History of onabotulinumtoxinA therapeutic

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2 History of onabotulinumtoxinA therapeutic

Mitchell F. Brin, Andrew Blitzer

Summary and Key Features

• Botulinum toxin has become a valuable therapy for treating selected neurological and urological disorders and managing the appearance of glabellar facial lines

• After identification of a muscle-relaxing substance present in sausages, scientists attributed these effects to a bacterium that became known as Clostridium botulinum. They isolated and characterized the neurotoxin, and described its mechanism of action on nerve terminals

• Dr Alan Scott, an ophthalmologist in San Francisco, began studying botulinum toxin type A (‘Oculinum’) in the 1960s and 1970s as a possible treatment for patients with strabismus

• Following Alan Scott’s successful studies in strabismus patients, he and others, including our group at Columbia University working under a research protocol, examined botulinum toxin type A in several neurological conditions, including blepharospasm, cervical dystonia, and also hyperfunctional facial lines, marked by the overactivity of facial or neck muscles

• Oculinum was approved for the treatment of strabismus and blepharospasm by the United Stated Food and Drug Administration in 1989

• Alan Scott’s first manufactured research therapeutic, Oculinum, was later acquired by Allergan and renamed Botox^®

• Other botulinum toxin products have subsequently been licensed, each having its own clinical profile and dosing strategy; today these products have unique non-proprietary names

• As of 2011, onabotulinumtoxinA (Botox^® / Botox^® Cosmetic) is approved for multiple indications worldwide, including eight indications in the United States

• In providing a treatment option for several rare neurological conditions, the clinical development of onabotulinumtoxinA may have contributed to an enhanced understanding of these disorders

Introduction

The development of botulinum toxin for therapeutic use is marked by its cross-disciplinary use for varied medical conditions. In particular, botulinum toxin has become a valuable therapy for selected disorders, treated by multiple specialists, whereby symptoms were inadequately managed with existing treatments.

In this chapter, we provide an overview of development events, interspersed with personal observations of historical and human interest. Due to the structure and format of this book, this chapter is not fully referenced. For full reference citations to the events described here, the reader is referred to the additional reading list at the end of this document and the references therein and is encouraged to seek supplementary sources.

Currently unapproved uses are mentioned for historical purposes, and health care providers should ascertain product licensure information regarding locally approved indications. In describing the formally developed uses of botulinum toxin, we confine ourselves to those for which Botox^® (onabotulinumtoxinA) has been approved by regulatory agencies in the United States or Europe.

Identification, isolation, and characterization

The first well-described cases of medical illness after oral ingestion of an apparent foodstuff that may have contained some botulinum toxin were reported between 1817 and 1822 by the German physician Justinus Kerner. Kerner noted that the active substance interrupted signals from the motor nerves to muscles, but spared sensory nerves and cognitive abilities. He also theorized that the substance could possibly be used as therapy for medical conditions when ingested orally.

The bacterial etiology of botulism was first noted by the microbiologist Emile Pierre van Ermengen who documented his findings in 1897, identifying and naming the responsible bacteria as Bacillus botulinus, which later became Clostridium botulinum. In 1905, Tchitchikine found that C. botulinum produced a substance that affected neurotransmitter function. In 1919, Professor Burke of Stanford University described an alphabetical classification for the different serotypes of botulinum toxin based on his toxin–antitoxin experiments.

Purification and crystallization of botulinum neurotoxin followed in the ensuing decades, eventually enabling mechanism of action studies. Dr Carl Lamanna and colleagues observed dissociation between the hemagglutinating activity of botulinum toxin type A and its toxicity, leading to further studies that identified both toxic and non-toxic proteins in the crystalline toxin complex. Lamanna also observed the extreme potency of botulinum toxin, which would later be recognized as a major advantage for a local, injectable therapy. In the late 1940s and early 1950s, Arnold Burgen and Vernon Brooks at McGill University discovered that botulinum toxin acted presynaptically to block the release of acetylcholine from motor nerve terminals. Brooks mentioned to a colleague, Edward Schantz, that the toxin might be useful for weakening hyperactive muscles.

Edward Schantz had worked in the Chemical Corps at Fort Detrick purifying botulinum toxin using the method established by Lamanna and Duff. Schantz then relocated to the University of Wisconsin where he perfected the purification and crystallization of botulinum toxin. In 1971, Daniel Drachman, with toxin purified and supplied by Edward Schantz, showed that injecting minute amounts of botulinum toxin type A in the hindlimbs of chicks caused local denervation. In 1979, Lance Simpson described the key elements of the mechanism of action: binding, internalization, translocation, and interruption of neurotransmitter release. Pamphlett clarified that there is neither cell death nor axonal degeneration and the affected nerve terminals do not degenerate. Although traditionally called a neurotoxin because of its potential to cause generalized muscle weakness at exceedingly high doses, in 2004 our group reported that botulinum toxin type A is not cytotoxic.

