Functional Respiratory Imaging

Transcription

1 Functional Respiratory Imaging Your solution for DELIVERY OPTIMIZATION DISEASE CHARACTERIZATION THERAPY ANALYSIS MARKETING EXCELLENCE

2 We can help. W e know that the respiratory field is one of the least understood and resource intensive domains within healthcare. We also know you will not back down from this challenge, because in the end, it is all about the patient. With one person dying every minute from lung disease, respiratorydiseased patients deserve better, faster and less costly treatment. At FLUIDDA, we are leading the way. Our mission is to optimize treatment pathways, reduce healthcare costs, bring therapies to the market faster and move toward value-based healthcare. FLUIDDA s clinicallyproven FRI (functional respiratory imaging) solutions provide the industry with the most sensitive respiratory biomarker tool and with it, a never before seen optimization of the therapy development pathway. Fluidda s goal is to help the respiratory field in its mission of better treatment Combining our expertise with our technology, we will help you optimize your therapy delivery and ensure it reaches the right patient population. We will detect any signal of efficacy or effectiveness in any population, making sure you save a substantial amount of time and resources. We will help you better understand your therapy benefits and therefore enable you to offer the best value proposition among your competitors. LET US HELP YOU to optimize therapy delivery for the right patients Discover our services and solutions AND DETECT any signal of efficacy within the right safety margins TO ENSURE the optimal value proposition 01

3 FRI Functional Respiratory Imaging Functional Respiratory Imaging (FRI) is a clinically meaningful and non-invasive measurement of the patient specific respiratory system. A set of distinct biomarkers analyzes exposure, structure and function of the lungs and airways in any respiratory disease. The usage of FRI biomarkers as endpoints in therapy development requires no introduction of new equipment into your clinical trials. 1 Image acquisition 2 Structure segmentation 3 Flow simulation The process starts with the acquisition of low dose, high-resolution computed tomography (HRCT) scans of the patient The measurements are performed on the segmented 3-dimensional geometries from these scans Computational fluid dynamics (CFD) is used to quantify airflow and exposure FDA encourages the use of FRI in: Idiopathic pulmonary fibrosis (IPF) FRI as prognostic biomarker in clinical trials to evaluate disease stage and progression, biological response to therapeutic intervention, provide quantifiable predictions about drug performance, and contribute to clinical development decisions (Letter of Support, June 2016) Bioequivalence studies FRI as pharmacodynamic/response (PD/R) biomarkers (Letter of Support, January 2018) 02 03

4 FRI ENDPOINTS AEROSOL DEPOSITION EXPOSURE At OUR RESPONSIBILITY FLUIDDA, we strive to continuously increase our knowledge, to continuously improve our imaging endpoints, and to continuously innovate. In doing so, we aim to provide the respiratory field (drug developers, medical device developers, researchers, clinicians) with the most meaningful, qualitative and efficient FRI solutions. LUNG AND LOBAR VOLUMES AT FRC AND TLC STRUCTURE AIRWAY VOLUMES AT FRC AND TLC AIRWAY WALL VOLUME BLOOD VESSEL VOLUME EMPHYSEMA 30 FLUIDDA is very conscious of the potential harm that exposure to high radiation doses can cause when patients undergo CT scans. Therefore, we take every precaution to minimize radiation exposure for each subject through tailored and qualitative scanning protocols, smart trial designs, strict scanner quality checks, and trainings at the scanning sites. We strongly support CT scanner innovations to limit doses even further. Currently, one FRI CT scan results in maximum 1.8 msv, which is less than half a year of normal background dose. In some cases, radiation levels down to 0.1 msv for 1 FRI scan can be achieved. INTERNAL AIRFLOW DISTRIBUTION AIRWAY RESISTANCE AT FRC AND TLC AIR TRAPPING VENTILATION/ PERFUSION RESERVE We are always at your disposal if you wish to receive more information regarding radiation dosage and FRI. FUNCTION 04 05

5 USE FRI FOR DELIVERY DISEASE OPTIMIZATION CHARACTERIZATION THERAPY ANALYSIS MARKETING EXCELLENCE Take control of your drug delivery processes by efficiently evaluating every aerosol deposition scenario, and simulating reality. Describe your population s airways holistically and identify or characterize disease (progression) easier and faster than ever in the respiratory field. Empower your clinical trial designs with relevant and highly sensitive clinical endpoints to build confidence during all development stages. Put meaningful data with attractive visuals at the centre of your communication and use actual scientific patient data that is intuitive to all of your stakeholders. PAGE PAGE PAGE PAGE BETTER TREATMENT, BETTER CARE 06 07

