Recombinant botulinum toxin with improved safety and effectiveness for treatment of dystonia

摘要 肉毒杆菌神经毒素（BoNT）是科学上已知的毒性最大的蛋白质。它也是活性成分， ® 像肉毒杆菌素（Allergan）这样的药物产品，已被证明对多种神经肌肉疾病安全有效。 迹象。所有目前的BoNT产品都是由肉毒梭菌培养物制造的，并且具有类似的 安全性特征，包括剂量限制和标签中的黑框警告。由于其 固有毒性和狭窄的治疗窗，在适应症中难以实现最佳临床结局 涉及大的肌肉群，如颈部肌张力障碍，中风后痉挛和小儿脑瘫。 虽然可以明显改善肌肉张力，但临床医生倾向于谨慎用药，总体而言， 临床结果留下显著的改进空间。我们在这里建议建立在使用 先前的候选“更安全的BoNT”药物（SBIR第1阶段1 R41 NS 086115 - 01 A1）发现， 对BoNT/A1的特定氨基酸取代可以产生具有改善的安全性的重组BoNT/A1 与wt BoNT/Al（US 8，865，186）相比的余量。最初设计和测试的主要候选人Cyto-012， 安全范围改善，但其绝对效力使得有效性所需的剂量也 免疫原性。在这里，我们建议测试一种新的重组BoNT/A1衍生物，称为Cyto-014，旨在 具有与wt BoNT/A1相似的效力和免疫原性，同时保持所需的安全性改善 根据我们的初步研究。本建议旨在比较剂量反应行为、安全性 在适当把握度的研究中，Cyto-014相对于wt BoNT/A1的边际和最大耐受剂量，以及 评价其免疫原性和重复治疗的有效性。圆满完成拟议的 研究将支持II期研究，重点关注旨在提交IND的临床前开发活动。

Abstract Botulinum neurotoxin (BoNT) is the most toxic protein known to science. It is also the active ingredient in ® pharmaceutical products like Botox (Allergan), which have proven safe and effective for multiple neuromuscular indications. All current BoNT products are manufactured from Clostridium botulinum cultures and have similar safety characteristics, which include limitations on dosing and a black box warning in labeling. Because of its inherent toxicity and narrow therapeutic window, optimal clinical outcomes are difficult to achieve in indications involving large muscle groups, such as cervical dystonia, post-stroke spasticity and pediatric cerebral palsy. Though improved muscle tone can clearly be achieved, clinicians tend to dose on the side of caution, and overall clinical outcomes leave significant room for improvement. We here propose building on data generated with a previous candidate for a “safer BoNT” pharmaceutical (SBIR Phase 1 1R41NS086115-01A1) which found that specific amino acid substitutions to BoNT/A1 can produce a recombinant BoNT/A1 with an improved safety margin compared to wt BoNT/A1, (US 8,865,186). The initial lead candidate designed and tested, Cyto-012, had an improved safety margin, but its absolute potency was such that doses required for efficacy were also immunogenic. Here, we propose testing a new recombinant BoNT/A1 derivative termed Cyto-014, designed to have potency and immunogenicity similar to wt BoNT/A1, while retaining the desired improvement in safety suggested by our Preliminary Studies. This proposal is intended to compare the dose-response behavior, safety margin and maximum tolerated dose of Cyto-014 relative to wt BoNT/A1 in appropriately powered studies, and to evaluate its immunogenicity and effectiveness for repeat treatment. Successful completion of the proposed studies will support a Phase II study to focus on pre-clinical development activities aimed at filing an IND.