2018-11-03 The 21st SAPA-NE Scientific Symposium

21st SAPA-NE Scientific Symposium Report

Huijuan Li, Lin Lin, James Cao

November 3rd, 2018

Richard E Griffin Academic Center

MCPHS University

670 Huntington Avenue Boston, MA 02115

Executive Summary

November 3rd 2018, Boston, the world’s renowned center for education and innovation in the global medical field, welcomed Sino-American Pharmaceutical Professionals Association (SAPA)’s New England Chapter (SAPA-NE) members, pharmaceutical giants, academic elites, world-renowned leaders and researchers to join a full day 21st SAPA-NE scientific symposium at the Massachusetts College of Pharmacy and Health Sciences University (MCPHS). More than 250 SAPA-NE members and friends gathered at the Richard E Griffin Academic Center Auditorium to listen to 12 invited speakers, representing academic institutions, healthcare providers, industry leaders and physician networks.

The conference began with opening remarks and warm welcome by Dr. Jun Johnny Yang, SAPA-NE president; Chairs of the symposium, Dr. Lin Lin and Dr. James Cao; and host of the symposium, Dean of the School of Pharmacy, MCPHS University, Dr. Paul Difrancesco.

Although the journey from concept to clinical success has been long, gene and cell therapy are beginning to bring new treatment options to multiple fields. Recent approvals in both gene and cell therapy, including Kymriah from Novartis; Yescarta from Kite, a Gilead Company; and Luxturna from Spark Therapeutics, and many entering clinical development, have certainly paved the way for the next decade possibly be the new era of evolving therapeutic treatment from phenotypic to genotypic interventions.

Exciting speeches delivered by 12 keynote speakers, including Dr. Khalid Shah, vice chair of Research at Brigham and Women's Hospital (BWH), director of the Neurosurgical Stem Cell Therapy and Imaging Center (CSTI); Dr. Daniel Bauer, Professor, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School; Dr. Tony Ho, EVP of CRISPR Therapeutics; Dr. Srinivas S. Rao, Global Head of Translation in vivo Model, Sanofi; Dr. Zdravka Medarova, Associate Professor, MGH, Harvard Medical School; Dr. Jeffrey Lasker, MORE Health Chief Physician Officer; Dr. Jay Hou, VP of Vector Engineering, Voyager Therapeutics; Dr. Alison McVie-Wylie, Ph.D., Head of Gene Therapy, Rare Disease Research, Sanofi; Dr. Zhenhua Wu, CEO of NeuExcell Therapeutics; Dr. Jian Chen, Founder & CEO, Celetrix LLC; Dr. Jing-Tao Wu, VP DMPK and Dr. Amy Zhang, Sr. Director Clinical Pharmacology, Alnylam, centered around the challenges and promises with presentations and interactive dialogues on “The Next Phase of Gene and Cell Therapy”. The topics covered a broad scope from early discovery, development to regulatory approval.

“The success of the symposium would not be possible without the support of event host MCPHS University, organizing committee members’ tireless effort, many volunteers’ commitment, and vendors and sponsors’ support”, summarized Dr. Jun Johnny Yang. “Appreciation goes to everyone who made this symposium a success, especially to our Chairs of the symposium, Dr. Lin Lin and Dr. James Cao for organizing such a quality event with all the speakers as leaders in the field, and our venue coordinator Dr. Hongwei Zhang, Assistant Professor and Director of Pharmaceutical Sciences at MCPHS University”, Dr. Yang continued.

The excitement and discussion continued through the networking session and dinner table. “I enjoyed the event and was really impressed by the quality of the science and the participation from your association”, commented by Dr. Alison J. McVie-Wylie. “It was a well-organized scientific symposium and we were happy to be part of it”, shared by Dr. Jay Hou and Dr. Jing-tao Wu. Many of us have and will continue to witness how innovation and technology have been revolutionizing pharmaceutical industry and our everyday work.

SAPA- NE continues our mission to inspire scientific discussion and exchange, foster collaboration and dialogues among discovery research, development and regulatory to ultimately deliver to patients of safe and cost-effective treatment for unmet medical needs. This dialogue will continue as the SAPA-NE 2019 annual conference theme “Developing and Delivering the Advanced Medicines to All Patients”, announced by our president-elect Dr. Qiying Hu. On behalf of the organizing committee, we all look forward to seeing you at the 21st SAPA-NE Annual Conference, Boston Marriott Cambridge, MA, USA on June 8th, 2019!