6 FRI SOLUTION DELIVERY optimization OVERCOME the difficulty of radiolabelling a compound and of running expensive, time consuming scintigraphy studies THROUGH THE USE OF FRI IN Deposition Observational studies to assess real life lung exposure Phase I to support dose finding Phase II as part of safety or efficacy Phase IV to improve value proposition TIME-SAVING ENDLESS SCENARIOS MATCHES REALITY not being able to assess a multitude of drug-device alterations in patients while maintaining full control over all the different input variables Particle delivery optimization Preclinical to optimize powder characteristics Device delivery optimization Preclinical to guide device selection DELIVERY DISEASE THERAPY MARKETING Avoid actively recruiting patients Investigate how your device or particle (alternatives) affect(s) deposition in a controlled environment Assess the influence of disease on your device performance or aerosol deposition at a very early stage Easily assess how the device s or particle s performance is influenced by the way the patient inhales Assess a near infinite number of different scenarios (devices, APSD, populations, breathing profiles) and change each parameter independently Fully validated against scintigraphy and SPECT/CT for a multitude of different devices, compounds and diseases [De Backer, J. et al., 2010] The regional concentration of an inhaled drug expressed as a percentage of delivered dose (yellow-red = high, blue-green = low). The colours of the lobes represent the peripheral deposition in that lobe. RUL right upper lobe RML right middle lobe RLL right lower lobe LUL left upper lobe 08 LLL left lower lobe 09 HIGH LOW Zone Delivery (% of DD) Extrathoracic IntrathoraciC 1.43 Central Peripheral RUL 4.01 RML 1.66 RLL 8.48 LUL 5.23 LLL 7.37 Suspended 0.00

7 1.75% difference from in vivo When comparing aerosol deposition with scintigraphy and SPECT/CT De Backer, J. et al., <6 weeks is the average time in which clients receive their results after having delivered all input data Internal BI analysis TIME-SAVING ENDLESS SCENARIOS MATCHES REALITY CLIENT EXPERIENCE We have found FRI to be a really useful mechanism via which to explore the potential differences in lung deposition for different inhalation delivery systems in specific patient populations Sandy Munro Vice President Pharmaceutical Development at Vectura DELIVERY DISEASE THERAPY MARKETING CASE STUDY Deposition patterns of different inhalation therapies in IPF patients Describing delivery performance of a device in relation to a patient s condition and the use of lung deposition modeling to optimize delivery in idiopathic pulmonary fibrosis Smart nebulization using FAVORITE (long-slow-deep) inhalation offers a number of advantages: Higher overall whole lung deposition Greatly enhanced targeting of small airways DPI performance (FCA formulation) offers reasonable lung deposition Even split between central and peripheral Standard nebuliser less good at targeting small airways Munro, S. et al., DDL

8 FRI SOLUTIONS DISEASE characterizationholistic EXPERT SUPPORT EARLY IDENTIFICATION OVERCOME Understand your target disease better with the same sensitive, clinically relevant endpoints as interventional trials DELIVERY DISEASE THERAPY MARKETING the challenge of defining sensitive parameters that describe disease phenotyping, evaluate disease progression, or predict disease events THROUGH THE USE OF FRI IN Conduct research prior to, or in parallel with, your interventional trials to increase confidence in your therapy in your target population Keep your longitudinal or crosssectional trials short and small by identifying your target population Use FLUIDDA s expertise to combine FRI endpoints that describe the target disease best or create new FRI endpoint derivatives Use FRI machine learning to predict disease events (e.g. exacerbation, lung rejection) FRI results showing that there is a significant reduction in lobe volume in idiopathic pulmonary fibrosis (IPF) as compared to a healthy population (lobe volume expressed as percentage predicted) Vos, W. et al., ATS 2015 Respiratory disease characterization Observational studies Forced expiratory volume in 1 second (FEV1) expressed as % predicted over the course of 3 years in a cystic fibrosis patient. FRI was performed twice and showed a clear deterioration (bronchiectasis and decreased lobar volumes) before FEV1 detected disease progression

