NEUROBLOC Solution for injection Ref.[6588] Active ingredients: Botulinum toxin type B

Pharmacotherapeutic group: muscle relaxant, peripherally acting agents
ATC code: M03AX01

Mechanism of action

NeuroBloc is a neuromuscular blocking agent. The mechanism of action of NeuroBloc in blocking neuromuscular conduction occurs by a three-step process:

1. Extracellular binding of the toxin to specific acceptors on motor nerve terminals.
2. Internalisation and release of the toxin into the cytosol of the nerve terminals.
3. Inhibition of acetylcholine release from nerve terminals at the neuromuscular junction.

When injected directly into a muscle, NeuroBloc causes a localised paralysis that gradually reverses over time. The mechanism by which muscle paralysis is reversed over time remains unknown, but may be associated with the intraneuronal turnover of the affected protein and/or sprouting of the nerve ending.

Clinical efficacy and safety

A series of clinical studies have been conducted to evaluate the efficacy and safety of NeuroBloc in the treatment of cervical dystonia. These studies have demonstrated the activity of NeuroBloc in both treatment-naïve patients, and patients who have previously received treatment with Botulinum Toxin Type A, including those that were considered clinically resistant to Botulinum Toxin Type A.

Two Phase III randomised, multicentre, double-blind, placebo-controlled studies were conducted in patients with cervical dystonia. Both studies enrolled adult patients (≥ 18 years) who had a history of receiving Botulinum Toxin Type A. The first study enrolled patients who were clinically resistant to type A toxin (A-non responders), confirmed by a Frontalis Type A test. The second study enrolled patients who continued to respond to type A toxin (A-responders). In the first study, type A resistant patients (A-non responders) were randomised to receive placebo or 10,000 U of NeuroBloc and in the second, type A toxin responsive patients (A-responders) were randomised to receive placebo, 5000 U or 10,000 U of toxin. The medicinal product was injected on a single occasion into 2 to 4 of the following muscles: splenius capitus, sternocleidomastoid, levator scapulae, trapezius, semispinalis capitus and scalene. The total dose was divided between the selected muscles and 1 to 5 injections per muscle were administered. There were 77 subjects enrolled into the first study and 109 subjects into the second. Patient evaluations continued for 16 weeks post injection.

The primary efficacy outcome variable for both studies was the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score (range of possible scores is 0-87) at Week 4. The secondary endpoints included Visual Analogue Scales (VAS) to quantify the Patient Global Assessment of change and the Physician Global Assessment of change, both from baseline to Week 4. On these scales, scores of 50 indicate no change, 0 much worse, and 100 much better. Results of comparisons of the primary and secondary efficacy variables are summarised in Table 1. Analysis of the TWSTRS sub scales revealed significant effects on the severity of cervical dystonia and its associated pain and disability.

Table 1. Efficacy Results from Phase III NeuroBloc Studies:

^* Analysis of covariance, two-tailed tests, α = 0.05

A further randomised, multicentre, double-blind study was conducted to compare the efficacy of NeuroBloc (10,000 U) to Botulinum Toxin Type A (150 U) in patients with cervical dystonia who have never previously received a botulinum toxin product. The primary efficacy assessment was the TWSTRS Total score, and secondary efficacy assessments included VAS assessment of change evaluated by patient and investigator, conducted at 4, 8 and 12 weeks after treatment. The study met the pre-defined criteria for non-inferiority of NeuroBloc compared to Botulinum Toxin Type A, both in terms of mean TWSTRS total score at week 4 after first and second treatment sessions, and in terms of duration of effect.

The non-inferiority of NeuroBloc compared to Botulinum Toxin Type A was further supported by a responder analysis where similar percentages of subjects showed improvement in the TWSTRS score at Week 4 of Session 1 (86% NeuroBloc and 85% Botox), and a similar proportion of subjects experienced at least a 20% decrease from baseline in the TWSTRS score at Week 4 of Session 1 (51% NeuroBloc, 47% Botox).

Further clinical studies and open label follow-up have shown that subjects can continue to respond to NeuroBloc for prolonged periods of time, with some subjects receiving more than 14 treatment sessions over a period of more than 3.5 years. In addition to improved function as demonstrated by a reduction in TWSTRS-total score, treatment with NeuroBloc was associated with a significant reduction in TWSTRS-Pain and pain VAS scores at each treatment session at weeks 4, 8 and 12 relative to baseline. In these studies, the average dosing frequency was approximately every 12 weeks.

The immunogenicity of NeuroBloc has been evaluated in two clinical studies and an open-label extension study. The presence of antibodies in these studies was assessed using the mouse protection assay (also known as the Mouse Neutralization Assay, MNA).

Immunogenicity data from three long-term clinical studies indicate that approximately one third of patients develop antibodies, as determined by the mouse neutralisation/mouse protection assay dependent on duration of exposure. Specifically, these studies showed approximately 19-25% seroconverted within 18 months of initiation of treatment, increasing to approximately 33-44% with up to 45 months of treatment. An investigation into the consequence of seroconversion showed that the presence of antibodies was not synonymous with a loss of clinical response, and did not have an impact on the overall safety profile. However, the clinical relevance of the presence of antibodies as determined by the mouse neutralisation/mouse protection assay is uncertain.

The extent and time course of seroconversion were similar in patients with prior toxin A exposure and those who were toxin A naïve, and between toxin A resistant and toxin A responsive patients.