Charles W. Flexner

Johns Hopkins University

Novel Approaches to HIV Treatment and Prevention using LA Drug Delivery

Oral antiretroviral regimens are extremely effective at suppressing HIV with minimal toxicity. They also offer the simplicity of once daily single-tablet dosing. However, long-acting regimens with infrequent dosing, for example weekly oral or long-acting parenterally administered agents, may be useful for treatment or prevention in circumstances where daily oral therapies are difficult to administer, and/or when adherence may be inadequate. In such circumstances, alternatives to oral therapy may be life-saving and reduce the transmission of infection to others. Limitations of such an approach to drug delivery include the management of toxicities, given that exposure to these agents is not easily reversed, and prevention of drug resistance when these drugs are discontinued and drug concentrations are slowly reduced over time. Agents with long-acting anti-HIV-1 activity are being tested in both treatment of chronic infection, and in pre-exposure prophylaxis for persons at risk of infection.  The combination of long-acting intramuscular cabotegravir and rilpivirine is likely to be the first such regimen to gain regulatory approval. These approaches appear to be especially attractive for patients complaining of pill fatigue, including adolescents, and for those experiencing HIV-associated stigma. Long-acting broadly-neutralizing anti-HIV monoclonal antibodies (bnAb’s) are in clinical trials, but carry possible drawbacks of substantial primary resistance and the promotion of secondary resistance if used as monotherapy. Newer bnAb’s with broader coverage, and combinations of bnAb’s, may solve a number of these problems. Additional formulations in development include inert and bioerodable implants, and transcutaneous drug delivery using microneedle patches. As these formulations are shown to be safe, well-tolerated, and economical, they are likely to gain broader appeal.

Charles W. Flexner, M.D., is Professor of Medicine in the Divisions of Clinical Pharmacology and Infectious Diseases, and Professor of Pharmacology and Molecular Sciences at the Johns Hopkins University School of Medicine.  He is also Professor of International Health at the Johns Hopkins University Bloomberg School of Public Health.  Dr. Flexner is an expert on the basic and clinical pharmacology of drugs for HIV/AIDS and related infections, including viral hepatitis and tuberculosis. His research teams developed a number of ways to reduce drug doses and toxicity while maintaining desired activity. He led clinical development teams for seven new drugs for HIV.  He has published extensively on antiviral and antibiotic drug transport and metabolism, and metabolic drug interactions. He has published nearly 250 peer-reviewed scientific manuscripts, reviews, and book chapters, and has authored two medical textbooks. His current research includes the discovery and development of new molecules and formulations for long-acting parenteral administration for treatment and prevention of HIV infection. He directs the Long Acting/Extended Release Antiretroviral Research Resource Program (LEAP; www.longactinghiv.org), which provides advice and support to an international audience that includes the World Health Organization (WHO) and Unitaid. He is Co-Director of the Johns Hopkins University Baltimore-Washington-India HIV Clinical Trials Unit (BWI CTU). Dr. Flexner is the Chief Scientific Officer of the Institute for Clinical and Translational Research at Johns Hopkins.  He also serves as Associate Vice-Chair for Academic Fellowship Programs in the Department of Medicine, and Associate Director of the Graduate Training Programs in Clinical Investigation of the Johns Hopkins University School of Medicine and Bloomberg School of Public Health.  He chairs the antiretroviral therapy committee of the AIDS Clinical Trials Group, an international consortium funded by NIH. Dr. Flexner served as President of the American Federation for Medical Research (AFMR) from 1999-2000, and was President of the AFMR Foundation from 2001-2002.  He is a member of the editorial board of 12 scientific journals, and served as a consultant for three dozen pharmaceutical and biotechnology companies. He is a Consultant for the Bill and Melinda Gates Foundation and the Clinton Health Access Initiative, and served as a Consultant on FDA Reform for the United States House of Representatives. He currently serves on the WHO Clinical Guidelines Development Group for Treatment and Prevention of HIV in Adults, Adolescents, and Children.

Diane J. Burgess

University of Connecticut

Development of IVIVCs for Complex Parenteral Products

This seminar will cover in vitro and in vivo release testing of complex parenterals (such as microspheres) and the development on IVIVCs for these drug products. Accelerated testing and the use of USP apparatus will be detailed. Case studies on qualitatively and quantitatively equivalent microsphere drug products will be detailed, including Naltrexone, Risperidone, Vivitrol and Lupron Depot. Level A IVIVCs will be presented for all these products.

Diane J. Burgess, Ph.D. Distinguished Professor, Pfizer Distinguished Chair in Pharmaceutical Technology, University of Connecticut.

B.Sc. Pharmacy, University of Strathclyde (1979) and Ph.D. Pharmaceutics, University of London (1984). Fellow of AAPS, CRS, APSTJ, and AIMBE. 2010 CRS President; 2002 AAPS President. Editor of International Journal of Pharmaceutics (2009 – 2018). Editorial board member of 13 international journals. Recipient of: 2018 AAPS Wurster Award in Pharmaceutics; 2014 AAPS Research Achievement Award; 2014 AAPS Outstanding Educator Award; 2014 CRS Distinguished Service Award; 2013 AAPS IPEC. Ralph Shangraw Award; 2010 CRSI Fellowship, 2011 APSTJ Nagai International Woman Scientist Award. Over 225 refereed publications, over 615 research presentations, over 310 invited presentations, 23 keynote and plenary addresses.

Hongwen Rivers

Allergan

To develop long-acting complex dosage forms of biologics for the eye: opportunities and challenges

Long-acting proteins and peptides have long been sought after to shift the treatment paradigm of chronic disease conditions.  By extending treatment intervals, long-acting dosages forms can help address patient adherence issue, align the treatment schedule with real world practice and medical capacities, and ultimately improve the overall therapeutic outcome for the patients.  Due to the restricted physical access and complex anatomical structure, the eye has been particularly recognized to present unmet clinical needs for local and long-acting protein products to treat chronic eye conditions such as wet AMD and DME.  In spite of the huge medical needs and extensive efforts in the past years, a successful long-acting protein drug still remains elusive on the market, highlighting both scientific and development challenges.  Recent progress, however, is promising to break the ground.  This presentation will review a variety of dosage forms for long-acting proteins for the eye, and discuss the current status, technical challenges as well as emerging opportunities with these products in development.

