Adalimumab Double Take: The Unexpected Return to Reference Humira

The launch of adalimumab biosimilars in the United States in 2023 marked a pivotal moment for health care cost savings and patient access, promising to disrupt the long-standing dominance of the originator biologic, Humira.1

However, a recent analysis from Truveta, spanning data through April 2025 unveils a concerning trend: more than 13% of patients who initially switched to an adalimumab biosimilar ultimately reverted to the reference drug.2

While the Truveta findings hint at patient dissatisfaction or adverse events, they leave a crucial question unanswered: Are the biosimilars themselves to blame? Delving into these critical missing pieces can offer a more comprehensive understanding of the evolving adalimumab biosimilar landscape and the true implications of patient switching patterns.

Summary of Truveta Research

The research analyzed switching patterns from bio-originator Humira to its biosimilars, finding a significant increase in biosimilar adoption, particularly peaking in April 2024 due to a major formulary change by CVS Health.3 Although biosimilar switching rates remained elevated compared to 2023, the study revealed that a notable proportion of patients—13.2% of those who initially switched—subsequently returned to reference drug Humira.1

This "switching back" phenomenon was more prevalent among specific patient demographics: older adults (aged ≥ 65 years), women, and individuals with rheumatoid arthritis or ankylosing spondylitis. A key finding was the rapid nature of these switchbacks, with nearly 40% occurring within 30 days of initiating a biosimilar. Truveta researchers suggested potential early dissatisfaction, adverse events, or patient resistance and uncertainty regarding the new medication. Rural patients also showed higher rates of early switchbacks compared with urban patients.

The study highlighted that although biosimilar uptake is growing, sustained use faces challenges. Patient perceptions, clinical uncertainty, and factors like pharmacy stock or complex health conditions in older adults may contribute to patients reverting to the originator. Understanding these real-world experiences is crucial for promoting broader and more sustained biosimilar adoption, despite clinical trials showing no meaningful differences in safety or efficacy between biosimilars and the originator.

Missing Context and the Noecbo Effect

At first glance, the analysis provides a stark insight into the switching patterns of patients receiving adalimumab treatments but there is a significant lack of investigation into the possible reasons behind patients switching back. Although there are mentions of patient perceptions and adverse events after switching to a biosimilar, there is missing context for whether the biosimilars themselves are to blame for patients’ choosing to switch back to Humira. Without this context, it could be implied that biosimilars fail for more than 10% of patients who switch to them, calling into question the safety and efficacy of switching to biosimilars generally.

Overall, a major factor that can cause a patient to switch back from a biosimilar to the reference agent is the nocebo effect, a phenomenon where a patients’ negative opinions about a drug lead to perceived worsened clinical outcomes or adverse events.4

Many studies, several of which concern switching between Humira and an adalimumab biosimilar,5-8 have looked at reference product to biosimilar switching and have found the nocebo effect to be the main cause for patients who switched back, suggesting that switching between biologic products of the same molecule is safe despite some patients still choosing to go back to Humira. Additionally, these studies are often conducted with patients undergoing multiple switches back and forth between products, which is an FDA data requirement to obtain interchangeability status.9

Interchangeability is a regulatory designation that allows for pharmacies to exchange a reference product with an approved biosimilar version without waiting for a provider to approve the change first.10 The policy is intended to give patients easier access to their medications and provide pharmacies with better flexibility to deal with supply chain issues and drug shortages. Of the 10 adalimumab biosimilars currently on the market, 8 have interchangeability designations (Cyltezo, Hadlima, Hyrimoz, Simlandi, Yuflyma, Abrilada, Hulio, and Amjevita).11

In addition, all states, as well as Puerto Rico, have individual laws regarding interchangeability, most of which concern requirements for patient and/or provider notification that a switch has occurred.12 Currently, 44 states either do not require patients to be notified or require patients to be notified but do not require them to give their consent for the switch, creating a breeding ground for the nocebo effect to occur in chronic patient populations who are typically unaware of what a biosimilar even is. These patients may also have taken many years and treatment failures to settle on a medication that works for them, and a new brand name or injector device could be jarring and anxiety-inducing.13

Although Truveta did not look into how interchangeability played into their results,2 it could be worth investigating as the FDA and other governmental bodies consider whether the US should continue to allow interchangeability policy or to follow in the footsteps of the European Union and UK, where regulatory agencies have declared all biosimilars interchangeable.14,15

Additionally, although Truveta did point out that CVS announced that its pharmacy benefit manager Caremark chose to prioritize adalimumab biosimilars on formulary over Humira as a big reason for growing adalimumab biosimilar adoption,2 it left out the several other PBMs that followed suit, overlooking the full extent of how the industry has been bolstering adalimumab biosimilars for success. Notably, the report omitted information on how PBMs Express Scripts, Optum Rx, Prime Therapeutics, Smith Rx, as well as private label pharmacies such as CarePartners Specialty Pharmacy and the Mark Cuban Cost Plus Drug Company have all chosen at least 1 adalimumab biosimilar to embrace.11,16 In fact, private labeling has also become popular in the ustekinumab space, another market in which a large number of biosimilars launched within the same year.17,18

Sustaining the Biosimilar Momentum: Addressing Perceptions and Policy

The Truveta analysis, although shedding light on the increasing uptake of adalimumab biosimilars, underscores the intricate challenges of maintaining patient adherence. The seemingly high rate of patients reverting to originator Humira, particularly those experiencing early switchbacks, could, at first glance, cast a shadow on biosimilar efficacy and safety.2 However, a deeper dive into the market dynamics reveals that these switchbacks are often less about inherent biosimilar failure and more about the powerful influence of patient perception and the nuances of policy implementation.

