Remifentanil-induced hyperalgesia (RIH) is directly mediated by altered mitochondrial dynamics. Moreover, anxiety is proven to worsen hyperalgesia. Voltage-gated sodium channel 1.8 (NaV1.8) is involved in both nociceptive initiation and anxiety. However, its role in modulating RIH, particularly in the coexistence of anxiety and RIH (CARIH), remains unexplored.

Methods:

A total of 148 Sprague-Dawley male rats were used to explore whether silencing NaV1.8 activation could alleviate CARIH. The behavioral effects were assessed using the open field, novelty suppressed feeding, and paw withdrawal tests. The mechanisms of antisense oligodeoxynucleotides (AS-ODN) targeting NaV1.8 (AS-NaV1.8) were investigated through western blot, RT-qPCR, electron microscopy, mitochondrial superoxide imaging, glutathione (GSH/GSSG) ratio, and malondialdehyde measurement.

Results:

NaV1.8 was upregulated at the mRNA level in the dorsal root ganglia (DRG) (P < 0.001) after CARIH. Meanwhile, spinal NR₂B and Drp1 began to increase at 4 hours (P = 0.021) and 24 hours (P < 0.001), respectively. AS-NaV1.8 decreased spinal NR₂B and Drp1 levels (P < 0.01), while increasing Mfn2 and OPA1 expression (P < 0.01). The MitoSox-positive cells in Group AS (AS-NaV1.8 injected into rats with CARIH) were fewer than those in Group AR (CARIH group) (P = 0.013) and Group MM (mismatch-ODN of NaV1.8 injected into rats with CARIH) (P = 0.018). Abnormal fission of spinal mitochondria was reduced in Group AS compared to Group AR (P = 0.023) and Group MM (P = 0.018).

Conclusions:

Anxiety exacerbates RIH, while NaV1.8 knockdown in DRG effectively attenuates CARIH by suppressing abnormal mitochondrial dynamics. Oral NaV1.8 inhibitors show promise in preclinical trials, suggesting NaV1.8 targeting as a novel approach to mitigate CARIH.

2026-01-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Advances in the discovery of selective NaV1.8 inhibitors for pain management

Review

作者: Wu, Zhixing ; Lu, Dai

Pain management remains an unmet healthcare need, particularly in the development of effective non-opioid analgesics with improved safety profiles. Among emerging molecular targets, the voltage-gated sodium channel NaV1.8 has garnered significant attention due to its pivotal role in pain signaling. VX-548 (also known as suzetrigine), one of the most promising NaV1.8 inhibitors, has demonstrated encouraging clinical efficacy and received FDA approval in January 2025. This milestone has further stimulated strong interest from pharmaceutical companies worldwide, driving ongoing research efforts to identify novel chemical scaffolds and optimize structure-activity relationships (SARs) for improved potency, selectivity, and drug-like properties. In this review, we provide a comprehensive overview of recent progress in the discovery and development of selective NaV1.8 inhibitors, highlighting findings from patents and literature, chemical optimization strategies, and reported in vitro and in vivo pharmacological data. We also discuss current challenges and future opportunities in advancing NaV1.8 inhibitors as a transformative therapeutic approach for pain management.

2025-09-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Conformational restriction enables discovering a series of chroman derivatives as potent and selective NaV1.8 inhibitors with improved pharmacokinetic properties

Article

作者: Wang, Linlin ; Yang, Bowen ; Liu, Tongchao ; Zheng, Yueming ; Gao, Zhaobing ; Gu, Yueling ; Li, Na ; Xiong, Bing ; Xu, Haiyan ; Hu, Xinyuan ; Cai, Yongjie ; Zhan, Li ; Chen, Xueqin

Voltage-gated sodium channel 1.8 (Na_V1.8) is a promising analgesic target due to its unique biophysical characteristics and specific role in nociceptive sensation. VX-150 initially completed proof-of-concept studies in clinical trials, but with high dosages and frequent administration. Herein, based on VX-150, we report the design, synthesis and structure-activity relationship (SAR) study aiming to identify novel, potent and selective Na_V1.8 inhibitors with improved pharmacokinetic properties. Conformational restriction strategy and subsequent optimization led to the identification of the chroman derivative (R)-40 as the most promising hNa_V1.8 inhibitor showing an IC₅₀ value of 5.9 ± 1.0 nM and good selectivity over other tested Na_V channels and hERG channel. More importantly, (R)-40 showed good in vitro metabolic stability in liver microsomes across multiple species and excellent in vivo PK profiles in rats and dogs. Notably, (R)-40 exerted dose-dependent analgesic activities in both rat models with postoperative and inflammatory pain, and a wide safety margin in neurotoxicity evaluation. Overall, these results confirmed conformational restriction as an effective strategy to improve PK profile, and our detailed study provided a valuable foundation for developing novel Na_V1.8 inhibitors.

