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Clinical utility of different botulinum neurotoxin preparations
Toxicon 67 (2013) 81–86
Contents lists available at SciVerse ScienceDirect
Toxicon journal homepage: www.elsevier.com/locate/toxicon
Review
Clinical utility of different botulinum neurotoxin preparations Steven B. Abrams a, Mark Hallett b, * a
Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467, USA The George Washington University School of Medicine and Health Sciences, Department of Neurology, Ross Hall, 2300 Eye Street NW, Suite 713W, Washington, DC 20037, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 June 2012 Received in revised form 27 November 2012 Accepted 29 November 2012 Available online 30 January 2013
Comparative literature assessing the relative safety and efficacy of different BoNT products is limited. The quantity and quality of data vary by preparation and indication. Clinicians seeking data relevant to the care of patients with specific conditions may find only reports about small numbers of patients with varying symptoms. While a literature search for “botulinum neurotoxins” will yield a large number of publications; only a fraction of these meet criteria for an academic evidence-based review. Patients may have been treated with a different BoNT formulation than that with which the physician is familiar, or there may be little or no clinical data on the use of a specific BoNT product for the proposed intervention. This paper is an introduction to a series of papers (which follow) in which an expert panel reviewed the BoNT clinical trial literature in order to provide evidence-based recommendations regarding the clinical use and efficacy of available BoNT preparations for four major therapeutic areas: movement disorders, spasticity, urology, and secretory disorders. Expert opinion is also included to address practical issues where more evidence and further research is needed. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: OnabotulinumtoxinA AbobotulinumtoxinA IncobotulinumtoxinA RimabotulinumtoxinB Chemodenervation Evidenced-based review
1. Introduction Botulinum neurotoxin (BoNT), produced by Clostridium botulinum, is a potent natural poison that blocks normal synaptic release of neurotransmitter at the muscle end plate and causes muscle relaxation. Historic steps in the discovery and characterization of BoNT span centuries (Table 1). The first practical application to human therapeutics occurred during the 1970s, when ophthalmologist Alan Scott, seeking an alternative to surgical correction of strabismus, injected BoNT into the extraocular muscles in primate and human subjects (Erbguth, 2008; Schantz and Johnson, 1992; Scott, 1981; Scott et al., 1973). These pioneering studies
* Corresponding author. E-mail address: [email protected] (M. Hallett). 0041-0101/$ – see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.toxicon.2012.11.024
established BoNT as the first microbial protein to be administered by injection for the treatment of human disease (Schantz and Johnson, 1992); they were the foundation for a body of research evaluating BoNT as a treatment for disorders characterized by excessive muscle tone. In contemporary medicine, the therapeutic injection of BoNT is performed in many clinical settings by an expanding population of clinicians. Several different BoNT preparations are available and provide potential alternative treatment options.
2. Botulinum neurotoxin therapeutics and the need for practical guidance There are seven serotypes (A–G) of BoNT, all of which block the exocytosis of acetylcholine into the neuromuscular junction, but only type A and type B are available for clinical use. These preparations are broadly utilized: In the
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Table 1 Major historic steps in the discovery and development of botulinum neurotoxin. Adapted from Erbguth (2008). 1700s 1817–1822 1895–1897 1910 1920–1930 1946 1949 1970s 1941–1972 1968 1973 1977–1980 1981–1988 1989 1989 1989 1990 1990s 2000
2002 2004 2005 2008 2009 2009
2009 2010
2010 2010 2011 2011
First documented endemic outbreaks of food-borne botulism (termed “sausage poisoning” in Europe) Justinus Kerner and botulinum toxin: Preliminary animal experiments, systematic descriptions of clinical effects; theoretic considerations of possible therapeutic use Emile Pierre van Ermengem: Discovery of neurotoxin-producing pathogen Clostridium botulinum J. Leuchs: Discovery of second botulinum toxin serotype (type B) H. Sommer: Purification of botulinum toxin C. Lamanna and J. Duff: Techniques of toxin concentration and crystallization A. Burgen: Description of toxin effect on acetylcholine release at neuromuscular junction Description of wound and infant botulism Edward Schantz: Production of toxin at Fort Detrick (US) Contact between Alan Scott and Edward Schantz; search for therapeutic agents (e.g., botulinum toxin) to relax eye muscles Alan Scott: Publication of animal experiments using injections of botulinum toxin into eye muscles Alan Scott: Treatment of strabismus patients with botulinum toxin; first publications of application in humans Development of type A toxin preparation in the UK; later renamed DysportÒ Alan Scott’s type A toxin preparation approved by FDA as Oculinum in the US; later renamed BotoxÒ Mark Hallett et al., show reproducible benefit for botulinum toxin injections in patients with hand dystonia (Cohen et al., 1989) Oculinum, Inc. receives FDA approval to market botulinum toxin type A in the United States as an orphan drug to treat strabismus, blepharospasm, and hemifacial spasm associated with dystonia in patients 12 years of age and older Dysport approved in the UK for blepharospasm and hemifacial spasm Discovery of molecular action of botulinum toxin (Schiavo, Montecucco, Dolly) The FDA approves BotoxÒ (botulinum toxin type A) for the treatment of abnormal head position and neck