NorCal SOT & PBSS Spring Symposium 2017
Combination Therapy: Fundamentals, Advances & Case Studies
May 16th, 2017
South San Francisco Conference Center, 255 South Airport Boulevard,
South San Francisco, CA 94080
Morning Session7:30 am – 8:30 am / Registration & Breakfast
8:30 am – 8:45 am / Opening message from The NorCal & PBSS Presidents
Toufan Parman, PhD, DABT, Director, General Toxicology, SRI
Shichang Miao, PhD, VP, Preclinical Development & Clinical DMPK, ChemoCentryx
8:45 am – 9:20 am / Introduction to the Preclinical Development of Combination Therapies
Joseph Francisco, CRL
9:20 am – 9:55 am / Safety Assessment of Combination Therapeutic Agents: Regulatory Guidance and Expectations
Philip Gatti, PhD, FDA
9:55 am – 10:30 am / Addressing The Challenges With The Discovery of Combination Peptide
Paul Feldman, PhD, Intarcia
10:30 am – 10:45 am / Coffee Break
10:45 am – 10:55 am / Sponsor Platform AM: Envigo
10:55 am – 11:30 am / Challenges and solutions in the development of multi-analytebioanalytical methods
Jonathan Wang, PhD, Genentech
11:30 am – 12:05 am / Manufacturing and Patient Administration Considerations for the Development of an Ocular Combination Therapy
Lynn Genarro, Genentech
12:05 pm – 1:30 pm / Lunch Break: Lunch with Experts, Posters
Afternoon Session
1:30 pm – 1:45 pm / Chapter announcements and acknowledgements
1:45 am – 2:05 am / NorCal Student Award presentation: Evaluation of DILI Predictive Hypotheses in Early Drug Development
Rosa Chan, BS, UCSF
2:05 pm – 2:40 pm / Combination Toxicity Study of 2 Approved Cardiovascular Drugs
Anne Chester PhD DABT, Gilead
2:40 pm – 3:00 pm / Coffee Break
3:00 pm – 3:10 pm / Sponsor Platform PM: Lovelace
3:10 pm – 3:45 pm / Combination Drug Applications: Nonclinical Reviewer Perspectives
Jessica Hawes, PhD, FDA
3:45 pm – 4:20 pm / Antibody-Drug Conjugates for the Treatment of Cancer
Thomas Pillow, PhD, Genentech
4:20 pm – 4:35 pm / Closing Remarks
4:35 pm – 5:50 pm / Reception & Networking
Abstracts
Introduction to the Preclinical Development of Combination Therapies
Joseph Francisco, CRL
Before embarking on the development of combination therapeutics it is essential to understand the regulatory expectations. The FDA guidance “Nonclinical Safety Evaluation of Drug or Biologic Combinations” in conjunction with ICH M3 and, for biologics, S6 provide the initial insight. However, as with most drug development scenarios there is no ‘one size fits all’ approach to combination drug development and each program must be tailored for the specific situation in question. The factors that must be considered to design an appropriate and efficient preclinical program for a proposed combination product include the regulatory status of each component (marketed drug or new molecular entity), the therapeutic indication(s) and intended patient population, the toxicity profile/target organs, intended duration of dosing, existing clinical experience using co-treatment with the proposed combination, and other factors. This presentation will introduce the key concepts and decision criteria to support combination therapies. Venturing outside the realm of fixed-dose combinations, some case examples recently presented at SOT by the FDA involving combination immuno-oncology agents will be reviewed to explore the FDA’s perspective in this hot area.
Safety Assessment of Combination Therapeutic Agents: Regulatory Guidance and Expectations
Philip Gatti, FDA
This presentation will review the regulatory guidances governing the approaches to combination drug development. These guidances cover combinations of 2 or more approved drugs, a combination of both approved and new molecular entities (NME’s), and a combinations containing only NME’s. Finally, case studies will provide examples of where the agency has requested new nonclinical studies for combination products and the rationale behind requesting these new studies.
Addressing The Challenges With The Discovery of Combination Peptide
Paul Feldman PhD, Head of Discovery and Translational Medicine, Intarcia
There has been surgent interest and activity in the use of peptide therapeutics to treat a variety of human diseases. In this lecture I will present our approaches to discover, optimize, assess, and deliver combination peptide therapeutics for treatment of metabolic diseases. Our target selection utilizes observations resulting from Roux-en-Y gastric bypass surgery and rigorous pre-clinical assessment of peptide singleton and combinations. Peptide optimization is conducted to select for highly in vivo selective and potent peptides and optimized peptide combinations are pre-clinically assessed to achieve maximal therapeutic benefit. Additionally, various considerations to deliver peptide combinations for efficient development and optimal patient benefit and adherence will be presented.
