abus半年度报告

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https://www.marketwatch.com/pres ... rma-corp-2018-08-03

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(EDGAR Online via COMTEX) -- ITEM 2. MANAGEMENT'S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS You should read the following discussion and analysis by our management of our financial position and results of operations in conjunction with our audited consolidated financial statements and related notes thereto included as part of our Annual Report on Form 10-K for the year ended December 31, 2017 and our unaudited condensed consolidated financial statements for the three and six month periods ended June 30, 2018. Our consolidated financial statements have been prepared in accordance with U.S. generally accepted accounting principles and are presented in U.S. dollars.

FORWARD-LOOKING STATEMENTS

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$5,000,000; the expected timing of certain triggering events for payments by Arbutus Inc. related to Enantigen's programs; the possibility of receiving total milestone payments of up to $18,000,000 on Alocrest and Brakiva; the potential of our LNP platform to provide royalties and significant additional capital to fund development of our many HBV assets; the potential of our drug candidates to improve upon the standard of care and contribute to curative combination treatment regimen; royalty entitlements for an LNP platform drug that may be approved in the second half of 2018 ; developing a suite of products that intervene at different points in the viral life cycle, with the potential to reactivate the host immune system; using preclinical results to adaptively design clinical studies for additional cohorts of patients, testing the combination and the duration of therapy; selecting combination therapy regimens and treatment durations to conduct Phase III clinical trials intended to ultimately support regulatory filings for marketing approval; expanding our HBV drug candidate pipeline through internal development, acquisitions and in-licenses; interim results from a 30-week Phase II study of ARB-1467 in combination with tenofovir and pegylated interferon expected in the second half of 2018, followed by final results in 2019; continuing to focus on rapidly advancing AB-506 into clinical testing before proceeding with additional clinical evaluation of AB-423; dosing of AB-506 in HBV patients later this year, with topline results by mid 2019; the potential of AB-506 to be a 'best-in-class' capsid inhibitor with once-daily dosing; an IND (or equivalent) filing for AB-452 in the third quarter 2018, with subject dosing to follow in the fourth quarter 2018, and the potential for once-daily oral dosing; an IND/CTA filing in 2019 for AB-729; first regulatory approval for patisiran in the second half of 2018; possible low to mid-single-digit royalty payments escalating based on sales performance as Alnylam's LNP-enabled products, including patisiran, are commercialized; payments from the Gritstone licensing agreement; the expectation for organizational changes to result in increased efficiency, a more flexible variable cost structure, and additional preservation of our cash reserves; the belief that current legal proceedings will not have a material adverse effect on our consolidated results of operations, cash flows, or financial condition; the expected return from strategic alliances, licensing agreements, and research collaborations; statements with respect to revenue and expense fluctuation and guidance; having sufficient cash resources to fund our operations for at least the next 12 months; obtaining funding to maintain and advance our business from a variety of sources including public or private equity or debt financing, collaborative arrangements with pharmaceutical companies and government grants and contracts; and the quantum and timing of potential funding.

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OVERVIEW

Arbutus Biopharma Corporation ("Arbutus", the "Company", "we", "us", and "our") is a publicly traded (nasdaq global market:ABUS) industry-leading therapeutic solutions company dedicated to discovering, developing, and commercializing a cure for patients suffering from chronic Hepatitis B Virus (HBV) infection. HBV represents a significant, global unmet medical need and is the cause of the most common serious liver infection in the world. The World Health Organization (WHO) estimates that more than 257 million people worldwide are chronically infected (WHO, 2017), and other estimates suggest this could include approximately 2 million people in the United States (Kowdley et al., 2012).

To pursue our strategy of developing a curative combination regimen for chronic HBV, we have assembled a robust pipeline consisting of multiple drug candidates with differing but complementary mechanisms of action (MOA), each of which have the potential to improve upon the standard of care and contribute to a curative combination treatment regimen. Our pipeline includes agents that have the potential to form a proprietary, orally administered, combination therapy.

In addition to our drug pipeline focused on HBV, we have additional assets that have the potential to provide value to Arbutus. The first is our 41% equity ownership interest in Genevant Sciences (Genevant), a newly created company to which we have licensed Arbutus' lipid nanoparticle delivery (LNP) platform and conjugate delivery platform (the Delivery Platforms) for all applications except HBV. Secondly, we retain a royalty entitlement on Patisiran, a drug being developed by Alnylam that incorporates our LNP technology and may be approved in the second half of 2018. This royalty entitlement has the potential to provide an active royalty stream or to be otherwise monetized in full or in part. These assets have the potential to provide significant additional non-dilutive capital to fund development of our pipeline of HBV assets.

HBV Product Pipeline

Our product pipeline is entirely focused on finding a cure for chronic HBV infection, with the objective of developing a suite of products that intervene at different points in the viral life cycle and reactivate the host immune system. We are conducting clinical and preclinical combination studies to evaluate combinations of our proprietary pipeline candidates with HBV SOC therapies and with our own proprietary assets. We expect to use the results from these studies to adaptively design additional clinical studies to test the combination and the duration of therapy in patients. We plan to continue this process to identify a regimen to conduct Phase III clinical trials intended to ultimately support regulatory filings for marketing approval.

