Novolizer Technical Aspects

Novolizer Technical Aspects Dr José Mª Negro Alvarez H.U. Virgen de la Arrixaca.. Murcia (España) a) Profesor Asociado de Alergología. Universidad de Murcia (España) a) Contents Design and function of the Novolizer Performance and efficacy, characteristics, robustness and reliability invitro inuse Conclusions 1 2 1

Features of the Novolizer Easy and safe handling Multiple feed back mechanism (audible, visual, sensoric) Low intrinsic resistance System preventing inadvertent multiple dosing Dose counter linked to correct inhalation Pocketsized No ingression of microorganisms Excellent accuracy / precision Consistent dose metering and delivery Relative independence of particle size on flow rate Ensured deposition of therapeutic agent in the bronchial tree High respirable fraction, good efficacy Reliable and durable Advanced technology Multidose Unique and superior dispersion system Novolizer What s in there? (1) Cartridge Powder Dosing channel Dosing chamber 3 4 2

Novolizer What s in there? (2) Dosing scheme and inhalation mechanism Dosage button Mouth piece Tapper Powder channel Novolizer What s in there? (3) Cyclone Laminar flow 5 6 3

Assured asthma drug delivery Remove cap Press the dosage button patient hears a double click colour change in inhalation window from red to green Inhale deeply a click indicates drug has been released Guaranteed drug deposition in the lungs There is only one way to use the Novolizer...... the right way! Operation of the Novolizer (1) Press dosage button (dosage counter will be activated) Device is ready for inhalation: colour change in inhalation window from red to green 7 8 4

Operation of the Novolizer (2) Inhale with maximum inspiratory effort (deeply and strongly, only an inspiration >35 l/min is necessary) Inhalation was successful: color change from green to red Cover mouth piece with cap Easy cartridge change Remove slide cap Remove empty cartridge Replace with new cartridge Replace slide cap 9 10 5

Multiple control feedback mechanism Indicates successful inhalation Guarantees inhalation of a correct & exact single dose, providing the patient with confidence, security, assurance and reassurance Easy to use for most asthmpatients Conclusion: The Novolizer is easy to use even for those patients with a reduced inspiratory flow rate (e.g. children and elderly people) 11 12 6

Dispersion system of the Novolizer The Novolizer has a very effective deaggregation system The cylcone: Improves separation of particles Improves flow of particles into the bronchial tree Minimises oropharyngeal deposition Uniformity of metered mass: budesonide 200 µg formulation 16.0 Metered mass [mg] 14.0 12.0 10.0 8.0 6.0 4.0 2.0 Cartridge 1 (25 C/60% sealed) Cartridge 3 (30 C/70% sealed) Specification limits Cartridge 2 (25 C/60% not sealed) Cartridge 4 (30 C/70% not sealed) 0.0 0 50 100 150 200 Dose No. Conclusion: The Novolizer exhibits excellent metering performance over the cartridge lifetime independent of temperature and humidity Berner B et al., ASTA Medica Multidose Dry Powder Inhaler. In: Respiratory drug delivery VI. Dalby RN et al. (eds.), Buffalo Grove: Interpharm Press, 1998, 475477 13 14 7

Emitted mass and fine particle fraction at various flow rates Budesonide 200 µg formulation (nominal mass = 10.0 mg) flow rate corresp. to a pressure drop of 4 kpa Emitted mass [mg] 16 14 12 10 8 6 4 2 0 9.1 24 Emitted mass 40 60 80 Flow rate (l/min) Conclusion: The Novolizer exhibits excellent emitting performance. The respirable fraction (FPF) is relatively independent on flow rate 10.5 28 Cascade 35 (FPF) 10.4 34 100 90 80 70 60 50 40 30 20 10 0 % Budesonide calculated on the emitted mass Stability testing: budesonide 400 µg Delivered dose / fine particle dose [in % of nom. dose] 120 110 100 90 80 70 60 50 40 30 20 10 0 Stored at 25 C/60%, 30 C/70%, 40 C/75% sealed 0 3 6 9 12 18 Months 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 Emitted mass [in % of nom. value] Conclusion: The Novolizer ensures stability under all tested climatic conditions 15 16 8

