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Arrowhead Issues Open Letter to Shareholders
PASADENA, Calif.--(BUSINESS WIRE)-- Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical company developing targeted RNAi therapeutics, today issued the following open letter to shareholders from President and CEO, Christopher Anzalone, Ph.D.:
Dear Arrowhead Shareholders,
Market reaction to our AASLD abstract took us by surprise because we have always believed that our public communications surrounding the ARC-520 Phase 2a study have been consistent and, more importantly, properly reflected the data we were seeing in the initial two cohorts. We still believe that, but the market clearly expected something different and/or misunderstood the data. Therefore, I wanted to clarify recent events for our shareholders.
Let us begin with our goal. We have said for some time that our goal was to identify a dose of ARC-520 capable of achieving HBsAg reduction of around 1 log (corresponding with 90% knockdown) after a single administration. This was a somewhat arbitrary goal since it is unknown what level of HBsAg reduction is necessary to de-repress the immune system and potentially enable a functional cure. Indeed, the entire concept of enabling a functional cure by suppressing HBsAg release remains an untested theory, but that is one of the challenges of being a pioneer in the field. We chose 1 log as a goal because, according to the scientific literature, the small number of patients who achieve functional cure from Interferon therapy demonstrate ½ log reduction in HBsAg (approximately 70% knockdown) after 12 weeks and 1 log (90% knockdown) after 24 weeks. We expected that if ARC-520 is active it should lead to more rapid reduction, particularly on repeat dosing, so a full log might not be needed after a single administration. Even so, we believed that a 1 log goal is intellectually honest and we wanted to share our thinking publicly rather than establish an artificially low goal just so we could beat it.
With this goal in hand and on the back of a Phase 1 study that suggested ARC-520 was well tolerated, we embarked on our ongoing Phase 2a dose-finding study. Given our animal data across multiple species we believed that we could achieve our goal, but we did not know what dose level would be needed in humans. As is always appropriate with a new technology, we started on the low end of what we expected to be the active dose range, 1 - 2 mg/kg. We characterized these doses as, in our view, potentially active but always added that we were prepared to go higher. On our August 12th quarterly conference call, we disclosed that the first 2 dose levels tested in patients with chronic HBV would not meet our goal. This was not alarming to us because the safety data from the Phase 1 study in healthy volunteers suggested that we could continue to dose-escalate with little risk of toxicity. Therefore, we began a new cohort at a higher dose: 3 mg/kg. At the time of our August update, the study was still blinded and ongoing but we wanted to provide some information about what we were seeing. Recognizing that we were still blinded to which patients had received ARC-520 and which received placebo, we described the apparent HBsAg knockdown at 1mg/kg as "modest" and 2mg/kg as "moderate." The study is now unblinded with respect to the first two cohorts and, as was reported in the recent AASLD abstract, we now know that the mean peak knockdown was 39% at 1 mg/kg and 51% at 2 mg/kg. Those numbers still feel "modest" and "moderate" to us, as we initially reported. Since the August conference call, we have remained consistent with that terminology.
We also said on the August conference call that we believed the knockdown we were seeing in humans was similar in magnitude to that which we have seen in previous studies with non-human primates at similar doses. More specifically, the chimpanzee with chronic HBV that we treated received two doses of ARC-520: 2 mg/kg on day 1 and then 3 mg/kg on day 15. Prior to receiving the second dose, HBsAg was reduced about 50% from baseline. To repeat, we reported mean peak HBsAg knockdown of 51% in patients receiving 2 mg/kg in the Phase 2a while the chimpanzee knockdown at that dose was approximately 50%. The chimpanzee ultimately experienced 80-85% reduction in HBsAg, but only after receiving the 3 mg/kg dose. That was not the only study with non-human primates that can be referenced. In a paper we published in the scientific journal Molecular Therapy in May 2013, we showed that doses around 2 mg/kg (using siRNAs targeting a different liver-expressed gene) inhibit Factor 7 activity between 30-60%. As with the chimpanzee study, this certainly feels similar in magnitude to the 51% HBsAg knockdown we saw in patients receiving 2 mg/kg ARC-520.
So where are we? We have only completed the first two dose levels in an ongoing dose finding study and have not yet identified a dose in humans that will meet our knockdown goal… but we are not yet finished. We now have unblinded Phase 1 safety data in healthy volunteers through 4 mg/kg and we continue to see a favorable safety profile: no dose-limiting toxicities or adverse events rated serious or severe. We have just finished dosing all 8 patients in the 3 mg/kg cohort and as data come in, we will decide whether to escalate to 4 mg/kg. We do not expect timing of the program to be impacted. We plan to submit regulatory filings by the end of the year in support of the multi-dose Phase 2b study whether or not we escalate to 4mg/kg in the Phase 2a study.