Our broad pipeline of HBV product candidates includes ARB-1467 (RNAi); AB-506 (capsid inhibitor); AB-452 (HBV RNA destabilizer); AB-729 (GalNAc RNAi), and multiple other preclinical agents in development with novel mechanisms of action (MOA).

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We will continue to expand our HBV pipeline through internal discovery and development and possibly acquisitions and in-licenses. We also have a research collaboration agreement with the Baruch S. Blumberg Institute that provides exclusive rights to in-license any intellectual property generated through the collaboration.

Agents for All-oral combination therapy

HBV core protein, or capsid, is required for viral replication and core protein may have additional roles in cccDNA function. The current standard of care therapy significantly reduces HBV DNA levels in the serum but HBV replication continues in the liver, thereby enabling HBV infection to persist. Effective therapy for patients requires new agents which will effectively block viral replication. We are developing core protein inhibitors (also known as capsid assembly inhibitors) as oral therapeutics for the treatment of chronic HBV infection. By inhibiting assembly of the viral capsid, the ability of HBV to replicate is impaired, resulting in reduced cccDNA.

AB-423 was our first-generation capsid inhibitor candidate, which was evaluated in a Phase I SAD and Multiple Ascending Dose (MAD) trial designed to assess the safety, tolerability, and pharmacokinetics (PK) of oral administration of the product in healthy volunteers. AB-423 was well-tolerated with no serious adverse events following single doses up to 800 mg. Multiple doses up to 400 mg twice daily were also well tolerated.

In addition to AB-423, our capsid inhibitor discovery effort generated promising back-up compounds in 2017, which led to the nomination of a next-generation capsid inhibitor AB-506 for Investigational New Drug (IND)/Clinical Trial Authorization (CTA)-enabling studies. We have received regulatory approval of our submitted CTA in Q2 2018, and have initiated dosing of healthy volunteers, to be followed by dosing in patients in the second half of this year. AB-506 is an orally administered, highly selective capsid inhibitor that has shown striking potency and improved PK in preclinical studies. We presented these preclinical data at AASLD annual meeting in October 2017 in a presentation titled, "Antiviral Characterization of a Next Generation Chemical Series of HBV Capsid Inhibitors In Vitro and In Vivo," which showed potent inhibition of HBV replication and pgRNA encapsidation, an accelerated rate of capsid assembly, and binding to the HBV core protein at the dimer:dimer interface that indicates improved target engagement compared to first generation capsid inhibitors. AB-506 has the potential to be a 'best-in-class' capsid inhibitor based on its favorable drug-like properties and potent inhibition of HBV replication. This molecule has the potential for once-daily oral dosing, making it an ideal candidate for inclusion in a combination regimen.

We will continue to focus on rapidly advancing AB-506 through clinical testing before proceeding with additional clinical evaluation of AB-423.

HBV RNA Destabilizer (AB-452)

Our most advanced preclinical program is an HBV RNA Destabilizer, AB-452 (formerly known as our oral HBsAg inhibitor program), which has novel activity in destabilizing HBV RNA, broad activity against HBV RNAs, and reduces HBsAg. This molecule has the potential for once daily, oral dosing. We presented preclinical data at AASLD annual meeting in October 2017 in a presentation titled, "Identification and Characterization of AB-452, a Potent Small Molecule HBV RNA Destabilizer In Vitro and In Vivo," which showed that AB-452 has shown synergistic effects when combined with two of our proprietary HBV RNAi agents in vitro. In vivo, twice-a-day oral administration of AB-452 resulted in up to 1.4 log10 reduction of serum HBsAg in a dose dependent manner and correlated well with liver HBV RNA levels. When combined, our capsid inhibitor AB-506 and HBV RNA destabilizer AB-452 show distinct but mechanistically compatible antiviral activities that suggest feasibility of inclusion in a clinical combination regimen. Pending successful completion of IND/CTA-enabling studies, this product candidate could be the subject of an IND/CTA filing in the third quarter of 2018.

RNAi Agents

Our RNA interference (RNAi) HBV candidates, ARB-1467 and AB-729, are designed to reduce Hepatitis B surface antigen (HBsAg) expression in patients chronically infected with HBV. Reducing HBsAg is thought to be a key prerequisite to enable a patient's immune system to raise an adequate immune response against the virus. The ability of ARB-1467 to inhibit numerous viral elements in addition to HBsAg increases the likelihood of affecting the viral infection.

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RNAi (ARB-1467)

Our lead RNAi HBV candidate, ARB-1467, is a multi-component RNAi therapeutic that simultaneously targets three sites on the HBV genome, including the HBsAg coding region. Targeting three distinct and highly conserved sites on the HBV genome is intended to facilitate potent knockdown of all viral mRNA transcripts and viral antigens across a broad range of HBV genotypes and lower the risk of developing antiviral resistance ARB 1467 was evaluated in a Phase I Single Ascending Dose (SAD) trial designed to assess the safety, tolerability, and pharmacokinetics of intravenous administration of the product in healthy adult subjects. In the Phase I SAD study, dosing healthy volunteer subjects was well tolerated to a dose of 0.4 mg/kg but a maximum tolerated dose was not reached.