Design of the consumer test Novolizers included in the study 10 Duration of the study 100 days Applications 2 actuations daily per inhaler (200 actuations per inhaler total) Investigation parameters Emitted mass: daily determination (Monday to Friday) Delivered dose: weekly determination Fine particle fraction: weekly determination The Novolizer consumer test results % of the nominal value 120 100 80 60 40 20 Budesonide 200 µg formulation Emitted mass Delivered dose Fine particle fraction 0 0 50 100 150 200 Dose No. Conclusion: The Novolizer produces stable emitted mass, delivered dose and FPF over the lifetime of the cartridge 17 18 9

Design Microbiological study: Novolizer 1Year inuse test Placebo controlled Group 1 (n=3) Two actuations daily according to instructions for use (n=3) Group 2 (n=3) Two actuations daily, Only 1 inhalation, One dose remains in the device (n=3) Group 3 (n=4) Two actuations daily under worst case conditions Inhalation or blowing into the device, Storage in bathroom, kitchen, outside,... Results Microbiological study: Novolizer 1Year inuse test Cartridges Timepoint Total viable Moulds/ Specific [months] aerobic count Yeasts microorg.* [cfu] 3 < 1 < 1 not detect. 6 < 1 < 1 not detect. 9 < 5 < 5 not detect. 12 < 5 < 5 not detect. * Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Salmonella species, Enterobacteriaceae Conclusion: the microbial status of the cartidges and inhalers afer use is excellent Berner B et al. In: Proceedings of the 46th Annual Congress of APV/APGI, 2000 19 20 10

The Novolizer ensures deposition of drug into the bronchial tree Unique flow trigger valve releases powder only after a certain flow rate has been achieved (I.e. 35 l/min) Represents a real step forward in DPI technology Assured delivery = reassured patient The Novolizer releases sufficient powder, followed by the desagglomaration of the effective drug form the lactose carrier at a minimum inspiratory flow rate of 35 l/min 60 30 Flow [l/min] 0,2 0,4 0,6 0,8 1,0 Time [sec] The Novolizer is forgiving of poor technique Novolizer : relative independence of particle size on flow rate Consistently emits 90% of the metered dose Little variation in emitted mass and FPF even when flow rates are halved 90% of particles are <5.3 µm and 50% are between 1.0 µm and 2.0 µm Budesonide 200 µg formulation (nominal mass = 10.0 mg) Emitted mass [mg] 16 14 12 10 8 6 4 2 0 Emitted mass Cascade 35 (FPF) 10.5 10.4 9.1 34 24 28 40 60 80 Flow rate (l/min) 100 90 80 70 60 50 40 30 20 10 0 % Budesonide calculated on the emitted mass 21 22 11

Novolizer : influence of temperature and humidity 16.0 Metered mass [mg] 14.0 12.0 10.0 8.0 6.0 4.0 2.0 Cartridge 1 (25 C/60% sealed) Cartridge 3 (30 C/70% sealed) Specification limits Cartridge 2 (25 C/60% not sealed) Cartridge 4 (30 C/70% not sealed) 0.0 0 50 100 150 200 Dose No. Conclusion: Uniformity of emitted mass of drug from the Novolizer is not influenced by varying conditions temperature and humidity Low intrinsic resistance Lower airflow resistance to Turbuhaler Assuming a flow rate of 60 L/min, resistance is two times higher with Turbuhaler Easy for patients to use Suitable for most patients even those with reduced inspiratory flow rate May improve patient compliance 23 24 12

Cost effectiveness The Novolizer is robust, can be used every day, twice a day for up to one year before it needs to be replaced The Novolizer is refillable The most expensive inhaler is one that patients cannot use correctly Novolizer = assured drug delivery Improved patient compliance The multiple control system positively reinforces to the patient that medication has been taken The dose counter works indirectly only after a correct inhalation Positive reinforcement to patients that drug has been taken Doctor can count how many doses have been taken The Novolizer is easy to use It has a low intrinsic resistance Patients are guided through the inhalation procedure by the triple control system Patients are extremely satisfied with the Novolizer (Kunkel and Chuchalin,2001) The Novolizer is pocketsized and easy to carry 25 26 13

