Day 2 :
Keynote Forum
Serge Braun
AFM-Telethon, France
Keynote: How patient organizations can change the game in innovation and drug marketing: Example of AFMTelethon
Time : 09:35-10:20
Biography:
Serge Braun is a Scientific Director of AFM-Telethon since 2005, the French Muscular Dystrophy Association and President of Genosafe, a CRO company dedicate to QC of biotherapeutic products. He has obtained his degree in Pharmacy, PhD in Pharmacology from the Louis Pasteur University of Strasbourg, France and was a Postdoctoral Fellow at the Neuromuscular Center, School of Medicine of the University of Southern California in Los Angeles, USA. In 1995, he has joined Transgene SA (Strasbourg, France), the largest French biotech company, where he became Vice-President Research and developed his career in the field of gene therapy of genetic diseases and of immunotherapy of cancer. He was also Co-Founder of Neurofit; a contract research organization specialized in preclinical testing of both the central and the peripheral nervous system. He is a Member of the French National Academy of Pharmacy.
Abstract:
Partnerships between industry, public institutions and charity organizations may lead to win-win situations and new models for advanced therapeutic medicinal products development. The example of AFMTelethon, a patient organization dedicated to rare diseases, will show why the caricatural vision of patient associations in an activism, awareness and emotional support holding pattern, should slip our mind. AFMTelethon has raised >$100M/year for 29 years, which helped to reframe the whole field, bringing it from a rather remote scientific and commercially unattractive area to a very active and innovative ground. A striking demonstration is the comprehensive genetic map of the human genome published in 1992 and 1996 by its non-for-profit biotech Genethon; a quantum leaps in the human genetics field. Not only patient organizations can serve as disease-specific experts, they more importantly work on reducing bottlenecks/barriers for all levels of the process of product development, initiate and drive research projects, provide tools (e.g., databases, registries, large animal facilities, high-throughput screening and even GMP biotherapeutics plateforms) and represent a voice for all aspects (ethical, regulatory, technical) of innovative drug developments. Through AFMTelethon initiatives, examples will be given of successful ecosystems, which also serve as models for frequent disorders. This includes shared scientific and financial risks in translational research by directly funding and supporting drug development programs in industry or in academia, putting in place its own research and development facilities, generating innovative drugs that are now either in the clinic or approved, founding start-up companies out of its own portfolio, taking equity shares in biotech companies, launching a venture capital fund and a new pharmaceutical entity together with the French Public Investment Bank and launching a new type of private company dedicated to cell and gene therapy. The different actions presented are also driven by the growing challenge of fair price of the therapeutics will be addressed.
- Track 8: Orphan Drugs, Development trends and strategies| Track 9: Orphan Drugs and Ethical Issues| Track 10: Future Hereditary and Rare Diseases e Prospects of Rare Diseases
Location: Chicago, Illinois, USA
Session Introduction
Daniel Cohen
Pharnext , France
Title: Network pharmacology based repurposed drugs combination for Orphan Diseases Treatment
Time : 10:20-10:40
Biography:
Daniel Cohen , MD Phd, former Professor of Medical Genetics in Paris University has authored more than 150 peer reviewed papers in hire wired Journal , including the first integrated map of the Human Genome back in the 90’s. While he has discovered or co discovered numerous genes for rare and common diseases, he has also pioneered several key technologies like Large Scale Biology at Genethon, he cofounded in France, but also Pharmacogenomics, Genome Wide Association Studies and Network Pharmacology. He was a confounder of Millenium pharmaceuticals in Boston, MA. He is now Chairman, CEO and cofounder of the France Based company, Pharnext, focusing on treatment of unmet Neurodegenerative disorders by using Network Pharmacology.
Abstract:
Charcot-Marie-Tooth type 1a is an orphan genetic progressive de/dysmyelinating peripheral neuropathy affecting 125 000 persons across US and Europe. Disease, although clinically heterogeneous, impairs and quite often badly disables life of patients who could be wheelchair bound. It is primarily due to Schwann cells PMP22 protein overexpression from gene duplication. PXT 3003 , a low dose combination of 3 drugs including Baclofen, naltrexone and sorbitol, each already approved for other indications, was designed from network pharmacology based screening. Preclinical experiments showed ability to lower of PMP 22 expression, to re-myelinate axons and to improve histological, electrophysiological and clinical endpoints in the CMT1A PMP22 transgenic rat model overexpressing PMP22 protein. An exploratory double blind placebo controlled multicenter phase 2 was conducted on 80 mild to moderate adult patients over one year testing 3 different doses of the combination at a given ratio against Placebo. Anticipated safety was confirmed. Eleven endpoints were analyzed, 2 widely used clinical composite Scores such as ONLS (disability) and CMTNS (impairment), and 9 clinical and electrical quantitative measures. The most significant response was obtained with the clinical scores and some relevant electrical measures with a clear global dose effect. Milder patients responded better. Under the highest dose, which was still a 1/10 of usual dose of these drugs, disease state was stabilized in half of the patients when, beyond stabilization, it was improved in the other half of patients. These encouraging results led us to design a pivotal phase 3 to start end of 2015 on 300 mild to moderate adult patients across US and Europe, with ONLS as a primary clinical efficacy endpoint. Highly encouraging preliminary data obtained at the Max Planck Institute in post-natal CMT1A young RAT has also paved the way towards a pediatric trial hoping to prevent symptoms when treating young children early enough. Network pharmacology based strategy can be systematically applied to any rare or common disorders.
