Anaerobic Manufacturing and Molecular Analytical Process Optimization to Support Clinical Development of Live Biotherapeutic Products

摘要 过敏性疾病包括特应性皮炎、食物过敏和过敏性哮喘是一个全球性的健康问题。 这对儿童的影响不成比例。令人惊讶的是，没有得到批准的方法来防止 这些疾病在高危人群中发展，导致慢性发病率和经济负担。这个 例如，仅在美国，哮喘的管理就承担着每年数十亿美元的巨额成本负担， 其中近200亿美元用于疗效不同的标准护理治疗。食物过敏管理 一般仅限于避免过敏原和从严重的急性过敏反应中抢救。有一个至关重要的需要 开发创新的策略来预防这些1型过敏性疾病的发病，而不是治疗他们的 症状。针对高危人群的预防性方法可以显著降低发病率和 与这些日益常见的疾病相关的医疗负担。 研究证实肠道微生物区系发育、免疫训练和过敏性疾病发病之间的联系 在儿童时期，现在很明显，过敏性疾病的风险与异常的微生物暴露有关 生命的第一年。婴儿和儿童的纵向肠道微生物区系研究表明，特定的 免疫调节共生细菌及其代谢网络先于过敏性疾病的发展。 使用婴儿肠道微生物区系数据集和体内过敏性疾病模型，西奥塔治疗公司设计了一种 活的生物治疗产品(LBP)，STMC-103H，刺激耐受性免疫发育和预防 变态反应性疾病发生在高危人群中。STMC-103H含有分离的三种不同活性成分的细菌 取自健康的人类粪便。西奥塔进行了广泛的cGMP制造开发，包括 配方、工艺和分析方法开发，以支持1期和2期临床试验 在FDA的IND下的STMC-103H。 在这个项目中，我们将在以前STMC-103H药物产品开发的基础上，提高稳定性， 为后期临床试验和随后的商业化提供效力和表征方法。 该项目的成功将直接支持STMC-103H的监管和商业开发。 间接地，这项工作将改进不同候选LBPS的制造和临床开发 含有具有很高治疗潜力的敏感活细菌。西奥塔还将寻求授权小说 向其他LBP开发商提供制造方法。

ABSTRACT Allergic diseases including atopic dermatitis, food allergy, and allergic asthma represent a global health problem that disproportionately impacts children. Surprisingly, there are no approved approaches to prevent the development of these diseases in at-risk individuals, resulting in chronic morbidity and economic burden. The management of asthma, for example, carries a steep cost burden of billions of dollars per year in the US alone, of which nearly 20 billion is spent on standard of care treatments with variable efficacy. Food allergy management is generally limited to allergen avoidance and rescue from severe acute anaphylaxis. There is a crucial need to develop innovative strategies to prevent the onset of these Type 1 allergic diseases rather than treating their symptoms. A preventative approach targeting at-risk individuals could significantly reduce the morbidity and healthcare burden associated with these increasingly common conditions. Studies confirm the link between gut microbiota development, immunological training, and allergic disease onset in childhood, and it is now clear that allergic disease risk is associated with aberrant microbial exposures over the first year of life. Longitudinal gut microbiota profiling studies in infants and children show that a loss of specific immunomodulatory commensal bacteria, and their metabolic networks, precedes allergic disease development. Using infant gut microbiota data sets and in vivo allergic disease models, Siolta Therapeutics has designed a live biotherapeutic product (LBP), STMC-103H, to stimulate tolerant immunological development and prevent allergic disease onset in at-risk individuals. STMC-103H contains three distinct active ingredient bacteria isolated from healthy human stool. Siolta has performed extensive cGMP manufacturing development, including formulation, process, and analytical method development, to support Phase 1 and Phase 2 clinical trials of STMC-103H under an IND with the FDA. In this project, we will build on our previous STMC-103H drug product development to improve the stability, potency, and characterization approaches for late-stage clinical trials and subsequent commercialization. Success of this project will directly support the regulatory and commercial development of STMC-103H. Indirectly, this work will improve the manufacturing and clinical development of diverse candidate LBPs containing sensitive live bacteria with high therapeutic potential. Siolta will also seek to license novel manufacturing approaches to other LBP developers.