PDHK1

▎药明康德肿瘤代谢，一个始于百年前的研究领域，但人们至今对其知之甚少。上世纪20年代，德国生理学家Otto Warburg发现，与健康细胞依靠线粒体氧化糖类分子释放大量能量不同，大多数肿瘤细胞是通过糖酵解作用为自身供能，这一现象后来被称作Warburg效应，打开了肿瘤代谢领域的大门。Warburg后来因为发现细胞呼吸氧化转移酶在1931年获得诺贝尔生理学或医学奖。然而，Warburg效应乍听起来有违常理：糖酵解方式产生能量的效率远低于线粒体氧化磷酸化，健康细胞只有在缺氧的情况下才会选择糖酵解，为什么能够快速增殖的肿瘤细胞会选择效率更低下的代谢方式？肿瘤细胞的糖代谢机制是什么？与正常细胞的糖代谢有没有区别？如今已是浙江大学转化医学院院长的吕志民回忆，正是这些原始的问题和好奇，驱动着自己在肿瘤代谢领域持续不断地探索。二十余年来，他在找寻答案的过程中，层层穿透肿瘤代谢奥秘，让肿瘤细胞内外部盘根交错的调控机制逐渐明晰。吕志民的多个研究颇具开创性，其率先证明了多种代谢酶具有蛋白激酶活性、蛋白磷酸酶活性，证明了许多代谢酶有着调控基因表达等重要的非代谢功能，并系统性地阐明了肿瘤代谢领域的奠基理论Warburg 效应的调控机制。这些基础研究为肿瘤精准治疗提供了众多新的代谢标记物和靶点。在今日揭晓的2022年第十六届药明康德生命化学研究奖中，吕志民因在肿瘤代谢领域机制研究方面的卓越贡献，获得了本届“杰出成就奖”。吕志民教授现任浙江大学转化医学研究院院长、欧洲科学院（Academia Europaea）外籍院士，原任美国M.D.安德森癌症中心杰出讲席终身教授、肿瘤代谢中心创始主任。吕志民教授是肿瘤代谢研究领域国际知名杰出科学家，先后在世界一流杂志Nature、Cell、Nature Cell Biology、Cancer Discovery、PNAS 等发表论文100 多篇。其原创性、里程碑式的发现深刻影响了业界对肿瘤代谢的认识，同时也对开拓新的肿瘤诊治方法提供了创新理论支持。“旧瓶装新酒”：代谢酶竟能调控表观遗传吕志民曾在本科毕业后做过5年医生，但当时始终为肿瘤患者没有太多治疗手段而苦恼，后来毅然决定“转型”，投身肿瘤基础科研。那是80年代末，肿瘤代谢领域正在经历沉寂。由于Warburg效应的因果论中存在一定错误，很长一段时间里，肿瘤代谢研究的重要性并未受到科学界的广泛认可。“新理论的提出，总要有一个被逐步认知和验证的过程。”吕志民在此后发表了众多开创性研究，也让他更理解了这种“孤独”的时刻。他始终相信的是，肿瘤治疗的革命性进展还是需要理论的突破，如果能把肿瘤代谢研究清楚，一定能为临床提供更多干预和治疗手段。1999年，吕志民在美国Salk Institute癌症研究中心读博士后，师从有“激酶之王”之称的Tony Hunter教授，后者是细胞信号转导领域最为权威的专家之一，其研究成果直接推动了酪氨酸激酶抑制剂、白血病药物格列卫（Gleevec）等十余种重要抗癌药物的成功。结束博后生涯后，吕志民开始在肿瘤领域享富盛名的M.D.安德森癌症中心“大展拳脚”。研究之初，其“瞄准”的是与Warburg效应相关的肿瘤细胞糖酵解过程，这是机体产生能量的基础过程之一，指的是细胞在胞浆中分解葡萄糖生成丙酮酸的过程中，伴有少量ATP能量产生。但吕志民逐渐发现，肿瘤代谢的过程远比其预想的复杂。在研究肿瘤转移的过程中，一次偶然的机会，吕志民发现原本应存在于细胞浆中的糖代谢酶出现在了细胞核内。他突然意识到，这些酶可能还有未被发现的功能。2011年，一篇Nature杂志上发表的论文引发业界高度关注。吕志民团队发现，当细胞受到生长因子EGF信号刺激时，会诱导M2型丙酮酸激酶（PKM2）易位进入细胞核。PKM2是在Warburg效应中发挥关键性作用的酶，但在细胞核中，其可以通过非代谢机制调控周期蛋白cyclin D1的表达，最终促进细胞增殖和肿瘤形成。这一研究让细胞代谢与细胞周期进程这两大肿瘤调控机制因一个代谢酶而产生关联。传统认为，调节糖代谢是代谢酶的“本职工作”，但吕志民发现，许多代谢酶实际上能够调控基因表达，影响表观遗传；有些酶并不直接参与葡萄糖代谢，而是通过反馈式的调节机制来调节葡萄糖代谢。“葡萄糖代谢过程中几个重要的酶，会跑到细胞核里进行基因转录，转录形成的正是葡萄糖代谢酶本身。”吕志民说，通过反馈式调节机制，葡萄糖代谢链条上的许多酶最终实现高表达，进而导致Warburg效应。此外，今年10月，吕志民团队在Nature Cell Biology杂志上发表的论文揭示，代谢酶不仅可以作为蛋白激酶，还可以作为蛋白磷酸酶，行使非代谢功能。研究发现，糖酵解的逆反应-糖异生过程的限速酶1，6-二磷酸果糖磷酸酶1（FBP1）可易位进入细胞核，作为蛋白磷酸酶使组蛋白H3的T11位点去酸化，抑制基因转录。而肿瘤细胞中FBP1的缺失或低表达去除了其抑癌功能，促进了肿瘤的发生发展。继PKM2和FBP1之后，吕志民团队陆续发现，包括果糖激酶A（KHK-A）、磷酸葡萄糖酸激酶（PGK1）、磷酸烯醇式丙酮酸羧基酶1（PCK1）、胆碱激酶（CHKα）、己糖激酶2（HK2）等在内的重要蛋白，都能够调控肿瘤细胞的基因表达、细胞有丝分裂、包括胞浆分裂等，促进肿瘤的发生发展，这些非代谢的“兼职”功能，是一片未知的汪洋。▲在糖酵解和糖异生通路中，代谢酶能够调控基因表达和表观遗传2021年，吕志民曾到西湖大学做报告，在报告题目中，他用“旧瓶装新酒”（Cancer metabolism, an old bottle with new wine）形容肿瘤代谢领域的发展，“肿瘤代谢的概念已经有了近百年的历史了，这是我们说的old bottle，但里面的认知内容一直在不断丰富。”揭示多维立体的代谢机制网络更意外的是，伴随着对“新酒”的探索，吕志民对“旧瓶”的认识也不断深入。传统上，科学家们已经认识到生长因子和肿瘤的形成密切相关，肿瘤表面的生长因子受体一直以来是抗肿瘤靶向药研发的热门靶点，比如针对ErbB受体酪氨酸激酶家族中的表皮细胞生长因子受体（EGFR）、HER2、HER3等靶点，都已经诞生了一批疗效显著的里程碑式抗癌药，但激活这些受体为什么能够促进肿瘤，更深层次的机制始终不清晰。吕志民针对那些会“跑进”细胞核的代谢酶的偶然发现，揭开了生长因子受体激活如何导致Warburg效应、进而导致肿瘤发生机制的一角——在关于PKM2的研究中，糖代谢酶会因受到生长因子受体激活而异构化，从细胞浆易位到细胞核，宏观调控基因表达，这就提示了Warburg效应能够通过细胞核的反馈性调节转录完成。更令人惊讶的是，当激活EGFR、KRAS和B-Raf一系列生长因子受体，另一种代谢酶PGK1则会“易位”到细胞的线粒体中——PGK1在那里发挥了蛋白质激酶作用，激活了一个抑制线粒体利用丙酮酸能力的关键酶PDHK1，阻碍糖代谢产物在线粒体中的使用，进而导致Warburg效应，促进肿瘤增殖和形成。