Yong Moon Choi
Bio-Pharm Solutions Co., Ltd, South Korea
Title: JBPOS0101: A new generation mGluR- and BBB-targeted broad spectrum antiepileptic drug for the treatment of super-refractory status epilepticus
Time : 11:00-11:20
Biography:
Dr. Yong Moon Choi completed his PhD from the State University of New York and his postdoctoral studies from Purdue University under 1979 Nobel Laureate Herbert C. Brown. He is currently the president and CEO of Bio-Pharm Solutions, based in South Korea. He founded SK Biopharmaceuticals (New Jersey, Seoul/DIT, Shanghai) in 1993, and while there, Dr. Choi discovered and developed drug candidates for central nervous system (CNS) disorders. Under Dr. Choi's leadership, SK Biopharmaceuticals was the first Korean company to receive an IND by the US FDA (YKP10A), and in total, Dr. Choi has received 10 IND's from the US FDA. While at SK Biopharmaceuticals, Dr. Choi established a global R&D network with NIH National Institute of Neurological Disorders and Stroke, university institutes and Johnson & Johnson. He has filed 104 patents and published 29 papers in renowned journals.
Abstract:
JBPOS0101 is an antiepileptic drug candidate which possesses highly potent and broad spectrum antiepileptic activity as demonstrated in testing done by Bio-Pharm Solutions and NIH NINDS Anticonvulsant Screening Program. NINDS has provided a Red Book for JBPOS0101 due to its promising anticonvulsant profile. JBPOS0101 shows efficacy in a broad range of animal models including electrically- and chemically-induced seizures. JBPOS0101 shows efficacy in pharmaco-resistant epilepsy models and also in the 6 Hz psychomotor seizure test, with similar ED50 values at both 32 mA and 44 mA stimulation. In particular, JBPOS0101 shows strong efficacy in several benzodiazepine-resistant status epilepticus models, in which lithium-pilocarine is administered 30 minutes after the first observed seizure: 1) behavioral seizures with 90 minute observation, 2) electrographic seizures, in terms of gamma wave power (20-70 Hz) on EEG, with 10 hour observation, 3) protection against hippocampal cell loss after 14 days of observation, and 4) spontaneous recurrent seizures with 14 day observation. JBPOS0101 is an antagonist of metabotropic glutamate receptors 1 and 7. Additionally, JBPOS0101 may have a strong functional role in blood-brain-barrier-related neuroprotection against lithium-pilocarpine-induced status epilepticus, collagenase-induced hemorrhage and tPA-induced cell death. JBPOS0101 has completed phase 1 clinical trials in Toronto, Canada. No serious or severe treatment-emergent adverse events occurred. All adverse events were characterized as mild. No subject in any treatment group experienced a treatment-emergent adverse event related to vital sign measurements. Regarding the pharmacokinetic profile observed in phase 1, plasma concentrations of JBPOS0101 were observed to increase proportionally with increasing dose levels of JBPOS0101. We are currently planning a phase 1/2 trial for the treatment of patients with super-refractory status epilepticus. The preclinical data, especially the refractory status epilepticus models, and phase 1 results suggest that JBPOS0101 is a promising drug candidate for the treatment super-refractory status epilepticus with antiepileptogenic and neuroprotective properties.
Biography:
Stephen Shrewsbury is currently an Executive Vice President of Development and Chief Medical Officer at Fortuna Fix, leading their novel cellular technology into multiple clinical programs focused on regenerative medicine, several of which are rare diseases. He moved to lead inhaled antibiotic programs at Chiron Corporation (in Cystic Fibrosis and other rare diseases) before becoming CMO sequentially to MAP Pharmaceuticals, Adamas Pharmaceuticals, AVI BioPharma (now Sarepta Therapeutics; where he opened their first IND for Eteplirsen in Duchenne muscular dystrophy and planned their oligomer programs against Ebola and Marburg Hemorrhagic Fevers) and Aquinox Pharmaceuticals. He is the author of Defy Your DNA and over 70 scientific papers, holds several patents and contributed to many awarded grants, mostly for work on rare diseases.
Abstract:
Clinical programs directed at rare diseases present many unique challenges for clinical research. Most druggable targets have been identified and exploited and the sciences of drug (be they small molecules including oligonucleotides or biologics) or device development has dramatically advanced in recent decades. With that advance, the opportunity to develop products for large populations of common diseases has largely disappeared. At the same time the phenotypes for many common diseases have been split into multiple smaller populations and even genotypes focusing more and more programs on smaller populations. Planning to complete increasingly complex studies in smaller but more homogeneous patient groups has become increasingly competitive and costly. Against this clinical research landscape, cellular therapies as the third major branch of clinical research have arrived. Initially working with fetal, embryonic, bone marrow, adipose or cord blood derived stem cells, the field has been less regulated than drugs and devices, leading to a proliferation of clinics and claims that have not all been through a rigorous and appropriate review. Attention is now evolving from the ethically and immunologically challenging programs involving allogeneic stem cells to autologous, organ specific stem cells. This can be best achieved by generating directly reprogrammed precursor cells for that organ. These promise greater safety and easier production, for a very complex product and will allow this third branch of medical research to start to tackle many rare diseases where cellular regeneration may be required for clinical benefit. To capitalize on this timely opportunity, time and cost efficient direct reprogramming to lineage-specific precursor cells is vital. With this advance, cellular therapies will take their rightful place in the physicians’armamentarium against injury, disease and degeneration, just as healthcare costs in advanced countries look set to spiral completely out of control.
