Abstract
Introduction: Botulinum toxins are biotherapeutic drugs with great applications in the field of neurology such as headache and abnormal movements. Due to the medical importance and the increase in therapeutic indications of botulinum toxin, this article aims to clarify the basic terminology regarding the nature of this drug, the structural differences with conventional drugs and important aspects in relation to its biological potency and immunogenicity in order to understand the potential differences between the available toxins and conceptualize regarding the non-interchangeability or substitution of one toxin for another.
Materials and methods: non-systematic review as recommended in the Scale for the Verification of Narrative Review Articles (SANRA).
Conclusions: biological drugs are not interchangeable with each other, even if they demonstrate bioequivalence. They do not meet the FDA's definition of a biosimilar. They cannot be evaluated as interchangeable generic drugs because they are biologics. There are no head-to-head comparative studies. They are different due to the individual manufacturing process.
References
Baethge C, Goldbeck-Wood S, Mertens S. SANRA - a scale for the quality assessment of narrative review articles. Res Integr Peer Rev. 2019;4:5. https://doi.org/10.1186/s41073-019-0064-8
U.S. Food & Drug Administration (FDA). Biosimilar and interchangeable products [consultado el 19 de junio del 2022]. https://www.fda.gov/drugs/biosimilars/biosimilar-and-interchangeable-products#generic
Verrill M, Declerck P, Loibl S, Lee J, Cortes J. The rise of oncology biosimilars: from process to promise. Future Oncol. 2019;15(28):3255-65. https://doi.org/10.2217/fon-2019-0145
Biosimilars info sheet. Generics and biosimilars. https://www.fda.gov/media/154912/download
U.S. Food & Drug Administration (FDA). Biosimilar product information [consultado el 19 de abril del 2021]. https://www.fda.gov/drugs/biosimilars/biosimilar-product-information
European Medicines Agency. Medicines type-biosimilars [consultado el 26 de abril del 2021]. https://www.ema.europa.eu/en/medicines/search_api_aggregation_ema_medicine_types/field_ema_med_biosimilar
Gherghescu I, Delgado-Charro MB. The biosimilar landscape: an overview of regulatory approvals by the EMA and FDA. Pharmaceutics. 2021;13(1):48. https://doi.org/10.3390/pharmaceutics13010048
Kresse GB. Biosimilars - science, status, and strategic perspective. Eur J Pharm Biopharm. 2009;72(3):479-86. https://doi.org/10.1016/j.ejpb.2009.02.014
Chiu SY, Burns MR, Malaty IA. An update on botulinum toxin in neurology. Neurol Clin. 2021;39(1):209-29. https://doi.org/10.1016/j.ncl.2020.09.014
Burstein R, Blumenfeld AM, Silberstein SD, Manack Adams, A, Brin MF. Mechanism of action of onabotulinumtoxinA in chronic migraine: a narrative review. Headache. 2020;60:1259-72. https://doi.org/10.1111/head.13849
Davletov B, Bajohrs M, Binz T. Beyond Botox: Advantages and limitations of individual botulinum neurotoxins. Trends Neurosci. 2005;28(8):446-52. https://doi.org/10.1016/j.tins.2005.06.001
Chen R, Karp BI, Goldstein SR, Bara-Jimenez W, Yaseen Z, Hallett M. Effect of muscle activity immediately after botulinum toxin injection for writer's cramp. Mov Disord. 1999;14(2):307-12. https://doi.org/10.1002/1531-8257(199903)14:2<307::AID-MDS1016>3.0.CO;2-3
Eleopra R, Tugnoli V, De Grandis D. The variability in the clinical effect induced by botulinum toxin type A: The role of muscle activity in humans. Mov Disord. 1997;12(1):89-94. https://doi.org/10.1002/mds.870120115
Rosales RL, Arimura K, Takenaga S, Osame M. Extrafusal and intrafusal muscle effects in experimental botulinum toxin-A injection. Muscle Nerve. 1996;19(4):488-96. https://doi.org/10.1002/(SICI)1097-4598(199604)19:4%3C488::AID-MUS9%3E3.0.CO;2-8
Trompetto C, Currà A, Buccolieri A, Suppa A, Abbruzzese G, Berardelli A. Botulinum toxin changes intrafusal feedback in dystonia: a study with the tonic vibration reflex. Mov Disord. 2006;21(6):777-82. https://doi.org/10.1002/mds.20801
Ramachandran R, Lam C, Yaksh TL. Botulinum toxin in migraine: Role of transport in trigemino-somatic and trigemino-vascular afferents. Neurobiol Dis. 2015;79:111-22. https://doi.org/10.1016/j.nbd.2015.04.011
Pellett S, Yaksh TL, Ramachandran R. Current status and future directions of botulinum neurotoxins for targeting pain processing. Toxins. 2015;7(11):4519-63. https://doi.org/10.3390/toxins7114519
Zhang X, Strassman AM, Novack V, Brin MF, Burstein R. Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors’ responses to stimulation of TRPV1 and TRPA1 channels: Are we getting closer to solving this puzzle? Cephalalgia. 2016;36(9):875-86. https://doi.org/10.1177/0333102416636843
Smith TJ, Hill KK, Raphael BH. Historical and current perspectives on Clostridium botulinum diversity. Res Microbiol. 2015;166(4):290-302. https://doi.org/10.1016/j. resmic.2014.09.007
Dashtipour K, Chen JJ, Espay AJ, Mari Z, Ondo W. Onabotulinumtoxin A and abobotulinumtoxin A dose conversion: a systematic literature review. Mov Disord Clin Pract. 2016;3(2):109-15. https://doi.org/10.1002/mdc3.12235 .