105

项与 Nav1.8抑制剂(阳光安津) 相关的新闻（医药）

2026-06-19

·爱自己随遇而安

Suzetrigine（Journavx）作用机制专题报告（中英双语对照）

执行摘要：Suzetrigine（商品名 Journavx™）是全球首款获批的选择性 NaV1.8（电压门控钠离子通道 1.8 型）抑制剂，用于治疗成人中重度急性疼痛。其通过高选择性（>31,000 倍）结合于 NaV1.8 通道的电压感受域 2（VSD2），以别构方式抑制通道，从而阻断外周伤害性信号向中枢的传递。该药无中枢暴露（脑血比 < 0.1），因此避免了传统阿片类药物的呼吸抑制、欣快感和成瘾性风险。关键 III 期临床试验（NAVIGATE-1/2）显示其镇痛效果与氢可酮/对乙酰氨基酚复方制剂相当，且 2026 年一项整形外科 IV 期研究显示 90.9%的患者实现了全程无阿片类药物镇痛。 Executive Summary: Suzetrigine (brand name Journavx™) is the world's first approved selective NaV1.8 (voltage-gated sodium channel type 1.8) inhibitor for the treatment of moderate-to-severe acute pain in adults. It achieves high selectivity (>31,000-fold) by binding to the Voltage-Sensing Domain 2 (VSD2) of the NaV1.8 channel, inhibiting it allosterically, thereby blocking the transmission of peripheral nociceptive signals to the central nervous system. The drug is peripherally restricted(brain-plasma ratio < 0.1), thus avoiding the risks of respiratory depression, euphoria, and addiction associated with traditional opioids. Key Phase 3 clinical trials (NAVIGATE-1/2) demonstrated analgesic efficacy comparable to hydrocodone/acetaminophen combination, and a 2026 Phase 4 plastic surgery study showed 90.9%of patients achieved opioid-free pain management throughout treatment.一、药物概览 / 1. Drug Overview1.1 关键信息 Suzetrigine（VX-548）是一种口服小分子药物，由 Vertex Pharmaceuticals 研发，于 2025年1月30日获得美国 FDA 批准，商品名为 Journavx™。其化学名为 4-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-甲酰胺基]吡啶-2-甲酰胺，分子式为 C₂₁H₂₂F₅N₃O₄，分子量为 473.39 g/mol。获批剂型为 50 mg 片剂，用于治疗成人中重度急性疼痛（如术后疼痛）。标准给药方案为：100 mg 负荷剂量，随后每 12 小时 50 mg维持。1.1 Key Information Suzetrigine (VX-548) is an oral small-molecule drug developed by Vertex Pharmaceuticals, approved by the U.S. FDA on January 30, 2025, under the brand name Journavx™. Its chemical name is 4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-amido]pyridine-2-carboxamide, with a molecular formula of C₂₁H₂₂F₅N₃O₄ and a molecular weight of 473.39 g/mol. The approved dosage form is a 50 mg tablet, indicated for the treatment of moderate-to-severe acute pain (e.g., postoperative pain) in adults. The standard dosing regimen is a 100 mg loading dose, followed by 50 mg every 12 hoursfor maintenance.二、靶点 NaV1.8 通道 / 2. Target: NaV1.8 Channel2.1 通道生物学 NaV1.8 通道由 SCN10A基因编码，是一种河豚毒素不敏感型（Tetrodotoxin-Resistant, TTX-R）电压门控钠离子通道。它在初级感觉神经元，特别是传递痛觉的小直径 C 纤维和薄髓鞘 Aδ 纤维中高表达。在伤害感受器的动作电位去极化阶段，NaV1.8 贡献了超过 70%的内向钠电流，是痛觉信号产生的关键驱动者。其生物物理特征包括较高的激活电压阈值、慢失活和快速从失活中恢复的特性，使其能够维持伤害感受器的高频放电。2.1 Channel Biology The NaV1.8 channel is encoded by the SCN10Agene and is a Tetrodotoxin-Resistant (TTX-R)voltage-gated sodium channel. It is highly expressed in primary sensory neurons, particularly in small-diameter C-fibersand lightly myelinated Aδ-fibersthat transmit pain signals. During the depolarization phase of action potentials in nociceptors, NaV1.8 contributes to more than 70%of the inward sodium current, making it a key driver of pain signal generation. Its biophysical properties include a high voltage threshold for activation, slow inactivation, and rapid recovery from inactivation, enabling it to sustain high-frequency firing in nociceptors.2.2 通道表达与组织分布 NaV1.8 的表达具有高度的组织选择性。它在背根神经节（Dorsal Root Ganglion, DRG）的感觉神经元中富集，但在中枢神经系统（CNS）和心肌细胞中基本缺失。这种分布特征是其成为理想镇痛靶点的关键，因为抑制它不会影响大脑认知功能或心脏电生理活动。2.2 Channel Expression and Tissue Distribution The expression of NaV1.8 is highly tissue-selective. It is enriched in sensory neurons of the Dorsal Root Ganglion (DRG), but is essentially absent from the central nervous system (CNS)and cardiac myocytes. This distribution profile is key to its appeal as an ideal analgesic target, as inhibiting it does not affect cognitive brain function or cardiac electrophysiology.2.3 遗传学证据人类遗传学研究为 NaV1.8 在疼痛中的作用提供了有力证据。SCN10A 基因的功能获得性突变（Gain-of-function mutations）与疼痛性周围神经病变相关。相反，功能丧失性变异（Loss-of-function variants）则与疼痛敏感性降低相关。这些遗传学发现从正反两方面验证了 NaV1.8 是调节人类痛觉的可行靶点。2.3 Genetic Evidence Human genetic studies provide strong evidence for the role of NaV1.8 in pain. Gain-of-function mutations in the SCN10A geneare associated with painful peripheral neuropathy. Conversely, loss-of-function variantsare linked to reduced pain sensitivity. These genetic findings validate NaV1.8 as a viable target for modulating human pain perception from both directions.三、Suzetrigine 分子作用机制 / 3. Molecular Mechanism of Suzetrigine3.1 结合位点：VSD2 的 S3–S4 环外区 Suzetrigine 并非结合在钠离子通道的中央孔区，而是高选择性、高亲和力地结合于 NaV1.8 通道的电压感受域 2（Voltage-Sensing Domain 2, VSD2），具体位于其细胞外的 S3–S4 连接环。