Level of scientific knowledge on exceptionally rare metabolic inherited diseases and their potential orphan medicinal products. To what extent is this linked to sponsors deciding to apply for an orphan designation ? A recent publication in the Orphanet Journal of Rare Diseases provides more insight into this matter.
The study was inspired by the observation that, although not abundantly, approved orphan medicinal products for exceptionally rare diseases (<10 patients per 1 million) certainly exist. The University of Utrecht and Rare Disease Matters wanted to know whether orphan designation applications for exceptionally rare metabolic diseases were associated with the level of available scientific knowledge and prevalence. Other factors included in the study were metabolic disease class, prognosis and time of first description of the disease in the literature.
In total, 166 rare metabolic genetic diseases were included in the analysis. For only 42 (25%) of the diseases an orphan designation application was submitted at either FDA or EMA before January 2012. A multivariate analysis identified preclinical proof of concept of a potential medicinal product as major knowledge related determinant associated with an orphan designation application. Prevalence of the disease was also found to be associated with filing an application for an orphan designation.
Drug innovation cycle: From clinical picture to product becoming available to patient
Proust once said “The real voyage of discovery consists not in seeking new landscapes, but in having new eyes”.
In a new book chapter “Why R&D into rare diseases matter“, I explain that translation of rare disease research into orphan drug development continues to represent one of the most important steps towards alleviating the burden for patients suffering from a rare disease. Developing an orphan drug is certainly feasible, but also tough, not without risk and requires a great deal of persistence. Countries across the globe have joined the fight against rare disorders. Apart from western world countries and Japan, other countries, like China, India and Turkey have stepped into the arena thereby really making it a global fight against rare disorders. Of course, this should be done in close interaction with all stakeholders, including patient organizations and learned societies.
Rare disease-focused foundations have been founded by patients or their relatives with the aim to generate sufficient disease understanding that can form the basis for a potential treatment. Well-known examples are the Cystic Fibrosis Foundation and the Muscular Dystrophy Association who grant tens of millions of dollars in the area of research. However, such endeavors are certainly not the exclusive domain of large foundations. There are many smaller ones who start small, but already think big.
Patient organizations have been instrumental in raising awareness for rare diseases. This is only one aspect of the central role that patient organizations continue to play in the field of rare diseases. Another one that allows them to make a difference is funding research. A 2009 survey by the European organization for rare diseases EURORDIS revealed that 37% of the patient organizations that responded to the survey (N=309; overall response rate 40%) had funded research in the last five years. Half of these organizations spend more than 30 000 euros yearly and one quarter spend more than 112 000 euros a year. Such a level of funding may come across as small, but please bear in mind that for some exceptionally rare diseases this may actually represent the first step into unravelling the pathobiology of these diseases.
These small foundations follow in the footsteps of larger ones, like the Cystic Fibrosis Foundation, the Muscular Dystrophy Foundation and the French Muscular Dystrophy Association (AFM). These large foundations have moved beyond the classical role of research funder. They have adopted a venture philanthropy business model to pro-actively accelerate the transition of basic research to product development. Part of the model is to form strategic partnerships with biotech and pharma companies. If you want to read more about this subject, I can highly recommend an article by Gambrill. It contains a concise overview of five (rare) disease-focused foundations who adapted their strategy to allow them to reap the benefits from their funded research.
Obviously, such a role may not be envisaged for smaller rare disease-focused foundations. Their limited resources and revenues have to be spent with even greater care than their large counterparts to ensure maximum impact. A study by Wood et al. in the August issue of Drug Discovery Today provides some anecdotal evidence that small foundations are capable of moving beyond the traditional patient role. The authors provide three inspiring stories of Jonah’s Just Begun, Hannah’s Hope Fund, and the Hereditary Neuropathy Foundation. What is fascinating about these stories is that all three foundations pursue rare disease research on a very small budget with very few resources at their disposal, but combine this with an extraordinary ability to connect with scientists and to raise the necessary funds that can make a difference.
These are just three examples of a large group of rare disease-focused foundations that may be small, but already think big.