Challenges and solutions in the development of multi-analytebioanalytical methods
Jonathan Wang, Genentech
Combination therapy often refers to a therapy that utilizes multiple medications to treat a single disease. Although combo therapy offers many appealing benefits, such as slow development of drug resistance, fewer side-effects, lower case-fatality ratios, and lower treatment failure rate, the successful development of such therapy also imposes additional challenges on many aspects of drug discovery, development and clinical application. From a bioanalytical perspective, the development of combo therapy requires the support of bioanalytical methods that are able to monitor and quantify multiple analytes simultaneously. Unlike mono-analytebioanalytical methods, a multi-analyte method can only be established after evaluating and solving certain unique issues such as analyte interference, analyteinterconversion, different curve ranges or sample preparations required for each analyte, large sensitivity difference caused by analytes’ physical and chemical properties, and many more. Challenges faced in the development of multi-analytebioanalytical methods are discussed here and possible solutions are proposed correspondingly.
Manufacturing and Patient Administration Considerations for the Development of an Ocular Combination Therapy
Lynn Genarro, Genentech
This talk will focus on Chemistry, Manufacturing and Controls (CMC) challenges associated with biologic combination therapies. These include:
· Advantages of co-mixtures vs. co-formulations
· Manufacturing, analytical, and QC challenges associated with a combination therapy
· Assessing the stability and shelf-life of a combination therapy
· How CMC challenges can affect clinical and non-clinical development plans
A FAb + MAb ocular combination therapy will be used as the primary example.
NorCal Student Award presentation: Evaluation of DILI Predictive Hypotheses in Early Drug Development
Rosa Chan, UCSF
Drug-induced liver injury (DILI) is a leading cause of drug failure in clinical trials and a major reason for drug withdrawals. DILI has been shown to be dependent on both daily dose and extent of hepatic metabolism. Yet, early in drug development daily dose is unknown. Here, we perform a comprehensive analysis of the published hypotheses that attempt to predict DILI, including a new analysis of the Biopharmaceutics Drug Disposition Classification System (BDDCS) in evaluating the severity of DILI warning in drug labels approved by the FDA and the withdrawal status due to adverse drug reactions (ADRs). Our analysis confirms that higher doses ≥ 50mg/day lead to increased DILI potential but this property alone is not sufficient to predict DILI potential. We evaluate prior attempts to categorize DILI such as Rule of 2, BSEP inhibition, and measures of key mechanisms of toxicity compared to BDDCS classification. Our results show that BDDCS Class 2 drugs exhibit the highest DILI severity, and that all of the published methodologies evaluated here, except when daily dose is known, do not yield markedly better prediction than BDDCS. The assertion that extensive metabolized compounds are at higher risk of developing DILI is confirmed, but can be enhanced by differentiating BDDCS Class 2 from Class 1 drugs. We do not propose that BDDCS classification, which does not require knowledge of the clinical dose, is sufficiently predictive/accurate of DILI potential for new molecular entities, but suggest that comparison of proposed DILI prediction methodologies with BDDCS classification is a useful tool to evaluate the potential reliability of newly proposed algorithms. Conclusion: The most successful approaches to predict DILI potential all include a measure of dose, yet there is a quantifiable uncertainty associated with the predicted dose early in drug development. Here we compare the possibility of predicting DILI potential using BDDCS classification versus previously published methods, and note that many predictive DILI metrics hypothesized do no better than just avoiding BDDCS Class 2 drugs.