Stephen Arneric
Critical Path Institute, USA
Title: Digital Measurements of Health- Regulatory Science Challenges Opportunities in Rare Diseases
Biography:
In 2015 Dr. Arneric joined the Critical Path Institute as Executive Director of the Coalition Against Major Diseases (CAMD), a consortium focused on developing Drug Development Tools for advancing innovative treatments of Alzheimer’s disease and related dementias. Previously he was VP Research/Preclinical Development (Neuromed Pharmaceuticals), CSO of the Pain/Migraine Drug Hunting Team (Lilly), and held senior management positions at Pfizer, Pharmacia, DuPont Pharmaceuticals, and Abbott. He has extensive leadership and scientific expertise in the areas of neurology, pain, psychiatry and urology, and over the last 25 years his teams have delivered more than 30+ drug candidates into clinical development. Dr. Arneric earned degrees in Physical Sciences (BS, Michigan State University), and Pharmacology (PhD, University of Iowa). He is an accomplished author with 145 peer-reviewed articles, 190 abstracts, 17 chapters, 1 book, numerous IND submissions, and is co-inventor of 15 patents. He is also President of Horizons Pharma Consulting, LLC.
Abstract:
Interest in identifying, evaluating and qualifying innovative technologies for use in drug development is growing. While FDA guidance documents exist for pursuing novel Drug Development Tools (DDTs) and Medical Devices Development Tools (MDDTs) for Qualification, the use of Digital Measurements of Health (DMH) (i.e., measured biological events or patient function captured through a device or sensor technology) for use in clinical development remains ill-defined. FDA issued in 4Q2015 a Federal Register request [Federal Register Docket No. FDA-2015-N-3579] for comments that could accelerate the assessment of innovative drug treatments. The Coalition Against Major Diseases (CAMD), a consortium within the Critical Path Institute, aims to accelerate the development of tools that increase the efficiency of delivering innovative treatments for Alzheimer’s Disease and related neurodegenerative/Rare Diseases that impair cognition and function. This presentation highlights CAMD’s perspective on use of DMHs as drug development tools, the challenges faced, and the need for: • Data Standards: Consensus on standardized ways to record, structure and report data generated by digital biosensors, employing CDISC standards to provide the consistent data model/structure to enable data sharing across technology platforms. • DMHs as Drug Development Tools: Development of standards for validating the analytic performance of devices. • Context of Use (COU) Statements: Implementation of COU statements based on the current state-of-evidence for their application in drug development. CAMD’s perspective supports the use of DMHs in clinical trials for: • Function: Electronic monitoring of activities in/outside of home (patterns of sleep, drug adherence, walking, social interactions via phone and computer, cognitive task assessments) and fine motor skills (e.g., typing or keystroking on computer/smartphone). • Physiological measures: ECG, EEG, movement (accelerometer), speech/voice analysis, etc. Having open/frequent dialogue with regulators is critical to shape the development, validation, and clinical relevance of this research.
Alan B Moy
The John Paul II Medical Research Institute and Cellular Engineering Technologies, USA
Title: Novel viral-free and oncogene-free induced pluripotent stem cell for orphan disease cell therapies
Time : 12:20-12:40
Biography:
Alan B Moy has established a successful career in academia, non-profits and industry. He has received his MD from Creighton University, completed his Internal Medicine Residency at St. Louis University and Pulmonary Fellowship at the University of Iowa. He has served on Faculty at the University of Iowa College of Medicine and College of Engineering with a research expertise in cellular and tissue engineering. He is the Founder and Scientific Director of the John Paul II Medical Research Institute, a 501 (C)(3) and is the CEO and Co-Founder of Cellular Engineering Technologies, a leading stem cell manufacturing company. He is listed in the Leading Physicians of the World by the International Association of Healthcare Professionals. His area of expertise includes pulmonary medicine, cytoskeletal biology, vascular biology, tissue engineering and industrial stem cell manufacturing.
