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Impact of Allergic Rhinitis (AR) Symptoms on Quality of Life

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1 Impact of Allergic Rhinitis (AR) Symptoms on Quality of Life
Moderate-to-severe allergic rhinitis symptoms are associated with Fatigue and daytime somnolence1–3 Daily activity impairment4,5 Reduced work productivity4–8 Disturbed cognitive functions9 Reduced learning abilities10,11 Adverse effects on adolescent behaviour6 1. Borres MP et al. Ann Allergy Asthma Immunol 1997; 78: 29–34; 2. Craig TJ et al. J Allergy Clin Immunol 2005; 116: 1264–1266; 3. Young T et al. J Allergy Clin Immunol 1997; 99: S757–S762; 4. Reilly MC et al. Clin Drug Invest 1996; 11: 278–288; 5. Tanner et al. Am J Manag Care 1999; 5(Suppl 4): S235–S247; 6. Juniper EF et al. J Allergy Clin Immunol 1994; 93: 413–423; 7. Corey JP et al. Otolaryngol Head Neck Surg 2000; 122: 681–685; 8. Blanc PD et al. J Clin Epidemiol 2001; 54: 610–618; 9. Marshall PS and Colon EA. Ann Allergy 1993; 71: 251–258; 10. Vuurman EF et al. Ann Allergy Asthma Immunol 1996; 76: 247–252; 11. Walker S et al. Eur Respir J 2005; 26(Suppl 49): 134s.

2 Epidemiology Of Allergic Rhinitis
Allergic rhinitis was reported the second most prevalent chronic condition in the United States in 1994 Affects 40 to 50 million people Incidence highest in people ages years Prevalence of Allergic Rhinitis is Increasing National Rhinitis Classification Task Force survey of 975 patients entering an allergist’s office complaining of chronic rhinitis. 43% had pure allergic rhinitis, 23% pure non allergic, and 34% had mixed rhinitis. 57% presented with non allergic rhinitis. Non allergic rhinitis may be a bigger problem than allergic rhinitis. When reviewing the literature there are literall thousands of articles on allergic rhinitis, only a few dedicated to non allergic rhinitis, and rarely does one find and article on mixed rhinitis. (Data presented at the National Allergy Advisory Council meeting:The Broad Spectrum of Rhinitis, Etiology, Diagnosis, and Advances in Treatment. St Thomas, US Virgin Islands. October 16, 1999)

3 Despite Available Treatment Nasal Symptom Burden Remains High
A population-based cross-sectional survey was carried out to assess the symptom burden of patients with rhinitis symptoms during an allergy season A total of 7069 individuals with complete data were analysed This survey showed that AR symptom sufferers, during an allergy season, have a large nasal symptom burden despite the availability of over-the-counter (OTC) and prescription medication treatments Nathan, R.A., Meltzer, E., Derebery, J., Stang, P., Campbell, U., & Stanford, R “Rhinitis symptom sufferers report a significant symptom burden during an allergy season”, AAAAI, Poster. During an allergy season AR symptom sufferers have a large nasal symptom burden despite the availability of over-the-counter and prescription treatments Nathan RA et al. AAAAI 2006.

4 Hay Fever Symptoms Have a Significant Impact on Exam Performance
A case-control study in UK students sitting national exams in three subjects (May–June 2004) 36% (673/1862) dropped at least one grade in at least one subject compared with winter exam Cases (dropped at least one grade) (n=673) Controls (n=1189) Mean diff (95% Cl) Hay fever symptoms, n (%) 389 (59.9%) 623 (53.9%) 5.4%* ( ) *P=0.001 Walker S et al. Eur Respir J 2005; 26(Suppl 49): 134s.