Award: golden safety material in medicine Acknowledges the unique position of the Novolizer Confirms that the Novolizer represents a new standard in inhalation devices Supports introduction of new standard in safe inhalation technology Clinical Aspects Newman et al, 2000 deposition Method Gamma scintigraphic evaluation 14 healthy volunteers (males/females) Target parameter In vivo deposition of a dry powder formulation from the Novolizer at various flow rates versus the Turbuhaler Eur Respir J 2000; 16: 178183 27 28 14

Clinical Aspects Newman et al, 2000 fractionation of dose (n=13) vs Turbuhaler Headline Headline Regimen % of metered dose; medians (ranges) Novolizer 90L/min Novolizer 60L/min Novolizer 45L/min Turbuhaler 60L/min Lung 32.1 (9.4 41.0) 25.0 (12.1 37.4) 19.9 (8.8 26.6) 21.4 (4.7 29.2) Oropharynx 57.0 (45.1 81.7) 61.6 (42.2 77.6) 60.9 (49.5 68.3) 71.9 (54.8 80.0) Device 9.5 (5.5 23.2) 15.6 (1.2 20.0) 17.3 (11.8 43.0) 11.6 (5.3 22.0) Exhaled Air 0.8 (0.2 1.8) 0.6 (0.2 3.0) 0.2 (0 0.9) 0.2 (0 0.7) Eur Respir J 2000; 16: 178183 Clinical Aspects Newman et al, 2000 lung deposition vs Turbuhaler At least as much deposition when used at similar rates When used optimally the Novolizer deposits more in lungs Turbuhaler deposits more drug in the mouth Lung deposition [% metered dose] 40 35 30 25 20 15 10 5 0 Novolizer 90L/min Novolizer 60L/min Novolizer 45L/min Turbuhaler 60L/min 29 30 15

Clinical Aspects Novolizer : Lung deposition Novolizer 90L/min Novolizer 60 L/min Novolizer 45 L/min Turbuhaler 60 L/min Conclusion: Superiority of the Novolizer vs Turbuhaler due to better drug deposition with less airflow resistance Clinical Aspects Turbuhaler = uncertainty Novolizer Precise dose delivery (FPF 30%) Flow trigger valve Guarantees sufficient drug deposited in lungs Turbuhaler High dose variation <60L/min results in: high oral deposition poor lung deposition Significantly better lung deposition 31 32 16

Equivalence Study Budesonide 200 Novolizer vs Pulmicort Turbuhaler Equivalence study outline Design Randomized, open, multicenter parallel group study. Centers 11 centers Patients 315 asthmatics (224 female, 91 male; 1875 years of age) Inclusion criteria Persistent mildtomoderate asthma, FEV1: 6090% predicted; >15% reversibility; patients with regular pretreatment except steroids and patients on steroids Treatment 2 weeks runin phase followed by 400 µg/d BUD (200 µg every 12 hours) delivered by either the Novolizer (n=153) or Turbuhaler (n=158) Kremer HJ et al. In: Scheuch G et al. Aerosole in der Inhalationsth. IV. Dusin: München, 2001; Chuchalin et al., Respiration 2002; 69: 502508 Clinical Aspects Equivalence Study Budesonide 200 Novolizer vs Pulmicort Turbuhaler Target parameters Primary efficacy parameter FEV 1 after 12 weeks of treatment Secondary efficacy parameters PEFR morning and evening, Circad. PEFR variability, Asthma symptoms, nocturnal awakening, Use of ß 2 agonists PC20FEV 1 after histamine provocation, Assessment of efficacy Safety AEs (incidence, severity) Cough and paradoxical bronchospasm, Laboratory, ECG, RR, HF, opthalmological screening Kremer HJ et al. In: Scheuch G et al. Aerosole in der Inhalationsth. IV. Dusin: München, 2001; Chuchalin et al., Respiration 2002; 69: 502508 33 34 17

