Phase II Trial of SGS-742 in Succinic Semialdehyde Dehydrogenase Deficiency

描述(由申请人提供)：琥珀酸半醛脱氢酶(SSADH)缺乏症仍然是GABA(4-氨基丁酸)代谢中最普遍和最难治疗的疾病。根据相应小鼠模型的临床前疗效结果，提出了一项针对SSADH缺乏患者的SGS742(GABA(B)受体拮抗剂)的安慰剂对照II期试验，该试验将评估治疗组与安慰剂组的安全性、耐受性以及SSADH严重程度的相关指标的变化。将采用交叉设计，患者随机进入SGS742与安慰剂的最初6个月试验。我们项目的创新在于实施了第一个针对这种疾病的安慰剂对照盲法试验，使用基于aldh5a1-/-小鼠临床前疗效研究的合理干预。我们单一的正式假设是，在SGS742干预期间，通过经颅磁刺激量化，SSADH缺陷患者的皮质静默期(CSP)将向正常值延长，并恢复长时间间隔皮质内抑制(LICI)。其次，探索性结果包括脑脊液中的代谢生物标记物(GABA、GHB)、神经心理评估和安全性。目的1将比较SGS742和PBO对TMS水平的影响作为主要结果，依靠SGS742和PBO组之间TMS差异的大小，以及相当于配对t检验来评估统计学意义水平。AIM 2采用了同样的程序，评估SGS742对生物标记物水平的影响，包括GABA和GHB，以及SGS742与不使用SGS742的神经心理评估的分数。在目标3中，我们转向安全评估。当我们评估不良事件或毒性事件的频率时，我们的分析框架将包括多个Logistic回归模型，以比较SGS742患者相对于PBO报告的不良事件和严重不良事件等离散事件的几率。合适的生物标记物结果，在牛磺酸在该患者队列中的类似试验中具有经验的研究团队，经过验证的实际试验设计，以及广泛的可招募队列 科目是突显我们成功潜力的特征。短期内，我们将就SGS742的进一步临床开发制定“通过/不通过”的决定。该项目的长期意义在于确定对SSADH缺乏症和相关疾病的有效治疗，在这些疾病中，神经认知功能障碍与GABA能系统相关。

DESCRIPTION (provided by applicant): Succinic semialdehyde dehydrogenase (SSADH) deficiency remains the most prevalent and untreatable disorder of GABA (4-aminobutyrate) metabolism. A placebo-controlled phase II trial of SGS742 (GABA(B) receptor antagonist) in SSADH-deficient patients is proposed, based upon preclinical efficacy findings in the corresponding murine model, which will evaluate safety, tolerability, and change in relevant indicators of SSADH severity in treatment vs. placebo groups. A crossover design will be employed where patients are randomized into an initial six month trial of SGS742 versus placebo. Our project's innovation resides in implementing the first placebo-controlled, blinded trial in this disorder using a rational intervention based upon preclinical efficacy studies in aldh5a1-/- mice. Our single formal hypothesis is that SSADH-deficient patients will have lengthening toward normal values of the cortical silent period (CSP), and return of long interval intracortical inhibition (LICI), during SGS742 intervention as quantified by transcranial magnetic stimulation. Secondary, exploratory outcomes include metabolic biomarkers in cerebrospinal fluid (GABA, GHB), neuropsychological evaluation, and safety. Aim 1 will compare the effect of SGS742 v. PBO on TMS levels as the primary outcome, relying both on the magnitude of the difference in TMS between the SGS742 and PBO group, as well as the equivalent of a paired t-test to assess the statistical significance level. The same procedure is employed in Aim 2 which evaluates SGS742 effects on biomarker levels, including GABA and GHB, as well as scores on neuropsychological assessments on vs. off SGS742. In Aim 3, we shift to the evaluation of safety. When we evaluate the frequency of adverse or toxic events, our analysis framework will comprise multiple logistic regression models to compare the odds of discrete occurrences such as reported adverse and serious adverse events in those on SGS742 relative to PBO. Appropriate biomarker outcomes, an investigative team with experience in a similar trial of taurine in this patient cohort, a proven, practical trial design, and a broad cohort of recruitable subjects are features that underscore our potential for success. In the short term, we will formulate a "go/no-go" decision regarding further clinical development of SGS742. The project's long term significance centers on identification of effective treatment for SSADH deficiency and related disorders in which neurocognitive dysfunction correlates with GABAergic systems.