, 6Medical University, Lodz - Lodz/PL, 7Jagiellonian University Medical College - Krakow/PL

RATIONALE: Inhaled corticosteroids (ICS) have limited anti-inflammatory activity in COPD, hypothesised to be due to reduced pulmonary histone deacetylase (HDAC) activity. Pre-clinical studies using tobacco smoke exposed mice support the hypothesis that inhaled low-dose theophylline (ADC4022) administered with an ICS might restore steroid responsiveness in the lungs of COPD patients.

METHODS: Following a 2 week washout of long-acting bronchodilators, 91 patients with moderate-severe COPD (mean post bronchodilator FEV1 % predicted of 62%, 72% males, 39 mean pack years, 45% current smokers) received 4 weeks treatment with nebulised budesonide (1mg twice daily) during the run-in period. Patients were then randomised to receive nebulised ADC4022 (12.5mg) (n=47) or placebo (n=44) twice daily in addition to nebulised budesonide for a further 4 weeks. Ipratropium bromide was allowed as rescue medication. Pulmonary function, safety and tolerability and sputum and bronchial biopsy inflammatory markers were examined.

RESULTS: Lung function was stable on ADC4022+budesonide treatment for 4 weeks but declined in the placebo+budesonide group producing a significant treatment difference of 142ml in FEV1 and 281ml in FVC (p<0.05). 20% fewer subjects required rescue medication on ADC4022+budesonide treatment compared to placebo+budesonide. Following treatment, % sputum neutrophils did not change in the placebo+budesonide group but increased in the ADC4022+budesonide group, producing a treatment difference of +5.5% (p=0.089). Concordantly, % macrophages decreased in the ADC4022+budesonide group. The total number of sputum neutrophils or macrophages did not change in either group following treatment. Bronchial biopsy inflammatory markers were examined in a small subset of patients (n=14 ADC4022+budesonide, n=16 placebo+budesonide). CD8+ T cells and CD68+ macrophages (sub-segmental carinae) were reduced following ADC4022+budesonide treatment compared with placebo+budesonide producing a treatment difference of -37 cells/mm2 (p=0.14) and -4.5 cells/mm2 (p=0.18) respectively. ADC4022 was safe and well-tolerated consistent with very low theophylline plasma exposure (Cmax <0.4 mg/L) achieved following inhalation of the 12.5 mg dose.

CONCLUSION: Nebulised ADC4022 (12.5 mg) co-administered with budesonide (1 mg) administered twice daily was well tolerated, maintained pulmonary function and appeared to modulate airway inflammatory cell populations in patients with COPD. This exploratory study suggests that low dose inhaled theophylline has the potential to restore the anti-inflammatory activity of ICS in patients with COPD and longer term therapy may improve patient outcomes. Follow up studies are currently being planned to demonstrate this.