Budesonide with multi-matrix technology as second-line treatment for ulcerative colitis: evaluation of long-term cost-effectiveness in the Netherlands

Abstract

Aims: Budesonide with multi-matrix technology (MMX) is an oral corticosteroid, shown to have high topical activity against ulcerative colitis (UC) while maintaining low systemic bioavailability with few adverse events. The aim of this study was to evaluate the cost-effectiveness of budesonide MMX versus commonly used corticosteroids, in the second-line treatment of active mild-to-moderate UC in the Netherlands.

Materials and methods: An eight-state Markov model with an 8 week cycle length captured remission, four distinct therapy stages, hospitalization, possible colectomy and mortality. Remission probability for budesonide MMX was based on the CORE-II study. Population characteristics were derived from the Dutch Inflammatory Bowel Disease South Limburg cohort (n = 598) and included patients with proctitis (39%), left-sided (42%) and extensive disease (19%). Comparators (topical budesonide foam and enema, oral budesonide and prednisolone) were selected based on current Dutch clinical practice. Treatment effects were evaluated by network meta-analysis using a Bayesian framework. Cost-effectiveness analysis was performed over a 5 year time horizon from a societal perspective, with costs, health-state and adverse event utilities derived from published sources. Outcomes were weighted by disease extent distribution and corresponding comparators.

Results: Budesonide MMX was associated with comparable quality-adjusted life year (QALY) gain versus foam and oral formulations (+0.01 QALYs) in the total UC population, whilst being cost-saving (EUR 366 per patient). Probabilistic sensitivity analysis evaluated an 86.6% probability of budesonide MMX being dominant (cost-saving with QALY gain) versus these comparators. Exploratory analysis showed similar findings versus prednisolone.

Limitations: Differing definitions of trial end-points and remission across trials meant indirect comparison was not ideal. However, in the absence of head-to-head clinical data, these comparisons are reasonable alternatives and currently offer the only comparison of second-line UC treatments.

Conclusions: In the present analysis, budesonide MMX was shown to be cost-effective versus comparators in the total UC population, for the second-line treatment of active mild-to-moderate UC in the Netherlands.

Keywords:

• Cost-effectiveness
• ulcerative colitis
• corticosteroid
• budesonide
• prednisolone

JEL classification codes:

• C51
• I19

Introduction

Ulcerative colitis (UC) is a chronic, ulcer-causing inflammatory bowel disease (IBD) that affects millions of people worldwide¹. UC is the most common IBD and affects more than half of all IBD sufferers in the US². The global incidence and prevalence of the disease is rising, with the highest incidences reported in northern Europe (24.3 cases per 100,000), Canada (19.2 cases per 100,000) and Australia (17.4 cases per 100,000)^3–5. Prevalence rates are also highest in Europe, with 505 cases per 100,000 people⁶. Prevalence of the disease in the Netherlands was estimated to be 7.7 per 10,000 people in populations from 1991–2003, while prevalence of IBD in Europe has been estimated at 432 per 100,000 people in 2010^7,8. IBD and UC represent a significant healthcare burden, with an annual direct healthcare cost for IBD in Europe estimated to be EUR 4.6–5.6 billion⁷. Indirect costs for IBD manifest as lack of productivity through unemployment (8% of European patients), sick leave (average of 3–6 weeks annually), and permanent work disability (two-fold increased)^7,9. New treatments are therefore crucial to ease the economic burden of UC.

