BHV-1300

近日，Biohaven公布了其下一代蛋白降解剂BHV-1400治疗IgA肾病（IgAN）的Ⅰ期临床试验数据，最低剂量组的BHV-1400就可实现快速、深度的Gd-IgA1水平降低，并且具有良好的安全性和耐受性。 基于此数据，Biohaven计划将其直接推上III期临床。 前所未有的快速降解？ BHV-1400是Biohaven开发的一种Gd-IgA1降解剂，基于该公司的胞外蛋白降解剂技术平台MoDE开发，旨在选择性降解Gd-IgA的同时保留正常的IgA。 IgA肾病（IgAN）是一种慢性肾病，主要病因是糖基缺陷型IgA1（Gd-IgA1）抗体在肾小球系膜区的异常沉积。IgAN在不同国家/地区的发病率差异较大，其中亚洲国家发病率较高，中国每年IgAN发病率约为50/百万人。 Biohaven在新闻稿中所称，BHV-1400的降解效果是目前针对Gd-IgA1药物中前所未有的，最低剂量给药BHV-1400（125mg）后4小时内便能够将Gd-IgA1降低60%，8小时内最大降幅超过70%。且单次给药后，BHV-1400对Gd-IgA1的降解效果能持续数天。 而对比Vertex的双重BAFF/APRIL拮抗剂Povetacicept，需要4天才能实现约10%的Gd-IgA1的降幅，大冢制药的抗APRIL药物Sibeprenlimab在4周后才可实现约60%的降幅。 BHV-1400安全性与耐受性良好，未观察到任何剂量限制性毒性（DLT），未见白细胞计数或免疫球蛋白（IgG、IgA、IgE、IgM）水平的临床显著变化，以及未见肝功能、白蛋白、胆固醇等指标出现明显异常。 Biohaven计划在完成I期试验后，通过加速审批路径进入III期临床阶段。 胞外蛋白降解剂 BHV-1400由Biohaven开发，去年Biohaven被辉瑞以116亿美金收购后，又原地拆分出一家仍以Biohaven名称运营的新公司。 不同于PROTAC通过蛋白酶体作用于胞内蛋白靶标，Biohaven的MoDE平台旨在通过将蛋白运送到溶酶体来实现对胞外蛋白的靶向降解。MoDE的一端特异性结合致病性蛋白，另一端结合肝细胞上的ASGPR，ASGPR可以将与其结合的致病性蛋白内吞到细胞内，最终被转运到溶酶体中被溶酶体蛋白酶所降解。 基于该平台，Biohaven已开发了四条管线，BHV-1310、BHV-1300、BHV-1400、BHV-1600，其中三条管线已进入Ⅰ期临床阶段。 BHV-1300是一种IgG降解剂，是该平台开发的首个分子，被开发用于治疗类风湿性关节炎和Graves病。 根据最近报告I期临床数据显示，最低剂量的BHV-1300可将致病性IgG水平降低60%，此外，血浆中IgG3水平第4周仍得到维持。BHV-1300的安全性和耐受性良好，未观察到对白蛋白或肝功能的显著影响，也未见胆固醇水平升高。所有不良事件（AEs）均为轻度，无因药物相关不良事件而中断治疗的情况。公司预计将在今年年中启动II期临床试验。 BHV-1600是一种β1AR的降解剂，被开发用于治疗围产期心肌病。在BHV-1600Ⅰ期临床的前两个剂量组中，未见白细胞计数或免疫球蛋白（IgG、IgA、IgE、IgM）水平的临床显著变化，并且耐受性良好，未见肝功能、白蛋白、胆固醇等指标出现异常。 BHV-1310也是一种IgG降解剂，被开发用于于治疗重症肌无力，已经获得FDA的IND批准，Biohaven计划今年上半年启动Ⅰ期临床。 参考出处： https://ir.biohaven.com/news-releases/news-release-details/biohaven-highlights-portfolio-progress-innovation-and https://www.biohaven.com/pipeline/

Interim Phase 1 data on Biohaven’s protein degrader are strong enough that the biotech is planning to move the drug straight into pivotal trials in the kidney disease IgA nephropathy (IgAN). BHV-1400 is a next-gen protein degrader designed to break down galactose-deficient IgA1 (Gd-IgA1), the antibody that causes IgAN. Data from the first human trial of the product showed a median reduction in Gd-IgA1 levels of 60% within four hours of administration of a single 125 mg dose. Reduction of more than 70% was seen within eight hours, Biohaven said in a Tuesday release . Analysts from Cowen wrote in a same-day note that this was a “significantly more rapid and robust” reduction in Gd-IgA1 than the approximate 10% reduction seen with Vertex’s dual BAFF/APRIL antagonist povetacicept after four days, as well as the cut of around 60% achieved by Otsuka’s anti-APRIL agent sibeprenlimab after four weeks. Biohaven claims this reduction of Gd-IgA1 is “unprecedented” in drugs targeting this antibody, and could permit better safety compared with complement inhibition or broad antibody suppression. Safety has been clear so far in the Phase 1, with no clinically significant alterations in white blood cells or immunoglobulins IgG, IgA, IgE, and IgM, the biotech said. No-dose limiting toxicities were seen, and further dose escalation is planned. Biohaven said it is planning to start a pivotal Phase 3 trial in IgAN using an accelerated regulatory path, should BHV-1400 continue to be safe and show Gd-IgA1 reductions. Products including Calliditas Therapeutics’ Tarpeyo and Travere Therapeutics’ Filspari obtained accelerated approval for IgAN and then converted this into full approval. However, these do not act in the same way as BHV-1400. Biohaven also said that the lead indication for its IgG degrader BHV-1300, which reported early data from a multiple ascending dose Phase 1 study in December , would be Graves’ disease. Dosing of BHV-1300 in the Phase 1 trial is expected to conclude in the first half of this year, with a Phase 2 starting mid-year.