The Phase II trial was a multi-dose study in virally suppressed (NA therapy) patients with chronic HBV. The study enrolled 4 cohorts and explored two doses of ARB-1467 (0.2 and 0.4 mg/kg) at two dose frequencies (monthly and bi-weekly) in two patient populations (HBeAg-negative and positive patients). Cohorts 1, 2, and 4 enrolled HBeAg- patients and Cohort 3 enrolled HBeAg+ patients. The first three cohorts each enrolled eight subjects; six received three monthly doses of ARB-1467, and two received placebo. Cohort 4 enrolled twelve patients, all of whom received five bi-weekly doses of ARB-1467, followed by monthly dosing if pre-defined criteria were met. ARB-1467 was administered at 0.2 mg/kg in Cohort 1 and 0.4 mg/kg in Cohorts 2, 3, and 4. Overall, treatment was well tolerated across all cohorts (Cohorts 1, 2, 3, and 4).

Results from monthly doses in Cohorts 1, 2 and 3 demonstrated a significant reduction in serum HBsAg and a step-wise, additive reduction in serum HBsAg with each subsequent dose. The HBsAg reduction achieved after three monthly doses of 0.4mg/kg in Cohort 2 was greater than that seen at 0.2 mg/kg in Cohort 1, demonstrating a dose-response with repeat dosing. We observed no significant differences in serum HBsAg reductions between HBeAg-negative and HBeAg-positive patients. In Cohort 4, five doses of ARB-1467 were administered on a bi-weekly dosing schedule. Results after 5 doses of bi-weekly administration demonstrated a deeper reduction in HBsAg levels compared to the results observed during the monthly administration, with a mean reduction of 1.4 log10 and a maximum reduction of 2.7 log10. Seven of the twelve patients met the predefined response criteria (a reduction greater than 1 log10 and HBsAg levels < 1000 IU/ml) at or before day 71. Five of the seven patients who met the response criteria had their serum HBsAg reduced to low absolute levels (below 50 IU/mL).

We have initiated a triple combination study of our RNAi agent ARB-1467 with tenofovir (TDF) and pegylated interferon (PegIFN) therapy to determine if this regimen will result in patients reaching undetectable HBV DNA and HBsAg levels. The Phase II combination trial is a 30-week multi-dose study in 20 HBV DNA -positive, HBeAg-negative, treatment na�ve, patients who will receive bi-weekly doses of ARB-1467 at 0.4 mg/kg and daily oral TDF doses for 30 weeks. Those patients who reach predetermined criteria 6 weeks will qualify for the addition of weekly PegIFN treatment, while continuing to receive bi-weekly doses of ARB-1467 and daily doses of TDF for the remaining 24 weeks. Patients will be followed for 24 weeks after the treatment period concludes. Interim on-treatment results from this trial are expected in the second half of 2018, followed by final results in 2019.

GalNAc RNAi (AB-729)

Early in 2018, we nominated for development a next-generation RNAi therapeutic, AB-729, targeted to hepatocytes using our novel covalently conjugated N-acetylgalactosamine (GalNAc) delivery technology to enable subcutaneous delivery. This is a promising new agent that acts on multiple HBV viral transcripts, enabling inhibition of viral replication and suppression of all viral antigens. AB-729 showed more durable in vivo preclinical activity than earlier-generation RNAi agents for the treatment of chronic HBV infection. We observed a significant dose response, and a stepwise reduction in viral proteins when multi-dosing. We have initiated IND/CTA enabling studies, and pending success of those studies, this product candidate could be the subject of an IND/CTA filing in the first half of 2019.

Additional Research Programs

In addition to our clinical candidates, we have a number of research programs aimed at discovery and development of proprietary HBV candidates with different and complementary MOAs. We have ongoing discovery efforts focused on cccDNA targeting and checkpoint inhibition to identify novel drug candidates to complement our pipeline of agents to form an all-oral combination therapy.

Proprietary Delivery Technology

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Our LNP technology represents the most widely adopted delivery technology in RNAi, which has enabled several clinical trials and has been administered to hundreds of human subjects. We are the leaders in LNP delivery and hold a dominant intellectual property position in this field. We have applied our extensive technical expertise and clinical experience gained from our LNP-based programs to further advance our platform technology and its broad application to mRNA delivery.

We have generated value from our LNP platform technology, which is well suited to deliver therapies based on RNAi, mRNA, and gene editing constructs. We have also developed a proprietary GalNAc conjugate technology to enable subcutaneous delivery of an RNAi therapeutic targeting HBsAg and/or other HBV targets.

In April 2018, we entered into an agreement with Roivant Sciences to launch Genevant Sciences, a jointly-owned company focused on the discovery, development, and commercialization of a broad range of RNA-based therapeutics enabled by our proprietary LNP and ligand conjugate delivery technologies (collectively, the Delivery Technologies) for all applications except HBV. See further discussion under Recent Developments below.

Development of RNAi therapeutic products is currently limited by the instability of the RNAi trigger molecules in the bloodstream and the inability of these molecules to access target cells or tissues following administration. Delivery technology is necessary to protect these drugs in the bloodstream to allow efficient delivery and cellular uptake by the target cells. Arbutus has developed a proprietary delivery LNP platform. The broad applicability of this platform to RNAi development and clinically proven safety profile has established it as a leader in this new area of innovative medicine.