Hongwen M Rivers, PhD, is Director, Protein Delivery, at Allergan, Plc.  During the fourteen year tenure with Allergan, Dr. Rivers has specialized in developing protein delivery products for therapeutic areas including eye care. Her current roles at Allergan include leading the research and development of innovative protein delivery platforms, driving the translation of platform technologies to create products that fullfill unmet medical needs, and advancing protein delivery projects through development stages as a global team lead or CMC lead.  Before joining Allergan, Dr. Rivers was Group Leader in Protein and Antibody Therapeutics at Immusol, Inc., responsible for early stage production, characterization and validation of protein and antibody therapeutics in cancer and ophthalmology.  Prior to Immusol, Dr. Rivers completed her postdoctoral trainings in biomedical areas.  Dr. Rivers earned her Ph. D. in Biochemistry from Ohio State University.  Dr. Rivers previously served as Chair for Ocular Drug Delivery and Disposition Focus Group of AAPS, and authored more than 45 research or review papers/conference presentations/book chapters/patents.

Jonathan K. Pokorski

University of California San Diego, Department of NanoEngineering

Melt Processing of Functional Protein/Polymer Blends

Biopharmaceuticals are the main growth area in pharmaceutical research and development and, most often, proteins are the active pharmaceutical ingredient. Recombinant protein production can be inexpensively scaled to multi-kilogram scales with the rapidly improving molecular biotechnology field. One technological hurdle, however, is the formulation of functional proteins into therapeutic reservoirs, also known as depots. Solvent based processes lose significant portions of the therapeutic protein (up to 70%) and proteins may lose potency due to processing conditions. This talk will describe melt-processing of several protein candidates and the effect on macromolecular structure and enzymatic activity of the processed proteins. Melt processing is exceptional scalable, with commercial extruders reaching throughputs of 1000 kg h^-1 and 100% of the active protein is encapsulated. Melt processing is thought to be possible because of the reduced hydration state in the melt, thus eliminating the driving force to form amorphous protein aggregates. The primary focus of this seminar will be a discussion of virus like nanoparticles (VLPs) derived from bacteriophage Qβ. Qβ is a combinatorial vaccine platform that has seen success in vaccine development for influenza, HIV, and hypertension. Melt processing conditions, physical models of processing, and vaccination data will be described in which Qβ is processed into slow-release depot delivery formulations.

Professor Pokorski began his career by earning his B.S. in biochemistry from UCLA, while working in private industry designing biomedical devices. Dr. Pokorski received his PhD in chemistry from Northwestern University, where he designed peptidomimetics for use in medical diagnostics and therapeutics. Dr. Pokorski then moved to The Scripps Research Institute as a post-doctoral fellow, where he engineered viral nanoparticles as drug-delivery systems. Pokorski’s laboratory at UCSD works to bridge chemical synthesis, molecular biology, and materials science to make new materials for biomedical applications. The Pokorski lab is particularly interested in marrying protein and polymer science to generate materials for drug delivery and immunotherapy. Pokorski’s research is funded through grants from the NIH, NSF, and ACS. He has been awarded several prestigious awards, including an ACS PRF New Investigator Award and an NIH Pathway to Independence Award. In 2016, he was elected a Kavli Fellow.

Joyce Hotz

AstraZeneca

Scale Up of Bydureon

Gila monster venom inspired the development of incretin mimetics, an important class of drugs that act like incretin hormones such as glucagon-like peptide-1 (GLP-1). These agents bind to GLP-1 receptors and stimulate glucose dependent insulin release in response to food intake. Synthetic GLP-1 analogues are now frequently used as part of an overall treatment regime for patients with Type II diabetes.

Exenatide, commercially available as Byetta BID since 2007, was the first synthetic GLP-1 used to treat diabetes and the first once-weekly PLG formulation, Bydureon, globally available since 2011.  The Bydureon product ensures patient tolerability of this highly potent drug while providing long-acting steady state drug release.

Alkermes developed the Bydureon microsphere formulation and process but the highly robust and scalable manufacturing process was developed in conjunction with industry partners for commercialization. This presentation discusses the development and process optimization challenges and decisions made throughout the Bydureon lifecycle.

Joyce Hotz has been engaged in the development, scale-up, and commercialization of parenteral sustained release products throughout her career.  Joyce initially worked as a formulator to develop GLIADEL WAFERS in partnership with Guilford Pharmaceuticals.  As an Alkermes employee, Joyce managed both formulation and process development of microsphere products, RISPERDAL CONSTA for Janssen Pharmaceuticals, as well as for Alkermes’ proprietary product, VIVITROL.  Joyce later led the BYDUREON microspheres development, which, in addition to formulation development, included several scale-ups, and the commercial transfer to manufacturing partner, Amylin. Joyce later assumed responsibility for Amylin technical operations in support of manufacturing all Bydureon products and presentations.  In her current role at AstraZeneca, Joyce is engaged in new modalities and the development of several novel drug delivery technologies and products.

Jukka Rantanen

University of Copenhagen, Denmark

Towards Commercial Scale Production of Quality by Design (QbD) based Nanomedicine

The huge investments on nanomedicine have not yet translated into a high number of commercial pharmaceutical products. There is one obvious limitation for the implementation of novel life-saving treatment strategies; scalable manufacturing solutions as well as robust and flexible processing chains do not exist for all enabling formulations and innovative patient oriented products. Production of pharmaceutical systems with well-defined nano-scale structures requires new thinking also in the process environment and acknowledgement of pharmaceutical manufacturing sciences.