Exploration of clinical potential

In the 1960s and 1970s, Alan Scott, an ophthalmologist in San Francisco, was seeking an alternative to surgery for the correction of strabismus. Scott has described the events that led to his clinical studies with botulinum toxin type A in several articles, and readers are encouraged to read his accounts. Scott and his colleague Carter Collins were studying the forces and actions of eye muscles, and they considered whether a long-acting muscle-weakening agent could be used for treatment of strabismus. Based on Daniel Drachman’s work, Scott thought that botulinum toxin might be an option. Drachman directed Scott to Edward Schantz, who provided him with botulinum toxin for testing. It was noted that, historically, outbreaks of type A botulism produced predominantly motor weakness, whereas type B caused a predominance of autonomic symptoms and thus type A was selected by Scott. Schantz provided the crystallized botulinum toxin type A by regular mail in a metal tube placed in another metal tube.

Scott took the crystalline toxin into his laboratory and diluted it into small aliquots, buffered it with albumin instead of gelatin, and developed testing and storage conditions. He found that injecting minute amounts into extraocular muscles of monkeys with electromyographic (EMG) guidance produced long-lasting effects for the correction of strabismus and, at the doses used, without any systemic effects. Scott published these preclinical results in 1973, performed additional preclinical toxicology studies to evaluate doses that produced systemic effects in primates and obtained an Investigational New Drug (IND) designation from the US Food and Drug Administration (FDA) to conduct the first clinical trial for humans with strabismus in 1977 by injecting minute amounts locally into the extraocular muscles. He called his formulation ‘Oculinum’ (Fig. 2.1). This clinical trial led to the 1980 publication of the first 19 patients, where efficacy in treating strabismus was reported.

Figure 2.1 Oculinum 100 units research vial.

In the early 1980s, at the Columbia University Neurological Institute, we were funded by the Dystonia Medical Research Foundation with the primary goal of identifying effective treatments for dystonia, in addition to exploring the disease’s genetic underpinnings. Stanley Fahn was the principal investigator of the Center, Mitchell Brin was a Movement Disorders Fellow and Center’s Program Coordinator, and Andrew Blitzer was acting Chairman of the Department of Otolaryngology. Dr Fahn learned directly from Dr Scott when he attended a workshop in which Dr Scott described his use of Oculinum. He submitted a protocol to the Columbia University Institutional Review Board and also obtained an IND from the FDA to evaluate the potential therapeutic use of Oculinum. The clinical protocol’s inclusion criteria enabled our broad research program.

During our first year of study, we examined the potential use of Oculinum in treating patients with primary and symptomatic inappropriate contractions, including those of the facial muscles (e.g. blepharospasm, hemifacial spasm, jaw (oromandibular dystonia, temporomandibular joint dysfunction), facial synkinesis, palatal myoclonus, tongue), neck (e.g. cervical dystonia), vocal cords (e.g. spasmodic dysphonia), limbs (e.g. arm dystonia, writer’s cramp, occupational / stenographer’s cramp, legs), various tremors, etc. and reported our initial findings in 1985. Many of our treatments were the first-described therapeutic assessments of Dr Scott’s botulinum toxin type A, and these were further elaborated upon in subsequent publications. Furthermore, the research contributed to the establishment of new areas for investigation.

In addition, we were interested in possible systemic effects. In our initial studies, we tested vital capacity with a hand-held spirometer and did not find an adverse effect on pulmonary function. We also initiated single-fiber electromyography studies, identified subclinical distant muscle effects, and reported our findings.

Nomenclature

Alan Scott called his manufactured research therapeutic ‘Oculinum’. The name Oculinum reflected the strabismus use and was a combination of linking the ‘ocul’ for eyes, with ‘lining’-up-the-eye and the Latinate ending ‘um’ added to legitimate drugs (personal communication, Alan Scott). At Columbia University, we coined and published the term ‘Botox’, which was the same product (Oculinum) manufactured by Dr Scott. This original formulation, Oculinum, was licensed to Allergan with the first approval for strabismus and blepharospasm in December 1989. Allergan subsequently acquired the product in 1991 as ‘Oculinum Injectable’, and then changed the trade name to ‘Botox^®; this name was accepted by the FDA in 1992.

