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Among key presentations at this year’s meeting of the American Academy of Neurology (AAN), a review of Guillain-Barré syndrome cases subsequent to H1N1 vaccine administration found overall rates to be not higher than usual; however, a cluster of cases in the period just subsequent to injection needs follow-up study. Clinical trial findings showed significant improvements in fibromyalgia symptoms with sodium oxybate, and two analyses of a new botulinum neurotoxin type A agent (NT-201) with potential advantages over the existing drug (Botox) demonstrate safety and efficacy in cervical and focal dystonias. The AAN meeting, which took place in Toronto from April 10 to 17, attracted 10,000 participants and included 2,500 abstract presentations.
An analysis aiming to describe the occurrence and characteristics of Guillain-Barré syndrome (GBS) after administration of H1N1 vaccine in the U.S. in 2009 found the rate to be only slightly higher than that noted by the same researcher (Dr. Souayah), who reported GBS rates incurred with the seasonal flu vaccine. In patients with GBS, the immune system attacks a part of the peripheral nervous system, causing tingling and weakness in the legs, spreading to the arms and upper body. Although recovery is usually complete, some individuals have long-term weakness. In severe cases, GBS can cause death.
As reported by the Centers for Disease Control and Prevention (CDC) and the FDA, the rate of GBS with the H1N1 vaccine was 6.2 cases per 10 million people vaccinated, and the rate of GBS with seasonal flu vaccine was 10.6 per 10 million vaccinations.
“Although preliminary, these reported cases of GBS do not appear to show an increased risk of GBS following vaccination with either the 2009 H1N1 or the seasonal flu strain and the safety record for these vaccines is excellent,” Dr. Souayah said.
However, he did note that 31 of the 62 GBS cases occurred within the first two weeks after vaccination. The odds against this distribution being attributed to chance are enormous (P < 0.0002). Still, he said that the vaccine benefits far outweigh the risks. Furthermore, to the question voiced at the AAN press conference—is there a subgroup of vaccine candidates who should avoid the H1N1 vaccine because they are more susceptible to GBS?—Dr. Souayah answered that he didn’t know.
Because of the lack of a treatment for the H1N1 virus, vaccination remains, in effect, the first-line prevention therapy, he commented.
A drug approved for the treatment of narcolepsy and cataplexy demonstrated significant improvements in fibromyalgia symptoms in a phase 3, 14-week, randomized, double-blind, placebo-controlled study. The study was conducted in eight countries (the U.S., Germany, Spain, France, the United Kingdom, Poland, Italy, and The Netherlands).
Fibromyalgia is characterized by widespread pain, often accompanied by fatigue, unrefreshing sleep, and psychological distress.
In an interview, Dr. Swick noted that sodium oxybate (SXB, Xyrem, Jazz Pharmaceuticals) robustly improved slow-wave sleep and consolidated sleep. Sleep is significantly impaired in fibromyalgia, and proof-of-concept studies have shown that improving sleep with mild-to-moderate doses of SXB relieved fibromyalgia symptoms. The mechanism by which SXB works in fibromyalgia is not understood, Dr. Swick said, but it is known to produce alterations in epinephrine, histamine, serotonin, and dopamine. SXB is a form of GHB, a known drug of abuse.
“It’s a complicated picture,” he commented. “We believe it helps by consolidating sleep.”
In the study, 573 patients with fibromyalgia received SXB 4.5 g each night (n = 195), SXB 6 g each night (n = 190), or placebo (n = 188) in a 1:1:1 ratio. Outcome measures included the percentage of patients who reported clinically relevant 30% and 50% reductions on the Pain Visual Analogue Scale (VAS), the mean reduction in Fatigue VAS, and global status, as measured by Patient Global Impression of Change (PGI–C) Scale.
Mean patient age was approximately 47 years (with about 90% female). After 14 weeks, significant pain reductions were achieved in both SXB groups (Table 1).
Significant reductions from baseline Pain VAS and Fatigue VAS scores were also reported for both doses of SXB, compared with placebo (P < 0.05 for both pain and fatigue). Also, a significantly higher proportion of subjects (P < 0.01) reported their global status to be much better or very much better on the PGI–C Scale with SXB 4.5 g (32.1%) or SXB 6 g (39.7%), relative to placebo (16%).
Overall, 14% of patients discontinued therapy because of adverse events (AEs)—6% in the placebo group, 15% in the SXB 4.5-g group, and 21% in the SXB 6-g group. AEs were generally mild or moderate in severity, and nausea was the most common AE (approximately 20%) in the SXB patients.
Dr. Swick concluded that this first international trial of SXB of fibromyalgia “confirmed and extended the data showing that SXB is efficacious and well tolerated in fibromyalgia patients.”
