Real-World Natalizumab Biosimilar Switch Reduced Treatment Satisfaction Despite Stable Outcomes

While most patients who switched from originator natalizumab (Tysabri; Biogen) to the biosimilar (Tyruko; Polpharma Biologics) for relapsing-remitting multiple sclerosis (RRMS) rated the 2 products as equivalent, a subset reported new adverse effects, and overall treatment satisfaction dropped after the switch, echoing a pattern seen across biosimilar classes: outcomes that look clean in blinded trials can shift once patients know which product they are receiving.1

Patient Satisfaction Declined Despite Stable Clinical Outcomes After Biosimilar Switch

In the real-world cohort study published in Multiple Sclerosis and Related Disorders, researchers at Amsterdam UMC followed 83 patients with RRMS who were switched from originator natalizumab to the first FDA-approved MS biosimilar as part of a hospitalwide, cost-driven conversion. Patients completed validated questionnaires and had serum drawn before and during biosimilar treatment, and all were aware of the brand switch.

Twelve patients (15%) reported experiencing more adverse effects with the biosimilar than with the originator, most commonly skin itching, fatigue, dizziness, headache, joint pain, and bowel issues. One patient developed a new skin rash that recurred with each biosimilar infusion and resolved only after switching back to the originator.

Overall treatment satisfaction, measured with the Treatment Satisfaction Questionnaire for Medication, was significantly lower during biosimilar treatment (mean score [SD], 71.74 [22.4]) than with the originator (76.84 [17.6]; P = .02). No other patient-reported measures, including MS symptom impact, perceived effectiveness, adverse effect frequency, treatment convenience, or wearing-off symptoms, differed significantly between products. Similarly, no clinical relapses occurred after the switch.

Nocebo Effect May Explain Lower Satisfaction After Switch

The authors attributed the drop in satisfaction and uptick in reported adverse effects to a possible nocebo effect, a phenomenon in which negative expectations about a switched medication produce perceived harm unrelated to the drug's actual pharmacology. Because the study was not blinded and patients knew about the brand change, the design could not rule out this influence.

The results diverged from the blinded phase 3 Antelope trial (NCT04115488), in which adverse event rates were similar between biosimilar and originator natalizumab.2 A separate Norwegian real-world study found an even higher rate, with 28% of patients reporting new adverse effects after switching.3 The authors added that 2 newspaper reports from the United Kingdom of relapses and worsening symptoms following the switch, although not peer-reviewed, add to a broader narrative of real-world experiences that do not fully match trial data.

Nocebo effects have been documented in other biosimilar classes, including adalimumab and infliximab in inflammatory bowel disease and rheumatologic conditions, respectively, where nonmedical switches have driven discontinuation rates far higher than those seen in blinded studies.4 A systematic review identified more than a dozen strategies, largely centered on patient and provider education and communication, to help mitigate nocebo-driven discontinuation during biosimilar switches.5

The authors were careful to note that a nocebo effect likely does not explain everything, with the patient whose skin rash resolved after switching back to the originator, for instance, suggesting a product-specific reaction rather than a purely psychological response.1

Biosimilar Shows Comparable Drug Levels, but John Cunningham Virus (JCV) Testing Raises Questions

Beyond patient-reported outcomes, the study assessed whether the biosimilar performed the same way pharmacologically. Among 31 patients with consistent dosing intervals, median trough natalizumab concentrations were 9.0 μg/mL with the originator and 7.6 μg/mL with the biosimilar; the difference, however, was not statistically significant, with a 90% CI for the geometric mean ratio (0.92-1.08) falling within standard equivalence margins.

A more complicated picture emerged around anti-JCV antibody testing, which is used to gauge risk of progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal brain infection associated with natalizumab. Because the originator's JCV assay (STRATIFY) is not licensed for use with the biosimilar, Sandoz introduced a new test, the ImmunoWELL assay.