The recent development of continuous manufacturing platforms has matured and commercial examples have been introduced mainly within primary manufacturing (synthesis) of small-molecule drugs. Similarly, increasingly robust secondary manufacturing solutions have been introduced, and the first products based on continuous manufacturing are reaching the market. This development is pointing towards the use of continuous production platforms, such as microfluidics based systems, for commercial scale manufacturing of nanomedicine.

The improvement of computational capacity and the innovative use of computational methods have enabled amazing development; in silico simulation of bulk scale particulate systems close to real-scale is a ground-breaking achievement from computational scientists. Same particulate systems should also be considered as molecular entities and the behavior can be analyzed in silico at the molecular level using molecular dynamics based methods. Bridging materials science to biology with a support of computational methods forms a basis for the development of manufacturing solutions for Quality by Design (QbD) based enabling formulations.

Jukka Rantanen is professor of pharmaceutical technology and engineering at the Department of Pharmacy (University of Copenhagen). He received his Ph.D. from the University of Helsinki in 2001, completed postdoctoral visit at the Department of Industrial and Physical Pharmacy (Purdue University, USA) in 2003, and joined the faculty at the University of Copenhagen in 2006 as a full professor. Jukka Rantanen was appointed 2017 as a guest professor at Shenyang Pharmaceutical University, China.

Jukka Rantanen has 250+ publications in scientific peer-reviewed journals (Web of Science h-index 40 with 5000+ citations) and he is an editorial board member of four leading scientific journals within pharmaceutical sciences and chemical engineering. He is a recipient of the APV (International Association of Pharmaceutical Technology) “Research Award for Outstanding Achievements in the Pharmaceutical Sciences” in 2016.

Jukka is a member of the Process Analytical Technology Working Party of the European Pharmacopoeia Commission. He is currently a chairman of the Steering Committee of the EUFEPS QbD and PAT Sciences Network (EUFEPS, European Federation for Pharmaceutical Sciences). Jukka has been a board member of Danish Council for Independent Research (DFF) within Technology and Production Sciences.

Karsten Mäder

Martin Luther University Halle-Wittenberg

Noninvasive In Vitro and In Vivo Characterization of Biodegradable Parenteral Depot Formulations.

The characterization of key parameters of drug release is prerequisite for the rational development of optimized controlled drug delivery systems (CR-DDS). Key parameters include size and shape, microviscosity, micropolarity and micro-pH. Preferentially, applied methods should be noninvasive and applicable both in vitro and in vivo. Computer tomography (CT) is a powerful method. Data will be shown for high resolution phase contrast based in vitro nano-CT measurements of microparticles and electrospun nonwovens. CT measurements have also been used to localize biodegradable cochlear implants in vitro. MRI is a capable to monitor the implant shape, size and physiological responses (e.g. encapsulation). The MRI signal intensity is dependent on the proton density, the mobility and the applied imaging sequence. MRI gives useful insights into the kinetics of water penetration and polymer erosion for preformed implants or the precipitation velocity of in situ forming implants in vivo. Unique information can be obtained by the use of spin probes as drug models and low frequency Electron Spin Resonance (ESR, EPR).  ESR permits the measurements of the molecular mobility and polarity. It is possible to follow solvent exchange and polymer precipitation of in situ forming implants in vivo. In addition, ESR is also capable to measure the microacidity inside PLGA implants. A very low pH-value of 2 has been found. Acidic pH-values and pH-gradients have been also found for in situ forming implants by Optical Imaging. In summary, MRI, CT, ESR and Optical Imaging are useful methods to understand and optimize CR-DDS.

Karsten Mäder, Professor of Pharmaceutics and Director of the Institute of Pharmacy, Martin Luther University Halle-Wittenberg

Diploma, PhD and Habilitation in Pharmacy at Humboldt-University Berlin. Postdoc stays at Dartmouth Medical School (NH, USA),  Philipps-University Marburg and Free University Berlin. Group leader at Roche (Basle). Since 2003 Full Professor of Pharmaceutics at Martin Luther University Halle-Wittenberg. 200+ publications, several book chapters and patents. APV Research Award for Outstanding Achievements in Pharmaceutical Sciences. Member editorial board JCR, EJPB, Int. J. Pharm. Main research areas: polymer and lipid based DDS, parenteral controlled release systems and noninvasive spectroscopy and imaging techniques

Mark Prausnitz

Georgia Institute of Technology

Rapidly Separable Microneedle Patch for the Sustained Release of a Contraceptive

Long-acting contraceptive methods enable effective family planning, but generally require administration by a healthcare professional. To increase access, we developed a microneedle patch-based reversible contraceptive that is simple to administer, slowly releases contraceptive hormone for >1 month and generates no biohazardous sharps waste. The microneedles are made of biodegradable poly(lactic-co-glycolic acid), and rapidly separate from the patch backing by incorporating effervescent material or placing a bubble at the base of each microneedle. In rats, the microneedle patch was well tolerated and maintained hormone plasma concentrations above the human therapeutic level for >1 month. Studies in human subjects showed that a placebo microneedle patch was well tolerated. Acceptability studies in women of reproductive age demonstrated interest in and preference for long-acting contraception using a microneedle patch compared to existing contraceptive options. Further development of the rapidly separable microneedle patch for self-administered, long-acting contraception could enable women to better control their fertility.

Mark Prausnitz is Regents’ Professor and J. Erskine Love, Jr. Chair of Chemical & Biomolecular Engineering at the Georgia Institute of Technology. He earned a BS degree from Stanford University and PhD degree from MIT, both in chemical engineering. Dr. Prausnitz and colleagues carry out research on biophysical methods of drug delivery using microneedles, lasers, ionic liquids and other microdevices for transdermal, ocular and intracellular delivery of drugs and vaccines. Dr. Prausnitz teaches an introductory course on engineering calculations, as well as two advanced courses on pharmaceuticals. He has published almost 280 journal articles and has co-founded five start-up companies including Micron Biomedical and Clearside Biomedical.

Raj Patel

Titan Pharmaceuticals, Inc.

