New Medicine Report Document Status Anakinra Classification RED (Adopted by the CCG until review and further notice) Post Suffolk D&TC Date of Last Revision 5 th July 2002 Approved Name Trade Name Manufacturer Legal Status Indication Dosage Cost Possible Number of Suffolk Patients Number Needed to Treat Treatment Alternatives (NB Costs quoted are just for the medication and exclude the nursing administration costs) Future Alternatives Possible Future Indications Anakinra Kineret Amgen POM Licensed Treatment of the signs and symptoms of rheumatoid arthritis in combination with methotrexate in patients with an inadequate response to methotrexate alone Adults - 100mg in 0.67ml once daily by subcutaneous injection at the same time each day <18 years of age - not recommended 573.08 for 28 syringes 7,450 per year Estimated prevalence of RA @ 1% - 6,700 Estimated incidence of RA @ 0.04% - 268 Suggested number in the region of 8 per 100,000 In the region of 6 over a 24 week period See text for details Etanercept 25mg s/c twice weekly 7,500/year Infliximab 3mg/kg IV 7,500/year Leflunomide 20mg once daily 560/year Sulphasalazine EC 500mg qds 140/year Methotrexate oral 10mg weekly 29/year Methotrexate IM 1 weekly 700/year Penicillamine 250mg bd 114/year Gold 50mg IM monthly 118/year Ciclosporin (200mg Neoral daily) 1832/year Possible joint use with one of the TNFinhibitors Asthma, diabetes, GVHD, IBS, 1 Price through Specials Manufacture
leukaemia, psoriasis
Reviewer s Comments Anakinra is a novel approach to the treatment of rheumatoid arthritis. There is some evidence of its action which suggests an NNT compared with placebo for an ACR50 at 24 weeks to be in the region of 6. Further long-term evidence will be required to confirm the possibility of the medication reducing the progression of the disease. Similar long term evidence will be required to ensure that the side effect profile is no worse than currently suggested and that it has no deleterious effect on the progress of the disease. I am concerned that the NNTs produced from the available information seem to suggest that the response is dose related. It can be seen in Table 3 that as the dose moves from 0.4mg/kg to 1.0mg/kg the NNT improves but that it worsens as the dose moves to 2.0mg/kg for all ACR results at 24 weeks. The significance of this is not clear but it is possible that there are two mechanisms in balance (see remark re Arend et al pg 5) which are being affected. If this is so then it would seem that the dose given may be a critical factor in achieving the desired outcome. It should be noted that neither of the trials used the standardised dose (100mg) that is now available thus the dose/kg will vary from patient to patient and is unlikely to reflect the dose given during the trials. The data sheet states that anakinra should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis. This would suggest that the product should initially be placed in the red (consultant only) section of the Suffolk Drug & Therapeutics Traffic Light document. It is suggested that patients should only be offered treatment with this agent in line with the British Association of Rheumatologists guidelines for the use of other biologic agents e.g. inhibitors. Evidence Reviewed Paper, Review, Abstract etc. Bresnihan B, Alvaro-Gracia JM, Cobby M et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis & Rheumatism Vol 41 No 12 December 1998 2198-2204 Jiang Y, Genant IW, Cobby M et al. A multicenter, double-blind, dose-ranging, randomised, placebocontrolled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Arthritis & Rheumatism Vol 44 No 5 May 2000 1001-1009 Level of evidence I I