UC is characterized by symptoms confined to the large intestine (colon) and rectum, such as diarrhea with blood or pus and abdominal discomfort¹⁰. Symptoms can last for several years, but the duration of outbreaks varies between patients and are often interspersed by periods of remission¹⁰. The disease can present at any age but is typically diagnosed (via colonoscopy) in patients under 30 years of age¹⁰. The goal of therapy is to improve patient quality of life by inducing and maintaining remission from active UC¹⁰. Treatment guidelines advise oral or rectal administration of 5-aminosalicylic acids (5-ASAs) for first-line therapy of mild-to-moderate cases, which is associated with remission rates of up to 50%^11–13. However, more severe forms of UC require more potent therapy, and second-line treatment with corticosteroids is generally recommended^13,14. Prevalent second-line treatments include prednisolone and budesonide. Although prednisolone is more commonly used and often effective at inducing remission, its adverse event profile and lack of long-term clinical data mean it should not be used for maintenance therapy^14,15. Additionally, adverse events associated with prednisolone have been linked with reduced patient adherence and increased healthcare and economic burden¹⁶. Oral budesonide, which utilizes a pH-dependent delivery mechanism, is well tolerated but fails to target the left colon, with release primarily at the distal ileum and proximal colon, making it less suitable for the treatment of UC^17,18. Topical corticosteroids, such as budesonide foam and enema formulations, offer improved tolerability but also lack the ability to target the entire colon, and are generally associated with lower remission rates^19,20. Moreover, these therapies are associated with lower patient adherence, owing to their multiple times daily, rectal-only administration²¹.

An oral, once daily formulation of budesonide with multi-matrix technology (MMX) was launched in 2013. It is designed to induce remission in patients with active mild-to-moderate UC, with release of budesonide at a controlled rate throughout the colon^22,23. The safety and efficacy of budesonide MMX versus placebo had been demonstrated in two randomized controlled trials (RCTs), CORE-I and CORE-II. Budesonide MMX once daily 9 mg formulations were associated with higher remission rates than placebo over 8 weeks of therapy in patients with active mild-to-moderate UC. In addition, budesonide MMX was shown to be well tolerated with few adverse events, in line with reports on other budesonide formulations^24,25. This data is consistent with a role for budesonide MMX as a first-choice second-line treatment for active mild-to-moderate UC ahead of oral prednisolone^18,26.

As budesonide MMX was recently approved for use in the Netherlands, the aim of the present analysis was to evaluate the cost-effectiveness of budesonide MMX versus commonly used corticosteroids for the second-line treatment of active mild-to-moderate UC in the Netherlands.

Methods

Modeling analysis

An eight-state Markov model was developed to reflect Dutch clinical practice, following Dutch guidelines for economic evaluations in healthcare (Figure 1)²⁷. The model has a cycle length of 8 weeks which is consistent with most steroids’ maximum treatment duration. Remission was assessed at 8 weeks in most of the clinical trials used in the model. There is no current supportive evidence that budesonide MMX is used for a longer or shorter time than 8 weeks in clinical practice, therefore the cycle length seems appropriate to characterize steroid treatment course. The model starts with second-line initiation of corticosteroid treatment for a cohort of patients with active disease (steroid treatment in Figure 1). From this health state, patients can go into remission, improve and transfer to 5-ASA maintenance therapy or worsen, meaning further treatments (immunomodulators and infliximab) are required. Disease progression eventually leads to hospitalization and colectomy. Three types of health states were used in the structure: tunnel states meaning that patients cannot stay in the health state more than one cycle (steroid treatment, third- and fourth-line treatment, hospital), semi-absorbing states allowing patients to stay more than one cycle in the same state or transition to another state (remission, 5-ASA maintenance therapy, post-surgery) and absorbing states from which no transition is allowed (death). Consequently, staying in the corticosteroid treatment state for more than one cycle is not allowed as the cycle duration represents a full steroid treatment course. As budesonide MMX is used only in induction and not in maintenance, re-treatment with steroids is allowed after relapse as indicated in Figure 1 (transition between remission and steroid treatment). Treatment duration of immunomodulators in the third line was simulated by using three sub-tunnel states. Model outputs were reported in quality of life benefits (measured in quality-adjusted life years [QALYs]) and cost breakdowns (expressed in 2016 Euros [EUR]).

Figure 1. Markov model of ulcerative colitis treatment progression. Abbreviation. 5-ASA, 5-aminosalicylic acid.

Comparators to budesonide MMX were chosen based on Dutch clinical practice in accordance with standard treatment guidelines for UC in the Netherlands and Europe, as well as guidance laid out by several Dutch physicians^28,29. Budesonide foam was used as the comparator for proctitis and left-sided UC, with oral budesonide as the comparator for extensive UC. Outcomes of QALYs and costs in the comparator arm were weighted according to the distribution of disease extent in the patient population. All treatment effects were defined in terms of remission, shown as the transition probability from any treatment stage to “remission” in the Markov model (Figure 1), and were derived by network meta-analysis (NMA) (Supplemental Appendix 1).

