作者: Cao, Kai ; Du, Shuyan ; Hayes, Wendy ; Seiders, Jon ; Huang, Yiyun ; Najafzadeh, Soheila ; Gallezot, Jean-Dominique ; Holden, Daniel ; Donnelly, David J ; Carson, Richard E ; Bonacorsi, Samuel ; Roppe, Jeffrey ; Ropchan, Jim ; Labaree, David ; Lin, Shu-Fei ; Nabulsi, Nabeel B

The lysophosphatidic acid receptor type 1 (LPA1) is 1 of 6 known receptors of the extracellular signaling molecule lysophosphatidic acid. It mediates effects such as cell proliferation, migration, and differentiation. In the lung, LPA1 is involved in pathways leading, after lung tissue injury, to pulmonary fibrosis instead of normal healing, by mediating fibroblast recruitment and vascular leakage. Thus, a LPA1 PET radiotracer may be useful for studying lung fibrosis or for developing LPA1-targeting drugs. We developed and evaluated the radiotracer ¹¹C-BMT-136088 (1-(4'-(3-methyl-4-(((1(R)-(3-¹¹C-methylphenyl)ethoxy)carbonyl)amino)isoxazol-5-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid) in rhesus monkeys to image LPA1 in the lung in vivo with PET. Methods: The study consisted of 3 parts: test-retest scans; self-saturation to estimate the tracer's in vivo dissociation constant, nondisplaceable volume of distribution (V_ND), and nondisplaceable binding potential (BP_ND); and dosimetry. In the first 2 parts, the radiotracer was administered using a bolus-plus-infusion protocol, the arterial input function was measured, and the animals underwent 2 scans per day separated by about 4 h. Lung regions of interest were segmented, and the tissue density estimated, from CT images. A fixed blood volume correction was applied. The tracer volume of distribution (V_T) was estimated using multilinear analysis 1 (MA1) or equilibrium analysis (EA). Results:¹¹C-BMT-136088 baseline V_T was 1.83 ± 0.16 (MA1, n = 5) or 2.1 ± 0.55 (EA, n = 7) mL of plasma per gram of tissue in the left and right lung regions of interest, with a test-retest variability of -6% (MA1, n = 1) or -1% ± 14% (EA, n = 2). For the self-saturation study, ¹¹C-BMT-136088 V_ND and BP_ND were estimated to be 0.9 ± 0.08 mL of plasma per gram of tissue and 1.1 ± 0.14, respectively. The unlabeled drug dose and plasma concentration leading to a 50% reduction of ¹¹C-BMT-136088 specific binding were 73 ± 30 nmol/kg and 28 ± 12 nM, respectively. The average plasma free fraction was 0.2%; thus, the tracer's in vivo dissociation constant was estimated to be 55 pM. For the dosimetry study, the highest organ dose was in the liver (43.1 ± 4.9 and 68.9 ± 9.4 μSv/MBq in reference human male and female phantoms, respectively), and the effective dose equivalent was 6.9 ± 0.6 and 8.7 ± 0.6 μSv/MBq, respectively. Conclusion: Specific binding of ¹¹C-BMT-136088 can be reliably measured to quantify LPA1 in the lungs of rhesus monkeys in vivo.

2012-02-10·Journal of neurotrauma2区 · 医学

The Antinociceptive Effect of the Asthma Drug Ibudilast in Rat Models of Peripheral and Central Neuropathic Pain

2区 · 医学

Article

作者: Broadhead, Alex ; Hama, Aldric T. ; Sagen, Jacqueline ; Lorrain, Daniel S.

