Therapeutic areas in focus
RARE DISEASES AND GENETIC RESEARCH
Not so rare diseases: The cumulative burden of underdiagnosis
Dr Anne Pariser from the NCATS illuminates the impact of under-research, underfunding and underrepresentation in the sphere of rare diseases, and looks ahead at the future of therapies and innovations for rare disease care
What are the significant changes we’ve seen in drug development for rare diseases in the past 10 years?
Dr Anne Pariser:
The overwhelming majority of rare diseases are single gene disorders – or monogenic disorders – where there’s a mutation in just one gene and sometimes as little as one base pair within the gene. If you can find the mutation in the gene, and then work backwards to find out what that gene does, what it transcribes, that gives us a target (to work towards). If we have a target to go after, we can design drugs, or genetic or other advanced therapeutics with considerable precision to go right after whatever that problem is. The vast majority of modern drug development is using this targeting strategy, so in addition to changing how we approach drug development, it also opens up the possibility of personalised medicine, and we’re starting to see some examples of this.
What role does genetic research play in advancing the standard of treatment available for rare disease patients?
A lot of rare disease patients go through what we call the diagnostic odyssey; it often takes years to get an appropriate diagnosis. Now it’s a lot easier and less expensive to do genomic analysis.
In England, for example, with the 100,000 Genomes Project, they’re trying to move more rapidly towards characterising young children and sick babies in the NICU to try to make these diagnoses earlier. Once you know what’s wrong, it opens the possibility of trying to develop targeted therapies that could be both highly efficacious, but also improve the safety of the drugs, because now you’re only treating a selected subset of patients who are likely to respond.
Previously, you have outlined the ‘large and growing medical footprint of rare diseases in society’. What are the effects of this footprint, and how has the footprint changed over the past five years?
It is hard to find rare disease patients and it can be very hard to diagnose patients. We know there are a lot of people out there who aren’t diagnosed. This is probably an underestimation, but here in the US we estimate about 25 to 30 million patients have a rare disease. That’s about one in 10 people, but it may actually be higher than that because there’s so many people that haven’t been diagnosed, and that percentage should be similar pretty much anywhere you would look around the world. These estimates are derived from some genomic studies based on what we know about diseases. We just published a paper on a project called ‘The Ideas Initiative’, where we were trying to do a pilot to estimate the cost burden of rare diseases, with cost being a surrogate for illness. People who are high users of a medical system tend to have serious illnesses. That’s not a huge surprise, but you can quantify costs, and it’s a lot more difficult to quantify pain and suffering. It is very difficult to even find rare disease patients in medical records or health system databases. The majority of rare diseases – probably about 75% – don’t have a specific medical record code. About 50% don’t even have a general code, so they’re often lumped into these very high level terms like ‘congenital anomaly unspecified’, ‘seizure disorder’, or ‘unspecified motor delay’. About one in ten people have rare diseases illnesses, and that’s a large public health problem which hasn’t really been identified. It also hasn’t been prioritised, and this leads to all kinds of downstream effects: difficulty getting appropriate care, and difficulty even telling people what they have. And 95% of rare diseases don’t have a treatment. Has this footprint changed over the past five years? Probably not, because these patients have always been there. I think our ability to recognise this now and try to call attention to it has been increasing.
How does suffering from a rare disease multiply the existing difficulties in access to healthcare?
I can only really speak from the US perspective; we have a very fragmented healthcare system. You add a serious illness – for which there are a few disease experts or expert centres to care for these patients – to the existing problems with fragmented care, lack of coverage, out of pocket expenses. People who don’t live in urban centres will need to be treated at a tertiary care centre or a super specialist, and there may only be a couple for each disease in the country, so they’re often having to travel long distance to access care. We suspect that it may take longer to get a diagnosis if you’re in a rural area, or in a place that does not have access to a medical expert. Think of any problem in a healthcare system, and then throw a rare disease on top of that, and it just makes it worse.
What changes are needed in the next two years to better meet the needs of patients with rare diseases, and which should be prioritised?