5 Očesni simptomi so pomembni pri zdravljenju alergijskega rinitisa
71% bolnikov trpi zaradi očesnih simptomov 50% jemlje več zdravil za AR These ocular symptoms are important as they are very prevalent Currently AR is treated by symptoms. INS for the nose and eye drops or AH for the eyes Polypharmacy means patients are not fully satisfied Majority of these still not satisfied with treatment Anti-histamines are not effective enough on nasal symptoms Current INSs do not work on eye symptoms

6 Systemic availability of INS
Systemic availability via swallowed portion Influenced by: INS bioavailability Degree of first-pass inactivation in liver Systemic availability via lungs Nose Liver Hepatic inactivation (first-pass metabolism)‏ Pharynx Stomach Oesophagus Lungs Key message: Intranasally administered drugs can be systemically absorbed. Therefore, it is important to have attributes that minimise the systemic availability. Key points of information: A Phase I pharmacokinetic study (FFR10008) using an oral solution of radiolabelled drug demonstrated that at least 30% of FF is absorbed and the oral bioavailability is, on average, 1.26%.1 This is indicative of extensive first-pass metabolism of FF. Although the contribution of direct nasal absorption to the overall bioavailability has not been determined, it is expected to be negligible. Clearance of FF is primarily by metabolism; FF is rapidly cleared (average total plasma clearance of 57.5 L/h) from the systemic circulation principally by hydrolysis in the liver by the cytochrome P450 enzyme CYP3A4 to a pharmacologically inactive 17 -carboxylic metabolite.2 References: GSK, data on file. Veramyst (fluticasone furoate) label information; Last accessed 16/05/07. Brand PL. Eur Respir J 2001;17:287–94. Daley-Yates PT, Richards DH. Clin Ther 2004;26:1905–19. Brand PL. Eur Resp J 2001;287–94. Daley-Yates PT, Richards DH. Clin Ther 2004;26:1905–19.

7 Nazalno okularni živčni refleks
1. FF ima visoko afiniteto do glukokortikoidnega receptorja1-3 2. To lahko povzroči boljšo inhibicijo nasalno okularnega refleksnega mehanizma 3. Sproščanje mediatorjev, ki povzročajo okularne simptome je zmanjšano Key message: FF consistently demonstrates efficacy against the ocular symptoms of AR. Key points of information: The mechanism of action of FF on the ocular symptoms of AR has yet to be established. A systemic effect is unlikely due to the low bioavailability, rapid first-pass metabolism, and low systemic concentration of FF; in addition, safety analyses show no evidence of ocular adverse events in patients. Evidence suggests a neural mechanism (portrayed visually in the diagram above): Bilateral nasal secretions occur post unilateral allergen exposure.1 Increased symptom scores on the side contralateral to allergen challenge have been observed.1–6 In a nasal challenge study, authors reported that approximately 20% of AR sufferers experienced ocular symptoms during nasal provocation with grass pollen.7 These data suggest that allergic ocular symptoms can occur without direct allergen contact to the conjunctiva. Additional point of information: The enhanced affinity for the GR, greater GR selectivity, longer duration of action compared with other INS are possibly the reasons why FF has consistent efficacy for the ocular symptoms of AR. References: Konno A, Togawa K. Ann Otol Rhinol Laryngol 1979;88:258–66. Wagenmann M et al. Clin Exp Allergy 1996;26:371–8. Malmberg H et al. Acta Otolarygol 1989;107:446–9. Raphael GD et al. J Allergy Clin Immunol 1991;88:33–42. Baroody FM et al. Am J Respir Crit Care Med 1998;157:899–906. Sheahan P et al. Clin Exp Allergy 2005;35:45–51. Lebel B et al. J Allergy Clin Immunol 1988;82:869–77.

8 Fluticasone furoate: glukokortikoid z večjo afiniteto do receptorjev
3000 2500 2000 Relative receptor affinity (RRA) 1500 1000 500 Fluticasone furoate Mometasone furoate Fluticasone propionate Beclometha- sone-17- monopropionate Ciclesonide active principle Dexamethasone Budesonide Valotis A, Högger P. EAACI 2006, Abstract 780.

