Sepranolone (Isopregnanolone)   中文名称: 异孕烯醇酮

Sepranolone (Isopregnanolone)是一种有效的 GABA A 受体拮抗剂。塞普拉诺龙（Sepranolone）——与治疗产后抑郁的新药布雷沙诺酮（brexanolone）类似——是一种GABA-A受体的变构调节剂。但与布雷沙诺酮不同的是，塞普拉诺龙属于负向变构调节剂；当其与GABA-A受体结合时，会拮抗阿洛孕烷醇酮（allopregnanolone）的作用。（相比之下，布雷沙诺酮是GABA-A受体的正向变构调节剂，能增强GABA活性。） 在一项概念验证研究中，科研人员对60名经前烦躁障碍（PMDD）女性患者进行了塞普拉诺龙的新型疗法测试。这项安慰剂对照试验表明，针对PMDD患者在黄体期给药时，塞普拉诺龙的治疗效果优于安慰剂，能将PMDD情绪症状评分降低75%（Bixo等研究者，2017年）。
Sepranolone（又称异别孕烯醇酮或UC1010）是一种天然存在的内源性神经甾体，是别孕烯醇酮的3β-羟基异构体。它是首创的GABAA受体调节类固醇拮抗剂。与增强GABA能抑制作用的激动剂不同，sepranolone选择性地拮抗别孕烯醇酮在GABAA受体上的正向调节作用，但不影响GABA本身的结合位点或苯二氮䓬类等其他别构调节剂 。通过阻断别孕烯醇酮的作用，它正被开发用于治疗与该神经甾体病理性升高相关的疾病，如经前焦虑症和抽动秽语综合征。

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Women with premenstrual dysphoric disorder (PMDD) experience mood symptoms related to the increase in progesterone and the neuroactive steroid allopregnanolone. Our hypothesis is that allopregnanolone is the symptom provoking factor. The rationale for the present study was to treat PMDD patients with the GABAA receptor modulating steroid antagonist, sepranolone (isoallopregnanolone). Patients (n = 206) with PMDD from 12 European centers were randomized in a parallel double-blind study and treated with placebo, sepranolone 10 mg and 16 mg. Patients administered sepranolone subcutaneously every 48 h during the 14 premenstrual days of three consecutive menstrual cycles. After obtaining informed consent, the PMDD diagnosis was confirmed according to DSM-5 and verified with two menstrual cycles of daily symptom ratings using the Daily Record of Severity of Problems (DRSP) scale in an eDiary. Inclusion and exclusion criteria stipulated that the women should be essentially healthy, not pregnant, have no ongoing psychiatric disorder or take interfering medications, and have regular menstrual cycles. The study's primary endpoint was the Total symptom score (Sum21, the score for all 21 symptom questions in the DRSP). In the prespecified statistical analysis the average score of the 5 worst premenstrual days in treatment cycles 2 and 3 were subtracted from the corresponding average score in the two diagnostic cycles. The treatment effects were tested using analysis of variance in a hierarchal order starting with the combined active sepranolone treatments vs. placebo. The prespecified analysis of Sum21 showed a large treatment effect of all three treatments but no statistically significant difference to placebo. However, the ratings of distress showed a significant treatment effect of sepranolone compared to placebo (p = 0.037) and the ratings of impairment showed a trend to greater treatment effect of sepranolone compared to placebo. Many women with PMDD had symptoms during a longer period than the late luteal phase. It has previously been shown that 9 premenstrual days may be more representative for comparison of PMDD symptom periods than the 5 worst premenstrual days. A post hoc analysis was undertaken in the per protocol population investigating the treatment effect during 9 premenstrual days in the third treatment cycle. The Sum21 results of this analysis showed that the sepranolone 10 mg was significantly better than placebo (p = 0.008). Similar significant treatment effects were found for the impairment and distress scores. A significantly larger number of individuals experienced no or minimal symptoms (Sum21 <42 points) with the 10 mg sepranolone treatment compared to placebo (p = 0.020). The results indicate that there is an attenuating effect by sepranolone on symptoms, impairment, and distress in women with PMDD especially by the 10 mg dosage. Sepranolone was well tolerated, and no safety concerns were identified. [3] Psychoneuroendocrinology. 2021 Nov:133:105426.

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NCT04102995; A Study Investigating the Efficacy and Safety of Sepranolone in Women With Menstrual Migraine (APH204)
Brief Summary
The objective of this phase 2 Proof.of Concept study is to evaluate the efficacy and safety of Sepranolone (UC1010) in preventing menstrual migraine attacks in adult women with migraine occurring between Day -2 and Day 5 of the menstrual cycle. Patients will be taking Sepranolone or Placebo (blinded to patient and study doctor) during the two week preceding the menstruation for three menstrual cycles. Effect (change from baseline) will be assessed by comparison of symptoms recorded daily by the patients using an electronic diary using validated scales for assessment of menstual migraine symptoms.
Sepranolone is identical to an endogenous steroid.


Detailed Description
The objective of this phase 2 Proof-of-Concept study is to evaluate the effect and safety of two doses of Sepranolone (UC1010) in preventing menstrual migraine attacks in adult women with migraine occurring between Day -2 and Day 5 of the menstrual cycle in comparison to placebo. Study treatment will be self-administrated as subcutaneous injections during the luteal phase of three consecutive menstrual cycles. Effect will be assessed by comparison of symptoms recorded daily by the patients using an electronic migraine diary and a validated rating scale for assessment the physical and functional impact of menstrual migraine symptoms (MPFID). Preceding the treatment period, the diagnosis of Menstrual Migraine will be established by verifying menstrual migraine in at least two out of three menstrual cycles of daily symptom ratings by the patients. This period will also constitute the baseline data. The effect of study medication will be assessed as the change in symptoms from baseline to during treatment. The reduction in average number of menstrual migraine days per menstrual cycle during the treatment period cycles vs. the three menstrual cycles of baseline will constitute the primary endpoint.
The study will also include a follow-up (no treatment) cycle before patients final visit.
The study is conducted in three European countries (Sweden, Finland and Denmark) and will randomize 84 patients. https://clinicaltrials.gov/study/NCT04102995