First and foremost, we must recognise rare diseases for the serious public health problem that they are. We have the rare diseases as a misnomer; collectively, they’re not rare at all. We are trying to educate people that rare diseases are rather common – not the individual diseases, but the patients with rare diseases. They have serious illnesses and need better care, and are as entitled to research and medical care and efficacious therapies as anyone else. That’s a real priority. We have the tools to improve this diagnostic odyssey, and we have the capability to do it now. What we’re trying to do, through education, is move on that faster. A lot of these diseases are slow, chronic, and progressive. For example, a child may have a delay, maybe not quite meeting their milestones. The tendency is to check again in six months, check again in a year, and this really starts to add up to years and multiple referrals. What we’re trying to do is try to escalate, particularly, our younger patients faster to get genetic testing, and preferably at an expert centre, or children’s hospital that is used to handling these diseases. Most of our diseases don’t have approved treatments, we know there are 1000s of diseases right now – we know the gene, and we know how to at least potentially treat that patient (a gene replacement, a gene silencing, or something that modulates the gene expression). We have the technology to do a lot of this for many more diseases; we now face more operational, logistical issues.
How can translational science help advance therapies for rare diseases?
This is predominantly now a translational problem. Once a person is appropriately diagnosed, it’s then trying to string all the pieces together to use some of the things we already know how to do. That can mean trying to speed up gene therapy development, for example. It’s the same for newer technologies, such as antisense oligonucleotides and gene editing. We estimate that it’s going to take about 2,000 years to get everybody an effective therapy at the rate we are going now. Can we approach this by looking at many diseases at the same time?
We’ve started a programme at NCATS called Platform Vector Gene Therapy (PaVe-GT) where we’re trying to develop four gene therapies at the same time.
The AAV gene therapy is a natural platform; you have the capsid of the virus, hollow out the virus DNA, and put in the human gene of interest. This hopefully will save time, money, and resources, and we can learn from one programme to another. Hopefully, that could set us up well enough that we wouldn’t have to keep repeating a lot of these steps, but we could just move a lot faster. The NIH also just stood up what they’re calling the Bespoke Gene Therapy Consortium, which is examining the commonalities around gene therapy development in the preclinical area and the clinical areas.
We can do these one at a time or share the knowledge from one programme to another. Gene editing and antisense oligonucleotides also have that potential as well. Oncology has done quite well in advancing therapeutics through platform approaches, and we’re trying to borrow from their experience with platforms, as well as treating multiple diseases or multiple drugs within a single protocol. We think translational science is the answer to this, so we just need more of it.
‘Rare disease’ encompasses a spectrum of up to 10,000 different disorders. Are there some diseases which are more neglected than others?
Almost all of them are neglected to some degree. We only have therapies for about 5% of rare diseases, so there are 95% to go. Most of these diseases are sometimes referred to as the ‘Ultra-rare Disorders’. That’s not a real definition; it’s rare or it’s not, and in this country, it’s less than 200,000 people with the disease in the US. In Europe, it’s a prevalence estimate of five per 10,000 people with the disease.
For most rare diseases, they will be classified as rare in either region, because 90% of the rare diseases are what would fall into this ultra-rare category (approximately one in a million or so people with the disease or less). We have lots of diseases, where there’s 100 or fewer patients, or a few thousand or fewer. The real distinction is it’s very hard, even with available financial incentives, to make a business case to develop a drug for 50 people or so. Even when we know what’s wrong, it is trying to harness resources to bring it through a drug development programme, so we really need better solutions.
Dr Anne Pariser
MD is the Director of the Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Sciences (NCATS) NIH. ORDR is dedicated to accelerating rare diseases research to benefit patients, through rare diseases programs such as the Rare Diseases Clinical Research Network, Genetic and Rare Diseases Information Center (GARD), and the NCATS Toolkit for Patient-focused Therapy Development. Dr. Pariser came to NCATS in 2017, and before this, she worked for 16 years at the FDA Center for Drug Evaluation and Research, where she founded the Rare Diseases Program in FDA CDER’s Office of New Drugs in 2010 and served as a Medical Officer and Team Leader for rare diseases drug and biologics product development, review and regulation. Dr. Pariser has 20 years of experience in rare diseases research, and her current research interests include “many diseases at a time” research approaches, such as platforms for gene therapies and other rare disease product development, and informatics approaches to diagnosis.
