标题: Absolute HBsAg Levels, Not Percent Decline May Be Goal of HBV RNAi(ZZ) [打印本页] 作者: disan 时间: 2015-5-20 22:44 标题: Absolute HBsAg Levels, Not Percent Decline May Be Goal of HBV RNAi(ZZ)
Thursday, April 23, 2015
Absolute HBsAg Levels, Not Percent Decline May Be Goal of HBV RNAi
I just walked into an early morning session at the International Liver Congress in Vienna and may have learned the most important nugget of information regarding RNAi treatment for HBV.
During the discussion in the ‘Banishing B’ session, Dr. Joerg Petersen referred to clinical analyses to be presented this Saturday showing that patients who achieve HBsAg levels of less than 500, or even better 200 IU/ml and then are given an interferon have a much better chance of eventually losing HBsAg, i.e. being functionally cured, than those that do not.
Dr. Petersen has been involved in clinical studies combining nukes and an interferon, and data presented at last year’s American Liver meeting (AASLD) showed that 9% treated with the combination for 1 year lost HBsAg in the year following combination therapy compared to just 2.8% receiving interferon alone.
Note that currently only interferons are thought to give you a chance of functionally curing HBV by medication and that HBsAg seroconversion attributed to interferon treatment may occur in the years after cessation of interferon therapy. It will therefore be important to see whether this increase in seroconversion with combination treatment continues to hold up in subsequent years. The nukes are ‘only’ thought to protect the liver from the ongoing damage from HBV replication and may have to be given indefinitely.
I am not sure whether the new insight comes from a fresh clinical study or are the result of a more detailed subgroup analysis of the previous study. Regardless, it hammers home a message that can be heard again and again, even more so in Vienna this year than at the London meeting last year: it is all about HBsAg lowering.
Implications for HBV RNAi
The implications of the new analysis for RNAi approaches for the treatment of HBV is obvious: use RNAi to get HBsAg below the threshold. In other words, it may be less about getting a magical 1log knockdown, but more about getting patients below 500IU/ml.
For this, Dr. Petersen recommended using 2 nukes so that the tiny and very slow HBsAg declines observed on nukes continue ( < 0.1 log per year). With RNAi agents, you would likely achieve this goal for a patient with an HBsAg at baseline of 1000IU/ml within a month, even with a single 2mg/kg dose of ARC520 from Arrowhead Research as reported last year.
The absolute knockdown potency of an RNAi agent would determine which fraction of the HBV population fall within this sweet spot. With a 1log knockdown e.g. you could start RNAi with patients with as much as 5000IU/ml.
For the clinical development of RNAi agents for HBV, the first step will be to determine the HBsAg decline on a background of nukes (just what Arrowhead is doing right now). For pivotal trials, an immunostimulatory agent such as an interferon should be added to the nukeà RNAi/nuke treatment regimen to finish off the virus.
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Thursday, April 23, 2015
How low must HBsAg levels go?
I wanted to write some commentary on HBsAg levels and the therapeutic goal for knockdown that must be achieved in order to have clinical responses. This is in response to some speculation from the current ILC 2015 meeting. I wanted to say as a disclaimer that I believe that siRNA and antisense drugs (Tekmira, Isis, Arrowhead, Analym) could very well work against HBV and mediate clinical response; I am just more apprehensive about the certainty of its clinical success. I also do not own any stock in the companies referenced here, and this is not meant to be investment advice, but a scientific discussion.
My fellow HBV commentator at the RNAi Therapeutics Blog suggests that if levels of HBsAg under 500 IU/mL are achieved, that a synergy between interferon and siRNA could be achieved and cure could happen. He suggested that a month treatment of siRNA could get this low level, and then interferon could finish the job.
Let's assume that theory is right. It makes me nervous that even in patients under this magical threshold, they only had 9% cure rate after an entire year of interferon treatment, which most patients can't even tolerate. Does that mean the siRNA combo plus interferon will only have a 9% cure rate? I would hope not, otherwise the therapy would not be very efficacious. Since siRNA knocks down all viral genes, there is the hope that other mechanisms could be at play that would increase this cure rate. (edit: @RNAianalyst clarified reported data was for all patients with different HBsAg levels, so 9% cure rate was for combined group. In the link below though, HBeAg negative patients with HBsAg levels of ~200 IU/mL and pegasys and adefovir treatment had 17% cure rate (defined as HBsAg loss) at 2 years after 48 weeks of treatment. Definite improvement over non-responders with higher levels of HBsAg, but not still not a home run like HCV blockbuster medications)
I also want to comment on applying a retrospective clinical cohort analysis to prognostications about the potential of this therapy. The study by Dr. Joerg Petersen is likely true and is similar to other clinical reports I've read on pubmed before, that patients with baseline HBsAg that is lower will respond to treatment better. The problem is that if you compare a patient with 5000 IU/mL vs 500 IU/mL, there are likely a host of differences in their baseline status, namely different levels of ongoing immune responses and/or viral genotype.