该位点包含一个 NaV1.8 特有的 KKGS（赖氨酸-赖氨酸-甘氨酸-丝氨酸）氨基酸序列基序。其他钠通道亚型（NaV1.1–1.7, NaV1.9）缺乏此基序，这构成了其超高选择性的结构基础。3.1 Binding Site: The Extracellular S3–S4 Loop of VSD2 Suzetrigine does not bind to the central pore of the sodium channel. Instead, it binds with high selectivity and affinity to the Voltage-Sensing Domain 2 (VSD2) of the NaV1.8 channel, specifically to its extracellular S3–S4 linker loop. This site contains a unique KKGS (Lys-Lys-Gly-Ser) amino acid sequence motifspecific to NaV1.8. Other sodium channel subtypes (NaV1.1–1.7, NaV1.9) lack this motif, forming the structural basis for its ultra-high selectivity.3.2 域互换实验证实关键实验证据来自域互换（Domain-swap）实验。研究人员将 NaV1.8 的 VSD2 移植到对 Suzetrigine 不敏感的 NaV1.2 通道上，结果使嵌合通道获得了对 Suzetrigine 的敏感性。这直接证明了 VSD2 是决定药物敏感性的充分且必要条件。3.2 Confirmation by Domain-Swap Experiment Key experimental evidence comes from a domain-swap experiment. Researchers transplanted the VSD2 of NaV1.8 into the NaV1.2 channel, which is insensitive to Suzetrigine. This conferred sensitivity to Suzetrigine upon the chimeric channel. This directly proves that VSD2 is both sufficient and necessary for determining drug sensitivity.3.3 别构抑制 vs 孔阻断 Suzetrigine 的作用机制是别构抑制（Allosteric inhibition）。它结合在 VSD2 上，稳定通道的关闭（静息）状态，从而抑制其激活。这与传统局部麻醉药（如利多卡因）或抗惊厥药（如卡马西平）的孔阻断（Pore-blocking）机制截然不同。孔阻断剂通常缺乏亚型选择性，且可能影响心脏（NaV1.5）和中枢神经系统（NaV1.1/1.2/1.6）功能。3.3 Allosteric Inhibition vs. Pore Blocking Suzetrigine's mechanism of action is allosteric inhibition. By binding to VSD2, it stabilizes the closed (resting) stateof the channel, thereby inhibiting its activation. This is fundamentally different from the pore-blockingmechanism of traditional local anesthetics (e.g., lidocaine) or anticonvulsants (e.g., carbamazepine). Pore blockers typically lack subtype selectivity and may affect cardiac (NaV1.5) and central nervous system (NaV1.1/1.2/1.6) functions. 关键数据：Suzetrigine 对人 NaV1.8 通道的半数抑制浓度（IC50）为 0.68 ± 0.16 nM，对猴 NaV1.8 的 IC50 为 0.75 nM。其对其他钠通道亚型（NaV1.1–1.7, NaV1.9）的选择性超过 31,000 倍。针对包括 44 个潜在滥用靶点在内的 180 多个脱靶分子进行测试，未发现显著结合。 Key Data: The half-maximal inhibitory concentration (IC50) of Suzetrigine for human NaV1.8 channels is 0.68 ± 0.16 nM, and 0.75 nMfor monkey NaV1.8. Its selectivity over other sodium channel subtypes (NaV1.1–1.7, NaV1.9) exceeds 31,000-fold. Testing against over 180 off-target molecules, including 44 potential abuse-liability targets, revealed no significant binding.3.4 “Reverse Use-Dependence” 现象 Suzetrigine 表现出独特的 “反向使用依赖性（Reverse use-dependence）”。这意味着在神经元处于静息状态时，药物的抑制效应最强。当神经元发生强烈去极化时，抑制会部分减轻（缓解时间常数 τ ≈ 40 ms），但在恢复静息电压后，抑制会重新建立。这种特性使其能够在疼痛相关的高频放电中维持强直性抑制（Tonic inhibition），同时可能减少对正常生理性电活动的影响。3.4 The "Reverse Use-Dependence" Phenomenon Suzetrigine exhibits a unique "reverse use-dependence". This means the inhibitory effect of the drug is strongest when the neuron is at resting state. When the neuron undergoes strong depolarization, the inhibition is partially relieved (relief time constant τ ≈ 40 ms), but re-establishes upon returning to resting voltages. This property allows it to maintain tonic inhibitionduring the high-frequency firing characteristic of pain states, while potentially minimizing impact on normal physiological electrical activity.四、神经环路与镇痛效应 / 4. Pain Pathway and Analgesic Effect4.1 外周伤害感受通路痛觉信号产生于外周组织的伤害感受器末梢，动作电位沿神经轴突传播至背根神经节（DRG）的胞体，再通过脊髓背角传入中枢，最终上传至大脑皮层产生痛觉。NaV1.8 在此通路的外周部分（末梢、轴突、DRG胞体）扮演核心角色。4.1 Peripheral Nociceptive Pathway Pain signals originate at the peripheral nociceptor terminals. Action potentials propagate along the axon to the cell body in the Dorsal Root Ganglion (DRG), then enter the central nervous system via the spinal cord dorsal horn, and ultimately ascend to the cerebral cortex to be perceived as pain. NaV1.8 plays a central role in the peripheral segmentof this pathway (terminal, axon, DRG cell body).4.2 Suzetrigine 的阻断效应 Suzetrigine 通过抑制 NaV1.8，减少钠离子内流，从而：降低膜去极化程度，阻止动作电位的起始。削弱已产生动作电位的传播能力。其结果是，伤害性信号无法有效传入脊髓，避免了中枢敏化（Central sensitization）的启动，后者是急性疼痛转为慢性疼痛的关键机制。4.2 The Blocking Effect of Suzetrigine By inhibiting NaV1.8, Suzetrigine reduces sodium influx, thereby: Reducing membrane depolarization, preventing the initiationof action potentials. Weakening the propagationcapability of generated action potentials.The result is that nociceptive signals cannot effectively reach the spinal cord, preventing the initiation of central sensitization, a key mechanism in the transition from acute to chronic pain.4.3 无成瘾性机制 Suzetrigine 不具备成瘾性，主要原因有二：作用靶点不同：它不作用于μ-阿片受体（μ-opioid receptor），这是阿片类药物产生欣快感和依赖性的直接靶点。