Clinical Aspects Equivalence Study Budesonide 200 Novolizer vs Pulmicort Turbuhaler Efficacy results Primary target parameters Mean FEV 1 baseline values and improvement in FEV 1 at the end of the study were comparable for the Novolizer and Turbuhaler Secondary target parameters No clinically relevant or statistically significant differences between the groups were observef for: PEFR (morning and evening), asthma symptoms, nocturnal awakening or rescue medication use Histamine provocation test: essential differences between patients with or without pretreatment with steroids, however, no significant differences between the Novolizer and the Turbuhaler groups. Global assessment of efficacy: investigators considered the efficacy of treatment to be good or very good in 87% of patients in the Novolizer group compared to 79% of patients in the Turbuhaler group. When delivering budesonide, the Novolizer is therapeutically equivalent to the Turbuhaler with respect to efficacy in mildtomoderate asthmatics Kremer HJ et al. In: Scheuch G et al. Aerosole in der Inhalationsth. IV. Dusin: München, 2001; Chuchalin et al., Respiration 2002; 69: 502508 Clinical Aspects Equivalence Study Budesonide 200 Novolizer vs Pulmicort Turbuhaler Safety and tolerability results Paradoxical bronchospasm FEV 1 decrease within 15 minutes after inhalation Novolizer group (4) Turbuhaler group (6) Incidence of adverse events comparable in both groups Blood pressure, heart rate, ECG, opthalmological examinations and laboratory values No signs of clinically relevant adverse reactions or differences between groups When deliverying budesonide, the Novolizer is therapeutically equivlaent to the Turbuhaler with respect to safety and tolerability in mildtomoderate asthmatics Kremer HJ et al. In: Scheuch G et al. Aerosole in der Inhalationsth. IV. Dusin: München, 2001; Chuchalin et al., Respiration 2002; 69: 502508 35 36 18

Clinical Aspects Equivalence Study Budesonide 200 Novolizer vs Pulmicort Turbuhaler Results (1) 450 400 PEFR [l/min] 350 300 Novolizer morning Novolizer evening Turbuhaler morning Turbuhaler evening 250 Baseline 12 34 56 78 910 1112 Week Kremer HJ et al. In: Scheuch G et al. Aerosole in der Inhalationsth. IV. Dusin: München, 2001; Chuchalin et al., Respiration 2002; 69: 502508 Equivalence Study Budesonide 200 Novolizer vs Pulmicort Turbuhaler Results (2) 4 Salbutamol puffs 3 2 1 Novolizer Turbuhaler 0 Baseline 12 34 56 78 910 1112 Week Kremer HJ et al. In: Scheuch G et al. Aerosole in der Inhalationsth. IV. Dusin: München, 2001; Chuchalin et al., Respiration 2002; 69: 502508 37 38 19

Equivalence Study Budesonide 200 Novolizer vs Pulmicort Turbuhaler Results (3) FEV1 [l] PEFR [l/min] 3,5 3 2,5 2 1,5 450 400 350 300 250 Novolizer Turbuhaler 0 4 8 12 Week Novolizer morning Novolizer evening Baseline 12 34 Course of FEV1 Course of PEFR (morning and evening) Week Turbuhaler morning Turbuhaler evening 56 78 910 1112 FEV1 changes vs basisline values [l] Salbutamol puffs 0,5 0,4 0,3 0,2 0,1 0 4 3 2 1 0 Baseline FEV1 changes Novolizer Turbuhaler 0 4 8 12 Week Course of Salbutamol consumption Novolizer 12 34 Week 56 78 Turbuhaler Kremer HJ et al. In: Scheuch G et al. Aerosole in der Inhalationsth. IV. Dusin: München, 2001; Chuchalin et al., Respiration 2002; 69: 502508 910 1112 Novopulmon 200 Novolizer Features Drug deposition in the lungs even at low flow rates Easy handling Suction power required for inhalation Multiple feedback mechanisms Correct inhalation manoeuvre feedback Accurate dosage counter Display of readiness to inhale (green field) Refillable Novolizer low tomoderate Turbuhaler () high Data on file 39 40 20

Pressure and flow comparison (1): Novolizer vs Turbuhaler Comparison of patient technique and inspiratory characteristics of the Novolizer and the Turbuhaler 60 patients with mild asthma Patients had never used a dry powder device previously Inhalation of placebo at least twice by Novolizer or Turbuhaler, respectively Cegla, ERS 2002, Stockholm Novolizer vs Turbuhaler (Prof. Cegla, Dernbach) Pressure and flow comparison (2): Novolizer vs Turbuhaler Flow rate not reached Novolizer (n) Turbuhaler (n) 30 l/min 0 3 60 l/min 8 25 Conclusion: More patients were unable to generate a peak inspiratory flow of either 30 l/min or 60 L/min through the Turbuhaler compared to the Novolizer N = 60 Cegla, ERS 2002, Stockholm 41 42 21

