Rare Diseases and Orphan Drugs Global Forum 2018

Co-chaired by:
Prof. Matthias Schonermark, M.D., Ph.D.,
Clevio Nobrega, Assistant Professor, University of Algarve

The Polyglutamine (PolyQ) diseases are a group of nine rare neurodegenerative disorders caused by an abnormal expansion of the trinucleotide CAG in the causative gene, which encodes a polyQ tract in their respective proteins. Contrasting with its understood monogenic etiology, we only now are starting to understand the complex cascade of molecular events leading to neurodegeneration. However, and despite the efforts, currently there is no effective treatment to delay or stop disease progression. In the last years, several preclinical studies provided important results concerning the development of new therapies, which might be translated in the next years to clinical trials. The present talk will focus in some of those studies, highlighting the results obtained in Machado-Joseph disease/Spinocerebellar ataxia type 3 and how these provide important hints to the future translation of these therapies to PolyQ patients.

Guido J.R. Zaman, Ph.D., Managing Director & Head of Biology, NTRC
NTRC supports the development of new precision medicines by linking cellular drug response to genetic features, the activity of enzymes and immunological markers. Two case studies will be presented. The first describes the identification of new predictive drug response biomarkers for approved kinase inhibitors for oncology. All forty protein kinase inhibitor drugs that have been approved for clinical use in cancer to date were profiled on a panel of 280 biochemical kinase assays and on a panel of more than hundred genetically characterized cancer cell lines from diverse tumour tissue origins. Biochemical cross-reactivities were linked to cellular response biomarkers. In this way, cell line genetics can lead to new therapeutic applications for approved cancer drugs. The second case study relates to the tryptophan metabolizing enzymes IDO1 and TDO. Tryptophan and its metabolites formed in the kynurenine pathway play a role in the body’s immune response against cancer cells and in the development of neurodegenerative disorders, such as Parkinson’s disease. In an ongoing study at NTRC,the expression and activity of tryptophan metabolizing enzymes and the levels of tryptophan andmetabolites in liquid biopsies from patients are related to disease status and drug response. In this way, patients with an overactive kynurenine pathway can be selected for treatment with IDO1 or TDO inhibitors.

Sonja Pavlovic PhD, Head of Laboratory for Molecular Biomedicine, University of Belgrade
Majority of rare diseases (RD) are genetic diseases (~80%) and therefore identification of specific gene defect in each patient is important. Recently, high throughput sequencing methodology based on a simultaneous analysis of a number of clinically relevant genes or of a complete genome, has been introduced into routine diagnostic practice. Next generation sequencing (NGS) methodology has enabled diagnosis of many RD, especially genetically heterogeneous diseases. Using NGS it has become possible to precisely identify genetic defect in one gene among a dozen of suspected genes. Moreover, different diseases with partially overlapping clinical manifestations are being easily and accurately diagnosed.
As a consequence of NGS application, identification of novel disease-causing and disease-related genetic variants becomes a frequent event. Therefore, the establishment of relevant databases and data sharing on an international scale become immensely important. Numerous newly discovered genetic markers have contributed to more precise classification of patients in distinct groups, leading to specific, more successful treatment protocols. Development of pharmacogenomic platforms and application of molecular–targeted therapy have led to the individualization of therapy, tailored to genetic profile of a disease in each patient. Several genomic, epigenomic, transcriptomic and proteomic markers have already been introduced in routine diagnostic, prognostic and therapeutic protocols for many RD. Advancement in the genomics and other "omics" is taken up with enthusiasm and hope that modern medicine will be able to provide treatment to people affected with RD, to improve their quality of life, allowing each and every of them to realize their full potentials.

Thomas Theelen Ph.D. MBA, BDO, Univercells
Biologics for orphan disease treatment are a blessing for patients, but the high price restricts affordability and availability. Manufacturing of such biologics is usually done in large factories, using high-volume bioreactors, requiring high CAPEX. This high CAPEX is a barrier preventing small- or medium-size players to enter the market, and limits the availability of therapeutic proteins to high-income countries. Even in high income countries, payers seek affordable biosimilar alternatives.
Univercells is proposing a disruptive biomanufacturing process able to reduce the CAPEX, while offering competitive COGS and productivity, therefore enabling the manufacturing of affordable biologics in emerging markets. We are focusing on processes implementing single-use cost-effective bioreactors operated in fed-batch or perfusion mode, with in-line clarification & capture processes operated in simulated continuous mode. We have introduced an innovative clarification technique in the form of host cell impurities precipitation operated directly in the production bioreactor. This significantly reduces the HCP/HCD burden on downstream processing and allows to use smaller chromatography columns/membranes in batch or continuous mode. It also favors implementation of monoclonal antibody capture steps different from protein A affinity chromatography. The same concept is applicable for producing biologics for lysosomal storage diseases (LSD), like Gaucher, Fabry, Pompe.
This innovative solution will allow to significantly reduce the cost of biologics manufacturing and offers an excellent opportunity for emerging countries to manufacture therapeutic proteins locally.