Combination Toxicity Study of 2 Approved Cardiovascular Drugs
Anne Chester PhD DABT, Gilead
To support a proposed clinical development plan with a fixed dose combination (FDC) of the marketed compounds ranolazine and dronedarone, a nonclinical evaluation of combination safety was undertaken. Based on individual safety evaluations and label information, the only overlapping safety concern was the potential for QT prolongation. The dog was chosen because the dog was the nonrodent species in both the ranolazine and dronedarone toxicology programs. The commercial formulations of ranolazine and dronedarone were evaluated in a single dose combination pharmacokinetic study; a single dose combination dog pharmacology study and a 4‑week repeat dose combination dog toxicity study. Neither the pharmacology study nor the 4‑week dog combination toxicity study revealed an effect on QT interval when each drug was administered alone or in combination; no unexpected toxicity was observed. Exposures in the 4‑week combination study were equal to or below anticipated therapeutic values. A 13-week combination repeat dose toxicity study with the fixed-dose combination (FDC) prior to Phase 3 trials and for registration was requested by the FDA citing insufficient exposure and study duration of the prior work. Toxicity, preferably at the MTD, was required to be shown with each individual drug and the FDC. Dose limiting adverse effects in dogs are convulsions (ranolazine) and emesis (dronederone). This presentation will discuss the issues surrounding the conduct of the 13-week combination toxicity study included dose selection, study design, and management of adverse effects. Despite dose reductions, the high dose combination group was terminated early due to tolerability issues; other early terminations of individual animals for tolerability also occurred in the low dose combination group and in the ranolazine only group. In the opinion of the Sponsor, the data from the 13-week combination toxicity study did not add to the overall risk evaluation of the FDC.
Combination Drug Applications: Nonclinical Reviewer Perspectives
Jessica Hawes PhD, FDA
An overview of regulatory requirements to support nonclinical safety assessments for combination drug products will be provided. Case studies of combination products for chronic indications in the Division of Metabolism and Endocrinology Products will be discussed with regard to additional nonclinical studies required to support NDA application.
Antibody-Drug Conjugates for the Treatment of Cancer
Thomas Pillow, PhD, Genentech
Linking a cytotoxic drug to a monoclonal antibody takes the strengths of both while potentially mitigating the liabilities. The resulting conjugates, known as antibody−drug conjugates (ADCs), have been validated clinically. Genentech’s HER2-targeted conjugate, Kadcyla™, was the first ADC approved for the treatment of solid tumors. This presentation will focus on Genentech’s efforts to develop the next generation of ADCs, investigating new cytotoxic drugs and improving the way they are attached to antibodies.
Biographies
Joseph Francisco, PhD, CRL
Joe Francisco is a Scientific Advisor at Charles River. In this role he provides scientific and regulatory guidance on the preclinical development of small molecule drugs and biotechnology derived therapeutics. His primary area of focus is the pharmacology and toxicology of therapeutic proteins (with an emphasis on monoclonal antibodies and antibody drug conjugates) and small molecule drugs. Previously within Charles River Joe was a Senior Program Advisor in the Navigator group. In these roles he has provided strategic and tactical guidance to a diverse array of domestic and international pharmaceutical and biotechnology companies ranging from small virtual companies to large multinational organizations. Joe also has experience as an independent consultant, working with small biotechnology companies to establish preclinical strategies to support the development of novel therapeutics. Prior to joining Charles River, Joe had spent seven years at Seattle Genetics in positions of increasing responsibility focusing on the research and development of therapeutic monoclonal antibodies and antibody-drug conjugates. Before joining Seattle Genetics Joe had been a scientist in the Protein Sciences division of Monsanto and a scientist in the Pharmaceutical Research Institute of Bristol-Myers Squibb. Joe received his PhD in Chemical Engineering from the University of Texas at Austin and his bachelor’s degree in Chemical Engineering and Biochemistry from Rice University. He has co-authored over 20 scientific publications and a number of US and international patent applications. Joe is a member of the Society of Toxicology (SOT), a member of the Pacific Northwest regional chapter of the SOT (PANWAT), and serves as a councilor in the Biotechnology Specialty Section; a member of the American College of Toxicology (ACT) and serves on the program committee (2015 and 2016); and an ACT representative on the Scientific Liaison Coalition.
Philip Gatti, PhD, FDA
Phil Gatti is currently a Pharmacologist/Toxicologist at the FDA in the Office of New Drugs, Division of Cardiovascular and Renal Products. Prior to coming to the FDA, he was an Associate Professor of Pharmacology at Howard University College of Medicine in Washington, DC. While there, he mentored 2 students who obtained the Ph.D. in his lab. He taught Medical, Dental, Pharmacy and PA students Cardiovascular Pharmacology and was course director for several years. His area of research focused on the vagal control of the heart, specifically the brainstem somatotopic organization of preganglionic vagal motoneurons. He utilized both anatomical (Transmission Electron Microscopy) and physiological recording of cardiovascular parameters in the whole animal. He published 50 peer-review papers in his time in academics. At FDA, he focuses on the regulatory aspects of combination drug applications and he co-chaired a symposium on this subject at the most recent annual meeting. He also has interests in the regulatory aspects of oligonucleotide based therapeutics and has co-authored a paper on the subject in 2016.
