Natalizumab Biosimilar Shows Limited Cost-Effectiveness in MS

A systematic review and economic model commissioned by the National Institute for Health and Care Excellence (NICE) and published in Health Technology Assessment found no randomized trials evaluating natalizumab (Tysabri; Biogen) or its biosimilar, natalizumab-sztn (Tyruko; Sandoz), specifically in patients with highly active relapsing-remitting multiple sclerosis (HARRMS).¹ The assessment was designed to evaluate these treatments within their marketing authorizations for HARRMS after at least 1 disease-modifying therapy (DMT).

A study found no direct trial evidence for natalizumab or its biosimilar in highly active relapsing-remitting MS and found limited cost-effectiveness vs most alternatives. | Image credit: Sweeann - stock.adobe.com

“Multiple sclerosis is an immune-mediated inflammatory disease, causing long-term disability in young adults,” wrote the researchers of the study. “Most cases begin as relapsing–remitting multiple sclerosis. Some people have a form of relapsing–remitting multiple sclerosis known as highly active relapsing–remitting multiple sclerosis, defined as multiple sclerosis with unchanged or increased disease activity despite prior treatment with at least one disease-modifying therapy.”

HARRMS is broadly defined as relapsing-remitting MS (RRMS) with ongoing disease activity despite treatment with at least 1 DMT. The review noted that the lack of a consensus definition for HARRMS makes it difficult to consistently identify and treat this population. Investigators from the Bristol Technology Assessment Group at the University of Bristol searched MEDLINE, EMBASE, and trial registries through April 2024 and identified 42 studies encompassing 22,409 participants. Most studies enrolled a general RRMS population, while only 2 studies specifically enrolled patients with HARRMS. Four studies evaluated natalizumab or its biosimilar, but none reported HARRMS-specific outcomes for either natalizumab product.

Indirect Comparisons Suggest Similar Efficacy to Comparators

Using network meta-analysis, the authors found no evidence of a difference between natalizumab and its biosimilar in relapse rate (rate ratio, 0.65; 95% credible interval [CrI], 0.34-1.26), gadolinium-enhancing lesions (HR, 1.29; 95% CrI, 0.69-2.37), T2-weighted lesions (HR, 1.07; 95% CrI, 0.73-1.57), any adverse events (HR, 1.06; 95% CrI, 0.77-1.46), or treatment discontinuation (HR, 0.48; 95% CrI, 0.13-1.76) in the general RRMS population.

The HARRMS evidence base was limited to 6 studies covering fingolimod, ocrelizumab, alemtuzumab, cladribine, interferon beta, and autologous hematopoietic stem cell treatment. All interventions except interferon beta-1a reduced relapse risk versus placebo. The analysis also incorporated natalizumab based on a study population considered close to, but not fully meeting, the HARRMS definition. Because of the limited and indirect evidence, the authors emphasized uncertainty about whether treatment effects observed in broader RRMS populations can be extrapolated to HARRMS.

Economic Model Finds Natalizumab Costlier Without a Clear QALY Advantage

To assess cost-effectiveness, the team built a discrete event simulation model using UK MS registry data and willingness-to-pay thresholds of £20,000 and £30,000 per quality-adjusted life-year (QALY), equivalent to approximately $27,000 and $41,000 per QALY, respectively, based on the August 27, 2026, exchange rate. The economic analysis used the UK thresholds; the dollar amounts are provided here for US readers.

With the exception of ocrelizumab, all comparators had greater net benefit than intravenous natalizumab, intravenous natalizumab biosimilar, and subcutaneous natalizumab at the £20,000-to-£30,000/QALY thresholds. The natalizumab products also had close to a 0% probability of having the highest net benefit. Costs were generally higher with natalizumab than with other treatments, while 95% CrIs for QALYs completely overlapped, indicating no evidence of a difference in QALYs. The biosimilar had lower costs and lower QALYs than intravenous originator natalizumab, but the 95% CrIs overlapped.

Compared with ocrelizumab, however, intravenous natalizumab had lower costs and higher QALYs, meaning the model did not favor ocrelizumab over natalizumab on cost-effectiveness. Across the broader comparison, interferon beta-1b and several glatiramer acetate and interferon-based regimens had the greatest modeled net monetary benefit at the £20,000-to-£30,000/QALY thresholds.

A value-of-information analysis found that uncertainty surrounding treatment effects—including network meta-analysis estimates for annualized relapse rate, confirmed disability progression, serious adverse events, and treatment discontinuation—had the greatest impact on the results, although costs, utilities, and MS registry inputs also contributed substantial uncertainty.

The authors concluded that additional trials enrolling patients who meet HARRMS criteria are needed to determine whether natalizumab and its biosimilar perform as expected in this population, rather than relying primarily on extrapolation from broader RRMS trials.

The analysis was limited by the absence of randomized trials directly evaluating natalizumab or its biosimilar in patients meeting the HARRMS criteria, according to the researchers. Much of the evidence was therefore drawn from broader RRMS populations or studies involving populations considered similar to HARRMS, requiring indirect comparisons and extrapolation. The economic model also relied on assumptions about treatment effects, disease progression, costs, utilities, and registry data, contributing to uncertainty around the cost-effectiveness estimates. The authors identified treatment-effect estimates as the largest source of decision uncertainty.

The findings arrive as NICE's companion guidance recommends natalizumab (originator or biosimilar) for rapidly evolving severe RRMS—a narrower subgroup of HARRMS—rather than endorsing use across the full highly active population, with pricing negotiated through a confidential national commercial arrangement.²

Overall, the assessment found no direct clinical evidence establishing the comparative effectiveness of natalizumab or its biosimilar specifically in HARRMS.¹ Although natalizumab had lower modeled costs and higher QALYs than ocrelizumab, most other comparators had greater net benefit at willingness-to-pay thresholds of approximately $27,000 to $41,000 per QALY. The findings underscore the need for trials specifically enrolling patients with highly active disease to determine whether treatment effects observed in broader RRMS populations can be reliably extrapolated to HARRMS.

“The economic model found that natalizumab and natalizumab biosimilar were not cost-effective compared to any of the included comparators in highly active relapsing-remitting multiple sclerosis, with similar quality-adjusted life-years but higher costs, with the only exception being ocrelizumab,” wrote the researchers.

References

1. Manzano CL, Sadek A, Cooper C, et al. Natalizumab and Tyruko (natalizumab biosimilar) for treating highly active relapsing-remitting multiple sclerosis after at least one disease-modifying therapy: a systematic review and economic model. Health Technol Assess. 2026;30(60):1-290. doi:10.3310/GJHT1811
2. Natalizumab (originator and biosimilar) for treating highly active relapsing–remitting multiple sclerosis after disease-modifying therapy. National Institute for Health and Care Excellence. Last reviewed January 28, 2026. Accessed August 27, 2026. https://www.nice.org.uk/guidance/ta1126