Reata Pharmaceuticals, Inc.

随着人口老龄化，以糖尿病性周围神经病理性疼痛（DPNP）、带状疱疹后神经痛（PHN） 为代表的周围神经病理性疼痛 （pNP）的发病率逐年增加。与此同时，过去20年对疼痛和痛觉的神经生物学研究也不断取得积极的进展，生物制药行业在探索不同机制pNP新药开发方面初见成效。 尽管已获批上市超过20年，加巴喷丁、普瑞巴林仍旧是周围神经病理性疼痛临床治疗的金标准。普瑞巴林作为第二代钙离子通道调节剂，与加巴喷丁相比，增强了与α2-δ 亚基的亲和力，滴定和起效更快，但仍旧不可避免嗜睡、头晕、周围性水肿、视物模糊等不良反应的发生。 第三代钙离子通道调节剂，通过提高对中枢神经系统α2δ亚基靶点亲和力，可进而提高疗效和降低不良反应发生率。2款第三代钙离子通道调节剂近年相续获得批准上市： 第一三共开发的Tarlige（Mirogabalin/美洛加巴林）2019年1月首次在日本获批上市用于神经性疼痛治疗。2024年6月在我国获批进口上市用于DPNP（商品名德力静）。 美洛加巴林对钙离子通道α2δ亚基具有较高的亲和力，且其与α2δ-1亚基解离缓慢，与α2δ-2亚基解离快速，该机制可能是其具有较好的镇痛治疗效果和较少不良反应的原因。 海思科开发的思美宁（Crisugabalin/克利加巴林）于2024年5月在我国获批上市用于DPNP，并随后于7月获批PHN，克利加巴林（HSK16149 ）抑制[ 3H ]加巴喷丁与α2δ的结合亚单位与美洛加巴林相当，作用比普瑞巴林强23倍。克利加巴林是全球首个无需滴定的第三代中枢神经系统钙离子通道调节剂，也是国内首个获批DPNP适应症的药物。 随着第三代钙离子通道调节剂在国内获批上市，我国DPNP临床治疗也正在迎来新格局。 2024年5月，我国发布的《国家基层糖尿病神经病变诊治指南（2024版）》就建议，对于DPNP，普瑞巴林或度洛西汀可作为首选，加巴喷丁、美洛加巴林、克利加巴林也可作为一种有效的初始治疗药物。 衔接蛋白2相关激酶1（AAK1）是丝氨酸/苏氨酸激酶Ark1/Prk1家族成员，在调节受体内吞作用中发挥作用。 AAK1被确定为治疗神经性疼痛的潜在治疗靶点是基于2016年的一项研究结果：AAK1基因敲除（KO）小鼠对小鼠福尔马林模型的急性疼痛期（I期）反应正常，但对持续疼痛期（II期）反应减弱。AAK1基因敲除小鼠在脊神经结扎（SNL）手术后也没有出现触觉异常性疼痛。 AAK1抑制剂治疗神经性疼痛的机制（行为和电生理学）与α2肾上腺素能信号传导有关，α2肾上腺素能信号传导是人类已知的抗伤害性通路。 Lexicon与百时美施贵宝（BMS）合作开发的AAK1抑制剂LX9211（BMS-986176）具有治疗DPNP、PHN和神经性疼痛潜力。 2023年6月，LX9211治疗DPNP的疗效和安全性IIa期概念验证研究（RELIEF-DPN1）结果发表在《糖尿病护理》杂志：对于中度至重度DPNP患者，低剂量LX9211治疗6周后，与安慰剂相比，达到了主要疗效终点。虽然高剂量LX9211的结果也表明疼痛在数值上有所减轻，但并未达到预先规定的显著性水平，这可能是因为高剂量组TEAE发生率较高，导致治疗中断有关。尽管两种剂量的LX9211发生TEAE的几率都高于安慰剂，但低剂量LX9211组总体上耐受性良好。 尽管II期概念验证研究存在治疗时间相对较短和仅在美国招募参与者限制，但主要疗效终点得到满足，支持将AAK1转化为治疗神经病理性疼痛的新型治疗靶点，如在动物模型中观察到的，使用AAKI抑制剂LX9211可缓解神经病理性疼痛。 基于概念验证研究结果而正在开展的剂量范围探索IIb期PROGRESS试验预计于2025年第二季度公布结果。与此同时，Lexicon与百时美施贵宝也正在筹划LX9211治疗DPN推进到Ⅲ期临床试验。 LX9211的IIa期概念验证研究成功开始引起国内多家公司fast-follow布局，包括海思科、人福、扬子江药业旗下的上海海雁等。 海思科开发的HSK36357用于周围神经病理性疼痛I期试验于今年5月结束，上海海雁的YZJ-1495盐酸盐胶囊正在进行神经病理性疼痛I期试验。尽管尚未公布研发项目信息，推测可能是AAK1抑制剂。 2022年1月，Biohaven公司（该公司已于2022年10月被辉瑞收购）与比利时天主教鲁汶大学（KU Leuven）药物设计和发现中心（CD3）与离子通道研究实验室（LICR）宣布，签署独家全球许可和研究协议，开发和商业化first-in-class的TRPM3拮抗剂，以解决全球越来越多的慢性疼痛患者问题。BHV-2100是基于天主教鲁汶大学研究平台开发的一种口服小分子TRPM3拮抗剂。 TRPM3是天主教鲁汶大学LICR发现的治疗疼痛的新靶点。 TRPM3是一种参与疼痛信号传导的Ca2+通透性非选择性阳离子通道，在背根神经节（DRG）和三叉神经节的痛觉神经元中高度表达，在疼痛感知中起关键作用，可能是内源性疼痛缓解途径的下游靶点。 动物实验数据表明TRPM3在神经性疼痛的自发性疼痛和热痛觉过敏中发挥作用，而且位于脊髓、中枢突起或DRG神经元细胞体中的TRPM3在调节热敏感性方面也发挥着重要作用。 与TRPM3在疼痛中的作用一致，天主教鲁汶大学的研究数据表明，BHV-2100可以减轻动物模型中的疼痛行为，而不会产生其他疼痛疗法和机制所见的严重不良反应。 2024年5月，Biohaven在公司2024年投资者研发日活动介绍了已完成的BHV-2100的I期研究药代动力学和安全性数据。结果表明，该药物吸收迅速，20分钟内即可达到治疗浓度。单剂量高达500mg时，耐受性良好，超过了预期的治疗剂量，远高于EC90浓度。这些发现为BHV-2100进入临床试验提供了有力的证据支持，可用于治疗急性偏头痛和疼痛，是一种对中枢神经系统副作用非常小的非阿片类药物疗法。 Biohaven计划于2024年下半年启动偏头痛急性治疗的II期研究和疼痛的概念验证研究（POC）。Biohaven也在筹备提交BHV-2100用于慢性疼痛IND 计划。 在国内，深圳晶蛋生物医药已开始进行TRPM3靶点的抗体专利布局。 热休克蛋白90（HSP90）是一种普遍存在的信号转导调节剂，Hsp90抑制剂作为癌症治疗药物已获得临床成功（全球首款HSP90抑制剂Jeselhy已于2022年在日本获批上市用于治疗癌症化疗后进展的胃肠道间质瘤）。 然而，Reata Pharmaceuticals公司（该公司已于2023年9月被渤健收购）尝试把Hsp90抑制剂推进到疼痛领域。 Reata Pharmaceuticals开发（从堪萨斯大学获得授权）的Cemdomespib（RTA901）是一种高效、选择性口服小分子Hsp90 C端调节剂。Cemdomespib可与Hsp90的C端结合，从而增加细胞保护基因和分子伴侣基因（包括Hsp70）的转录和 Hsp70蛋白的表达。调节HSP90和诱导HSP70有可能减轻糖尿病神经痛。 在过去十年中，大量研究证据表明，通过诱导Hsp70可改善糖尿病周围神经病变和快速发作的脱髓鞘性神经病变。Cemdomespib是一种进入临床研究的第二代新型药物，在人体研究中表现出了良好的药代动力学和安全性。Cemdomespib具有改善病因与蛋白聚集无关的周围神经病方面的疗效。 Cemdomespib对DNDP患者的安全性和有效性的II期研究目前正在研究中。 内容来源于网络，如有侵权，请联系删除。