The RANKL cytokine acts as the primary signal for bone removal, and as such plays a crucial role in bone homeostasis. In 2010, Amgen’s denosumab, a monoclonal antibody against RANKL was approved in the US and EU for the treatment of postmenopausal osteoporosis and cancer-related osteolysis. In a recent review in Clinical and Developmental Immunology, Iacono et al. describe that genetic defects in the RANKL cytokine are linked to a specific form of autosomal recessive osteopetrosis (ARO), a rare bone disease. This link may hold a key to a cure for this form of osteopetrosis.
Normal bone growth is accomplished by a balance between bone synthesis and bone resorption. Two cell types play a central role in bone homeostasis: osteoblasts (synthesis) and osteoclasts (resorption).
A shift in the balance towards bone resorption leads to a decrease in bone mass – better known as osteoporosis. An increased bone synthesis leads to osteopetrosis, an extremely rare inherited disorder. Despite this excess bone formation, people with osteopetrosis tend to have bones that are more brittle than normal. Osteopetrosis is not one disease, but actually comprises a clinically and genetically heterogeneous group of conditions, ranging in severity from asymptomatic to fatal in infancy. Patients with a severe form of the disease experience very severe growth retardation and bone defects including deformities. They can develop anemia and become transfusion dependent, requiring the use of chelating agents. Also blindness, deafness and severe headaches are not uncommon. Currently, Hematopoietic stem cell transplantation (HSCT) is considered the only durable cure for the majority of patients affected by osteopetrosis.
In 2007 the group of Sobacchi identified mutations in the RANKL gene in a number of families affected by autosomal recessive osteopetrosis (ARO). These mutations were found to affect the conformation and binding activity of the cytokine, but can also result in protein instability or misfolding. Since it was already known that the RANKL cytokine plays a central role in bone resorption, the authors hypothesized that the RANKL cytokine could be an interesting therapeutic approach for patients suffering from RANKL-dependent ARO. Since HSCT is not effective in patients suffering from RANKL-dependent ARO, an alternative therapeutic approach is clearly warranted. Several pre-clinical studies have confirmed that the administration of soluble RANKL has a great impact on metabolism and structure. However, it was the group of Sobacchi, using a RANKL gene knock-out mouse model, who provided evidence that administration of soluble RANKL almost completely rescued the bone defect by restoring bone removal.
As Iacono et al. conclude:“the recognition of direct RANKL involvement in a genetic rare disease can constitute one of the few cases in which the result of a genetic study could also be translated into a replacement therapy.” Of course the proof of the pudding is in the eating. Next step is to determine whether soluble RANKL is effective in patients affected by RANKL-dependent ARO, and represents a viable therapy for these patients.
Within Europe consensus exists that future public expenditure on health care requires greater scrutiny and efficiency, in particular in pharmaceutical spending. Although not completely clear, being an integral part of the healthcare system, the field of rare diseases is under scrutiny as well. Flexibility will be required from all parties involved to effectively adapt to the changing healthcare climate. Being flexible has always been a trade of the rare disease community, but the current challenge is a formidable one. This time we may have to come up with really unconventional solutions through a considerable amount of healthy “out of the box” or creative thinking. When it comes to “out of the box” thinking our young and bright scientists and entrepreneurs may hold a key to successfully cope with the challenge that lies ahead of us.
During one of my many google searches I came across the Forbes annual listing of 30 under 30. The listing contains for a total of 15 fields a description of 30 of the brightest young disruptors, innovators and entrepreneurs. In the field of science & healthcare Joshua Sommer, age 24, was at the top of the list. Joshua Sommer is the executive director of the Chordoma Foundation. At the age of 18, he was diagnosed with chordoma, a rare bone cancer for which there was a 30% cure rate and no approved drugs. When he discovered that a lack of research funding was a major cause for little research being done into chordoma he took the initiative to found the Chordoma Foundation. Since its inception the foundation has raised over $2.5 million, funding research in 11 labs.
“Sommer’s advice to people diagnosed with a potentially fatal disease? You have a lot of power” (Forbes website)
Why am I sharing this with you ? Well for one thing there are many more young people like Joshua Sommer out there that are trying to make a difference. Apart from starting foundations, they also start their own companies like Dutch entrepreneur Daniel de Boer did (ProQR Therapeutics). Moreover, there are many young bright scientists that I consider the engine behind the advancement of our understanding of the 6000-8000 rare diseases.
