John A Chaddock and Keith Foster at Syntaxin Ltd break down the therapeutic benefits of botulinum neurotoxins
Botulinum neurotoxins (BoNTs), the causative agents of botulism, are the most potent acute lethal toxins known, with lethal doses of 10-9g/kg of body weight (1). Perhaps surprisingly, therefore, BoNTs are also a first-line Regulatory Authority approved therapy for a variety of debilitating conditions, have been reported to be effective in the treatment of over 100 conditions, and have a worldwide market value of well over US$1 billion.
BOTULINUM NEUROTOXINS AS THERAPEUTICS
Research to investigate the therapeutic potential of BoNTs was initiated in the early 1970s by Alan Scott, whose goal was to identify a drug that would benefit the correction of strabismus (squint) and to be used as an alternative to the approach of the time, which was surgery. Having injected a number of drugs into the extraocular muscles, BoNT was identified as the preferred candidate for further investigation. Its paralytic effect lasted for several weeks, with a lack of systemic side effects as well as a controllable dosage/response relationship. Scott and colleagues developed the techniques and dosing protocols to such a degree that by the 1980s BoNT was being used in the clinic to treat strabismus (2). Following this pioneering report, BoNT/A was used throughout the 1980s to treat a range of dystonias (involuntary muscle spasms), including blepharospasm (closure of the eyelids), and was shown to be a safe and effective therapy for a large number of neurological diseases.
FDA approval of BoNT/A as an orphan drug for the treatment of strabismus, blepharospasm and hemifacial spasm was given in December 1989. The drug has subsequently been approved for the treatment of cervical dystonia, glabellar wrinkles and hyperhydrosis (excessive sweating) and has been used off-label and reported to be effective in more than 100 different clinical conditions (3). In addition to their effects on muscle contraction and autonomic conditions, BoNT preparations, particularly BoNT/A, have recently been reported to relieve pain. In this, as in other indications, the toxins’ prolonged duration of action is a major advantage.
RISING SALES
The FDA-approved BoNT/A product is manufactured under the trade name BOTOX® by Allergan Inc. An alternative BoNT/A preparation, DYSPORTTM, which is not currently FDA approved but is used extensively in Europe, is manufactured by Ipsen Ltd. Although BOTOX® and DYSPORTTM are both formulations of BoNT/A, they are not interchangeable products. A preparation of BoNT/B has more recently received regulatory approval for use in cervical dystonia. This product is available from Solstice Neurosciences Inc as MYOBLOC® in the US, and NEUROBLOCTM in Europe.
THE BIOLOGY OF BONTS
There are seven immunologically distinct serotypes of botulinum neurotoxin, named BoNT/A to BoNT/G. All BoNTs exert their effect at the neuromuscular junction where they inhibit secretion of the neurotransmitter, acetylcholine, causing a flaccid paralysis. The neurotoxins have their effect by proteolytically cleaving members of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein family. These SNARE proteins are essential for the fusion of synaptic vesicles to the presynaptic membrane, and secretion of the vesicles’ contents, so their cleavage prevents neurosecretion.