Cunnane G, Madigan A, Murphy E, et al. The effects of treatment with interleukin-1 receptor antagonist on the inflamed synovial membrane in rheumatoid arthritis. Rheumatology 2001;40:62-69 Cohen S, Hurd E, Cush J, et al. Treatment of rheumatoid arthritis with anakinra a recombinant human interleukin-1 receptor antagonist in combination with methotrexate Arthritis & Rheumatism Vol 46(3), March 2002: 614-624 Arend WP, Dayer JM. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis and Rheumatism 1990;33(3): 305-315 American College of Rheumatology. Guidelines for the management of Rheumatoid Arthritis. Arthritis & Rheumatism;46(2) February 2002: 328-346 Anakinra Advanced Evaluated Information. UKMi June 2001 Monograph 3/01/02 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 Assessment Tools American College of Rheumatology classification of functional status in RA I I IV III III Class I II III IV Criteria a Able to perform usual activities of daily living (self-care, vocational and avocational) Able to perform self-care and vocational activities but limited in avocational activities Able to perform self-care activities, but limited in vocational and avocational activities Limited in ability to perform self-care, vocational and avocational activities a Self-care activities include dressing, feeding, bathing, grooming and toileting; vocational activities include work, educational and/or homemaking activities; avocational activities include recreational and/or leisure activities. American College of Rheumatology (ACR) core set of disease activity measures in RA Area of disease activity Swollen joints Tender joints Patient s assessment of pain Physician s assessment of disease status Patient s assessment of disease status Measure Based on assessment of 28 joints Based on assessment of 28 joints Assessed with a 10cm visual analogue scale Assessed with a 10cm visual analogue scale Assessed with a 10cm visual analogue scale
Acute phase reactant (either ESR of C- reactive protein level) Clinically significant improvement is defined as a 20% reduction in the number of swollen joints, a 20 % reduction in the number of tender joints, plus a 20% improvement in 3 of the 5 remaining criteria. Additional ACR points are defined at 50% or 70% using the same measures. There is a widely held view that ACR50, rather than ACR20, should be taken as the clinically significant marker with ACR70 being taken as an exceptional result. Review Rheumatoid arthritis (RA) is a progressive disease associated with severe morbidity, functional decline, permanent disability and an increase in mortality. Patients are at high risk of developing joint erosions. Disease progression is rapid in the early phases and thus there has been a trend to treat the disease aggressively with disease modifying anti-rheumatic drugs (DMARDs). Whilst there would appear to be consistent use of DMARDs in patients with moderate or long standing RA few have been shown to retard disease progression, although sulphasalazine has shown this effect. DMARDs can rarely be given for long periods in RA because of their lack of sustained efficacy and the associated toxicity. In patients who fail to respond to DMARD mono-therapy combinations of drugs, usually methotrexate plus another DMARD, are often used. In RA an excessive (pathological) inflammatory response within the synovium, as well as other tissues, leads to damage. Tumour Necrosing Factor alpha (TNFα) is a cytokine released by cells within the immune system when inflammation occurs. It plays a rôle in the initiation and maintenance of the immune response. TNFα induces activation of T and B lymphocytes and increases the production of cyclo-oxygenase-2 (COX-2) which synthesizes further pro-inflammatory factors. High levels of TNFα are found in the blood of patients with RA and the level of TNFα in the synovium correlates with joint disease activity. The levels of soluble TNFα receptors are increased in the blood and joint fluid of patients with RA. Reduction in the activity of TNFα by various experimental mechanisms has been shown to lead to a decrease in disease activity. Two biologic products, etanercept and infliximab have been developed to block TNFα.