The lower HBsAg patient possibly has a more vigorous ongoing polyclonal T cell response against HBV that is keeping the levels of HBsAg low - there must be a reason for the difference in the first place after all. It is likely then that adding interferon to this patient can help push that person's immune system over the top. In the example above, the HBeAg negative patients are negative for that antigen because of a more active immune response against HBV, which lent themselves for a 17% cure rate with IFN added versus HBeAg+ patients who had an 11% cure rate (differing levels of HBsAg modified this as well). Indeed, the type of immune response a person has greatly influences the effect of IFN on the course of HBV.
This situation is analogous to how checkpoint inhibitors for certain tumors are very efficacious, likely because the tumors are more immunogenic, so there is a better immune system at the site ready to fight the tumor. The checkpoint inhibitors can easily push the anti-tumor T cells over the top. On the other hand, the patient with the 5000 IU/mL baseline, even if artificially induced to have lower HBsAg levels to 500 IU/mL, still has a poor ongoing immune response that might not be boosted well by interferon. It's certainly possible that the HBsAg drop could help DC presentation and augment T cell polyclonality, but I don't know how long that might take and I'm not sure if anyone in the field does either. It's possible that their viral antigen specific T cells are already exhausted against the given epitopes and are beyond recovery. The siRNA is analogous to holding the target still, interferon could be bullets, but if the patient doesn't have a gun, ie effective adaptive immunity, it all might be a waste.
There is also the black box of how different viral genotypes secrete HBsAg at different levels, and different viral genotypes respond to interferon differently. This has been reported in several papers on pubmed, and I wonder how this might influence the goal biomarker levels of any siRNA treatment. I would guess in Dr. Peterson's previous study that the patients were all controlled for the same genotype (typically these studies are at centers in a certain area, so the geography dictates similar genotypes), but this is one confounder to look at in any future clinical reports.
In summary, I believe siRNA and ASO drugs are definitely exciting therapeutic modalities and potential game changers for HBV treatment, since they offer a new mechanism to fight the virus. I just want to add caution, though, to benchmarking certain data points and prognosticating success. HBV is one virus, but with a heterogeneous course across patients, the natural history of which is still being learned. The key immunological studies being discussed above have been limited since we can only really gain relevant data from chimpanzees and humans. It will be fascinating as an HBV researcher to see if knockdown could truly reactivate the immune system in all patients. Even if it doesn't in all, there could be a treatment cohort where a 100% cure rate is achieved, like the patients with better baseline status (<500IU/mL) discussed above. However this goes, it will at least be interesting from a basic science perspective.
我的同胞HBV评论员在RNAi疗法博客认为，如果在500 IU / mL的乙肝表面抗原水平实现的，即干扰素和siRNA之间的协同效应可以实现和治疗可能发生。他建议的siRNA的治疗一个月能拿这种低级别，然后干扰素可以完成这项工作。
假设理论是正确的。这让我很紧张，即使在在这片神奇的门槛的患者，他们只有9％的治愈率干扰素治疗，其中大部分患者不能耐受，甚至一整一年后。这是否意味着siRNA的组合加干扰素将只有9％的治愈率？我希望不是，否则治疗效果不会很有效。由于的siRNA击倒所有的病毒基因，还有就是希望其他的机制可能是在玩耍，将增加本治愈率。 （编辑：@RNAianalyst澄清报告的数据是所有患者不同HBsAg水平，所以9％，治愈率为合并后的集团在下面虽然链接，HBeAg阴性患者的约200 IU / mL的HBsAg水平和派罗欣和阿德福韦治疗。有17％的治愈率治疗48周后（定义为HBsAg消失）在2年。明显改进无应答者有更高水平的HBsAg，但仍然不喜欢不卖座HCV药物本垒打）
我也想对应用的回顾性临床队列分析，预言这个疗法的潜力发表评论。由约尔格·彼得森博士的研究可能是真实的，类似于我以前读过关于考研等临床报告，该患者的HBsAg基线是将较低的治疗更好地应对。问题是，如果比较5000 IU / ml对500 IU / mL的患者中，有可能的主机在其基准状态的差异，即不同级别的持续的免疫应答和/或病毒的基因型。
这种情况类似于如何检查点抑制剂某些肿瘤是非常有效的，可能是因为该肿瘤的免疫原性，因此有一个更好的免疫系统在现场准备战斗的肿瘤。检查点抑制剂可以很容易地推抗肿瘤的T细胞在上面。另一方面，患者与5000 IU / mL的基线，即使人工诱导的有较低的HBsAg水平至500国际单位/毫升，仍具有可能无法通过干扰素被升压以及一个差持续免疫应答。这当然有可能是HBsAg的下降可能有助于DC介绍和增加T细胞多克隆，但我不知道过了多久，可能采取和我不知道是否有人在现场确实无论是。这可能是因为他们的病毒抗原特异性T细胞已经耗尽针对给定的表位，并无法恢复。所述siRNA是类似于保持的目标仍然，干扰素可以是子弹，但如果患者不具有枪，即实际适应性免疫，这一切都可能是一种浪费。