Tyruko and Tysabri: biosimilars and their differences

In 2023, the Medicines and Healthcare products Regulatory Agency (MHRA) granted approval in the UK for the first, and only, biosimilar available for the treatment of multiple sclerosis (MS). Tyruko, (developed by Sandoz), is a biosimilar of Tysabri (developed by Biogen). Both Tysabri and Tyruko contain the active ingredient natalizumab, which is a disease modifying drug (DMD) for the treatment of relapsing-remitting MS, a chronic, progressive autoimmune disorder.

Tysabri and Tyruko are considered interchangeable by the MHRA, which has determined that there are no clinically meaningful differences between the two versions. Given the lower cost of the biosimilar, health providers in the UK began switching their patients from Tysabri to Tyruko in April 2024. However, a subset of MS patients, notably those at Charing Cross hospital in London, have reported significant adverse side effects and/or a worsening of their MS symptoms after switching to the biosimilar (1), (2). An investigation into why some patients have responded so poorly to the biosimilar is currently underway.

The similarities
Biosimilars, such as Tyruko, are biological medicines that have undergone extensive comparative tests to confirm that they are highly similar in terms of structure, safety and efficacy to an originator medicine which has already been approved by the relevant regulatory body (known as a ‘reference medicinal product [RMP]’). However, due to the inherent variability of biological medicines, combined with their more complex manufacture in living cells, exact replication of the originator medicine is not possible. The biosimilar molecule may, for example, possess subtly different post-translational modifications or levels of impurities.

Less extensive evidence is usually required for a biosimilar to be awarded marketing approval than is necessary for an originator medicine, as the biosimilar, to some extent, can rely on the supporting evidence already available regarding the originator medicine. An accelerated approval process has been established for biosimilars, based on demonstrating comparability, as opposed to an independent assessment of efficacy.

Both Tyruko and Tysabri contain the active substance natalizumab, a recombinant humanised antibody which binds to α4-integrin on white blood cells. Approval of Tyruko was based on the demonstration of identical primary and indistinguishable higher order structures with the active substance in Tysabri. Sandoz also successfully demonstrated that Tyruko shares pharmacokinetic and pharmacodynamic similarity to Tysabri (4), (5), and a comparative study conducted in patients with relapsing-remitting multiple sclerosis confirmed matching efficacy, safety, and immunogenicity (Antelope study; (6)). Overall, a conclusion was made based on this evidence that there are no clinically meaningful differences between the two medicines.

The differences
However, there are differences between the two medicines. Although the amino acid sequence of the active substance, natalizumab, is identical in both medicines, Tyruko nonetheless differs from Tysabri in respect of several physicochemical and functional characteristics. These disparities were assessed during the approval process, and deemed by the regulatory authorities either to be “comparable” between the two medicines, or to be insufficiently clinically relevant so as to prevent Tyruko’s approval.

As one example, in Tyruko, natalizumab was found to have a slightly higher level of methionine oxidation than in Tysabri (7), (8). Methionine oxidation can significantly impact the properties of an antibody, including its stability and affinity. However, since the major oxidation sites of natalizumab are found within the constant region of the antibody, and functional assessment confirmed that potency and Fc receptor binding of Tyruko is comparable to Tysabri, the regulatory authorities concluded that these differences are justified, and that no clinically meaningful effect would be expected to arise therefrom. Similar conclusions were made regarding deviations between Tyruko and Tysabri for several other properties, including the levels of free thiols, open disulfide bonds, charge heterogeneity and C-terminal amidation.

Interestingly, some of this variability appears to be directly attributable to differences in the manufacture of Tyruko and Tysabri. Tyruko, for instance, is produced using a Chinese Hamster Ovary (CHO) cell expression system, whereas Tysabri is manufactured using murine cells (7). These different expression systems have the potential to influence translation and post-translational modifications, as well as to affect the quantity and nature of impurities or contaminants present in the final product.

Another key difference between Tyruko and Tysabri is in their formulation. The originator medicine, Tysabri, is available as both an intravenous (IV) infusion and a subcutaneous (SQ) injection, whereas the biosimilar, Tyruko, is currently available only as an intravenous infusion. The compositions of Tyruko and Tysabri are detailed below (9), (10).

* final dosage diluted solution has a concentration of 2.6 mg/mL

Clearly, these formulations are very similar, and contain the same concentration of natalizumab (for IV infusion). The notable difference is that Tyruko uses a histidine buffer rather than a sodium phosphate buffer.