Partner Programs

Patisiran (ALN-TTR02)

Alnylam Pharmaceuticals, Inc., or Alnylam ALNY, -3.75% has a license to use our intellectual property to develop and commercialize products. Alnylam's patisiran (ALN-TTR02) program represents the most clinically advanced application of our LNP delivery technology, and results demonstrate that our LNP has been well tolerated and efficacy maintained with long-term (>36 months) treatment. Alnylam may only grant access to our LNP technology to its partners if it is part of a product sublicense. Alnylam's license rights are limited to patents that we have filed, or that claim priority to a patent that was filed, before April 15, 2010.

Patisiran is Alnylam`s most clinically advanced RNAi therapeutic in development, targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR). In September 2017, Alnylam successfully completed its APOLLO Phase III clinical trial of LNP-enabled patisiran, which initiated in November 2013. Results showed that patisiran met its primary efficacy endpoint and all secondary endpoints in this trial. As a result, Alnylam completed a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) and a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for patisiran. Alnylam has estimated that first regulatory approval may be obtained in the second half of 2018. We retain full rights to royalties on patisiran global sales and are entitled to low-to-mid single-digit royalty payments escalating based on sales performance as Alnylam's LNP-enabled products are commercialized. We could receive our first royalty payments in the second half of 2018, or seek to otherwise monetize all or part of this royalty stream as a source of non-dilutive cash.

Gritstone Oncology

In October 2017, we entered into a license agreement with Gritstone Oncology (Gritstone) that granted them worldwide access to our portfolio of proprietary and clinically validated LNP products and associated intellectual property to deliver Gritstone's RNA-based neoantigen immunotherapy products. Gritstone paid us an upfront payment and agreed to future payments for achievement of development, regulatory, and commercial milestones as well as royalties, and reimbursements for conducting technology development, manufacturing and regulatory support for Gritstone's product candidates. Genevant will be entitled to 50% of any milestones and royalties that may be payable by Gritstone.

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Marqibo(R)

Marqibo, originally developed by Arbutus, is a novel, sphingomyelin/cholesterol liposome-encapsulated formulation of the FDA-approved anticancer drug vincristine. Marqibo's approved indication is for the treatment of adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-ALL) in second or greater relapse or whose disease has progressed following two or more lines of anti-leukemia therapy. Our licensee, Spectrum Pharmaceuticals, Inc. (Spectrum), launched Marqibo through its existing hematology sales force in the United States. Spectrum has ongoing trials evaluating Marqibo in three additional indications, which are: first line use in patients with Philadelphia Negative Acute Lymphoblastic Leukemia (Ph-ALL), Pediatric ALL and Non-Hodgkin's lymphoma. We are receiving mid-single digit royalty payments on sales of Marqibo.

Recent Developments

Genevant Sciences

In April 2018, we entered into an agreement with Roivant to launch Genevant, a jointly-owned company focused on the discovery, development, and commercialization of a broad range of RNA-based therapeutics enabled by our proprietary Delivery Technologies. We have licensed exclusive rights to our LNP and ligand conjugate delivery platforms to Genevant for RNA-based applications outside of HBV. Genevant plans to develop products in-house and pursue industry partnerships to build a diverse pipeline of therapeutics across multiple modalities, including RNAi, mRNA, and gene editing.

Under the terms of the agreement, Roivant contributed $37.5 million in transaction-related seed capital for Genevant, consisting of an initial $22.5 million and a subsequent investment of $15 million at a pre-determined, stepped-up valuation. We retain all rights to our LNP and conjugate delivery platforms for HBV, and are entitled to a tiered royalty from Genevant on future sales of products enabled by those delivery platforms. We also retain the entirety of our royalty entitlement on the commercialization of Alnylam's patisiran. The initial investment and the subsequent investment were completed during the second quarter 2018, therefore at June 30, 2018 Arbutus holds an equity interest in Genevant equal to 41%. We recorded a $24.9 million non-cash gain in the second quarter of 2018 as a result of this transaction.

Genevant is led by Executive Chairman Paris Panayiotopoulos, former CEO of ARIAD Pharmaceuticals, accompanied by a management team of RNA experts including Dr. Bo Rode Hansen as President, Chief Scientific Officer, and Head of R&D; Dr. Peter Lutwyche as Chief Technology Officer; Dr. Konstantin Linnik as General Counsel; Dr. James Heyes as Senior VP; and a scientific team with decades of RNA development experience.

Acuitas Therapeutics Inc.

In accordance with a settlement agreement signed in November 2012, we finalized and entered a cross-license agreement with Acuitas Therapeutics Inc. (Acuitas) in December 2013. The terms of the cross-license agreement provided Acuitas with access to certain of our earlier IP generated prior to mid-April 2010 in the fields of gene replacement therapy and antisense. Acuitas was only able to grant access to our LNP technology to its partners if it is part of a product sublicense. At the same time, the terms provided us with certain access to Acuitas' technology and licenses in the RNAi field, along with a percentage of each milestone and royalty payment with respect to certain products. Acuitas had agreed that it would not compete in the RNAi field for a period of five years, ending in November 2017. Arbutus considered Acuitas to be in material breach of their cross-license agreement and provided notice to Acuitas in August 2016 to terminate the cross license agreement, resulting in litigation between the two parties. In February 2018, Arbutus and Acuitas reached a settlement terminating Acuitas' right to further use or sublicense Arbutus' LNP technology. Please refer to "Item 1. Legal Proceedings" for additional information.