Abstract:
Pluripotent stem cells represent a potential regenerative medicine for several orphan diseases because the cells exhibit broad plasticity. Induced pluripotent stem cells (IPSC) have the potential to serve as an autologous as well as an allogeneic cell therapy. However, IPSC therapy has not yet been fully realized because the IPSC reprogramming methods have historically required viral gene delivery and oncogenes in order to create a final IPSC product. Non-integrating IPSC reprogramming approaches like self-replicating ribonucleic acid and Sendai virus have been developed to reduce the tumorgenicity risk. However, these reprogramming methods still pose significant costs and oncogenic risk because they utilized the oncogenes, c-Myc and Lin28. Episomal reprogramming is a safe reprogramming approach to produce clinical-grade IPSC therapies. However, the reprogramming efficiency of episomal vectors has been inefficient and has required c-Myc and Lin28 to compensate for the low efficiency. We have developed a combinatorial reprogramming approach of small molecules and a novel episomal construct that is free of c-Myc and Lin28. The combinatorial approach significantly increased the reprogramming efficiency. Further, the reprogramming method also utilized a well-defined tissue cultured media that is feeder-free, xeno-free and matrigel-free. This combinatorial reprogramming approach is now poised to transition into GMP operations, which would satisfy regulatory requirements. The opportunity now exists to develop clinical-grade and safe IPSC for a variety of orphan diseases.
Duygu Kuyuncu Irmak
INC Research, Turkey
Title: Orphan drugs: getting arms around rare diseases
Time : 12:40-13:00
Biography:
Irmak Duygu Kuyuncu has joined the clinical research industry in 2003 and worked as CRA. She has worked as a Clinical Operations Manager for more than 5 years in CROs and Pharma having responsibilities in clinical resources management, ensuring successful and compliant clinical operations, management of the process improvement in Turkey and in Middle East Countries. She was an Advisory Board Member and Consultant of the Scientific and Technological Research Council of Turkey in 2013. She has been a Board Member of the Clinical Research Association in Turkey and one of the Board Members in the Neuromuscular Diseases Research Association in Turkey. She has been involved in publication projects with close co-authoring with key opinion leaders from regulatory, academy and industry. She is currently leading the INC Research Turkey as Clinical Operations Associate Director.
Abstract:
Finding ways to bring drugs for rare diseases to patients is an important public health challenge. The complexity of the rare diseases, incomplete understanding of disease pathophysiology, limited population and heterogeneity of the patients suffering from rare conditions, difficulties in diagnosis, ‘rare physicians’ availability, high-cost of the R&D of orphan drugs, regulatory risks in the road of clinical trials conduct, marketing authorization and reimbursement are all factors having an impact on this challenge. Undoubtedly, the most challenging part of this is the clinical trials conduct on the orphan drug molecules. The limited number of patients together with the diversity of the rare conditions makes the protocol design a sensitive topic to consider; access to the rare patients, getting interest and the engagement of the physicians are also amongst the challenges in this process. There are a number of stakeholders playing key roles in the Orphan drug R&D including regulatory authorities, policymakers, patient advocacy groups, scientists and clinical investigators, research institutes, academic or non-academic associations. In the speech, we will focus on the ways to overcome all difficulties, discussing how to find the most cost-effective and having the least or no regulatory risks during the clinical trials conduct and evaluate the value of local and global expertise and the cooperation of the stakeholders.
Anne Marie Finley
Biotech Policy Group LLC, USA
Title: Pricing, public health, & politics: policy considerations for orphan products
Time : 13:40-14:20
Biography:
Anne Marie Finley is the FDA Regulatory and Health Care Policy Strategist. She is the President of Biotech Policy Group, a consulting firm she founded in 2001 that focuses on development of products for rare diseases and unmet medical needs. She has more than 25 years’ experience in senior management positions at the Food and Drug Administration, US Department of Health and Human Services, the US Congress. She was named a top 50 Thought Leader in Orphan Drugs and Rare Diseases in 2014.
Abstract:
Drug prices in the United States are higher than anywhere else in the world. Orphan products have long been perceived as pricier than many other drugs by payers, manufacturers and consumers. The Affordable Care Act’s expansion of insurance coverage and pharmaceutical benefits, along with a growing resistance to higher priced therapies, have added to the pharmaceutical pricing stress on the healthcare system and ultimately rare disease patients. Innovative responses to the current pharmaceutical pricing crisis have been developed by some drug companies, patient organizations, payers, regulators and legislators. The new Congress and new Administration have a number of options and opportunities by which to address pricing concerns in 2017.
Karen S Ho
Lineagen, Inc, USA
Title: The role of clinical genomic testing in treatment discovery for rare neurodevelopmental diseases
Time : 14:20-14:40
Biography:
Karen S Ho is a Principal Scientist of Translational Research Initiatives at Lineagen, Inc., where she is working since five years. She holds MSc degree in Genetics from Cambridge University where she was a Marshall Scholar after graduating summa cum laude from Washington University with a BSc in Biochemistry. She holds a PhD in Developmental Biology from Stanford University and completed her Postdoctoral training as a Howard Hughes Medical Institute Fellow and National Sleep Foundation Fellow in the Department of Neuroscience at the University of Pennsylvania. She is also an Assistant Adjunct Professor in the School of Medicine, Department of Pediatrics at the University of Utah and serves on the Board of two non-profit foundations, NGLY1.org and Rare and Undiagnosed Network, both of which are dedicated to rare disease.
