New Medicine Report (Adopted by the CCG until review and further

New Medicine Report (Adopted by the CCG until review and further GRASS ALLERGEN TREATMENT notice) Document Status Decision following Suffolk D&TC meeting Traffic Light Decision Red for 2007 with review in September 2007 Prescriber s Rating A real advance Date of Last Revision 03.01.2007 Approved Name Trade Name Manufacturer Legal Status Indication Dosage Cost Grass Allergen treatment Grazax ALK-Abelló (Denmark) Expected POM Expected to be - Treatment of moderate to severe seasonal allergic rhinitis One tablet daily starting at least eight weeks before the grass pollen season, continued through the pollen season and then without a break for at least a further two years Estimated by The Times from German prices as 67.50 per 30 tablets

Possible Number of Suffolk Patients Number Needed to Treat Treatment Alternatives Future Alternatives Possible Future Indications Up to 64,000 in Suffolk PCT Up to 14,000 in Waveney 4 to 6 to achieve benefit in one season Oral antihistamines Intranasal corticosteroids Intranasal decongestants Sodium Cromoglicate Ipratropium Bromide Pollinex (grass pollen) Kenalog None known None known Reviewer s Comments Grazax is a new sublingual allergy vaccine in tablet form for moderate to severe seasonal allergic rhinitis (grass pollen hay fever) which is shortly to be launched in the UK given that it is most effective if started at least eight weeks before the pollen season.

The published research is reviewed below and a number of questions arise. The major rating scales were subjective and given the side effect profile of the treatment it is possible that some bias may have been introduced although the publishers claim this is not the case. In addition it is not clear from the papers how the rescue medication scoring system was derived and the scores seem to differ between papers. All patients entering the trials were required to have a prick test to establish sensitivity. It is not clear whether this will be a requirement of the licence but if this is not performed then some patients will receive medication but gave no benefit due to their allergy being due to another pollen type. It has been shown that the tablet does not exacerbate asthma symptoms in those who suffer concomitant asthma during the pollen season. However no long-term asthmatic patients were involved in the trials and thus it is not clear if this result holds true in all cases. It will be important to ensure that patients begin treatment eight weeks before the start of the pollen season to ensure maximum benefit. There are a number of side effects and it will be interesting to see whether in general use these reduce the compliance to the daily schedule and thus reduce the efficacy of treatment. Finally it is not clear that the results are repeatable over a period of time. Certainly one study is continuing at the moment but year two and three results will not be published until late 2006 and late 2007. It is also not clear whether treatment will have to continue for the rest of the patient s life or whether a course of three years will be sufficient to reduce symptoms significantly in future years.

Evidence Reviewed Paper, Review, Abstract etc. Malling HJ, Lund L, Ipsen H, Poulsen L Safety and immunological changes during sublingual immunotherapy with standardised quality grass allergen tablets J Investig Allergol Clin Immunol 2006;16(3):163-168 Kleine-Tebbe J, Ribel M, Herold DA Safety of a SQstandardised grass allergen tablet for sublingual immunotherapy: a randomized, placebo-controlled trial Allergy 2006;61:181-184 Durham SR, Yang WH, Pedersen MR et al Sublingual immunotherapy with once-daily grass allergen tablets: A randomized controlled trial in seasonal allergic rhinoconjunctivitis J Allergy Clin Immunol 2006;117:802-9 Dahl R, Kapp A, Colombo G et al Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis J Allergy Clin Immunol 2006;118:434-440 Dahl R, Stender A, Rak S Specific immunotherapy with SQ standardised grass allergen tablets in asthmatics with rhinoconjunctivitis Allergy 2006;61:185-190 National Horizon Scanning Centre New & Emerging Technology Briefing Grazax allergy vaccine for moderate to severe seasonal allergic rhinitis (grass pollen hay fever) January 2006 Level of evidence I I I I I III