The NMA was performed using a Bayesian framework, in accordance with the standard Bayesian Markov Chain Monte Carlo methods outlined by NICE technical support documents³⁰. Eligible studies were defined by inclusion of RCTs and references to remission, with ineligible studies excluded for lack of these features. The proportion achieving remission was defined as a binary outcome and analyses were performed using binomial fixed (FE) and random effects (RE) models. Placebo was used as the reference treatment, as it was ubiquitous in all but one trial. Monte Carlo simulations were fitted using JAGS software, with the Markov chain Monte Carlo estimator being run for 50,000 burn-in simulations and monitored for a further 250,000. Inconsistencies between indirect and direct evidence were checked analytically by node splitting. Probabilities of remission were ranked by combining odds ratios of each regimen (relative to placebo) with the average estimate of the odds of response (with placebo) across studies. The probability of remission at 8 weeks was therefore defined as: $$\mathit{\text{odds}}=\frac{p}{1-p}$$ $$p=\frac{\mathit{\text{odds}}}{1+\mathit{\text{odds}}}$$

Prednisolone could not be included in the NMA because literature trials were not randomized. Instead, its remission rate was estimated by dividing the reported remission rate from Lennard-Jones et al. (68.42%) by the remission rate of its placebo (16.70%), then multiplying this by the remission rate of the placebo from the CORE-II study (4.5%)^25,31. The resulting probabilities of remission at 8 weeks are displayed in Table 1.

Table 1. Network meta-analysis results.

Compound	Odds ratio of budesonide MMX vs. comparator (CI)	Probability of remission at 8 weeks (%)	Difference (%)	Studies used
Budesonide MMX	–	17.40	–	^24^,^25
Budesonide enema	1.1 (0.49–2.4)	16.07	+1.33	^43
Budesonide foam	1.4 (0.67–2.9)	13.08	+4.32	^44^,^46^,^68
Oral budesonide	1.4 (0.65–3.0)	13.08	+4.32	^24^,^25
Prednisolone^a	–	18.44	−1.04	^25^,^31

Abbreviation. CI, confidence interval.

^aPrednisolone probability was not calculated by NMA, rather a unique method outlined in Modeling analysis.

Remission probabilities for 5-ASA maintenance therapy (37.2%), third-line azathioprine (53.0%), and fourth-line infliximab (33.9%) were estimated using data from published sources^32–34. Probabilities for relapse (10.68%), severe disease (1.64%), surgery (7.82%) and death (0.13%) were also based on published data^35–39 (Table 2). This data was converted to an 8 week cycle length according to the equations by Fleurence and Hollenbeak⁴⁰. Treatment specific probabilities for adverse events were taken from published sources^25,41–46.

Table 2. Transition matrix with probabilities shared between interventions.

	Steroid	BSC	3rd line	4th line	Hospital	Remission	Post-surgery	Death
Steroid	–	^a	1.64%	–	–	See Table 1	–	0.13%
BSC	–	61.03%	1.64%	–	–	37.20%	–	0.13%
3rd line	–	–	–	–	–	53.00%	–	0.13%
4th line	–	–	–	–	–	33.90%	–	0.13%
Hospital	–	–	–	–	–	92.05%	7.82%	0.13%
Remission	10.68%	–	–	–	–	89.19%	–	0.13%
Post-surgery	–	–	–	–	–	–	99.87%	0.13%
Death	–	–	–	–	–	–	–	100%

Abbreviation: BSC, Best Supportive Care.

^aTransition probability from steroid to BSC is 100% – 1.64% – 0.13% – probability of remission according to Table 1.