Abstract:
Genomic testing by high resolution chromosomal microarray (CMA) is the guideline-recommended first tier test for neurodevelopmental disorders. Widely used in the clinical setting, accurate and informative interpretation of CMA results can enhance not only the diagnostic understanding of, but also the medical management of, these often rare genetic conditions. We will present the results of our efforts to bring the power of ultra-high resolution microarray analysis, combined with newly developed tools and relational databases, to bear on the complex challenges of interpretation of genomic data. Using our custom microarray optimized for the detection of known critical genomic changes associated with neurodevelopmental disorders, we have performed over 10,000 consecutive CMAs on a US-based, neurodevelopmentally-affected pediatric population. We detected relevant copy number variants (CNV) in approximately 30% of this population, a rate which depends on patient age and indication for testing. A significant proportion (~20%) of these finding were classified as variants of unknown significance (VOUS). We have developed novel technologies and approaches in partnership with patient support groups and members of the medical and academic research communities to bring additional interpretative power to bear on these VOUS. As an example of the clinical utility of ultra-high resolution CMA to map critical genes, we recently reported the identification of a seizure susceptibility candidate region/gene for Wolf-Hirschhorn Syndrome (WHS). Subsequent work using novel analysis techniques has led to identification of additional genes potentially related to congenital heart defects and other conditions associated with WHS. Using these strategies, we have correlated fine-resolution genetic mapping with other rare conditions and predicted potential molecular mechanisms connecting various rare diseases to one another. This in turn impacts the potential for common pharmacotherapeutic development strategies for previously unrelated orphan disorders.
Gail Adinamis
GlobalCare Clinical Trials, LLC, USA
Title: Rare disease studies facilitated by taking study visits to the patients
Time : 14:40-15:00
Biography:
Gail Adinamis is the Founder and CEO of GlobalCare Clinical Trials LLC, USA and has over 35 years of comprehensive global clinical trials experience including over 12 years of global trials management at Abbott Laboratories and Astellas. She has founded the in-home business model for study visits in 1992 and established and headed clinical trials divisions for three national home infusion companies and was the Founder, President and CEO of the first independent ambulant care service company for clinical trials. She is a Member of the Women Presidents’ Organization, National Association of Professional Women and DIA and has been an invited speaker at several industry conferences and recipient of numerous awards/recognitions including twice being among INC 5000’s fastest growing private companies and Game Changer and CEO of the Year.
Abstract:
Patient recruitment and retention are key factors in establishing the objectives and ultimate success of clinical trials. These can be particularly challenging in rare disease studies where patients reside distant to investigator sites and may suffer from debilitating diseases making travel difficult. Patient advocacy groups have been playing a more influential role in drug development and commercialization especially in rare diseases. Advocacy groups represent the voice of the patient contributing to better clinical trial design by helping to remove barriers that made participation difficult or impossible. But many challenges remain. A patient-centric service model has evolved over the past years allowing study visits to be conducted at the patient's home where it is more convenient and comfortable than at the investigator site. By conducting selected protocol visits at home, workplace or other alternate location, ambulant healthcare providers offer a way for patients to participate in trials regardless of study duration, frequency of visits, disease state, distance to site and family, school, work or community obligations. By making trials more convenience and comfortable for patients, more patients are willing and able to participate and remain in the study. This innovative service model is available on a global basis and has been shown to triple enrollment rates and reduce patient dropout rates to 3 percent. Services include study drug administration, blood draws, clinical assessments, patient training and education and study compliance checks in all age groups, a variety of therapeutic areas and in all phases of development. This ambulant care service model provides a win-win benefit for all stake holders by providing patient's a convenient and comfortable way to participate in studies, offering investigators the ability to recruit patients from broader geographic areas, reducing development times for sponsors developing new therapeutics and ultimately getting life enhancing products to consumers sooner.
Alan B Moy
The John Paul II Medical Research Institute and Cellular Engineering Technologies, USA
Title: A robust reprogramming approach to create viral-free and oncogene-free, orphan-disease specific induced pluripotent stem cells from peripheral blood mononuclear cells
Time : 15:00-15:20
Biography:
Alan B Moy has established a successful career in academia, non-profits and industry. He has received his MD from Creighton University, completed his Internal Medicine Residency at St. Louis University and Pulmonary Fellowship at the University of Iowa. He has served on Faculty at the University of Iowa College of Medicine and College of Engineering with a research expertise in cellular and tissue engineering. He is the Founder and Scientific Director of the John Paul II Medical Research Institute, a 501 (C)(3) and is the CEO and Co-Founder of Cellular Engineering Technologies, a leading stem cell manufacturing company. He is listed in the Leading Physicians of the World by the International Association of Healthcare Professionals. His area of expertise includes pulmonary medicine, cytoskeletal biology, vascular biology, tissue engineering and industrial stem cell manufacturing.