21st SAPA-NE 科学研讨会---波城秋日一抹绚丽的学术风景线

2018年11月3日，在这姹紫嫣红的金秋时节，全球医药领域教育、研发、创新的圣地---波士顿迎来了新英格兰美中医药开发协会（SAPA-NE）有史以来最为火热的第21届科学研讨会， SAPA-NE会员、医药界大牛、学界精英、世界名企领袖和广大科研人员等专业人士欢聚在位于波士顿哈佛医学中心地带的麻州药学院Richard E Griffin 学术中心礼堂，聆听来自哈佛医学院等高等学府、全球知名药企、科技创新新锐的12位知名科学家及药物研发领袖的精彩演讲。会议围绕着“基因和细胞疗法的未来”这个主题，对话了这一领域的突破性进展、面临的挑战机遇及未来的发展愿景等。内容丰富多彩，涵盖了从药物的早期研发、后期开发和监管审批等各个环节。在基因和细胞治疗日渐火热的时下，本次研讨会创历史记录地吸引了250多位来自波士顿地区各大药企、初创公司、著名高校等高层次科研人员参会，人满爆棚、异常火热、所有入场票全部售罄。会议演讲精彩、讨论热烈、所有内容结束后人们仍余兴未了、久久不愿离去，成为波士顿秋日的一抹绚丽学术风景线。

研讨会在SAPA-NE现任会长Jun Johhny Yang（杨军）博士、科学研讨会主席Lin Lin（林琳）博士和James Cao（曹建明）博士、东道主MCPHS大学药学院院长Paul Difrancesco博士的热情洋溢的欢迎下揭开帷幕。

来自哈佛医学院附属布列根妇女医院（Brigham and Women's Hospital， BWH）科研副院长，并兼任神经外科干细胞治疗和成像中心（CSTI）主任、哈佛干细胞研究所研究员等数职的 Khalid Shah博士，来自儿科排名世界第一的著名的哈佛医学院附属波士顿儿童医院（Boston Children’s Hospital）及世界闻名的癌症专科医院（Dana-Farber Cancer Institute）的Daniel Bauer博士，享誉全球的哈佛医学院附属马萨诸塞州总医院的Zdravka Medarova博士，具有从前期研发到后期申报等一系列丰富经验的现任CRPSPR Therapeutics执行副总裁Tony Ho博士, 来自世界著名大型制药企业Sanofi（赛诺菲）的高级主管Srinivas S. Rao博士及罕见病基因治疗及药理学研究的负责人Alison J. McVie-Wylie博士，来自以AAV基因治疗见长的Voyager Therapeutics的副总裁Jay Hou博士，来自致力于创新性神经系统药物研发的 NeuExcell Therapeutics的首席执行官Zhenhua Wu (吴振华) 博士，来自于MORE Health （爱医传递）首席执行官Jeffrey Lasker博士，来自于专业开发细胞转染技术的公司Celetrix的首席执行官Jian Chen (陈健)博士，来自著名药企Alnylam的掌管毒理研究的副总裁Jingtao Wu (吴惊涛)博士与临床药理总监Amy Zhang博士等12位讲演嘉宾分别围绕基因和细胞治疗进行了主题演讲。从肿瘤干细胞治疗到第一个被FDA批准上市的RNAi药物Onpattro诞生，嘉宾的演讲各个精彩，高潮迭起。

“本次研讨会得到了MCPHS大学的大力支持，研讨会的成功是和组织委员会成员的不懈努力，许多志愿者的无私奉献，以及供应商和赞助商的支持分不开的”，Jun Johnny Yang博士总结道。 “感谢所有使本次研讨会取得成功的人，尤其是我们的研讨会主席Lin Lin博士和James Cao博士, 我们的场地协调员Hongwei Zhang博士，MCPHS大学助理教授和药学科学主任，“杨博士继续说道。

会议尾声，SAPA-NE继任会长Qiying Hu（胡琪颖）博士进行了总结发言，宣布SAPA-NE 将于2019年6月8在位于查尔斯河畔的Boston Marriott Cambridge, MA, USA 举行主题为“为所有患者开发创新药物”的第21届SAPA-NE年会，热烈欢迎广大医药界朋友光临2019 SAPA-NE年会，期待在年会的学术大餐上重聚首、再相逢！

Annual scientific symposium is one of Sino-American Pharmaceutical Professionals Association (SAPA)’s New England Chapter (SAPA-NE)’s traditions. Relevant and exciting topics are selected and academic and industry leaders are invited to share and discuss the most advanced progress in the selected fields. Given the rapid proceedings made in the gene and cell therapy in the last few years, it is due for us to repeat this topic though it was covered in 2015 (18th SAPA-NE SS).

