Development of TP-317 in Ulcerative Colitis

摘要 溃疡性结肠炎(UC)是一种以结肠炎症和溃疡为特征的慢性复发性疾病 在美国大约有150万人受到影响。1不幸的是，现有的疗法 有很大的局限性。5-ASA或美沙拉明被批准为UC的一线治疗方法，对 只有50%的UC患者和皮质类固醇因潜在的严重问题而不建议长期使用 副作用。6最近几类生物制品和免疫调节剂已被批准用于UC 十年(例如，抗肿瘤坏死因子-α、IL-12/23、α4、β7、JAK和S1P)，这些药物仅被批准用于中到重度 UC是不完全有效的，并且严重感染和恶性肿瘤的风险增加。 生物制品需要肠外给药，这既不方便又昂贵，而且对 因此，作为替代治疗的一种安全的口服治疗，存在着一种尚未得到满足的迫切需求。 免疫抑制药适用于5-ASA控制不佳的轻中度UC患者。 西蒂斯制药公司正在开发TP-317，这是一种治疗UC的一流解决方案E1(RvE1)口服疗法。TP-317是 一种获得专利的新分子实体，与RvE1相比具有更高的稳定性，作为一种可以 作为口服剂型配制。在2021年完成的先前NIH SBIR快速通道拨款(RDK116460)下， Thetis成功地使用TP-317进行了多项研究性新药(IND)研究，包括 疗效和药代动力学研究、非临床毒理学以及专利产品的开发和扩大 TP-317的合成工艺。在IND前的一次会议上，FDA表示Thetis可以进行临床 在健康志愿者的第一阶段研究下开发，没有额外的毒理学研究。第一阶段将 将于2023年启动。该IIB期SBIR计划的目标是完成关键的非临床毒理学研究 使TP-317能够迅速进入UC患者的第二阶段临床试验。 目的1：研究TP-317在1岁大鼠亚慢性毒理学研究中的作用。我们将进行为期13周的GLP TP-317灌胃给药对SD大鼠的毒理学和毒代动力学研究 目的：研究TP-317在犬(2岁)亚慢性毒理学研究中的作用。我们将进行为期13周的 TP-317经口灌胃对Beagle犬的GLP毒理学和TK研究 目的3：TP-317在生殖毒理学研究(3年级)中的评价。在目标3a中，一次生育和早期 将在SD大鼠身上进行胚胎胚胎发育安全性研究，以评估TP-317的作用 配子成熟、附睾精子成熟、生殖功能、交配行为、受精率 和植入，以及植入前的发育。在目标3b中，胚胎胚胎发育研究将评估 TP-317对妊娠大鼠和兔胚胎器官形成、生长发育的影响。 IIB阶段计划的成功完成将使Thetis能够在UC启动第二阶段临床试验。

ABSTRACT Ulcerative colitis (UC) is a chronic, relapsing disease characterized by inflammation and ulceration of the colon and rectum that affects approximately 1.5 million people in the United States.1 Unfortunately, existing therapies have significant limitations. 5-ASA or mesalamine, which is approved as first-line therapy for UC, is effective in only 50% of UC patients and corticosteroids are not recommended for long-term use due to potentially serious side effects.6 While several classes of biologics and immunomodulators have been approved for UC in the last decade (e.g., anti-TNF-α, IL-12/23, α4β7, JAK and S1P), these drugs are approved only for moderate-to-severe UC, are incompletely effective, and have an increased risk of serious infection and malignancy.2 Moreover, biologics require parenteral administration, which is inconvenient and costly, and do not have durable effects for many patients.7 Thus, there is a critical unmet need for a safe, oral treatment as an alternative to immunosuppressive drugs for mild-to-moderate UC patients who are not well controlled by 5-ASA. Thetis Pharmaceuticals is developing TP-317, a first-in-class Resolvin E1 (RvE1) oral therapy for UC. TP-317 is a patented new molecular entity with enhanced stability compared to RvE1 as the natural material that can be formulated as an oral dosage form. Under a prior NIH SBIR Fast Track grant (RDK116460) completed in 2021, Thetis successfully conducted multiple investigational new drug (IND)-enabling studies with TP-317, including efficacy and pharmacokinetic studies, non-clinical toxicology and development and scale-up of a proprietary process for synthesis of TP-317. In a pre-IND meeting, the FDA indicated that Thetis can undertake clinical development under a Phase 1 study in healthy volunteers with no additional toxicology studies. The Phase 1 will be initiated in 2023. The goal of this Phase IIB SBIR program is to complete key non-clinical toxicology studies to enable rapid advancement of TP-317 into Phase 2 clinical trials in UC patients. Aim 1: Investigate TP-317 in Sub-chronic Toxicology Study in Rat (Year 1). We will conduct a 13-week GLP toxicology and toxicokinetic (TK) study in Sprague Dawley Rat with TP-317 administered via oral gavage. Aim 2: Investigate TP-317 in Sub-chronic Toxicology Study in Dog (Year 2). We will conduct a 13-week GLP toxicology and TK study in Beagle dog with TP-317 administered via oral gavage. Aim 3: Evaluation of TP-317 in Reproductive Toxicology Studies (Year 3). In Aim 3a, a fertility and early embryofetal development safety study will be conducted in Sprague-Dawley rats to assess the effects of TP-317 on gamete maturation, epididymal sperm maturation, reproductive function, mating behavior, rates of fertilization and implantation, and pre-implantation development. In Aim 3b, embryofetal development studies will evaluate the effects of TP-317 on embryonic organ formation, growth, and development in pregnant rat and rabbit. Successful completion of the Phase IIB program will enable Thetis to initiate a Phase 2 clinical trial in UC.