Moderator:
Christian Girard, Corporate Advisor-Orphan Drugs-Alternative Financing, ORPHAN DRUGS INDUSTRY Advisory & Intelligence

Panelist:
Dr. med. univ. Jama Nateqi, Co-Founder, SYMPTOMA

Panelist:
Cesare Spadoni, Chairman, aPODD Fundation

Panelist:
Guido J.R. Zaman, Ph.D., Managing Director & Head of Biology, NTRC

Panelist:
Thomas Theelen Ph.D. MBA, BDO, Univercells

Cesare Spadoni, Chairman, aPODD Fundation
All childhood cancers can rightly be classified as rare diseases. Therefore, the typical challenges of orphan drug development apply, such as small patient populations and limited financial returns. However, additional roadblocks are present, which make drug development in this area even more challenging. The big industry focus on adult oncology indications is shifting resources away from paediatric studies, often delaying paediatric access and creating needs for compound prioritisation across the industry pipeline. Moreover, the financial returns may be even smaller than many other rare diseases. In response to these challenges, the regulatory environment is changing and childhood cancer-specific initiatives are being introduced in the US and being discussed in Europe. In this context it becomes essential to explore new business and operational modes to increase the chances of success. Drug re-purposing, drug co-development and academic-industry collaborations hold the potential to achieve real progress in this area.

Prof. Matthias Schonermark, M.D., Ph.D., Managing Partner, SKC Beratungsgesellschaft
The number of gene therapy products in the pre-clinical and clinical stages has doubled in the past several years. Several individual fields, such as oncology (cancer treatment) and treatment of rare (monogenetic) diseases, have emerged as preferred areas of potential gene therapy research; many such treatments are already in advanced phase II and III clinical trials. The FDA and the EMA have already approved five one-time gene therapies between them, although no uniform regulations are currently in place to clarify how usage of these one-time therapies is to be regulated or monitored, nor how they are to be covered by insurance. The costs associated with developing, implementing, and completing clinical trials for these products are enormous, which raises questions regarding adequate reimbursement and also poses new challenges for both pharmaceutical companies and payers. In light of this wide range of challenges, the talk will present the positions relevant to the approval and reimbursement of gene therapies at the national and international levels, and then build upon these positions in order to identify the strategic options and room for maneuver available. From the perspective of the pharmaceutical company as well as those of the payer, the approval authorities, and the national agencies, it seems logical to use a collaborative approach when adjusting or re-developing regulations and systems in response to the future challenges posed by these new, innovative therapies, in order to guarantee that patients receive optimum care.

Co-chaired by:
Malcolm Allison, Director and Owner, InterComm International Ltd and
Cesare Spadoni, Chairman, aPODD Fundation

A journey into the science and effect of Occipital Horn Syndrome. David's presentation will coverprevalence and inheritance as well as how his poor health has affected his work life, education, relationships with friends and family and his aims for the future. David will speak openly about the condition and the uncertainties that come with it, especially in the stage of his life now. David will also speak about how being born with this ultra-rare condition and always being in and out of hospital has made him the man he is today and how he appreciates the life he has - despite always being different to most of his peers.

Despite recent scientific progress many rare diseases remain poorly understood. Although all doctors will see patients with rare diseases during their career, it is unlikely they will see sufficient numbers of patients with any one rare disease to be able to form a comprehensive picture of the condition and its implications. Patients and families, on the other hand, live with the condition all day and every day. They have a unique insight into what it means and how they are affected. Unless patients and families, and the clinicians who support them come together, building a holistic view of any given condition will be much more difficult than might otherwise have been the case. And if doctors and their patients are not working together to a common agenda, the critical mass that will make research possible, and attracting the investment necessary for the development of innovative therapies will not be forthcoming. In my talk I will explore how giving patients and families a seat at the table alongside the other stakeholders improves the quality of health care and brings about better, more effective and relevant research leading to the prospect of disease modifying interventions being developed where little currently exists.

Passionate about appropriate and accessible resources Rebecca will talk about why bringing science to rare patients is not just important for patients but is essential for the whole rare disease community. Frustrated with experiences of patients being told "you wouldn't understand" Rebecca and Nicola are driven to closing the information gap and promoting empowerment through knowledge. Hungry for information rare disease patients are unwavering in their quest for knowledge, so how can science support their learning and harness their immense force and drive for improvements whether that be in care, cures or social acceptance.

Marketing techniques that worked for conventional drugs, are not really working for orphan drugs. Three in four rare disease patients don't even have their diagnosis yet, comprising the biggest business challenge as 75% of potential revenues are lost due to misdiagnosis alone. But how to empower patients and doctors to think of your rare disease?

Hands-on workshop based on participant's target diseases including best practices in orphan drug marketing.

I thought it would be useful to dissect a couple of pieces of writing and turn them into a more patient friendly approach. I want to work through the medical writer`s process.

- Policy and practice associated with Orphan Drugs in Turkey
- Market access mechanisms for treatments for rare diseases
- Impact of Patient and Industry Associations