9 Fluticasone furoate: a novel molecule
SCH2F CH2CI O O O O SCH2F O COCH2CH3 O O HO HO O O CO HO 17 F O CI F O O F F Mometasone furoate (MF)‏ Fluticasone furoate Fluticasone propionate (FP)‏ Key message: The chemical structure of FF differs significantly from FP and mometasone furoate (MF), the key difference being its 17-α furoate ester and steroid backbone. Key points of information: FF: Has the combination of a furoate ester group at the 17-α position with the metabolically labile fluoromethylthioester group at the 17-β position on the fluticasone backbone.1,2,3 Differs from FP due to its 17-α furoate ester.1,2,3 Differs from MF due to its different steroid backbone.4 Additional points of information: FF is only active in the body as the intact molecule and is, therefore, neither a pro-drug, like beclomethasone dipropionate and ciclesonide, nor an alternative salt of FP.1,2,3 FF is rapidly metabolised and inactivated by the liver after it enters the systemic circulation by removal of the 17-β fluoromethylthioester.1,2,3 Rapid inactivation ensures that systemic glucocorticoid-mediated side effects are minimised.1,2,3 At no point does fluticasone exist alone during corticosteroid metabolism, therefore, FF and FP have no metabolites in common.1,2,3 A mode of action video demonstrating the difference between the chemical structures of FF and FP and the potential implications of this is available and could be shown at this point. References: USAN. USP Dictionary of USAN and International Drug Names 2006 USP Dictionary Supplement 3. Pharmacopeial Forum 2006;32:1393–605. Biggadike K et al. Presented at the XXV Congress of the European Academy of Allergology and Clinical Immunology, Vienna, Austria, June 10–14, 2006; Abstract 783. Biggadike K et al. J Med Chem 2008;51:3349–52. Sahasranaman S et al Drug Metab Dispos 2006;34:225–33. Fluticasone furoate is a different active chemical entity from fluticasone propionate or mometasone furoate Biggadike K et al. EAACI 2006, Abstract 783. Biggadike K et al. J Med Chem 2008;51:3349–52. 9 Key slide

10 Fluticasone furoate tissue retention in human lung epithelial cells
Fluticasone propionate (10-10M) Fluticasone furoate (10-10M) 4 h Key message: FF binds more effectively to human lung epithelial cells than other clinically used glucocorticoids, thereby enhancing its duration of action. Key points of information: Please note this slide is based on in vitro data. Previous slides have shown that FF binds to the GR with a long half-life and shows sustained anti-inflammatory activity in vitro with prolonged incubation. An additional way that FF may increase its duration of action in vivo is through its high affinity for respiratory tissue. The slide above shows that FF binds for longer to human lung epithelial cells than FP.1,2 Experiments with BEAS 2B human lung epithelial cells show that FF remains bound to the fluorescently labelled GR in the nucleus for up to 30 hours.1,2 The very high association of FF with tissue will increase the likelihood that sufficient FF will be contained in the tissue to maintain full anti-inflammatory activity over 24 hours. Additional points of information: This phenomenon has also been seen with nasal epithelia. Furthermore, studies with the isolated human GR show that FF dissociates very slowly from the GR with a half-life of 10–11 hours which will further enhance the duration of action of FF. References: Adcock I, Ito K, data on file. Valotis A, Högger P. Respir Res 2007;8:54. 30 h Fluticasone furoate remains bound to glucocorticoid receptor at its cellular site of action for >24 hours High retention of fluticasone furoate in tissues enhances its duration of action Adcock I, Ito K, data on file. Valotis A, Högger P. Respir Res 2007;8:54.

