History of onabotulinumtoxinA therapeutic

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2 History of onabotulinumtoxinA therapeutic

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

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.

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).

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.

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.

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.