This brings me to the question I would like to share with you. Do we sufficiently “exploit” the energy and brain power of the Joshua Sommers and Daniel de Boers of this world ? When it comes to “out of the box” thinking this generation may hold a key to successfully cope with the challenge that lies ahead of us. They may think of really unconventional solutions. Please remember that this generation through Mark Zuckerberg also delivered Facebook.
The question is how do we channel all this energy and potential flow of radical ideas ? Perhaps it is an idea to create some sort of social platform of the bright and young that acts as a radical think tank. Maybe in Europe perhaps the EU Committee of Experts on Rare Diseases (EUCERD) could take the lead in supporting such a platform. Some of you will remark that EUCERD was formally established via the European Commission (EC) Decision of 30 November 2009 (2009/872/EC). As such the idea may be too radical as the EUCERD can only act within the mandate given by the EC. Fortunately, EC Decision 2009/872/EC allows some maneuverability in this respect. According to Article 7 of the Decision “The Committee may set up temporary working groups”. Furthermore “Working groups consist of external experts selected according to their specific expertise”. A “Working group” of bright young disruptors, innovators and entrepreneurs in the field of rare diseases could certainly fall into this category.
I would love to hear from such a YoungEUCERD platform how they believe we can secure the future of rare diseases.
Napoleon Bonaparte once said of China, “Let her sleep, for when she wakes, she will shake the world.” When it comes to rare diseases China has awoken and belongs to the top-10 countries based on scientific output. China doesn’t just stop at research.
China is quickly becoming a medical research powerhouse to reckon with. A recent literature search revealed that articles related to basic medical science and clinical research from China increased each year between 2000 and 2009 [Hu]. On average by 31% and 22%, respectively. In 2011, China was ranked fourth according to number of medicine-related publications in the SCImago Country Ranking (In 2000: rank 18). A truly remarkable achievement, although some concern has been expressed with regard to the quality and trustworthiness of the published research. China’s contribution to rare disease understanding is growing as well. A comparison of scientific output for 88 rare metabolic disorders and a dataset of 84 rare nervous system diseases between 1996-1998 and 2009-2011 revealed that China now belongs to the top-10 countries (see Figures below).
China’s growing role in (rare) medical research will certainly make a difference in our understanding of a number of rare diseases. However, to make a truly meaningful difference for the patient, disease understanding has to be translated into orphan drug development or some form of health care innovation. Therefore, it is important to know that China is not only making a difference in understanding disease, but is also focussing more and more on biopharmaceutical innovation [Rezzai]. A recent publication by Rezzai et al.revealed that China has built close to 20 high-tech parks with a life sciences component in the last fifteen years. R&D expenditures as a portion of its gross domestic product has doubled between 2002 and 2007 (~ US$102 billion in purchasing power parity). Finally, between 1999 and 2007 approximately US$200 Million of public funds was devoted to financing biotechnology companies. Perhaps China’s innovation power is best exemplified by SiBiono’s innovative gene therapy product, marketed as Gendicine for treatment of head and neck cancer since 2009.
The combined progress in research and innovation provides China the means to not only generate disease knowledge, but at the same time capitalize on this newly acquired knowledge in drug development. The first “Made in China” orphan drug approved in the EU or US may become a reality soon.
Relative contribution of Top-15 countries to the total scientific output for 88 rare metabolic disorders (1996-1998) - click to enlarge
Relative contribution of Top-15 countries to the total scientific output for 88 rare metabolic disorders (2009-2011) - click to enlarge
Relative contribution of Top-15 countries to the total scientific output for 84 rare nervous system disorders (1996-1998) - click to enlarge
Relative contribution of Top-15 countries to the total scientific output for 84 rare nervous system disorders (2009-2011) - click to enlarge
Note on Methodology: In brief, PubMed was used to determine for every “SCImago” top-15 country the total scientific output. For every disease (prevalence 0,1-50/100,000) a PubMed search string according to Heemstra et al.  was prepared. Via concatenation search strings were combined into one PubMed search string.