Although the finished, marketed botulinum neurotoxin products do not have the same properties, publications have discussed the neurotoxins without referring to brand names. Historically, basic science colleagues used the abbreviations BoNT, Botx, and BoTX and BoTx for the research, raw material botulinum toxin, with BoNT/A referring to serotype A. ‘BTX’ had also been used for more than two decades to refer to finished products, with BTX-A referring to serotype A. This nomenclature should not be confused with Batrachotoxin (‘poison dart frog’ poison), which has also been abbreviated as BTX. In the early 2000s, ‘BTXA’ was used for the product manufactured by the Lanzhou Institute of Biological Products (LIBP) of the People’s Republic of China (PRC). Consequently, most authors discontinued the use of BTXA or BTX-A when referring generally to type A botulinum toxin, and adopted the BoNTA or BoNT-A terminology. However, in 2009, the FDA applied the United States Adopted Names Council terminology to botulinum toxins, with onabotulinumtoxinA referring to Botox^®, abobotulinumtoxinA to Dysport^® and rimabotulinumtoxinB referring to Myobloc^®, and subsequently, incobotulinumtoxinA for Xeomin^®, Merz’s formulation of BoNTA.

When discussing different botulinum neurotoxin products, it is important to note their differences in clinical dosing. Botulinum toxin doses are expressed in units of biological activity, which differ for each product. For instance, the units of onabotulinumtoxinA and abobotulinumtoxinA are different and in 1993 we published the statement that ‘these products are distinct, and dosing is significantly different so that if one administers the same number of Dysport^® units as when delivering Botox^®, serious side effects may occur.’ Regulatory agencies worldwide have issued language stating that units are neither interchangeable nor convertible between different botulinum products. Thus, unit doses of one product cannot be used to generate doses of another.

Developed indications for onabotulinumtoxinA

OnabotulinumtoxinA is approved for eight different indications in the United States, which are described in Table 2.1 along with their year of approval and the US FDA indication. Table 2.1 also lists the approval years for these indications in the European Union (EU).

Table 2.1 Approved indications for onabotulinumtoxinA in the United States and Europe

Strabismus

As noted previously, the therapeutic use of botulinum toxin type A began with strabismus, in 1978 when Alan Scott used the toxin to treat the disorder in children after successful experiments in monkeys. The rationale for treating strabismus was that the toxin would create weakness in the injected ocular muscles, causing them to relax over time. This would enable the antagonist muscles contract more effectively, achieving the desired result. Scott noted in 1980 that, along with its efficacy in strabismus correction, botulinum toxin type A was an appropriate therapeutic agent because it had no known effects other than muscle paralysis, had no antigenic effects at small doses and, based on his experience at the time, did not diffuse to muscles adjacent to those injected, produced dose-dependent effects that could last for several weeks, and, in the treatment of strabismus, did not show systemic effects.

Scott’s work, including a combination of double-blind and open-label studies under his original IND, led to the initial FDA approval for botulinum toxin type A as Oculinum in 1989 for the treatment of strabismus.

Blepharospasm

After his initial success with onabotulinumtoxinA for the treatment of strabismus, Scott postulated that the toxin could also be used to treat blepharospasm by weakening the orbicularis oculi muscles. He proved his theory correct when he injected 39 cases and observed improvement in all of them. Several case series, open-label and double-blind placebo-controlled (DBPC) studies, including our own, confirmed the efficacy of onabotulinumtoxinA for blepharospasm. OnabotulinumtoxinA was approved by the FDA in 1989, along with strabismus, for the treatment of blepharospasm associated with dystonia in patients at least 12 years of age.

Cervical dystonia

Alan Scott treated the first three cervical dystonia patients with his product in 1983. Joseph Tsui et al at the University of British Columbia then extended this work and published a pilot study in which 12 patients received onabotulinumtoxinA injections into relevant neck muscles for the treatment of spasmodic torticollis (cervical dystonia). In both their pilot study and a follow-up DBPC study, they observed that onabotulinumtoxinA not only decreased abnormal movement but provided pain relief as well; our studies demonstrated similar results.

Shortly after beginning our research with onabotulinumtoxinA, we were funded by the FDA’s Office of Orphan Product Development to conduct a double-blind study examining the efficacy of onabotulinumtoxinA in the treatment of cervical dystonia, the results of which were reported by Greene et al in 1990. Later, based on an Allergan-sponsored, pivotal Phase III study, onabotulinumtoxinA was approved by the FDA in 2000 for the treatment of cervical dystonia in adult patients, to reduce the severity of abnormal head position and neck pain.