Ibudilast, an asthma drug, has demonstrated antinociceptive effects in several rat models of peripheral neuropathic pain, and a proposed mechanism of action is the inhibition of release of the cytokine tumor necrosis factor-α (TNF-α) from activated spinal microglia. Spinal glial activation has also been demonstrated in rat models of central neuropathic pain following spinal cord injury (SCI). The current study evaluated the effect of a short course of treatment with ibudilast on SCI-induced pain, and for comparison, following a chronic constriction injury (CCI; the Bennett model) of the sciatic nerve in rats. The effects of ibudilast treatment on spinal (SCI and CCI rats), and nerve tissue (CCI only) TNF-α content were also evaluated. Following an acute midthoracic SCI with a microvascular clip (20-g force), hindpaw withdrawal thresholds were significantly decreased, indicating below-level cutaneous tactile hypersensitivity. Likewise, unilateral loose ligation of the sciatic nerve led to a robust ipsilateral tactile hypersensitivity. Rats were treated with either ibudilast (10 mg/kg IP) or vehicle (2 mL/kg) during the period of robust and steady hindpaw hypersensitivity for each model--CCI rats were treated 14-16 days post-surgery, and SCI rats were treated 30-32 days post-surgery--and tested daily. Ibudilast ameliorated hindpaw hypersensitivity in both SCI and CCI rats, whereas vehicle treatment had no effect. Interestingly, repeated treatment led to increased baseline thresholds, beyond the duration of the drug half-life, suggesting persistent changes in neuropathic pain processing. In SCI rats, an increase in TNF-α content in spinal tissue rostral to the SCI was observed. Ibudilast treatment did not significantly alter this increase. In rats with a CCI, TNF-α content was markedly increased in the ipsilateral sciatic nerve and was partially reduced following ibudilast, but not vehicle, treatment. Ibudilast could be useful for the treatment of neuropathic pain of central as well as peripheral origin.

2012-01-01·International archives of allergy and immunology3区 · 医学

DP2 (CRTh2) Antagonism Reduces Ocular Inflammation Induced by Allergen Challenge and Respiratory Syncytial Virus

3区 · 医学

Article

作者: Musiyenko, Alla ; Prasit, Peppi ; Stebbins, Karin J. ; Scott, Jill M. ; Hutchinson, John H. ; Truong, Yen P. ; Lorrain, Daniel S. ; Broadhead, Alexander R. ; Barik, Sailen ; Stearns, Brian A. ; Evans, Jilly F.

Background: Allergic conjunctivitis is characterized by itchy, watery and swollen eyes which occur in response to exposure to seasonal or environmental allergens. The early phase reaction of allergic conjunctivitis is primarily mediated by mast cell degranulation while the late phase reaction is driven by Th2 cells and eosinophils. Prostaglandin D₂ (PGD₂), released from mast cells, is present in allergic conjunctival tears and may elicit classical allergic responses via interaction with the high-affinity DP2 receptor (chemoattractant receptor-homologous molecule expressed on Th2 cells, CRTh2). Furthermore, antagonism of this receptor is well known to inhibit eosinophil chemotaxis, basophil activation and Th2 cytokine production. PGD₂, therefore, may be involved in both early and late phase reactions in response to allergen challenge. Methods: Thus, we explored whether our novel and selective DP2 antagonist AM156 would be efficacious in animal models of allergic conjunctivitis. Furthermore, as respiratory syncytial virus (RSV) has been implicated in the pathogenesis of allergic conjunctivitis, we examined the effects of DP2 antagonism in a murine model of RSV ocular infection. Results: Utilizing a guinea pig ovalbumin model and a murine ragweed model we demonstrated that AM156 reduces redness, discharge and swelling in response to allergen challenge. These effects were equal to or greater than those of current clinical treatment options for allergic conjunctivitis including topical corticosteroids and a dual-mechanism antihistamine and decongestant. AM156 significantly reduced RSV-induced ocular inflammation and IL-4 production. Conclusion: These results suggest that a topical DP2 antagonist such as AM156 may represent a novel therapeutic for allergic conjunctivitis.