For those working in the field of orphan drug development there is quite some interesting scientific literature available. An overview with hyperlinks of relevant scientific publications on orphan drug development has been included in this Month’s blog. However, although the science is interesting, what is important is to learn from the experience of orphan drug developers themselves. Orphan drug development is do-able, but tough and requires persistence.
In my last blog I provided an overview of orphan drugs (OD) approved in the EU in the period 2000-2010. The overview by Joppi et al. covers in depth preclinical and clinical information for each OD. As such it provides very useful background information for those currently working on the (clinical) development of an orphan drug. What I didn’t share with you is that the authors not only provided an overview, but also expressed considerable criticism with regard to the quality of the registration dossiers. The authors in particular questioned the level of clinical development programmes. In their opinion “the number of patients studied, the use of placebo as control, the type of outcome measure and the follow-up have often been inadequate”.
Several of these aspects have been studied by Heemstra [2008, 2011] and Putzeist . In particular pivotal clinical trial stage, size/experience of the sponsor and regulatory dialogue were found to be critical factors for successful orphan drug development. There is more literature out there that provides quite interesting reading material (see table below).
The routes to orphan drug designation–our recent experience at the FDA
Science certainly helps to better understand orphan drug development. However, it is always good to also learn from practice: the orphan drug developers themselves.
I was in luck. At 29-30 November I attended the World Orphan Drug Congress in Geneva to present some of my work. The meeting allowed me to learn about the clinical development programmes of UniQure, Genzyme and Vertex Pharmaceuticals. For those unfamiliar in the OD-field these are not just any companies. Genzyme is generally considered as one of the frontrunners in orphan drug development. UniQure has developed the first gene therapy product Glybera that has been approved in the western world. Vertex pharmaceuticals has been responsible for the development of the new innovative Cystic Fibrosis product Kalydeco. What these companies clearly showed is that clinical development of an orphan drug is certainly not impossible, but tough and not without risk. To name a few: the number of patients is limited, regulators seem to be uneasy with innovative products and rare diseases can be highly heterogeneous in phenotypic expression.
Above all the companies expressed an incredible amount of persistence to reach their goal: Making a therapy available to the patient.
I wish everybody a merry Christmas and for 2013: Be persistent in whatever you do, I certainly will !
This week a wonderful overview of orphan drugs (OD) by Joppi, Bertele and Garattini was published in the October issue of the European Journal of Clinical Pharmacology. The overview covers in depth preclinical and clinical information for each OD approved in the EU in the period 2000-2010. As such it provides very useful background information for those currently working on the (clinical) development of an orphan drug.
Those thinking of entering or those that have just entered the orphan drug arena, should be aware. Approval of an orphan drug is certainly feasible, but is accompanied by difficulties, in particular during the clinical development stage. The crucial question that every orphan drug developer will (have to) address is: which development strategy is most likely to be successful. SMEs are faced with the decision to license or sell promising products to larger companies or to develop the product under their own steam. Larger pharma, although not new in the OD area, are not always aware of the peculiarities that surround clinical development of an OD. A standard clinical development strategy in OD development is the exception rather than the rule.
The latter is best demonstrated by the recent overview of orphan drugs approved in the EU provided by Joppi, Bertele and Garattini and published in the October issue of the European Journal of Clinical Pharmacology. For those unaware, the authors provided a similar overview in 2009. The 2012 overview provides in depth preclinical and clinical information for each OD approved between 2000 and 2010. Apart from general details, like product name and indication, the overview includes: whether protocol assistance was used; dose finding study performed; the type of pivotal trial, including details (control, end-point, number of patients and duration of the study).
Last year I received a request for a detailed overview of approved ODs from the CEO of a quite successful OD company. The 2009 overview not only contained the necessary information, but allowed me to fulfill the request within a matter of minutes. As such, I consider the 2012 overview a real added-value for orphan drug developers, be it an SME or larger pharma. Moreover, it emphasizes the added-value of this kind of research as well as the need for research that enhances our understanding of the orphan drug development process. There is much more information out there. Some of it I will present at the World Orphan Drug Congress in Geneva on 30 Nov. Hope to see you there !