Probuphine Product Development 

Probuphine® is an implantable, long‐term delivery formulation of buprenorphine that delivers medication continuously maintaining stable blood levels of buprenorphine, starting at approximately 4 weeks after implant and lasting for a period of 6 months. PROBUPHINE is indicated for the maintenance treatment of opioid dependence in patients who have achieved and sustained prolonged clinical stability on low‐to‐ moderate doses of a transmucosal buprenorphine‐ containing product (i.e., doses of no more than 8 mg per day). Unlike some other implant formulations, Probuphine does not utilize a reservoir system. Probuphine is based on Proneura® technology, a novel and proprietary implant technology That was developed to achieve continuous long‐term (3+ months) drug delivery. Probuphine consists of buprenorphine blended with a non‐biodegradable ethylene‐vinyl acetate (“EVA”) co‐polymer and extruded to formulate a solid‐matrix implant. EVA is an inert, biocompatible polymer used in many approved implantable pharmaceutical and dental products. The drug/EVA solid‐state matrix manufacturing process and commercial scale production capability have been validated with the commercial launch of Probuphine. The implants are inserted sub‐dermally, in the inner upper arm, in a simple office‐based procedure under local anesthesia, and removed in a similar manner at the end of the treatment period. The drug is delivered from the implant through the process of dissolution‐ controlled diffusion resulting in passive tissue absorption of the target drug and a stable blood level over time. This technology can potentially be applicable to various drugs with varying solubility, hydrophobicity, and molecular weight. Beyond Probuphine, the company has a number of other products using the same technology that are currently in non‐clinical development, including nalmefene implants for preventing relapse following detoxification in opioid use disorder funded by an NIH grant, treatment of chronic pain with a peptide and malaria prophylaxis treatment, all funded and supported by other institutions.

Dr. Patel has extensive hands-on and management experience in the design and development of various dosage forms for the pharmaceutical and biopharmaceutical industries spanning over 30-plus years. With his combined comprehensive knowledge of formulation design and development and unique industrial pharmacy and pharmacokinetics background, he has successfully developed and helped to launch several products including solid dosage forms, such as tablets and capsules, liquid injectable and oral dosage forms, as well as novel delivery systems such as controlled and implantable drug delivery systems.
Dr. Patel has an outstanding reputation for problem solving and multi-tasking, and a proven track record for product development and commercialization having steered several drug candidates from early stages of development through to commercialization. He is a reputed scientist with multiple publications and he was invited to speak at many national and international symposia. He has been awarded various grants from the NIH and the DoD, and has also been granted several patents.
Dr. Patel was part of a core team involved in product development using the ProNeura® implantable technology and he set up the commercial manufacturing and preparation of the respective CMC sections for US, Canada and European regulatory filings of a novel 6-month implantable product, Probuphine®, for the treatment of opioid addiction. Currently, he oversees the development of other drug candidates using the ProNeura technology, and also the commercial manufacturing and supply chain for Probuphine marketed in the US, Canada and Europe.

Sheng Qi

University of East Anglia

3D printing of personalised long-acting pharmaceutical implants: Conceptual analysis and printing design

One of the unique advantages of three-​dimensional (3D) printing, as a form of additive manufacturing, is the ability to produce small batch, individualised products. It has been widely used for this purpose as a prototyping method in many industrial sectors. For the pharmaceutical and medical fields, this individualisation capability allows 3D printing to be used as a direct manufacturing method to produce personalised pharmaceutical and medical products to suit each individual patient’s treatment requirements. Computer-​aided design and computer-​assisted manufacturing with 3D printing offers a high degree of flexibility in structural design and allows the printing of complex 3D objects that can carry drugs or diagnostic agents. This concept has been widely explored by pharmaceutical scientists for personalised pharmaceutical oral dosage forms but is yet to be developed for personalised implantable applications. This presentation will analyse the concept of using 3D printing for personalised implants including of therapeutic advantages/disadvantages and challenges in technological and regulatory aspects. It will be followed by the discussion of fundamental rules of design and optimisation for extrusion based 3D printing. Proof-of-concept data will be presented which build a foundation for guiding the design of drug-eluting implants. Finally, potential solutions that could address the technological challenges in 3D printing of long-acting implants will be discussed.

Dr. Sheng Qi is a Reader at the School of Pharmacy, University of East Anglia. She has a keen interest in developing innovation in the pharmaceutical manufacturing process and controlled drug delivery technology development. She has to date over 60 peer-reviewed publications and 5 book chapters in this field. Her recent work on Fused Deposition Modelling 3D Printing (FDM 3DP) of solid dispersions based oral controlled delivery of poorly soluble drugs demonstrated the potential as well as identified the technological challenges of adapting FDM 3DP for manufacturing oral solid dosage forms. She has been working academic collaborators in engineering, manufacturing design, and computational simulation alongside industrial end users and partners to build upon process optimisation and design principles of FDM 3DP which is crucial for the healthcare industry in moving forward and adopting 3DP for future personalised medicine development and manufacturing.

Tassos Nicolaou

Delpor, Inc.

Prozor™ Technology and the Potential for Once-Yearly Therapies

Delpor’s Prozor technology enables the sustained release of certain insoluble drugs (including several CNS agents) from a non-mechanical (passive) implantable drug delivery device based on a unique formulation. A typical formulation is a mixture of the drug and a group of excipients designed to regulate the pH inside the device and promote drug release. Preclinical and Clinical studies have shown pseudo zero-order release kinetics with the potential to create once-yearly therapies for chronic conditions.  Benefits include complete medication adherence for as long as one year after a single administration, full reversibility in case treatment interruption is required, and a smooth PK profile ensuring therapeutic plasma levels while avoiding unnecessary drug exposure.

Tassos has 25 years of business experience working with life sciences companies as an executive, strategy consultant, and entrepreneur.

Prior to founding Delpor, he served as the CEO at AlphaDetail, a rapidly growing online marketing company focused on the pharmaceutical industry. While at AlphaDetail he grew the company from an idea to an established company with over 60,000 physician members, and a long list of blue chip life sciences clients.  AlphaDetail was acquired by the Symphony Technology Group (a Private Equity firm) and is currently part of IQVIA.