pain associated with cervical dystonia The FDA also approves MyoblocÒ (botulinum toxin type B) to reduce the severity of abnormal head position and neck pain associated with cervical dystonia MyoblocÒ is the US trade name for BoNT-B (NeuroblocÒ in Europe) FDA approves BotoxÒ Cosmetic (botulinum toxin type A) for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity FDA approves BotoxÒ (botulinum toxin type A) for the treatment of severe axillary hyperhidrosis that is inadequately managed by topical agents Approval of XeominÒ (botulinum toxin type A) in Germany for blepharospasm and cervical dystonia FDA issues “Early Communication, Ongoing Safety Review of BotoxÒ” and BotoxÒ Cosmetic (botulinum toxin type A) and MyoblocÒ (botulinum toxin type B) FDA issues new established names for botulinum toxin products FDA approves DysportÒ (abobotulinumtoxinA) for: Treatment of adults with cervical dystonia to reduce the severity of abnormal head position and neck pain Temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity FDA issues “Update of Safety Review of onabotulinumtoxinA (marketed as Botox/BotoxÒ Cosmetic), abobotulinumtoxinA (marketed as DysportÒ) and rimabotulinumtoxinB (marketed as MyoblocÒ)” FDA approves BotoxÒ (onabotulinumtoxinA) for treatment of upper limb spasticity in adult patients to decrease severity of increased muscle tone in elbow flexors (biceps), wrist flexors (flexor carpi radialis and flexor carpi ulnaris), and finger flexors (flexor digitorum profundus and flexor digitorum sublimis) FDA approves XeominÒ (incobotulinumtoxinA) to decrease severity of abnormal head position and neck pain in adults with cervical dystonia and to treat blepharospasm in patients previously treated with onabotulinumtoxinA (BotoxÒ) FDA approves BotoxÒ (onabotulinumtoxinA) for prophylaxis of headaches in adult patients with chronic migraine FDA approves BotoxÒ (onabotulinumtoxinA) for the treatment of urinary incontinence due to detrusor overactivity associated with a neurogenic condition in adults who have an inadequate response to or are intolerant of an anticholinergic medication FDA approves XeominÒ (incobotulinumtoxinA) for temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity
United States, 17 million treatments with one commercial botulinum product have been reported since 1994, and in the United Kingdom, over 1 million first-time exposures are now reported annually for facial cosmesis (Poulter, 2011; Singer, 2009). Clinical indications for BoNT treatment have expanded considerably since the first preparation was used for this purpose nearly two decades ago. BoNT is now considered first-line therapy for patients with certain movement disorders, including blepharospasm and cervical and focal limb dystonias. BoNT injection is also an established treatment option for spasticity in the setting of traumatic brain injury, cerebral palsy, and postcerebrovascular accident. Additionally, BoNT therapy has been shown to be effective for improving hyperactivity of
the detrusor muscle of the bladder, for conditions characterized by hypersecretion (such as hyperhidrosis and sialorrhea), for the prevention of chronic migraine, and for the treatment of facial lines. Its use remains exploratory for chronic pain management and a variety of gastrointestinal conditions. Clinical trials, case reports, and basic science investigations are continually published. A simple database search for publications of any type since 1990 with “botulinum” in the title returns over 14,000 citations; limiting the query to guidelines, meta-analyses, or clinical trials of any design returns over 1000 publications, and of these, approximately 800 appeared in the most recent decade (based on query results from pubmed.gov on November, 2011).
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BoNT therapy is not only heterogeneous in terms of clinical applications but also with regard to available BoNT formulations. First, there is pharmacologic heterogeneity, which is reflected by the availability of four different products (three type A and one type B) (Table 2). Each product has a unique dosing profile, and there are key differences in the structural attributes between type A and type B molecules (Fig. 1). The potency of each BoNT product is specific to the preparation and assay method employed, such that units of biological activity for one BoNT formulation cannot be compared or converted into units of any other preparation (Dysport [package insert], 2009; Botox [package insert], 2010; Myobloc [package insert], 2010; Xeomin [package insert], 2011). There also may be differential dosing relative to different indications. Second, there is mechanistic heterogeneity. While the primary effect of BoNT is relaxation, there is evidence to suggest that BoNT injected peripherally may also influence central nervous system (CNS) function and modulate sensory input (Abbruzzese and Berardelli, 2006; BachRojecky and Lackovic, 2009; Durham and Cady, 2011; Gazerani et al., 2010; Matak et al., 2011). Third, there is heterogeneity of clinical guidance, as the literature may have a preponderance of data for one preparation and a paucity of data for another preparation for the same indication. Finally, there is an inevitable regulatory heterogeneity due to discrepancy between approved indications for the various preparations and actual patterns of clinical use, e.g., use for management of spasticity in children with cerebral palsy (Table 3). As a practical matter, it is likely that all BoNT formulations will ultimately demonstrate efficacy across the same range of indications (Gollomp, 2011). Botulinum neurotoxin potency units are specific to each product, and the doses or units of biological activity cannot be compared or converted from one product to any other botulinum neurotoxin product. The unique established names reinforce these differences and the lack of interchangeability among products.