A full day 21st SAPA-NE scientific symposium, on Nov 3rd 2018, brought together more than 250 members and friends of SAPA-NE including industry leaders, scientists, academic researchers, and physicians.

The central dogma of Molecular Biology, the transfer of information from gene sequence to a protein product, has been part of the biotechnology medicine revolution in the past 40 years. Over 400 recombinant proteins including antibodies have been approved which revolutionized the industry to become biological based in the last 10 years as illustrated in the Figure below.

Saltzman E and Rice M, 2018, Advanced Therapeutic Webinar, Defined Health, a Cello Health business.

Although the journey from concept to clinical success has been long, gene and cell therapy are beginning to bring new treatment options to multiple fields. A historical overview of HSC and AAV gene therapy, and CAR-T cell therapy is outlined as the following (Dunbar CE et al, 2018, Collins FS and Gottlieb S, 2018).

Dunbar CE et al, 2018, Gene therapy comes of age. Science.12; 359(6372).

Recent approvals in both gene and cell therapy, including Kymriah from Novartis; Yescarta from Kite, a Gilead Company; and Luxturna from Spark Therapeutics, and many entering clinical development, have certainly paved the way for the next decade possibly be the new era of evolving therapeutic treatment from phenotypic to genotypic interventions (illustrated in the table below).

Saltzman E and Rice M, 2018, Advanced Therapeutic Webinar, Defined Health, a Cello Health business.

The invited speakers, representing academic institutions, healthcare providers, industry and physician networks, discussed the challenges and promises with presentations and interactive dialogues on “The Next Phase of Gene and Cell Therapy”. The topics covered a broad scope from early discovery, development to regulatory approval.

The morning session started with keynote Speaker Dr. Khalid Shah, vice chair of Research at Brigham and Women's Hospital (BWH), director of the Neurosurgical Stem Cell Therapy and Imaging Center (CSTI). Dr. Shah provided an assessment for the current state of cancer stem cell therapy and shared the rationale design for translating the most promising preclinical studies into the clinic. Dr. Shah’s laboratory has shown that different stem cell types home to sites of cerebral pathology and thus can be armed with therapeutic transgenes, a strategy that can be used to inhibit tumor growth by targeting angiogenesis or selectively inducing apoptosis in proliferating tumor cells in the brain. They have engineered different stem cells types to release therapeutic proteins to specifically induce apoptosis in tumor cells and anti-angiogenic to inhibit tumor angiogenesis and tested them in primary and metastatic mouse tumor models. In recent years his laboratory has also focused on targeting tumors that are resistant to different therapeutic drugs and oncolytic viruses.

Dr. Shah shared insights how CRISPR (clustered regularly interspaced short palindromic repeats) technology can potentially engineer cancer, NK and T- cells for the continued advancement in the personalized treatment by introducing a “safety switch” and “bifunctional receptor”; differentiating “Hot and Cold tumors” and “Resistant and Sensitive Patients”. Dr. Shah concluded his talk by summarizing the following: 1) developing tumor models that mimic the clinical setting of tumor growth and pathology is necessary for developing novel therapeutics for cancer; 2) engineering bimodal therapeutics and incorporation of mechanism based therapies that allow targeting multiple pathways is important to develop next generation of cell base therapies for cancer; 3) understanding the current treatment regimen for each cancer type is necessary for translation of novel therapies into clinical settings.

Dr. Daniel Bauer, a physician-scientist, whose research utilizes genome editing to understand the causes of blood disorders and to develop innovative therapeutic strategies. His clinical work in pediatric hematology focuses on the care of patients with hemoglobin disorders. Dr. Brauer presented therapeutic gene editing for hemoglobin disorders. Recent advances, including hematopoietic gene therapy by globin gene addition, gene editing to correct the disease-associated mutations directly, and genetic manipulations to enhance fetal hemoglobin production, a potent modifier of the clinical phenotype, raise prospects for improved, and perhaps efficacious and safe genetic approaches to cure for β-hemoglobinopathies.