Site Consolidation

In February 2018, we announced a site consolidation and organizational restructuring to better align our HBV business in Warminster, PA. These organizational changes are expected to result in increased efficiency, a more flexible variable cost structure, and additional preservation of our cash reserves. To achieve this alignment, during the second quarter of 2018 we reduced our global workforce by approximately 35% and closed our Burnaby BC facility. These activities were successfully completed during the second quarter . . .

Aug 03, 2018

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5000000美元;Arbutus Inc.与Enantigen's program相关的某些触发事件的预期时间;在Alocrest和Brakiva上获得高达1800万美元的里程碑付款的可能性;我们的LNP平台提供特许权使用费和大量额外资金以资助开发我们的许多HBV资产的潜力;我们的候选药物可能会提高治疗标准，并有助于治疗联合治疗方案;可在2018年下半年获得批准的LNP平台药物的特许权使用费;开发一套产品，在病毒生命周期的不同阶段进行干预，有可能重新激活宿主免疫系统;利用临床前的研究结果，为更多的患者群体自适应地设计临床研究，测试联合治疗和疗程;选择联合治疗方案和治疗时间进行III期临床试验，以最终支持监管申报市场批准;通过内部开发、收购和授权扩大HBV候选药物管道;在为期30周的ARB-1467二期研究中，将于2018年下半年与泰诺福韦和pegylated干扰素联合进行研究，最终结果将于2019年完成;继续专注于快速推进AB-506的临床试验，并进一步对AB-423进行临床评价;今年晚些时候在HBV患者中剂量为AB-506，到2019年中期达到topline结果;AB-506是一种“最佳级”衣壳抑制剂，每日一次用量;2018年第三季度申报IND -452(或同等金额)，2018年第四季度跟进受试者剂量，每日一次口服给药的可能性;在2019年为AB-729申请的IND/CTA文件;2018年下半年首次获得patisiran的监管批准;由于Alnylam支持lnp的产品(包括patisiran)被商业化，基于销售业绩，可能出现的低至中位数的特许权使用费支付将会升级;从Gritstone许可协议付款;对组织变革的预期将导致提高效率、更灵活的可变成本结构和更多地保留我们的现金储备;认为现行法律程序不会对我们的业务、现金流或财务状况造成重大不利影响;战略联盟、许可协议和研究合作的预期回报;关于收入和费用波动和指导的声明;有足够的现金资源为我们的业务提供至少12个月的资金;从公共或私人股本或债务融资、与制药公司的合作安排、政府赠款和合同等各种渠道获得维持和促进我们业务的资金;以及潜在资金的数量和时间。