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3. Rationale for the neurotoxin expert panel The goal of the Neurotoxin Expert Panel was to update information regarding the clinical efficacy of BoNT across four major areas of clinical conditions: movement disorders, urologic conditions, spasticity secondary to the upper motor neuron syndrome, and hypersecretory disorders. Within each therapeutic area, the panel evaluated BoNT as a class and also, when the evidence allowed, assessed individual BoNT formulations. In this group of articles, the panel describes the results of their investigations, including advances in knowledge regarding the basic science of BoNT and mechanistic processes that may contribute to therapeutic outcome beyond muscle relaxation alone. As well, in these articles, the panel provides clinical guidance for practical concerns associated with effective use of BoNT. It is important to remember that although randomized, controlled trials represent the preferred form of clinical evidence, important clinical and practical considerations may remain unresolved despite publication of their results. Recruitment of participants into a randomized, controlled trial is challenging; the number of individuals ultimately enrolled may be only a small subset of the target population, and they may not represent the range of clinical phenotypes seen in usual practice (Appel, 2006). Subgroup analysis is problematic, since only portions of the total trial population are evaluated (loss of statistical power), and confounding variables may no longer be randomly distributed among groups (Hennekens and Demets, 2009). Guideline development is further complicated by the continual reporting of new information from clinical trials that may supersede previous recommendations or confirm them with additional evidence; similarly, new data of unclear clinical relevance may emerge. Numerous systematic reviews and guidelines put forth by major American and European specialty societies (Esquenazi et al., 2010; Karsenty et al., 2008; Naumann et al., 2008; Simpson et al., 2008a,b; Ward et al., 2003) as well as independent auditors of evidence-based medicine (Ade-
Table 2 Available botulinum neurotoxin formulations (Dysport [package insert], 2009; Botox [package insert], 2010; Myobloc [package insert], 2010; Xeomin [package insert], 2011; Gollomp, 2011). Trade name Generic name Manufacturer
BotoxÒ OnabotulinumtoxinA Allergan, Inc. Type A 1989 Single-use vials containing 100 Units or 200 Units Refrigeration
DysportÒ AbobotulinumtoxinA Ipsen Biopharmaceuticals, Inc. Type A 2009 Single-use vials containing 300 Units or 500 Units Refrigeration
MyoblocÒ RimabotulinumtoxinB Solstice Neurosciences, LLC (US WorldMeds, LLC) Type B 2000 Single-use vials containing 5000 Units Refrigeration
C botulinum serotype FDA approval (year) How supplied
Reconstitution diluent
Preservative-free 0.9% sodium chloride injection USP
Preservative-free 0.9% sodium chloride injection, USP
Warning
Distant spread of toxin effect
Distant spread of toxin effect
Not required (vial contains sterile injectable solution) May be diluted with normal saline Distant spread of toxin effect
Storage requirement
XeominÒ IncobotulinumtoxinA Merz Pharmaceuticals, LLC Type A 2010 Single-use vials containing 50 Units or 100 Units Room temperature, refrigeration, or freezer Preservative-free 0.9% sodium chloride injection, USP
Distant spread of toxin effect
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Fig. 1. Structural characteristics of botulinum neurotoxin (BoNT)-A and BoNT-B. Top: BoNT-A, YASARA (http://www.yasara.org) rendering. Middle: BoNT-B, Ribbons (http://www.cbse.uab.edu/ribbons) rendering. Bottom: Stereo views of BoNT-A and BoNT-B surfaces, shown in same orientation, electrostatic potential rendering (Montal, 2010; Swaminathan and Eswaramoorthy, 2000). Top figure adapted with permission of Annual Reviews, Inc. from Botulinum neurotoxin: a marvel of protein design, Montal, M., 79, 2010. Permission conveyed through Copyright Clearance Center, Inc. Middle and bottom figures adapted with permission from MacMillan Publishers Ltd: Nature Structural & Molecular Biology. Swaminathan S., Eswaramoorthy S., 2000. Structural analysis of the catalytic and binding sites of Clostridium botulinum neurotoxin B. Nat. Struct. Biol. 7, 693–699. Copyright 2000.
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Table 3 FDA-approved indications for available preparations of botulinum neurotoxin (Dysport [package insert], 2009; Botox [package insert], 2010; Myobloc [package insert], 2010; Xeomin [package insert], 2011). Preparation
FDA-approved indications
BotoxÒ (onabotulinumtoxinA)
DysportÒ (abobotulinumtoxinA)
XeominÒ (incobotulinumtoxinA)
MyoblocÒ (rimabotulinumtoxinB)
Treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (e.g., spinal cord injury, multiple sclerosis) in adults who have an inadequate response to or are intolerant of an anticholinergic medication Prophylaxis of headaches in adult patients with chronic migraine (15 days per month with headache lasting 4 h a day or longer) Treatment of upper limb spasticity in adult patients, to decrease the severity of increased muscle tone in elbow flexors (biceps), wrist flexors (flexor carpi radialis and flexor carpi ulnaris), and finger flexors (flexor digitorum profundus and flexor digistorum sublimis) Treatment of adults with cervical dystonia, to reduce the severity of abnormal head position and neck pain associated with cervical dystonia Treatment of severe axillary hyperhidrosis that is inadequately managed with topical agents Treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age Temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients 65 years of age (BotoxÒ Cosmetic) Treatment of adults with cervical dystonia to reduce the severity of abnormal head position and neck pain in both toxin-naïve and previously treated patients The temporary improvement in the appearance of moderate to severe glabellar lines associated with procerus and corrugator muscle activity in adult patients <65 years of age Treatment of adults with cervical dystonia, to decrease the severity of abnormal head position and neck pain in both botulinum toxin-naïve and previously treated patients Treatment of adults with blepharospasm who were previously treated with onabotulinumtoxinA (BotoxÒ) Temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients Treatment of adults with cervical dystonia to reduce the severity of abnormal head position and neck pain associated with cervical dystonia
