SAPA 29TH ANNUAL CONFERENCE: “BUILDING A HEALTHIER FUTURE” — PARALLEL SESSION 2

Frontiers in Drug Discovery and Development: From Academia to Industry

Dr. Dexi Yang from Merck welcomed speakers and audience to the session

The first speaker, Dr. Jingjun Yin, Executive Director in Process Research & Development at Merck, started his talk from two well-known products from Merck: Ivermectin, on which the inventor won the 2015 Nobel Prize in Physiology or Medicine. Merck made it free for more than 10 million patients worldwide. The other drug is HBV vaccine. Merck transferred the technology at no cost to China in the 1980s, and immunized all newborn babies from HBV ever since.

After exemplifying Merck’s mission, Dr. Yin then switched to the importance of drug development. On average it takes 10-15 years for a drug from project launch to its approval by the FDA. But in most cases, patients cannot wait for that long. New technology is required to develop drugs to meet urgent needs. Dr. Yin exemplified the acceleration of drug development with HCV drug Elbasvir. Finally, Dr. Yin discussed the scale up of Molnupiravir, the potential COVID-19 oral drug that showed promising clinical results. This is also a great example of accelerating drug development via innovation in chemistry.

Accelerating Drug Discovery and Development through Innovation in Chemistry by Dr. Jingjun Yin

Following Jingjun, Dr. Steven Townsend, Associate professor of Chemistry at Vanderbilt University, started his talk with his research in human milk science, focusing on understanding how breastfeeding can boost the immune systems of newborn babies. He then introduced cancer as a burden for the whole society: 40% of people have the chance to develop cancer in their lives. Patients’ out-of-pocket cost is $5.6 billion per year.

To alleviate this burden, chemotherapy is an effective and common treatment for cancer patients. Anthracycline is a common chemotherapy drug with major limitations: cardiotoxicity and drug resistance. His talk focused on the cardiotoxicity part. Usually there are two options to reduce cytotoxicity: increase drug potency, so less drug is needed for the treatment; and decrease toxicity. Professor Townsend concluded his talk by mentioning how his research group achieved lower cytotoxicity of Anthracycline by organic chemistry synthesis.

Synthesis and Evaluation of Arimetamycin A & Novel Anthracycline Chemotherapeutics by Dr. Steven Townsend

After coffee break, we welcomed 3^rd speaker, Dr. Haojing Rong, VP of preclinical development at Kymera Therapeutics. She began her talk with an overview of targeted protein degradation field. She then introduced Kymera, a biotech company. It has ongoing collaborations with SANOFI, Vertex and GSK to develop novel protein degradation therapies. Kymera’s pipeline focuses on two pathways: IL-1R/TLR and JAK/STAT pathways.

In the first pathway, IRAK4 is an important kinase in innate immunity whose overexpression leads to autoimmune diseases. IRAK4 is a novel drug target with unmet medical need, validated biology and undrugged node. Kymera’s IRAK4 degrader KT-474 showed superiority compared to small-molecule inhibitor in preclinical trials. In its phase I clinical trial, KT-474 achieved 85% target degradation, which is the first degrader proof-of-mechanism in target protein degradation in a placebo-controlled trial. Dr. Rong also introduced STAT3 degrader KTX-201, which serves as a potent, highly selective degrader in heme malignancies and solid tumors. In the preclinical experiments, KTX-201 could degrade greater than 90% STAT3.

Targeted Protein Degradation in Oncology and Beyond by Dr. Haojing Rong

Next, Dr. Zhi-Fu Tao, Principal research scientist II in Oncology Discovery at Abbvie, discussed strategies of targeting the BCL-X_L from small molecule inhibitors to the Antibody Drug Conjugate (ADC) clinical candidates. He first introduced cell apoptosis and BCL-X_L. BCL-2 family proteins (including BCL-2 and BCL-X_L) play critical roles in intrinsic apoptosis pathway.