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概述
Arbutus Biopharma Corporation(“Arbutus”，“公司”，“我们”，“我们”，“我们”)是一家上市的(纳斯达克全球市场:ABUS)行业领先的治疗解决方案公司，致力于发现、开发和商业化治疗慢性乙型肝炎(HBV)感染患者的疗法。乙型肝炎病毒是一种重大的、全球尚未满足的医疗需求，是世界上最常见的严重肝感染的原因。世界卫生组织(WHO)估计，全球有超过2.57亿人慢性感染(WHO, 2017)，其他估计表明，这可能包括美国约200万人(Kowdley et al.， 2012)。
追求我们的战略发展为慢性乙肝病毒治疗组合方案,我们已经组建了一个健壮的管道组成的多个候选药物不同但互补机制的行动(农业部),每一种都有可能改进的标准护理和有助于治疗联合治疗方案。我们的管道包括有潜力形成一个专有的，口服的，联合治疗。
除了我们专注于乙型肝炎病毒的药物管道外，我们还有额外的资产，这些资产有潜力为Arbutus提供价值。首先是我们对Genevant Sciences (Genevant) 41%的股权权益。Genevant Sciences是一家新成立的公司，我们已向该公司授予了Arbutus的脂质纳米颗粒递送(lipid nanoparticle delivery, LNP)平台和除HBV以外的所有应用的共轭递送平台(delivery platform)的许可。第二，我们在Patisiran上保留特许权使用费，这是一种由Alnylam开发的药物，结合了我们的LNP技术，可能在2018年下半年获得批准。这种版税权利有可能提供一个活跃的特许权使用费流，或在其他方面完全或部分货币化。这些资产有可能为我们的HBV资产的开发提供额外的非稀释性资本。
乙肝病毒的产品线
我们的产品管道完全专注于寻找慢性乙肝病毒感染的治疗方法，目标是开发一套在病毒生命周期的不同阶段进行干预并重新激活宿主免疫系统的产品。我们正在进行临床和临床前联合研究，以评估我们的专有管道候选方案与HBV SOC治疗和我们自己的专有资产的组合。我们希望利用这些研究的结果，自适应地设计更多的临床研究，以测试联合治疗和患者治疗的持续时间。我们计划继续这一过程，以确定一种方案，以进行第三阶段临床试验，以最终支持监管备案申请获得市场批准。
我们的HBV产品候选产品包括ARB-1467 (RNAi);ab - 506(衣壳抑制剂);ab - 452(乙型肝炎病毒RNA破坏);abn -729 (GalNAc RNAi)和其他多种临床前药物在发展中，具有新的作用机制(MOA)。
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我们将通过内部发现和开发、可能的收购和许可继续扩大我们的HBV管道。我们还与巴鲁克·布隆伯格研究所(Baruch S. Blumberg Institute)达成了一项研究合作协议，该协议提供了通过合作产生的任何知识产权的授权专有权。
全口联合治疗药物
病毒复制需要HBV核心蛋白(或衣壳)，而核心蛋白可能在cccDNA功能中有额外的作用。目前的治疗标准显著降低了血清中的HBV DNA水平，但HBV在肝脏继续复制，从而使HBV感染得以持续。有效的治疗需要新的药物来有效的阻断病毒的复制。我们正在开发核心蛋白抑制剂(也称为衣壳组装抑制剂)作为治疗慢性HBV感染的口服疗法。通过抑制病毒衣壳的组装，HBV的复制能力受损，导致cccDNA减少。
AB-423是我们的第一代衣壳抑制剂候选，在第一阶段SAD和多次增加剂量(MAD)试验中进行了评估，该试验旨在评估健康志愿者口服该产品的安全性、耐受性和药代动力学。AB-423耐受性良好，单次剂量可达800毫克，无严重不良反应。每天两次的多重剂量高达400毫克也是很好的耐受性。
除了AB-423之外，我们的衣壳抑制剂发现工作在2017年产生了有希望的备用化合物，这导致了对新药物(IND)/临床试验授权(CTA)研究的下一代衣壳抑制剂AB-506的提名。我们已经在2018年第二季度收到了监管部门对我们提交的CTA的批准，并且已经开始给健康的志愿者注射，接下来在今年下半年给病人注射。AB-506是一种口服的高选择性衣壳抑制剂，在临床前研究中显示出显著的疗效和改善的PK。我们提出这些在肝病临床前数据年度会议于2017年10月在演讲题为“抗病毒特性的新一代化学系列的乙肝病毒衣壳抑制剂在体外和体内,“显示有效的抑制乙肝病毒复制和pgRNA衣壳化,衣壳组装的加速,和绑定到乙肝病毒核心蛋白二聚体:二聚体接触界面,表明改进的目标与第一代相比,衣壳抑制剂。AB-506由于其良好的药物样特性和对HBV复制的有效抑制，有可能成为一种“最好的”衣壳抑制剂。这种分子具有每日一次口服剂量的潜力，使它成为一种理想的包含在组合方案中。
我们将继续专注于通过临床测试快速推进AB-506，然后继续对AB-423进行临床评价。
乙型肝炎病毒RNA破坏(ab - 452)
我们最先进的临床前计划是一种HBV RNA不稳定剂AB-452(以前称为我们的口服HBsAg抑制剂程序)，它具有新的破坏HBV RNA的活性，对HBV RNAs具有广泛的活性，并减少HBsAg。这种分子有每天一次口服给药的潜力。我们提出在肝病临床前数据年度会议于2017年10月在演讲题为“识别和表征ab - 452,一个强有力的小分子破坏乙肝病毒RNA在体外和体内,“这表明,ab - 452显示协同效应当结合两个我们的专有HBV体外RNAi代理。在体内，每天两次口服AB-452可使血清HBsAg以剂量依赖性方式减少1.4 log10，且与肝HBV RNA水平相关性良好。当我们的衣壳抑制剂AB-506和HBV RNA不稳定因子AB-452结合在一起时，显示出明显但机械上兼容的抗病毒活性，表明在临床联合方案中纳入存在的可行性。在成功完成IND/CTA支持研究之前，该产品候选对象将在2018年第三季度成为IND/CTA文件的主题。
RNAi代理
我们的RNA干扰(RNAi) HBV候选体ARB-1467和AB-729被设计用于减少慢性乙肝病毒感染者的乙肝表面抗原(HBsAg)的表达。减少HBsAg被认为是使病人的免疫系统提高对病毒的充分免疫反应的关键先决条件。ARB-1467在HBsAg之外抑制大量病毒元素的能力增加了影响病毒感染的可能性。