Costs and quality of life utilities

All costs were expressed in 2016 Euros (EUR). Pharmacy costs were taken from published 2016 prices inclusive of value added tax in the Netherlands⁴⁷ (Table 3). Drug delivery costs were applied as recommended in the Dutch guidelines for economic evaluation in healthcare⁴⁸. Treatment regimens were based on those used in published studies for all therapies: budesonide MMX and oral budesonide (CORE-II²⁵), budesonide foam (Sandborn et al.⁴⁶), budesonide enema (Hanauer et al.⁴³), prednisolone (European Consensus⁹), 5-ASA maintenance therapy (Sandborn et al.⁴⁹), azathioprine/further prednisolone (Ardizzone et al.³³) and infliximab (Rutgeerts et al.³⁴).

Table 3. Pharmaceutical unit costs.

Drug	Price VAT^a	Number of units
Primary drug
Budesonide MMX 9 mg	48.70€	15 tablets
Budesonide foam 2 mg/dose 14 doses per vial	84.69€	1 vial
Budesonide enema 2.3 mg +115 mL solvent	105.35€	15 tablets
Budesonide oral MGA 3 mg	47.86€	45 capsules
Prednisolone tablet 5 mg	0.98€	30 tablets
BSC
Mesalazine tablet MGA 1.2 g	19.63€	18.75 tablets
Subsequent treatment (3rd and 4th line)
Infliximab infusion powder 100 mg	305.42€	1 flask
Azathioprine tablet 50 mg	8.92€	45 tablets
Prednisone tablet 5 mg	1.58€	30 tablets

Abbreviations: VAT, Value Added Tax included; MMX, Multi-Matrix; MGA, Met Gereguleerde Afgifte (controlled-release); BSC, Best Supportive Care.

^aDelivery cost not included (first: 12.00€, subsequent: 6.00€).

Additional healthcare costs were categorized into inpatient care (for cases where surgery was required, covering colectomy and post-surgery recovery) and outpatient care (covering physician visits and diagnostic procedures). Unit costs were estimated based on an economic evaluation of IBD in the Netherlands, and from the costing manual of the Institute for Medical Technology Assessment^48,50 (Table 4). The adverse event profiles of budesonide MMX and comparators were conservatively assumed to be similar, despite clinical trial evidence indicating a reduction in associated adverse events with budesonide MMX treatment. Furthermore, no additional costs were included for adverse events associated with budesonide MMX or comparator treatment as it is assumed that no healthcare resource is required for the management of adverse events related to budesonide MMX and comparators according to three Dutch physicians. Costs for adverse effects associated with third- and fourth-line treatments were based on those reported by Blommestein et al., inflated with consumer price index^51,52. Indirect costs were estimated using a human capital approach (workplace absenteeism) and based on a Dutch study on UC patients³⁶. Based on this source, model inputs for employed patients with UC were absent for 0.21 days of paid work and 0.14 days of unpaid work per 8 week cycle³⁶. Loss of productivity per day was estimated at EUR 207.52 for paid work and EUR 83.58 for unpaid work⁴⁸.

Table 4. Unit costs of additional healthcare.

Resource	Unit cost	Source
Outpatient
Physician visit
General hospital	70.10€	^50
University medical center	141.29€	^50
Weighted average	134.17€^a	^50
IBD or stoma nurse visit	48.26€	^50
Diagnostic procedure
Colonoscopy	372.82€	^50
CT scan	165.87€	^50
MRI scan	203.83€	^50
Ultrasound	40.85€	^50
Gastroscopy	210.91€	^48
Inpatient
Hospital day
General hospital	476.45€	^50
University medical center	629.78€	^50
Weighted average	614.45€^a	^50
Surgery	1871.73€	^50
Ileostomy supplies	352.44€^b	^50
Transport
Taxi	43.14€	^48

All cost values in 2016 Euros.

^aIn 2014, there were eight university hospitals and 72 general hospitals according to CBS statline.

^bBased on 975€ for a 3 month period converted to a 1 month period.