这意味着，代谢酶可以通过丰富的结构变化和功能发挥同时参与糖酵解与线粒体三羧酸循环两大能量产生过程，促进Warburg效应。吕志民一边系统性还原Warburg效应复杂的调控机制，一边将肿瘤的多种代谢方式交织起来。▲代谢酶在基因表达、DNA修复、细胞周期、细胞增殖、凋亡和肿瘤微环境重塑中具有众多“兼职”（moonlighting）功能伴随着他的研究，肿瘤细胞在体内代谢的机制图景愈发广阔和清晰。在糖代谢之外，吕志民目前也正探究肿瘤细胞特殊的脂质代谢机制，以及糖脂代谢之间的关联，“更广一点说，代谢不只是细胞本身的代谢，肿瘤的代谢也会影响到它周边的细胞，也就是肿瘤微环境的代谢，包括免疫系统的代谢。”吕志民说。今年8月，吕志民团队在Cell Metabolism上发表论文，报道了Warburg效应会影响肿瘤免疫细胞的逃逸，影响细胞程序性死亡-配体1（PD-L1）的高表达，进而导致肿瘤细胞不再受到免疫细胞攻击。肿瘤代谢自此也与免疫逃逸建立了联系，并为目前研发火热的PD-1/PD-L1疗法带去了更多联合用药的启示。从糖代谢，到脂代谢，再到微环境代谢，乃至与其他肿瘤特性产生关联，吕志民的研究已经逐步形成了一个立体、多维的肿瘤代谢活动交织的网络，“我们一步步，做出了肿瘤代谢从点、到线、到面、到网络的研究。”调节肿瘤代谢，找到精准治疗的突破口肿瘤基础研究，绝不只是停留在实验室里的工作。吕志民希望，理论上的突破能带给人们更多临床诊疗启示。他的研究为肿瘤精准治疗提供了一系列具有潜力的分子靶点和抑制肿瘤增殖转移的新思路，比如，通过了解糖代谢酶能够直接调控基因表达，研究者可以尝试阻断代谢酶核转位的信号通路，可以设计能够特异性靶向细胞核代谢酶的抑制剂，可以考虑阻断细胞核内代谢酶与转录复合物的结合，抑或是尝试“精准”抑制代谢酶的蛋白激酶活性，而不影响其本身催化代谢反应的活性。“我们期待可以调节肿瘤代谢，而不影响正常代谢，找到精准治疗肿瘤的突破口。”吕志民说。▲通过抑制代谢酶非经典功能治疗人类疾病的策略肿瘤代谢领域已经有过成功转化的里程碑案例。2017至2018年，美国生物制药公司Agios的两款靶向药先后在美国上市，用于治疗异柠檬酸脱氢酶-1/2（IDH-1/2）突变的成人复发或难治性急性髓系白血病（AML）患者。但除此之外，其他基于代谢的药物研发进展并不算快。有一定特殊性的肿瘤代谢酶听起来是颇具吸引力的“精准”靶点，但实际研究发现，肿瘤细胞的代谢途径常与正常细胞交织，微环境往往“牵一发而动全身”，如何在消灭肿瘤细胞的情况下不抑制自身免疫功能，不伤害正常细胞，成为巨大的难题。“IDH1/2靶点之所以能够快速成药，是因为他存在变异，有特异性，因此可以精准地针对变异来做药，但是肿瘤代谢酶的变异相对来说是比较少的，这就给大家提出挑战。”吕志民说，对于不存在特异性基因突变的肿瘤患者，想要基于代谢机制对其进行治疗，需要复杂的动态分析。他解释道，比如同样是胰腺癌患者，其变异的基因和发病机制可能完全不同，即使是同一个病人，在疾病的早期、中期和晚期，在肿瘤增殖、侵袭和转移过程中，其代谢表现都有可能不一样，研究者必须能从患者的动态变化中找到特异性结构或特异性状态，针对治疗患者的“命门”设计出特定的药物或复合式的治疗方案，既能抑制肿瘤代谢，也不影响正常细胞的运转。吕志民始终相信，“没有理论突破，临床转化研究也就是无源之水。”肿瘤代谢，这个百年前就被开启的研究领域，如今依然隐藏着众多未解之谜，吕志民期待着，针对这些谜团的不懈探索，能够孕育出更多患者生命的希望。有奖问答你对获奖者的科学贡献了解有多深？即刻扫码答题，我们将抽取5位医药产业同仁，随机赠送好书盲盒一份！吕志民的研究发现，以下哪种代谢酶具有非代谢的“兼职”功能？A. PKM2B. FBP1C. PGK1D. 以上都对注：文中配图来自吕志民团队提供。分享，点赞，在看，聚焦全球生物医药健康创新

医学博士V. Koneti Rao分享了接受leniolisib治疗的APDS（一种罕见的原发性免疫缺陷疾病）患者长期安全性和血液学疗效的新证据 中期分析表明leniolisib具有良好的耐受性，并表明了II/III期随机对照试验中疗效结果的持久性 荷兰莱顿 2022年12月16日 /美通社/ -- Pharming Group N.V.（以下简称"Pharming"或"公司"）（阿姆斯特丹泛欧交易所代码：PHARM）（纳斯达克代码：PHAR）宣布了其开放标签拓展研究的中期分析数据，该研究评估试验性药物leniolisib（一种口服选择性磷酸肌醇-3激酶δ（PI3Kδ）抑制剂）用于治疗成人和青少年磷酸肌醇-3激酶δ过度活化综合征（APDS，一种罕见的原发性免疫缺陷疾病）患者的治疗。宣布的数据中包括了新的证据。主要研究者医学博士V. Koneti Rao是美国马里兰州贝塞斯达国立卫生研究院原发性免疫缺陷诊所的一名医师，他在2022年美国血液学会（ASH）年会上的口头报告中分享了乐观的研究结果。 荷 兰鹿特丹 Erasmus MC 的主要研究者、 临床免疫学顾问 Virgil Dalm 博士 评论说： "Pharming的研究结果让我激动不已，这项结果进一步支持了将leniolisib作为一种耐受性良好并使APDS患者受益的试验性治疗药物。结果显示出了leniolisib的长期耐受性，研究治疗的中位持续时间刚好到2年（102周），有5例受试者接受了5年或更久的治疗。APDS患者经常反复受到感染，需要终生免疫球蛋白替代疗法（IRT）来减轻这一负担。值得一提的是，leniolisib治疗显示年化感染率显著降低，接受IRT治疗的研究患者有37%能够减少或完全停止他们的IRT治疗方案。对于任何免疫出生错误研究来说，这是一个了不起的成果，通过对leniolisib的持续研究，我期待为APDS患者更好治疗选择的知识作出贡献。" 正在进行的拓展研究包括37例12岁或以上的APDS患者，在中期分析的数据截止时间，他们每天两次接受70 mg选择性PI3Kδ抑制剂leniolisib的治疗，时间最长达六年零三个月，研究治疗的中位持续时间为102周。研究主要旨在评估长期leniolisib治疗在先前参与过II/III期leniolisib研究的青少年和成年APDS患者中的安全性和耐受性。拓展研究的次要终点在于评估长期leniolisib治疗药物在这些患者中的疗效和药代动力学。 中期分析发现，leniolisib在研究进行到此时耐受性良好。分析还表明了随机对照试验中所看到疗效结果的持久性，与安慰剂相比在淋巴结大小减小和幼稚B细胞增加的共同主要终点方面显示出显著改善。中期结果表明，APDS患者中经常看到对于免疫失调和缺陷（临床表现包括感染、淋巴细胞增殖、自身免疫、肠病、支气管扩张、更高淋巴瘤风险和早期死亡率）的良好长期影响。 