Scratching the surface of eczema care in the UK
Pharmafile speaks to
In light of a recent report by Allergy UK about treatments for eczema patients, we spoke to Head of Clinical Services, Amena Warner, about the future of diagnosis, treatment, and support for this prevalent condition
In the new Allergy UK report, you reported 30 out of 30 healthcare professionals felt there was not adequate mental health support provided for patients with eczema – what measures do you believe are needed to combat this?
There is a need for more awareness of the very significant impact on quality of life, mental health and a person’s lived experience that living with eczema can bring. We believe that psychodermatology services should be commissioned and made more widely available within the new integrated care system/primary care network infrastructure, and attached to secondary/ tertiary dermatology/allergy services to address this need. There are support groups and organisations that can also help, such as Allergy UK, and there is a need for healthcare professionals to direct patients to these sources for ongoing support.
Waiting times for diagnosis, and access to effective treatments, are often lengthy (sometimes even over a year) for eczema patients. How can the healthcare system effectively respond to this statistic?
Prioritisation within the healthcare infrastructure of eczema as a disease area that can be treated and managed effectively, if a correct and timely diagnosis is made with accurate assessment, is key. There is a need for early interventional services and investment into this area. Service provision needs to be addressed and increased to bring down long waiting times.
How does Allergy UK support those living with eczema?
We are the leading patient support and information charity for people living with all kinds of allergies. We have a helpline and webchat with a response team supported by our own clinical team. Our website is also a source of free information, factsheets and leaflets to help support people living with allergic conditions. At the same time, we run masterclasses, and produce videos and podcasts aimed at healthcare professionals on all aspects of allergy, including eczema.
Our work is focused on improving the lives of people impacted by allergic conditions.
What are some of the greatest challenges experienced by people living with eczema, and how have these been exacerbated by COVID-19?
Eczema is a very visual skin condition which can flare and can become very problematic at the most inconvenient times. People often say the itch is the worst aspect, and this often leads to sleepless nights, infection, and scarring of the skin. The huge impact this can have on the individual should not be underestimated, and this is backed up with data from many research studies, as well as what we hear on our helpline. Imagine this on a regular or daily basis and you can begin to understand why so many people affected have difficulty with work/school, with relationships, with concentration, with social situations, etc. Getting an accurate and timely diagnosis can be a challenge for many; as can gaining treatment to control and manage their condition without giving them serious long-term side effects. While COVID-19 has been unkind to everyone, having a condition like eczema can be isolating in itself, causing psychological, as well as physical, distress. The changes in our daily lives caused by COVID-19 are inevitably going to exacerbate those issues. Online consultations are challenging because they do not give a full picture of the condition, and many people are reluctant or embarrassed to expose the full extent of how eczema affects them.
What guidelines would you like to see implemented for better patient outcomes?
We would like to see the prioritisation of the development of NICE guidelines for children, young people, and adults. Also, creating patient pathways for people affected by atopic eczema, with a standardised approach to diagnosis, treatment and management of eczema across the whole of the UK in order to put the patient at the heart of the decisionmaking process for best practice care.
What are your hopes and visions for the future of eczema care and support?
That best practice care, treatment and support be received by those who need it. No one with eczema should feel alone with their condition and the impact it has on their lives. Finally, of course, that a cure will mean that eczema will be eradicated as a health condition.
is Head of Clinical Services at Allergy UK, a national charity that works to raise awareness of allergic disease both nationally and internationally. She took up this appointment after working as a Clinical Nurse Specialist in Immunology and Allergy at an NHS Hospital Trust. She trained at University College Hospital, followed by paediatric training at Great Ormond Street Hospital in London. She also holds a Public Health and Specialist Practice in School Nursing qualification gained in 1994. Visiting schools and carrying out health assessments made Amena very aware of the rising incidence of allergy in the UK and was instrumental in developing her interest in the field.