乌鸦传媒

SEATTLE -- A new botulinum toxin formulation kept cervical dystonia symptoms down for a solid 16 weeks in most patients treated in a manufacturer-sponsored phase III trial, a researcher said here.

Median time to maintain at least 80% of the peak treatment effect was 20-24 weeks, depending on the dosage of daxibotulinumtoxinA (Daxi for short) administered, reported Robert A. Hauser, MD, of the University of South Florida in Tampa. About two-thirds of patients still had at least 80% of the maximum effect at week 16, he told attendees at the American Academy of Neurology's (AAN) annual meeting.

At week 12 -- when symptoms would have returned in most patients receiving conventional botulinum toxin injections -- nearly all patients receiving Daxi still met the 80% threshold.

These results support a better efficacy profile for Daxi in comparison with ordinary paralytic agents such as onabotulinumtoxinA (Botox). Labels for these agents stress that patients shouldn't be retreated in less than 12 weeks (this is true for aesthetic applications as well as for movement disorders), and insurers generally won't pay for more frequent injections. Yet the injections' effects often don't last that long. Hauser cited earlier research indicating that fully 88% of patients on conventional therapy see symptoms returning before 12 weeks are up.

Daxi comes with a peptide-based excipient that binds the toxin to cell membranes, prolonging its duration of action, Hauser said.

Called , the main registration study for Daxi randomized 301 cervical dystonia patients 1:3:3 to single doses of placebo (n=46) or Daxi at 125 U (n=125) or 250 U (n=130).

The primary outcome measure was average score on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) taken at weeks 4 and 6. Duration of at least 80% of the maximum reduction from the baseline TWSTRS score was a key secondary endpoint. There was also a responder analysis based on clinician- and patient-assessed global change, and patients were asked about their level of satisfaction.

Patients needed TWSTRS scores of at least 20 to be eligible for the trial; the mean among participants was 43. Adults ages 18 to 80 were enrolled. Besides the assessments at weeks 4 and 6, participants were evaluated at week 12 and every 4 weeks after through week 36.

About 65% of participants were women; mean age was 58. One limitation of the study was that 95% were white. Some 85% had received another botulinum toxin agent previously, and the mean duration of illness was 11 years.

Mean declines in TWSTRS score over weeks 4 to 6 stood at -12.7 and -10.9 points for the low and high Daxi doses, respectively, versus -4.3 points in the placebo group, with P values well below 0.001.

Ratings of at least "a little better," "moderately better," or "very much better" were reported for 77% to 78% of patients by their clinicians (versus 46% in the placebo group); patient-reported assessments were very similar, both for their global impression of change and their satisfaction with treatment.

Adverse events were more common with Daxi, but most were mild and injection-site reactions were the most common. Muscular weakness, pain, and dysphagia were seen in 10 or fewer Daxi patients, compared with none in the placebo group.

An open-label follow-up study, , examined longer-term outcomes in a total of 357 patients, including 271 continuing from ASPEN-1 and 86 recruited afresh. In this study, patients were assessed periodically and were given repeat injections when symptom suppression fell below 80% of maximum, or at patient request and clinician approval. Dosage adjustments were possible at clinicians' discretion, based on individual patients' responses, with doses up to 300 U allowed.

As of data cutoff, all 357 in the extension received at least one dose, 234 received three, and 65 had gotten four. Change from baseline in TWSTRS score fell even further with subsequent doses, according to this report, reaching a mean of -17.9 points with three doses and -19.9 with four. Mean duration of treatment effect until another dose was required ranged from 19.9 to 26.0 weeks depending on the treatment cycle and dose.

No new safety signals were seen in the extension, and rates of new treatment-emergent adverse events edged downward with subsequent doses.

Daxi's manufacturer, Revance Therapeutics, is also targeting a range of aesthetic applications for the drug, with smoothing of glabellar "frown" lines the first for which it is seeking approval.

The clinical program for cervical dystonia is now complete, but regulatory filings are on hold until the drug is OK'd for glabellar lines, according to Revance. Approval has been delayed due t0 FDA concerns about the manufacturing process. The company made some modifications and a month ago. Once approved for glabellar lines, the company plans to seek a supplementary BLA for dystonia.

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