A separate pro-inflamatory cytokine, interleukin-1 (IL-1), is known as a central mediator in RA. Patients with RA will show an elevated level of IL-1 in the synovial fluid. Patients with erosive RA have higher synovial and circulating levels of IL-1 than patients without erosions. Anakinra is a recombinant form of naturally occurring IL-1 receptor antagonist (IL-1Ra) with an identical mode of action. It blocks the biological activity of IL-1 via competitive inhibition of the binding of IL-1 to the IL-1 type 1 receptor (IL- 1RI). It should be noted that a full understanding of the actions of cytokines and cytokine inhibitors is still being developed. Arend and Dayer have suggested that IL-1 may, in addition to its inflammatory activity, have anti-inflammatory effects, such as the induction of the synthesis of collagen and enzyme inhibitors by chondrocytes and synovial fibroblasts. In a trial by Bresnihan 472 patients with active and severe RA with a duration of <8 years were recruited into a 24 week double-blind, randomised, placebocontrolled multicentre study. Non-steroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroid treatment was kept constant throughout the study but DMARDs were discontinued at least 6 weeks before the study commenced. Please note that no patients were receiving methotrexate in this trial. The primary efficacy measure was the ACR score and the results are shown in Table 1. Table 1 To show clinical response to treatment with IL-1Ra according to ACR 20 criteria Dosage (mg/day) n Improved at 24 weeks, number (%) P NNT at 24 weeks compared with placebo 0 119 32 (27) 0.020* 30 119 47 (39) 0.054 8 75 115 39 (34) 0.258 14 150 115 49 (43) 0.014 6 *placebo group versus combined treatment group In a paper by Cohen 419 patients with moderate to severe active RA who were receiving methotrexate (MTX) for 6 consecutive months with stable doses for 3 months but with disease for no longer than 12 years were randomised into 6 groups. The groups received either placebo or varying doses of anakinra together with their dose of MTX. The primary efficacy end point was measured
using the ACR20 response measure. The results are shown in Table 2 with the NNTs shown in Table 3. Table 2 To show the percentages of patients achieving the primary end point ACR20 together with those attaining ACR50 and ACR75 at weeks 12 and 24 Dose of Week 12 Week 24 Anakinra n ACR20 ACR50 ACR75 ACR20 ACR50 ACR75 Placebo 74 19 4 0 23 4 0 0.04mg/kg 63 25 5 2 19 13 5 0.1mg/kg 74 35 15 3 30 20 7 0.4mg/kg 77 25 5 3 36 11 2 1.0mg/kg 59 46 19 5 42 24 10 2.0mg/kg 72 38 24 11 35 17 7 Given an average weight of 75Kg the dose equivalent for 1mg/kg would be 75mg per day and for 2mg/kg it would be 150mg per day, the licensed product is a single dose of 100mg. All patients also on methotrexate Table 3 To show the NNT compared to placebo to achieve the primary end point ACR20 together with ACR50 and ACR75 at weeks 12 and 24 Dose of NNT at Week 12 NNT at Week 24 Anakinra n ACR20 ACR50 ACR75 ACR20 ACR50 ACR75 Placebo 74 0.04mg/kg 63 17 100 50 25 11 20 0.1mg/kg 74 6 9 33 14 6 14 0.4mg/kg 77 17 100 33 8 14 50 1.0mg/kg 59 4 7 20 5 5 10 2.0mg/kg 72 5 5 9 8 8 14 Given an average weight of 75Kg the dose equivalent for 1mg/kg would be 75mg per day and for 2mg/kg it would be 150mg per day, the licensed product is a single dose of 100mg. All patients also on methotrexate Adverse Effects etc. For full information please see the SOPC. The safety of anakinra is based on an integrated database of 2606 patients including 570 who have been prescribed the medication for more than one year. The SOPC gives the following information (Table 4) on very common and common side effects. Table 4 To show the incidence of very common and common side effects for anakinra
Frequency Body system Undesirable effect Very common (>10%) Skin and subcutaneous tissue disorders Nervous system disorders Injection site reaction Headache Common (1%-10%) Blood and lymphatic system disorders Infections and infestations Neutropenia Serious infections requiring hospitalisation The incidence of serious infection was higher in anakinra patients than in patients receiving placebo (1.8% versus 0.7%). These infections consisted mainly of bacterial events such as cellulitis, pneumonia and bone and joint infections. There are no adequate data to support the use of anakinra in pregnant women. Anti 1L-Ra antibodies have been detected in three patients with neutropenia although no neutralising antibodies have been detected. The ACR suggests that, in common with other biologic therapies, there is concern about the risk of serious infections and malignancy but the safety data are limited. Patients with asthma/chronic obstructive pulmonary disease had a higher rate of pulmonary infections in trials; thus anakinra should be used with caution in patients with these comorbid conditions. They suggest that anakinra should not be given to patients with active infections of any type. Health Economics RA affects about 1% of adults in the UK with around 10% of these progressing to a severe form of RA. Many of these patients will be adequately treated with current medications, however some will not. If the uptake of this new agent is similar to that of TNF-inhibitors then it is likely that about 8 patients per 100,000 population may be suitable for anakinra. Using these figures and an average cost of 7,450 per year then the following table (Table 5) can be constructed. However it is likely that these 8 patients would be the same 8 patients eligible for TNF-inhibitor therapy. Some funding has already been made available for these patients. Thus the increase in budget may be less than the figures suggest. If the products are found to be particularly effective there may, however, be a move in the future to use them at an earlier stage in the treatment cycle thus increasing the costs significantly.