With the insights from structural biology, Abbvie scientists discovered two small molecules targeting BCL-2. One is ABT-199(Venetoclax), and the other is ABT-263(Navitoclax). By targeting tumor cells with the specific antigen-antibody interaction, ADC drug could potentially reduce side effects. Next, Dr. Tao introduced the basic principle of ADC drugs and Abbvie’s ADC drug ABBV-155. ABBV-155 is a first-in-class BCL-X_L inhibitor ADC currently in phase I. It targets an antigen called B7H3, which is highly expressed in tumor and has high overlap with BCL-X_L in key patient population.

Targeting BCL-X L: From Small Molecule Inhibitor to Antibody-Drug Conjugate (ADC) Clinical Candidate by Dr. Zhi-Fu Tao

The last speaker of Drug Discovery session is Dr. Jin Wang, Professor of Pharmacology in the department of pharmacology at Chemical Biology at Baylor College of Medicine. He introduced his research interest on chemical biology, cancer and Alzheimer’s disease. He shared two stories of developing new oncology drugs. The first story started from immunogenic cell death (ICD). He introduced a first-in-class target X PROTAC degrader LD4172, which triggers ICD, reshapes tumor microenvironment, and synergizes with anti-PD1 in an immunocompetent mouse model.

In the second story, he tried to improve PROTAC degradation efficiency. He compared three different warhead chemistry in BTK degradation. They developed RC-1 as the first reversible covalent BTK PROTAC with high target occupancy. RC-1 forms a stable ternary complex with BTK and E3 ligase Cereblon. Additionally, RC-1 has shown promising cell viability and target engagement, as well as reasonable plasma half-life.

Applications of PROTACs to Overcome Resistance in Targeted Therapies and Immunotherapies by Dr. Jin Wang

Clinical Development, Data Sciences and Regulatory Affairs – Cross the Finish Line: Multiple Team Efforts in Drug Development at Clinical Stage

Dr. Jerry J. Li from Daiichi Sankyo welcomed speakers and audience to the session

Dr. Jerry J. Li from Daiichi Sankyo welcomed speakers and audience to Clinical Development session and introduced Dr. Caleb Lee, Senior Director of Global Oncology Clinical Development at Daiichi Sankyo. He first reviewed Daiichi Sankyo’s 5-year plan which launched in 2016 and pivoted the company vision to oncology and clinical development. Then he reviewed the history of topo I inhibitors at Daiichi Sankyo. He explained the 7 key attributes of T-DXd (DS8201-A) design and discussed preclinical activity of T-Dxd by looking at xenograft animal models which showed it has high efficacy observed in various tumor types.

Early results from the DS8201-A-J101 Ph1 trial led to acceleration of Ph2 and Ph3 trials. He showed the Ph2 DESTINY-Breast01 trial demonstrated that T-DXd has durable antitumor activity in heavily pretreated patients with HER2-positive metastatic breast cancer, and led to accelerated approval in the US and Japan. He also introduced multiple ongoing collaborations with AstraZeneca. Lastly, he presented DESTINY-Breast03, the first randomized phase 3 clinical trial of T-DXd, recently reported positive results for trastuzumab deruxtecan.

Fruition of a Vision: Clinical Development of Trastuzumab Deruxtecan (T-DXd) by Dr. Caleb Lee

Next, Dr. Yue Shentu, Distinguished Scientist (Executive Director) of Global Clinical Development at Merck, introduced the concept of statistical fallacies. He used statistical methods to discuss COVID-19 vaccination rate and hospitalization of vaccinated people. He also used an example of US Army Airplane to bring up survivor bias, and to ask the audience to correctly interpret the data. He then talked about Table 1 fallacy, understanding of randomization, and understanding of stratified randomization. He stated that researchers shall properly analyze clinical trials with stratified randomization using two components, one is estimation of treatment effect, and the other is estimation of uncertainty of the treatment effect.