Scaglione F. Conversion ratio between Botox®, Dysport®, and Xeomin® in clinical practice. Toxins (Basel). 2016;8(3):65. https://doi.org/10.3390/toxins8030065
Brin MF, James C, Maltman J. Botulinum toxin type A products are not interchangeable: a review of the evidence. Biologics. 2014;8:227-41. https://doi.org/10.2147/BTT.S65603
Car H, Bogucki A, Bonikowski M, Dec-?wiek M, Dru?d? A, Koziorowski D, et al. Botulinum toxin type-A preparations are not the same medications - basic science (part 1). Neurol Neurochir Pol. 2021;55:133-40. https://doi.org/10.5603/PJNNS.a2021.0027
Becker WJ. Botulinum toxin in the treatment of headache. Toxins (Basel). 2020;12(12):803. https://doi.org/10.3390/toxins12120803
Bentivoglio AR, Del Grande A, Petracca M, Ialongo T, Ricciardi L. Clinical differences between botulinum neurotoxin type A and B. Toxicon. 2015;107(Pt A):77-84. https://doi.org/10.1016/j.toxicon.2015.08.001
Fonfria E, Maignel J, Lezmi S, Martin V, Splevins A, Shubber S, et al. the expanding therapeutic utility of botulinum neurotoxins. Toxins. 2018;10(5):208. https://doi.org/10.3390/toxins10050208
Allergan I. Package insert, Botox (botulinum toxin type A purified neurotoxin complex). Madison, NJ: Irvine Allergan; 2019.
Merz Pharmaceuticals. Package insert, Xeomin (incobotulinumtoxintype A). Frankfurt: Merz Pharmaceuticals GmbH; 2018.
Solstice Neurosciences. Package Insert, Myobloc (botulinum toxin type B injectable solution). Louisville (KY): Solstice Neurosciences, LLC; 2019.
Ipsen. Package insert, Dysport (abobotulinumtoxin A). Basking Ridge (NJ): Ipsen Biopharmaceuticals; 2019.
Field M, Splevins A, Picaut P, van der Schans M, Langenberg J, Noort D, et al. AbobotulinumtoxinA (Dysport®), OnabotulinumtoxinA (Botox®), and IncobotulinumtoxinA (Xeomin®) Neurotoxin content and potential implications for duration of response in patients. Toxins (Basel). 2018;10(12):535. https://doi.org/10.3390/toxins10120535
Wenzel R, Jones D, Borrego JA. Comparing two botulinum toxin type A formulations using manufacturers’ product summaries. J Clin Pharm Ther. 2007;32(4):387-402. https://doi.org/10.1111/j.1365-2710.2007.00835.x
Rupp D, Nicholson G, Canty D, Wang J, Rhéaume C, Le L, et al. OnabotulinumtoxinA displays greater biological activity compared to IncobotulinumtoxinA, demonstrating non-interchangeability in both in vitro and in vivo assays. Toxins (Basel). 2020;12(6):393. https://doi.org/10.3390/toxins12060393
Hunt T, Clarke K. Potency evaluation of a formulated drug product containing 150-kd botulinum neurotoxin type A. Clin Neuropharmacol. 2009;32(1):28-31. https://doi.org/10.1097/WNF.0b013e3181692735
Brown M, Nicholson G, Ardila MC, Satorius A, Broide RS, Clarke K, et al. Comparative evaluation of the potency and antigenicity of two distinct BoNT/A-derived formulations. J Neural Transm. 2013;120(2):291-8. https://doi.org/10.1007/s00702-012-0854-3
Hunt T, Clarke K, Rupp D, Shimizu G, Weidler J. 50-U incobotulinumtoxinA drug product demonstrates lower potency when compared to 50-U onabotulinumtoxinA drug product with concurrent lower light-chain activity and atypical substrate cleavage; Poster presented at 6th European Master’s in Aesthetic and Anti-Aging Medicine; October 15–17, 2010; París, Francia.