Tassos spent the first half of his career as a strategy consultant at Strategic Decision Group, where assisted Fortune 100 companies in strategy development and selection.

He holds a Master’s in Management Science & Engineering from Stanford University, and a BA in Physics from Franklin and Marshall College.

Tejal Desai

University of California, San Francisco

Nanostructured Materials for Long Acting Biologic Delivery

The field of nanomedicine offers great potential to revolutionize clinical care, including medical devices, regenerative medicine, and molecular imaging approaches. Recent advancements in nanofabrication applied to biocompatible materials lay the groundwork for creating biomaterials with a high level of control at the molecular scale.    In this talk, I will present an overview of our recent work in developing implantable nanoporous devices for protein based ocular drug delivery as well as injectable nanostructured materials for the modulation of fibrosis and immune activation.  Specifically, I will how polymeric biomaterials can be impacted with nanoscale structure in order to control properties such as drug kinetics and particle assembly.  Long aspect ratio nanostructues conjugated with antibodies can be designed to capture and potentiate endogenous cytokines demonstrating both tissue- and cell- specific immune activation. By gaining a better understanding of how small scale topographies can influence the biological microenvironment, we can design platforms for applications in therapeutic delivery.

Tejal Desai is the Ernest L Prien Endowed Professor and Chair of the Department of Bioengineering & Therapeutic Sciences, Schools of Pharmacy and Medicine at University of California, San Francisco (UCSF); also, the Deborah Cowan Endowed Professor at UCSF, Professor in Residence – UC Berkeley Department of Bioengineering, Executive Committee Member of the Kavli Institute for Fundamental Neuroscience, director of the NIH training grant for the Joint Graduate Program in Bioengineering at the University of California, Berkeley (UCB) and UCSF, and founding director of the UCSF/UC Berkeley Masters Program in Translational Medicine.  She is Director of the UCSF Engineering and Applied Sciences Initiative known as HIVE (Health Innovation Via Engineering).

Desai’s research spans multiple disciplines including materials engineering, cell biology, tissue engineering, and pharmacological delivery systems to address issues concerning disease and clinical translation. She has published over 200 peer-reviewed articles. Her research is at the cutting-edge in precision medicine, enabled by advancements in micro and nanotechnology, engineering, and cell biology directed to clinical challenges in disease treatment. She seeks to design new platforms to overcome existing challenges in therapeutic delivery.

Her research efforts have earned recognition including Technology Review’s “Top 100 Young Innovators,” Popular Science’s Brilliant 10, and NSF’s New Century Scholar. She is Chair of the American Institute for Medical and Biological Engineering College of Fellows.  In 2015, she was elected to the National Academy of Medicine.  Desai is also a 2019 Fellow of the International Academy of Medical and Biological Engineering (IAMBE)

Desai is a vocal advocate for STEM education and outreach to underrepresented minority students. She received her B.S. from Brown University in biomedical engineering and was awarded a Ph.D. in bioengineering jointly from UCSF and UCB.

Tom Tice

Evonik Health Care

The APIs of LAIIs

The traditional method of assessing long-acting injectables and implantables (LAIIs) has been to compare and contrast applicable, commercially-proven drug delivery technologies. Through this approach, it is possible to assess drug product performance, and the ability to scale up these technologies for commercial manufacturing. Another method is to assess the compositional makeup of LAIIs. With this approach, processing materials and formulation components including functional excipients can be assessed to determine how their biocompatibility, bioabsorption and safety characteristics can be best utilized for parenteral use. In addition to these methods, this presentation will review how APIs can be assessed in relation to LAIIs. Information on APIs in marketed LAIIs will be summarized and analyzed. Suitable API physical / chemical properties for LAIIs; as well as API classes, key indications, concentrations, formulation properties, stability factors and process conditions will be highlighted.  Candidate APIs now trending in LAII product development will also be explored, together with best practices in the “design of drugs for delivery”.

Dr. Tice is internationally recognized for his research and product development of complex parenteral, drug delivery dosage forms based on bioabsorbable polymer excipients. He is known for his accomplishments involving injectable, extended-release microparticles made with bioabsorbable lactide/glycolide polymers designed for systemic and local drug delivery.

He led the team and is one of the inventors that developed the first commercial, injectable, extended-release microparticle product. This product is a one-month LHRH formulation indicated for the treatment of prostate cancer (Decapeptyl^® SR), a product that is still on the market today.

At Evonik, Dr. Tice, provides scientific support to Evonik’s innovation, sales, product development, research, intellectual property and M&A teams.

Dr. Tice earned his BSc in Chemistry and PhD in Biophysics from Syracuse University, New York. He held a postdoctoral fellow position at the University of Alabama at Birmingham (UAB) in Microbiology. He holds 48 US patents with many foreign equivalents and has more than 180 publications, presentations and invited lectures to his credit. He flew experiments on two Space Shuttle flights. He currently serves on the Board of McWhorter School of Pharmacy at Samford University and serves on the United States Pharmacopeia General Chapters-Dosage Forms Expert Committee and United States Pharmacopeia, Nomenclature and Labeling Expert Committee.

Wim Hennink

Utrecht University

Diels-Alder in Situ Forming Hydrogel for Sustained Intraocular Release of Bevacizumab

Delivery of therapeutic proteins to the posterior segment of the eye faces significant challenges because of frequent intraocular injections, related adverse effects and high treatment costs. Therefore  we developed an in situ forming hydrogel, that can be easily injected in the vitreous cavity using a small needle. After injection, the polymeric solution undergoes a phase transition to form a cross-linked hydrogel at the site of administration, entrapping bioactives, which will be released over a prolonged period. In this study, hyaluronic acid-modified with furan moieties (HAFU) was successfully crosslinked with four arm-PEG10K-maleimide (4APM) yielding stable hydrogels. The potential use of this system for ocular applications was shown by testing the injectability, sustained release of a therapeutic protein and cytocompatibility to retinal cells.