Repeated injections of NT-201 (botulinum neurotoxin type A), known as BoNT/A (Merz), produced significant improvements in symptoms of patients with cervical dystonia throughout a treatment period of at least 48 weeks. NT-201 has shown comparable efficacy and safety to onabotulinumtoxinA (Botox, Allergan) in treating cervical dystonia in a 1:1 dosing comparison. Cervical dystonia is characterized by involuntary neuromuscular hyperactivity in the neck and shoulder, leading to abnormal head movements and postures.
Dr. Marx noted that NT-201 is a purified form of BoNT/A that is free from the complexing proteins known to induce formation of neutralizing antibodies. These antibodies contribute to secondary treatment failure.1
At 37 centers in the U.S., patients with cervical dystonia who completed a placebo-controlled, double-blind study of NT-201 for 20 weeks or less were then entered into an extension phase. They received NT-201 at doses of 120 or 240 units (U) at five or fewer injection intervals over a period of one year (48 weeks plus a 20-week follow-up). Injection intervals were at least six weeks, with a mandatory visit four weeks after each injection. Injection intervals were chosen at the discretion of the patient and physician. Outcome measures included the Toronto Western Spasmodic Torticollis Rating Scale, or TWSTRS, and the frequency of AEs.
A first long-term safety analysis included 153 patients (mean age, 53 years, with about 33% male) from a total of 217 who were entered into the double-blind extension. Sixty-six patients (43.1%) received the maximum of five injections. Although re-injection was allowed after six weeks, the mean duration before re-injection was 10 to 12.7 weeks for patients receiving 240 U and 11 to 14.5 weeks in the 120-U group. TWSTRS–total scores were significantly improved at four weeks after each injection (P ≤ 0.05) as well as at the study termination visit, compared with the first injection visit of the extension phase (P < 0.001). There were no significant differences between TWSTRS total scores for NT-201 240 U and NT-201 120 U or in TWSTRS subscores in terms of severity, disability, or pain.
During the extension period, 37.2% of patients receiving 240 U and 30.7% of patients receiving 120 U experienced AEs related to the study medication. No serious AEs were considered to be related to NT-201. The incidence of AEs lessened with each injection interval, indicating a lack of cumulative effects. No withdrawals were attributed to AEs.
Dr. Marx concluded, “Repeated doses of NT-201 were well tolerated and effective in significantly improving the symptoms of cervical dystonia at each injection interval over a treatment period of 48 weeks or longer.”
More than 50% of patients with focal dystonias (e.g., blepharospasm or cervical dystonia) reported at least moderate symptomatic improvement with injected doses of Merz’ botulinum toxin type A (NT-201) in an analysis of four pooled studies. Blepharospasm is characterized by involuntary contractions of the orbicularis oculi muscle of the eye; cervical dystonia involves involuntary contractions of the throat and neck. Direct injection of botulinum toxin into overactive muscles produces local muscle relaxation in focal dystonias.
Dr. Marx stated that NT-201 is the only available preparation of botulinum toxin type A that is free from the complexing proteins known to induce formation of neutralizing antibodies that can lead to treatment failure. He also pointed out that unlike onabotulinumtoxinA (Botox), NT-201 does not need to be refrigerated, allowing for greater ease of transport.
Dr. Marx presented pooled data from four randomized, double-blind, multicenter studies, including 613 patients treated with NT-201 and 108 receiving placebo. Two of the studies, with the FDA-approved botulinum toxin agent (Botox) as a comparator, tested for non-inferiority of NT-201. The other two studies were placebo-controlled.
The majority of patients had received previous treatment with botulinum neurotoxin preparations containing complexing proteins. In all studies, patients received one set of injections with NT-201or placebo or Botox. Patients in the NT-201 groups received 35 to 50 U per eye for blepharospasm and 70 to 300 U for cervical dystonia. Patients were monitored for up to 20 weeks in the placebo-controlled studies or for 16 weeks in the comparator-controlled studies.
Outcome measures were change in TWSTRS severity scores (baseline to week 4 in the cervical dystonia studies) and Jankovic Rating Scale (JRS) scores (baseline to weeks 3 and 6 in the blepharospasm studies), onset, duration, and waning of treatment effect and patient-evaluated global response.
In the placebo-controlled studies, the mean percentage of improvement over placebo for NT-201 in the primary efficacy criterion of local muscle relaxation was similar across studies (23.8% to 25.4%). Reductions in scores with NT-201 were significant when compared with placebo in the individual placebo-controlled studies (P < 0.001) as well.
Investigators globally rated the efficacy of NT-201 treatment as good or very good in more than half of the patients in the placebo-controlled studies (51.3 to 65.3%). Overall, 53.4% of patients receiving NT-201 reported moderate, marked, or complete symptomatic improvement compared with 12% of placebo patients. Measures of onset (6–7.7 days), waning (6.5–10.6 weeks), and duration (10.6–14 weeks) of treatment effects were similar in all four individual studies.
Dr. Grafe concluded, “The efficacy of NT-201 has been consistently demonstrated across several controlled clinical studies of patients with focal dystonia.”