THE COST OF TREATING MUCORMYCOSIS WITH ISAVUCONAZOLE COMPARED WITH LIPOSOMAL AMPHOTERICIN B FOLLOWED BY POSACONAZOLE IN THE : ECONOMIC EVALUATION OF THE PHASE III VITAL STUDY AND FUNGISCOPE™ MATCHED CASE-CONTROL ANALYSIS

Kuessner D1, Bagshaw E2, Blackney M2, Cornely O A3,4, Heimann S3, Posthumus J1 1Basilea Pharmaceutica International Ltd., , , 2Covance Market Access, London, UK, 3University Hospital of Cologne, Department I of Internal Medicine, Cologne, , 4Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Clinical Trials Centre Cologne (ZKS Köln), University of Cologne, Cologne, Germany

BACKGROUND AND OBJECTIVES RESULTS • Mucormycosis is a rapidly progressive invasive fungal disease, with a high risk of mortality, which mainly affects immunocompromised or critically ill people1–3. Base case • The cost of treating patients with mucormycosis is substantial, due to prolonged use of high-cost antifungals4,5, lengthy hospital stays4–6, and the management of adverse events (AEs)7. • Total per-patient mucormycosis treatment costs were estimated to be £26,810 with ISAV versus £41,855 with L-AMB + POSA; Figure 2 and Table 3. • Until recently, the only licensed antifungals for mucormycosis were formulations of amphotericin B (AMB): • This represents a saving of 36% with ISAV relative to L-AMB + POSA. −− Liposomal AMB (L-AMB) – the standard treatment for mucormycosis in the United Kingdom (UK) – carries a risk of renal toxicity, particularly at the high doses (over 5 mg/kg)8,9 commonly used in mucormycosis10, which increases the likelihood of dose reductions and • The greatest driver of savings was drug acquisition costs, due to a lower daily drug cost for ISAV than for L-AMB + POSA, combined with a discontinuations9. shorter duration of IV therapy. −− L-AMB is not available as an oral formulation8, which means that, if outpatient maintenance therapy is required, a step-down to off-label • Hospitalisation costs were considerably lower for ISAV than for L-AMB + POSA, as the IV-to-oral switch occurred earlier for ISAV patients than oral posaconazole (POSA) may be made10. for those given L-AMB + POSA. • Isavuconazole (ISAV) is an intravenous (IV) and oral, broad-spectrum, triazole antifungal indicated in the European Union (EU) for the treatment • Monitoring and administration costs were also lower with ISAV than with L-AMB + POSA. of mucormycosis in adults for whom AMB is inappropriate, and for invasive aspergillosis11. • ISAV has comparable efficacy to AMB ± POSA in the primary treatment of mucormycosis, and an acceptable safety profile12. Figure 2. Base case per-patient cost of mucormycosis treatment • A health-economic model was developed to explore the per-patient cost to the UK healthcare system of treating mucormycosis with ISAV alone compared with L-AMB followed by off-label, maintenance POSA.d with managing these events, over a five-year period 50,000 £ 40,000 £,

METHODS Per-patient cost 30,000 £ Cost factors: • The model took a cost-minimisation approach. The rationale for this was that a matched case-control analysis comparing the ISAV VITAL of mucormycosis £, £, Monitoring and study with the FungiScope™ registry of emerging fungal infections showed no significant difference in Day 42 all-cause mortality between treatment (£) 20,000 administration mucormycosis patients treated with ISAV or AMB (mainly L-AMB) ± POSA12. £, Hospitalisation • ISAV is licensed in the EU for use only in patients for whom AMB is deemed inappropriate. However, L-AMB, the standard of care, is the most 10,000 appropriate comparator for ISAV as, in clinical practice, in cases of intolerance, L-AMB treatment may be continued but at a reduced dose10. rug acquisition 0 Figure 1. Model structure L-AMB + POSA ISAV Total cost 41,855 26,810 Total cost L-AMB + POSA Total cost ISAV Values have been rounded. Length of treatment daily Length of treatment daily drug costs (IV oral) drug costs (IV oral) Table 3. Base case per-patient cost of mucormycosis treatment

Length of hospital stay Length of hospital stay L-AMB + POSA ISAV Saving ISAV versus daily hospitalisation cost daily hospitalisation cost L-AMB + POSA, Cost source Resource use Cost, £ Resource use Cost, £ £ (% change) Monitoring costs (tests applied Monitoring costs (tests applied test costs) + administration test costs) + administration IV drug 27.2 days 18,189 15.5 days 4,978 13,210 (73) costs (IV treatment days IV costs (IV treatment days IV administration cost) administration cost) Oral drug 121.8 days 9,163 133.5 days 11,668 -2,504 (-27) Results of cost-minimisation analysis Total drug Formula: 149.0 days 27,352 149.0 days 16,646 10,706 (39) (total cost of L-AMB + POSA) – (total costs of ISAV) acquisition

Including loading dose as applicable see Table . Hospitalisation 27.2 days 14,235 19.3 days 10,100 4,134 (29)