Glabellar lines

The use of onabotulinumtoxinA for cosmetic purposes dates back to the 1980s and the history of these investigations is described in another chapter. Allergan initiated a development program for the treatment of glabellar lines that ultimately led to worldwide approvals of this indication. OnabotulinumtoxinA was approved in several countries in South America by 2000, as Botox^® Cosmetic in Canada in April 2001 and in the USA on 12 April 2002 for the treatment of moderate to severe glabellar lines.

Primary focal hyperhidrosis

In the 1950s, Ambache reported on animal studies that explored the potential blocking effect of botulinum toxin on sweat glands. Human data were not available until 1994, when Bushara & Park reported areas of anhidrosis around botulinum toxin type A injection sites in hemifacial spasm patients.

Allergan initiated a series of registration clinical trials examining onabotulinumtoxinA for the treatment of axillary hyperhidrosis. Two global pivotal studies were conducted, with additional long-term follow-up extensions. Whereas the benefit typically experienced by patients treated with skeletal muscle disorders is approximately 3–4 months, the average duration of effect in axillary hyperhidrosis is 6–7 months, with 28% of patients experiencing benefit exceeding 1 year in one study. These studies led to global registration of onabotulinumtoxinA for the treatment of severe axillary hyperhidrosis, with approval by the FDA in 2004.

Adult post-stroke spasticity

In 2009 Alan Scott reported treating the first patients with thigh adductor spasms, ‘Rather large doses of 300 units in two patients with thigh adductor spasms showed systemic safety…’. Many years after his initial treatments, reports of possible systemic effects were described in other patients.

In 1989, Das & Park of the Southend District Stroke Unit of Rochford Hospital in Essex, United Kingdom reported on the use of botulinum toxin type A to treat eight post-stroke patients refractory to conventional therapy and observed improvement in spasticity with an acceptable side effect profile. Many open-label and several double-blind trials followed and have confirmed these findings.

Allergan initiated a global registration program focused on treating patients with upper-limb post-stroke spasticity. Approved in Europe in 2001, US approval was granted in 2010.

Juvenile cerebral palsy

Most neurotoxin development programs of botulinum toxin type A in children with cerebral palsy have focused on equinus gait deformity, a common motor manifestation of prolonged focal muscle spasticity in this population. Approved for equinus gait deformity due to spasticity in Europe in 1997 and currently in most of the world, onabotulinumtoxinA is not approved for this indication in the United States, and development continues.

Chronic migraine

The migraine history, similar to that of cosmetic, was serendipitous. Drs Blitzer and William Binder were residents at the Mount Sinai Hospital and together they published their first manuscripts in 1978. In the early 1990s, Dr Blitzer trained Dr Binder on the cosmetic treatment approach, and he collaborated on our research and co-authored our initial hyperfunctional facial lines manuscripts. Also in the 1990s, Dr Binder observed that, when treating patients with onabotulinumtoxinA for cosmetic enhancement, some of his patients with a history of migraine headaches reported a reduction or elimination of the number or intensity of their headaches concurrently with the cosmetic effect. Having later contacted us, we pooled our observations and reported our findings in 1998, with a full manuscript published in 2000. Allergan initiated a headache development program and explored dose, treatment paradigm, and patient selection in multiple studies. Two large Phase III studies were conducted and onabotulinumtoxinA was approved for chronic migraine in the UK and US in 2010.

Neurogenic detrusor overactivity

Schurch first reported the use of onabotulinumtoxinA to treat detrusor overactivity in spinal cord-injured patients in 2000. Allergan initiated a development program examining the effects of onabotulinumtoxinA treatment for detrusor overactivity in patients with spinal cord injury and multiple sclerosis. This program resulted in the issuance of licenses for onabotulinumtoxinA for neurogenic detrusor overactivity in North America, Europe and other regions in 2011.

Cell-based potency assay

The mouse LD₅₀ potency assay is required by global regulatory agencies for testing final commercial neurotoxin product prior to release. This assay has been the standard for potency and stability testing for all botulinum neurotoxins, and involves determining the median lethal dose of botulinum neurotoxin in mice at 72 hours following intraperitoneal injection. The ‘3R’ principles of refinement, reduction and eventual replacement of laboratory animals in manufacturing have been an objective of many pharmaceutical companies.

