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Mar 18, 2014 - Eisai, Frankfurt/M) in a dosage scheme converted from the last incobotulinumtoxinA injection scheme using a 1:40 conversion factor. As a result ...

J Neural Transm (2014) 121:769–771 DOI 10.1007/s00702-014-1165-7

NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - SHORT COMMUNICATION

IncobotulinumtoxinA (XeominÒ) can produce antibody-induced therapy failure in a patient pretreated with abobotulinumtoxinA (DysportÒ) Dirk Dressler • Fereshte Adib Saberi Hans Bigalke



Received: 5 December 2013 / Accepted: 18 January 2014 / Published online: 18 March 2014 Ó Springer-Verlag Wien 2014

Abstract IncobotulinumtoxinA has not produced a single case of antibody-induced therapy failure after 8 years of worldwide usage. We are reporting a patient with progressive hereditary juvenile onset generalised dystonia who was pretreated with abobotulinumtoxinA for 15 years, before she received incobotulinumtoxinA. To the fifth and sixth applications, she responded with complete therapy failure. Mouse hemidiaphragm assay testing revealed a maximal botulinum toxin antibody titre. Improved specific biological activity and lack of complexing proteins seem to reduce the antigenicity of incobotulinumtoxinA. However, this first ever report indicates that it does not eliminate it entirely. Keywords Botulinum toxin type A  Therapeutic use  IncobotulinumtoxinA  Antibodies  Therapy failure

Introduction IncobotulinumtoxinA (XeominÒ, Merz Pharmaceuticals, Frankfurt/M, Germany) is a novel botulinum toxin (BT) drug that does not contain complexing proteins (Dressler 2012). Based upon calculations about its specific biological activity and based upon hypotheses about the immunological role of the complexing proteins it was predicted that D. Dressler (&)  F. Adib Saberi Movement Disorders Section, Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany e-mail: [email protected] H. Bigalke Institute of Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany

it should have a lower antigenicity than conventional BT drugs (Dressler and Bigalke 2009). Indeed, after now being marketed worldwide for up to 8 years, no case of antibodyinduced therapy failure (ABF) in patients receiving incobotulinumtoxinA has been reported so far, and none was seen in our own large series of incobotulinumtoxinAtreated patients over the last 8 years. We are now reporting the first patient worldwide who developed ABF under incobotulinumtoxinA.

Case report AL, a 64-year-old lady, suffered from hereditary juvenileonset generalised dystonia. Her treatment history is shown in Table 1. With the advent of BT, she was treated elsewhere with abobotulinumtoxinA (DysportÒ, Ipsen, Slough, UK) from 1991 until 2001 with satisfactory results. In 2001, she was offered deep brain stimulation also producing satisfactory results. In 2005 with the progress of her disease, she required additional BT therapy. This was given until 2006 when she requested our services. Until May 2010, she received abobotulinumtoxinA under variable treatment schemes. Total doses were slowly increased reflecting the progression of her dystonia. When her treatment effect became suboptimal with reduced intensity, but at normal duration, she was changed to incobotulinumtoxinA and her stimulation parameters were optimised. After the second incobotulinumtoxinA injection series, her treatment effect was as before for three more injection series before she complained of total lack of response to two subsequent injection series. Based on previous experience, we suspected complete ABF (Dressler 2002) and performed BT antibody testing with the mouse hemidiaphragm assay (Toxogen, Hannover, Germany). When the result came back as

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Table 1 Synopsis of antidystonic treatments in patient UL

BT drug botulinum toxin drug, D abobotulinumtoxinA, DBS deep brain stimulation, II interinjection interval, n/a not applicable, X incobotulinumtoxinA, ? not known, ? done

maximally positive, she was treated with rimabotulinumtoxinB (NeuroBlocÒ, Eisai, Frankfurt/M) in a dosage scheme converted from the last incobotulinumtoxinA injection scheme using a 1:40 conversion factor. As a result, the patient reported original therapy effects.

Discussion Antibody-induced therapy failure is a well-known problem of BT therapy. Risk factors include BT single dose, interinjection intervals and the immunological quality of the BT drug used. IncobotulinumtoxinA, the BT drug most recently introduced, differs from other BT drugs by an improved specific biological activity and lack of complexing proteins (Dressler 2012). Although the immunological role of the complexing proteins remains unclear, the improved specific biological activity of incobotulinumtoxinA suggests a reduced antigenicity. Indeed, lack of any reports on ABF with incobotulinumtoxinA despite its worldwide use for 8 years together with other observations (Adib Saberi et al. 2010)

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support this suggestion. We are now reporting the first patient worldwide who developed ABF while receiving incobotulinumtoxinA. After we had reported several remarkable cases of ABF with extremely unusual risk factors constellations including extremely small BT doses, very few BT applications and prolonged interinjection intervals, we had predicted that ABF can occur even in patients with the most favourable risk factor constellations including reduced BT drug antigenicity. Additionally, previous exposure to abobotulinumtoxinA, a BT drug for which ABF has been well described before, may have primed our patient’s immune system. Acknowledgments DD received honoraria for consultations from Allergan, Eisai/Solstice, Ipsen, Merz and Syntaxin. He is a shareholder in Allergan. He holds patents in botulinum toxin research. FAS has nothing to disclose. HB is CEO of Toxogen.

References Adib SF, Bigalke H, Dressler D (2010) Antigenicity differences between botulinum toxin drugs. Mov Disord 25(Suppl 2):S227 (Abstract)

IncobotulinumtoxinA (XeominÒ) can produce antibody-induced therapy failure Dressler D (2002) Clinical features of secondary failure of botulinum toxin therapy. Eur Neurol 48:26–29 Dressler D (2012) Five-year experience with incobotulinumtoxinA (XeominÒ): the first botulinum toxin drug free of complexing proteins. Eur J Neurol 19:385–389

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Dressler D, Bigalke H (2009) Pharmacology of botulinum toxin drugs. In: Truong D, Dressler D, Hallett M (eds) Manual of botulinum toxin therapy. Cambridge University Press, Cambridge

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