中期分析中报告的大多数不良事件 (AE) 为1级和2级，包括上呼吸道感染、头痛和发热。1级不良事件最轻微，5级则最严重。总体而言，13.5%的不良事件与研究药物有关；这些不良事件影响了五例患者，包括体重增加、关节痛、高血糖和中性粒细胞计数减少。对于分析中评估的所有不良事件，16.2%被归为严重，但没有一例被确定为与研究治疗有关。研究参与者中有一人死亡，被确定与研究治疗无关。 在研究参与者中，一些人出现了APDS疾病标志物的减少，个体之间的疗效水平各异。疗效包括： 淋巴结肿大与脾肿大的减小和IgM水平降低 贫血症状、血小板减少症和淋巴细胞减少症改善或解除；以及 所有受影响患者中性粒细胞减少症解除。 重要的是，37%接受免疫球蛋白替代疗法（IRT）的参与者在服用leniolisib期间能够减少IRT的使用。六例患者摆脱了对IRT的依赖，其中四例患者在数据截止时不依赖IRT已达1至2.5年。截至中期分析的数据截止日期，在试验前有淋巴瘤病史的三例患者中，参与研究时无人出现复发或新发淋巴瘤。 Pharming 首席医学官、医学博士、公共 卫生硕士 Anurag Relan 对此评论道： "Pharming很高兴分享关于leniolisib长期安全性和疗效方面乐观的中期研究结果。2022年ASH年会上宣布的结果建立在今年早些时候宣布并于2022年11月发表在《Blood》（血液） 1 上的II/III期研究结果，其强调了leniolisib在控制出现APDS免疫相关症状方面的潜力。我们非常自豪能够开发出可能成为第一种针对APDS病因的药物，从而帮助填补尚未得到满足的需求。" 中期分析结果与2022年2月2日首次报告的II/III期临床试验数据一致，试验研究了作为成人和青少年APDS患者治疗药物的leniolisib。与安慰剂相比，II/III期临床试验中的患者实现了指示性淋巴结尺寸的显著降低以及外周血中幼稚B细胞百分比的增加。 根据II/III期临床试验结果和长期、开放标签拓展数据，美国食品和药物管理局（FDA）正在对Pharming的leniolisib用于治疗青少年和成人APDS的新药申请进行优先审查，并且指定了2023年3月29日的《处方药使用者付费法案》（PDUFA）目标日期。此外，Pharming针对leniolisib用于相同患者群体的上市许可申请（MAA）已根据欧洲药监局（EMA）人用医药产品委员会（CHMP）的加速评估得到了验证。预计将在2023年上半年获得在欧盟的leniolisib上市许可授权。 关于磷酸肌醇 3 激 酶 δ 过度活化综合征（APDS） APDS是一种罕见的原发性免疫缺陷，每百万人大约有1至2人感染。APDS由两种调节白血球成熟度的基因（ PIK3CD 或 PIK3R1 ）的任意一种发生变异而引起。这些基因发生变异会导致PI3Kδ（磷酸肌醇3激酶δ）通路过度活化。 2,3 PI3Kδ通路中的平衡信号对于生理免疫功能至关重要。当这一通路过度活化时，免疫细胞无法成熟和正常工作，导致免疫缺陷和调节异常。 2,4 APDS的主要特征是严重复发性窦肺感染、淋巴细胞增殖、自身免疫和肠道病变。 5,6 由于这些症状可能与包括其他原发性免疫缺陷在内的各种病况相关，APDS患者经常被误诊并遭受平均7年的诊断延迟。 7 由于APDS是一种进行性疾病，诊断延迟可能会导致身体损伤随着时间的推移而不断积累，包括永久肺损伤和淋巴瘤。 5-8 确诊这种疾病的唯一方法就是进行基因检测。 关于 leniolisib Leniolisib是IA PI3K类110 kDa催化亚基δ异构体的小分子抑制剂。PI3Kδ主要在血液细胞中表达，将磷酸酯肌醇-4-5-三磷酸肌醇（PIP2）转换为磷酸酯肌醇-3-4-5-三磷酸肌醇（PIP3），对正常免疫系统功能至关重要。Leniolisib可以抑制PIP3的产生。PIP3作为一种重要的细胞信使，通过PDK1激活AKT，同时调节多种细胞功能，如增殖、分化、细胞因子生产、细胞生存、血管生成和代谢。与普遍表达的PI3Kα和PI3Kβ不同，PI3Kẟ和PI3Kγ主要在造血细胞中表达。PI3Kẟ的核心作用是调节适应性免疫系统（B细胞以及少部分T细胞）和先天免疫系统（中性粒细胞、肥大细胞以及巨噬细胞）的多种细胞功能，这强烈表明PI3Kẟ是针对APDS等免疫疾病可行且可能有效的治疗靶标。迄今为止，在对健康受试者进行的1期首次人类试验以及对APDS患者的II/III期允许注册研究中，Leniolisib均表现出良好耐受性。 关于 Pharming Group N.V. Pharming Group N.V.（阿姆斯特丹泛欧交易所股票代码：PHARM/纳斯达克股票代码：PHAR）是一家全球生物制药公司，致力于改变罕见、致人衰弱和危及生命疾病患者的生活。Pharming正在开发蛋白质替代疗法和精准药物的创新组合并将其商业化，包括处于早期到后期开发阶段的小分子、生物制剂和基因疗法。Pharming总部位于荷兰莱顿，员工遍布全球，为北美、欧洲、中东、非洲和亚太地区30多个市场的患者提供服务。 欲了解更多信息，请访问 www.pharming.com 或通过 LinkedIn 与我们联系。 前瞻性 陈述 本新闻稿可能包括"前瞻性陈述"。前瞻性陈述是管理层基于当前预期和假设对未来预期的陈述，受到风险和不确定性的影响。这些风险和不确定性可能导致实际结果、表现获活动与陈述中所明示或暗示的结果有重大差异。这些前瞻性陈述可通过其中使用的"旨在"、"雄心"、"预计"、"相信"、"可以"、"估计"、"期待"、"目标"、"打算"、"可能"、"里程碑"、"对向"、"展望"、"计划"、"可能"、"预测"、"风险"、"时间表"、"寻求"、"应该"、"目的"，"将要"和类似的术语和短语来识别。前瞻性陈述的示例包括涉及以下内容的陈述：Pharming的临床前研究及候选产品临床试验的时间和进展、Pharming的临床和商业前景，以及Pharming对其预计营运资本需求和现金资源的相关预期，这些陈述受到多种风险、不确定性和假设的影响，包括但不限于Pharming临床试验的范围、进展和扩展以及由此产生的成本后果；以及临床、科学、监管和技术发展。鉴于这些风险和不确定性，以及Pharming在提交给美国证券交易委员会（SEC）的2021年度报告和截止到2021年12月31日的表格20-F年度报告中所描述的其他风险和不确定性，这些前瞻性陈述中所讨论的事件和情况可能不会发生，故而Pharming的实际业绩表现可能与预期或暗示的表现存在重大不利差异。本新闻稿中包含的所有前瞻性陈述均由本节中包含或提及的警告声明明确限定。读者不应过分依赖前瞻性陈述。任何前瞻性陈述仅于本新闻稿发布之日作出，并且基于截止本新闻稿发布之日可供Pharming使用的信息。