Novolizer vs Turbuhaler (Prof. Cegla, Dernbach) Pressure and flow comparison (3): Novolizer vs Turbuhaler Parameter Novolizer (n) Turbuhaler (n) Time to max. pressure (s) Peak flow (l/s) Time (s) flow >60 l/min Time (s) flow >30 l/min Resistance (cm H 2 O.s/l) 0.375 1.336 0.770 1.450 5.071 0.569 0.905 0.333 1.494 28.453 Conclusion: Overall, the Novolizer has a better inhalation performance to the Turbuhaler Cegla, ERS 2002, Stockholm PIF Values in Children suffering from asthma (Prof. Leupold, Dresden) Can children use the Novolizer? Aim: to determine if children aged between 4 and 11 years withstable bronchial asthma are able to generate sufficient peak inspiratory flow (PIF) through the Novolizer? 136 children. Multicenter, randomised, open label study design Parameters assessed FEV 1 PIF withouth the Novolizer PIF with the Novolizer (PIFN) Leupold et al., ERS 2002, Stockholm 43 44 22

PIF Values in Children suffering from asthma (Prof. Leupold, Dresden) Results: can children use the Novolizer? Without the Novolizer children could generate a PIFof 147 ± 46 L/min (mean ± SD) With the Novolizer children could generate a PIFof 76 ± 19 L/min (mean ± SD) Both PIF and PIFN showed a linear dependence on age (older children could generate higher values) The threshold value for activating the Novolizer (i.e. 30 L/min) was exceeded by >40 l/min The high PIFN generated by children is due to the lowtomedium resistance of the Novolizer Conclusion: the Novolizer is suitable for inhalation therapy in asthmatic children Leupold et al., ERS 2002, Stockholm PIF Values in Children suffering from asthma (Prof. Leupold, Dresden) Trigger threshold of the Novolizer and PIFN by age in children with stable asthma 100 90 80 76 86 83 PIVN (l/min) 70 60 50 40 40 60 30 20 10 0 Trigger threshold 4 5 years 6 7 years 8 9 years 10 11 years Conclusion: The Novolizer is suitable for inhalation therapy in children aged 411 years with stable asthma Leupold et al., Clinical Evaluation of the Peak Inspiratory Flow Generated by Asthmatic Children Through the Novolizer, Eur Respir J 2002; 20 Suppl 38: 430s 45 46 23

Novolizer vs. Turbuhaler : Clinical Study of Maximum Inspiratory Flow in Children Study Outline Aim: to investigate the maximum inspiratory flow which children with stable asthma can achieve during inspiration through the Novolizer compared to the Turbuhaler 48 children aged between 4 11 years with stable asthma Parameters assessed FEV 1, PIF (without device) PIFN (Novolizer ) PIFT (Turbuhaler ) Conclusion: The trigger threshold for activating the Novolizer (i.e. 30 L/min) was easily exceeded by children aged between 411 years with stable asthma. The PIF generated through the Novolizer was significantly higher than the PIF generated through the Turbuhaler for all age groups studied van Berg, et al, Eur. Respir. J. 2003 Novolizer vs. Turbuhaler : Clinical Study of Maximum Inspiratory Flow in Children PIFN and PIFT by age Age [y] N PIF [l/min] PIFN PIFT PIFN/Tratio [l/min] [l/min] 45 2 78.9 ± 14.0 72.3 ± 5.5 57.9 ± 11.5 1.26 ± 0.15 67 16 150.2 ± 46.7 82.6 ± 16.7 62.3 ± 13.1 1.33 ± 0.10 89 14 186.3 ± 69.5 100.6 ± 16.4 74.7 ± 10.7 1.36 ± 0.20 1011 16 217.8 ± 59.0 98.4 ± 18.8 71.7 ± 12.2 1.37 ± 0.14 All 48 180.3 ± 66.2 92.7 ± 18.9 68.9 ± 13.0 1.35 ± 0.15 PIFN was significantly higher than PIFT in all age groups (p<0,0001, ANOVA). Conclusion: The Novolizer can be activated more easily than the Turbuhaler by children in all studied age groups. van Berg, et al, Eur. Respir. J. 2003 47 48 24