The Wellcome Trust Pathfinder Award scheme represents an important new funding opportunity for early stage R&D projects in the area of rare diseases. Review of the eligibility criteria raises the question whether the Trust is fully aware of the central role that Small and Medium-sized Enterprises (SMEs) play in orphan drug development.
One of the major hurdles in the rare disease area is translating specific disease knowledge into an orphan drug development program. When I learnt about the Wellcome Trust Pathfinder Award scheme, my response was one of great enthusiasm. Although funding isn’t the only solution, the aim to kick-start early R&D studies in rare diseases certainly contributes to overcoming the translational hurdle. The focus of the scheme on public-private partnerships will also help. After all, apart from funding, there is general consensus that when it comes to developing an orphan drug; collaboration is considered a key success factor. What’s not clear to me is why one of the eligibility criteria of the Pathfinder Award scheme is “Evidence that the company has previously developed and subsequently taken to market one or more product lines arising from its own research and development is required“. In my opinion what would make the scheme even more appealing is if SMEs with no prior experience in bringing a product to the market would also be eligible.
Author: J. Patrick Fischer
Since the introduction of specific orphan drug legislation SMEs have played a central role in the development of the majority of orphan drugs [Torrent-Farnell, ICORD 2005]. In a way this group can be regarded as the engine behind orphan drug development. Besides kick-starting many orphan drug development programs, SMEs have shown to be able to move orphan products from proof of concept into the early clinical trial stage thereby adding significant value. Some have tried to reach the market on their own, but for the late stage clinical development many SMEs sought some sort of partnership with a larger pharmaceutical company. Of course, not every orphan drug development program has been successful, but that’s part of the business. We should focus on the success stories. At the start of the Orphan Drug Act in the US in 1983, companies like Amgen, Genentech and Genzyme were just starting up. These companies were one of the first that profited from the economic incentives to stimulate product development for rare diseases. It allowed them to bring their first products to the market, but more importantly it made a difference for children and adults suffering from Gaucher disease, severely growth retarded children and patients with kidney failure.
A more recent example is AMT/Uniqure, a Dutch SME. Seed funding from public and private sources enabled the company to establish a proof of concept for its technology platform. Additional venture capital and an initial public offering allowed the company to develop the first gene therapy product that has been approved in the western world !
Therefore, my plea to allow SMEs with no prior experience in bringing a product to the market to benefit from the Wellcome Trust Pathfinder Award scheme. I believe this will provide a real boost to pharmaceutical innovation in the area of rare diseases.
Source: Fresh Water, Author: Ferdinand Reus, Arnhem
The Myrovlytis Trust, a UK-based charity, is making a difference for patients suffering from Birt-Hogg-Dubé syndrome. It does so in many different ways and is accompanied by many more charities.
Since its foundation in 2007 the Myrovlytis Trust has been funding research into Birt-Hogg-Dubé syndrome (BHD), an inherited genetic condition linked to benign skin growths, collapsed lung and kidney cancers. Recently, the Orphanet Journal of Rare Diseases published a Letter from Vicki Colledge and John Solly of the Myrovlytis Trust. Using BHD as example, the authors argue that symposia, focused on a specific disease, provides a platform to promote research collaboration. Moreover, for extremely rare disorders symposia may be the ultimate way to promote a productive rare disease community and an important information source for patients and other stakeholders. The Myrovlytis Trust is currently expanding its work into related rare genetic kidney disorders.
The Myrovlytis Trust is certainly not the exception to the rule. Many rare disease charities exist (see 200 other examples) and they complement the great work performed by rare disease patient organizations. Some are (still) small, others are huge. Rare disease charities have been around for over 50 years, but it seems that many have been founded in the last decade (See figure below). Whatever their size or foundation year, their work and ambitions go far beyond pump-priming research. Some examples:
Distribution of 200 rare disease charities based on foundation year
starting a company
Fund raising tools.
Be sure to visit the Myrovlytis Trust website and get a flavour of what a rare disease charity is all about. Besides funding research rare disease charities have something else in common.
They have the conviction that they can make a difference in the lives of rare disease patients. I for one am thoroughly convinced that they are succeeding.