外周限制性：其脑血比 < 0.1，意味着极少进入中枢神经系统，因此不会直接激活大脑的奖赏环路。临床数据显示，在超过 2400 名患者中未观察到滥用、依赖或戒断信号。4.3 Mechanism of Non-Addictiveness Suzetrigine lacks addictive potential, primarily for two reasons: Different Target: It does not act on the μ-opioid receptor, the direct target through which opioids produce euphoria and dependence. Peripheral Restriction: Its brain-plasma ratio is < 0.1, meaning minimal penetration into the central nervous system, thus it does not directly activate the brain's reward circuitry. Clinical data show no signals of abuse, dependence, or withdrawal in over 2,400 patients.五、药代动力学 / 5. Pharmacokinetics Suzetrigine 在禁食状态下口服吸收良好，达峰时间（Tmax）约为 3 小时；高脂饮食会延迟 Tmax 至约 5 小时并降低峰浓度（Cmax）。其有效半衰期（t½）约为 23.6 小时，约需 3 天达到母体药物稳态，活性代谢物约需 5 天。稳态时，母体药物的药时曲线下面积（AUC₀-₂₄h）为 11.5 μg·h/mL，活性代谢物 M6-SUZ 为 34.7 μg·h/mL。 Suzetrigine is well absorbed orally under fasting conditions, with a time to maximum concentration (Tmax) of approximately 3 hours; a high-fat meal delays Tmax to about 5 hours and reduces the maximum concentration (Cmax). Its effective half-life (t½) is approximately 23.6 hours, requiring about 3 daysto reach steady state for the parent drug and about 5 daysfor the active metabolite. At steady state, the area under the curve (AUC₀-₂₄h) is 11.5 μg·h/mL for the parent drug and 34.7 μg·h/mL for the active metabolite M6-SUZ. 参数 / Parameter 数值 / Value 蛋白结合率 / Protein Binding 母体药物 99% / 代谢物 M6-SUZ 96% 主要代谢酶 / Primary Metabolizing Enzyme CYP3A4 活性代谢物 / Active Metabolite M6-SUZ(也抑制 NaV1.8) 排泄途径 / Excretion Routes 尿 ~44% (代谢物) / 粪 ~49.9% (其中 9.1% 为原形药) 脑血比 / Brain-Plasma Ratio < 0.1(外周限制性) 药物相互作用 / Drug Interaction CYP3A 底物：避免与强效抑制剂或诱导剂合用六、关键临床证据 / 6. Key Clinical Evidence6.1 III 期临床试验（NAVIGATE-1 & NAVIGATE-2）两项关键 III 期试验（跖骨截骨术 NAVIGATE-1，腹壁成形术 NAVIGATE-2）均达到主要终点。与安慰剂相比，Suzetrigine 治疗组在 48 小时内疼痛强度差异总和（SPID48）的改善值为 +29.3 至 +48.4（p < 0.0001）。其镇痛效果与氢可酮/对乙酰氨基酚复方制剂相当，起效时间约为 2 小时。最常见的不良事件为恶心、头晕，程度多为轻至中度。6.1 Phase 3 Clinical Trials (NAVIGATE-1 & NAVIGATE-2) Both key Phase 3 trials (bunionectomy NAVIGATE-1, abdominoplasty NAVIGATE-2) met their primary endpoints. Compared to placebo, the Suzetrigine treatment groups showed an improvement in the Sum of Pain Intensity Difference over 48 hours (SPID48)of +29.3 to +48.4(p < 0.0001). Its analgesic efficacy was comparable to the hydrocodone/acetaminophen combination, with an onset of action of approximately 2 hours. The most common adverse events were nausea and dizziness, mostly mild to moderate in severity. 2026年最新数据：一项于 2026 年 3 月公布的整形外科 IIIb/IV 期研究（N=99）结果显示，90.9%的患者在整个治疗期间实现了无阿片类药物镇痛。同时，90.7%的患者整体评估（Patient Global Assessment, PGA）为“优秀/非常好/好”。 Latest 2026 Data: A Phase IIIb/IV plastic surgery study (N=99) reported in March 2026 showed that 90.9%of patients achieved opioid-free pain management throughout the treatment period. Concurrently, 90.7%of patients rated their Patient Global Assessment (PGA) as "excellent/very good/good".七、急性 vs 慢性疼痛：机制层面的解释 / 7. Acute vs Chronic Pain — Mechanistic Explanation7.1 急性疼痛的有效性对于急性疼痛（如术后痛、创伤痛），伤害性信号的产生和传入严重依赖外周伤害感受器的 NaV1.8 通道。Suzetrigine 在源头阻断信号输入，因此能有效镇痛。7.1 Efficacy in Acute Pain For acute pain (e.g., postoperative, traumatic), the generation and transmission of nociceptive signals heavily rely on NaV1.8 channels in peripheral nociceptors. By blocking signal input at the source, Suzetrigine is effective in analgesia.7.2 慢性疼痛的挑战慢性疼痛（如神经病理性疼痛）的维持涉及复杂的中枢机制，包括：脊髓背角神经元的中枢敏化小胶质细胞的激活大脑皮层痛觉矩阵的重塑一旦这些中枢改变确立，仅靠减少外周输入可能不足以完全缓解疼痛。这解释了为什么 Suzetrigine 在急性疼痛中表现卓越，但其在慢性疼痛（如腰骶神经根痛）的 II 期试验未能达到主要终点，针对糖尿病周围神经病变（DPN）的 III 期试验仍在进行中。7.2 The Challenge in Chronic Pain The maintenance of chronic pain (e.g., neuropathic pain) involves complex central mechanisms, including: Central sensitization of spinal dorsal horn neurons Activation of microglia Reorganization of the brain's pain matrixOnce these central changes are established, merely reducing peripheral inputmay be insufficient for complete pain relief. This explains Suzetrigine's excellent performance in acute pain, while its Phase 2 trial for chronic pain(lumbosacral radiculopathy) failed to meet the primary endpoint, and its Phase 3 trial for diabetic peripheral neuropathy (DPN) is ongoing.八、关键科学洞见 / 8. Key Scientific Insights8.1 超高选择性的实现 31,000 倍的选择性源于对 NaV1.8 特有结构（VSD2 的 KKGS 基序）的精准靶向，而非传统的孔区保守结构。8.1 Achievement of Ultra-High Selectivity The >31,000-fold selectivity stems from precise targeting of a structure unique to NaV1.8 (the KKGS motif in VSD2), rather than the conserved pore region common to all channels.8.2 “静息状态”抑制的独特性 “反向使用依赖性”意味着药物优先结合并稳定通道的静息状态，这可能在提供强效镇痛的同时，对正常生理性电活动干扰更小，是一种精巧的作用机制。