Table 5 To show the possible anakinra costs for each PCT in Suffolk PCT Population Expected number Cost ~( ) of patients Central 96,000 8 59,600 Ipswich 143,000 11 81,950 Suffolk Coastal 99,000 8 59,600 Suffolk West 203,000 16 119,200 Waveney 114,000 9 67,050 Total for Suffolk 655.000 52 387,400 Total for East Commissioning 338,000 27 201,150 There will be additional costs required for the initial monitoring of patients and they will require some training in the use of the sub-cutaneous injections. In addition all patients will be on other medication. The total cost may be offset by reductions in the costs of managing the progression of the disease. However some of the direct health costs will not be able to be realised as the specialist staff will remain employed although there will be the possibility of their being able to treat other patients. Given the debilitating nature of the disease the social care costs saved could be significant.. Reviewer s Comments 1. Data to support the use of anakinra at the licensed dose of 100mg/day - two key clinical studies have been conducted in which a total of 366 patients with RA received anakinra at the licensed dose of 100mg/day. The first is an ongoing, randomised, double-blind, placebo-controlled study in 906 patients to assess the efficacy and safety of anakinra in combination with methotrexate. The primary endpoint of this study is the impact of anakinra on the progression of radiographic damage, as measured by the Sharp score. However, interim data on the effects of anakinra on the signs and symptoms of rheumatoid arthritis (RA) has been examined for the first 501 patients enrolled onto this study. The results of this analysis indicate that treatment with anakinra plus methotrexate results in significant and sustained improvements in the signs and symptoms of RA compared to methotrexate plus placebo, as measured by the ACR score. These data were presented at the American Society of Rheumatology annual conference last year 1. Results from a second study of anakinra at a dose of 100mg /day were also presented at the same meeting 2. This was a randomised, placebo-controlled
safety study designed to prospectively examine the overall safety of anakinra in 1414 patients in the average clinical practice, by including patients receiving a variety of concurrent RA medications including multiple disease modifiying antirheumatic drugs (DMARDs), as well as patients who were DMARD-free. The study population also included patients predisposed to infection due to a history of underlying disease, and patients with a variety of comorbidities. The data from these studies have yet to be published in peer-reviewed journals (data from the efficacy study currently remains blinded to the primary endpoint of radiographic joint damage). However, they were a critical component of our regulatory submissions to both the European Medicines Evaluation Agency and the Food and Drug Administration, and supported the granting of a product licence for anakinra at a dose of 100mg/day in both Europe and the USA. The clinical trial data for both trials can be reviewed in full on http//:www.fda.gov/ohrms/dockets/ac/01/briefing/377961b1.htm [Confirmatory Efficacy Study number 990145, Safety Study number 990757] 3. 2. Anakinra should be prescribed by consultant rheumatologists, as indicated by your statement: anakinra should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of RA. Review 1. p5, paragraph 4. The wording could be altered to clarify that: In addition to its inflammatory activity IL-1 has pro-destructive effects, such as the inhibition of the proteoglycan synthesis and the stimulation of collagen breakdown by chondrocytes and synovial fibroblasts 4-6. 2. p6 Table 2 and associated text. The number of patients achieving ACR70 was calculated, not ACR75 7. Adverse Effects The data presented gives a fair representation of the information contained on the Summary of Product Characteristics. However, additional points could be highlighted given the current interest in the safety of the biological agents with regards to infection. As discussed on page 6 of the submission, the safety of anakinra is based on a safety database of 2606 patients. Of these patients 1414 were included in the prospective study designed to examine the safety profile of anakinra in the average clinical practice (reviewed above 2 ). Patients included in this trial were receiving a variety of concurrent RA medications or no concurrent treatment; were predisposed to infection due to a