HAFU-4APM hydrogels were prepared by mixing aqueous solutions of HAFU and 4APM at physiological conditions to obtain transparent hydrogels. Rheological analysis showed rapid hydrogel network formation at 37^oC. The gelation time and final hydrogel stiffness are strongly dependent on polymer concentration. Hydrogel solutions could be injected to the vitreous body of a porcine eye through a 29G needle. Swelling and degradation analysis showed that the hydrogel system is degradable at physiological conditions. The hydrogels showed no toxicity to retinal cells at the used concentrations. HAFU-4APM hydrogels could sustain the delivery of bevacizumab for 70 days.

This formulation has potential for the treatment of age-related macular degeneration and diabetic retinopathy.

ACKNOWLEDGEMENTS: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 722717.

Wim Hennink obtained his Ph.D. degree in 1985 at the Twente University of Technology on a thesis with a biomaterials research topic. From 1985 until 1992 he had different positions in the industry. In 1992 he was appointed as professor at the Faculty of Pharmacy of the University of Utrecht. From 1996 on he is head of the Pharmaceutics division. At present he is the head of the Department of Pharmaceutical Sciences, Utrecht University. His main research interests are in the field of polymeric drug delivery systems. He published over 580 papers and book chapters and is the inventor of 20 patents.

Wim Jiskoot

Leiden University

Long-Acting Injectables & Implantables: Immunogenicity Concerns

When developing drug delivery systems, such as long-acting injectables and implantables, the main focus obviously is on optimizing the drug release properties in relation to achieving an optimum PK/PD profile. However, most of these systems have inherent properties that my lead to unwanted immune responses that potentially compromise PK and PD, and consequently safety and efficacy. In this presentation I will discuss factors affecting the immunological risk of drug delivery systems, based on insights obtained within (i) the vaccine delivery field, where the aim is to improve the immunogenicity of vaccines by optimizing the formulation, and (ii) the therapeutic protein formulation field, where simple solutions of recombinant proteins have turned out to be highly immunogenic in a significant number of patients.

Wim Jiskoot is professor at the Division of BioTherapeutics at Leiden University (since 2006), the Netherlands, and scientific advisor at Coriolis Pharma, Martinsried, Germany (since 2013). His main research areas are vaccine delivery, protein formulation, and structural aspects of unwanted immunogenicity of therapeutic proteins. Previous positions: staff member at the Department of Pharmaceutics at Utrecht University, the Netherlands (1998-2006); head of the Department of Bacterial Vaccine Development at the National Institute of Public Health and the Environment (RIVM), Bilthoven, the Netherlands (1994-1998); postdoctoral fellow at the University of Utah, USA (1991-1993). He obtained his PhD degree (1991; pharmaceutical aspects of monoclonal antibodies) and his pharmacy degree (1987) at Utrecht University. He (co)edited 3 books about protein characterization and (co)authored more than 300 scientific papers and book chapters.

Viera Lukacova

Simulations Plus, Inc.

What does it take to develop a PBPK model that mimics in vivo behavior of LAIs – Part II.

The motivation for developing LAI microsphere formulations is to provide a means to release drug over a long period of time (weeks to months) to improve patient comfort and compliance while maintaining therapeutic efficacy and avoiding adverse effects due to fluctuations in drug concentrations.  Unfortunately, developing LAI formulations is complicated by the lack of standardized in vitro dissolution/release experiments, the long release times involved, and the large variabilities observed with in vivo dosing tissue environments among patient populations.

Thus, more predictive preclinical methods are needed to assess the sensitivities of critical quality attributes and their impact on the performance of LAI products. These include not only in vitro dissolution/release experiments but also mechanistic models to simulate such in vitro experiments and physiologically based pharmacokinetic (PBPK) models that facilitate translation of in vitro data into in vivo performance of these formulations.

Last year we presented models for in vitro and in vivo simulations of polymeric (PLGA) LAI microspheres. The focus of this follow up presentation will be on the PBPK modeling of LAI products relying on the low solubility of the drug, rather than polymer, to limit the dissolution rate in vivo. The possible influences of drug- and formulation-dependent parameters (solubility, particle size, diffusion rate) and physiological response (inflammation, immune response) will be discussed and demonstrated through simulations of low-solubility injectable drugs.

Dr. Lukacova is Director of Simulation Sciences at Simulations Plus, Inc. Over the last decade she has been contributing to the research in the area of mechanistic absorption and PBPK modeling and the development of GastroPlus®, DDDPlus™, and MembranePlus™ software packages widely used throughout the pharmaceutical industry in early drug development, formulation, pre-clinical, and clinical research.

She also contributes to modeling studies helping companies with their drug development programs in the early discovery stage, formulation development, clinical pharmacology applications and interactions with regulatory agencies. She authored a number of papers in computational chemistry, basic research of transport of small molecules through artificial membranes, and pharmacokinetic and pharmacodynamic modeling in peer-reviewed journals and served as a reviewer of publications in the same areas.

Ved Srivastava

Intarcia Therapeutics Inc,

Patient-Centric Peptide Drug Design and Sustain Delivery for Metabolic Disease

Peptide therapeutics have continued to be an innovative strategy for the development of biopharmaceutical pipelines both in biotech and pharmaceutical industries. Recently, the number of peptide drugs entering into the market have increased significantly despite inherent challenges of peptide instability, patient-friendly delivery and regulatory constrain. This presentation will cover (a) addressing challenges in peptide optimization for sustained delivery using Medici Drug Delivery System^TM , using an example of a highly selective novel glucagon agonist for T2 Diabetes/Obesity and (b) placing a control strategies for peptide manufacturing from regulatory perspective for clinical development.

