In-Vitro /In-Vivo Comparisons of Formoterol MDI to ... · PDF fileIn-Vitro /In-Vivo Comparisons of Formoterol MDI to Formoterol DPI: Lessons Learned ... IMRB Conclusion

In-Vitro /In-Vivo Comparisons of Formoterol MDI to Formoterol DPI: Lessons Learned

Colin Reisner, MDChief Medical Officer, and Executive Vice President of Clinical Development and Medical AffairsPearl Therapeutics

March 20, 2014

IPAC-RS/UF Orlando Inhalation Conference

R&D | Innovative Medicines | IMRBName | day month year

Disclaimer

The views and opinions expressed herein are those of the presenter and are not intended to represent or reflect the views of Pearl Therapeutics and/or AstraZeneca

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R&D | Innovative Medicines | IMRBName | day month yearDarken 19 March 2014

Pearl FF MDI (PT005)Considerations for initial dose selection• In USA, no MDI approved at the start of development

(either alone or in combination)• Only Foradil Aerolizer (FA) available as a reference

product- FA label is 12 mcg/capsule, which delivers 10mcg formoterol

fumarate dihydrate (FFDH)- Pearl delivered dose is 9.6µg of FF anhydrous (per dose comprised

of 2 actuations), equivalent to 10µg FFDH• Overall NGI profile of MDI vs DPI known to be different

when tested at the same flow rates. 1

• Dilemma: Design studies to match on fine particle dose (FPD) vs total delivered dose (DD)?

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1: Stephan Meuller, Barbara Haeberlin, Stephen Edge, "Comparision of Performance Characteristics for ForadilAerolizer and Foradil Concept 1 (a New Single Dose Dry Powder Inhaler) at Different Test Flow Rates", Respiratory Drug Delivery Proceedings 2008


In Vitro ComparisonsRepresentative Pearl MDI vs Foradil Aerolizer

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* Delivered dose determined using total impactor massfrom aerodynamic particle size distribution measurement.

Differences in flow rate dependence of devices make selecting clinical doses based on in vitro comparisons difficult and potentially misleading


Decision Taken to Match Highest Emitted Dose

• Both products deliver approximately 10 µg formoterol fumarate dihydrate, (FFDH).

• Decision taken to match on DD• If the FPD impacted either PK or lung function, could be

assessed in clinic• Initial study was a randomized, double-blind, single

ascending dose design that included open label FA12 µg; the study had clearly defined patient withdrawal criteria.

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PT0050801: Comparable Efficacy and Systemic Exposure at Same Nominal Dose (10µg FFDH)

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PT0050801: Non-inferiority Assessment vs Foradil®Data Support Non-inferiority for 9.6 µg Dose (LL 95%CI = -45 ml)

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-0.20

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Mea

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adil®

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Time (hours)

FF MDI 9.6 mcgFF MDI 4.8 mcgFF MDI 2.4 mcg

Delivered using 1, 2 or 4 act from 2.4 mcg/act FF MDI


PT0050801: FF MDI 9.6 µg Comparable to FA12 (same nominal dose)

• Efficacy:- FF MDI 9.6 µg non inferior to FA 12 µg (lower bound 95%CI = -45 ml)

• PK: - Ratio of geometric LS Means for Cmax and AUC0-12 within 100% ± 4%- Bioequivalence met for AUC0-12

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AUC0-12 Ratio of Geometric LS Mean (90% CI)

CmaxRatio of Geometric LS Mean (90% CI)

PT0050801 96.8% (81.5 , 114.96) 98% (79.59, 120.91)


2 hrs

4hrs

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ean

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) FF MDI 9.6 µg

Time

Foradil 12 µg

11.5hrs

0.3

1 hr

Placebo MDI

Mean Change in FEV1 Over Time on Day 7 by Treatment vs Test Day Baseline (MITT Population)

PT0031002: FF MDI 9.6 µg Comparable to FA 12 µg


PT0031002: FF MDI 9.6 µg Non-inferior to Foradil Aerolizer 12 µg at Steady State (Day 7)Difference between FF MDI 9.6 µg and Foradil Aerolizer 12 µg was -0.016L (95% CI: -0.054, 0.022 L)

2 hrs

4hrs

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FF MDI 9.6 µg

Time

Foradil 12 µg

11.5hrs

0.06


Study PT0031002: FF MDI 9.6 µg Bioequivalent to Foradil Aerolizer 12 µg at Steady State

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97.78 98.3 99.0894.82

60708090

100110120130140

Cmax AUC last AUC 0-12 AUC 0-inf

FF MDI 9.6 µg vs Foradil Aerolizer 12 µg PharmacokineticsRatio of Geometric LS Means (90% confidence intervals)

Bioequivalencetarget

Rat

io G

eom

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LS

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PT005003 - Assay Sensitivity Demonstrated within Formulation Change from Baseline in FEV1 AUC0-12

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52 mLP = 0.002

42 mLP = 0.013

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FA 24 vs FA 12 FF 19.2 vs FF 9.6

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• Assay sensitivity demonstrated within Foradil Aerolizer (Foradil) formulation• Foradil 24 µg is superior to Foradil12 µg for FEV1 AUC0-12 (Difference = 52 mL; p-value =0.002)

• Assay sensitivity demonstrated within FF MDI formulation:- FF MDI 19.2 µg superior to FF 9.6 µg for FEV1 AUC0-12 (Difference of 42 mL; p-value = 0.013)


PT005003: FF MDI 9.6 µg and FA 12 µg Clinical Comparability and Bioequivalence

CONFIDENTIAL

AUC0-12Ratio of Geometric LS Mean (90% CI)

CmaxRatio of Geometric LS Mean (90% CI)

FF MDI 9.6 µg vs Foradil 12 µg 96 (87, 105) 96 (87, 107)


PT003003: Cardiovascular Safety Study

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Comparable 24-hour mean heart rate with FF MDI 9.6 µg and FA12 µg administration

• The bars represent the most extreme data points still within the 1.5 times above and below the inter-quartile range. The diamond represent the mean with the horizontal line within the interquartile range indicating the median.

• Individual extreme data points represent values more than 1.5 times above or below the inter-quartile range (the distance between the 25th

and 75th percentile shown as the shaded areas)


Summary: FF MDI 9.6 μg Compared with Foradil Aerolizer 12 μg

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Study Design Non-inferiority

Assay sensitivity

BE Safety 24-hourHolter

PT0050801 Single dose √ √ § §§ √ n/a

PT0031002 Chronic dose √ n/a √ √ n/a

PT005003 Single dose √ √ √ √ n/a

PT003003 Chronic dose n/a n/a n/a √ √

§ Assay sensitivity demonstrated within FF MDI formulation, 1 dose of FA evaluated.§§ Study not powered for BE, comparability established with point estimates within 100 ± 4% for Cmax and AUC0-12


Conclusion

• FA 12 µg and FF MDI 9.6 µg deliver similar delivered dose (~10 µg of formoterol fumarate dihydrate).

• Differences were observed in FPD with clear flow rate dependence for FA 12 µg

• FA 12 µg and FF MDI 9.6 µg had equivalent PK, PD and comparable safety profile.

• Based on these results, both FPD and DD should be evaluated and considered when comparing test to reference, especially when delivery devices differ.

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In-Vitro /In-Vivo Comparisons of Formoterol MDI to ... · PDF fileIn-Vitro /In-Vivo Comparisons of Formoterol MDI to Formoterol DPI: Lessons Learned ... IMRB Conclusion