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Emergent Antibodies Remain a Concern in Long-Term Botulinum Toxin Therapy



ARTICLE IN BRIEF

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KAPLAN-MEIER analysis of the probability of remaining neutralizing antibody (NAB) negative in all five patient subgroups. With duration of treatment, the decline of the Kaplan-Meier curves becomes steeper and steeper. In the other dystonia (ODT), cervical dystonia (CD), and spasticity (SPAS) subgroups, up to 40 percent of the patients had become NAB positive after a duration of treatment of 15 years. BSP=blepharospasm; FHS=facial hemispasm.

New data finding that neutralizing antibodies are present in patients who have been on botulinum toxin therapies long-term suggest that neurologists should aim to use the lowest doses of botulinum toxin therapies consistent with a desired clinical outcome. Independent commentators agreed, noting that the new data underscore that the risk for emergent antibodies to the therapy, previously thought to have been addressed in newer formulations, remains a clinical concern, which neurologists should monitor.

Nearly 14 percent of patients on long-term botulinum neurotoxin therapy have neutralizing antibodies to it, a large observational study from researchers in Germany has found, a rate far higher than seen in previous, shorter-duration studies.

The rate varied based on the dose patients received, with higher doses associated with higher risk of neutralizing antibodies (NAB). The findings, published in the November 21 online issue of Neurology, suggest that neurologists should aim to use the lowest doses consistent with a desired clinical outcome, the authors of the paper said.

Independent commentators agreed, noting that the new data underscores that the risk for emergent antibodies to the therapy, previously thought to have been addressed in newer formulations, remains a clinical concern, one neurologists should monitor.

The cross-sectional study of 596 outpatients treated at Heinrich-Heine-Universtät Düsseldorf, in Germany, found that 83 patients, or 13.9 percent overall, had measurable NABs. Much of that risk was found in those patients who had switched from one formulation to another over the course of their treatment: of those who had switched formulations, 33 percent had NABs, compared with 6 percent of those treated solely with abobotulinum toxin (Dysport), and 7 percent of those given onabotulinum toxin (Botox).

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DR. CARLOS SINGER: “The less you give, and the less frequently you give, the more you can assure that patients will not develop antibodies.”

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DR. PHILIPP ALBRECHT: “Its possible that some doctors will now consider prescribing incobotulinum toxin rather than one of the older formulations. But we would really like to see longer follow-up times with it first, to really show if it does have a lower degree of antigenicity.”

Presumably those who had switched to a different therapy formulation had higher rates because many of them had developed NABs in response to their initial treatment, the paper's authors reasoned.

The study found no risk of NABs in patients taking incobotulinum toxin (Xeomin), suggesting that its complete lack of complexing proteins all but eliminates the antigenicity seen in other formulations. But because incobotulinum toxin has been available for only a few years, that finding needs to be interpreted with caution until longer studies are published, the first author of the paper told Neurology Today.

“It's possible that some doctors will now consider prescribing incobotulinum toxin rather than one of the older formulations,” said Philipp Albrecht, MD, consulting neurologist and head of the botulinum toxin outpatient clinic at the University Hospital of Düsseldorf. “But we would really like to see longer follow-up times with it first, to really show if it does have a lower degree of antigenicity.”

For now the main takeaway for clinicians is that dose matters, said Richard L. Barbano, MD, PhD, FAAN, professor of neurology and chief of the movement disorders division at the University of Rochester, who was not involved with the study.

“This paper suggests that the rate of neutralizing antibodies might be higher than we suspected, based on shorter studies,” Dr. Barbano said. “It does lead us to ask whether neurologists should alter their practices to minimize or use the lowest effective dose of botulinum toxin for their patients.”

STUDY DETAILS

The study group included patients receiving botulinum toxin for any indication, including facial hemispasm, blepharospasm, cervical dystonia, other dystonia (which included oromandibular dystonia, Meige syndrome, and limb dystonias), and spasticity. The rate of NABs for the latter three indications was almost identical, whereas treatment of hemifacial spasm was associated with no NABs, and blepharospasm also had a low rate. The authors explained this disparity by pointing to the far lower doses of botulinum toxin used in patients being treated for facial hemispasm or blepharospasm, compared with the doses used in the other indications.

The average duration of treatment in the higher-dose patients was about five years, Dr. Albrecht said, although some patients had been continuously treated for as long as 25 years.

“We have a very long-standing botulinum toxin outpatient clinic that started from the very, very early days,” he said.

The long duration of treatments in the study group is what enabled Dr. Albrecht's group to see the real-world, long-term effect on NABs, he said.

“A lot of doctors were thinking that the percentage of neutralizing antibodies is low, based on data from the big phase 2 trials,” he said. “Those [trials] offered short-term data, in patients treated for two years. They found an incidence of neutralizing antibodies of between 0.5 to 1.5 percent per year. Our data suggest the rates are much higher, especially in those indications where high doses are indicated.”