Health state utility associated with corticosteroid treatment was estimated to be 0.59 QALYs by Prenzler et al., with health state utility associated with 5-ASA maintenance therapy assumed to be the same (Table 5)⁵³. Utilities for subsequent health states (third- and fourth-line treatment, hospitalization, remission, post-surgery and death) were sourced from a publication by Arseneau et al.⁵⁴. Disutilities for hirsutism, insomnia, acne, fever, nausea, rash and fatigue experienced during third- and fourth-line treatment states were obtained from published studies (Supplemental Appendix 2)^55–58. These disutilities were multiplied by 0.75 to give a more conservative estimate when combined. Disutilities for all other adverse events during third- and fourth-line treatment states were assumed to be 0.02 with no adjustment for combinations.

Table 5. Utility inputs.

Health state	Utility	Studies used
Steroid treatment	0.59	^53
BSC	0.59	^53
3rd line	0.32	^54
4th line	0.32	^54
Hospitalization	0.32	^54
Remission	0.79	^54
Post-surgery	0.68	^54
Death	0.00	^54

Abbreviation: BSC, Best Supportive Care.

Patient population

The population comprised patients with mild-to-moderate ulcerative colitis with characteristics based on the Dutch Inflammatory Bowel Disease South Limburg cohort (n = 598), diagnosed between 2006 and 2010³⁷. The population was 49.7% male, with a mean age of 48.2 years and a mean weight of 77 kg. Disease extents at diagnosis were 38.8% proctitis, 41.6% left-sided UC and 19.6% extensive UC.

Time horizon and discounting

The time horizon was set at 5 years, with a cycle length of 8 weeks, matching the duration of treatment for budesonide MMX in induction used in the CORE-I and CORE-II trials^24,25. Discounting was applied at annual rates of 4% and 1.5% for future costs and clinical benefits, respectively, in line with the guideline for economic evaluation in healthcare in the Netherlands²⁷.

Sensitivity and scenario analyses

One-way, deterministic sensitivity analysis was performed to evaluate the effect of variation of each model input parameter on budesonide MMX cost-effectiveness, including the relative effectiveness of budesonide MMX versus other corticosteroids, transition probabilities, unit costs, resource use and disutilities. Additionally, probabilistic sensitivity analysis with 1000 replications was performed by simultaneously varying these parameters. Comparators for the sensitivity analysis were budesonide foam for extensive and left-sided disease, and oral budesonide for proctitis. For both one-way and probabilistic sensitivity analyses, each model input was varied according to upper and lower estimates (using 95% confidence interval [CI] bounds, or when these are unavailable, ±20% and ±10% of the average value). Distributions associated with each parameter were based on the recommendations by Briggs et al.⁵⁹.

All clinically plausible combinations of comparators and disease extents were analyzed in scenario analyses to evaluate the impact of using different comparators for varying disease extents relative to the base case. Eight different combinations were evaluated, with budesonide foam and enema used as comparators for proctitis and left-sided UC, oral budesonide for left-sided and extensive UC, and prednisolone for extensive UC only. All possible combinations of these treatments for the specified disease extent were explored.

Results

Base case analysis

Budesonide MMX treatment was associated with a comparable improvement in quality of life versus comparators in a Dutch patient mix, gaining approximately 0.01 QALYs versus commonly used treatments (Table 6). Clinical benefits were mainly driven by higher remission rates with budesonide MMX than with other second-line therapies. As treatment effects of corticosteroids were applied for only one cycle, the slight improvement in QALYs result mostly from the difference in 8 week remission probabilities between comparators. Budesonide MMX was associated with mean cost savings of EUR 366 per patient versus comparators. This was primarily due to the lower cost of the drug itself, saving EUR 288 per patient versus comparators. Additional costs originating from 5-ASA maintenance therapy and progression health states (EUR -50), supplementary healthcare (EUR -14) and indirect costs (EUR -14) were all lower with budesonide MMX, but comparable to current treatments (Table 3).

Table 6. Budesonide MMX and comparator cost-effectiveness.

Aspect	Budesonide MMX	Comparators	Difference
Primary drug cost	651	939	−288
Additional drug cost	1227	1277	−50
Healthcare cost	3831	3845	−14
Indirect cost	524	538	−14
Total cost	6233	6599	−366
Total QALYs gained	3.471	3.462	+0.009

Abbreviation. QALYs, quality-adjusted life years.

All cost values in 2016 Euros.