Pharming不承担任何公开更新或修订的义务。 内幕信息 本新闻稿涉及符合或可能符合《欧盟市场滥用条例》第7条第1款所定义的"内幕信息"的信息披露。 参考文献 1.  Rao VK, et al. Blood. 2022. https://doi-org.libproxy1.nus.edu.sg/10.1182/blood.2022018546 . 2.  Lucas CL, et al. Nat Immunol. 2014;15:88-97. 3.  Elkaim E, et al. J Allergy Clin Immunol. 2016;138(1):210-218. 4.  Nunes-Santos C, Uzel G, Rosenzweig SD. J Allergy Clin Immunol. 2019;143(5):1676-1687. 5.  Coulter TI, et al. J Allergy Clin Immunol. 2017;139(2):597-606. 6.  Maccari ME, et al. Front Immunol. 2018;9:543. 7.  Jamee M, et al. Clin Rev Allergy Immunol. 2019; May 21 . 8.  Condliffe AM, Chandra A. Front Immunol. 2018;9:338. 如需了解更多公开信息， 请联系： Pharming Group ，荷 兰莱顿 Michael Levitan ，投 资者关系和企业传播副总裁 电话： +1 (908) 705 1696 Heather Robertson，投资者关系和企业传播经理 电子邮箱： investor@pharming.com FTI Consulting，英国伦敦 Victoria Foster Mitchell / Alex Shaw / Amy Byrne 电话：+44 203 727 1000 LifeSpring Life Sciences Communications，荷兰阿姆斯特丹 Leon Melens 电话：+31 6 53 81 64 27 电子邮箱： pharming@lifespring.nl 美国公关： Ethan Metelenis 电子邮箱： Ethan.Metelenis@precisionvh.com 电话： +1 (917) 882 9038 欧盟公关： Dan Caley 电子邮箱： Dan.caley@aprilsix.com 电话：+44 (0) 787 546 8942

V. Koneti Rao, MD, shared new evidence of long-term safety and hematologic response in patients who received leniolisib to treat APDS, a rare primary immunodeficiency Interim analysis demonstrated leniolisib to be well tolerated and indicated the durability of the efficacy results seen in the Phase II/III randomized, controlled trial LEIDEN, Netherlands, Dec. 15, 2022 /PRNewswire/ -- Pharming Group N.V. ("Pharming" or "the Company") (EURONEXT Amsterdam: PHARM) (Nasdaq: PHAR) announces data, including new evidence, from an interim analysis of its open-label extension study evaluating the investigational drug leniolisib, an oral, selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, to treat adult and adolescent patients with activated phosphoinositide 3-kinase delta syndrome (APDS), a rare primary immunodeficiency. Principal investigator V. Koneti Rao, M.D., a staff physician in the Primary Immune Deficiency Clinic at the National Institutes of Health in Bethesda, Maryland, U.S., shared the positive findings in an oral presentation at the 2022 Annual Meeting of the American Society of Hematology (ASH). Dr. Virgil Dalm, Principal Investigator, Consultant Clinical Immunology, Erasmus MC, Rotterdam, the Netherlands, commented: "I'm excited about Pharming's findings that further support leniolisib as a well-tolerated investigational treatment benefitting patients with APDS. The results demonstrate the long-term tolerability of leniolisib, with a median duration on study therapy of just over 2 years (102 weeks) and 5 subjects being treated for 5 years or more. Individuals with APDS frequently suffer from recurrent infections and lifelong Immunoglobulin Replacement Therapy (IRT) is required to reduce this burden. Notably, leniolisib