Neurotoxin Therapy: A Closer Look at the Four Options

Botulinum neurotoxin, available for clinical use in the US market as two serotypes, is a potent inhibitor of acetylcholine release from the presynaptic terminal. Since its development for therapeutic use more than 30 years ago, the agent has proven extremely versatile for a range of neurologic indications and even for cosmetic uses. Currently, there are four preparations of botulinum toxin available in the US, three for botulinum toxin type A and one for botulinum toxin type B. The type A serotype is available as onabotulinumtoxinA (Botox, Allergan), abobotulinumtoxinA (Dysport, Ipsen and Medicis for cosmetic use), and incobotulinumtoxinA (Xeomin, Merz), while the type B serotype is available as rimabotulinumtoxinB (Myobloc, Solstice Medical). (Table 1) Although all three preparations of the type A serotype have similar mechanisms of action, the available forms of botulinum toxin type A are pharmacologically distinct and may differ in their chemical formulation, clinical potency, and migration and diffusion characteristics.^1,2 The clinical implications of the differences between the preparations has not been definitively established. The three types of A preparations also have distinct indications, based upon regulatory approval. There are differences in dosing between the agents, and there may be other practical differences between them, such as variation in cost or insurance coverage. Following is a review of the four “flavors” of botulinum toxin currently available.

Molecular Weight and Complexing Proteins

Each botulinum toxin preparation contains botulinum neurotoxin, comprised of a heavy amino acid chain (100kD) and a light chain (50kd). Preparations of onaand abobotulinumtoxinA contain the toxin complexed with naturally occurring non-toxic proteins, producing a molecular weight of approximately 450kD. Two BNT (botulinum neurotoxin) molecules form a dimer with a molecular weight of approximately 900kD. For the incobotulinumtoxinA preparation, the complexing proteins are removed, yielding a molecular weight of 150kD.² Upon injection, complexing proteins, if present, rapidly disassociate from the toxin. When one discusses characteristics of these proteins, issues surrounding potential immunoresistance arise. The development of clinically relevant immunoresistance to BNT is no longer a significant clinical concern, as analyses of data involving large pools of patients show that it currently rarely develops.^3,4 The formulation of onabotulinumtoxinA was changed in 1997 to reduce the amount of protein, which has been directly linked to a reduction in clinical resistance.⁴

Host formation of botulinum neurotoxin antibodies (called blocking or neutralizing antibodies) leads to resistance, while antibodies formed against non-toxic proteins (called non-neutralizing antibodies) do not.² It has been accepted for some time that high single doses of botulinum toxin at each injection cycle and brief inter-injection intervals increase the risk of developing resistance. Antigenicity is inversely proportional to biological activity, because highly biologically active formulations contain low levels of inactivated toxin, which can nonetheless act as antigen. The specific biological activity (SBA) of the formulation is expressed as MU (mouse units)/ng BNT, while the protein load is expressed as the inverse: ng BNT/MU. The SBA of the available toxin preparations is 60MU-EV/ng BNT for abobotulinumtoxinA, 100MU-EV/ng BNT for onabotulinumtoxinA, 167MU-EV/ng BNT for incobotulinumtoxinA, and 5MU-EV/ng BNT for rimabotulinumtoxinB. ² While increasing levels of SBA are associated with reduced risk for resistance, there are no specific correlates of specific biological activity to resistance risk. Therefore clinical incidence of resistance is likely the best indicator of risk. Current clinical experience suggests a low risk with all currently available formulations. This observation dovetails with the laboratory observations that the development of clinical immunoresistance requires the induction of antibodies directed at several different molecular epitopes within the toxin complex. In addition, patient-specific factors, such as immune system reagibility, immunocompetence, and female sex appear to play a role in resistance induction.² Of note, cross-reactivity of toxin type A and toxin type B does not occur.
From a clinical standpoint, a patient who develops resistance to A serotype preparation can be successfully transitioned to serotype B. Unfortunately, a significant number of these patients have eventually developed clinical immunoresistance to the B serotype within 18 months of the therapy transition.⁵ There is little available evidence to suggest that transitioning to a different serotype A preparation will be effective for the serotype A resistant patient

Onset of Action and Diffusion

There has also been speculation that a smaller molecular weight could contribute to more rapid onset of action and perhaps to different diffusion rates, though this is unlikely, due to the fact that the native toxin rapidly dissociates from the complexing proteins upon injection. The issue of diffusion has been discussed more widely in the aesthetic arena, perhaps because cosmetic surgeons are particularly averse to inducing any undesirable cosmetic outcomes due to toxin spread. However, the presence or absence of complexing proteins does not appear to influence diffusion.^6,7 Furthermore, studies do not suggest a notable difference in the diffusion of the three botulinum toxin typeA preparations.⁸ In fact, a recent study involving injections into mouse legs found no significant difference in diffusion rates between the three preparations.⁹ Given that diffusion is expected to be equal for equal doses of toxin, it has been suggested that any clinically perceived difference in diffusion rates may relate to differences in dosing.⁸ For example, a pilot study of diffusion of onabotulinumtoxinA versus abobotulinumtoxinA for forehead hyperhidrosis suggested greater and therapeutically beneficial diffusion with abobotulinumtoxinA.¹⁰ However, abobotulinumtoxinA was provided at ratios from 2.5 up to 4 to 1 relative to onabotulinumtoxinA.

The possibility of diffusion is a clinical reality and an important clinical consideration, as indicated by the fact that FDA has added boxed warnings to all neurotoxins regarding this risk, as part of their REMS Risk Evaluation and Mitigation Strategies) program.