B cell CLL/lymphoma 11A (BCL11A) is a transcription factor and regulator of hemoglobin switching that has emerged as a promising therapeutic target for sickle cell disease and thalassemia. Dr. Bauer shared exciting findings by using an ex vivo BCL11A enhancer editing with optimized CRSPR/Cas9 (CRISPR associated 9) in long-term reconstituting self-renewing human hematopoietic stems cells, demonstrating improved potency and undetectable genotoxicity. Preferential engraftment of cells edited by the non-homologous end joining (NHEJ) repair suggests potential advantage over alternative therapeutic editing approaches, i.e. the homology-dependent repairs.

Dr. Tony Ho, EVP of CRISPR Therapeutics, is a highly accomplished R&D leader with experience across all phases and multiple modalities of R&D. As a pharmaceutical veteran, Tony oversaw development, regulatory approval and commercialization of several key drugs – Lynparza, a first-in-class PARP inhibitor for ovarian cancer, Imfinizi (anti-PD-L1), AstraZeneca’s first immuno-oncology drug for bladder cancer, Maxalt for pediatric migraine and Zioptan for glaucoma.

Tony’s passion to what the new “digital” technology CRISPR can bring to the industry and patients was felt by the audience. Tony discussed the powerful gene-editing technology CRISPR/Cas9 to precisely disrupt, delete or correct disease-causing abnormalities at their genetic sources. In addition, Tony shared that the lead program targeting the blood diseases β-thalassemia and sickle cell disease has entered clinical testing, and the immuno-oncology programs, focused on CRISPR/Cas9-edited allogeneic CAR-T cell therapies, have the potential to deliver a new generation of cancer therapies to patients. Lines of allogenic CAR-T cell therapies against CD19, CD70 and BCMA and development of these programs and associated data were also discussed. Potential of multiplexing up to 5 edits opens broader application for regenerative medicine, improved immune evasion, cell function and directed cell fate.

It is clear that CRISPR Therapeutics has established a portfolio of programs by selecting disease targets based on criteria, including unmet medical need, technical feasibility, advantages of CRISPR/Cas9 relative to other approaches and time required to advance the product candidate into and through clinical trials.

The translatability of animal models to human disease pathways is frequently questioned or unknown, presenting a challenge to biopharmaceutical drug development. Across the scientific community, there is an increasing emphasis on the need for model validation, study design, application of rigorous statistical analyses, and to acknowledge the benefits and limitations of animal models. Technological advances in several fields have helped improve the interpretation of animal studies and their relevance to the human clinical situation. These advances include noninvasive translational imaging modalities, cellular and molecular imaging techniques, and genetically-modified humanized mouse models. These technologies are particularly impactful in their ability to enable the generation of data which can lead to translatable, successful clinical development program. The use of novel technology to generate preclinical data is particularly relevant with novel therapeutic modalities such as gene therapy and biologics.

Dr. Srinivas S. Rao, Head of Translation in vivo Model at Sanofi, highlighted the integrated approach taken at Sanofi to help scientists generate decision- enabling data from preclinical animal models at various stages of drug discovery and development. Dr. Rao emphasized the importance of the translatability of animal models with three ‘R's, Rigor, Relevance and Reproducibility. Dr. Rao shared his perspectives on some key enablers for making the preclinical discovery a success includes: 1) translational in vivo bioimaging biomarkers and imaging enabled biodistribution; 2) dedicated discovery pathology support for analysis of preclinical and clinical samples; 3) end to end support for access to transgenic models and technology/humanized mouse models. Dr. Rao concluded his talk by stressing the criticality of “Compliance” in all studies.

Our afternoon session continued with topics on innovation and delivery. Dr. Zdravka Medarova, Professor of Massachusetts General Hospital, described her team’s innovative work on the design and application of ultra-small iron oxide nanoparticles as imaging-capable carriers of siRNA to tumors, which illustrated the value of these nanoparticles for the delivery of small RNA therapy to challenging organ targets with increased circulation half-life and drug stability. Dr. Medarova described an approach for the noninvasive monitoring of small RNA delivery. The latter property was particularly novel and important, considering the overall lack of direct knowledge about the bioavailability of small RNA after in vivo delivery and the crucial relevance of adequate delivery to therapeutic success.