history of underlying disease such as pneumonia, asthma, controlled diabetes and chronic obstructive pulmonary disease; and had co-morbidities such as hypertension, coronary artery disease and congestive heart failure. Despite the inclusion of these patients, there have been no on-study deaths due to serious infections in clinical trials with anakinra. In addition, there have been no reported cases of tuberculosis or opportunistic infection 3. Health Economics 1. p7 paragraph 3. As stated, we would expect that patients treated with anakinra would be the same patients eligible for TNF-inhibitor therapy. 2. p8 paragraph 1. Costs required for the initial monitoring of patients receiving anakinra would be those associated with the monthly assessment of neutrophil numbers in the first 6 months of treatment, and quarterly thereafter. However, blood count assessment is likely to occur as part of the ongoing monitoring of disease. References: 1. Cohen, SB et al. Anakinra (recombinant interluekin-1 receptor antagonist) : a large, placebocontrolled efficacy trial of anakinra in patients with erosive rheumatoid arthritis disease. Latebreaking abstract-1, American Society of Rheumatology Annual Conference, 2001. can be viewed at http://www.abstracts-on-line.com/abstracts/acr/aol/asp 2. Fleischmann, R et al. A safety trial of anakinra: Recombinant interleukin-1 receptor antagonist (IL-1Ra) in a large, placebo controlled heterogeneous populations of patients with rheumatoid arthritis. Arthritis and Rheumatism, 2001, supplement, abstract S84 3. Kineret (anakinra) FDA Briefing Information, August 16, 2001: available on: http//:www.fda.gov/ohrms/dockets/ac/01/briefing/377961b1.htm 4. van den Berg, WB. Anti-cytokine therapy in chronic destructive arthritis. Arthritis Research, 2001, 3:18-26 5. Arend, WP. Interleukin-1 receptor antagonist. Advances in Immunology, 1993; 54:167-227 6. Joosten, LA et al. IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates inflammation. Journal of Immunology, 1999, 163:5049-5055 7. Cohen SB et al. Treatment of Rheumatoid Arthritis with Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist, In Combination with Methotrexate. Arthritis and Rheumatism, 2002, 46(3): 6134-621
SUFFOLK DRUG AND THERAPEUTICS COMMITTEE New Drug Bulletin: Anakinra (Kineret TM ) SUFFOLK DRUG AND THERAPEUTICS COMMITTEE RECOMMENDATION: Suffolk Drug and Therapeutics Committee has considered the use of anakinra for rheumatoid arthritis in conjunction with methotrexate and considers that it should be a RED drug, i.e. hospital-only - GPs should not be expected to prescribe it. In addition it should be used only when patients have not responded to etanercept or infliximab, or cannot tolerate these drugs. FURTHER DETAILS Licensed indication: Dosage: Cost: Treatment of the signs and symptoms of rheumatoid arthritis in combination with methotrexate in patients with an inadequate response to methotrexate alone. Adults - 100mg in 0.67ml once daily, by subcutaneous injection at the same time each day <18 years of age - not recommended 573.08 for 28 syringes 7,450 per year PRESCRIBING COMMENTS FROM THE SUFFOLK DRUG AND THERAPEUTICS COMMITTEE: The numbers needed to treat (NNTs) from trial work on anakinra are not so good as those achieved in trials of etanercept and infliximab, although head to head trials have not taken place. The cost of using anakinra is similar to that of using infliximab or etanercept. Local rheumatologists suggested that anakinra might have a place in the treatment of rheumatoid arthritis if patients were unable to tolerate etanercept or infliximab. Monitoring of the use of anakinra, etanercept and infliximab can be done via hospital pharmacies. Anakinra carries a black triangle in common with all new drugs. All suspected adverse reactions should be reported to the CSM on a yellow card.
Paul Berry Prescribing Medical Advisor October 2002 These notes are only intended to provide brief guidance. Please refer to the latest Summary of Product Characteristics (Data Sheet) for full prescribing details.