Positioning Biosimilar Ustekinumab Early Reduces Burden on Spain's National Health System

Patients with moderate to severe Crohn disease in Spain could experience improved outcomes and lower treatment costs when biosimilar ustekinumab is used as a first-line therapy rather than reserved for later lines, according to a cost-effectiveness analysis published in PharmacoEconomics - Open.¹

Early use of ustekinumab biosimilars in Spain shows cost-effective Crohn disease care, boosting QALYs and cutting NHS spend—insights for Europe. |Image credit: mi_viri - stock.adobe.com

Crohn disease imposes a considerable economic burden on national health systems, with annual costs per patient in Spain reported to range from €11,000 to €18,000—differences driven largely by pharmacological expenses rather than other direct health care costs.

A 2025 review published in United European Gastroenterology Journal offered important context for why this economic question matters at the bedside.² Reviewers noted that despite ustekinumab's established efficacy in moderate to severe Crohn disease, its high acquisition cost had historically confined it to later lines of therapy, typically after patients experienced treatment failure on 1 or more antitumor necrosis factor agents. The availability of biosimilar versions, the review argued, carries the potential to shift that calculus—reducing financial barriers and enabling earlier use in the treatment algorithm, where evidence increasingly supports more aggressive initial intervention. Biosimilar ustekinumab candidates have demonstrated comparable efficacy, safety, pharmacokinetics, and immunogenicity to the reference product in studies conducted to date, though the review noted that real-world data specific to Crohn disease remain limited.

As biologic therapies have become the cornerstone of moderate to severe disease management, appropriate sequencing has grown more consequential both clinically and financially.¹ The 2024 ECCO guidelines positioned ustekinumab as a first-line induction and maintenance option for moderate to severe Crohn disease, but until recently, the high acquisition cost of reference ustekinumab limited its appeal as an early-line choice in Spain. The entry of biosimilar ustekinumab (bsUST) into the Spanish market in mid-2024, at an assumed 30% price reduction vs the reference product, prompted investigators to formally evaluate whether repositioning bsUST to the front of treatment sequences would be cost-effective from the perspective of Spain's National Healthcare System (NHS).

Markov Model Evaluated Seven Biosimilar-Inclusive Treatment Sequences

Investigators developed a Markov model with 2-week cycles and a lifetime horizon to compare 7 treatment sequences in adults with moderate to severe Crohn disease. Health states included active disease, response, remission, surgery, and death. Funnel states simulated induction periods, and patients who lost response transitioned to the next treatment line after a 3-month delay to reflect real-world clinical practice. Surgery was considered only after 4 pharmacological lines had been exhausted.

The sequences incorporated biosimilar adalimumab (bsADA), biosimilar intravenous infliximab (bsIFX), bsUST, risankizumab, upadacitinib, and vedolizumab. Sequence 1—bsADA followed by bsUST, upadacitinib, risankizumab, and surgery—served as the reference comparator because it carried the lowest total lifetime cost at €157,224 per patient.

Patient characteristics were drawn from the UNITI-2 trial (NCT01369329) population and validated against Spanish real-world data from the ENEIDA registry. The modeled cohort had a mean age of 39.2 years, was 46.7% women, and had a mean weight of 73.4 kg. Clinical efficacy data were sourced from a published network meta-analysis, with maintenance efficacy for biologic-experienced patients drawn from pivotal trials. A willingness-to-pay (WTP) threshold of €27,000 per quality-adjusted life year (QALY), a benchmark commonly referenced in Spain, was used to assess cost-effectiveness.

Only One Sequence Met Spain's Cost-Effectiveness Threshold

Of the 7 sequences evaluated, only sequence 2—which placed bsUST first, followed by bsADA, upadacitinib, risankizumab, and surgery—met the €27,000/QALY threshold. That sequence yielded an incremental cost-effectiveness ratio (ICER) of €8,672.6/QALY compared with the reference, representing a gain of 0.36 QALYs at an incremental cost of €3080 per patient. All other sequences exceeded the threshold, with ICERs ranging from €42,594/QALY to €372,446/QALY.

Within the base case, the first treatment line in sequence 2 had a mean duration of 3.9 years, compared with 2.2 to 3.3 years in the remaining sequences. Time to surgery ranged from 7.9 years in sequences 2 and 4 to 9 years in sequences 6 and 7.

Probabilistic sensitivity analysis, based on 10,000 Monte Carlo simulations, confirmed the robustness of these findings: sequence 2 was identified as cost-effective in 98.03% of simulations at the €27,000/QALY threshold. Deterministic sensitivity analysis indicated that the ICER was most sensitive to patient weight, first-line pharmacological costs, and the probability of achieving remission during maintenance.

In an alternative reference-analysis setting with sequence 2 as the comparator, all remaining sequences were either dominated or associated with QALY losses, thereby reinforcing the economic case for early bsUST placement.

Cost Savings Driven by Efficacy and Lower Acquisition Costs

The investigators attributed sequence 2's favorable profile to a combination of bsUST's clinical durability and its lower biosimilar price point. "Positioning bsUST as a first line of treatment appears to be cost effective and an efficient alternative from the NHS perspective in Spain," they wrote, adding that "bsUST may significantly impact Crohn disease management in Spain, improving patient access due to its lower drug acquisition costs."

The study carried several limitations. Markov models assume transition probabilities depend only on the current health state, which may not fully capture the influence of prior treatment history. Efficacy for third- and fourth-line treatments was estimated by carrying forward second-line biologic-experienced data, a conservative approach driven by limited available data. The number of analyzed sequences, while validated by expert gastroenterologists, did not capture all possible treatment pathways. Additionally, the existence of a dual pricing system in Spain, with confidential reimbursement prices negotiated separately from official list prices, means that actual per-sequence costs in practice could differ from those modeled.

References

1. Rodríguez-Lago I, Peinado-Fabregat JI, Guigini M, Cerezales M, Ibáñez F, Crespo C, Barreiro-de Acosta M. Cost-effectiveness analysis of sequential treatment strategies for moderate to severe Crohn's disease in Spain: where should biosimilar ustekinumab be positioned? PharmacoEconomics Open. 2026;10:557-566. doi:10.1007/s41669-026-00642-1
2. D'Amico F, Bencardino S, Gonçalves A, et al. Unlocking hope: the future of ustekinumab biosimilars in Crohn's disease treatment. United European Gastroenterol J. 2025;13(2):186-200. doi:10.1002/ueg2.12682