9 85% accuracy in predicting Bronchiolitis Obliterans Syndrome (BOS) developers at baseline Barbosa et al., 2018 CLIENT EXPERIENCE I just about fell out of my chair looking at these FRI results on how wildfire is affecting the respiratory system. It s unbelievable. I m so glad that we had your team work on this! Lisa A. Miller, Ph.D. Respiratory Diseases Unit Unit Leader Inhalation Exposure Core Lead Professor, Dept. of Anatomy, Physiology, & Cell Biology, UC Davis School of Veterinary Medicine HOLISTIC EXPERT SUPPORT EARLY IDENTIFICATION CASE STUDY Regional assessment seems inevitable to examine COPD exacerbation recovery rate Patients with a large expression of expiratory air trapping in the lower lobes (out of exacerbation) have a worse recovery (expressed as change in FEV1) from acute COPD exacerbation. This finding indicates the relevance of obtaining regional quantification of disease expression such as air trapping in COPD patients in a clinical setting. Abstract Vos, W. et al., ERS GSK supported DISEASES ANALYZED WITH FRI Asthma Chronic obstructive pulmonary disease (COPD) Alpha 1 antitrypsin deficiency (A1AD) Cystic fibrosis (CF) Idiopathic pulmonary fibrosis (IPF) Bronchiolitis obliterans syndrome (BOS) Bronchopulmonary dysplasia (BPD) Idiopathic diaphragmatic paralysis (IDP) Sleep apnea Sinusitis Acute respiratory distress syndrome (ARDS) Scleroderma Non-CF bronchiectasis DELIVERY DISEASE THERAPY MARKETING Lower lobe expiratory air trapping (% of lobe volume) out of exacerbation LUNG FUNCTION DECLINE Forced expiratory volume in 1 second (FEV1) and image based airway resistance Chronic bronchitis (iraw) measured in asthma patients with different levels of severity. FEV1 has a step-wise decline versus iraw declining gradually with increasing severity. Data from Airprom Consortium; Principal Investigator: Prof C. Brightling

10 FRI SOLUTIONS THERAPY analysis OVERCOME SENSITIVE CLINICALLY RELEVANT CONFIDENT DELIVERY DISEASE THERAPY MARKETING challenges posed by the often unclear link between labelled dose and pharmacokinetics (PK) values large, long and expensive trials to demonstrate the pharmacodynamic effect given the high degree of variance of efficacy endpoints the difficulty of obtaining conclusive results in a highly variable, less controllable real life situation the difficulty of detecting clinically relevant differences between two therapies THROUGH THE USE OF FRI IN Safety Efficacy Effectiveness Therapy comparison Phase I and Phase II to support dose finding Phase I to support early therapy activity Phase II to understand therapy activity Phase III to derisk the registration file Phase IV to improve value proposition Observational studies to demonstrate therapy performance Phase IV to improve value proposition Preclinical to investigate device differences Phase I to support early hypothesis Phase II to understand comparison Phase III to complement the registration file Phase IV to improve value proposition 16 17

11 DELIVERY SAFETY EFFICACY EFFECTIVENESS DISEASE THERAPY MARKETING THERAPY COMPARISON Efficiently assess treatment efficacy with high sensitivity levels, detecting the smallest changes Assess pharmacodynamics (PD) with FRI endpoints reducing the necessary sample size with a factor up to 16 Lanclus, M. et al., 2017 Assess the true regional PD effect and link it to regional aerosol deposition Extensively validated against clinically relevant parameters De Backer, J. et al., 2008 FEV1 De Backer, W. et al., 2018 FEV1 Hajian et al., MWT Vos, W. et al., 2013 ACS Assess what safe lung dosage allows maximum efficacy by linking blood safety measures to lung dose (without the need of a full-on PK trial) Combine safety and efficacy in your trial to gain maximum confidence and time when advancing to further clinical development stages Changes (green = improvement, red = worsening) of the image based airway volumes caused by an inhaled bronchodilator (top image) and of the image based blood vessel volumes caused by a systemic vasodilator (bottom image) 18 Use state-of-the-art technology to assess quality characteristics and to determine: Superiority Non-inferiority Bioequivalence 19