Dr. Ved Srivastava is Vice President of Chemistry at Intarcia Therapeutics and President of the American Peptide Society. Prior to that, he was the Head of Peptide Chemistry at GlaxoSmithKline (USA), and in the senior leadership role at Amylin Pharmaceuticals. He co-founded, Phoundry Pharmaceuticals, a biotech company focused on the discovery of peptide hormone therapeutics. Phoundry was acquired by Intarcia Therapeutics in 2015. Ved has over 25 years of experience with expertise in drug discovery and development in metabolic diseases, CNS, and inflammation with major emphasis in peptide medicinal chemistry, peptide drug delivery and chemistry manufacturing and control (CMC).  He is the Editor of four recent books on peptide: (1) Peptide Therapeutics CMC – Strategy for Chemistry Manufacturing and Control (2019) (1) Peptide-based Drug Discovery: Challenges and New Therapeutics (2018), (2) Comprehensive Medicinal Chemistry III – Biologics Medicine -Vol 6 (2017) (4) ‘Peptide 2015’ (2016). Ved is also the Editor-in-Chief for Drug Development Series books with Royal Society of Chemistry. Ved is an appointed members and vice chair of the Peptides and Insulins Expert Committee – Bio1 of the United State Pharmacopeia. Ved earned a Ph.D. in organic chemistry from the University of Lucknow, India.

Steven P. Schwendeman

University of Michigan

A Cage Implant to Study Drug Release from Microspheres In Vivo

Despite the use of poly(lactic-co-glycolic acid) (PLGA) microspheres in long-acting release (LAR) depots for more than 3 decades we still do not understand key aspects of these commercial products.  One important example is why drug release kinetics is different when evaluated in vitro and in vivo.  Such differences can impede successful development of LARs as well as their ultimate safety and efficacy.  In order to evaluate this question, it is important to perform experiments directly on the microspheres to determine relationships between key kinetics of rate-determining phenomena (e.g., mass loss and water uptake) and drug release.  However, recovery of microspheres in vivo is problematic, therefore a cage composed of silicone rubber and surgical grade stainless still mesh (opening 37 mm) was used to encapsulate the microspheres before subcutaneous implantation in the flanks of rats.  After validating the cage model by comparing pharmacokinetics after administration of drug-releasing microspheres with and without the cage, the cage was employed to assess drug release and mechanism from steroids and small peptides.  Key findings will be discussed including: (a) a typically higher polymer water uptake found in vivo than in vitro and (b) a change in the release mechanism between various in vitro conditions relative to that found in vivo.  The results have obvious implications on in vitro-in vivo correlations and may help better understand in vivo performance of PLGA microspheres.

Steven P. Schwendeman is the Ara G. Paul Professor and Chair of Pharmaceutical Sciences and Professor of Biomedical Engineering at the University of Michigan Biointerfaces Institute.  He is also Associate Editor of the Journal of Controlled Release since 2007.  He received his B.S.E. in Chemical Engineering in 1986 and his Ph.D. in Pharmaceutics in 1992 also from the U. of M.  He was an NIH postdoctoral fellow at M.I.T. until 1995.  His first academic appointment was in the College of Pharmacy at the Ohio State University before he returned to U. of M. in 2000.  He received the CRS Young Investigator Award in 2002 and a CRS Best paper award in 2010.  He is a Fellow of CRS, AAPS, and the National Academy of Inventors.  He has co-authored > 110 publications, trained > 20 PhD and 12 postdoctoral students, delivered > 110 invited lectures, consulted for > 25 companies, published > 130 abstracts and has 9 issued and several pending patents.  His principal contribution to science involves the theory and application of microencapsulation, stabilization, and controlled release of bioactive agents of all sizes with/in poly(lactic-co-glycolic acid) delivery systems.  More recently his lab has investigated buccal, nasal, and pulmonary delivery of hydrophobic drugs, vaccine antigens and nitric oxide.  He is currently funded by NIH, US FDA, large corporations and private foundations.

Frederic Dargelas

DelSiTech

Parenteral delivery of therapeutic proteins using biodegradable silica.

DelSiTech Silica Matrix is an advanced delivery technology for parenteral and local administration of injectable depot, implant and eye drop dosage forms. The proprietary technology is based on Silica (silicon dioxide, SiO2 ) Matrix into which the active ingredient is embedded. The matrix can be designed to biodegrade at the required rate to assure a tightly controlled release of the active substance over extended periods of time, providing a unique therapeutic effect in situ and causing low systemic and local adverse events compared to alternative delivery systems.

The dissolution of the matrix takes place mainly through an erosion mechanism. The biodegradation process does not change the pH within silica gel nor in the surrounding tissue in contrast to most commonly used alternative drug delivery matrices. The Silica Matrix is inert and can stabilize the APIs, from small molecules to large proteins.

In this presentation we will review the case of parenteral delivery of therapeutic proteins using biodegradable silica, and how non-porous silica matrix can provide long-acting protein delivery and  protein stabilization for monoclonal antibodies as a case study.

Dr. Frederic Dargelas, PhD, MBA Director, Head of Business Development and Alliance Management, at DelSiTech, with an almost 20-year career in the international biopharmaceutical industry, has extensive R&D and business development experience as a former Business Manager and Development Manager for Orion Pharma. Dr. Dargelas has also held a variety of management positions in prominent pharmaceutical companies such as GSK, accruing expertise in drug delivery technologies, product development, industrialization and manufacturing of small molecule drugs, biologics and vaccines as well as strategic collaborations in the pharma/biotech industry.

Omid Veiseh

Rice University

Immune Modulatory Biomaterials for Cell-Based Therapeutics

Immune cell recognition of implanted biomedical devices initiate a cascade of inflammatory events that result in collagenous encapsulation of implanted materials which leads to device failure. These adverse outcomes emphasize the critical need for biomaterials that do not elicit foreign body responses. One prime example for the use of this technology towards the development of immunoisolation strategies to engineer implantable cell-based biologic delivering factories. These systems termed “living therapeutics” is comprised of polymer encapsulated engineered cells that produce and secrete of biologic (cytokine, hormones, and antibodies) of interest with sense and respond capabilities to match physiological needs for therapies. We have developed this technology towards to treatment of a number of diseases. Here, I will highlight our advances towards the treatments of: 1) Type1 diabetes by delivering glucose responsive insulin producing cells, and 2) peritoneal cancers by delivering therapeutic cytokines to stimulate cancer immunotherapy.