Deterministic sensitivity analysis

Budesonide MMX showed comparable improvements to quality of life and remained less costly across all one-way sensitivity analyses (Table 7). The largest variations in costs and QALYs were seen with the application of the upper and lower limits (95% CI) for remission probability with budesonide foam, ranging from EUR −424 to EUR −261, respectively. Quality of life benefit with budesonide MMX dropped slightly when the upper limit for remission probability of budesonide foam was applied but remained comparable. Conversely, budesonide MMX was projected to be notably more effective than budesonide foam when applying the lower limit for remission probability for the latter treatment. Applying adverse event costs for corticosteroids only slightly reduced the cost savings associated with budesonide MMX, and it remained dominant versus comparators.

Table 7. Deterministic sensitivity analysis inputs and outcomes.

Parameter	Lower and upper estimates	Cost (EUR)			QALYs			ICER (EUR per QALY gained)
		Budesonide MMX	Comparator	Difference	Budesonide MMX	Comparator	Difference
Base case	–	6233	6599	−366	3.471	3.462	0.009	Budesonide MMX dominant
Risk of relapse	±20%	5775	6107	−332	3.506	3.498	0.009	Budesonide MMX dominant
		6650	7045	−395	3.438	3.429	0.010	Budesonide MMX dominant
Proportion of patients requiring hospitalization and surgery	±20%	6229	6595	−366	3.471	3.462	0.009	Budesonide MMX dominant
		6237	6602	−366	3.471	3.461	0.009	Budesonide MMX dominant
Proportion of patients with severe disease	±20%	6107	6470	−363	3.476	3.467	0.009	Budesonide MMX dominant
		6357	6725	−368	3.466	3.456	0.009	Budesonide MMX dominant
Mortality	±20%	6256	6622	−367	3.486	3.476	0.009	Budesonide MMX dominant
		6211	6575	−364	3.456	3.447	0.009	Budesonide MMX dominant
OR versus oral budesonide	95% CI	6233	6524	−291	3.471	3.471	0.000	Budesonide MMX dominant
		6233	6640	−407	3.471	3.457	0.014	Budesonide MMX dominant
OR versus budesonide foam	95% CI	6233	6494	−261	3.471	3.475	−0.004	Budesonide MMX less costly, less effective
		6233	6658	−424	3.471	3.454	0.017	Budesonide MMX dominant
Adverse event costs for corticosteroids	1 day of hospitalization (EUR 614.45)	6368	6638	−270	3.471	3.462	0.009	Budesonide MMX dominant
Indirect costs	±20%	6128	6491	−363	3.471	3.462	0.009	Budesonide MMX dominant
		6338	6706	−368	3.471	3.462	0.009	Budesonide MMX dominant
Utilities	±10%	6233	6599	−366	3.124	3.115	0.008	Budesonide MMX dominant
		6233	6599	−366	3.818	3.808	0.010	Budesonide MMX dominant

Abbreviations. EUR, 2016 Euros; ICER, incremental cost-effectiveness ratio; OR, odds ratio; QALYs, quality-adjusted life years.

Probabilistic sensitivity analysis

Probabilistic sensitivity analysis showed that budesonide MMX treatment was associated with a comparable mean improvement (+0.01 QALYs, approximately) and mean cost savings of EUR 354 per patient versus comparators. Budesonide MMX was associated with a mean of 3.477 QALYs (2.870–3.939 QALYs with 95% CI) and a mean cost of EUR 6248 (EUR 5075–7680, 95% CI), while comparators were associated with a mean of 3.468 QALYs (2.868–3.935 QALYs, 95% CI) and a mean cost of EUR 6601 (EUR 5364–8012, 95% CI) over the 5 year time horizon. A majority of iterations (86.6%) showed budesonide MMX to be dominant to comparators, with comparable improvements in quality of life but at a lower cost (Figure 2).

Figure 2. Cost-effectiveness plane for budesonide MMX versus comparator. Abbreviation. QALYs, quality-adjusted life years. Incremental costs displayed in 2016 Euros.