Hall and Moore, 2000; Costa et al., 2005a–e; Duthie et al., 2007; Hoare et al., 2010; Wasiak et al., 2004a,b; Watts et al., 2004) have supported the efficacy of BoNT preparations as a class or have accepted the need for further study and incorporation of primary findings into future publications. Guidelines warrant periodic reassessment, as signals for updating may occur in a relatively short time (Oxman et al., 2006; Shojania et al., 2007). Such signals are apparent with regard to BoNT therapy and contribute to the rationale for this panel. A major objective of this panel is to complement the class-based focus of prior guidelines with information relevant to specific BoNT preparations. Sufficient clinical experience exists at this time to support pragmatic recommendations for effective clinical use not otherwise available from systematic reviews or randomized trials, particularly in regard to optimal dosage range and dilution for each preparation, by specific indication, as well as localization and guidance techniques. The large number of patients treated since the issuance of earlier major society guidelines may support comments regarding the relative efficacy of individual BoNT formulations, and efficacy in specific patient subgroups. The recommendations of this panel are therefore based on strict review of clinical evidence whenever available, while recognizing that BoNT studies enrolling patients with neurologic issues present the above-mentioned recruitment and methodological challenges. The panel also assessed both the strengths and limitations of available evidence to satisfy pertinent clinical questions; the panel’s grading of the evidence is a result of these assessments. In
instances in which clinical issues are not resolved satisfactorily by a review of findings from clinical studies, expert opinion based on the panel members’ collective clinical experience is provided in a separate paper within this series. 4. Conclusion BoNT can be injected to achieve therapeutic benefit across a large range of approved and investigative clinical indications. Treatment with BoNT has become a familiar feature of the contemporary medical landscape, offering the promise of improved patient outcomes and inspiring an extraordinary range of clinical investigation. We welcome this opportunity to expand available evidence-based guidance for clinicians utilizing BoNT therapy. Conflict of interest statement Mark Hallett receives funding from the Neurotoxin Institute. References Abbruzzese, G., Berardelli, A., 2006. Neurophysiological effects of botulinum toxin type A. Neurotox. Res. 9, 109–114. Ade-Hall, R.A., Moore, A.P., 2000. Botulinum toxin type A in the treatment of lower limb spasticity in cerebral palsy. Cochrane Database Syst. Rev.. CD001408. Appel, L.J., 2006. A primer on the design, conduct, and interpretation of clinical trials. Clin. J. Am. Soc. Nephrol. 1, 1360–1367. Bach-Rojecky, L., Lackovic, Z., 2009. Central origin of the antinociceptive action of botulinum toxin type A. Pharmacol. Biochem. Behav. 94, 234–238.
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Botox [Package Insert], 2010. Allergan Pharmaceuticals, Irvine, CA. Cohen, L.G., Hallett, M., Geller, B.D., Hochberg, F., 1989. Treatment of focal dystonias of the hand with botulinum toxin injections. J. Neurol. Neurosurg. Psychiatry 52, 355–363. Costa, J., Borges, A., Espirito-Santo, C., Ferreira, J., Coelho, M., Moore, P., Sampaio, C., 2005a. Botulinum toxin type A versus botulinum toxin type B for cervical dystonia. Cochrane Database Syst. Rev.. CD004314. Costa, J., Espirito-Santo, C., Borges, A., Ferreira, J.J., Coelho, M., Moore, P., Sampaio, C., 2005b. Botulinum toxin type A therapy for blepharospasm. Cochrane Database Syst. Rev.. CD004900. Costa, J., Espirito-Santo, C., Borges, A., Ferreira, J.J., Coelho, M., Moore, P., Sampaio, C., 2005c. Botulinum toxin type A therapy for hemifacial spasm. Cochrane Database Syst. Rev.. CD004899. Costa, J., Espirito-Santo, C., Borges, A., Ferreira, J.J., Coelho, M., Moore, P., Sampaio, C., 2005d. Botulinum toxin type B for cervical dystonia. Cochrane Database Syst. Rev.. CD004315. Costa, J., Espirito-Santo, C., Borges, A., Ferreira, J.J., Coelho, M., Sampaio, C., 2005e. Botulinum toxin type A versus anticholinergics for cervical dystonia. Cochrane Database Syst. Rev.. CD004312. Durham, P.L., Cady, R., 2011. Insights into the mechanism of onabotulinumtoxinA in chronic migraine. Headache 51, 1573–1577. Duthie, J., Wilson, D.I., Herbison, G.P., Wilson, D., 2007. Botulinum toxin injections for adults with overactive bladder syndrome. Cochrane Database Syst. Rev.. CD005493. Dysport [Package Insert], 2009. Ipsen Group, Brisbane, CA. Erbguth, F.J., 2008. From poison to remedy: the chequered history of botulinum toxin. J. Neural Transm. 115, 559–565. Esquenazi, A., Novak, I., Sheean, G., Singer, B.J., Ward, A.B., 2010. International consensus statement for the use of botulinum toxin treatment in adults and children with neurological impairments – introduction. Eur. J. Neurol. 17 (Suppl. 2), 1–8. Gazerani, P., Au, S., Dong, X., Kumar, U., Arendt-Nielsen, L., Cairns, B.E., 2010. Botulinum neurotoxin type A (BoNTA) decreases the mechanical sensitivity of nociceptors and inhibits neurogenic vasodilation in a craniofacial muscle targeted for migraine prophylaxis. Pain 151, 606–616. Gollomp, S., 2011. Neurotoxin therapy: a closer look at the four options. Pract. Neurol. 9, 27–33. Hennekens, C.H., Demets, D., 2009. The need for large-scale randomized evidence without undue emphasis on small trials, meta-analyses, or subgroup analyses. JAMA 302, 2361–2362. Hoare, B.J., Wallen, M.A., Imms, C., Villanueva, E., Rawicki, H.B., Carey, L., 2010. Botulinum toxin A as an adjunct to treatment in the management of the upper limb in children with spastic cerebral palsy (UPDATE). Cochrane Database Syst. Rev.. CD003469. Karsenty, G., Denys, P., Amarenco, G., De Seze, M., Game, X., Haab, F., Kerdraon, J., Perrouin-Verbe, B., Ruffion, A., Saussine, C., Soler, J.M., Schurch, B., Chartier-Kastler, E., 2008. Botulinum toxin A (Botox) intradetrusor injections in adults with neurogenic detrusor overactivity/neurogenic overactive bladder: a systematic literature review. Eur. Urol. 53, 275–287. Matak, I., Bach-Rojecky, L., Filipovic, B., Lackovic, Z., 2011. Behavioral and immunohistochemical evidence for central antinociceptive activity of botulinum toxin A. Neuroscience 186, 201–207. Montal, M., 2010. Botulinum neurotoxin: a marvel of protein design. Annu. Rev. Biochem. 79, 591–617.