In this cohort, ImmunoWELL flagged significantly more patients as JCV-positive than STRATIFY did, with several testing negative on STRATIFY but positive on ImmunoWELL, at index values suggesting meaningful PML risk. ImmunoWELL results were largely stable when patients were retested months later, but the researchers explained that the disagreement between the 2 assays could affect who is deemed eligible to start or continue natalizumab therapy. Similar assay discrepancies have prompted UK neurologists to publish interim consensus guidance on interpreting JCV results for patients on the biosimilar.6

Successful Biosimilar Switching May Depend on Communication, JCV Monitoring

The findings come as the natalizumab biosimilar gains traction in a therapeutic area where drug costs have long limited access.7 Budget-impact modeling has projected substantial savings from biosimilar natalizumab adoption, and health system–wide conversions like the one in this study illustrate how payers and providers are already pursuing those cost-saving opportunities.8

The current study suggests that although biosimilar natalizumab appears pharmacologically and clinically comparable to the originator, successful implementation may hinge on factors beyond the drug itself: how switches are communicated to patients and whether JCV testing protocols can be reconciled across assays.1 For managed care organizations weighing formulary conversions, the study reinforces that safety and efficacy equivalence alone may not guarantee smooth implementation, as patient communication and consistent risk-monitoring infrastructure may matter just as much.

The authors acknowledged several limitations, including that the nonblinded design may have influenced patient-reported outcomes through increased symptom awareness or observer bias. Additional limitations included the lack of clinical and MRI data, as well as the single-center design, which may limit generalizability. Still, they expressed confidence in their findings.

“…patients can safely switch from originator to biosimilar natalizumab, although they may experience more side effects with the biosimilar, possibly due to a nocebo effect,” the authors wrote. “While the biosimilar appears highly similar to the originator in all aspects, discrepancies in JCV results of the ImmunoWELL assay compared to the STRATIFY assay may complicate the clinical use of biosimilar natalizumab.”

References

1. Gelissen LMY, Strijbis EMM, van Oosten BW, et al. Safety and patient experiences with the natalizumab biosimilar in multiple sclerosis treatment. Mult Scler Relat Disord. 2026;109:107147. doi:10.1016/j.msard.2026.107147
2. Santoro C. Biosimilar natalizumab-sztn shows comparable efficacy and safety to Tysabri in RRMS. Center for Biosimilars®. March 25, 2025. Accessed July 20, 2026. https://www.centerforbiosimilars.com/view/biosimilar-natalizumab-sztn-shows-comparable-efficacy-and-safety-to-tysabri-in-rrms
3. Høgestøl EA, Brustad ÅW, Celius EG, et al. Real-world experience with switching from originator to biosimilar natalizumab. medRxiv. Published online February 7, 2025. doi:10.1101/2025.02.05.25320428
4. Jeremias S. Study on nonmedical switching for adalimumab biosimilars warns about nocebo effect. Center for Biosimilars. April 27, 2023. Accessed July 20, 2026. https://www.centerforbiosimilars.com/view/study-on-nonmedical-switching-for-adalimumab-biosimilars-warns-about-nocebo-effect
5. Jeremias S. 13 strategies to avoid the nocebo effect during biosimilar switching. Center for Biosimilars. December 17, 2024. Accessed July 20, 2026. https://www.centerforbiosimilars.com/view/13-strategies-to-avoid-the-nocebo-effect-during-biosimilar-switching
6. Jeremias S. UK experts publish guidance on JC virus testing for natalizumab biosimilar Tyruko. Center for Biosimilars. November 5, 2025. Accessed July 20, 2026. https://www.centerforbiosimilars.com/view/uk-experts-publish-guidance-on-jc-virus-testing-for-natalizumab-biosimilar-tyruko
7. Jeremias S. First natalizumab biosimilar Tyruko launches, expanding access in multiple sclerosis. Center for Biosimilars. December 18, 2025. Accessed July 20, 2026. https://www.centerforbiosimilars.com/view/first-natalizumab-biosimilar-tyruko-launches-expanding-access-in-multiple-sclerosis
8. Li E, Goh A, Gupta S, et al. Budget impact analysis of biosimilar natalizumab in the US. Am J Manag Care. 2024;30(7):e191-e197. doi:10.37765/ajmc.2024.89558