A novel botulinum neurotoxin topical gel: Treatment of allergic rhinitis in rats and comparative safety profile.

BACKGROUND: Rhinitis affects a significant proportion of adults and children with typically seasonal or chronic symptoms. Botulinum neurotoxin type A (BoNTA) is a well-known cholinergic antagonist widely used in a number of approved neurological and esthetic indications. This study was designed to assess the therapeutic effect of RT001, a novel topical gel formulation of BoNTA, in the treatment of allergic rhinitis using a rat model and to compare its safety profile with that of an aqueous formulation of BoNTA complex. METHODS: A rat model of allergic rhinitis was used involving induction of classic rhinitis signs (sneezing and nasal itch) in addition to nasal inflammatory pathology to assess the degree of therapeutic effect of RT001. Comparative safety of RT001 and BoNTA complex was assessed in guinea pigs based on lethality and body weight gain. RESULTS: Clinical signs of rhinitis were significantly (p < 0.01) relieved after a single intranasal administration of RT001 and resolved to normal baseline levels within 5 days after treatment. Mucosal inflammation characterized by edema, congestion, and vascular dilatation along with increased expression of vasoactive intestinal peptide was noted in control animals after allergy induction, whereas RT001 treatment resolved inflammation to essentially normal baseline levels. Safety studies in guinea pigs via intranasal dosing revealed ∼31-fold greater safety factor for RT001 when compared with BoNTA complex. CONCLUSION: These results suggest that topical intranasal application of RT001 is effective in relief of clinical signs and inflammatory pathology associated with allergic rhinitis in a rodent model and may provide a safe treatment for rhinitis.

Characterization of diffusion and duration of action of a new botulinum toxin type A formulation.

RT002, an injectable form of botulinum neurotoxin type A (BoNTA), comprised of a purified 150 kDa neurotoxin formulated in a novel formulation, is designed to limit the extent of diffusion and permit safe administration of longer acting doses. The aim of this study was to evaluate the degree of diffusion of RT002 in comparison to another commercially available BoNTA product, Botox® Cosmetic (OnabotulinumtoxinA, Allergan, Inc., Irvine, CA, USA), and establish the relative duration of effect for diffusion matched doses of the two BoNTA formulations using quantitative measurements in mice. Measurement of muscle paralysis by muscle force generation (MFG) in mice at the injected gastrocnemius muscles indicated that RT002 and Botox are equipotent. Measurements of MFG inhibition in an adjacent muscle, the tibialis anterior muscle, indicated significantly less diffusion for RT002 as compared to Botox. When RT002 and Botox were dosed using the established diffusion matched doses, RT002 treatment resulted in an extended duration of drug effect as compared to Botox by 58-100% as assessed by either partial or complete recovery endpoints. Use of a daily voluntary running activity model provided confirmation that the two BoNTA formulations are equipotent by daily running distance and further confirmed the diffusion matched dose ratio assessed by degree of drug effect on body weight gain. Using these diffusion matched doses, RT002 treatment resulted in an extended duration of drug effect as compared to Botox (100-126% increase in duration) as assessed by either partial or complete recovery endpoints. Use of this model provides further evidence that the RT002 formulation limits diffusion with equipotency and thereby may permit safe administration of higher and more efficacious doses. In summary, data from two murine models suggest that RT002 may represent a next generation of BoNTA drug formulation offering superior degree and duration of effect at the intended target while controlling the unwanted diffusion and accompanying adverse effects of BoNTA at neighboring muscles and distal systemic targets.