Myobloc [Package Insert], 2010. Solstice Neurosciences, Inc, South San Francisco, CA. Naumann, M., So, Y., Argoff, C.E., Childers, M.K., Dykstra, D.D., Gronseth, G.S., Jabbari, B., Kaufmann, H.C., Schurch, B., Silberstein, S.D., Simpson, D.M., 2008. Assessment: botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 70, 1707–1714. Oxman, A.D., Schunemann, H.J., Fretheim, A., 2006. Improving the use of research evidence in guideline development: 16. Evaluation. Health Res. Policy Syst. 4, 28. Poulter, S., 2011. More women try the Botox way to stay young: over one million treatments carried out each year for the first time. The Daily Mail. http://www.dailymail.co.uk/femail/article-1298835/Overmillion-Botox-treatments-carried-year-time.html (accessed 30.04.12). Schantz, E.J., Johnson, E.A., 1992. Properties and use of botulinum toxin and other microbial neurotoxins in medicine. Microbiol. Rev. 56, 80–99. Scott, A.B., 1981. Botulinum toxin injection of eye muscles to correct strabismus. Trans. Am. Ophthalmol. Soc. 79, 734–770. Scott, A.B., Rosenbaum, A., Collins, C.C., 1973. Pharmacologic weakening of extraocular muscles. Invest. Ophthalmol. 12, 924–927. Shojania, K.G., Sampson, M., Ansari, M.T., Ji, J., Doucette, S., Moher, D., 2007. How quickly do systematic reviews go out of date? A survival analysis. Ann. Intern. Med. 147, 224–233. Simpson, D.M., Blitzer, A., Brashear, A., Comella, C., Dubinsky, R., Hallett, M., Jankovic, J., Karp, B., Ludlow, C.L., Miyasaki, J.M., Naumann, M., So, Y., 2008a. Assessment: botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 70, 1699–1706. Simpson, D.M., Gracies, J.M., Graham, H.K., Miyasaki, J.M., Naumann, M., Russman, B., Simpson, L.L., So, Y., 2008b. Assessment: botulinum neurotoxin for the treatment of spasticity (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 70, 1691–1698. Singer, N., 2009. So Botox isn’t just skin deep. http://query.nytimes.com/ gst/fullpage.html?res¼9404E3D9103BF931A25757C0A96F9C8B63& pagewanted¼all (accessed 30.04.12). Swaminathan, S., Eswaramoorthy, S., 2000. Structural analysis of the catalytic and binding sites of Clostridium botulinum neurotoxin B. Nat. Struct. Biol. 7, 693–699. Ward, A.B., Aguilar, M., De Beyl, Z., Gedin, S., Kanovsky, P., Molteni, F., Wissel, J., Yakovleff, A., 2003. Use of botulinum toxin type A in management of adult spasticity – a European consensus statement. J. Rehabil. Med. 35, 98–99. Wasiak, J., Hoare, B., Wallen, M., 2004a. Botulinum toxin A as an adjunct to treatment in the management of the upper limb in children with spastic cerebral palsy. Cochrane Database Syst. Rev. 3. CD003469. Wasiak, J., Hoare, B., Wallen, M., 2004b. Botulinum toxin A as an adjunct to treatment in the management of the upper limb in children with spastic cerebral palsy. Cochrane Database Syst. Rev. 4. CD003469. Watts, C.C., Whurr, R., Nye, C., 2004. Botulinum toxin injections for the treatment of spasmodic dysphonia. Cochrane Database Syst. Rev.. CD004327. Xeomin [Package Insert], 2011. Merz Pharmaceuticals, LLC, Greensboro, NC.
Contents lists available at SciVerse ScienceDirect
Toxicon journal homepage: www.elsevier.com/locate/toxicon
Review
Clinical utility of different botulinum neurotoxin preparations Steven B. Abrams a, Mark Hallett b, * a
Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467, USA The George Washington University School of Medicine and Health Sciences, Department of Neurology, Ross Hall, 2300 Eye Street NW, Suite 713W, Washington, DC 20037, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 June 2012 Received in revised form 27 November 2012 Accepted 29 November 2012 Available online 30 January 2013
Comparative literature assessing the relative safety and efficacy of different BoNT products is limited. The quantity and quality of data vary by preparation and indication. Clinicians seeking data relevant to the care of patients with specific conditions may find only reports about small numbers of patients with varying symptoms. While a literature search for “botulinum neurotoxins” will yield a large number of publications; only a fraction of these meet criteria for an academic evidence-based review. Patients may have been treated with a different BoNT formulation than that with which the physician is familiar, or there may be little or no clinical data on the use of a specific BoNT product for the proposed intervention. This paper is an introduction to a series of papers (which follow) in which an expert panel reviewed the BoNT clinical trial literature in order to provide evidence-based recommendations regarding the clinical use and efficacy of available BoNT preparations for four major therapeutic areas: movement disorders, spasticity, urology, and secretory disorders. Expert opinion is also included to address practical issues where more evidence and further research is needed. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: OnabotulinumtoxinA AbobotulinumtoxinA IncobotulinumtoxinA RimabotulinumtoxinB Chemodenervation Evidenced-based review
1. Introduction Botulinum neurotoxin (BoNT), produced by Clostridium botulinum, is a potent natural poison that blocks normal synaptic release of neurotransmitter at the muscle end plate and causes muscle relaxation. Historic steps in the discovery and characterization of BoNT span centuries (Table 1). The first practical application to human therapeutics occurred during the 1970s, when ophthalmologist Alan Scott, seeking an alternative to surgical correction of strabismus, injected BoNT into the extraocular muscles in primate and human subjects (Erbguth, 2008; Schantz and Johnson, 1992; Scott, 1981; Scott et al., 1973). These pioneering studies
* Corresponding author. E-mail address: [email protected] (M. Hallett). 0041-0101/$ – see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.toxicon.2012.11.024
established BoNT as the first microbial protein to be administered by injection for the treatment of human disease (Schantz and Johnson, 1992); they were the foundation for a body of research evaluating BoNT as a treatment for disorders characterized by excessive muscle tone. In contemporary medicine, the therapeutic injection of BoNT is performed in many clinical settings by an expanding population of clinicians. Several different BoNT preparations are available and provide potential alternative treatment options.