8.2 Uniqueness of "Resting-State" Inhibition "Reverse use-dependence" means the drug preferentially binds to and stabilizes the resting state of the channel. This may provide potent analgesia while causing less interference with normal physiological electrical activity, representing a sophisticated mechanism.8.3 在钠通道家族中的定位 NaV 通道家族成员功能各异： NaV1.1, 1.2, 1.3, 1.6：主要分布于 CNS，阻断会导致认知/运动副作用。 NaV1.4：骨骼肌。 NaV1.5：心脏（Brugada 综合征相关基因）。 NaV1.7：外周感觉（遗传学验证充分，但尚未成功药物化）。 NaV1.8：外周伤害感受器（Suzetrigine 的靶点，遗传学与临床双重验证）。 NaV1.9：外周感觉，调节阈下兴奋性（难以成药）。8.3 Positioning within the Sodium Channel Family Members of the NaV channel family have distinct functions: NaV1.1, 1.2, 1.3, 1.6: Primarily in CNS; blockade causes cognitive/motor side effects. NaV1.4: Skeletal muscle. NaV1.5: Cardiac (gene associated with Brugada syndrome). NaV1.7: Peripheral sensory (strong genetic validation, not yet successfully drugged). NaV1.8: Peripheral nociceptor (target of Suzetrigine, validated both genetically and clinically). NaV1.9: Peripheral sensory, modulates subthreshold excitability (difficult to drug).九、结语 / 9. Conclusion Suzetrigine（Journavx）代表了一种基于精准靶点生物学和创新作用机制的镇痛新范式。通过高选择性抑制外周痛觉关键驱动因子 NaV1.8，它实现了与阿片类药物效力相当的镇痛效果，同时规避了其呼吸抑制、成瘾和滥用的核心风险。其在急性疼痛领域的成功，验证了“外周阻断”策略的有效性，也为未来针对其他疼痛类型的药物研发提供了重要的机制参考和方向启示。 Suzetrigine (Journavx) represents a new paradigm in analgesia based on precise target biologyand an innovative mechanism of action. By selectively inhibiting NaV1.8, a key driver of peripheral pain, it achieves analgesic efficacy comparable to opioids while avoiding their core risks of respiratory depression, addiction, and abuse. Its success in acute pain validates the "peripheral blockade" strategy and provides important mechanistic insights and direction for future drug development targeting other pain types.引用与参考文献 / References Osteen JD et al. "Pharmacology and mechanism of action of suzetrigine..." Pain Ther14:655–674 (2025). doi:10.1007/s40122-024-00697-0 Rajasingham R, Qi Y. "Suzetrigine, a Non-Opioid Small-Molecule Analgesic..." Clin Transl Sci18(11):e70414 (2025). https://ascpt.onlinelibrary.wiley.com/doi/full/10.1111/cts.70414 Pham A et al. "Beyond Opioids: A Review of Suzetrigine for Acute Pain Management." Int J Mol Sci26(20):9865 (2025). doi:10.3390/ijms26209865 Mach M et al. "Suzetrigine as a Novel Non-opioid Analgesic Drug in Pain Management." Cureus17(8):e90755 (2025). DOI:10.7759/cureus.90755 Vaelli P, et al. "State-Dependent Inhibition of NaV1.8 Sodium Channels by VX-150 and VX-548." Mol Pharmacol106:298–308 (2024). doi:10.1124/molpharm.124.000944 Jo S, et al. "Differential state-dependent NaV1.8 inhibition by suzetrigine, LTGO-33, and A-887826." J Gen Physiol157:e202413719 (2025) Wang H, et al. "Drug discovery targeting NaV1.8: Structural insights and therapeutic potential." Curr Opin Chem Biol83:102538 (2024) Yuan Y et al. "Suzetrigine: A Novel Non-Opioid Analgesic for Acute Pain Management—A Review." MDPI Reports4(3):32 (2025). https://mdpi.com/2813-2998/4/3/32 Patil A et al. "Suzetrigine: A First-in-class NaV1.8 Inhibitor for Opioid-free Pain Management." Drug Res(2026). doi:10.1177/0976500X251412549 U.S. FDA Journavx Prescribing Information, NDA219209, revised 2025-09. https://www.accessdata.fda.gov/spl/data/d12ef02f-97c7-4d35-9808-6b1abd1a3fba/d12ef02f-97c7-4d35-9808-6b1abd1a3fba.xml Yin H et al. "Prevalence of Halogens in 2025 FDA-Approved Drugs: Highlight on Suzetrigine." J Med Chem(2026). https://pubs.acs.org/doi/10.1021/acs.jmedchem.6c00417 MedNess "Nav1.8 and Suzetrigine" (2026-03-25). https://medness.org/nav1-8-and-suzetrigine/ Gorantla S et al. "Targeting NaV1.8 for Acute Pain: Mechanism, Biomarkers, and Early Clinical Evidence." Res J Innov Stud Med Health Sci2(2):07-11 (2025) Yu G et al. "Suzetrigine, a Non-Opioid NaV1.8 Inhibitor for Treatment of Moderate-to-Severe Acute Pain: Two Phase 3 Randomized Clinical Trials." Anesthesiology142:1085 (2025) Bertoch T et al. "Suzetrigine for the treatment of moderate-to-severe acute pain: Two phase 3 randomized clinical trials." Anesthesiology(2025) Vertex Phase 4 Plastic Surgery Press Release (2026-03-05). https://news.vrtx.com/news-releases/news-release-details/vertex-present-new-data-journavxr-demonstrates-effective-pain Xie YF. "NaV1.8 and chronic pain: from laboratory animals to clinical patients." Biomolecules15(5):694 (2025). doi:10.3390/biom15050694