Although treatment duration was significantly associated with the risk of developing NABs, Dr. Albrecht pointed out that neurologists cannot choose how long a patient requires treatment, as most require the treatment indefinitely.

“The only way we can influence our patients' risk of NABs is by reducing their dose,” he said. “This suggests that...the doses of botulinum toxin should be kept as low as possible.”

To determine the effect of dosage level, the investigators divided patients into three dose groups: 0-350 unified dose units (uDU), 351-700 uDU, and greater than 700 uDU. The rate of NABs was significantly higher in patients who had received mean doses of more than 350 uDU compared with those treated with smaller doses (p<0.003). The rate of NABs was highest in those who had been treated with greater than 700 uDU (p<0.003).

Unlike most previous studies of NABs, which involved primarily patients with secondary treatment failure, the new paper looked only at patients still receiving treatment. As a result, the study authors noted, “some patients from our cohort may have discontinued therapy due to secondary treatment failure before they could be enrolled in the study, and the rates of NABs might have been even higher if these would have been included.”

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DR. DAVID M. SIMPSON: We believe short intervals with low doses have a low risk of antibodies. But we need to prove that in the trials were doing.”

A regression analysis of children receiving botulinum toxin for cerebral palsy found no influence of age of onset of the therapy on the occurrence of NABs. But the fact that up to 30 percent of such children had NABs provided support for the theory that dose per kilogram of body weight may play a significant role, not only in children with cerebral palsy but perhaps in patients receiving treatment for other indications as well.

EXPERT COMMENTARY

David M. Simpson, MD, FAAN, professor of neurology and director of the neuromuscular division at the Icahn School of Medicine at Mount Sinai, said he commends the authors of the paper for performing the study. “This is important information as to whether or not there are still immunogenic concerns with the botulinum toxins,” he said.

The earliest formulation of onabotulinumtoxinA, back in the late 1980s and early 1990s, had a relatively high incidence of NABs, he said. “But after a newer formulation became available in which the protein load was about five times lower than in the original formulation, the general perception was that the incidence of antibodies had gone down dramatically. If the data in this new study are true, it tells us that the antibody issue has not gone away. That kind of data will be a surprise to many neurologists.”

But most neurologists already use the lowest effective dose possible, said Carlos Singer, MD, professor of neurology and chief of the Center for Parkinson's Disease and Movement Disorders at the Leonard M. Miller School of Medicine at the University of Miami. He tries to spread out the dosing intervals to longer than three months when possible, he said.

“If I can do it every four months, or even every five or six, I do it,” he said. “The less you give, and the less frequently you give, the more you can assure that patients will not develop antibodies.”

Dr. Simpson offered a different point of view regarding the intervals between treatments. Because nearly all patients in the study were treated every 12 to 13 weeks, he said, no firm conclusions can be drawn as to whether shorter intervals would be associated with increased risk. He is currently conducting randomized clinical trials for patients with focal dystonia using low doses given at intervals as small as every two to four weeks.

“We believe short intervals with low doses have a low risk of antibodies,” Dr. Simpson said. “But we need to prove that in the trials we're doing.”

How clinically meaningful the development of NABs is another question not answered by the current study, Dr. Singer said. “We can surmise that in the next two or three years, some of the patients with NABs will develop secondary treatment failure,” he said. “But the authors of the study would need to do a follow-up study to find out.”

Dr. Albrecht said his group is already planning such a study, although he pointed out that prior studies have found that 50 percent of patients with secondary treatment failure have NABs. “It's not a good thing to have these neutralizing antibodies,” he said. “There isn't a lot of argument about that.”

Given the imperfect correlation between NABs and treatment failure, many neurologists do not go to the expense of testing for NABs, said Catherine L. Gallagher, MD, professor of neurology at the University of Wisconsin School of Medicine and Public Health. “Practically speaking, if we have a patient who presents as a new treatment failure after responding for years, we may put a small test dose into the frontalis muscles and evaluate one to two weeks later for loss of forehead wrinkling, which indicates toxin sensitivity,” she said. “If the patient proves insensitive, we may then switch the formulation. It's a functional rather than a laboratory-based test.”

Dr. Singer noted the paper's disclosure that the NAB testing in the study had been funded by a grant from Merz Pharmaceuticals, maker of incobotulinum toxin.

Even so, Dr. Simpson said, if the finding of no NABs associated with incobotulinum toxin holds up in future studies, “that would be a very, very important finding. That needs to be replicated.”

DISCLOSURES

Dr. Albrecht reported no disclosures relevant to the study. Simpson declared research support and consulting fees from Allergan, Merz, and Ipsen. Dr. Barbano declared honoraria for advisory board meetings with Allergan, Ipsen, and Dysport, as well as salary and stock options from VisualDx. Dr. Singer had no financial or commercial relationships to disclose.

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