treatment demonstrated a significant reduction in the annualized infection rate, while 37% of study patients on IRT were able to either reduce or altogether stop their IRT regimens. This is a remarkable outcome for any study of inborn errors of immunity and through the continued study of leniolisib, I look forward to contributing to the knowledge of an improved treatment option for individuals with APDS." The ongoing extension study includes 37 patients with APDS aged 12 years or older who, at the time of data cutoff for the interim analysis, had received 70 mg of the selective PI3Kδ inhibitor leniolisib twice a day for up to six years and three months, with a median duration on study therapy of 102 weeks. The study was primarily designed to assess the safety and tolerability of long-term leniolisib treatment in adolescent and adult patients with APDS who previously participated in a Phase II/III leniolisib study. The extension study's secondary endpoints are intended to evaluate the efficacy and pharmacokinetics of long-term leniolisib treatment in these patients. The interim analysis found that leniolisib was well tolerated to this point in the study. It also indicated the durability of the efficacy results seen in the randomized, controlled trial, which showed significant improvement over placebo in the co-primary endpoints of reduction in lymph node size and increase in naïve B cells. The interim results indicate a favorable long-term impact on the immune dysregulation and deficiency often seen in patients with APDS, with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. The majority of adverse events (AEs) reported in the interim analysis were grades 1 and 2, and included upper respiratory tract infection, headache and pyrexia. Grade 1 AEs are the least severe and grade 5 the most severe. Overall, 13.5% of AEs were study drug-related; these affected five patients and included weight gain, arthralgia, hyperglycemia, and decreased neutrophil count. Of all AEs assessed in the analysis, 16.2% were classified as serious, but none of these were identified as related to study treatment. There was one death among study participants which was identified as not related to study treatment. Among study participants, some experienced reductions in APDS disease markers, with levels of response varying between individuals. Responses included: reduced lymphadenopathy, splenomegaly, and IgM levels; improved or resolved anemia, thrombocytopenia, and lymphopenia; and resolved neutropenia in all affected patients. Importantly, 37% of participants who were on immunoglobulin replacement therapy (IRT) were able to reduce their IRT use while taking leniolisib. Six patients became IRT-independent, with four of those patients having been IRT-independent for 1 to 2.5 years at the data cutoff. As of the data cut-off for the