PHILADELPHIA — IncobotulinumtoxinA (Xeomin, Merz Pharmaceuticals) conveys long-term safety and efficacy in patients with benign essential blepharospasm (BEB) who are botulinum toxin-naïve, new research suggests.
BEB is a focal dystonia that causes involuntary and excessive closure of the eyelids. The intramuscular injectable study drug is currently indicated for patients with BEB who have been previously treated with onabotulinumtoxinA (Botox), but the investigators wanted to assess it in patients who had not tried a toxin in the previous 12 months.
A phase 3 trial of 61 adult patients with the disorder showed that those who received single injections of a higher dose of incobotulinumtoxinA (50 U) had significantly greater improvement on symptom severity scores than their counterparts who received matching placebo.
The improvements were sustained during a 6- to 20-week open-label extension period that followed a single dose of the study drug at less than 70 U.
Although there were more adverse events (AEs) in the higher-dose incobotulinumtoxinA group than in the lower-dose (25 U) or placebo groups, most AEs were mild to moderate in severity, the researchers report.
Study author Fernando L. Pagan, MD, professor and vice chair of the Department of Neurology at MedStar Georgetown University Hospital, Washington, DC, told Medscape Medical News that labeling changes are now needed so that a patient with BEB — regardless of whether he or she is toxin-naïve or not — can still receive this treatment.
"Now we know that if a patient has blepharospasm, this is an option and incobotulinumtoxin-type A can be used right off the bat," he said.
Pagan presented the results here at the American Academy of Neurology (AAN) 2019 Annual Meeting.
Mechanism Differs From Other Toxins
The drug at 100 U was approved by the US Food and Drug Administration (FDA) recently for the treatment of sialorrhea (excessive drooling) through injection into glands. It is also used to treat muscle stiffness in the arm, cervical dystonia, and BEB via injection into muscle.
The current study is the first randomized phase 3 trial to assess the medication in toxin-naïve patients with BEB.
"We wanted to do this because there were no data to support the use of this drug in this type of patient with blepharospasm. A lot of times, when you tried to get approval for this drug, you couldn't get it because the data were only there for switch-over," Pagan said.
"In the original studies, the switch-over from onabotulinumtoxin-type A to incobotulinumtoxin-type A would be the only thing that would have indication. Now you have level A evidence with studies to show that incobotulinumtoxin-type A can be beneficial for patients both in a switch-over and in toxin naïve situations," he added. "Now you have the evidence to do what a lot of us in clinics were already doing. Sometimes that would be part of the push-back from some of the payers saying, 'No, there's no data for that.' So that's the purpose for this particular study."
He also noted that incobotulinumtoxinA has a different mechanism from many of the other toxins. "There aren't as many accessory proteins with it — and in the clinics we sometimes see a little bit better tolerability and not as many systemic side effects, yet it's just as good as the other toxins. It's a little bit cleaner, a little bit less protein load," Pagan said.
In the study, the investigators enrolled 61 patients ages 18 to 80 years (mean age, 55 years; 59% women) who had BEB, "characterized by spontaneous, spasmodic, intermittent, or persistent involuntary contractions of orbicularis oculi muscles," Pagan reported. They also had received no treatment with any botulinum neurotoxin serotype during the previous 12 months.
All participants were randomly assigned to receive single intramuscular injections of incobotulinumtoxinA at 25 U (12.5 U/eye, n = 19) or at 50 U (25 U/eye, n = 22), or matching placebo (n = 20). This was followed by an observation period of 6 to 20 weeks.
Measures included safety and mean change from baseline on Jankovic Rating Scale (JRS) severity subscores — with scores of 0 indicating no spasms and 4 indicating severe spasms.
Improved Symptom Severity
Six weeks after injection, the group receiving the higher-dose of the study drug showed significant improvement from baseline on the JRS severity subscore compared with the placebo group (mean change, -1.2; P = .0004), meeting the study's primary efficacy endpoint.
Although not statistically improved, the lower-dose group showed numerically improved severity subscores vs the placebo group (mean difference, -0.5; P = .15).
Patients with a JRS severity subscore of 2 or greater, signaling need for reinjection, were enrolled in an open-label extension period. They received single injections of the study at 70 or less units (≤35 U /eye), with the total dose left to the investigator's discretion.
Of all participants, 55 completed the main study period and 39 entered and completed the extension phase, which included another 6- to 20-week observation period.
Those in the extension phase showed significant reductions on the JRS severity subscore from the extension period's baseline to week 6 (mean change, -1.2) and to final visit (-0.7), and from the main treatment period's baseline to the extension period's final visit (-1.0; all comparisons with placebo, P < .0001).
They also showed improvement in scores on the Blepharospasm Disability Index (BSDI) from extension period baseline to week 6 (P < .0001) and to end of study (P = .0003).
AEs during the main treatment period were reported by 42.1% of the higher-dose group, 31.8% of the lower-dose group, and 30% of the placebo group. However, only 28.2% of the participants in the open-label extension period reported any AE.
At the end of the main treatment period, the only AE reported in more than 1 patient was eyelid ptosis, which occurred in 3 members of the higher-dose group (15.8%) and 2 members of the lower-dose group (9.1%).
During the extension phase, the most common treatment-emergent AEs were dry eye and eyelid ptosis (each occurring in 2 different patients); nervous system disorders (occurring in 1 of the original placebo-group members and 1 of the original high-dose group members); and respiratory, thoracic, and mediastinal disorders (occurring in 2 of the original placebo group members).
"IncobotulinumtoxinA showed sustained efficacy in toxin-naïve subjects with BEB. Long-term safety results were in line with the known safety profile," the investigators write.
Pagan noted that finding toxin-naïve patients "is not the easiest thing to do because there are so many toxins out there." Interestingly, most of the patients in the current study were in Greece, where "there were plenty of toxin-naïve patients compared with here in the US," he said.
"Still, this is an important study to really show clinical evidence that we can start off with this [drug]. We didn't have that evidence before; we assumed it but didn't have the evidence until now," Pagan said.
"I think the next step is to change the labeling to make it more accessible for patients. That's what it's all about: helping patients to have a better quality of life and symptomatic relief of whatever dystonia they have," he added. "The takeaway message is: this toxin works. And now we have another choice to be able to help our patients."
Session co-moderator Melissa Ko, MD, associate professor of neurology and ophthalmology at SUNY Upstate Medical University, Syracuse, New York, told Medscape Medical News that she would say the study's take-home message is that incobotulinumtoxinA "is not inferior in any way to the existing treatments" for BEB.
"It shows another option out of the myriad of botulinumneurotoxins that are available out on the market. It's another opportunity within the armamentarium that's available," Ko said.
"What they didn't discuss is that over time with the various neurotoxins, there can be the development of antibodies. From my understanding of these products, this particular one — because of its formulation — has the lowest likelihood of development of antibodies that can then, over time, decrease its effectiveness," she added.
Ko noted that BEB is a common "absolutely treatable condition. And this treatment absolutely adds to the tool kit of what's already available for blepharospasm."
Pagan and Ko have disclosed no relevant financial relationships.
American Academy of Neurology (AAN) 2019 Annual Meeting: Abstract S28.005. Presented May 7, 2019.
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Cite this: Botulinum Toxin Effective for Blepharospasm in Toxin-Naïve Patients - Medscape - May 10, 2019.