Smith L Pill offers release from hay fever misery for millions of sufferers The Times 12 th December 2006 Pg 7 Level of evidence adapted from Quick and Clean : authorative health technology assessment for local health care contracting Andrew Stevens, Duncan Collin-Jones & John Gabbay Health Trends Vol 27 No 2 1995 IV Review Allergic rhinoconjunctivitis induced by the inhalation of grass pollen is a common cause of significant discomfort to many particularly during the summer months. Whilst in many it is a mild discomfort in others it may impair daily activity and may contribute to sleep disturbance and learning problems. Given the seasonality of the allergen it is suggested that either through its own action or the action of medication taken to alleviate the symptoms people undergoing examinations may perform less well than expected. Whilst the use of medication to alleviate the symptoms is common, the only currently available specific immunotherapy is a sub-cutaneous injection, which is required to be administered in a place where suitable resuscitation equipment is available. Grazax is a sublingual grass allergen tablet designed to allow a wider population access to self administered immunotherapy. However it is suggested that the first dose should be administered in a clinical setting. The active ingredient is a standardised allergen extract derived from grass pollen from Phleum pratense which has been shown to have extensive cross reactivity with other grass pollens. In the trial reported by Dahl, Kapp et al a total of 634 patients were entered into a multicentre trial of Grazax. Patients had at least a two year history of significant grass pollen induced allergic rhinoconjunctivitis, specific IgE against Phleum pratense, a positive prick test and a FEV 1 higher than 70% of predicted value. Significant amongst a number of exclusions was the indication of significant asthma outside the grass pollen season. Subjects rated their symptoms on a 0-3 score (0 no symptom, 1 slight, 2 moderate, 3 severe). In addition there was a daily score for the use of rescue medication (see Table 1). It is not clear how this scale was derived although patients were not aware of the scale during

the trial. The results for the first season of treatment are shown in Table 2. Patients were also asked to compare this season with last (Table 3). Table 1 Daily scoring of rescue medication Step Rhinoconjunctivitis Score/dose 1 Desloratidine 5mg once daily 6 2 Budesonide nasal spray (as much as 1 per spray 32microgram 2 puffs per nostril per day) 3 Prednisolone (as much as 50mg once daily) 1.6 per 5mg Table 2 To show the average daily scores and medication usage during the grass pollen season Treatment Group Grazax Placebo Number of subjects for the entire season 282 286 Entire-season rhinoconjunctivitis syptom score Mean (SD) 2.4 (1.6) 3.4 (2.2)# Median 2.1 3.2 Nose symptom score Mean (SD) 1.7 (1.2) 2.3 (1.5) Median 1.4 2.2 Eye symptom score Mean (SD) 0.7 (0.6) 1.1 (0.8) Median 0.5 0.9 Entire-season rhinoconjunctivitis mediation score

Mean (SD) 1.5 (1.9) 2.4 (2.5)# Median 0.8 1.7 N % T N % T Any rhinoconjunctivitis 191 68 3284 229 80 4278 medication Desloratidine 5mg 186 66 2966 224 78 3957 Budesonide 32 microgram 107 38 1186 164 57 1970 Prednisolone 5mg 13 5 137 21 7 115 T = Total number of days with use of rescue medication by all subjects # = Statistically significant difference between treatment and placebo groups (p<0.0001) Table 3 Global evaluation of treatment effect. Grazax Placebo N % N % No of subjects 316 318 Overall assessment of 2005 compared with previous season N 278 275 Much better 96 35 45 16 Better 132 47 106 39 The same 41 15 89 32 Worse 7 3 25 9 Much worse 2 1 10 4 Improved 228 82 151 55 Not improved 50 18 124 45