Similarly, discussion of onset has been more prevalent in the cosmetic arena, where at least anecdotally some clinicians report more rapid onset of action with abobotulinumtoxinA.¹¹ In reality, the literature contains injector and patient reports of onset within 24 hours of injection for both abobotulinumtoxinA and onabotulinumtoxinA.^12,13There are no head-to-head-tohead comparison trials to assess onset of efficacy in any indication. Again, differences in onset of action, if they exist, may be attributable to variability of dosing. Furthermore, the clinical significance of a 24- to 36- hour difference in onset may not be a primary consideration in treatment selection.

FDA-Approved Indications and Clinical Use

The FDA-approved indications for the available neurotoxin formulations vary. (Table 2) OnabotulinumtoxinA boasts the most indications. There is no reason to believe that the three prepartions of type A serotype cannot all be used for the same indications, and Medicare carriers, as referenced in their Local Carrier Determinations (LCD) in many parts of the country treat the agents as interchangeable. Botulinum toxin type B presents a notable exception. Given the low pH of the formulation, injection into sensitive areas is associated with significant burning and patient discomfort. Therefore, rimabotulinumtoxinB is not recommended for injection anywhere above the neck, discouraging its use for most cases of blepharospasm, migraine, and cosmetic indications.

Dosing

One clear, practical difference between neurotoxin preparations relates to dosing. One analysis showed the mean concentration¹⁴ of BNT/A neurotoxin in onabotulinumtoxinA is 0.73ng per 100 unit vial; in abobotulinumtoxinA is 3.24ng per 500 unit vial; and in incobotulinumtoxinA is 0.44ng per 100 unit vial
While the marketed preparations of onabotulinumtoxinA and incobotulinumtoxinA are equipotent and dosed at a 1:1 ratio,¹⁵ abobotulinumtoxinA is not. The potency of abobotulinumtoxinA relative to onabotulinumtoxinA has been estimated from 2:1 up to 6:1.¹⁶ A 2009 study concluded that dose-conversion ratios be-tween abobotulinumtoxinA and onabotulinumtoxinA of 4:1 and greater are not supported by the literature. The authors identified four key areas of evidence: nonclinical and preclinical studies; studies exploring the diffusion characteristics and effects of complexing proteins; comparative experimental data from human studies; and clinical studies. Randomized, controlled clinical studies indicate that 3:1 is more appropriate than 4:1, but the two products still are not equivalent at this ratio.7 In clinical practice, I have found a conversion ratio of 2.75:1 to work reasonably well.
It should be noted that the product literature for each preparation cautions against dosing conversion from one preparation to another. Rather, injectors should be familiar with the recommended dosing for each agent for specific indications. However, it is difficult for clinicians familiar with one agent not to think in terms of dosing for that agent. Nonetheless, recommended dosing for common indications for each preparation are provided in Table 3.

Each preparation comes with specific instructions for product reconstitution; individual preference often leads clinicians to develop preferred dilutions. For example, many clinicians typically use about a concentration 100U/cc with onabotulinumtoxinA or incobotulinumtoxinA, but I generally prefer to use 50U/cc. It is worth noting that due to the design of the vial, only 2cc of saline can be reliably used to dilute abobotulinumtoxin B, leading to a dilution of 250U/cc.

Cost and Insurance Coverage

Another practical consideration, and the one most likely to play a role in clinical decision-making, is the cost of therapy. Insurance coverage for neurotoxin therapy varies from plan to plan and region to region, but private insurers frequently follow the example of Medicare, making it worthwhile to assess how Medicare approaches treatment.

Medicare coverage decisions vary by region per the regional LCD (Table 4). Generally, carriers seem to cover onabotulinumtoxinA therapy for all of its FDAapproved therapeutic indications (not cosmetic use). However, in my experience, one national carrier, Aetna, has aggressively and excessively restricted coverage of botulinum toxin therapy, even in circumstances when it is universally recognized as being appropriate therapy. The newest indication, chronic headache, is also covered by many carriers, but with conditions placed on coverage, such as failure of conventional therapies. Some carriers view the serotype A preparations as virtually interchangeable and will cover abobotlinumtoxinA or incobotulinumtoxinA therapy for all the same indications for which onabotulinumtoxinA is covered. Others cover each agent only for its approved indications.

AbobotulinumtoxinA has instituted competitive pricing per unit relative to onabotulinumtoxinA or incobotulinumtoxinA. Even accounting for the need for more units of abobotulinumtoxinA, treatment is probably about 20 percent less with this agent. incobotulinumtoxinA and onabotulinumtoxinA have similar standard pricing. Recently, incobotulinumtoxinA launched a patient co-payment program that reduces an individual's out-of-pocket costs for treatment, thus potentially reducing the cost of treatment relative to onabotulinumtoxinA on a sustained basis. They alos launched a patient assistance program to provide no-cost therapy to the un- or under-insured OnabotulinumtoxinA has a patient assistance program for those patients who are uninsured or underinsured and who have incomes at three times the federal poverty level. AbobotulinumtoxinA provides samples to clinicians, which can be used to off-set therapy costs for a patient or provide therapy to a patient without the means to pay for the drug.

Making Comparisons

Botulinum neurotoxin A is exceptionally effective in the therapy of a vast array of conditions. Now that there are three preparations of this serotype on the market, physicians must be familiar with the perceived, actual, and potential differences between these pharmacologically distinct agents. In reality, the clinical consequences of differences in molecular weight, protein content, and diffusion are probably negligible. Dosing and cost are likely the main differences between the preparations. Costs and insurance restrictions may drive selection of a preparation for a given patient, suggesting that clinicians may need to be comfortable with more than one preparation.

Botulinum neurotoxin type B largely remains a second- line option for the rare patient who demonstrates clinical resistance to serotype A therapy.

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