项与 Amira Pharmaceuticals, Inc. 相关的新闻（医药）

2024-08-29

·新药前沿

IPF也疯狂：新药开发“三剑客”突围

First in Class类新药虽是全球生物医药公司的最高追求，但对于国内多数医药公司来说，以目前的实力可能还难以企及。follow策略仍旧是目前国内多数创新药开发者的首选。而在现实中，国内企业仍旧面临着follow（信息、研发等）速度慢、动态评估不科学和关键节点决策不果断等问题（或风险）。【中国follow式创新药系列】将通过一些案例的介绍，希望能够给国内生物医药公司follow First in Class类新药提供经验和思考。特发性肺纤维化（IPF）是一种主要发生在老年人群中的慢性、进行性、不可逆、纤维化和致命的慢性纤维化性间质性肺炎。全世界约有300万人患有此病，目前国内缺乏IPF发病率及患病率数据，在我国预计有40-60万患者，每年发病率新增11%。 IPF病因不明，病因多样，治疗方法不多，预后差，因此该领域新药研发远远不能满足临床需求。争食两强重磅市场份额自2014年10月FDA相续批准基因泰克（罗氏）的Esbriet（吡非尼酮）和勃林格殷格翰的Ofev（尼达尼布）用于治疗特发性肺纤维化（IPF），两强之间的市场份额之争异常激烈。以“孤儿药”地位获批并不影响Esbriet和Ofev能到达“重磅炸弹”级销售额的能力。Esbriet在美国失去独占保护的2021年实现了10.4亿美元的销售额（其中约7.32亿美元来自美国市场），而即将于2025年在美国失去专利保护的Ofev在2023年全球销售额更是达到35.10亿欧元（约38亿美元）。目前，在美国有4款Ofev仿制药获得FDA暂时性批准(Tentative Approval)等待原研专利到期后上市，而Esbriet 仿制药已上市的竞争者多达7家。在中国，据米内网数据显示，2023年中国城市公立医院、县级公立医院、城市社区中心以及乡镇卫生院（简称中国公立医疗机构）终端吡非尼酮、尼达尼布合计销售额超过9亿元，同比增长57.06%。两款产品快速增长的市场，再加上在中国已失去专利保护，同样面临着仿制药的激烈竞争：尼达尼布仿制药获批上市6家（齐鲁、人福普克、江苏万高、四川科伦、江苏豪森、石药恩必普）。另外还有瑞阳制药、沈阳红旗正在ANDA审评中。尽管吡非尼酮仿制药目前仅有北京凯因科技获批上市，不过正在ANDA审评中的厂家同样不少（包括重庆赛维、成都倍特药业、四川依科制药、山东华铂凯盛/安徽泰恩康、江苏知原、浙江金华康恩贝），此外，在吡非尼酮改良药物方面，浙江金华康恩贝和越洋医药分别正在开发吸入用吡非尼酮溶液和吡非尼酮双释片。有意思的是，还有3家公司正在开发吡非尼酮的me-too/better类药物：广州嘉越的舒非尼酮、广东东阳光的伊非尼酮和爱科百发AK3280。现有疗法局限性尽管机制不完全相同，吡非尼酮通过抑制细胞因子转化生长因子β(TGF-β)来抑制纤维化过程。而尼达尼布可广泛抑制成纤维细胞和肌成纤维细胞中的下游信号通路。这两种药物都能抑制成纤维细胞增殖、阻碍胶原蛋白的产生并减少纤维化介质的产生，有效改善肺功能和减缓疾病进展，但不可避免的是吡非尼酮和尼达尼布都会产生显著的不良反应，从而限制临床给药及其全部疗效潜力。如近期发表于《欧洲临床药理学杂志》的一项真实世界研究的系统评价与荟萃分析显示，吡非尼酮和尼达尼布的不良反应发生率分别高达56.4%和69.7%，因不良反应中断治疗率分别为16.6%和16.2%，IPF相关死亡率分别为13.4%和7.2%，全因死亡率分别为20.1%和16.6%。 IPF的发病机制是多方面的且目前尚未完全了解，再加上非尼酮和尼达尼布临床治疗的局限性，因此该领域更具疗效和安全性的新药研发对满足IPF临床未满足需求更加必需和紧迫。新药开发初露锋芒 IPF新药研发尽管屡屡遭遇失败挫折，但近期已有3款新机制的项目进入到临床试验晚期阶段，如能成功该领域有望取得新的突破。 Nerandomilast：PDE4B抑制剂勃林格殷格翰开发的Nerandomilast (BI 1015550) 是一种口服的选择性磷酸二酯酶4B (PDE4B) 抑制剂。