Aurora SK, Dodick DW, Turkel CC, DeGryse RE, Silberstein SD, Lipton RB, et al; PREEMPT 1 Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the Preempt 1 trial. Cephalalgia. 2010;30(7):793-803. https://doi.org/10.1177/0333102410364676
Diener HC, Dodick DW, Aurora SK, Turkel CC, DeGryse RE, Lipton RB, et al; PREEMPT 2 Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the Preempt 2 trial. Cephalalgia. 2010;30(7):804-14. https://doi.org/10.1177/0333102410364677
Chankrachang S, Arayawichanont A, Poungvarin N, Nidhinandana S, Boonkongchuen P, Towanabut S, et al. Prophylactic botulinum type A toxin complex (Dysport®) for migraine without aura. Headache. 2011;51(1):52-63. https://doi.org/10.1111/j.1526-4610.2010.01807.x
Simpson DM, Hallett M, Ashman EJ, Comella CL, Green MW, Gronseth GS, et al. Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016;86(19):1818-26. https://doi.org/10.1212/WNL.0000000000002560
Jackson JL, Kuriyama A, Hayashino Y. Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA. 2012;307(16):1736-45. https://doi.org/10.1001/jama.2012.505
Shamliyan TA, Kane RL, Taylor FR. Migraine in adults: preventive pharmacologic treatments. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013.
Tassorelli C, Sances G, Avenali M, De Icco R, Martinelli D, Bitetto V, et al. Botulinum toxin for chronic migraine: Clinical trials and technical aspects. Toxicon. 2018;147:111-5. https://doi.org/10.1016/j.toxicon.2017.08.026
Bellows S, Jankovic J. Immunogenicity associated with botulinum toxin treatment. Toxins (Basel). 2019;11(9):491. https://doi.org/10.3390/toxins11090491
Albrecht P, Jansen A, Lee JI, Moll M, Ringelstein M, Rosenthal D, et al. High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy. Neurology. 2019;92(1):e48-54. https://doi.org/10.1212/WNL.0000000000006688
Lange O, Bigalke H, Dengler R, Wegner F, deGroot M, Wohlfarth K. Neutralizing antibodies and secondary therapy failure after treatment with botulinum toxin type A: much ado about nothing?. Clin Neuropharmacol. 2009;32(4):213-8. https://doi.org/10.1097/WNF.0b013e3181914d0a
Naumann M, Carruthers A, Carruthers J, Aurora SK, Zafonte R, Abu-Shakra S, et al. Meta-analysis of neutralizing antibody conversion with onabotulinumtoxinA (Botox(R)) across multiple indications. Mov Disord. 2010;25(13):2211-8. https://doi.org/10.1002/mds.23254
Gelb DJ, Yoshimura DM, Olney RK, Lowenstein DH, Aminoff MJ. Change in pattern of muscle activity following botulinum toxin injections for torticollis. Ann Neurol. 1991;29(4):370-6. https://doi.org/10.1002/ana.410290407
Dressler D. Clinical presentation and management of antibody-induced failure of botulinum toxin therapy. Mov Disord. 2004;19 Suppl 8:S92-S100. https://doi.org/10.1002/mds.20022
Fabbri M, Leodori G, Fernandes RM, Bhidayasiri R, Marti MJ, Colosimo C, et al. Neutralizing antibody and botulinum toxin therapy: a systematic review and meta-analysis. Neurotox Res. 2016;29(1):105-17. https://doi.org/10.1007/s12640-015-9565-5
Brashear A, Bergan K, Wojcieszek J, Siemers ER, Ambrosius W. Patients’ perception of stopping or continuing treatment of cervical dystonia with botulinum toxin type A. Mov Disord. 2000;15(1):150-3. https://doi.org/10.1002/1531-8257(200001)15:1%3C150::AID-MDS1024%3E3.0.CO;2-X
Srinoulprasert Y, Wanitphakdeedecha R. Antibody-induced botulinum toxin treatment failure: A review and novel management approach. J Cosmet Dermatol. 2020;19(10):2491-6. https://doi.org/10.1111/jocd.13637
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