interim analysis, among three patients who had a history of lymphoma prior to the trial, none had a recurrence or new lymphoma while participating in the study. Anurag Relan, MD, MPH, Chief Medical Officer of Pharming, commented: "Pharming is pleased to share positive interim findings on the long-term safety and efficacy of leniolisib. The results announced at the 2022 ASH Annual Meeting build on the Phase II/III study findings announced earlier this year and published in Blood1 in November 2022, which highlighted leniolisib's potential to control the development of immune-related symptoms of APDS. We're proud to help fill an unmet need by developing what could become the first approved drug to target the cause of APDS." The interim analysis findings are consistent with the data, first reported on February 2, 2022, for the Phase II/III clinical trial investigating leniolisib as a treatment for adult and adolescent patients with APDS. Compared with placebo, patients in the Phase II/III clinical trial achieved significant reductions in index lymph node size and increases in the percentage of naïve B cells in peripheral blood. Based on the results of Phase II/III clinical trial and the long-term, open-label extension data, the U.S. Food and Drug Administration (FDA) is conducting a priority review of Pharming's New Drug Application for leniolisib as a treatment for adolescents and adults with APDS and has an assigned Prescription Drug User Fee Act (PDUFA) goal date of March 29, 2023. In addition, Pharming's Marketing Authorisation Application (MAA) for leniolisib in the same patient population has been validated for evaluation under an accelerated assessment by the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP). Marketing authorization for leniolisib in the European Union is anticipated in H1 2023. About Activated Phosphoinositide 3-Kinase δ Syndrome (APDS) APDS is a rare primary immunodeficiency that affects approximately 1 to 2 people per million. APDS is caused by variants in either of two genes, PIK3CD or PIK3R1, that regulate maturation of white blood cells. Variants of these genes lead to hyperactivity of the PI3Kδ (phosphoinositide 3-kinase delta) pathway.2,3 Balanced signaling in the PI3Kδ pathway is essential for physiological immune function. When this pathway is hyperactive, immune cells fail to mature and function properly, leading to immunodeficiency and dysregulation.2,4 APDS is characterized by severe, recurrent sinopulmonary infections, lymphoproliferation, autoimmunity, and enteropathy.5,6 Because these symptoms can be associated with a variety of conditions, including other primary immunodeficiencies, people with APDS are frequently misdiagnosed and suffer a median 7-year diagnostic delay.7 As APDS is a progressive disease, this delay may lead to an accumulation of damage over time, including