抑制PDE4可提高细胞内环磷酸腺苷(cAMP)水平，减轻炎症和纤维化相关的炎症，这表明，激活cAMP通路可为治疗IPF提供新的靶点。除了抗炎作用外，Nerandomilast还在临床前模型中表现出抗纤维化作用，因为Nerandomilast抑制了TGF-β刺激的成纤维细胞转化为肌成纤维细胞。 Nerandomilast在IPF患者中开展的II期试验表明，该药物在预防肺功能下降方面取得了良好的效果，且安全性良好。然而，这项概念验证研究的局限性在于其持续时间为12周，样本量相对较小（147名患者，按2:1的比例随机分配接受BI1015550或安慰剂）。腹泻是所有患者（>10%的患者）中报告最多的事件，所有事件均报告为非严重事件。勃林格殷格翰目前正在进行Nerandomilast治疗IPF和进行性肺纤维化 (PPF) 的III期试验。国内海思科和人福医药也在布局选择性PDE4B抑制剂，其中海思科8月初发布公告称，其开发的HSK44459用于间质性肺疾病IND申请获得CDE批准，即将开展临床试验。 BMS-986278：LPA1拮抗剂百时美施贵宝于2011年斥资3.25亿美元收购Amira Pharmaceuticals，从而获得了强效小分子溶血磷脂酸（LPA）1拮抗剂候选药物BMS-986278。LPA通过溶血磷脂酸受体1（LPAR1）诱导成纤维细胞迁移/积聚和血管渗漏，从而促进纤维化的进展。BMS-986278可阻断循环和局部的成纤维细胞被招募至损伤部位；抑制上皮细胞通过上皮间质转化（EMT）分化为成纤维细胞。 BMS-986278的II期研究表明，与安慰剂相比，BMS-986278治疗26周可将预测用力肺活量百分比(ppFVC)的下降率降低62%。BMS-986278在两个治疗组中均耐受性良好，不良事件发生率（包括胃肠道副作用发生率）和治疗中断率与安慰剂组相当。 BMS-986278治疗IPF 的III期试验正在进行中。而安进同类项目AMG 670紧随其后也正在进行IIb期临床试验。 Bexotegrast：αvβ6和αvβ1整合素双选择性抑制剂 Pliant Therapeutics开发的Bexotegrast(PLN-74809)是一种口服小分子αvβ6和αvβ1整合素双选择性抑制剂。αvβ6和αvβ1整合素在正常组织中的表达水平非常低，但在特发性肺纤维化患者的肺组织中表达上调。这两种整合素都是TGF-β的激活剂，可导致胶原蛋白生成增加，并最终导致这些组织纤维化。通过阻断αvβ6和αvβ1对TGF-β的激活，Bexotegrast可能减缓并可能阻止此类患者群体的纤维化进展。 IIa期研究表明，Bexotegrast治疗的患者总肺胶原减少，而安慰剂组的总肺胶原增加，表明纤维化可能逆转。与安慰剂组相比，接受Bexotegrast治疗的患者在所有时间点均表现出用力肺活量(FVC)改善和咳嗽严重程度降低。Bexotegrast耐受性良好，没有药物相关的严重不良事件(SAE)且没有停药。 Bexotegrast治疗IPF 的II/III期试验正在进行中。除上述项目外，目前还有多达十多种不同作用机制的IPF新药进入到临床试验阶段，期待未来有更多新突破。注：本文已刊载于8月22日《医药经济报》往期推荐 01 Nav1.8抑制剂fast-follow者恒瑞快速调转船头 02 吸入PDE3/4抑制剂fast-follow凑齐3家：正大天晴领跑，恒瑞延缓后被海思科追赶 03 DPP1抑制剂fast-follow者海思科的完美“变现” 04 神经疼痛新靶点AAK1：IIa期POC已成功，引国内多家公司fast-follow布局 05 PDE4B抑制剂fast-follow者海思科和人福，紧追勃林格殷格翰本文由「新药前沿」微信公众号根据公开资料整理编辑，欢迎个人转发至朋友圈。媒体或机构转载授权请在「新药前沿」微信公众号留言公众号名称，审核通过后开通白名单获取转载授权，转载请标识来源。免责声明：本文仅作信息交流之目的，非投资建议或者治疗方案推荐，「新药前沿」微信公众号不对任何主体因使用本文内容而导致的任何损失承担责任。限于作者水平和专业知识所限，如有谬误，欢迎指正！