2. Botulinum neurotoxin therapeutics and the need for practical guidance There are seven serotypes (A–G) of BoNT, all of which block the exocytosis of acetylcholine into the neuromuscular junction, but only type A and type B are available for clinical use. These preparations are broadly utilized: In the
82
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Table 1 Major historic steps in the discovery and development of botulinum neurotoxin. Adapted from Erbguth (2008). 1700s 1817–1822 1895–1897 1910 1920–1930 1946 1949 1970s 1941–1972 1968 1973 1977–1980 1981–1988 1989 1989 1989 1990 1990s 2000
2002 2004 2005 2008 2009 2009
2009 2010
2010 2010 2011 2011
First documented endemic outbreaks of food-borne botulism (termed “sausage poisoning” in Europe) Justinus Kerner and botulinum toxin: Preliminary animal experiments, systematic descriptions of clinical effects; theoretic considerations of possible therapeutic use Emile Pierre van Ermengem: Discovery of neurotoxin-producing pathogen Clostridium botulinum J. Leuchs: Discovery of second botulinum toxin serotype (type B) H. Sommer: Purification of botulinum toxin C. Lamanna and J. Duff: Techniques of toxin concentration and crystallization A. Burgen: Description of toxin effect on acetylcholine release at neuromuscular junction Description of wound and infant botulism Edward Schantz: Production of toxin at Fort Detrick (US) Contact between Alan Scott and Edward Schantz; search for therapeutic agents (e.g., botulinum toxin) to relax eye muscles Alan Scott: Publication of animal experiments using injections of botulinum toxin into eye muscles Alan Scott: Treatment of strabismus patients with botulinum toxin; first publications of application in humans Development of type A toxin preparation in the UK; later renamed DysportÒ Alan Scott’s type A toxin preparation approved by FDA as Oculinum in the US; later renamed BotoxÒ Mark Hallett et al., show reproducible benefit for botulinum toxin injections in patients with hand dystonia (Cohen et al., 1989) Oculinum, Inc. receives FDA approval to market botulinum toxin type A in the United States as an orphan drug to treat strabismus, blepharospasm, and hemifacial spasm associated with dystonia in patients 12 years of age and older Dysport approved in the UK for blepharospasm and hemifacial spasm Discovery of molecular action of botulinum toxin (Schiavo, Montecucco, Dolly) The FDA approves BotoxÒ (botulinum toxin type A) for the treatment of abnormal head position and neck pain associated with cervical dystonia The FDA also approves MyoblocÒ (botulinum toxin type B) to reduce the severity of abnormal head position and neck pain associated with cervical dystonia MyoblocÒ is the US trade name for BoNT-B (NeuroblocÒ in Europe) FDA approves BotoxÒ Cosmetic (botulinum toxin type A) for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity FDA approves BotoxÒ (botulinum toxin type A) for the treatment of severe axillary hyperhidrosis that is inadequately managed by topical agents Approval of XeominÒ (botulinum toxin type A) in Germany for blepharospasm and cervical dystonia FDA issues “Early Communication, Ongoing Safety Review of BotoxÒ” and BotoxÒ Cosmetic (botulinum toxin type A) and MyoblocÒ (botulinum toxin type B) FDA issues new established names for botulinum toxin products FDA approves DysportÒ (abobotulinumtoxinA) for: Treatment of adults with cervical dystonia to reduce the severity of abnormal head position and neck pain Temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity FDA issues “Update of Safety Review of onabotulinumtoxinA (marketed as Botox/BotoxÒ Cosmetic), abobotulinumtoxinA (marketed as DysportÒ) and rimabotulinumtoxinB (marketed as MyoblocÒ)” FDA approves BotoxÒ (onabotulinumtoxinA) for treatment of upper limb spasticity in adult patients to decrease severity of increased muscle tone in elbow flexors (biceps), wrist flexors (flexor carpi radialis and flexor carpi ulnaris), and finger flexors (flexor digitorum profundus and flexor digitorum sublimis) FDA approves XeominÒ (incobotulinumtoxinA) to decrease severity of abnormal head position and neck pain in adults with cervical dystonia and to treat blepharospasm in patients previously treated with onabotulinumtoxinA (BotoxÒ) FDA approves BotoxÒ (onabotulinumtoxinA) for prophylaxis of headaches in adult patients with chronic migraine FDA approves BotoxÒ (onabotulinumtoxinA) for the treatment of urinary incontinence due to detrusor overactivity associated with a neurogenic condition in adults who have an inadequate response to or are intolerant of an anticholinergic medication FDA approves XeominÒ (incobotulinumtoxinA) for temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity
United States, 17 million treatments with one commercial botulinum product have been reported since 1994, and in the United Kingdom, over 1 million first-time exposures are now reported annually for facial cosmesis (Poulter, 2011; Singer, 2009). Clinical indications for BoNT treatment have expanded considerably since the first preparation was used for this purpose nearly two decades ago. BoNT is now considered first-line therapy for patients with certain movement disorders, including blepharospasm and cervical and focal limb dystonias. BoNT injection is also an established treatment option for spasticity in the setting of traumatic brain injury, cerebral palsy, and postcerebrovascular accident. Additionally, BoNT therapy has been shown to be effective for improving hyperactivity of
the detrusor muscle of the bladder, for conditions characterized by hypersecretion (such as hyperhidrosis and sialorrhea), for the prevention of chronic migraine, and for the treatment of facial lines. Its use remains exploratory for chronic pain management and a variety of gastrointestinal conditions. Clinical trials, case reports, and basic science investigations are continually published. A simple database search for publications of any type since 1990 with “botulinum” in the title returns over 14,000 citations; limiting the query to guidelines, meta-analyses, or clinical trials of any design returns over 1000 publications, and of these, approximately 800 appeared in the most recent decade (based on query results from pubmed.gov on November, 2011).