Allergan addressed these principals for onabotulinumtoxinA manufacturing, recognizing the hurdle to overcome the technical challenges of establishing a non-animal assay that: (1) reflected the four distinct mechanisms of neurotoxin action (binding, internalization, translocation, cleavage of SNAP-25); (2) established an appropriate level of assay sensitivity; and (3) met quality standards for commercial use and hurdles that regulatory agencies established for approval of changes to product-related procedures. In 2011, a cell-based potency assay (CBPA) for onabotulinumtoxinA was approved by the FDA, and subsequently additional regulatory agencies. The CBPA is used, where approved, for stability and potency testing with the goal of reducing the use of animal-based assay testing.

Commentary

The seminal work of Dr Alan Scott has opened doors to numerous patients and scientists, and botulinum toxin therapy joins other biopharmaceuticals that have impacted medical care by safely and effectively relieving a spectrum of chronic and previously often ineffectively treated human disorders. In the field of aesthetics, onabotulinumtoxinA has advanced the science of facial rejuvenation. In addition to the direct medical benefits for patients, botulinum toxin therapy has elevated the general awareness of many conditions, particularly uncommon ones where patients were enrolled into clinical research studies, and also those approved by regulatory agencies for treatment. This increased awareness afforded the medical research community the opportunity to further characterize and study these disorders, often with remarkable results. Historically, at the authors’ original Columbia University Center, the availability of onabotulinumtoxinA as a research therapy brought patients into the clinic where descriptive, genetic, pathophysiology, and other studies were conducted. It seems possible that the increased number of patient consultations, coupled with funding from governmental, patient, and other organizations, helped advance the original mission of the Dystonia Medical Research Foundation and those of other organizations, and accelerated scientific progress.

None of this work could have been performed without the broad contributions of so many patients, investigators, scientists and clinicians.

Acknowledgments

The authors gratefully acknowledge the editorial assistance of Mary Ann Chapman, PhD.

Further reading

Ambache N. A further survey of the action of Clostridium Botulinum toxin upon different types of autonomic nerve fibre. Journal of Physiology (Lond). 1951;113:1–17.

Brin MF, Aoki KR, Dressler D. Pharmacology of botulinum toxin therapy. In: Brin MF, Comella C, Jankovic J. Dystonia: etiology, clinical features, and treatment. Philadelphia: Lippincott, Williams & Wilkins; 2004:93–112.

Brin MF, Blitzer A. Botulinum toxin: dangerous terminology errors [letter] [see comments]. Journal of the Royal Society of Medicine. 1993;86:493–494.

Brin MF, Fahn S, Moskowitz C, et al. Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Movement Disorders. 1987;2:237–254.

Brooks VB. Vernon Brooks. In: Squire LR, ed. The history of neuroscience in autobiography. New York: Academic Press; 2001:76–117.

Burgen AS, Dickens F, Zatman LJ. The action of botulinum toxin on the neuro-muscular junction. Journal of Physiology (Lond). 1949;109:10–24.

Burke GS. Notes on Bacillus botulinus. Journal of Bacteriology. 1919;4:555–570.

Bushara KO, Park DM. Botulinum toxin and sweating. Journal of Neurology, Neurosurgery and Psychiatry. 1994;57:1437–1438.

Das TK, Park DM. Effect of treatment with botulinum toxin on spasticity. Postgraduate Medical Journal. 1989;65:208–210.

Fahn S, List T, Moskowitz CB, et al. Double-blind controlled study of botulinum toxin for blepharospasm. Neurology. 1985;35(Suppl1):271.

Greene P, Kang U, Fahn S, et al. Double-blind, placebo-controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology. 1990;40:1213–1218.

Kerner J. Das Fettgift und die Fettsaure und ihre Wirkungen auf den thierischen Organismus. Ein Beytrag zur Untersuchung des in verdorbenen Wursten giftig wirkenden Stoffes. Stuttgart, Tubingen: Cotta-Verlag; 1822.

Scott A. Development of botulinum toxin (Foreword). In: Jankovic J, Albanese A, Atassi MZ, et al. Botulinum toxin – therapeutic clinical practice and science. Philadelphia: Saunders, 2009.

Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Journal of Pediatric Ophthalmology and Strabismus. 1980;17:21–25.

Scott AB. Preface. In: Jankovic J, Hallett M. Therapy with botulinum toxin. New York: Marcel Dekker; 1994:vii–ix.

Scott AB. Development of botulinum toxin therapy. Dermatologic Clinics. 2004;22:131–133. v

Simpson LL. The origin, structure, and pharmacological activity of botulinum toxin. Pharmacological Reviews. 1981;33:155–188.

Snipe PT, Sommer H. Studies on botulinus toxin. 3. Acid precipitation of botulinus toxin. Journal of Infectious Diseases. 1928;43:152–160.

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