孤儿药专利到期

2024-05-10

·药智网

应用AiDMET成药性评估，诠释全球首创LPA1抑制剂的优化历程

肺纤维化是一种长期的，可能危及生命的肺部间质疾病（ILD），截至2021年，全球有超过70万的成年患者。现今对于肺纤维化和间质性肺纤维化的治疗还未有有效且让人满意的疗法。BMS-986278作为全球首个溶血磷脂酸受体1LPA1抑制剂，目前正在开展治疗肺纤维化和间质性肺纤维化的三期临床，有望成为“first in class”，为肺纤维化和间质性肺纤维化患者提供新的医疗选择。BMS-986278的研发历程与大部分新药研发过程一样，充满了艰辛，2021年BMS的科学家们发表的文章《Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1(LPA1)Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases》披露了BMS-986278研发最精彩的部分，通过临床中失败的分子BMS-986020进行结构优化，最终成功获得理想化合物BMS-986278。下面我将采用AiDMET成药性预测平台对这一优化阶段进行评估和解释，从中可以看到AiDMET的预测结果与真实临床结果非常接近，这也提示我们，如果在早期设计中采用AiDMET预测平台对化合物进行最优化的设计，可以提高临床成功率并节约上市时间。表1 全球进入临床的LPA1抑制剂注：BMS在临床2期暂停研究的BMS-986020分子结构的基础上进行改进，获得BMS-986278数据来源：药智数据图1 BMS-986020和BMS-986278（Admilparant）化学结构2011年，Bristol-Myers Squibb通过收购Amira Pharmaceuticals，将一款首创的抗纤维化药物BMS-986020（AM-152）纳入研发管线，但在后续的一项6个月的IPF患者Ⅱ期临床试验中，BMS-986020虽然证明了其有希望的疗效机制，但是由于严重胆汁淤积症的发生，BMS主动终止了其临床计划。1.BMS-986020存在的问题BMS后续对BMS-986020进行回顾性的非临床毒理学研究，表明BMS-986020的肝胆毒性很可能是由于结构和（或）化学类型所导致的脱靶效应，而不是LPA1的靶点本身引起的。化合物BMS-986020存在的问题：（1）BMS-986020的N-氨基甲酸酯在人体内容易裂解，生成没有活性代谢产物1a（Mlo_1），因此需要较大的起效给药剂量，导致后期临床中存在安全性隐患。图2 AiDMET预测的BMS-986020的代谢产物和文献中给出的主要代谢产物一致（2）肝脏毒性，关于BMS-98602的临床肝胆毒性的原因，最合理的机制假说是肝脏胆汁酸水平的增加。这种毒性通常归因于BSEP（胆盐输出泵）等关键转运体破坏正常的胆汁酸稳态，以及导致胆汁磷脂水平的降低。BMS-986020抑制一些重要的胆汁酸转运体（BSEP、MPR3和OATP1B1），这些转运体被证明会介导肝胆毒性。图3 AiDMET预测出BMS-986020的肝毒性和转运体抑制，肝毒性以及对BSEP的抑制，是BMS-986020产生严重副作用的主要原因2.结构优化方向基于BMS-986020存在问题的问题BMS提出了化合物结构的改进方法，（1）先降低亲脂性（cLogP）和（2）增加C(sp3)分数（定义为分子中C(sp3)碳/总碳的数量）[即分子中较少的芳香碳，这是降低毒性风险的一种方法]，（3）降低对关键肝转运蛋白（如BSEP、MPR3和OATP1B1）抑制作用，（4）用一个代谢上药效更强的基团取代不稳定异恶唑N-氨基甲酸酯部分。3.结构优化过程BMS-986020（化合物1）是一种亲脂性羧酸，具有相对较高的cLogP值5.87（在pH 6.5条件下，摇瓶测得的logD=3.60）、少量的可旋转键和0.21的低C(sp3)分数。