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BoNT therapy is not only heterogeneous in terms of clinical applications but also with regard to available BoNT formulations. First, there is pharmacologic heterogeneity, which is reflected by the availability of four different products (three type A and one type B) (Table 2). Each product has a unique dosing profile, and there are key differences in the structural attributes between type A and type B molecules (Fig. 1). The potency of each BoNT product is specific to the preparation and assay method employed, such that units of biological activity for one BoNT formulation cannot be compared or converted into units of any other preparation (Dysport [package insert], 2009; Botox [package insert], 2010; Myobloc [package insert], 2010; Xeomin [package insert], 2011). There also may be differential dosing relative to different indications. Second, there is mechanistic heterogeneity. While the primary effect of BoNT is relaxation, there is evidence to suggest that BoNT injected peripherally may also influence central nervous system (CNS) function and modulate sensory input (Abbruzzese and Berardelli, 2006; BachRojecky and Lackovic, 2009; Durham and Cady, 2011; Gazerani et al., 2010; Matak et al., 2011). Third, there is heterogeneity of clinical guidance, as the literature may have a preponderance of data for one preparation and a paucity of data for another preparation for the same indication. Finally, there is an inevitable regulatory heterogeneity due to discrepancy between approved indications for the various preparations and actual patterns of clinical use, e.g., use for management of spasticity in children with cerebral palsy (Table 3). As a practical matter, it is likely that all BoNT formulations will ultimately demonstrate efficacy across the same range of indications (Gollomp, 2011). Botulinum neurotoxin potency units are specific to each product, and the doses or units of biological activity cannot be compared or converted from one product to any other botulinum neurotoxin product. The unique established names reinforce these differences and the lack of interchangeability among products.
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3. Rationale for the neurotoxin expert panel The goal of the Neurotoxin Expert Panel was to update information regarding the clinical efficacy of BoNT across four major areas of clinical conditions: movement disorders, urologic conditions, spasticity secondary to the upper motor neuron syndrome, and hypersecretory disorders. Within each therapeutic area, the panel evaluated BoNT as a class and also, when the evidence allowed, assessed individual BoNT formulations. In this group of articles, the panel describes the results of their investigations, including advances in knowledge regarding the basic science of BoNT and mechanistic processes that may contribute to therapeutic outcome beyond muscle relaxation alone. As well, in these articles, the panel provides clinical guidance for practical concerns associated with effective use of BoNT. It is important to remember that although randomized, controlled trials represent the preferred form of clinical evidence, important clinical and practical considerations may remain unresolved despite publication of their results. Recruitment of participants into a randomized, controlled trial is challenging; the number of individuals ultimately enrolled may be only a small subset of the target population, and they may not represent the range of clinical phenotypes seen in usual practice (Appel, 2006). Subgroup analysis is problematic, since only portions of the total trial population are evaluated (loss of statistical power), and confounding variables may no longer be randomly distributed among groups (Hennekens and Demets, 2009). Guideline development is further complicated by the continual reporting of new information from clinical trials that may supersede previous recommendations or confirm them with additional evidence; similarly, new data of unclear clinical relevance may emerge. Numerous systematic reviews and guidelines put forth by major American and European specialty societies (Esquenazi et al., 2010; Karsenty et al., 2008; Naumann et al., 2008; Simpson et al., 2008a,b; Ward et al., 2003) as well as independent auditors of evidence-based medicine (Ade-
Table 2 Available botulinum neurotoxin formulations (Dysport [package insert], 2009; Botox [package insert], 2010; Myobloc [package insert], 2010; Xeomin [package insert], 2011; Gollomp, 2011). Trade name Generic name Manufacturer
BotoxÒ OnabotulinumtoxinA Allergan, Inc. Type A 1989 Single-use vials containing 100 Units or 200 Units Refrigeration
DysportÒ AbobotulinumtoxinA Ipsen Biopharmaceuticals, Inc. Type A 2009 Single-use vials containing 300 Units or 500 Units Refrigeration
MyoblocÒ RimabotulinumtoxinB Solstice Neurosciences, LLC (US WorldMeds, LLC) Type B 2000 Single-use vials containing 5000 Units Refrigeration
C botulinum serotype FDA approval (year) How supplied
Reconstitution diluent
Preservative-free 0.9% sodium chloride injection USP
Preservative-free 0.9% sodium chloride injection, USP
Warning
Distant spread of toxin effect
Distant spread of toxin effect
Not required (vial contains sterile injectable solution) May be diluted with normal saline Distant spread of toxin effect
Storage requirement
XeominÒ IncobotulinumtoxinA Merz Pharmaceuticals, LLC Type A 2010 Single-use vials containing 50 Units or 100 Units Room temperature, refrigeration, or freezer Preservative-free 0.9% sodium chloride injection, USP
Distant spread of toxin effect
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Fig. 1. Structural characteristics of botulinum neurotoxin (BoNT)-A and BoNT-B. Top: BoNT-A, YASARA (http://www.yasara.org) rendering. Middle: BoNT-B, Ribbons (http://www.cbse.uab.edu/ribbons) rendering. Bottom: Stereo views of BoNT-A and BoNT-B surfaces, shown in same orientation, electrostatic potential rendering (Montal, 2010; Swaminathan and Eswaramoorthy, 2000). Top figure adapted with permission of Annual Reviews, Inc. from Botulinum neurotoxin: a marvel of protein design, Montal, M., 79, 2010. Permission conveyed through Copyright Clearance Center, Inc. Middle and bottom figures adapted with permission from MacMillan Publishers Ltd: Nature Structural & Molecular Biology. Swaminathan S., Eswaramoorthy S., 2000. Structural analysis of the catalytic and binding sites of Clostridium botulinum neurotoxin B. Nat. Struct. Biol. 7, 693–699. Copyright 2000.