He then used chronic fatigue syndrome as one example to walk through the following concepts: confounder, mediator, collider, collider and Berkson’s Paradox, and directed acyclical graph (DAG). He summarized the talk as science can be tricky, sometimes even for seasoned researchers; researchers shall be aware of common fallacies; one shall raise more awareness of causal interference and consult with statisticians if needed.

Statistical Fallacies in Clinical Research – Science to the Rescue Where Intuition Fails by Dr. Yue Shentu

We then welcomed the 3^rd speaker of the session, Dr. Ke Liu, Senior Vice President of Head of Regulatory Affairs & Strategy at Sana Biotech, Inc. He began his talk with defining of human gene therapy and introducing human gene therapy products. He then talked about basic criteria for Gene therapy approvals, and reviewed definitions of regular and accelerated approvals. He listed a few examples of US FDA gene therapy approvals and presented the lessons learned from approvals.

He summarized the current landscape of gene landscape: (1) significant increase in the number of therapies in 2021 compared to 2020; (2) current commonly targeted areas are oncology and rare disease; (3) current commonly used vectors are AAV and lentiviral; (4) increasing growth of IND submissions. At the end, he also reviewed regulatory perspective-clinical considerations such as early phase clinical trial designs.

Clinical Considerations for Cell and Gene Therapy – Regulatory Perspectives by Dr. Ke Liu

Finally yet importantly, we had invited Dr. Patricia Keegan, Chief Medical Officer at TopAlliance Biosciences, Inc as our 4^th speaker of the session. She first introduced the concept of rare disease and current challenges and opportunities of rare disease. She talked about challenges of rare disease: adequate accrual of patients to clinical trials; small sample sizes that may present challenges in the risk:benefit assessment of new drugs; limited characterization of the safety profile of new drugs; limited evaluation of treatment effects across diverse populations.

Next, she reviewed opportunities of rare disease: tumor genome atlas and tumor registries that facilitates design of tumor agnostic trials; use tumor registry information to establish natural history; increase samples size through tumor agnostic clinical development. She then reviewed rare disease-applicable US legislation over the years and showed a few examples of expedited development for serious and life-threatening rare disease. At the end, she also addressed the requirements of treatments designed for rare diseases but were developed outside the US.

Clinical Development in Rare Diseases: Opportunities and Challenges by Dr. Patricia Keegan

Group photo of session speakers and moderators

Challenges and Opportunities in Developing New Drugs and Treatment Modalities in CMC

Dr. Yong Guo from Fairleigh Dickinson University welcomed the speakers and audience to CMC session. The first speaker, Dr. Rao V. Mantri, is the Vice president and head of drug product development at Bristol Myers Squibb. Dr. Mantri gave a comprehensive review of the current state, future trend and opportunities in drug product development with examples. Firstly, Dr. Mantri gave an overview of the variety of treatment modalities and corresponding challenges to formulation development. To solve the formulation challenges, Dr. Mantri suggested the following considerations and approaches: chemical modification of drug entity, application of novel excipients, and utilization of novel drug delivery systems.

Next, Dr. Mantri introduced the concept of patient-centric drug product design. He suggested that drug product design should be developed for the target patient population and therefore performance, manufacturability, and stability of drug product should be developed in order to meet patient needs. Finally, through examples about predictive process design and data science, he successfully demonstrated how emerging science and technology can significantly improve drug product development process.

Evolving Role of Pharmaceutical Science & Technology to Meet the Needs of Emerging Modalities by Dr. Rao V. Mantri

Next, Dr. Duxin Sun from University of Michigan presented anti-tumor nanomedicine design. Dr.Sun first introduced current nanomedicine design criteria and tumor enhanced permeability effect (EPR). Then he talked about the current inconsistency in nanomedicine’s efficacy between preclinical cancer models and cancer patients. While the preclinical data is promising, most nanomedicines fail in clinical trials due to efficacy or safety issues.