这些性质的组合可能会导致药剂学不理想，经过初步的SAR发现，化合物4反式(±)-3-氧苯基环己基酸具有更高的C(sp3)值0.35和略低的cLogP值4.84，因此化合物4为系统地探索分子中的其他药效团提供了一个很好的起点。图4 文献中给出的化合物1、3、4的理化活性数据以及AiDMET预测的理化性质数据由于N-氨基甲酸异恶唑部分在人体内代谢不稳定，因此对化合物4的N-氨基甲酸酯部分的SAR进行了广泛的研究。研究者主要从下图的三个方向进行SAR研究，最终发现了N-环丁基甲基N-甲基氨基甲酸酯类似物25（BMS-986234），这是在该项目这一阶段的第一个临床候选物。化合物25的C(sp3)分数（0.625）和极性（cLogP=3.16；logD（pH6.5）=2.30）均显著高于BMS-986020（化合物1）。化合物25具有良好抑制效力和成药性质。图5 以化合物4为起点的三种SAR研究图6 AiDMET预测化合物1和化合物25的性质，化合物25与初始化合物1（BMS-986020）相比，极性显著升高（logD降低）溶解度增大，血浆蛋白结合率降低（游离部分升高），肝毒性降低，BSEP的抑制降低。BMS对化合物25的进一步SAR研究，想进一步改善代谢以及清除率，研究集中在25的N-氨基甲酸酯部分和两个杂芳环的变化上，最终获得极性较高且活性、转运体和PK特性均较好的化合物33，作为目前的LPA1拮抗剂临床候选药物BMS-986278进入开发阶段。图7 化合物25和化合物33（Admilparan）的结构在BMS-986020的成药性优化过程中，AiDMET平台预测出的结果与真实试验结果高度吻合，包括有代谢产物的预测、转运蛋白抑制的评估以及结构优化后的成药性提升预测，这充分证明了该平台的强大的预测能力和精准度。天智药成团队开发的AiDMET成药性预测平台是一款功能强大的分子成药性预测工具，利用人工智能预测模型从分子结构出发全面呈现出一种新化学物质的潜在ADMET成药性参数：从简单的物理化学性质（如氢键能力、分子质量、溶解度和亲脂性等）到完整的ADMET参数预测（例如吸收百分比、生物利用度、清除率、分布体积和半衰期等），能够为新药小分子提供吸收、分布、代谢、排泄、毒性等160多项参数的预测服务，让您的新药设计更高效。AiDMET成药性预测平台已经上线，我们诚邀您体验这一新平台，如有兴趣请联系我们。参考文献：1.Cheng,PTW.;Kaltenbach,RF.;et al.;Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1(LPA1)Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases.J Med Chem.2021 Nov 11;64(21):15549-15581.2.Gill,MW.;Murphy BJ.;et al.;Mechanism of hepatobiliary toxicity of the LPA1 antagonist BMS-986020 developed to treat idiopathic pulmonary fibrosis:Contrasts with BMS-986234 and BMS-986278.Toxicol Appl Pharmacol.2022 Mar 1:438:115885.3.Sivaraman,L.;GillStructure,M.;Structure dependence and species sensitivity of in vivo hepatobiliary toxicity with lysophosphatidic acid receptor 1(LPA1)antagonists.Toxicol Appl Pharmacol.2022 Mar 1:438:115846.声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 罗燕阅读原文，是受欢迎的文章哦