11 Fluticasone furoate shows greatest in vitro cell retention
20 60 40 Epithelial cell association after 6 hours (% of total recovered) FF FP MF Budesonide Flunisolide Triamcinolone acetonide Key message: FF binds more avidly to respiratory tissue than other currently used glucocorticoids. Key points of information: The aim of this study was to investigate the binding of FF to epithelial tissue compared with other glucocorticoids. The transport of FF across respiratory tissue was investigated using a monolayer of human lung epithelial cells. FF (500 nM) was added to one side of the monolayer; the concentration of FF reached in the monolayer were greater than that for other glucocorticoids, including MF, FP and BUD. Furthermore, the rate of transport from the cell layer was lower with FF than that with the other glucocorticoids. These data support the greater cellular retention of FF and the rationale for once-daily dosing. Additional points of information: Prolonged retention time is a desirable property with topically applied glucocorticoids because it increases the retention time at the site of action In turn, this reduces the risk of systemic transport and associated side effects. The high tissue association, extended binding to the GR, and high potency suggest that FF should maintain efficacy over the entire 24-hour dosing period. Reference: Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667. Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667.

12 Fluticasone furoate shows enhanced affinity for the glucocorticoid receptor
500 1000 1500 2000 2500 3000 3500 Fluticasone furoate Fluticasone propionate Mometasone furoate Ciclesonide active principle Relative Receptor Affinity (RRA) Dexamethasone Budesonide Key message: FF binds to the human GR with a greater affinity than any of the other clinically used glucocorticoids; this permits a greater duration of anti-inflammatory action in the body. Key points of information: Please note this slide is based on in vitro data. The most fundamental and focused biological test for glucocorticoids is to see how effectively they bind to the GR. In preclinical studies, FF displayed a higher affinity for the GR than currently available glucocorticoids: relative receptor affinity (RRA) of FF for the human GR is 2988±135 with reference to dexamethasone RRA = 100±5.1,2 FF also dissociates from the GR very slowly which will increase its anti-inflammatory duration of action in the body. Additional points of information: X-ray diffraction studies with the crystals of the GR ligand binding domain have shown that the improved affinity of FF appears to be due to the 17-α furoate ester group of fully occupying a key pocket in the ligand binding site of the GR. Conversely, the propionate ester group of FP only partially occupies this pocket giving a weaker interaction with the GR. Reference: Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667. Valotis A, Högger P. Respir Res 2007;8:54. FF has the highest GR affinity compared with other currently available INS Valotis A, Högger P. Respir Res 2007;8:54. Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667. Key slide

13 Fluticasone furoate – nudi boljšo zaščito pred poškodbo celic
Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;doi: /ajplung

14 Fluticasone furoate: highly selective for GR
10 20 30 40 50 500 600 700 Fluticasone propionate Fluticasone furoate Human steroid hormone receptor selectivity Mometasone furoate Ciclesonide active principle Budesonide 800 900 Mineralocorticoid receptor Progesterone receptor-b Key message: FF demonstrates greater selectivity for the GR than other glucocorticoids, thereby limiting the potential for unwanted side effects. Key points of information: Please note this slide is based on in vitro data. The GR is structurally related to other receptors from the steroid hormone family. Since the receptors are similar, some glucocorticoids also bind to these other receptors. It is important that a therapeutic glucocorticoid has high potency for the GR and minimal potency for the other steroid hormone receptors (i.e. high selectivity), to avoid unwanted effects. Of the steroids tested, FF has the highest selectivity for the GR and lowest selectivity for other receptors. This is in contrast to MF and budesonide (BUD), which have the same potency for the progesterone receptor as for the GR and also poor selectivity for the GR vs the mineralocorticoid receptor (MR), which indicates that they are equally likely to bind to these receptors as the GR, thereby allowing for reduced efficacy and the potential for other unwanted effects. The arrow in this slide depicts that the greater the value, the greater the selectivity for the GR. If a glucocorticoid has the same potency against a steroid hormone receptor as its potency against GR (i.e. totally non-selective) it will have a selectivity ratio of 1. Additional points of information: The log EC50 values of FF, FP, MF, ciclesonide active principal (CIC-AP) and BUD have been negatively logged to show potency as a molar concentration (i.e. the concentration that produces 50% of the maximal effect on either the progesterone-b receptor, MR, androgen receptor or the alpha and beta subtypes of the oestrogen receptor). The negative log of the molar concentration that produces 50% of the maximal effect on GR-mediated inhibition of the NFkB pathway is also included as an indicator of GR activity. The potency for each steroid hormone receptor is divided by the potency for GR-mediated NFkB inhibition to give each selectivity value. Reference: Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667. 1:1 Lower selectivity for GR Greater selectivity for GR 800:1 FF has greater selectivity for the GR than other INS Key slide Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667.