Later he shared his opinion on current nanomedicine which is primarily designed based on EPR effect. He presented the observed EPR heterogeneity and explained possible cause for nanomedicine preclinical and clinical inconsistency. Finally, he pointed out that the current universal nano-delivery system oversimplifies the cancer treatment and novel nanomedicine delivery systems are required to be specific to drug type, nanocarrier type, cancer type, and cell type.

What Went Wrong with Anticancer NanoMedicine Design and How to Make It Right by Dr. Duxin Sun

After coffee break, Daniel Roberts, Senior Specialist of Pharmaceutical and Biotechnology Practice at Hogan Lovells continued discussions of CMC-related topics. He shared his experience from a regulatory perspective. He used to be a United States FDA investigator for 8 years and currently works as senior specialist in pharmaceutical and biotechnology practice at Hogan Lovells.

He first introduced the concept of Good Laboratory Practice (GLP) and Good Manufacturing Practice (GMP) and some common confusions between them. Next, he talked in detail about cGMP requirements for Phase 1 IND. He mentioned the importance of managing outsource manufacturers in phase 1, including CMO and academic institutions, to meet the cGMP requirement. After that, he talked about Good Documentation Practice (GDP) and data integrity. He shared some common GDP observations and key points to look out for. Lastly, he described how the FDA pre-approval inspection program is conducted and the objective of FDA inspections.

Drug GMPs and CAR-T Therapies by Daniel Roberts

As last speaker of the session, Dr. San Kiang, Chief technology officer of J-star talked about innovations at the API-drug product interfaces. Firstly, Dr. Kiang introduced the current API crystallization and drug product development process in the pharmaceutical industry. Usually, API scientists and formulators are from different departments in a CMC organization and have their own different objectives. This leads to inefficiency and impacts development timeline.

Next, he mentioned both drug substance property and drug product process affect the final drug product quality. He introduced that at his current company J-star, API chemist and chemical engineers work closely with formulation scientists and the boundary between API and drug product is minimized. Finally, he introduced the co-processed concept and showed four case studies to apply the co-processed method to solve the product development challenges. This co-process strategy has been applied in two approved and commercially available drug products.

Development Efficiency and Innovation at the API-Drug Product Interface by Dr. San Kiang

Group photo of session speakers and moderators

Update and Advancement in Precision Medicine, Clinical Diagnostics and Medical Device

Dr. Wei Ding from Admera Health welcomed speakers and audience to the session

As 1^st speaker of the session, Dr. Yaji Xu is Senior Staff Biostatistician from Illumina. Dr. Yaji Xu presented the general framework for validating CDx devices, with an emphasis on the studies to demonstrate CDx clinical performance. Particularly, he discussed some practical issues and challenges in conducting CDx clinical validation studies. He stated precision medicine, particularly, applications in drug-diagnostic device co-development are becoming increasingly prominent.

He also mentioned that a well-characterized market-ready companion diagnostic (CDx) assay is usually desired for patient enrollment in device drug pivotal clinical trial(s) so that CDx clinical performance can be demonstrated from the single trial directly. However, he said that such study design may be difficult or impractical in reality. Hence, he concluded that a bridging study needs to be conducted subsequently to estimate the efficacy of the drug in the population defined by CDx.

On the Basis of Drug-Device Co-Development – A Device Perspective by Dr. Yaji Xu

Next, Dr. Mike Sheldon, Senior Director of Scientific Affairs at Infinity BiologiX, shared with his insights into advanced Biobanking by first talking about the history of Infinity BiologiX. RUCDR Infinite Biologics was established as a biobank built by scientists for scientists with a mission at its core and grew into the world’s largest academically based biobank, maintaining the repositories of several agencies of the NIH and numerous clients. In 2020 RUCDR Infinite Biologics became Infinity BiologiX (IBX). He emphasized that while the name changed, the core mission did not. He then focused on discussing the efforts of IBX to continue to support its expanding commercial and academic client base in the 21st Century by offering a range of cutting-edge services that is constantly evolving with the times.