Scenario analyses

Budesonide MMX continued to show comparable, or slightly improved, QALYs at a lower cost versus comparators across various scenario analyses, with only two comparator combinations causing a change in outcomes (Table 8). Budesonide MMX was associated with an improvement of 0.015 QALYs but a higher cost of EUR 87 per patient against a combination of budesonide enema for proctitis, oral budesonide for left-sided UC and prednisolone for extensive UC. This translated to an incremental cost-effectiveness ratio (ICER) of EUR 5692 per QALY gained for budesonide MMX versus these comparators. Against a combination of budesonide foam for proctitis, oral budesonide for left-sided UC and prednisolone for extensive UC, budesonide MMX was associated with an improvement of 0.016 QALYs but a higher cost of EUR 47 per patient. The corresponding ICER of budesonide MMX versus these comparators was EUR 2848 per QALY gained.

Table 8. Scenario analysis with alternative comparator combinations.

Treatment regimen			Cost (EUR)	Cost difference (EUR)	QALYs	QALY difference	ICER (EUR per QALY gained)
Proctitis	Left-sided UC	Extensive UC
Budesonide MMX			6233	–	3.471	–	–
BE	OB	OP	6146	+87	3.455	+0.015	5692
BE	OB	OB	6352	−119	3.462	+0.009	Budesonide MMX dominant
BE	BE	OB	6474	−241	3.465	+0.005	Budesonide MMX dominant
BE	BE	OP	6268	−35	3.459	+0.012	Budesonide MMX dominant
BF	OB	OP	6186	+47	3.454	+0.016	2848
BF	OB	OB	6392	−159	3.460	+0.010	Budesonide MMX dominant
BF	BF	OB	6599	−366	3.462	+0.009	Budesonide MMX dominant
BF	BF	OP	6393	−160	3.455	+0.015	Budesonide MMX dominant

Abbreviations. BE, budesonide enema; BF, budesonide foam; EUR, 2016 Euros; ICER, incremental cost-effectiveness ratio; OB, oral budesonide; OP, oral prednisolone; QALYs, quality-adjusted life years.

Discussion

The present modeling analysis evaluated the cost-effectiveness of budesonide MMX for the treatment of UC versus commonly used comparators in the Netherlands. Budesonide MMX was projected to reduce costs from healthcare payer and societal perspectives over a 5 year time horizon, whilst maintaining patients’ quality of life in the majority of analyses. Base case analysis estimated a mean cost saving of EUR 366 per patient with budesonide MMX over comparators, with a comparable improvement in quality-adjusted life years (+0.009 QALYs). Sensitivity analysis of the model design and input parameter values showed robust results in a majority of analyses. Assumptions regarding parameter values for comparator remission rates resulted in a less costly, less effective outcome.

Previous studies have evaluated similar extended-release oral medications for UC. Mesalazine MMX, a 5-ASA utilizing the same multi-matrix release technology, was associated with a higher rate of remission versus placebo with no increase in adverse events, similar to budesonide MMX^49,60–62. Taken together with the CORE trials, the data suggests that MMX is very well tolerated^24,25. In a UK analysis, mesalazine MMX was shown to be cost-effective versus oral mesalazine from a healthcare payer perspective, with an ICER of EUR 899 per QALY gained⁶³. In the present analysis, budesonide MMX was comparable in terms of quality of life benefits but less costly versus all comparators (including oral budesonide) in the base case and all but one sensitivity analysis. Economic evaluation has provided evidence of value for MMX technology in both cases. However, differences in setting, comparators and perspective make any comparison between the two studies challenging. In a Polish analysis, budesonide MMX was shown to be dominant versus systemic oral corticosteroids, with cost savings of US$1505.86 and 0.47 QALY gain over a life-time horizon⁶⁴. The authors considered similar efficacy in terms of remission, but a better safety profile and bioavailability of budesonide MMX compared to systemic corticosteroids. Hence, the favorable safety profile of budesonide MMX helps to avoid severe steroid related adverse events while reducing costs and slightly improving QALYs which is consistent with the present analysis. However, differences in comparators and time horizon make comparison of the QALY gains in the two studies challenging. In a recent cost-minimization analysis submitted to the Scottish Medicines Consortium (SMC), budesonide MMX led to cost saving of £57 versus a weighted average comparator of other budesonide treatments over a time horizon of 1 year, which seems consistent with the present analysis⁶⁵.

