FRI aerosol. deposition. A unique way to look at regional inhaled drug deposition.

FRI aerosol deposition A unique way to look at regional inhaled drug deposition www.fluidda.com

EXECUTIVE SUMMARY FRI - AN UPDATE OF SCINTIGRAPHY FRI deposition technology is based on CT imaging, and uses segmentation and computational fluid dynamics (CFD) calculations to provide regional deposition metrics of inhaled products. FRI s patient specific nature and core characteristics make it the ideal alternative to scintigraphy, providing similar results in a more time and cost effective manner. Since 2005, Functional Respiratory Imaging (FRI) has been used many times to evaluate the regional lung deposition of inhaled drugs. This document aims to show how accurate FRI is in the evaluation of lung deposition on a patient specific level, as compared to the gold standard scintigraphy. FRI SCINTIGRAPHY + 2-3 months running time - 1-2 years running time + 30-200k euro (ballpark figure) - 500k-1.5M euro (ballpark figure) + Option for no active recruitment - Clinical trial - active recruitment + Very high spatial resolution - Low spatial resolution + 3D - 2D + No radiolabeling required - Drug needs to be radiolabeled www.fluidda.com 01

THE BUILDING BLOCKS OF FRI AEROSOL DEPOSITION FRI METHODOLOGY AND OUTCOMES A Patient s airway geometries obtained from CT Accurate inhalation profile (measured or fixed) For FRI deposition, the trajectories of inhaled particles are calculated in function of: Device s reverse engineered 3D model Particle dimensions (aerodynamic size) REAL PATIENT & DEVICE Device s plume characteristics The device and patient geometry, these are the physical boundaries in which the particle can travel B Complex mathematical calculations describing the movement of air/particles Validated technology used as vital component in the automotive and aeronautic industry The way the patient breathes (breathing profile) The plume of the device (MDI) or nebulizer flow The internal airflow distribution to the different parts of the lung HIGHLY ACCURATE AND ADVANCED SIMULATIONS FRI deposition results provide global and (very) regional information on where drugs end up in the lung. This data can be quantified and visualized as per your specific needs. Local concentration of inhaled product (red=high, green=low) Particle size distribution based on impactor or laser diffraction data C MEASURED PARTICLE DATA 02 03

VALIDATION Using SPECT REFERENCES In De Backer et al. [1], a cross-over study evaluating regional lung deposition obtained by FRI and SPECT was performed in a population of asthma patients. Not only was there an excellent agreement between measured SPECT and calculated FRI deposition distribution (around 2% difference on a lobar level), but also regional hotspot formation was picked up equally by both techniques. 1. De Backer, J. W. et al. Validation of computational fluid dynamics in CTbased airway models with SPECT/CT. Radiology 257, 854 862 (2010). 2. De Maria, R. et al. Foster : A High-Efficiency Combination Metered Dose Inhaler with Consistent Particle Size Distribution at Alternative Flow Rates. Comb. Prod. Ther. 4, (2014). 3. De Backer, W. et al. Lung Deposition of BDP/Formoterol HFA pmdi in Healthy Volunteers, Asthmatic, and COPD Patients. J. Aerosol Med. Pulm. Drug Deliv. 23, 137 148 (2010). 4. Usmani, O. et al. Lung deposition of extrafine inhaled corticosteroid (ICS)-containing fixed combinations drug in COPD patients using Functional Respiratory Imaging. Eur. Respir. Soc. (2018). 5. Kappeler, D. et al. Lung deposition of fluticasone propionate/formoterol administered via a breath-triggered inhaler. Eur. Respir. J. 50, PA522 (2017). A regional deposition hotspot can be detected both using SPECT and FRI With scintigraphy Lobar particle deposition distribution for SPECT (black) and FRI (white) averaged over all patients 30 6. 7. Iwanaga, T. et al. Aerosol Deposition of Inhaled Corticosteroids/Long-Acting β2-agonists in the Peripheral Airways of Patients with Asthma Using Functional Respiratory Imaging, a Novel Imaging Technology. Pulm. Ther. 3, 219 231 (2017). Hirst, P. H., Bacon, R. E., Pitcairn, G. R., Silvasti, M. & Newman, S. P. A comparison of the lung deposition of budesonide from Easyhaler, Turbuhaler and pmdi plus spacer in asthmatic patients. Respir. Med. 95, 720 727 (2001). Various FRI studies conducted since 2005 have been compared in parallel with scintigraphy studies for the same situation (same device, same compound, same population, breathing profile). The table below indicates that for no matter which disease, device, or compound, FRI aerosol deposition results in the same deposition values as their respective scintigraphy results. 8. 9. Leach, C. L., Kuehl, P. J., Chand, R. & McDonald, J. D. Respiratory Tract Deposition of HFA-Beclomethasone and HFA-Fluticasone in Asthmatic Patients. J. Aerosol Med. Pulm. Drug Deliv. 29, 127 133 (2016). Nikander, K., Prince, I., Coughlin, S., Warren, S. & Taylor, G. Mode of Breathing Tidal or Slow and Deep through the I-neb Adaptive Aerosol Delivery (AAD) System Affects Lung Deposition of 99mTc-DTPA. J. Aerosol Med. Pulm. Drug Deliv. 23, S-37 (2010). PRODUCT FRI [%] SCINTIGRAPHY [%] FOSTER IN COPD 28 [4] 31-34 [2,3] FLUTIFORM IN ASTHMA 42 [6] 41 [5] SYMBICORT IN ASTHMA 23 [6] 22 [7] QVAR IN ASTHMA 54 [+] 53 [8] INEB NEBULIZATION 45 [10] 42 [9] EFLOW NEBULIZATION 18 [10] 17 [11] LC SPRINT NEBULIZATION 9 [13] 10-15 [12] AKITA NEBULIZATION 34 [13] 31 [12,14] 10. 11. 12. 13. 14. Hull, D., Black, A. & Vos, W. Use of computational fluid dynamics (CFD) to model aerosol deposition in the lungs of patients with cystic fibrosis. Eur. Cyst. Fibros. Soc. (2018). Lenney, W., Edenborough, F., Kho, P. & Kovarik, J. M. Lung deposition of inhaled tobramycin with eflow rapid/lc Plus jet nebuliser in healthy and cystic fibrosis subjects. J. Cyst. Fibros. 10, 9 14 (2011). Fischer, A., Stegemann, J., Scheuch, G. & Siekmeier, R. Novel devices for individualized controlled inhalation can optimize aerosol therapy in efficacy, patient care and power of clinical trials. Eur. J. Med. Res. 14 Suppl 4, 71 77 (2009). Munro, S., Main, M. & Vos, W. The application of computational deposition modelling, to study the impact of delivering a model standardised inhalation product using a variety of different delivery platforms to the lungs of IPF patients with varying disease severity. What is best for the patient? Drug Deliv. Lungs (2017). Müllinger, B. et al. Intra-pulmonal deposition of two different tobramycin formulations. J. Cyst. Fibros. 4, S53 (2005). 04 Lung deposition values are expressed in percentage of labelled dose (% LD)