15 Wound area (% of control) Glucocorticoid concentration (nM)
Fluticasone furoate: protection against mechanically induced inflammatory damage 120 Fluticasone furoate Fluticasone propionate Mometasone furoate Budesonide 110 100 90 80 Key message: FF is a powerful anti-inflammatory INS, as demonstrated by its highly effective protection against elastase-induced and mechanically induced damage of the human lung epithelia. Key points of information: Please note this slide is based on in vitro data. Mechanically induced damage to cells can be reduced by steroids. The presented data indicate that FF has the greatest protective potency against elastase-induced monolayer damage as assessed by cell detachment. Moreover, the more potent the steroid, the greater the protection at the lowest doses. FF protected the cells at very low doses; doses at which other steroids did not prevent damage. This indicates that FF has a powerful anti-inflammatory effect. Additional points of information: The maintenance of epithelial monolayer integrity is monitored by measuring the detachment of the cell layer from the cell membrane after treatment of the monolayer with the protease elastase. In addition, pre-treatment of an epithelial monolayer with glucocorticoid can also mitigate some of the secondary inflammatory damage caused as a consequence of an initial mechanical insult. FF also shows the most potent protective effect of all glucocorticoids when tested in this system. Reference: Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667. 70 Wound area (% of control) 60 50 40 30 20 0.001 0.01 0.1 1 10 Glucocorticoid concentration (nM) Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667.

16 Fluticasone furoate: low bioavailability
Bioavailability of currently used INS Key message: The absolute bioavailability of FF is 0.5%, which minimises potential for unwanted systemic effects. Key points of information: The bioavailability of FF is similar to FP and MF and less than that of other INS, for example budesonide. Additional points of information: Older drugs with high bioavailability have been associated with steroid-related adverse events, for example growth suppression.1–3 The levels of FF are generally below the limit of quantitation (LLQ) at the clinically relevant dose for adults and adolescents (110 µg/day).4 Therefore, to enable estimation of absolute bioavailability, supra-therapeutic doses of 880 µg were administered at 8-hourly intervals for 10 doses (total dosage µg/day).4 The slide shows that the resulting absolute bioavailability of FF is 0.5%.4 This data indicates that systemic exposure to intranasal FF is very low, which minimises the potential for unwanted systemic effects at the maximum therapeutic dose (110 µg/day).4 References: Bryson HM, Faulds D. Drugs 1992;43:760–75. Daley-Yates PT, Baker RC. Br J Clin Pharmacol 2001;51:103–5. Daley-Yates PT et al. Eur J Clin Pharmacol 2004;60:265–8. Allen A et al. Clin Ther 2007;29:1415–20. Bryson HM, Faulds D. Drugs 1992;43:760–75. Daley-Yates PT, Baker RC. Br J Clin Pharmacol 2001;51:103–5. Daley-Yates PT et al. Eur J Clin Pharmacol 2004;60:265–8. Allen A et al. Clin Ther 2007;29:1415–20. Key slide