Table 1. Model specifications Monitoring and 68.9 tests* 269 11.6 tests* 64 204 (76) administration Country UK Total cost 41,855 26,810 15,045 (36) Perspective National Health Service Values have been rounded. Time horizon Until end of treatment at resolution of infection or death *ISAV patients underwent 11.6 liver function tests; L-AMB + POSA patients underwent 22.3 of each of the following: urinalysis, serum creatinine tests and liver function tests, plus 2.0 instances of therapeutic drug monitoring. Comparators ISAV, L-AMB followed by POSA

Eligible population Adults receiving primary therapy for mucormycosis Scenario analyses

Costs 2016 GBP; source values adjusted where necessary using a UK consumer price index13 • When 100% of ISAV patients were initiated on either IV or oral therapy, ISAV remained cost saving relative to L-AMB + POSA; Figure 3.

Figure 3. Results of scenario analysis: variation in proportion of ISAV patients starting on oral or IV therapy

MODEL PARAMETERS 50,000 £ 40,000 Drug acquisition £, Cost factors: • Antifungal drug administration regimens are described in Table 2. Per-patient cost 30,000 £ of mucormycosis £ • Based on data from the VITAL study, 14.3% of patients receiving ISAV were assumed to start on oral therapy14. The remainder were assumed £, £, Monitoring and to start on IV therapy, and move to oral therapy when considered appropriate by the treating physician. treatment (£) 20,000 £, administration • 100% of L-AMB + POSA patients started on IV L-AMB, and moved to oral POSA when appropriate. £, Hospitalisation 10,000 £, • UK list prices were used for all drugs: rug acquisition −− L-AMB: £82.19 per 50 mg vial15. 0 −− POSA: £596.96 per 24-pack of 100 mg tablets16. L-AMB + POSA ISAV IV oral ISAV oral only −− ISAV: £599.28 per 14-pack of 100 mg capsules and £297.84 per 200 mg vial17. • Any drug wastage incurred through weight-based dosing of L-AMB – which is available in 50 mg vials that should not be stored for future Total cost £41,855 £27,402 £23,263 8 administration once partially used – was included in the calculation of total drug volume used. Values have been rounded.