We continue to be excited about ARC-520 and the potential to enable a functional cure for patients with chronic HBV infection. There is still much we do not know about ARC-520 and how effective a therapy it may be one day, but there are some important things that we do know. It appears to be well tolerated at all doses tested in our prior Phase 1 study: 1 mg/kg - 4 mg/kg. The drug appears to do what it is designed to do. We have seen clear knockdown in the first 2 doses tested in patients and the favorable safety profile enables us to increase the dose to see if we can induce deeper knockdown. Interestingly, we have seen unexpectedly durable knockdown in patients, even though the low doses provided relatively shallow depth of HBsAg reductions. At the final time points studied, nearly 3 months after a single injection, we continue to see knockdown. We believe that this is important and quite unique. We expect that it will provide significant advantages, particularly as we increase dose and initiate planned multi-dose studies.
We remain committed to long term value creation for our shareholders, and this includes timely and honest communication. We have always provided as much information as possible and have tried to be transparent about our thinking and planning, and we will continue to do so.
Sincerely,
Christopher Anzalone, Ph.D.
President and CEO
About ARC-520
Arrowhead's RNAi-based candidate ARC-520 is designed to treat chronic HBV infection by reducing the expression and release of new viral particles and key viral proteins. The goal is to achieve a functional cure, which is an immune clearant state characterized by hepatitis B s-antigen negative serum with or without sero-conversion. The siRNAs in ARC-520 intervene at the mRNA level, upstream of where nucleotide and nucleoside analogues act. In transient and transgenic mouse models of HBV infection, a single co-injection of Arrowhead's Dynamic Polyconjugate (DPC) delivery vehicle with cholesterol-conjugated siRNA targeting HBV sequences resulted in multi-log knockdown of HBV RNA, proteins and viral DNA with long duration of effect. Arrowhead has completed enrollment in a Phase 1 single ascending dose study in normal volunteers. The company is conducting a single dose Phase 2a study in chronic HBV patients, and expects to follow with multi-dose, multi-national Phase 2b studies. Approximately 350 million people worldwide are chronically infected with the hepatitis B virus. Chronic HBV infection can lead to cirrhosis of the liver and is responsible for 80% of primary liver cancers globally.
箭头的问题打开致股东函
帕萨迪纳，加利福尼亚州 - （美国商业资讯） - 慈姑研究公司（纳斯达克股票代码：ARWR），一家生物制药公司，开发有针对性的RNAi疗法，从今天的总裁兼首席执行官克里斯托弗Anzalone博士发表如下公开信给股东：