临床2期并购

2024-04-05

·BioSpace

Contineum Dials Back Plans with $110M IPO to Fund Neuroinflammatory Trials

Pictured: Nasdaq signage and building in New York City/iStock, hapabapa Contineum Therapeutics went public on Friday, trading on the Nasdaq Global Select Market under the ticker symbol CTNM and dialing back its expectations to raise $110 million for clinical trials of a challenger to Boehringer Ingelheim and Roche. The San Diego-based biotech filed to go public in March 2024 to fund development of two clinical-phase candidates. Johnson & Johnson paid $50 million upfront for one of the assets, PIPE-307, in April 2023 but Contineum still needs to fund a Phase II trial in relapsing-remitting multiple sclerosis (MS). The biotech also wants cash to trial its wholly owned idiopathic pulmonary fibrosis (IPF) and MS prospect, PIPE-791. Earlier this week, Contineum set out plans to sell 8.8 million shares for $16 to $18 a piece. The biotech downgraded its target to secure its transition on to the Nasdaq, ultimately agreeing to sell almost 6.9 million shares for $16 each. Contineum expects gross proceeds of around $110 million, before deducting underwriting discounts and commissions and other offering expenses. The company is planning to spend around $66 million on the development of PIPE-791. The candidate is an oral small molecule inhibitor of LPA1, a receptor implicated in scarring in the lung disease IPF and the promotion of neuroinflammation in MS. Studies also suggest LPA1 may limit remyelination, the holy grail of MS outcomes. Drug developers have tried for decades to promote remyelination, without success. Contineum is planning Phase II trials of PIPE-791 in IPF and progressive MS. Boehringer Ingelheim’s Ofev and Roche’s Esbriet currently compete for the IPF market. Preclinical studies and a Phase I trial suggest PIPE-791 may have a convenience advantage. Contineum plans to study once-daily doses of PIPE-791, whereas Ofev and Esbriet are respectively taken two and three times a day. The biotech is part of a clutch of drug developers that want to treat IPF by targeting LPA1. Bristol Myers Squibb shared Phase II data on a LPA1 antagonist in 2023, more than a decade after entering the space through the $325 million acquisition of Amira Pharmaceuticals. Contineum founder and chief scientific officer Daniel Lorrain used to work at Amira. Other companies are racing BMS to market. Amgen’s acquisition of Horizon Therapeutics included a Phase II LPA1 drug candidate. AbbVie joined the fray by buying DJS Antibodies for $255 million in 2022. Contineum’s exploration of LPA1 in progressive MS sets it apart from the competition. The biotech said PIPE-791 is the only brain-penetrant LPA1 receptor antagonist in clinical development progressive MS, an indication that has thwarted other companies. The IPO will also support the Phase II trial of PIPE-307 that got underway last year. Contineum agreed to complete the study of the M1R inhibitor in relapsing-remitting MS when J&J struck a deal for the asset. The biotech has earmarked $16.2 million from the IPO haul for the study. Contineum contends inhibition of M1R may directly promote remyelination. Contineum’s listing on the Nasdaq makes it part of the resurgence of IPOs seen in the first few months of this year. Like many other members of the class of 2024, the biotech has advanced deeper into the clinic before going public than the early-stage biotechs that listed during the IPO peak of 2021. Nick Paul Taylor is a freelance pharmaceutical and biotech writer based in London. He can be reached on LinkedIn.

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