Many of the manufacturing and formulation choices made by biosimilar companies will be driven in part by the need to “design” around the originator’s patent portfolio. While patent protection for the active ingredient will have expired by the time the biosimilar launches, originators are likely to have a series of secondary patents covering various aspects of product development, including cell lines, manufacturing methods, characterising tests, product formulations, delivery devices etc. For example, Biogen have several pending European applications related to natalizumab, including an application which includes medical use claims to a high concentration formulation of natalizumab comprising a sodium phosphate buffer, sodium chloride, and polysorbate 80, and having a pH between 5-7. As noted above, Tyruko is formulated in a histidine buffer rather than a sodium phosphate buffer, such that this formulation is outside the scope of Biogen’s claim.

Increased pharmacovigilance
The NHS has been in conversation with the MHRA to discuss the future of the roll-out of Tyruko across the UK and to determine if any measures need to be taken (2).

Typically, the focus on comparability studies rather than large-scale efficacy studies means that a biosimilar medicine may have only been tested on a small number of patients prior to approval. Accordingly, Tyruko, like all biosimilars, carries black triangle status, which signals that the medicine is subject to enhanced surveillance after approval. As a result, all adverse drug reactions must be reported to the MHRA via the Yellow Card Scheme. This scheme encourages the gathering of additional safety and efficacy data from routine clinical use over time. The black triangle symbol is not removed until the safety of the drug is well established.

Presently, it is unclear why some patients have deteriorated after switching to the biosimilar. Whether this reflects a subtle biological difference between the two products (such as those described above), the nocebo effect, or some combination, is still under investigation. For the moment, Tyruko’s use in the UK will continue, albeit with increased pharmacovigilance measures and monitoring at the recommendation of the Commission on Human Medicine’s Neurology, Pain and Psychiatry Expert Advisory Group. This includes a specific follow up questionnaire, and a requirement that the marketing authorisation holder (i.e. Sandoz) reviews the risk of allergic reactions every 4 months (11). In addition, the NHS has stated that patients who experience severe adverse events or deterioration on Tyruko should be allowed to revert to the branded version, Tysabri.

References

1. Multiple sclerosis: Investigation into side effects of switching patients to natalizumab biosimilar. Mahase, Elisabeth. r403, s.l. : BMJ, 2025, BMJ, Vol. 388, p. 388 :r403.
2. Campbell, Denis. MS patients suffer side-effects after NHS England switches to cheaper drug. [Online] The Guardian, 24 February 2025. [Cited: 15 5 2025.]
3. European Medicines Agency. Biosimilars in the EU: Information guide for healthcare professional. [Online] 13 11 2023. [Cited: 13 5 2025.]
4. Medicines & Healthcare products Regulatory Agency. Public Assessment Report; National Procedure; Tyruko 300 mg concentrate for solution for infusion; natalizumab. European Medicines Agency.
5. Introducing the Biosimilar Paradigm to Neurology: The Totality of Evidence for the First Biosimilar Natalizumab. Selmaj K, Roth K, Höfler J, Vitzithum K, Derlacz R, von Richter O, Hornuss C, Poetzl J, Singer B, Jacobs L. 6:755-767, s.l. : BioDrugs, 2024, Vol. 38.
6. National Library of Medicine. Efficacy and Safety of the Biosimilar Natalizumab PB006 in Comparison to Tysabri® (Antelope). [Online] 3 7 2023. [Cited: 2025 5 13.]
7. European Medicines Agency. Assessment report; Tyruko; International non-proprietary name: natalizumab. l. : European Medicines Agency, 2023. EMEA/H/C/005752/0000.
8. European Medicines Agency.Tyruko : EPAR – Product information. ANNEX I: SUMMARY OF PRODUCT CHARACTERISTICS. [Online] 28 9 2023. [Cited: 5 13 2025.]
9. FULL PRESCRIBING INFORMATION: Tyruko. [Online] 8 2023. [Cited: 13 5 2025].
10. Food and Drug Administration. FULL PRESCRIBING INFORMATION: Tysabri. [Online] 3 2024. [Cited: 21 4 2026]
11. Department of Health and Social Care. Multiple Sclerosis: Drugs, Question for Department of Health and Social Care. [Online] 12 5 2025. [Cited: 21 4 2026].