Ultimately, the real-world data on adalimumab switchbacks serves as a vital call to action.19 To truly unlock the full potential of biosimilars in the US health care system, stakeholders must move beyond simply encouraging the initial switch. A concerted effort is needed to educate both patients and providers about the robust science underpinning biosimilar safety and interchangeability, actively mitigating the nocebo effect through transparent communication.3

Furthermore, ongoing evaluation of interchangeability policies, potentially aligning with the broader European approach of universal biosimilar interchangeability, could further streamline access and build sustained patient confidence. By addressing these challenges, the US adalimumab biosimilar market might be able to fulfill its promise of delivering high-quality, affordable care to the masses.15

References

1. Jeremias S. US welcomes first adalimumab biosimilar, Amjevita. The Center for Biosimilars®. January 31, 2023. Accessed June 29, 2025. https://www.centerforbiosimilars.com/view/us-welcomes-first-adalimumab-biosimilar-amjevita

2. Truveta Research. Biosimilar use is on the rise – but 1 in 8 patients return to Humira. Truveta Research. June 23, 2025. Accessed June 29, 2025. https://www.truveta.com/blog/research/research-insights/biosimilar-use-humira/

3. CVS to remove Humira from some reimbursement lists in favor of biosimilar options. The Center for Biosimilars. January 6, 2024. Accessed June 29, 2025 . https://www.centerforbiosimilars.com/view/cvs-to-remove-humira-from-some-reimbursement-lists-in-favor-of-biosimilar-options

4. Jeremias S. 13 strategies to avoid the nocebo effect during biosimilar switching. The Center for Biosimilars. December 18, 2024. Accessed June 29, 2025. https://www.centerforbiosimilars.com/view/13-strategies-to-avoid-the-nocebo-effect-during-biosimilar-switching

5. Jeremias S. Etanercept biosimilar switch shows stable outcomes and disease control in RA. The Center for Biosimilars. May 13, 2025. Accessed June 29, 2025. https://www.centerforbiosimilars.com/view/etanercept-biosimilar-switch-shows-stable-outcomes-and-disease-control-in-ra

6. Ferreri D. Switching from Avastin to bevacizumab-bvzr in CRC, NSCLC can reduce Medicare costs. The Center for Biosimilars. May 10, 2025. Accessed June 29, 2025. https://www.centerforbiosimilars.com/view/switching-from-avastin-to-bevacizumab-bvzr-in-crc-nsclc-can-reduce-medicare-costs

7. Ferreri D. High acceptance levels after switching to an adalimumab biosimilar for IBD. The Center for Biosimilars. June 14, 2025. Accessed June 29, 2025. https://www.centerforbiosimilars.com/view/high-acceptance-levels-after-switching-to-an-adalimumab-biosimilar-for-ibd

8. Jeremias S. New data support Hulio as an interchangeable adalimumab option. The Center for Biosimilars. June 16, 2025. Accessed June 29, 2025. https://www.centerforbiosimilars.com/view/new-data-supports-hulio-as-an-interchangeable-adalimumab-option

9. Considerations in demonstrating interchangeability with a reference product. FDA. May 2019. Accessed June 29, 2025. https://www.fda.gov/media/124907/download

10. Interchangeable biological products. FDA. Accessed June 29, 2025. https://www.fda.gov/media/151094/download

11. Jeremias S. Happy Birthday adalimumab biosimilars: reflecting on the first year of US competition. The Center for Biosimilars. January 31, 2024. Accessed June 29, 2025. https://www.centerforbiosimilars.com/view/happy-birthday-adalimumab-biosimilars-reflecting-on-the-first-year-of-us-competition

12. Biosimilar interchangeability laws by state. Cardinal Health. Updated January 2024. Accessed June 29, 2025. https://www.cardinalhealth.com/en/product-solutions/pharmaceutical-products/biosimilars/state-regulations-for-biosimilar.html

13. Mazzoni D, Vener C, Mazzocco K, Monzani D, Pravettoni G. The psychological risks associated with the non-medical switch from biologics to biosimilars. Front Psychol. 2021;12:605643. doi:10.3389/fpsyg.2021.605643

14. Biosimilar medicines can be interchanged. EMA. September 19, 2022. Accessed June 29, 2025. https://www.ema.europa.eu/en/news/biosimilar-medicines-can-be-interchanged

15. Guidance on the licensing of biosimilar products. UK MHRA. Accessed June 29, 2025. https://www.gov.uk/government/publications/guidance-on-the-licensing-of-biosimilar-products/guidance-on-the-licensing-of-biosimilar-products

16. Jeremias S. The Age of adalimumab is upon us: how stakeholders can prepare. The Center for Biosimilars. June 28, 2023. Accessed June 29, 2025. https://www.centerforbiosimilars.com/view/the-age-of-adalimumab-is-upon-us-how-stakeholders-can-prepare

17. Jeremias S. Welcome Wezlana: the first Stelara biosimilar to launch in the US. The Center for Biosimilars. January 31, 2025. Accessed June 29, 2025. https://www.centerforbiosimilars.com/view/welcome-wezlana-the-first-stelara-biosimilar-to-launch-in-the-us

18. Jeremias S. Eye on pharma: interchangeability, private labels, and patent settlements for biosimilars. The Center for Biosimilars. May 9, 2025. Accessed June 29, 2025. https://www.centerforbiosimilars.com/view/eye-on-pharma-interchangeability-private-labels-and-patent-settlements-for-biosimilars

19. Jeremias S. European data confirm real-world benefits of adalimumab biosimilars. June 11, 2025. Accessed June 29, 2025. https://www.centerforbiosimilars.com/view/european-data-confirms-real-world-benefits-of-adalimumab-biosimilars