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本帖最后由 StephenW 于 2018-8-24 18:33 编辑
灵魂不屈 发表于 2018-8-23 22:27 
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效果这么好？为什么一直在二期临床？是有什么问题吗？ ...
效果这么好？是的，10年前的结果已知是好的.
为什么一直在二期临床？被问了很多次, 也多次回复. 基本上，我不知道.
是有什么问题吗？
请阅读这个:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892580/
NAPs are phosphorothioated oligonucleotides (PS-ONs) whose antiviral effect against HBV infection is independent of nucleotide sequence [11, 12]. Unlike standard antisense compounds, NAPs can be more easily engineered to remove the secondary pro-inflammatory / immunostimulatory effects of single stranded nucleic acids while maintaining their antiviral activity in vivo [13, 15]. The primary tolerability issue with REP 2055 in the REP 101 study was IV administration related side effects similar to those reported for other PS-ONs administered to humans by IV infusion [16, 17] which was well controlled with REP 2139-Ca in the REP 102 study. Additionally, short term combination therapy with REP 2139-Ca and thymosin or peg-IFN up to 26 weeks was well tolerated. The liver flares during monotherapy with either REP 2055 or REP 2139-Ca occurred following initial reductions of serum HBsAg and HBV DNA, were self-resolving with continued NAP therapy and were not accompanied by any symptoms or serological evidence of liver dysfunction. These liver flares are also routinely observed with treatment with interferons, and are thought to be evidence of re-activation of immune function in the liver [18]. These liver flares may be evidence of reactivation of the immune response in the liver with reduction of circulating HBsAg (discussed below) but additional analysis of T-cell response during transaminase flares concomitant with serum HBsAg reduction in future trials will be required to address this hypothesis.
PS-ONs increase mineral elimination in the urine [19] and the resulting compensatory response includes liberation of mineral stores (along with heavy metals if present) from the bones into the circulation. All study patients and untreated control subjects at the trial site were shown to have substantial pre-existing heavy metal loads (data not shown) as a result of chronic heavy metal exposure known to be endemic at the trial site [20–22]. The 2’ ribose modifications present in REP 2139 are absent in REP 2055 (Fig 2) and serve to reduce immunoreactivity [23, 24] but also block degradation by endonucleases [25], rendering REP 2139 substantially more stable than REP 2055 and leading to greater accumulation of REP 2139-Ca in pre-clinical models with chronic exposure (A. Vaillant, unpublished data). Thus chronic exposure to REP 2139-Ca likely establishes a greater mineral elimination (and heavy metal liberation) than REP 2055, consistent with development of hair loss, dysphagia and dysgeusia observed in patients with REP 2139-Ca therapy but not with REP 2055.
These symptoms have not been previously reported with the clinical use of PS-ONs, however, these studies are the first to be conducted in a locale where substantial heavy metal exposure is highly endemic in the population. Importantly, in a currently ongoing clinical trial with REP 2139-Ca in Caucasian patients (REP 301 study, NCT02233075) in a European locale where patients with heavy metal exposure were excluded from participation, none of these symptoms have been observed with comparable REP 2139-Ca exposure in combination with peg-IFN (A. Vaillant, unpublished data).
These clinical observations underscore the importance of being aware of the potential complications of the enhanced mineral elimination known to occur with PS-ON therapy in general and further suggest that mineral supplementation should accompany any oligonucleotide based therapy, regardless of the disease state in patients receiving therapy.
NAP是硫代磷酸酯寡核苷酸（PS-ONs），其对HBV感染的抗病毒作用不依赖于核苷酸序列[11,12]。与标准反义化合物不同，NAPs可以更容易地工程化，以消除单链核酸的二次促炎/免疫刺激作用，同时保持其在体内的抗病毒活性[13,15]。 REP 101在REP 101研究中的主要耐受性问题是IV给药相关的副作用，与通过静脉输注给予人类的其他PS-ON报道的相似[16,17]，其在REP中用REP 2139-Ca控制良好102研究。此外，对REP 2139-Ca和胸腺素或peg-IFN的短期联合治疗长达26周，耐受性良好。在最初用血清HBsAg和HBV DNA减少后，REP 2055或REP 2139-Ca单药治疗期间肝脏发作，在持续NAP治疗后自行消退，并未伴有肝功能障碍的任何症状或血清学证据。通过干扰素治疗也可以常规观察到这些肝脏眩光，并且被认为是肝脏中免疫功能重新激活的证据[18]。这些肝脏突发可能是肝脏中免疫反应再次激活的证据，同时减少了循环中的HBsAg（下文讨论），但在转氨酶发作期间对T细胞反应的额外分析伴随着未来试验中血清HBsAg的降低将需要解决这一假设。 。
PS-ONs增加尿液中的矿物质消除[19]，由此产生的补偿反应包括从骨骼到循环中释放矿物质储存（以及重金属，如果存在）。由于已知在试验部位流行的慢性重金属暴露，试验部位的所有研究患者和未治疗的对照受试者显示具有大量预先存在的重金属负荷（数据未显示）[20-22]。 REP 2139中存在的2'核糖修饰在REP 2055（图2）中不存在，并且用于降低免疫反应性[23,24]，但也阻止内切核酸酶降解[25]，使REP 2139比REP 2055更稳定并导致REP 2139-Ca在慢性暴露前临床模型中的积累更多（A. Vaillant，未发表的数据）。因此，与REP 2055相比，慢性暴露于REP 2139-Ca可能建立更大的矿物质消除（和重金属释放），这与REP 2139-Ca治疗但在REP 2055患者中观察到的脱发，吞咽困难和味觉障碍的发展一致。
这些症状以前没有报道PS-ON的临床应用，然而，这些研究首先在人群中大量重金属暴露的地方进行。重要的是，在目前正在进行的白种人患者REP 2139-Ca临床试验（REP 301研究，NCT02233075）的欧洲现场，重金属暴露患者被排除在参与之外，没有观察到这些症状与可比较的REP 2139-与peg-IFN组合的Ca暴露（A.Vaillant，未发表的数据）。
这些临床观察结果强调了了解PS-ON治疗中已知的增强矿物质消除的潜在并发症的重要性，并进一步表明，无论接受治疗的患者的疾病状态如何，矿物质补充都应伴随任何基于寡核苷酸的治疗。 。
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楼主: 东海以东
发表于 2018-8-24 18:32