Abstract:
Innovations are needed to reduce the time, cost and failure rate of drug discovery. 58% of new molecular entities approved by the FDA in the past ten years have utilized phenotypic screening; a drug screening process that uses patient-specific cultured cells that reflect the patient’s diseased characteristics. Induced pluripotent stem cells (IPSC) are excellent patient-specific stem cells for phenotypic drug screening platforms for orphan disease. Disease-specific IPSC has the advantage over prior conventional approaches to better predict drug efficacy and safety and for patient stratification in clinical trials. Yet, one major hurdle in creating disease-specific IPSC for infants and children has been developing reliable methods to reprogram target cells derived from peripheral blood, which is the ideal minimally invasive approach to transform target cells. However, efficient reprogramming of peripheral blood mononuclear cells has not been achieved without viral and the oncogenes, c-Myc and Lin28. These oncogenic transcriptional factors and viral elements may alter the native phenotype of a patient’s cell and skew drug screening outcomes. We have solved this problem by developing a combinatorial approach of small molecules and a novel episomal construct to reprogram adherent cells and peripheral blood mononuclear cells. While the combinatorial approach is efficient for reprogramming adherent cells, the approach requires an additional intermediate conversion of peripheral mononuclear cells (PMNC) into CD34+ hematopoietic stem cells. PMNC were exposed to a defined tissue cultured media that converted PMNC into a sufficient number of hematopoietic stem cells. Upon conversion to hematopoietic stem cells, IPSC reprogramming became feasible. Without an intermediate hematopoietic stem cell conversion, we observed no IPSC colony formation. The opportunity now exists to develop a repository of IPSC for infants and children suffering from orphan diseases from a simple venipuncture, which should accelerate hit to lead identification, drug optimization and drug formulation.
Moji C. Adeyeye
Roosevelt University, USA
Title: Challenges and opportunities in development of orphan drugs
Time : 15:20-15:40
Biography:
Moji C Adeyeye is the Founding Chair of Biopharmaceutical Sciences Department and Professor of Pharmaceutics and Drug Product Evaluation at the College of Pharmacy, Roosevelt University (RU) in Schaumburg, Illinois. Her research interest include pre-formulation, pediatric and adult drug product (solids, liquids and semisolids) development and evaluation investigational new drug application-driven bench-to-bedside translational research, preclinical and clinical trials, analytical/bioanalytical assay development, bioavailability and bioequivalence quantitation, fixed dose combination dosage forms for various drug classes including antiretrovirals, anti-malarials and anti-sickling agents. She is a Senior William J. Fulbright Scholar and Specialist, 2016 Nigeria National Academy of Science Fellow and 2008 American Association of Pharmaceutical Scientists (AAPS) Fellow. She has earned her BS and MS/PhD from the University of Nigeria, Nsukka, Nigeria and University of Georgia, Athens, GA, respectively. She has 5 patents, 57 peer-reviewed manuscripts, book chapters and books, more than 150 scientific presentations and has successfully mentored many MS and PhD candidates.
Abstract:
Development of orphan drugs for rare diseases is fraught with opportunities and challenges globally, in legislative policies, research and development, clinical trials, time to reach the market and disparity in affordability and accessibility. The opportunities include incentivizing of researchers and manufacturers in fee reduction or no fees for protocol assistance, preauthorization inspections, marketing authorization, grant funding, priority review voucher for rare pediatric disease and granting of market exclusivity. These were stimulated by the US 1983 Orphan Drug Act and heightened awareness of the public health impact and ramifications in many countries. The number of orphan drug designations has increased in recent years and so is the number of marketing approvals. However, there challenges that could limit the development include understanding the disease and sometimes the co-morbidities, establishing the clinical relevance and cost effectiveness, difficulties in setting up clinical trials for the small populations and high cost of bringing a new product to market especially an orphan drug with limited target population and market opportunities. The purpose of the presentation is to underscore the opportunities, successes in orphan drug development and challenges using relevant case studies. Review of orphan drugs categories and designations for rare diseases in several countries, opportunities that include legislative and regulatory incentives, challenges in development and recent successes were done. Using USA as a reference country, examples of opportunities and challenges in the development of pediatric orphan drugs for rare diseases such as pediatric HIV/AIDS and sickle cell disease were given. Perspectives on academic-industry-government collaboration relating to the opportunities and challenges were also presented. The significance in the successes in orphan drug approvals, ongoing and increasing awareness of impact of development of orphan drugs on the life of the patients and the low market opportunities and difficulty in bringing the products to market were emphasized.
Jacques P. Tremblay
Université Laval, Canada
Title: Potential treatments for rare diseases:Cell therapy, gene therapy and genome editing
Time : 15:40-16:00
Biography:
Jacques P. Tremblay has completed in 1974 his PhD in Neurosciences at University of California at San Diego. He has published 261 articles in peer-reviewed journals and has been serving as deputy editor of Molecular Therapy and Cell Transplantation. His laboratory is currently working on cell and gene therapies for Duchenne Muscular Dystrophy, Friedreich ataxia and Alzheimer disease.