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RNAi(arb - 1467)
我们的领导RNAi HBV候选，ARB-1467，是一个多组分RNAi治疗，同时针对HBV基因组的三个位点，包括HBsAg编码区。针对三个不同的和高度保守的网站乙肝病毒基因组的目的是促进有效的可拆卸的所有病毒mRNA转录和病毒抗原在广泛的HBV基因型和降低开发抗病毒药物抵抗的风险套利基金1467年评估阶段我单一剂量提升(SAD)试验旨在评估安全、耐受性和静脉注射的药物管理产品的健康成年受试者。在第一阶段的SAD研究中，给健康的志愿者服用0.4毫克/公斤的剂量是很好的耐受性，但并没有达到最大耐受性剂量。
第二阶段试验是对慢性乙型肝炎病毒的病毒抑制(NA治疗)患者的多剂量研究。该研究纳入了4组人群，并在两个患者群体(hbeag阴性和阳性患者)中，以两个剂量频率(月和双周)研究了两剂ARB-1467(0.2和0.4 mg/kg)。同期组1、2和4个纳入组的HBeAg-患者和3个纳入组的HBeAg+患者。前三组分别纳入8个科目;其中6人每月服用3剂ARB-1467, 2人服用安慰剂。第4组登记了12名患者，他们所有人都接受了5次双周剂量的ARB-1467，然后按照预先确定的标准进行每月剂量的剂量。ARB-1467在队列1和0.4 mg/kg的队列中以0.2 mg/kg的水平进行，2、3和4。总的来说，治疗在所有队列(队列1、2、3和4)中都有很好的耐受性。
同期组1、2和3的月剂量结果显示血清HBsAg显著降低，每增加一次剂量，血清HBsAg逐级增加减少。在队列2中，三个月剂量为0.4mg/kg的HBsAg的减少量大于第1组的0.2 mg/kg，这表明了重复剂量的剂量反应。我们观察到hbeag -阴性和hbeag阳性患者血清HBsAg的降低无显著性差异。在第4组中，五剂ARB-1467在双周给药计划下进行。结果5次双周给药后，HBsAg水平较月给药期间观察到的结果明显降低，平均降低1.4 log10，最大降低2.7 log10。在第71天或之前，12例患者中有7例符合预定的反应标准(减少量大于1 log10, HBsAg水平小于1000 IU/ml)。在符合反应标准的7例患者中，有5例的血清HBsAg降低到低绝对水平(低于50 IU/mL)。
我们已经启动了RNAi药物ARB-1467与泰诺福韦(TDF)和pegylated干扰素(PegIFN)治疗的三重联合研究，以确定该方案是否会导致患者达到无法检测的HBV DNA和HBsAg水平。第二阶段试验组合四周多剂量研究20 HBV DNA阳性,HBeAg-negative,治疗na�ve、患者将接受每两周剂量的arb - 1467 0.4毫克/公斤和日常口语TDF剂量30周。达到预定标准6周的患者将有资格获得每周PegIFN治疗，同时在剩下的24周内继续接受两周剂量的ARB-1467和每日剂量的TDF。治疗期结束后，患者将被随访24周。这项试验的中期治疗结果预计将于2018年下半年进行，随后将于2019年进行最终结果。
GalNAc RNAi(ab - 729)
在2018年初，我们提名开发下一代RNAi治疗药物AB-729，使用我们的新型共价键结合的n -乙酰半乳糖胺(GalNAc)传递技术使皮下传递成为可能。这是一种很有前途的新制剂，可以作用于多种HBV病毒转录本，抑制病毒复制和抑制所有病毒抗原。与早期RNAi制剂相比，AB-729在治疗慢性乙型肝炎病毒感染的体内前活动更持久。我们观察到一个显著的剂量反应，以及当多剂量时病毒蛋白的逐步减少。我们已经启动了IND/CTA授权研究，在这些研究成功之前，这个候选产品将在2019年上半年成为IND/CTA文件的主题。
额外的研究项目
除了我们的临床候选人，我们还有许多研究项目，旨在发现和开发具有不同和互补的MOAs的专有HBV候选人。我们正在进行的发现工作集中在cccDNA靶向和检查点抑制，以确定新的候选药物，以补充我们的药物管道，形成一种全口联合治疗。
专有的交付技术

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F - 20
我们的LNP技术代表了RNAi中最广泛采用的交付技术，该技术已使多个临床试验得以实施，并已被用于数百个人体实验对象。我们是LNP交付领域的领导者，在这一领域拥有主导的知识产权地位。我们运用我们从基于lnp的项目中获得的广泛技术专长和临床经验，进一步推进我们的平台技术及其在mRNA传递中的广泛应用。
我们已经从我们的LNP平台技术中产生了价值，该技术非常适合基于RNAi、mRNA和基因编辑结构来提供治疗。我们还开发了一种专有的GalNAc结合技术，使皮下注射RNAi治疗靶向HBsAg和/或其他HBV靶点。
2018年4月,我们进入与Roivant科学推出Genevant科学达成协议,共同拥有公司专注于发现、开发和广泛的商业化RNA-based疗法通过我们专有的现况和配体共轭交付技术(集体,交付技术)为所有应用程序除了乙肝病毒。请参阅下面最近事态发展的进一步讨论。
目前，RNAi治疗产品的开发受到血液中RNAi触发分子的不稳定性以及这些分子在给药后无法进入目标细胞或组织的限制。传递技术是必要的，以保护这些药物在血液中，以允许有效的传递和细胞吸收的目标细胞。Arbutus开发了一种专用的LNP平台。该平台在RNAi技术开发和临床验证的安全性方面的广泛应用，使其成为这一创新医学新领域的领导者。
合作伙伴计划
Patisiran(ALN-TTR02)
Alnylam Pharmaceuticals, Inc.或Alnylam ALNY拥有使用我们的知识产权开发和商业化产品的许可。Alnylam的patisiran (ALN-TTR02)项目代表了我们的LNP递送技术在临床上最先进的应用，结果表明，我们的LNP在长期(>36个月)的治疗中得到了很好的耐受性和有效性。如果Alnylam是产品子许可的一部分，那么它只能向其合作伙伴授予使用我们的LNP技术的权限。Alnylam的许可权利仅限于我们已经申请的专利，或者是在2010年4月15日之前申请的专利的优先权。
Patisiran是Alnylam临床发展中最先进的RNAi治疗方法，靶向transthyretin (TTR)治疗TTR介导的淀粉样变性(ATTR)。2017年9月，Alnylam成功完成了自2013年11月开始的lnp支持患者阿波罗III期临床试验。结果表明，在本试验中，患者组达到了主要疗效终点和所有次要终点。结果，Alnylam公司向美国食品和药物管理局(FDA)提交了一份新的药物申请(NDA)，向欧洲药物管理局(EMA)提交了一份用于patisiran的营销授权申请(MAA)。Alnylam估计，第一次监管审批可能在2018年下半年获得。我们保留了patisiran全球销售的版权使用费的全部权利，并且由于Alnylam的支持lnp的产品被商业化，根据销售业绩，我们有权获得从低到中个位数的版权使用费。我们可以在2018年下半年收到我们的第一笔特许权使用费，或者寻求将所有或部分特许权使用费收入货币化，作为一种非稀释性现金来源。
粗砂岩肿瘤学
2017年10月，我们与Gritstone Oncology公司(Gritstone Oncology)签署了一项许可协议，允许它们在全球范围内使用我们的专利和临床验证的LNP产品组合和相关知识产权，以分发Gritstone公司基于rna的neoantigen immuntherapy产品。Gritstone支付了我们一笔预付款，并同意为实现开发、监管、商业里程碑以及特许权使用费以及为Gritstone的候选产品提供技术开发、生产和监管支持的补偿。Genevant将有权获得Gritstone可能支付的50%的里程碑和特许权使用费。