Table 2. Drug regimens Amount Regimen Source ISAV CONCLUSIONS

Summary of Product Characteristics In this study: IV dose, mg/day 200* 1 X 200 mg (SmPC)11 • Use of isavuconazole for the treatment of mucormycosis in the UK was associated with cost savings relative to Mean IV duration of ISAV received by liposomal amphotericin B + posaconazole. IV duration, days 15.5† VITAL mucormycosis primary therapy • Isavuconazole remained cost saving regardless of whether patients started treatment with the IV or oral formulation. patients14 While isavuconazole appears to be a cost-effective option for the treatment of mucormycosis, further evaluation of treatment 11 Oral capsule dose, mg/day 200* 2 X 100 mg SmPC modalities and costs in other settings is warranted. Mean total duration of ISAV received by Oral duration, days 133.5† VITAL mucormycosis primary therapy patients minus IV duration14 REFERENCES L-AMB + POSA 1. Chamilos G et al. Delaying amphotericin B–based frontline therapy 14. Data-on-File Sheet: Isavuconazole VITAL study. Basilea Pharmaceutica, 2015 Median L-AMB dose received significantly increases mortality among patients with hematologic malignancy 15. British National Formulary. AmBisome. Available at: http://www.evidence. IV L-AMB dose, mg/day 5 X body weight‡ Single infusion by FungiScope™ cohort12 and who have zygomycosis. Clin Infect Dis. 2008;47:503–9. nhs.uk/formulary/bnf/current/5-infections/52-antifungal-drugs/523- recommended in guidelines18 2. Roden MM et al. Epidemiology and outcome of zygomycosis: A review of polyene-antifungals/amphotericin. Accessed: Feb 2016. 929 reported cases. Clin Infect Dis. 2005;41:634–53. 16. British National Formulary. Posaconazole. Available at: https://www. Mean AMB duration received by 3. Skiada A et al. Zygomycosis in Europe: Analysis of 230 cases accrued by evidence.nhs.uk/formulary/bnf/current/5-infections/52-antifungal- L-AMB duration, days 27.2 FungiScope™ cohort19 the registry of the European Confederation of Medical Mycology (ECMM) drugs/521-triazole-antifungals/posaconazole. Accessed: May 2016. Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol 17. Monthly Index of Medical Specialities. Cresemba. 2016. Available at: http:// Infect. 2011;12:1859–67. POSA tablet dose, mg/day 300§ 3 X 100 mg SmPCII20 www.mims.co.uk/drugs/infections-and-infestations/fungal-infections/ 4. Ceesay MM et al. Prospective evaluation of the cost of diagnosis and cresemba. Accessed: Jul 2016. treatment of invasive fungal disease in a cohort of adult haematology 18. Cornely OA et al. ESCMID and ECMM joint clinical guidelines for the Mean total duration of ISAV received by patients in the UK. J Antimicrob Chemother. 2015;70:1175–81. diagnosis and management of mucormycosis 2013. Clin Microbiol Infect. POSA duration, days 121.8 mucormycosis primary therapy patients 5. Ibrahim AS et al. Economic burden of mucormycosis in the Unites States: 2014;20(Suppl 3):5–26. can a vaccine be cost-effective? Med Mycol. 2009;47:592–600. minus duration of L-AMB14,19 19. Data-on-File Sheet: Isavuconazole fungiscope case control study. Basilea 6. Zilderberg MD et al. Hospital days, hospitalization costs, and inpatient Pharmaceutica, 2015. mortality among patients with mucormycosis: a retrospective analysis of US 20. Noxafil 100 mg gastro-resistant tablets (posaconazole) Summary of Product *If initiating treatment, loading dose on day 1 and 2 of 600 mg (3 x 200 mg); †Patients initiated on oral therapy received 0.0 days IV and 149.0 days oral therapy; ‡Based on weight hospital discharge data. BMC Infect Dis. 2014;14:310. distribution of VITAL mucormycosis primary therapy population (mean 75.87 kg, standard deviation 19.88 kg; §Loading dose on day 1 of 600 mg (2 x 300 mg); IIDose for refractory Characteristics. Merck Sharp & Dohme Limited. Jun 2015. Available at: invasive fungal infections used. 7. Bates DW et al. Mortality and costs of acute renal failure associated with http://www.medicines.org.uk/emc/medicine/28880. Accessed: Jun 2016. amphotericin B therapy. Clin Infect Dis. 2001;32:686–93. 21. Information Services Division Scotland. Scottish Health Service Costs. R130x 8. AmBisome 50 mg powder for solution for infusion (liposomal amphotericin Laboratory Services 2014-15. Available at: http://www.isdscotland.org/ B) Summary of Product Characteristics. Gilead Sciences Ltd. Feb 2015. Health-Topics/Finance/Costs/Detailed-Tables/Laboratory.asp. Accessed: Monitoring and administration Available at: https://www.medicines.org.uk/emc/medicine/1236. Accessed: May 2016. Jan 2016. 22. Mycology Reference Centre. Manchester. Available at: http://www. 21 • The costs of performing urinalysis, serum creatinine tests and liver function tests were included at £0.83 per test . Based on the AEs and 9. Cornely OA et al. Liposomal amphotericin B as initial therapy for invasive mycologymanchester.org/antifungal.php. Accessed: Jul 2016. precautions listed in each product’s SmPC8,11,20, it was assumed that patients treated with L-AMB + POSA required weekly monitoring with all mold infection: A randomized trial comparing a high–loading dose regimen 23. Ashbee HR et al. Therapeutic drug monitoring (TDM) of antifungal agents: tests while ISAV patients required fortnightly liver function testing. with standard dosing (AmBiLoad Trial). Clin Infect Dis. 2007;44:1289–97. guidelines from the British Society for Medical Mycology. J Antimicrob • Therapeutic drug monitoring, at £58.51 per sample22, was assumed to be required twice over the course of treatment for the L-AMB + POSA 10. Tacke D et al. Our 2014 approach to mucormycosis. Mycoses. 2014;57:519– Chemother. 2014;69(5):1162-76. regimen only, based on British Society for Medical Mycology recommendations23. 24. 24. van Zanten ARH et al. Importance of nondrug costs of intravenous antibiotic • A cost of £3.53 was applied per IV administration of ISAV or L-AMB, based on an administration time of 5 minutes and 51 seconds24, and 11. Cresemba 200 mg powder for concentrate for solution for infusion Summary therapy. Crit Care. 2003;7(6):R184–R190. nursing salaries as reported by the Personal Social Services Research Unit25. of Product Characteristics. Basilea Pharmaceutica International Ltd. Mar 25. Personal Social Services Research Unit. Unit Costs of Health and Social 2016. Available at: https://www.medicines.org.uk/emc/medicine/31236. Care 2015. Available from: http://www.pssru.ac.uk/project-pages/unit- Accessed: Jun 2016. costs/2015/index.php. Accessed: May 2016. Hospitalisations 12. Marty FM et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis. 2016;doi:10.1016/ 4 • Hospitalisation costs were calculated by multiplying a daily ward cost of £523.33 by the mean duration of initial hospitalisation in VITAL for S1473-3099(16)00071-2. ISAV (19.3 days), and the mean duration of AMB therapy in the FungiScope™ cohort for L-AMB + POSA (27.2 days). 13. Inflation Great Britain. Inflation.eu Worldwide Inflation Data. Available from: http://inflation.eu/inflation-rates/great-britain/inflation-great-britain.aspx. Scenario analyses Accessed: Feb 2016. • Two scenario analyses were performed: This study was sponsored by Basilea Pharmaceutica International Ltd., Basel, Switzerland. −− 100% of ISAV patients were initiated on IV therapy, before moving to oral therapy as appropriate. −− 100% of ISAV patients received oral therapy only. ISPOR 19th Annual European Congress, 29 October–2 November 2016. Austria Center Vienna, Vienna, Austria