A potential limitation of the present analysis was the paucity of clinical data on prednisolone for the NMA, which forms the basis of the present analysis. Budesonide MMX was shown to have a higher probability of remission (17.4%) than budesonide foam (13.1%), enema (16.1%) and oral formulations (13.1%), but the probability for prednisolone (18.4%) was estimated via a different method, as clinical trials did not fit the NMA criteria (Table 1). UC studies also often contain differing definitions of trial end-points, particularly regarding remission classification, which can make comparison of direct and indirect data problematic⁶⁶. However, in absence of suitable RCTs for prednisolone and head-to-head trials for all comparators, NMA data is a reasonable alternative (being endorsed by NICE in the UK) and currently offers the only comparison of remission probabilities across multiple second-line treatments for UC³⁰. While the NMA did not show a statistically significant difference in remission rates between budesonide MMX and comparators, conducting a cost-effectiveness analysis is still relevant to explore the QALY gains related to the better safety profile of budesonide MMX compared to other corticosteroids.

The shortcomings of current treatments have been widely reported and include multiple daily dosing regimens, rectal administrations and associated adverse events. These can all reduce patient adherence in routine clinical practice, particularly when the disease itself is inactive¹⁶. This increases the risk of relapse and associated economic burden. Budesonide MMX may therefore offer an attractive alternative for patients, with a once daily oral regimen and fewer adverse events, particularly in comparison with prednisolone, the current first-choice second-line medication¹⁴. The present health economic analysis can be considered conservative in that it did not capture the potential benefits of improved tolerability and patient adherence with budesonide MMX relative to other second-line treatments¹⁶. In routine clinical practice, patients may prefer a therapy like budesonide MMX that offers a reduction in associated adverse events, potentially increasing adherence¹⁴. Incorporating these factors into the model inputs could potentially yield further clinical benefits with budesonide MMX versus comparators. Fewer adverse events associated with corticosteroid treatment for UC would also likely reduce clinical dependence and healthcare burden. However, economic assessment of such hypotheses requires further real-world evidence of budesonide MMX patient adherence versus comparators.

Conclusions

Budesonide MMX was estimated to be cost saving versus other commonly used second-line treatments for active mild-to-moderate UC in the Netherlands, reducing costs from a societal perspective and displaying comparable patient quality of life improvements, while offering reduced adverse events compared with current first-choice second-line treatment prednisolone. Further long-term and head-to-head trials are required to assess its place in the treatment paradigm and potential role as a maintenance therapy, but its current 9 mg formulation appears well suited as an alternative second-line induction therapy for UC in the Dutch setting.

Transparency

Declaration of funding

HEVA-HEOR received funding from Ferring Pharmaceuticals for analyzing the cost-effectiveness of budesonide MMX in the Netherlands, including the production of a technical report. Ossian Health Economics and Communications received funding from HEVA-HEOR for the writing of the present manuscript. Employees from HEVA-HEOR, Ossian Health Economics and Communications, and Ferring Pharmaceuticals were involved in reviewing and revising aspects of this manuscript.

Author contributions: A.G. and S.R. were involved in conception and design of the cost-effectiveness analysis, and drafting a technical report that was used as the basis of the final manuscript. O.G., Y.L.Y.S. and J.K. provided feedback on several drafts of the manuscript.

Declaration of financial/other relationships

A.G. and S.R. have disclosed that they are employees of HEVA-HEOR. O.G. and Y.L.Y.S. have disclosed that they are employees of Ferring Pharmaceuticals. J.K. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article.

JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgements

Audrey Petitjean (HEVA-HEOR) was involved in the review of the technical report of the analysis, on which the manuscript is based. Michel Cucherat (University Lyon I) was involved in conducting the NMA used in the analysis, on which the manuscript is based. Sam Malkin and William Valentine (Ossian Health Economics and Communications) were involved in writing of the present manuscript.