Advanced Biobanking: Learn How to Harness the Potential of Biobanks from IBX by Dr. Mike Sheldon

We then welcomed Heather Haselmann, Director Business Development from Canfield Scientific, Inc. to introduce Canfield Scientific. It is a global leader in imaging systems, services and products for scientific research and healthcare applications, including the pharmaceutical, biotechnology, cosmetics, medical and skin care industries. In particular, she mentioned that Clinical Services Team specialize in photographic documentation to help demonstrate drug efficacy in clinical drug trials worldwide.

She next talked about how Canfield pioneered the use of specialized devices in medical photography and developed a wide range of innovative solutions for research and practice. She then listed a few patented technologies including multi-spectral and multi-modal 2D and 3D image capture systems, digital asset management, aesthetic simulation, and applications for detection, measurement and analysis for various skin conditions. Lastly, she stated these technologies have contributed to the development of numerous treatments and procedures and have significantly advanced the use of optical imaging in both clinical research and practice.

Canfield Digital Imaging and Analysis by Heather Haselmann

After coffee break, Dr. Janos Luka, CSO of Danuvius Biosciences, LLC, discussed about development of diagnostic assays. Dr. Luka talked about the most recent development made with Danuvius Biosciences. He stated identification of the key antigens and epitopes targeted by immune responses is the most vital step in development of diagnostic assays and therapeutic antibodies. He then mentioned, in order to develop fully human antibodies for therapy, human sera from previously infected patients were screened for presence of antibodies against antigens.

Next, he showed that human monoclonal antibodies were identified from the antibody library established from these individuals and were evaluated in vivo and in vitro. He described this mouse and human hybridoma library approach has significant advantages over other methods. He concluded the presentation with the emphases on this novel procedure allowing development of rapid diagnostic assays for bacterial infections which can differentiate between infection and colonialization.

In Vivo Antigen Discoveries Translated into Development of Therapeutic Human Antibodies for Treatment of Microbial Infections by Dr. Janos Luka

Next, we had Annamarie Saarinen, Co-founder and CEO of Bloom Standard as the 5^th speaker of the session. Annamarie first talked about Bloom Standard and their products. She mentioned that small, nimble early-stage innovators are tackling unmet needs in underserved clinical ecosystems including pediatrics and rare diseases. She affirmed these teams are often multidisciplinary and they focused on how best to integrate with public health priorities, clinical infrastructure, referral patterns, and accessible treatments/therapies. She acknowledged this approach that it creates a “medtech stack”, from screening to diagnostics to patient flow and precision pharma and biotech therapies, which can best serve patients and those treating them throughout the care continuum.

How Startups are Accelerating Diagnostic + Therapeutic MedTech Stack by Annamarie Saarinen

Lastly, Gerald Commissiong, CEO of Todos Medical, introduced main functions of Todos Medical Ltd. He stated that Todos Medical is a developer and distributor of medical diagnostics addressing cancers, Alzheimer’s Disease and viruses. He also shared thoughts on how Todos Medical acts as a provider of Covid-19 testing supplies and automation solutions. In addition, he pointed out that Todos Medical is also a developer and distributor of immune support products and antivirals that target the inhibition of 3CL protease for the treatment of Covid-19. He concluded the talk with the idea of combining Covid-19 CLIA-CAP testing and diagnostic reagent sales as one stop shop for comprehensive COVID-19 testing solution.

Todos Medical Covid Antiviral and Cancer Diagnostics by Gerald Commissiong

Group photo of session J speakers and moderators

Interactive Network Breakout Sessions

In addition to the impressive presentations and splendid panel discussions, SAPA also planned a series of interactive network breakout sessions to provide opportunities for the conference attendees to participate in conversations with the speakers and panelists. SAPA Annual Conference Organizing Committee concluded the successful two-day event and welcomed everyone to stay tuned to social media for more upcoming SAPA events.