Dr. Omid Veiseh, Ph.D., is an Assistant Professor and CPRIT Scholar in Cancer Research in the Department of Bioengineering at Rice University. He is also the co-founder of Sigilon Therapeutics, a Cambridge, MA- based biopharmaceutical company that discovers and develops immune-privileged living therapeutic implants for the treatment of chronic diseases.

Dr. Veiseh received a dual Ph.D. in Materials Science & Engineering and Nanotechnology from the University of Washington. He completed his postdoctoral research with Prof. Robert Langer and Prof. Daniel Anderson at MIT and Harvard Medical School. Over the course of his career he has authored, or co-authored more than 50 peer-reviewed publications including those in Nature, Nature Biotechnology, Nature Materials, Nature Medicine, Nature Biomedical Engineering and is an inventor on 20 pending or awarded patents, many of which have been licensed for commercialization by 3 separate biotechnology companies. He has received numerous awards and fellowships including: a $2 million CPRIT Scholar In Cancer Research Award from state of Texas, and was recently named one of MedTech Boston’s 40 Under 40 Healthcare Innovators for 2017.

David Friend

Daré Bioscience, Inc.

An Innovative Long-Acting Implant for Contraception

Medical products designed to improve patient compliance and convenience offer meaningful potential to increase medication effectiveness and improve outcomes.  The Microchip technology is a pioneering platform in implantable drug delivery designed to address this unmet need.  This platform is uniquely suited to deliver a variety of drugs including small molecules, peptides, and proteins at the required dose and frequency.  The technology, which has been validated in a first-in-human clinical study in osteoporosis patients, is designed to store and precisely deliver hundreds of therapeutic doses over months or years in a single implant.  The implant is intended to be operated by either the patient or a health care worker to deliver medication on demand or on a pre-determined schedule that can be activated or deactivated wirelessly, as required.  A long-acting reversible contraceptive implant based on the Microchip technology is currently under development through funding from the Bill and Melinda Gates Foundation.

Dr Friend is currently Chief Scientific Officer at Daré Bioscience located in San Diego, CA. Daré is developing new therapies that provide additional choices, enhanced outcomes, and ease of use for women. By developing and bringing these products to market, Daré plans to make a difference in the lives of women worldwide. Prior to joining Daré, he as Chief Scientific Officer at Evofem Bioscience.  From 2007 to 2015 he was Director, Product Development and Associate Professor of Obstetrics and Gynecology at the CONRAD program, Eastern Virginia Medical School. At CONRAD he was responsible for developing a range of products to prevent acquisition of HIV in women and long-acting contraceptives.  Prior to this he worked at a number pharmaceutical and biotech companies focusing on novel drug delivery systems.

Jeff Haley

Celanese Engineered Materials

Ethylene-vinyl acetate polymers for long-acting dosage forms

Ethylene-vinyl acetate (EVA) copolymers are used in a variety of drug delivery systems, including subcutaneous implants, intravaginal rings, intravitreal implants, ocular inserts, and transdermal films. Varying the ethylene to vinyl acetate ratio in the polymer provides a simple means to tune release rate of many active pharmaceutic ingredients. This presentation will review the basic methods that can be used to tune release rate with EVA, showing how both material chemistry and device construction interact to produce a desired release profile. Additionally, it will contemplate the possibilities of releasing much higher molecular weight APIs from an EVA-based system.

Jeff Haley provides technical support for medical and pharmaceutical applications for Celanese Engineered Materials. He received a B.S. in Chemical Engineering from The University of Texas, a Ph.D. in Chemical Engineering from the University of Minnesota and spent two years as a postdoctoral fellow in the Chemistry department at the University of Toronto. Jeff then took a role in polyethylene product development at the Lyondell Chemical Company. He joined Celanese in 2011, where he has previously held positions in product development and technical service in EVA Polymers. Jeff has coauthored over 20 scientific publications and is a coinventor on eight granted US patents.

Robert Lee Ph.D.

Lubrizol Life Science

President | CDMO Division

Overcoming Development Challenges for Long-Acting Injectables & Implantables

Before joining LLS Health, Dr. Lee held senior management positions at Novavax, Inc., Lyotropic Therapeutics, Inc., and Imcor Pharmaceutical Co. He holds Bachelor of Science degrees in both Biology and Chemistry from the University of Washington and a PhD in Physical Bioorganic Chemistry from the University of California, Santa Barbara. Rob has published articles in numerous peer-reviewed journals and three book chapters, plus holds 11 issued patents and 14 provisional or PCT patent applications. He has over 23 years of experience in pharmaceutical research and development of both therapeutic drugs and diagnostic imaging agents. Rob maintains strong academic ties, including an appointment as Adjunct Associate Professor of Pharmaceutical Chemistry at the University of Kansas in 1992, and serving as a reviewer for both the International Journal of Pharmaceutics and Journal of Pharmaceutical Sciences.

Opportunities to Address Global Health Challenges With Long-Acting Technologies

The goal of this panel is to engage with long-acting experts and developers to increase and advance the pipeline of products for low- and middle-income countries. Dinner and drinks will be served courtesy of our sponsors MedinCell and Medicines Patent Pool.

Organized by: MedinCell, Medicines Patent Pool, Unitaid, Bill & Melinda Gates Foundation and LAII 2020

Panelists include:

Charles Flexner (chair) – Long-Acting/Extended Release Antiretroviral Resource Program (LEAP) Carmen Pérez Casas – Unitaid Dennis Lee – The Bill & Melinda Gates Foundation Andrew Owen – University of Liverpool

Rodney Ho – University of Washington Stephanie Barrett – Merck Christophe Roberge – MedinCell Esteban Burrone – Medicines Patent Pool