In a trial reported by Durham et al which had similar inclusion and exclusion criteria as above 855 patients were admitted to a 55 centre trial. This was a dose ranging trial and patients were given either a daily dose of Grazax or placebo plus access to a daily dose of rescue medication (loratidine 5mg) or placebo. A dose-response was noted and for those patients taking a 75,000 SQ-T dose (the intended product), a moderate improvement in symptom score of 16% (p = 0.071) and an improvement in the medication score of 28% (p = 0.047). In addition it was noted that additional benefits were accrued with pre-seasonal treatment of at least 8 weeks. In a trial reported by Dahl, Stender et al which once again had similar inclusion and exclusion criteria 114 patients across 15 sites were randomised to treatment or placebo. Primary endpoints were average asthma medication and symptom scores during the grass pollen season and secondary variables were average rhinoconjunctivitis symptom and medication scores during the grass pollen season. Additionally the number of well days was defined. Differences in the asthma medication and symptom scores were negligible. The mean difference in the asthma medication score was below 0.1 and 0.3 for the asthma symptom score ( a single inhalation of salbutamol was scored 2 and there were a maximum of 32 points available). A reduction in the rhinoconjunctivitis symptom score of 37% (p=0.004) and a 41% (p=0.036) reduction in the medication score was found in the grass pollen season for subjects treated with Grazax compared to placebo. Well days increased by 54% (p=0.002) Adverse Effects etc. For full information please refer to the Summary of Product Characteristics The trial by Dahl, Kapp et al reported the following side effects (Table 4)

Table 4 Treatment-emergent adverse events reported by 5% of subjects Grazax Placebo N % N % No of subjects 316 318 Oral pruritus 145 46 13 4 Nasopharyngitis 47 15 60 19 Edema mouth 58 18 2 1 Influenza 23 7 24 8 Ear pruritus 38 12 3 1 Throat irritation 30 9 3 1 Headache 9 3 19 6 The trial reported by Durham et al noted that 53% of patients had treatment related adverse events, mainly oral pruritus or throat irritation. In a trial reported by Dahl, Stender et al a number of adverse events were noted and these are shown in Table 5 Table 5 Most frequently reported treatment-emergent adverse events Grazax Placebo No of subjects 61 32 Oral pruritus 53% 5% Nasopharyngitis 36% 25% Throat irritation 32% 25%

Economic Information Seasonal allergic rhinitis is thought to affect in the order of 26% of the population. In Suffolk this would equate to 144,300 persons in Suffolk PCT and 31,720 in the Waveney area. Given that there are many causes of allergic rhinitis it is clear that not all of these will have an allergy to grass pollen but it is thought likely that between 52% and 90% of this group will have an allergy to grass pollens. Taking this as 66% then there will be 96,000 people in Suffolk PCT and 21,000 in Waveney with an allergy related to grass pollen. Further it is known that 30% to 62% of this group will have moderate to severe symptoms. Thus between 32,000 and 64,000 people in Suffolk PCT and 7,000 to 14,000 people in Waveney may be eligible for this treatment Currently many patients are treated through the use of OTC medication although there will be some prescribed medication. Very few patients will be receiving Pollinex (grass pollen) at 320 per course. The cost of the medication is not yet known, however it is unlikely to be cheap and a detailed cost benefit analysis will need to be produced before agreement for use can be reached. If only 10% of patients were to receive the medication in Suffolk PCT (say 5,000 people) and the yearly cost was in the region of 810 per person then an estimated cost for one year s treatment would be in the region of 4,050,000. The full course cost per person would be in the region of 2,800 allowing for the treatment period being in excess of three years.

SUFFOLK DRUG AND THERAPEUTICS COMMITTEE www.sphn.nhs.uk New Drug Bulletin SUFFOLK DRUG AND THERAPEUTICS COMMITTEE RECOMMENDATION: Grazax for moderate to severe seasonal allergic rhinitis Suffolk Drug and Therapeutics Committee decision on Grazax: Prescriber s Rating 2: A real advance. Traffic Light decision Red Hospital Only. Grazax Indication: Dosage: Cost: Treatment of grass pollen induced rhinitis and conjunctivitis in adult patients with clinically relevant symptoms and diagnosed with a positive skin prick test and/or specific IgE test to grass pollen. One sublingual tablet daily starting at least eight weeks before the grass pollen season, continued through the pollen season and then without a break for at least a further two years a total of 3 years UK price 67.50 per 30 sublingual tablets Further Comments: Oral desensitising vaccines are a common method of treatment of this condition in many other countries. They are usually given in liquid form. The new tablet formulation offers increased convenience to patients. The medicine needs to be taken every day for 3 years once a treatment course commences. The manufacturer recommends that the drug is started by a physician with experience of treating allergic diseases because diagnosis needs to be by skin prick testing or IgE levels, together with appropriate clinical features.