microRNA-10b (miRNA-10b) has been implicated in the development of a wide range of human cancers including colorectal, gastric, bladder, pancreatic, ovarian, hepatocellular and brain cancer. Recent studies have linked miRNA-10b to migration, invasion, cell viability, and proliferation in non-small cell lung cancer (NSCLC) and cervical cancer, and have suggested new roles for miR-10b in oncogene-induced tumorigenesis and metastasis through inhibition of tumor-suppressive mechanisms in mammary carcinoma. Dr. Medarova continued to discuss the rational design of a therapy against metastatic cancer. A nanodrug consisting of magnetic nanoparticles is conjugated to miR-inhibiting oligonucleotides (MN-anti-miR) for the specific inhibition of selected miRNAs in primary tumors and metastases. Intravenous injection of MN-anti-miR10b led to inhibition of the well-known metastamir miR-10b in the primary tumors and lymph node metastases in a murine model of metastatic breast cancer. While delivery to the primary tumor resulted in complete prevention of tumor cell dissemination to secondary organs, delivery to the lymph nodes arrested metastatic progression. When combined with low-dose doxorubicin (Dox), it was shown that it is possible to achieve complete and persistent regression of metastatic disease.

Headquartered in the Silicon Valley, MORE Health provides patients with access to the best physicians in the world when needed the most: when patients are faced with a critical, potentially life-changing illness, such as cancer or heart disease. More Health’s collaborative approach to diagnosis puts the patient at the center of the process – empowering them to make informed decisions regarding their own healthcare. They offer all of the benefits of a second opinion, while also ensuring that the attending doctor and our expert physician specialist are aligned, thus minimizing errors while also resolving potential conflicts regarding the diagnosis and treatment plan development.

Dr. Jeffrey Lasker is a senior physician executive with a deep understanding of healthcare systems and consumer healthcare needs, and a track record of building and leading highly successful physician organizations affiliated with academic medical centers. Dr. Lasker shared the impressive platform developed by MORE Health to improve worldwide access to advance therapies. It’s easy to navigate and use, with all information and data in one place. especially coming from physician networks who have practiced for many years. Multiple layers of protection to all patient information and privacy are put in place with utmost seriousness. MORE Health currently has a network of 700,000+ patients in China and US and 700 + US based physician specialists, who are recruited based on multiple criteria; expertise, research, publications, institutional associations, the empathy that they express towards patients, and their ability to look at the big picture when establishing a diagnosis.

Adeno-associated virus (AAV) is a non-enveloped single strand DNA virus found in many healthy people and the virus is not currently known to cause disease. It can effectively transduce dividing and non-dividing cells and can be readily engineered. The virus was discovered in 1960s. Since then, tremendous effort has been made to engineer AAV vectors for discovery, preclinical studies and therapeutic applications. AAV vectors have unique biological properties and have been shown to be safe, effective and can be readily engineered. Tremendous effort has been spent in recent years to develop AAV vectors, as a result, gene therapy using AAV vectors advances rapidly in both preclinical and clinical settings as a promising treatment for a variety of diseases. AAV vectors have been approved by regulatory agents to treat for lipoprotein deficiency (Glybera) and inherited retinal disease (Luxturna) and used in more than 160 clinical trials. Neurodegenerative disorders have been very difficult to treat due to the nature of the diseases even when the underlying causes are understood, AAV gene therapy could have the transformative potential for slowing or, optimistically speaking, stopping the progression of the diseases for patients and possibly preventing the diseases for prospective patients.

Dr. Jay Hou, VP of Vector Engineering of Voyager Therapeutics, discussed the achievements, challenges and major directions for the development of AAV platform. Vector is the foundation of AAV gene therapy, which plays a key role in the development of successful treatment. Vector engineering to screen and identify AAVs with tailored tropism and transduction efficiency is essential for effective therapeutic application. Dr. Hou shared his insights on the key aspects of vector engineering. These include cross species evolution to enhance the translatability to human; to overcome manufacturing challenges by production system construction and selection; to evade immune surveillance; and to increase the packaging capacity. Dr. Hou continued to share the promise of Capsid discovery in mouse using proprietary RNA recovery technology.

Gene therapy is changing the way we see genetic diseases. By targeting faulty or missing genes, this innovation is creating a new world of opportunities. 80% of rare diseases are genetic in origin and 50% present in childhood. Therapies are only available for about 5% of orphan diseases.