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Marqibo(右)
Marqibo最初由Arbutus开发，是fda批准的抗癌药物vincristine的新配方，sphingomyelin/胆固醇脂质体胶囊。Marqibo的批准适应症是治疗成年费城染色体阴性的急性淋巴细胞白血病(Ph-ALL)在第二次或更大的复发或其疾病在两种或更多的抗白血病治疗后发展。我们的执照持有者，Spectrum Pharmaceuticals, Inc. (Spectrum Pharmaceuticals, Inc.)，通过其在美国的现有血液学销售团队推出了Marqibo。Spectrum对Marqibo的三个附加指标进行了持续的试验评估，这些指标包括:费城阴性急性淋巴细胞白血病(Ph-ALL)、小儿全淋巴和非霍奇金淋巴瘤。我们正在收到Marqibo销售的中位数特许权使用费。
最近的进展
Genevant科学
2018年4月，我们与Roivant达成协议，成立Genevant，这是一家合资公司，专注于发现、开发和商业化广泛的基于rna的疗法，我们的专有交付技术使其成为可能。我们已经授权我们的LNP和配体结合交付平台给Genevant，用于HBV以外的基于rna的应用程序。Genevant计划在内部开发产品，并寻求行业合作伙伴关系，在包括RNAi、mRNA和基因编辑在内的多种治疗方法中建立一个多样化的治疗管道。
根据协议条款，Roivant为Genevant提供了3,750万美元的交易相关种子资金，其中包括最初的2,250万美元，以及随后的1,500万美元投资，按预先确定的、逐步提高的估值。我们保留了我们的LNP和HBV的结合交付平台的所有权利，并且有权从Genevant中获得一种分级使用费，用于未来销售的产品。我们还保留了我们对Alnylam露台商业化的全部版税权利。初始投资和后续投资在2018年第二季度完成，因此在2018年6月30日，Arbutus持有Genevant 41%的股权。由于这笔交易，我们在2018年第二季度录得2,490万美元的非现金收益。
Genevant由执行董事长Paris Panayiotopoulos领导，他曾担任ARIAD Pharmaceuticals的首席执行官，由RNA专家组成的管理团队组成，其中包括Bo罗德·汉森博士担任总裁、首席科学官和研发负责人eter Lutwyche博士担任首席技术官;康斯坦丁·林尼克博士担任总法律顾问;James Heyes博士担任高级副总裁;一个拥有几十年RNA开发经验的科学团队。
Acuitas疗法。
根据2012年11月签署的和解协议，我们于2013年12月与Acuitas Therapeutics Inc. (Acuitas)签订了交叉许可协议。交叉许可协议的条款为Acuitas提供了在2010年4月中旬之前在基因替代疗法和反义领域产生的某些早期知识产权。只有当我们的LNP技术是产品子许可的一部分时，它才能够授予合作伙伴使用我们的LNP技术的权利。与此同时，这些条款为我们提供了在RNAi领域获得Acuitas技术和许可的渠道，以及每一个里程碑的百分比，以及针对某些产品的特许权使用费。该公司已同意，将在2017年11月结束的五年时间里，不参与racunai领域的竞争。Arbutus认为Acuitas严重违反了双方的交叉许可协议，并于2016年8月向Acuitas发出终止交叉许可协议的通知，导致双方发生诉讼。在2018年2月，阿伯图斯和明塔斯达成了一项协议，终止了明爱进一步使用或许可Arbutus的LNP技术的权利。请参阅“项目1”。“法律程序”以获取更多信息。
网站整合
2018年2月，我们宣布进行场地整合和组织重组，以更好地整合我们在宾夕法尼亚州沃明斯特的HBV业务。这些组织的变化预期将导致效率的提高、更灵活的可变成本结构以及对我们现金储备的额外保留。为了实现这一目标，在2018年第二季度，我们将全球员工减少了大约35%，并关闭了我们的Burnaby BC工厂。这些活动在第二季度顺利完成。
2018年8月3日
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