Abstract:
All hereditary diseases are due to modification in the patient genome: insertion, deletion or modification of one or several nucleotides among the 6 billion nucleotides of the human genome. Several potential therapeutic approaches to treat these hereditary diseases have been developed over the years. For some recessive diseases the transplantation of allogenic cells obtained from a healthy donor can permit to deliver the normal gene to compensate for the mutated gene. This approach is under clinical trial for Duchenne Muscular Dystrophy. A compensatory normal gene to treat a recessive hereditary disease may also be introduced in the patient own cells in culture or directly in vivo by using viral vectors. The Adeno Associated Viruses (AAV) are currently the vectors of choice for such a therapeutic approaches. Various specific nucleases (meganucleases, Zinc Finger Nucleases, TALENs and the CRISPR/Cas9 system) have been investigated during the lasts 10 years and now permit to precisely correct a gene responsible for a hereditary disease. This type of approaches is the only one that can be used for dominant diseases. This approach may also be used to correct large genes, which are too big to be delivered by AAV. My team and several others have already used this approach to correct the dystrophin gene, as a treatment for Duchenne Muscular Dystrophy. Indeed by using these specific nucleases, it is possible to induce double strands breaks in the dystrophin gene to restore the normal reading frame by micro-insertions, micro-deletions or by deleting complete exons or parts of exons. My team is also attempting to restore a completely normal dystrophin protein by inserting the exons, which are missing in the patient genome. My team has also been able to remove with the CRISPR/Cas9 system the long trinucleotide repeat in intron 1 of the frataxin gene responsible for Friedreich ataxia and thus increase the expression of frataxin in patient cells. The TALE proteins and a defective Cas9 nuclease (dCas9) may also be fused with a transcription activation domain, such as VP64, to target a gene promoter to increase specifically the expression of that gene. My team has successfully used that approach in cells of Friedreich patients. The CRISPR/Cas9 technology may also be used to correct a gene by a process called homology directed repair. This technique permits to modify one or several nucleotides in the whole human genome. Thus the progress in cell therapy, gene therapy and genome editing permits to dream of developing therapies for all hereditary diseases over the coming years. The main limiting factor is the financial support for this type of research.
Abida Syed M Haq
Ministry of Health Malaysia, Malaysia
Title: Access to Orphan Drugs: The Malaysian Perspective
Biography:
Ms. Abida Syed M Haq holds a Master’s Degree in Clinical Pharmacy from University Science Malaysia and is currently Director, Pharmacy Practice & Development, and Ministry of Health Malaysia and is responsible for the overall delivery of pharmacy services involving formulary development, logistics, dispensing and quality use of medicines. She has extensive experience in drug regulatory affairs having served in the National Pharmaceutical Control Bureau over a period of 12 years. Her current areas of interest include health sector reforms, pharmaceutical care delivery and medication safety initiatives.
Abstract:
In the Malaysian context, challenges faced by patients with rare diseases amongst others include delayed treatment due to late diagnosis, limited availability to genetic medicine services and high treatment costs which have a significant bearing on access to these medicines. Recognizing the needs of patients with rare diseases, the National Medicines Policy states that there shall be appropriate procedures to enhance accessibility of life-saving products and orphan medicines without compromising safety, quality and efficacy. The Ministry of Health (MOH) is in the process of drafting the Malaysian Guidelines for the Management of Orphan Drugs which will provide a framework for the effective management of orphan drugs for all relevant stakeholders. It will address issues pertaining to the designation, regulation, marketing and procurement procedures for orphan drugs and will serve to increase availability of non-commercially viable products without compromising on patient safety. The major issue however, being faced by MOH is on the question of affordability. Healthcare in the public sector is highly subsidized by the government and patients almost never pay for medicines listed in the MOH drug formulary. As it is a challenge to do a pharmacoeconomic evaluation and budget impact analysis on drugs used for rare diseases, most of these drugs are not listed in the MOH formulary and are procured through special approval processes. With the advent of more drugs being approved for the management of rare diseases and the expansion of genetic medicine services in the country, ensuring access to these lifesaving medicines has taken on a new dimension. Options such as Managed Entry Agreements, increased private-public partnerships and international collaborations may be the way forward to ensure timely, sustainable access to safe, efficacious and cost effective medicines in the management of rare diseases.
Serge BRAUN
AFM-Telethon, FRANCE
Title: How patient organisations can change the game in innovation and drug marketing: the example of AFMTelethon
Biography:
Serge Braun, PharmD, is Scientific Director of AFM-Telethon since 2005, the French Muscular dystrophy Association, and President of Genosafe, a CRO company dedicate to QC of biotherapeutic products. He obtained his degree in Pharmacy and a Ph.D in Pharmacology from the Louis Pasteur University of Strasbourg, France; was a postdoctoral fellow at the Neuromuscular Center, School of Medicine of the University of Southern California in Los Angeles, USA. In 1995, he joined Transgene SA (Strasbourg, France), the largest French biotech company, where he became Vice-President Research and developed his career in the field of gene therapy of genetic diseases and of immunotherapy of cancer. He was also co-founder of Neurofit, a contract research organization specialized in preclinical testings of both the central and the peripheral nervous system. He is member of the French National Academy of Pharmacy.
Abstract:
Partnerships between industry, public institutions and charity organizations may lead to win-win situations and new models for advanced therapeutic medicinal products development. The example of AFMTelethon, a patient organization dedicated to rare diseases, will show why the caricatural vision of patient associations in an activism, awareness, and emotional support holding pattern, should slip our mind. AFMTelethon has raised >$100M/year for 29 years, which helped to reframe the whole field, bringing it from a rather remote scientific and commercially unattractive area to a very active and innovative ground. A striking demonstration is the comprehensive genetic map of the human genome published in 1992 and 1996 by its non-for-profit biotech Genethon; a quantum leap in the human genetics field. Not only patient organizations can serve as disease-specific experts, they more importantly (1) work on reducing bottlenecks/barriers for all levels of the process of product development, (2) initiate and drive research projects, (3) provide tools (e.g. databases, registries, large animal facilities, high-throughput screening, and even GMP biotherapeutics plateforms,…), and (5) represent a voice for all aspects (ethical, regulatory, technical) of innovative drug developments. Through AFMTelethon initiatives, examples will be given of successful ecosystems, which also serve as models for frequent disorders. This includes shared scientific and financial risks in translational research by (1) directly funding and supporting drug development programs in industry or in academia (2) putting in place its own Research and Development facilities, generating innovative drugs that are now either in the clinic or approved (3) founding start-up companies out of its own portfolio (4) taking equity shares in biotech companies, (5) launching a venture capital fund and a new pharmaceutical entity together with the French Public Investment Bank, and (6) launching a new type of private company dedicated to cell and gene therapy. The different actions presented are also driven by the growing challenge of fair price of the therapeutics will be addressed.