临床3期临床结果上市批准临床研究

2026-06-17

·药时代

礼来又双叒出手了！这一次，它押注一个无人敢碰的疼痛靶点

益生菌疫苗平台寻找合作企业! 研发团队基于自有的益生菌平台技术，可以开发多种疫苗，周期和成本非常有优势。如果贵公司有需要，请立即联系药时代BD团队。 BD@drugtimes.cn 2026年6月16日，礼来宣布收购神经科学公司4E Therapeutics。这是礼来2026年以来宣布的第11笔并购交易，也是其在疼痛领域的又一关键落子。 4E Therapeutics的核心资产是一系列口服MNK抑制剂，靶向MNK-eIF4E信号通路。MNK（MAPK相互作用激酶）通过磷酸化eIF4E调控特定蛋白的翻译，在外周感觉神经元中参与疼痛信号的放大与慢性化。与作用于中枢神经系统的传统镇痛药不同，MNK抑制剂仅在外周发挥作用，有望在提供显著镇痛效果的同时，避免成瘾、认知损害等中枢副作用。目前，尚无其他知名生物制药企业针对该靶点开展神经系统疾病相关研究。公司先导化合物4ET1103是首个进入人体临床试验的疼痛治疗用MNK抑制剂，已在I期研究中显示出良好的安全性特征。4ET1103的潜在适应症涵盖神经病理性疼痛、下背痛、偏头痛及类风湿关节炎等。自2019年创立以来，4E累计获得近1000万美元的私人融资及美国国立卫生研究院（NIH）资助。礼来在非阿片类疼痛治疗上的并购步伐不曾停歇。去年5月27日，公司即以最高10亿美元的价格将SiteOne Therapeutics收入囊中，后者同样致力于开发外周作用机制的非阿片类镇痛药。SiteOne的核心资产STC-004（现代号LY4515100）是一款Nav1.8抑制剂，作用于主要分布于外周神经系统的钠离子通道。除4E和SiteOne资产外，公司还在开发一款表皮调节素抗体turigrobart（LY3848575），已进入II期临床；另一款血管紧张素II 2型受体拮抗剂LY4065967，针对糖尿病周围神经病理性疼痛的II期试验于今年2月启动。当然，礼来也会当断则断，秉承着快速失败才是最大成功的理念。2025年，礼来先后终止了两项非阿片类疼痛领域中期资产的开发：从Asahi Kasei引进的P2X7抑制剂LY3857210，以及从Centrexion引进的SSTR4激动剂mazisotine。P2X7项目虽已完成涵盖慢性下背痛、骨关节炎疼痛和糖尿病周围神经病理性疼痛的II期主方案研究，但数据“未达到礼来内部的高标准”。此次4E收购，正值礼来凭借替尔泊肽带来的巨额现金流，开启了一场史无前例的并购浪潮。2026年以来，礼来已宣布超过200亿美元的收购与合作交易，创下公司年度并购金额历史新高。公司市值已突破1万亿美元，成为首家跻身“万亿美元俱乐部”的医疗健康企业。礼来业务发展负责人Jake Van Naarden近日接受采访时，将公司的并购策略概括为两套并行模式。模式一：播种。大量进行早期阶段的小额交易，呈现出早期快速筛选、后期果断止损的鲜明特点。 Naarden表示：大多数项目最终不会成功，但总体投入有限，只要有一两个成功，就足以覆盖全部成本。2025年，礼来签署了约40笔交易，总支出仅40亿美元。“早期快速筛选、后期果断止损” 的鲜明特点模式二：买树苗。聚焦已有概念验证数据的候选药物，即“交易时便已确认其临床价值”。这类资产价格更高但确定性更强。63亿美元收购Centessa Pharmaceuticals及其睡眠障碍管线、23亿美元收购Ajax Therapeutics均属此类。 4E Therapeutics的收购更接近“播种”逻辑：靶点新颖、资产早期、投入有限，但一旦成功，有望开辟全新的疼痛治疗范式。参考资料： 1.https://4etherapeutics.com/ 2.https://www.fiercebiotech.com/biotech/eli-lilly-ma-spree-continues-acquisition-non-opioid-pain-drugmaker-4e 3.其他公开资料封面图来源：药时代股价暴跌近50%！没打赢安慰剂，抗抑郁药三连败 2026-06-16 紧急撤回5亿美元融资！原因竟是…… 2026-06-15 被百亿并购后，CEO究竟能拿多少钱？12个黄金降落伞案例 2026-06-13 头对头完胜BMS，武田的背水一战能翻盘吗？ 2026-06-12 裁撤多名顶尖科学家！基因泰克再爆裁员 2026-06-11 版权声明/免责声明本文为原创文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢! 药时代官方网站:www.drugtimes.cn 联系方式: 电话:13651980212 微信:27674131 邮箱:contact@drugtimes.cn 点击查看更多精彩内容！