Paul Feldman, PhD, Intarcia
Paul L. Feldman joined Glaxo Pharmaceuticals, Research Triangle Park, North Carolina in 1987 after receiving his PhD from the University of California, Berkeley. From 1987-1995 Paul worked on a variety of drug discovery programs one of which led to the discovery of the marketed ultra short-acting analgesic opioid agonist remifentanil (Ultiva). In addition, he and academic collaborators worked on the biochemistry of nitric oxide production and first demonstrated that N-hydroxyarginine is an intermediate in the biosynthesis. From 1995-2000 Paul’s department worked on the discovery of antiviral agents for treatment of HIV and HSV. One of the highlights during this period was the discovery of the marketed HIV protease inhibitor, fosamprenavir (Lexiva/Telzir). In 2000 Paul became Vice President of Chemistry for the Metabolic and Viral Diseases for GlaxoSmithKline (GSK) Pharmaceuticals. His group discovered two assets, the HIV integrase inhibitor dolutegravir (Tivicay) approved in 2013, and the ultra short-acting benzodiazepine, remimazolam (outlicensed), currently in Phase 3 trials. In 2010 Paul was named Senior Vice President and his responsibilities included leading the Enteroendocrine Discovery Performance Unit, part of GSK’s Metabolic Pathways Cardiovascular Unit, and leader of GSK’s R&D Medicinal Chemistry Center of Excellence. The Enteroendocrine Unit focused on the discovery and early stage development of optimized combination peptide hormones, luminally restricted small molecules, and GRAS potentiators to treat diabetes and obesity. Several of these agents advanced into phase 2 clinical studies. In 2015 Paul left GSK and helped co-found and was CEO of the biotechnology company, Phoundry Pharmaceuticals, Inc. which was focused on discovering peptide hormone therapeutics. In September, 2015 Phoundry was acquired by Intarcia Therapeutics, Inc. Paul currently is Head of Discovery and Translational Medicine and part of the executive management team for Intarcia. Paul has served as an adjunct Professor of Chemistry, Duke and North Carolina State Universities, chair of Heterocyclic Compounds Gordon Research Conference (2000), member at large (2000-2003) and alternate councilor (2012-2014) to the Executive Committee in the Division of Organic Chemistry of the American Chemical Society, and chair of the Division of Organic Chemistry Fellowship Evaluation Committee (2003). In 2014 Paul received the North Carolina Section of the American Chemical Society’s Distinguished Lecturer award. Paul is currently on the editorial board for Organic Reactions. Paul has >100 scientific disclosures including scientific articles, invited lectures, book chapters, patents, and poster presentations.
Jonathan Wang, PhD, Genentech
Dr. Jonathan Wang obtained his PhD degree in chemistry from University of California at Riverside in 2011. After graduation, Jonathan moved to Madison, Wisconsin and worked for Covance Laboratories as a staff scientist for a little over two years. At Covance, Jonathan successfully conducted a number of small molecule method development and validation projects. Since Joining Genentech in 2013, Jonathan has been working on overseeing bioanalysis outsourcing activities to support pre-clinical and clinical studies, IND/NDA filling, as well as continuing to develop novel bioanalytical assays for small molecule biomarkers. Currently, Jonathan is a scientist in the regulated bioanalysis group within the DMPK department supporting development activities for small molecule oncology programs.
Lynn Genarro, Genentech
Lynn Gennaro is an Associate Director in the Analytical Development and Quality Control group at Genentech, with 15 years experience in CMC development of biotechnological products.
Rosa Chan, BS, MPH, UCSF
Rosa Chan received her B.S. in Molecular Toxicology from UC Berkeley in 2011. She is currently a 5th year graduate student at the University of California San Francisco’s Pharmaceutical Sciences and Pharmacogenomics Ph.D. Program, where she is completing her thesis work in Dr. Benet’s laboratory. Her thesis work is focused on evaluating the application of the Biopharmaceutics Drug Disposition Classification System (BDDCS) for the risk assessment of skin and liver toxicity potential of small molecules using in vitro and human clinical data. She was awarded the 1st Place Graduate Student Winner from the NorCal Graduate Student Achievement Award SOT in 2017.