Patients need to have only grass pollen allergy those with multiple allergies do not respond well. Administration of the sublingual tablet can cause tingling of the mouth and throat and slight swelling, and staff with experience of the medicine should be on hand to reassure the patient. Standard therapy (eg antihistamines, intranasal corticosteroids) is still required although the need reduces with prolonged treatment. Local consultants noted that the cost-effectiveness of Grazax is not proven, and that it should be prescribed in secondary care because of the risk of anaphylaxis. However it could solve clinical problems because of the low use of desensitisation at present. The Committee s assessment of Grazax pointed to an Amber rating. However, the Committee felt strongly that a shared care agreement would be needed for this drug, and that this could not be prepared and agreed in time for this season. This led the Committee to classify Grazax as Red Hospital Only initially, with a review in November 2007 with a view to re-grading it as Amber. Grazax carries a black triangle in common with all new drugs. All suspected adverse reactions should be reported to the CSM on a yellow card. *Suffolk D&T s Prescriber s Rating ranges from Grade 1: Bravo! The drug is a major therapeutic advance in an area where previously no treatment was available to Grade 7 Not acceptable - product without evident benefit over others but with potential or real disadvantages. Paul Berry Prescribing Medical Advisor January 2007 These notes are only intended to provide brief guidance. Please refer to the latest Summary of Product Characteristics (Data Sheet) for full prescribing details. Charts to be used in the decision making process in Suffolk Quality of Evidence categories Cost utility categories Per life year gained I Strong evidence from at least 1 RCT A Less than 3,000 II-1 Evidence from a well designed CT without randomisation B 3,000 to 20,000 II-2 Evidence from well designed cohort or case controlled study C > 20,000 II-3 Evidence from multiple time series or dramatic results D Negative life years III Opinions of respected clinicians or expert committees IV Evidence inadequate

Recommendations informed by cost utility and quality of evidence Key to Table at Right Quality of evidence A B C D ++ Strongly recommended I ++ (high) ++ - X + Recommended II ++ + - X - Beneficial but high cost III + - - X X Not recommended IV 0 0 0 0 (low) 0 Not proven Adapted from Quick and Clean : authorative health technology assessment for local health care contracting Andrew Stevens, Duncan Collin-Jones & John Gabbay Health Trends Vol 27 No 2 1995

To Decide If A Medication Is To Be Used In Suffolk Criterion Tends to poor 2 Medium 4 Tends to good Quality of evidence in the papers reviewed IV III II-2 II-1 I Magnitude of effect inferred from the trials reviewed Low xxxx Medium xxxx High Known Side Effect Profile High xxxx Medium xxxx Low Known Interactions High xxxx Medium xxxx Low Concern re Possible Side Effects Not Yet Uncovered High xxxx Medium xxxx Low Balance of Benefit To Harm (side effects toxicity interactions etc) Poor xxxx Medium xxxx Good NNT High xxxx Medium xxxx Low Comparison Of Effectiveness With Other Medicines In Use For Poor xxxx Medium xxxx Good The Same Condition Severity of Condition to be Treated Trivial xxxx Medium xxxx Severe Cost Utility Score D C B?A A Recommendations informed by cost utility and quality of evidence 0 X - + ++ Prescriber s Rating Definitions Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. A real advance - The product is an important therapeutic innovation but has certain limitations. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are me-too products. Not acceptable - Product without evident benefit over others but with potential or real disadvantages. With acknowledgement to Prescrire

To Decide Where A Medication Is To Be Used In Suffolk Skills of the prescriber Criterion Red Amber Green D Green Experience Of The Condition Specific Specific Specific General Diagnosis Specific Specific Specific General Monitoring Progress Of Treatment Difficult Specific General General Therapy Patient Selection Difficult Specific Specific Easy Initiation Of Treatment Difficult Difficult Easy Easy Dose Titration Difficult Specific Easy Easy Monitoring Of Side Effects Complex Easy Easy Easy Method Of Administration Complex Normal Normal Normal Discontinuation Of Treatment Complex Complex Easy Easy