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Table 3 FDA-approved indications for available preparations of botulinum neurotoxin (Dysport [package insert], 2009; Botox [package insert], 2010; Myobloc [package insert], 2010; Xeomin [package insert], 2011). Preparation
FDA-approved indications
BotoxÒ (onabotulinumtoxinA)
DysportÒ (abobotulinumtoxinA)
XeominÒ (incobotulinumtoxinA)
MyoblocÒ (rimabotulinumtoxinB)
Treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (e.g., spinal cord injury, multiple sclerosis) in adults who have an inadequate response to or are intolerant of an anticholinergic medication Prophylaxis of headaches in adult patients with chronic migraine (15 days per month with headache lasting 4 h a day or longer) Treatment of upper limb spasticity in adult patients, to decrease the severity of increased muscle tone in elbow flexors (biceps), wrist flexors (flexor carpi radialis and flexor carpi ulnaris), and finger flexors (flexor digitorum profundus and flexor digistorum sublimis) Treatment of adults with cervical dystonia, to reduce the severity of abnormal head position and neck pain associated with cervical dystonia Treatment of severe axillary hyperhidrosis that is inadequately managed with topical agents Treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age Temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients 65 years of age (BotoxÒ Cosmetic) Treatment of adults with cervical dystonia to reduce the severity of abnormal head position and neck pain in both toxin-naïve and previously treated patients The temporary improvement in the appearance of moderate to severe glabellar lines associated with procerus and corrugator muscle activity in adult patients <65 years of age Treatment of adults with cervical dystonia, to decrease the severity of abnormal head position and neck pain in both botulinum toxin-naïve and previously treated patients Treatment of adults with blepharospasm who were previously treated with onabotulinumtoxinA (BotoxÒ) Temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients Treatment of adults with cervical dystonia to reduce the severity of abnormal head position and neck pain associated with cervical dystonia
Hall and Moore, 2000; Costa et al., 2005a–e; Duthie et al., 2007; Hoare et al., 2010; Wasiak et al., 2004a,b; Watts et al., 2004) have supported the efficacy of BoNT preparations as a class or have accepted the need for further study and incorporation of primary findings into future publications. Guidelines warrant periodic reassessment, as signals for updating may occur in a relatively short time (Oxman et al., 2006; Shojania et al., 2007). Such signals are apparent with regard to BoNT therapy and contribute to the rationale for this panel. A major objective of this panel is to complement the class-based focus of prior guidelines with information relevant to specific BoNT preparations. Sufficient clinical experience exists at this time to support pragmatic recommendations for effective clinical use not otherwise available from systematic reviews or randomized trials, particularly in regard to optimal dosage range and dilution for each preparation, by specific indication, as well as localization and guidance techniques. The large number of patients treated since the issuance of earlier major society guidelines may support comments regarding the relative efficacy of individual BoNT formulations, and efficacy in specific patient subgroups. The recommendations of this panel are therefore based on strict review of clinical evidence whenever available, while recognizing that BoNT studies enrolling patients with neurologic issues present the above-mentioned recruitment and methodological challenges. The panel also assessed both the strengths and limitations of available evidence to satisfy pertinent clinical questions; the panel’s grading of the evidence is a result of these assessments. In
instances in which clinical issues are not resolved satisfactorily by a review of findings from clinical studies, expert opinion based on the panel members’ collective clinical experience is provided in a separate paper within this series. 4. Conclusion BoNT can be injected to achieve therapeutic benefit across a large range of approved and investigative clinical indications. Treatment with BoNT has become a familiar feature of the contemporary medical landscape, offering the promise of improved patient outcomes and inspiring an extraordinary range of clinical investigation. We welcome this opportunity to expand available evidence-based guidance for clinicians utilizing BoNT therapy. Conflict of interest statement Mark Hallett receives funding from the Neurotoxin Institute. References Abbruzzese, G., Berardelli, A., 2006. Neurophysiological effects of botulinum toxin type A. Neurotox. Res. 9, 109–114. Ade-Hall, R.A., Moore, A.P., 2000. Botulinum toxin type A in the treatment of lower limb spasticity in cerebral palsy. Cochrane Database Syst. Rev.. CD001408. Appel, L.J., 2006. A primer on the design, conduct, and interpretation of clinical trials. Clin. J. Am. Soc. Nephrol. 1, 1360–1367. Bach-Rojecky, L., Lackovic, Z., 2009. Central origin of the antinociceptive action of botulinum toxin type A. Pharmacol. Biochem. Behav. 94, 234–238.
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