Dr. Alison J. McVie-Wylie, Senior Director and the Head of Gene Therapy and Biologics Pharmacology within Rare Disease Research at Sanofi, shared the promise and cutting-edge approach that gene-based therapies can bring to the treatment of rare diseases. Alison leads a group of scientists working to transition innovative gene therapy programs from research into development. Dr. McVie-Wylie provided an overview of AAV gene therapy for rare genetic diseases, highlighted recent advances including both technical progress and regulatory landscapes. For a long time, gene therapy are largely theoretical constructs, they are now a therapeutic reality. Currently 500 active INDs involving gene therapy with 40 approvals expected by 2022.

Dr. McVie-Wylie continued with a case study of AAV gene therapy for inherited retinal diseases (IRDs) caused by genetic defects resulting in dysfunction, degeneration or maldevelopment of rod or cone photoreceptors or the retinal pigment epithelium cells of the retina. In summary, significant progress in the field of AAV gene therapy has opened the possibility of treating and potentially curing many rare genetic diseases; the roadmap for AAV gene therapy development is maturing; and novel approaches on the horizon utilizing AAV as a delivery vehicle, e.g. in vivo gene editing.

Neurological diseases such as brain injuries and neurodegenerative diseases are becoming the world’s newest epidemics. In neurodegenerative or acutely injured brains, neural cells die while glial cells, a group of supporting cells surrounding neurons such as astrocytes, are activated and proliferate.

Dr. Zhenhua Wu, CEO of NeuExcell Therapeutics, shared NeuExcell’s proprietary and patented in vivo cell conversion technology regenerates neurons from glial cells in diseased brain/spinal cord. NeuExcell has developed a game-changing therapy pipeline to treat a variety of neurological disorders including stroke, Alzheimer’s disease, ALS, spinal cord injury, Huntington’s disease, Parkinson’s disease, traumatic brain injury and age-related macular degeneration. These world-leading gene therapy products can convert activated astrocytes into neurons and replenish dead neurons in injured or aged brains, and thus fundamentally cure otherwise irreversible neurodegeneration. Preclinical proof- of-concept validation in mouse and monkey models of ischemic stroke has been achieved. NXL-AAV001, an AAV-based gene therapy not only converts astrocytes into new neurons, but also protects existing neurons from inflammation-mediated secondary injury. Newly generated neurons are functional and able to incorporate into the existing neuronal network in animal models. NXL-AAV001 reverses behavioral deficits caused by ischemic stroke. A Phase I/II clinical trial to test the safety, tolerability, behavior and imaging biomarker improvement of NXL- AAV001 gene therapy is planned to take place in 12-18 months.

Electroporation is a widely used cellular delivery method for DNA, RNA and proteins. Celetrix has revamped the traditional procedures of cell electroporation with the introduction of innovative devices and methods.

Dr. Jian Chen, CEO of Celetrix, presented products of his company and how their technology and instrumentation can provide support in gene and cell therapy including immunotherapy, stem cell therapy and gene editing. Celetrix electroporation improves human T cells, iPSC (e.g. ACS-1030 from ATCC), human iPSC with Cas9/gRNA electroporate efficiency. For example, T cells can be transfected any time from the fresh PBMC stage to the stimulated or cultured stage. The Celetrix efficiency is highest compared to all other electroporation methods on the market. The technology enables high level of cell survival and expansion, allowing immunotherapy applications such as CAR, TCR-T generation and CRISPR knock-down of T cell genes.

Dr. Chen shared the promise of Celetrix’s electroporation, with the potential to provide

improved efficacy by utilizing stronger T cells, speed with reduced cell culture time and affordability with the saving from virus production and cell culture.

RNA interference (RNAi) is a natural biological pathway involved in the regulation of gene expression in all mammalian cells and is mediated by small interfering RNA (siRNA) molecules. It was first discovered in 1998 by US molecular biologists Andrew Fire and Craig Mello. The pair won the Nobel prize in physiology or medicine in 2006 for their discovery. By harnessing this natural biologic pathway, RNAi therapeutics offer the potential to treat various diseases with unmet needs. A major challenge associated with RNAi therapeutics is the delivery of siRNA molecules to the target organ and cells.