permanent lung damage and lymphoma.5-8 The only way to definitively diagnose this condition is through genetic testing. About leniolisib Leniolisib is a small-molecule inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA PI3K. PI3Kδ is expressed predominately in hematopoietic cells and is essential to normal immune system function through conversion of phosphatidylinositol-4-5-trisphosphate (PIP2) to phosphatidylinositol-3-4-5-trisphosphate (PIP3). Leniolisib inhibits the production of PIP3 and PIP3 serves as an important cellular messenger activating AKT (via PDK1) and regulates a multitude of cell functions such as proliferation, differentiation, cytokine production, cell survival, angiogenesis, and metabolism. Unlike PI3Kα and PI3Kβ, which are ubiquitously expressed, PI3Kẟ and PI3Kγ are expressed primarily in cells of hematopoietic origin. The central role of PI3Kẟ in regulating numerous cellular functions of the adaptive immune system (B-cells and, to a lesser extent, T cells) as well as the innate immune system (neutrophils, mast cells, and macrophages) strongly indicates that PI3Kẟ is a valid and potentially effective therapeutic target for immune diseases such as APDS. To date, leniolisib has been well tolerated during both the Phase 1 first-in-human trial in healthy subjects and the Phase II/III registration-enabling study in patients with APDS. About Pharming Group N.V. Pharming Group N.V. (EURONEXT Amsterdam: PHARM/Nasdaq: PHAR) is a global biopharmaceutical company dedicated to transforming the lives of patients with rare, debilitating, and life-threatening diseases. Pharming is commercializing and developing an innovative portfolio of protein replacement therapies and precision medicines, including small molecules, biologics, and gene therapies that are in early to late-stage development. Pharming is headquartered in Leiden, Netherlands, and has employees around the globe who serve patients in over 30 markets in North America, Europe, the Middle East, Africa, and Asia-Pacific. For more information, visit and find us on LinkedIn. Forward-Looking Statements This press release may contain forward-looking statements. Forward-looking statements are statements of future expectations that are based on management's current expectations and assumptions and involve known and unknown risks and uncertainties that could cause actual results, performance, or events to differ materially from those expressed or implied in these statements. These forward-looking statements are identified by their use of terms and phrases such as "aim", "ambition", ''anticipate'', ''believe'', ''could'', ''estimate'', ''expect'', ''goals'', ''intend'', ''may'', "milestones", ''objectives'', ''outlook'', ''plan'', ''probably'', ''project'', ''risks'', "schedule", ''seek'', ''should'', ''target'', ''will'' and similar terms and phrases. Examples