New Clinical Data: Novolizer and Ease of Use in Severe Asthma 120 100 PIFN and PIFT for different age groups PIFT PIFN 80 L/min 60 40 20 0 Trigger threshold all patients 6 to 7 years 8 to 9 years 10 to 11 years Inhalation Inspiration Innovation van Berg, et al, Eur. Respir. J. 2003 Post Marketing Surveillance (PMS) in Patients with Bronchial Asthma Novolizer budesoinde 200 µg Scope: 3057 patients in 963 centers Collection of data on clinical efficacy, tolerability and patient acceptance of the device Patients with or without inhaled asthma pretreatment Duration of observation per patient: 4 weeks Parameters assessed Lung function (PEFR, FEV 1 ) Symptoms (cough, rhonchus, nocturnal dyspnea, dyspnea on exertion) Satisfaction with control functions Assessment of patient compliance by the treating physician Moeller et al, Drug Research 53, No 8, 562567, 2003 49 50 25

Post Marketing Surveillance (PMS) in Patients with Bronchial Asthma Novolizer budesonide 200µg: results (1) Parameters of lung function Median PEF increased from 5 Ll/s to 6.3 L/s Median FEV 1 increased from 2250 ml to 2700 ml Symptoms improved in most patients Median symptom score fell from 8 before therapy to 2 after therapy The proportion of patients complaining of each assessed symptom decreased Cough: 93.0% at baseline to 56.5% posttreatment Wheezing: 87.9% at baseline to 37.9% posttreatment Diurnal dyspnea: 87.2% at baseline to 40.3% posttreatment Nocturnal dyspnea: 80.5% at baseline to 37.0% posttreatment Dyspnea on exertion: 97.3% at baseline to 75.2% posttreatment Moeller et al, Drug Research 53, No 8, 562567, 2003 Post Marketing Surveillance (PMS) in Patients with Bronchial Asthma Novolizer budesonide 200µg: results (2) Satisfaction with multiple inhalation control features (all patients) 62% of the patients: excellent 37% of the patients: good Satisfaction with multiple inhalation control features (patients pretreated with other inhalation system before) 93% of the patients: better / much better 96% of the patients reported better compliance due to the control mechanisms Assessment by the treating physicians Improvement of compliance due to control mechanisms in 98% of the patients Better control of compliance was rated by 95% of the physicians Moeller et al, Drug Research 53, No 8, 562567, 2003 51 52 26

Post Marketing Surveillance (PMS) in Patients with Bronchial Asthma Novolizer budesonide 200µg : results (3) Control of drug intake by different control mechanisms was confirmed by 97% of patients 88%: optical control mechanism 81%: acoustic control mechanism 46%: taste control mechanism Dose counter control 92% of the patients were satisfied with the counter 81% of the patients assessed the dosage stop as good 79% of the patients were pretreated with another inhalation system, (Diskus and Turbuhaler ) Evaluation will follow Novolizer budesonide 200µg proved to be clinically effective with high acceptance of the control functions and improved compliance Moeller et al, Drug Research 53, No 8, 562567, 2003 Novolizer : Clinical Aspects Commonly prescribed DPIs vs Novolizer Novolizer s features TH Diskus Aerolizer Easy, reliable & convenient to use Easy to teach, learn & remember how to use correctly / Accurate & consistent dose delivery High deposition rate Patient feedback of dose taken * * Accurate dose counter Delivers a range of molecules CFCfree & conveniently carried Certainty given to patient and doctor * taste only 53 54 27

Novolizer : Clinical Aspects Gina Guidelines 2002 Level of Severity (US est. Diagnosed cases* (16M) ) Daily Medications Quick Relief & Prevention ** Intermittent Asthma (7M) none necessary shortacting ß 2 agonist Mild Persistent Asthma (3M) glucocorticosteroid shortacting ß 2 agonist Moderate Persistent Asthma (3M) glucocorticosteroid longacting ß 2 agonist shortacting ß 2 agonist Severe Persistent Asthma (3M) glucocorticosteroid + longacting ß 2 agonist + sustainedrelease theophylline leukotriene modifier longacting oral ß 2 agonist * Decision Resources, NHIS, ALA Reports oral glucocorticosteroid one or more if needed shortacting ß 2 agonist also recommended for prevention ** of exercise induced asthma Novolizer therapies cover all levels of asthma severity 55 28