The kidney hasn’t always gotten much love from genetic medicine. The organ is vital to our health, but is often viewed as a liability for drug developers. It can flush out otherwise helpful therapies, and many efforts to deliver medicines to it have been foiled by its intricate and effective plumbing. A new startup says that it’s finally figured out how to shuttle RNA-based medicines directly into specific cells of the kidney. After three years in stealth, the Cambridge, MA-based startup, Judo Bio, launched on Monday with $100 million in a combined seed and Series A financing, co-led by Atlas Venture, The Column Group and Droia Ventures. CSO Alfica Sehgal said the idea for the company came during a brainstorming session about the lack of precise treatments in kidney care. “The kidney is not straightforward. It’s a very complex organ with dozens of specialized cell types,” Sehgal told Endpoints News in an interview. To try and solve the problem, the company borrowed a page from one of genetic medicine’s best-known delivery targets — the liver. Alnylam, which pioneered the first gene-silencing treatments, figured out that attaching a sugar molecule known as GalNAc to a siRNA drug would help the treatment get swept up by certain receptors on liver cells. So Judo’s team began to wonder if a similar pairing could be discovered to shuttle siRNA medicines into kidney cells. The startup focused on a kidney receptor known as megalin, which acts like a hungry scavenger, sucking up all manner of proteins and other biomolecules, Sehgal said. Judo has been working on finding molecules that they can use to get siRNA drugs swept up by megalin receptors in the proximal tubular epithelial cells of the kidney, she added. Judo isn’t disclosing the chemical makeup of its megalin-targeting molecules, but in a poster presentation at an RNA conference in Montreal this week, it revealed that in a mouse study, its approach increased the exposure of siRNA in the kidney up to 30-fold compared with naked RNA molecules. One injection lowered gene expression by 50% to 70%, and the effect lasted four weeks. Now more genetic medicine developers are beginning to look at the organ. In August, Versant Ventures and Novartis launched Borealis Biosciences with $150 million to develop RNA medicines for kidney diseases — it disclosed even fewer details about how it plans to deal with delivery. Alnylam leaders have also pointed to the kidney as a potential area of interest as part of its effort to expand the reach of its siRNA medicines beyond the liver. Judo CEO Rajiv Patni, who was recruited to lead the startup last month, told Endpoints it will initially use its siRNA drugs to shut down the production of solute carrier proteins, which line the tubes of the kidney and control levels of molecules like amino acids and glucose in the blood. A class of diabetes drugs known as SGLT2 inhibitors works by blocking certain solute carrier proteins. The startup Jnana Therapeutics, which Otsuka Pharmaceutical bought in a deal worth at least $800 million in August, was focused on making small molecule inhibitors to some of the hundreds of other proteins in the solute carrier family. Judo aims to make genetic medicines that tamp down on these proteins with longer-lasting effects. Patni, who was most recently the head of R&D at Reata Pharmaceuticals before Biogen acquired the company for $7.3 billion last year, won’t say what diseases Judo will focus on first, but he is interested in both rare metabolic diseases like phenylketonuria and urea cycle disorders, as well as more common conditions including diabetes, gout, heart failure and hypertension. “We’re using kidneys as the access point,” Patni said. The company also plans to target kidney cells known as podocytes to directly treat renal diseases, Patni added. But he declined to say when he expects Judo to have a drug candidate ready for the clinic or how long the company’s new funding will last.