of forward-looking statements may include statements with respect to timing and progress of Pharming's preclinical studies and clinical trials of its product candidates, Pharming's clinical and commercial prospects, and Pharming's expectations regarding its projected working capital requirements and cash resources, which statements are subject to a number of risks, uncertainties and assumptions, including, but not limited to the scope, progress and expansion of Pharming's clinical trials and ramifications for the cost thereof; and clinical, scientific, regulatory and technical developments. In light of these risks and uncertainties, and other risks and uncertainties that are described in Pharming's 2021 Annual Report and the Annual Report on Form 20-F for the year ended December 31, 2021, filed with the U.S. Securities and Exchange Commission, the events and circumstances discussed in such forward-looking statements may not occur, and Pharming's actual results could differ materially and adversely from those anticipated or implied thereby. All forward-looking statements contained in this press release are expressly qualified in their entirety by the cautionary statements contained or referred to in this section. Readers should not place undue reliance on forward-looking statements. Any forward-looking statements speak only as of the date of this press release and are based on information available to Pharming as of the date of this release. Pharming does not undertake any obligation to publicly update or revise any. Inside Information This press release relates to the disclosure of information that qualifies, or may have qualified, as inside information within the meaning of Article 7(1) of the EU Market Abuse Regulation. References 1. Rao VK, et al. Blood. 2022. . 2. Lucas CL, et al. Nat Immunol. 2014;15:88-97. 3. Elkaim E, et al. J Allergy Clin Immunol. 2016;138(1):210-218. 4. Nunes-Santos C, Uzel G, Rosenzweig SD. J Allergy Clin Immunol. 2019;143(5):1676-1687. 5. Coulter TI, et al. J Allergy Clin Immunol. 2017;139(2):597-606. 6. Maccari ME, et al. Front Immunol. 2018;9:543. 7. Jamee M, et al. Clin Rev Allergy Immunol. 2019;May 21. 8. Condliffe AM, Chandra A. Front Immunol. 2018;9:338. For further public information, contact: Pharming Group, Leiden, The Netherlands Michael Levitan, VP Investor Relations & Corporate Communications T: +1 (908) 705 1696 Heather Robertson, Investor Relations & Corporate Communications Manager E: [email protected] FTI Consulting, London, UK Victoria Foster Mitchell/Alex Shaw/Amy Byrne T: +44 203 727 1000 LifeSpring Life Sciences Communication, Amsterdam, The Netherlands Leon Melens T: +31 6 53 81 64 27 E: [email protected] US PR: Ethan Metelenis E: [email protected] T: +1 (917) 882 9038 EU PR: Dan Caley E: [email protected] T: +44 (0) 787 546 8942 Logo - SOURCE Pharming Group N.V.