The scientific session concluded by dual speakers Dr. Jing-Tao Wu, Vice President of DMPK and Investigative Toxicology, and Dr. Amy Zhang, Sr. Director of Clinical Pharmacology and Pharmacometrics at Alnylam Pharmaceuticals, titled “OnpattroTM: The First Approved RNAi Therapeutics”. Dr.Wu introduced two platforms, 1) Lipid Nanoparticles (LNP); and 2) GalNAc-siRNA conjugates, that have been developed to successfully overcome the challenges associated with delivery to liver. Dr. Wu focused on the delivery system used in the first ever approved RNAi therapeutic: OnpattroTM (patisiran) for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy. hATTR amyloidosis is an autosomal dominant, multi-systemic, progressive, life-threatening disease caused by mutations in the transthyretin (TTR) gene. The pathogenic TTR mutations result in misfolded TTR proteins that accumulate as amyloid deposits at multiple sites including peripheral nerves, heart, kidney, and gastrointestinal tract, resulting in polyneuropathy and/or cardiomyopathy. Patisiran, a hepatically-delivered RNAi therapeutic by a unique LNP system, harnesses the natural process of RNAi to reduce production of mutant and wild-type TTR by targeting TTR mRNA in hepatocytes. Dr. Zhang discussed the APOLLO trial, a randomized, placebo-controlled Phase 3 study conducted in patients with hATTR amyloidosis with polyneuropathy. APOLLO trial results showed improved polyneuropathy in patients on patisiran treatment group compared to placebo treatment group and demonstrated encouraging safety profile. Relative to placebo, data from APOLLO showed that treatment with patisiran resulted in significant and clinically meaningful improvements in measures of polyneuropathy and quality of life. In addition, compared to baseline and after 18 months of patisiran treatment, improvement was observed in a majority of patients in the primary endpoint, mNIS+7 score (a composite measure of neuropathy), and in the key secondary endpoint, Norfolk QOL-DN (a quality of life questionnaire). The improvement in mNIS+7 was shown to be correlated with degree of TTR knockdown. Significant effects on muscle strength, activities of daily living, ambulation, nutritional status, and autonomic symptoms were also noted in patisiran patients relative to placebo. Moreover, patisiran patients with echocardiographic evidence of cardiac amyloid involvement at study entry demonstrated favorable effects on exploratory endpoints related to cardiac structure and function when compared to placebo.

All promises come with challenges and opportunities. A recent report of a CAR-T cell therapy used to treat an aggressive form of leukemia backfired in a previously unknown way, resulting in the death of a patient (Ruella M et al 2018). Though the case was a rare event but the treatment still warrants close monitoring and improvement of the manufacturing process. SAPA- NE will continue our mission to inspire scientific discussion and exchange, foster collaboration and dialogues among discovery research, development and regulatory to ultimately deliver to patients of safe and cost-effective treatment for unmet medical needs. This dialogue will continue as SAPA-NE 2019 annual conference theme “Developing and Delivering the Advanced Medicines to All Patients”, announced by our president-elect Qiying Hu. On behalf of the organizing committee, we all look forward to seeing you at the 21st SAPA-NE Annual Conference at Boston Marriott Cambridge (50 Broadway, Cambridge, MA) on June 8th, 2019!

References

Saltzman E and Rice M, 2018, Pharma and Biotech M&A in Gene & Cell Therapy: What’s Next in Deal Making in the Emerging Advanced Therapeutics Space? Advanced Therapeutic Webinar, Defined Health, a Cello Health business.Dunbar CE et al, 2018, Gene therapy comes of age. Science.12; 359(6372). Collins FS and Gottlieb S, 2018, The Next Phase of Human Gene-Therapy Oversight. N Engl J Med. 11;379(15):1393-1395.Ruella M et al, 2018, Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med. 2018 Oct;24(10):1499-1503.

Sino-American Pharmaceutical Professionals Association (SAPA) is a major US not-for-profit organization for pharmaceutical professionals with Chinese-heritage. Founded in 1993 and headquartered in the NJ/NY/CT tri-state area, SAPA grew rapidly and has become one of the most active and well-recognized Chinese-heritage enduring professional organizations in the United States. SAPA is an independent, not-for-profit organization with more than 6000 members in USA, Mainland China, Hong Kong, Taiwan and Japan united by a commitment to promoting pharmaceutical science and technology and their essential roles in fostering member's career development.

SAPA's New England Chapter, SAPA-NE, aims to promote pharmaceutical exchanges and cooperation in both industry and academia between China and the USA and to assist career opportunities and development for our members in New England area. SAPA-NE currently has more than 2000 members, most have advanced degrees. SAPA publishes "SAPA Newsletter", organizes the annual conferences, and seminars/symposia on specific topics of scientific, technological, and professional development, hosts or co-hosts pharmaceutical forum in US and China.

2018-11-03 The 21st SAPA-NE Scientific Symposium

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