Frazier Life Sciences has added more than $630 million to its evergreen public fund, the firm said Wednesday. The long-only fund, which is based in Palo Alto, CA, has been marketed to investors as a “hybrid structure to navigate volatility and liquidity in SMID-cap biotech,” according to materials posted by the New Mexico State Investment Council, which is committing up to $50 million to the public fund. “We are seeking to strategically take advantage of market volatility,” the firm said in June in its investor presentation. It now has $1.7 billion in total commitments after debuting with $830 million in 2021 and raising $243 million a year later. The biotech landscape is far different than when Frazier unwrapped its public fund in the fall of 2021. In September of that year, the number of life sciences companies with a negative enterprise value was 21. As of Sept. 20 of this year, that tally stood at 133, according to a recent Stifel report . “The number of early-stage companies going public has just exploded over the course of the last five-plus years,” general partner Jamie Brush told Endpoints News in 2021. “So the opportunity set for early-stage companies where Frazier wants to be investing has really increased on the public side.” The biotech IPO market cratered soon after that unveiling. Since then, initial public offerings have been few and far between, though there’s been a string of debuts this fall and more interest-rate cuts could be a positive signal for the market going forward. Follow-on offerings, meanwhile, have had a “ very strong year ,” according to Stifel. Frazier’s strategy Frazier has five main strategies for the fund. The first is “fallen angels,” which Frazier has described as companies that have “fallen out of favor but have promising assets,” like BridgeBio and Immunovant. Bain Capital Life Sciences, which just raised a $3 billion fourth fund, employs a similar strategy . Another bucket is “proprietary information,” in which Frazier gets data that are not publicly available, as it has done in the case of Rocket Pharmaceuticals and Mirum Pharmaceuticals. The third is “structured terms” or “creative” deals. The firm also invests in companies that are newly public like CG Oncology, which had the largest biotech IPO of the year at $380 million in January . And the final strategy is “off-the-beaten path,” or companies that are “lesser known” such as Egetis Therapeutics and Chinook Therapeutics. Novartis bought Chinook in a deal worth up to $3.5 billion last year. Frazier has said its public fund portfolio companies have secured a dozen FDA approvals, including Acadia’s Daybue, bluebird’s three gene therapies, Iovance’s Amtagvi and Phathom’s Voquezna. Some companies have been acquired, including Iveric Bio, which sold to Astellas for $5.9 billion ; Reata’s $7.3 billion exit to Biogen; Alpine Immune Sciences’ $4.9 billion sale to Vertex; and Sierra Oncology’s $1.9 billion exit to GSK. On the venture side, Frazier last disclosed a $987 million life sciences fund in March 2022.