17 Nazalno okularni živčni refleks
1. FF ima visoko afiniteto do glukokortikoidnega receptorja1-3 2. To lahko povzroči boljšo inhibicijo nasalno okularnega refleksnega mehanizma 3. Sproščanje mediatorjev, ki povzročajo okularne simptome je zmanjšano Key message: FF consistently demonstrates efficacy against the ocular symptoms of AR. Key points of information: The mechanism of action of FF on the ocular symptoms of AR has yet to be established. A systemic effect is unlikely due to the low bioavailability, rapid first-pass metabolism, and low systemic concentration of FF; in addition, safety analyses show no evidence of ocular adverse events in patients. Evidence suggests a neural mechanism (portrayed visually in the diagram above): Bilateral nasal secretions occur post unilateral allergen exposure.1 Increased symptom scores on the side contralateral to allergen challenge have been observed.1–6 In a nasal challenge study, authors reported that approximately 20% of AR sufferers experienced ocular symptoms during nasal provocation with grass pollen.7 These data suggest that allergic ocular symptoms can occur without direct allergen contact to the conjunctiva. Additional point of information: The enhanced affinity for the GR, greater GR selectivity, longer duration of action compared with other INS are possibly the reasons why FF has consistent efficacy for the ocular symptoms of AR. References: Konno A, Togawa K. Ann Otol Rhinol Laryngol 1979;88:258–66. Wagenmann M et al. Clin Exp Allergy 1996;26:371–8. Malmberg H et al. Acta Otolarygol 1989;107:446–9. Raphael GD et al. J Allergy Clin Immunol 1991;88:33–42. Baroody FM et al. Am J Respir Crit Care Med 1998;157:899–906. Sheahan P et al. Clin Exp Allergy 2005;35:45–51. Lebel B et al. J Allergy Clin Immunol 1988;82:869–77.

18 Delivery system is designed to meet the needs of patients
Easy to use device Patient-friendly spray No taste or smell Little or no drip down the throat (half the spray volume of other intranasal steroids Gentle spray, a consistent amount each time Key message: The new FFNS nasal drug delivery system was designed with patients in mind to overcome the issues experienced by patients with devices used to administer other currently available INS. Key points of information: Patients remain reluctant to use INS owing to the negative sensory characteristics of the nasal spray formulation, and to issues relating to ease-of-use of the device.1 The FFNS delivery system has been designed with the patient in mind and demonstrates a number of advantages:1-3 The FFNS is formulated to be delivered as a gentle mist with a favourable sensory characteristics profile, in terms of reduced odour, aftertaste and drip down the throat. Consistent delivery of the recommended 50 µl volume ensures that effectiveness against the symptoms of AR is achieved and sustained. The delivery system is ergonomically designed with a contoured grip and side-actuated device to ease grip and triggering, making it user-friendly to a wide population of patients, including the elderly and young children. The short delivery nozzle ensures comfort and eases administration in children. The see-through window ensures that the patient can visualise the precise amount of medication remaining to prevent wastage and aid with timely refill. The features of the FFNS delivery system may aid in promoting patient acceptance of, and compliance with, prescribed INS.1 Additional points of information: The FFNS delivery device has been tested in clinical efficacy and safety studies conducted in adult/adolescent patients. In a 2-week, US-based, randomised, double-blind, placebo-controlled, parallel-group study (FFR104861), 90% of patients were satisfied with the FFNS delivery system and FFNS formulation; while two-thirds found the delivery system to be extremely easy to carry and operate and over 50% reported that the mist spray was gentle with minimal or no aftertaste.4 References: Berger W et al. Expert Opin Drug Deliv 2007;4:689–701. Berger W et al. J Allergy Clin Immunol 2007;119(1 Suppl):S231. Godfrey JW et al. J Allergy Clin Immunol 2007;119(1 Suppl):S230. FFR (patients with SAR aged ≥12 years). Kaiser HB et al. J Allergy Clin Immunol 2007;119:1430–7. Comfortable for patients Nozzle is short and ergonomically designed Easy to grip with side actuation Viewing window See how much is left Key slide


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