12 Up to 16 times less patient enrolment needed to establish significant results with FRI when compared to FEV1 or FVC as endpoint Lanclus, M. et al., 2017 Vos, W. et al., 2013 De Backer, LA. et al., 2012 SENSITIVE CLINICALLY RELEVANT CONFIDENT CLIENT EXPERIENCE The insights provided by the FRI technology have been extremely useful for the understanding of regional lung deposition, to differentiate potentially similar products beyond in vitro and to design appropriate clinical investigations. I strongly endorse this innovative approach and look forward to use it also in the future. Giovanni Caponetti Managing Director at Eratech The application of Functional Respiratory Imaging in early clinical development can be done with relatively few patients per treatment arm and results in clear and detectable differences. It will be exciting to determine how FRI parameters correlate with more known and established outcomes, such as exacerbations or patient-reported outcomes in the respiratory field. CASE STUDY FRI correlates significantly with clinically relevant improvements DELIVERY DISEASE THERAPY MARKETING The figure shows the correlation between the change in FEV1 and the change in CT-based airway resistance for 19 COPD patients who were treated with a bronchodilator and placebo (cross-over). Treatment with GFF MDI resulted in a 71% decrease in airway resistance vs. placebo MDI while FEV1 only showed a 28% increase of GFF versus placebo (2.5 times larger signal with FRI). De Backer, W. et al., 2018 Change in specific airway resistance [kpa.s] Dr. Edith M Hessel Vice President, Respiratory Therapy Area Unit at GSK

13 FRI SOLUTIONS MARKETING excellence OVERCOME the difficulty of translating complicated, scientific study results into meaningful visualizations INTUITIVE MEANINGFUL SCIENTIFIC DELIVERY DISEASE THERAPY MARKETING Convince your stakeholders (e.g. regulatory agencies, investors, reimbursement agencies, doctors) with study results by means of visualization, using real scientific data for individual patients Prepare marketing materials for your clients that are intuitive and meaningful, and at the same time scientific Combine any clinical trial using FRI directly with scientific marketing THROUGH THE USE OF FRI IN Scientific Marketing Phase III biobetter or biosimilar Phase IV clinical trials 22 23

14 CLIENT EXPERIENCE DELIVERY DISEASE THERAPY MARKETING BRONCHIECTASIS FLUIDDA s technology is a high level tool that supported our communication with science and valuable insights. We would like to continue to develop other collaborations with FLUIDDA to make our data more and more robust. Greta Pizzamiglio Brand Manager Cystic Fibrosis at Zambon INTUITIVE MEANINGFUL SCIENTIFIC MUCUS PLUGGING

15 MORE ABOUT REFERENCES OUR EXPERIENCE SINCE 2005 DELIVERY OPTIMIZATION [PG 08-11] De Backer, J. et al. Validation of Computational Fluid Dynamics in CT based Airway Models with SPECT/CT. Radiology 2010; 257(3): Munro, S. et al. Matching delivery device to a patient s condition: use of lung deposition modelling to optimise delivery in idiopathic pulmonary fibrosis. DDL 2017 DISEASE CHARACTERIZATION [PG 12-15] Barbosa, EJM Jr. et al. Machine Learning Algorithms Utilizing Quantitative CT Features May Predict Eventual Onset of Bronchiolitis Obliterans Syndrome After Lung Transplantation. Acad Radiol 2018; 25(9): Vos, W. et al. Comparison of IPF disease pathology to healthy subjects using functional respiratory imaging. Am J Respir Crit Care Med 191; 2015:A4377 Vos, W. et al. Lower Lobe Air Trapping Is Linked to Exacerbation Recovery Rate. Am J Respir Crit Care Med 193; 2016:A5214 THERAPY ANALYSIS [PG 16-21] De Backer, J. et al. Computational fluid dynamics can detect changes in airway resistance in asthmatics after acute bronchodilation. J Biomech 2008; 41: De Backer, LA. et al. The acute effect of budesonide/formoterol in COPD: a multi-slice computed tomography and lung function study. Eur Respir J 2012; 40(2): De Backer, W. et al. A randomized study using functional respiratory imaging to characterize bronchodilator effects of glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler using co-suspension delivery technology in patients with COPD. Int J COPD 2018; 13:1-12 Hajian, B. et al. Changes in ventilation-perfusion during and after an COPD exacerbation: an assessment using fluid dynamic modeling. Int J COPD 2018; 13: Lanclus, M. et al. Assessment of disease progression in IPF patients using functional respiratory imaging (FRI). ERJ 50(61); 2017:OA1952 Vos, W. et al. Novel Functional Imaging of Changes in Small Airways of Patients Treated with Extrafine Beclomethasone/Formoterol. Respiration 2013; 86: Clients Patients analyzed Clinical centers trained Conducted studies Delivery optimization Disease characterization Therapy analysis Marketing excellence 26 27

16 INTERNATIONAL PRESENCE PROUD TO HAVE COLLABORATED WITH BE THE NEXT ONE TO MAKE A DIFFERENCE 28

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