亲爱的箭头股东，
市场的反应，我们AASLD摘要出乎我们意料，因为我们始终认为，我们周围的ARC-5202a期研究公共通信是一贯的，更重要的是，适当地反映我们在最初的两个队列中看到的数据。我们仍然认为，但市场预期明显不同的东西和/或误解的数据。所以，我想澄清最近发生的事件为我们的股东。
让我们开始我们的目标。我们已经说过了一段时间，我们的目标是确定的ARC-520能够实现乙肝表面抗原减少约1日志的单次给药后（对应90％击倒）的剂量。这是一个有点武断的目标，因为它是未知的什么水平的HBsAg减少必要去抑制免疫系统，并有可能使功能性治愈。事实上，通过抑制乙肝表面抗原的释放使功能性治愈的整体概念仍然是一个未经测试的理论，但毕竟是被该领域的先行者的挑战之一。我们选择1日志为目标，因为根据科学文献，数量不多，谁获得功能治愈干扰素治疗的患者表现出的乙肝表面抗原（约70％击倒）半对数下降12周和1个对数（90％击倒）后24周。我们预计，如果ARC-520有效时，它应该导致更快速的减少，尤其是在重复给药，这样一个完整的记录可能不需要单次给药后。即便如此，我们认为，1日志的目标是理智的诚实，我们希望分享我们的想法公开，而不是建立一个人为的低目标，只是让我们能够战胜它。
有了这个目标，在手和一个第1阶段的研究，提出的ARC-520耐受性良好的后面，我们开始了我们正在进行的2a期剂量探索研究。跨多个品种给予我们的动物数据，我们相信，我们能够实现我们的目标，但我们不知道什么剂量水平将需要在人。由于始终是合适的一个新的技术，我们开始了我们预期将有效剂量范围内，1低端 - 2毫克/公斤。我们的特点这些剂量的，在我们看来，潜在的活跃，但总是说，我们是准备去更高。我们8月12日的季度电话会议上，我们透露，在慢性乙肝病毒检测的第2剂量水平不会达到我们的目标。这不是惊人的我们，因为从健康志愿者的第1阶段研究的安全性数据表明，我们可以继续剂量升级与毒性的风险不大。因此，我们开始了一个新的队列在较高剂量：3毫克/千克。我们八月更新的时间，研究仍在盲和持续的，但我们希望能够提供什么，我们都看到了一些信息。认识到我们仍然失明的患者接受了ARC-520并接受安慰剂，我们描述了明显的HBsAg击倒在1毫克/公斤的“谦虚”和2毫克/千克为“中等”。该研究是现在非盲相对于所述第一两个队列，正如报道在最近AASLD摘要，我们现在知道的是，平均峰值敲低为39％，在1毫克/公斤，并在2毫克/公斤51％。这些数字仍然觉得“谦虚”和“适度”对我们来说，因为我们最初的报道。自8月的电话会议中，我们一直保持与该术语是一致的。
我们也说，我们相信，我们在人类中看到击倒在幅度，与我们所看到的在以前的研究中使用非人类灵长类动物在类似剂量相似八月召开电话会议。更具体地，我们处理过接受两剂ARC-520慢性HBV的黑猩猩：2毫克/公斤，第1天，然后在此之前3毫克/千克的15天接受第二剂，HBsAg的减少约50％，从基准。重复时，我们报道的51％在接受2毫克/公斤的2a期患者的平均峰的HBsAg击倒而拦截在该剂量的黑猩猩为约50％。黑猩猩最终经历了HBsAg的80-85％的减少，而只接收到3毫克/千克剂量后。这是不与可被引用的非人类灵长类动物的唯一研究。在我们发表在科学期刊分子疗法2013年5月的论文中，我们发现，约2毫克剂量/千克（使用的siRNA针对不同的肝脏表达的基因）抑制之间的30-60％因子7的活动。作为与黑猩猩研究中，这当然感觉在大小为51％的HBsAg击倒我们对收到2毫克/公斤的ARC-520的患者看到的相似。
所以，我们在哪里？我们只是完成了一个持续的剂量探索研究的前两个剂量水平，但尚未确定在人类身上，将满足我们击倒目标的剂量......但我们还没有完成。现在，我们有过4毫克/千克健康志愿者非盲法第1阶段安全性数据，我们将继续看到一个良好的安全性：无剂量限制性毒性或额定严重或严重的不良反应。我们刚刚完成加药共8例患者在3毫克/千克队列和数据到来时，我们会决定是否升级为4毫克/千克。我们不希望受到影响的程序时间。我们计划通过支持多剂量阶段在今年年底前提交监管文件2B研究我们是否升级为4毫克/千克的2a期研究。
我们继续兴奋的ARC-520和潜力，使功能性治愈慢性HBV感染。还有很多我们不知道的ARC-520，以及如何有效的疗法也可能是一天，但有一些我们不知道的一些重要的事情。这似乎是很好的耐受性在我们之前的第1阶段研究测试的所有剂量：1毫克/公斤 - 4毫克/千克。这种药物似乎做它是专门做。我们已经看到了明显的击倒在第2剂的患者进行测试和良好的安全性，使我们能够增加剂量，看看我们是否能诱发更深击倒。有趣的是，我们已经看到了出乎意料耐用击倒的患者，即使低剂量提供的HBsAg减量的相对较浅的深度。在研究的最后一个时间点，近3个月单次注射后，我们继续看到击倒。我们认为，这是重要的，相当独特。我们预计它将提供显著的优势，尤其是当我们增加剂量并启动规划的多剂量研究。
我们将继续致力于长期价值创造为我们的股东，这包括及时和坦诚的交流。我们一直提供尽可能多的信息尽可能，并力求做到透明化我们的思考和规划，我们将继续这样做。
此致
克里斯托弗Anzalone博士
总裁兼首席执行官
关于ARC-520
箭头的基于RNAi的候选ARC-520被设计成通过减少新病毒颗粒和关键的病毒蛋白的表达和释放来治疗慢性HBV感染。的目标是实现一个功能的固化，这是其特征在于，乙肝表面抗原阴性血清有或无血清转换的免疫clearant状态。在ARC-520的siRNA的介入在mRNA水平，其中核苷酸和核苷类似物作用的上游。在HBV感染的瞬态和转基因小鼠模型，一个共同注资箭头的动态Polyconjugate（DPC）交付车辆与胆固醇结合的siRNA干扰乙肝病毒序列导致乙肝病毒的RNA，蛋白质和病毒DNA与持续时间长的多日志击倒效果。箭头已完成招生在正常志愿者第一阶段单剂量递增研究。该公司正进行慢性乙肝患者单剂量2a期研究，预计跟随与多剂量，多国2b期研究。全球大约有3.5亿人感染慢性B型肝炎病毒。慢性HBV感染可导致肝硬化和负责全球80％的原发性肝癌。
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楼主: 林伍伍
发表于 2014-10-9 19:30