2026-06-17

·药事纵横

以“快败”谋长效：礼来管线取舍的十年逆袭与行业启示

在新药研发领域，“九死一生”曾是根深蒂固的行业共识，临床失败、技术瓶颈一直是药企管线终止的核心原因。但2025年底《Nature Reviews Drug Discovery》发布的十年临床数据分析，彻底打破了这一传统认知：2013至2023年，全球II/III期临床试验终止数量实现翻倍增长，其中36%的管线终止源于战略布局、商业价值、赛道竞争等主动决策，远超临床失败、运营不畅等被动终止因素。这组数据印证了一个全新的行业趋势：创新药研发早已告别被动承压的时代，主动止损、战略取舍，正在成为头部药企的核心竞争力，而礼来十年的蜕变之路，正是这一趋势最鲜活的实践样本。十年前的礼来，在跨国药企阵营中始终处于边缘位置。管线青黄不接、新品迭代乏力，营收和市值高度依赖存量老药，在肿瘤、代谢、神经等主流赛道均无绝对优势，成长性常年垫底。但短短十年间，这家曾经稳健平庸的药企逆势翻盘，成长为万亿级平台型创新药企、全球创新标杆。这场华丽逆袭的核心密码，并非依靠海量管线的“广撒网”式研发，而是一套贯穿十年的“早期快速筛选、后期果断止损”的“快速失败”管线运营体系，用主动舍弃劣质项目的勇气，换来了核心重磅产品的极致突破。 2017年至2022年三季度，礼来累计终止、失败53个研发项目，数据背后藏着其极具智慧的研发节奏：I期早期阶段终止项目占比超50%，III期后期重大失败项目不足20%。这一结构彻底颠覆了行业“前期投入少、后期赌成败”的传统模式，通过在研发低成本阶段快速证伪、及时止损，规避了后期巨额投入后的资源浪费。纵观礼来十年管线调整，其取舍逻辑贯穿神经、肿瘤、免疫炎症、代谢四大核心赛道，每一次管线精简都是精准的战略布局，而非盲目收缩。神经领域的阿尔茨海默病（AD）研发，是礼来“屡败屡战、择机突破”的典型缩影。AD素来是新药研发的“死亡之谷”，全球药企数十年投入无数却收获寥寥，礼来深耕该领域近四十年，完整经历了行业研发范式的迭代。近十年，礼来主动终止12款神经领域管线，其中11款为AD适应症，接连砍掉多款行业经典研发项目。曾经被寄予厚望的Solanezumab，依托经典“外周水槽”假说研发，却在2016年三项III期试验中全线失利，无法有效减缓患者认知衰退，这场失败让礼来彻底认清“靶向可溶性Aβ单体”的技术局限，明确了精准干预病理窗口期的研发新方向。紧随其后终止的Lanabecestat，曾是礼来与阿斯利康联手布局的BACE1抑制剂，试图从源头阻断Aβ生成，最终因无临床获益宣告失败，直接动摇了全行业BACE抑制剂的研发逻辑。无数企业因此退出该赛道，而礼来并未彻底放弃，而是沉淀失败经验、重构研发策略，摒弃传统靶点思路，精准靶向N3pG特殊Aβ变体，最终打磨出多奈单抗。这款历经数次技术迭代的新药，在2024年实现历史性获批，让礼来在最难的神经赛道，以多次主动止损换来了颠覆性突破。肿瘤赛道的调整，则彰显了礼来“去冗存精、理性收缩”的战略定力。肿瘤赛道市场空间广阔，但竞争内卷程度位居全行业首位，同质化研发、激烈的竞品碾压，让大量中小管线难以实现商业价值。近十年，礼来持续清退非重磅肿瘤管线，动作果断决绝。18亿美元收购所得的Pegilodecakin项目，III期临床失利后立刻终止开发；2023年耗资14亿美元收购的核药企业核心管线，两款主力项目在两年内接连终止；曾经获批上市的RAMUCIRUMAB、Lartruvo，也因适应症拓展失败、确证性试验未达标，先后被终止适应症、撤市退市。一系列管线关停背后，是礼来清晰的赛道转型逻辑：放弃肿瘤领域“大而全”的粗放布局，转向“小而精”的差异化深耕。随着GLP-1管线崛起成为营收支柱，礼来主动下调肿瘤赛道研发权重，集中资源布局高壁垒、高确定性的细分领域。而2025年礼来23亿美元收购Ajax Therapeutics，精准布局骨髓增生性肿瘤（MPN）赛道，拿下下一代II型JAK2抑制剂核心资产，更是其肿瘤管线精细化布局的最新落地，通过淘汰低效存量、吸纳优质增量，完善血液肿瘤赛道短板。免疫炎症作为礼来的传统优势赛道，十年间经历了最大规模的管线精简，累计20项临床项目被终止，且多数集中在2021年行业内卷加剧之后。巴瑞替尼SLE适应症、Mirikizumab银屑病扩展适应症、多款自研及合作抗炎药物，均因临床疗效无优势、竞品迭代过快、缺乏差异化壁垒被果断清退。值得注意的是，这些项目终止极少源于技术缺陷或安全问题，核心都是商业与疗效的综合考量。礼来摒弃了“传统优势赛道必须持续堆量”的固化思维，对无竞争力、无市场前景的项目绝不姑息，通过大规模出清低效管线，实现研发资源的最优配置。代谢赛道的管线取舍，最能体现礼来的前瞻性战略眼光，也是其登顶全球创新药企的关键。