Francois Nader
Acceleron Pharma Founder, Jesra Advisors LLC
Title: Value creation and transformative opportunities in the rare diseases space: Lessons learned & what lies ahead
Biography:
Francois Nader, MD, MBA was President, CEO and Board Director of NPS Pharma from 2008 to 2015, when the company was acquired by Shire for $5.3 Billion. During his tenure, Dr. Nader transformed NPS Pharma into a leading global biotechnology company focused on rare diseases. He was recognized as the Ernst and Young National Life Science Entrepreneur of the Year® in 2013. Dr. Nader currently serves as chairman of Acceleron Pharma Inc. (XLRN) and board director of Advanced Accelerator Applications, SA (AAAP) and Clementia Pharmaceuticals, Inc. Before NPS, he was a venture partner at Care Capital. Prior to that, he served on the North America Leadership Team of Aventis and its predecessor companies holding a number of executive positions. Dr. Nader earned his French Doctorate in Medicine from St. Joseph University in Lebanon and his Physician Executive MBA from the University of Tennessee.
Abstract:
Rare Diseases have been a source of value creation for the Biopharma industry in the last 10 years. The transformational journey of NPS Pharma from a failing company to a $5.2 billion exit is a vivid example of a success story with significant value delivered to patients, shareholders and employees. The presentation will share the lessons learned along the way as they are continue to be applicable to public and private companies that are in the space. Yet, the winds could be turning when it comes to pricing and reimbursement of orphan drugs, especially within the context of the US presidential elections and the shift in the public opinion regarding drug costs. If not addressed, they could put significant damp on this vertical. However, innovation and patients can still win the battle through understanding cost-containment and cost-cutting approaches that are currently in play and proactively developing and executing the necessary strategies to address them. Part two of the presentation will details these challenges and offer practical options to dealing with them.
Taosheng Huang
Cincinnati Children's Hospital Medical Center, USA
Title: Discovery of novel genes associated with mitochondrial diseases by NGS
Biography:
Dr. Taosheng Huang is a physician-scientist. Currently he is a professor with tenure in Human Genetics, Director, Program of Mitochondrial Medicine, Associate Director of the Molecular Diagnostic laboratory at Cincinnati Children's Hospital Medical Center (CCHMC). Dr. Huang graduated from Fujian Medical University in 1983 and received his Ph.D. study at Mount Sinai Medical School in 1991. Dr. Huang completed his pediatrics residency at Georgetown University Hospital in 1996 and his clinical genetics and clinical molecular genetics fellowship at Harvard Medical School in 1999. Dr. Huang was a faculty member at the Children’s Hospital, Harvard from 1999-2001. In 2001, Dr. Huang moved to the University of California, Irvine as an independent investigator to study the molecular basis of genetic syndromes. Clinically, Dr. Huang is interested in mitochondrial disorders, genetic syndromes with congenital cardiac defects. He has been actively engaged in many programs in China. Dr. Huang is an honorable professor of Peking Union Medical School, a member of the special committee for Yusheng Yuyou of People’s Republic of China, advisory board member to Chinese Ministry of Health for targeted therapy and a principal investigator for birth defect control program of Chinese Ministry of Health.
Abstract:
Advances in next generation sequencing technology have resulted in a rapid increase in the molecular characterization of mitochondrial disease. Recent years, our laboratory has successfully used whole-exome sequencing to identify many novel disease causing genes associated with mitochondrial disease. The mitochondrial asparaginyl-tRNA synthetase (NARS2) mutations cause Leigh syndrome and nonsyndromic hearing loss (DFNB94). We found that some mutation can disrupt dimerization of NARS2 and decrease steady-state levels of mt-tRNAAsn without aminoacylation defects. The cells with NARS2 mutations also display impaired oxygen consumption rate and OXPHOS deficiency that can be rescued by overexpression of wild type NARS2. Recently, we found that recessive SLC25A46 mutations cause optic nerve atrophy and axonal peripheral neuropathy. SLC25A46, putative mitochondrial carrier gene, is human homologs of Ugo1p. Furthermore, we demonstrate the SLC25A46 role in mediating mitochondrial morphology in vitro and in vivo. In zebrafish we found that loss-of-function affects the development and maintenance of neuronal processes and causes abnormal mitochondrial fusion morphology. Our result show many disease causing genes associated with mitochondrial disease are yet to be identified and whole-exome sequencing is very cost-effective for this process.