作为当前礼来的核心支柱赛道，它并未陷入“全面布局”的误区，反而主动终止17项低效管线，为核心产品让路。早期潜力分子Oxyntomodulin因给药繁琐、药效弱于竞品被提前淘汰，多款降糖、脂肪肝小分子药物因疗效不足、赛道同质化严重陆续退场。这种主动舍弃，本质是精准的战略聚焦：放弃碎片化、低壁垒的普通代谢管线，将60%-70%的核心研发资源集中投向GLP-1长效多靶点赛道。正是这种极致取舍，让替尔泊肽、瑞他鲁肽等核心产品得以持续迭代、拓展适应症，构筑起难以超越的技术与商业壁垒。 2025年礼来疼痛管线的接连折戟，更是对其“快速失败”策略的又一次印证。半年内，LY3857210、LY3556050两款重金引进的中期项目接连终止，合计6750万美元首付投入付诸东流，叠加临床研发投入，交出了一笔天价研发学费。P2X7、SSTR4两大热门靶点早已是行业“研发坟场”，全球多家巨头折戟且无获批产品，疼痛赛道本身存在终点指标模糊、安慰剂效应极强、患者体感差异大的研发难题。礼来没有因前期投入选择硬扛，而是严格遵循内部疗效标准，果断终止未达预期的项目。同时，其并未彻底退出疼痛赛道，而是保留确定性更高的Nav1.8抑制剂管线，依托GLP-1产品跨界探索镇痛新方向，在舍弃与坚守之间找准平衡。纵观礼来十年管线调整，其“快速失败”绝非简单的砍项目、控成本，而是一套成熟完善的研发决策体系。依托内部独立的Chorus研发模式，礼来以“低成本求真、快速度证伪”为核心，在项目早期通过小规模、高针对性的压力测试，提前排查药物核心缺陷，将早期临床时间缩短30%、研发成本降低40%。同时，礼来确立了“疗效为王、拒绝平庸”的核心准则，不接受“尚可、可用”的普通成果，只追求颠覆性、差异化的临床价值。哪怕项目已投入数亿资金、研发数年，只要疗效未达内部高标准、缺乏商业壁垒，一律果断终止。此外，极致的战略聚焦思维，让礼来始终保持清醒，顺应行业政策与市场趋势，主动适配行业变革，规避IRA政策等外部因素带来的投资风险。礼来的十年逆袭，为整个创新药行业重构了研发底层逻辑。过去药企比拼管线数量、布局广度，追求“多点开花”；如今行业竞争的核心，变成了取舍能力、聚焦能力和精准创新能力。“新药十不成一”的被动失败时代已然落幕，主动战略止损、精准资源倾斜，成为药企穿越行业周期的核心能力。粗放式的广撒网研发模式早已失效，真正的高回报，从来不是平均分配资源，而是及时淘汰劣质资产、对优质赛道进行饱和式投入。在创新药内卷加剧、政策持续调整、研发成本高企的当下，礼来的发展之路极具借鉴意义。对药企而言，研发的核心从来不是追求永不失败，而是学会快速失败、从容取舍；不是堆砌海量管线，而是打造能够改变行业格局的核心产品。敢于舍弃无效投入、敢于否定存量布局、敢于聚焦核心优势，这份“舍得”的智慧，正是头部药企穿越行业周期、实现长期增长的终极密码。参考文献： 1.Bowling H, Cocucci A, Koo DCE, Harrison RK. Analysis of phase II and phase III clinical trial terminations from 2013 to 2023. Nat Rev Drug Discov. 2026 May;25(5):345-346. doi: 10.1038/d41573-025-00208-6. PMID: 41413264. 2.Harrison RK. Phase II and phase III failures: 2013-2015. Nat Rev Drug Discov. 2016 Dec;15(12):817-818. doi: 10.1038/nrd.2016.184. Epub 2016 Nov 4. PMID: 27811931. 3.Bowling H, Cocucci A, Koo DCE, Harrison RK. Analysis of phase II and phase III clinical trial terminations from 2013 to 2023. Nat Rev Drug Discov. 2026 May;25(5):345-346. doi: 10.1038/d41573-025-00208-6. PMID: 414 立即扫码加入药事纵横交流群

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适应症	最高研发状态	国家/地区	公司	日期
急性疼痛	临床前	中国	阳光安津（南京）生物医药科技有限公司	2026-06-01
慢性疼痛	临床前	中国	阳光安津（南京）生物医药科技有限公司	2026-06-01