RARE DISEASE POLICY

There is nothing rare about rare diseases, and 3.5 million people in the UK will be impacted by one at some point in their lives. The diagnostic odyssey for patients in the UK is 4-7 years.1,2

Having received a diagnosis, what is unfortunately still rare are treatments for the condition – of the 7,000 rare diseases identified, only 400 have a licensed treatment.3However, obtaining a license is only the start of the challenge – approved medicines must navigate the daunting barriers of access and adoption to realise their promise for patients. Could the Innovative Medicines Fund (IMF) be that catalyst for improving access to innovative orphan medicines, just as the Cancer Drugs Fund (CDF) has been for cancer treatments? 4

Before we explore that question, let’s look at how issues are improving for people with rare disease, namely the global leadership the UK is showing, in respect of accelerating diagnosis of rare disease.

In 2015, the National Disease Registration Service (NDRS) was set up to develop and run a comprehensive population-based registration service, collecting and qualityassuring data on congenital anomalies and rare diseases across the whole population in England.5 Since 2015, it has realised national coverage of over 1,400 congenital anomaly or rare disease datasets out of over 6,000 collected.

In 2013, the UK Government launched the 100,000 Genomes Project to investigate whether whole genome sequencing (which involves reading through 3 billion pairs of letters in the human genome) could help improve diagnosis and accelerate the discovery of precision medicines.6Five years later, the UK became the first national health system in the world to offer WGS to people with undiagnosed rare diseases and cancer as part of routine care. The 100,000 Genomes Project has transformed the diagnosis of the 8-in-10 rare diseases with genetic causes, and the creation of the NHS’s Genomic Medicines Service – as well as the 50-fold goal of achieving five million sequences, offering further new hope to people with a rare disease. 7

Earlier this year, Genomics England announced the Newborn Genomes Programme (NGP) in which up to 200,000 babies’ genomes will be sequenced and analysed for a set of actionable genetic conditions which may affect their health in early years.8 The programme aims to ensure timely diagnosis, access to treatment pathways, and enable better outcomes and quality of life for babies and their families. The NGP will co-design and run an ethics-approved research pilot embedded in the NHS to explore how, and whether, to offer whole genome sequencing (WGS) to all newborns, to accelerate diagnosis and access to treatments for rare genetic conditions.

On the 11th November 2021, a study published in The New England Journal of Medicine,led by Professor Mark Caulfield and Professor Damian Smedley, analysed the diagnostic and clinical impact of genetic sequencing within the NHS. 9 Analysing the genomes of 4,660 people from 2,183 families led to a new diagnosis in 25% of patients. Many of these patients have spent years enduring the diagnostic odyssey. One such patient in the study is a 10-year-old girl who endured multiple hospital visits during her seven-year journey to diagnosis at an estimated cost to the NHS of £375,000. Once the WGS had identified her underlying problem, she went on to have a bone marrow transplant which cured her disease, costing £70,000.

As a result of Caulfield and Smedley’s work, 25% patients received more focussed care, such as family screening and therapies to help manage the condition. For patients with conditions such as intellectual disability, vision, and hearing disorders, the diagnostic yield was even higher at 40-55%. This will pave the way for accelerating the discovery of precision medicines, and attract even more clinical research to the UK for paediatric and rare disease.

In August 2021, IQVIA conducted primary market research amongst global C-Suite pharma and biotech leaders regarding the overall attractiveness of the UK for conducting clinical trials and launching new medicines, following the UK’s exit from the EU Bloc.10 Over 200 global industry leaders participated in the survey, and the results were a vote of confidence in the UK. Respondents called out the UK’s performance in respect of research and discovery of COVID-19 vaccines and treatments, and the impactful new UK Government Life Sciences Policies, from the MHRA, NICE and the Office for Life Sciences.

79% confirmed that the UK will remain a priority launch country for their company, with 74% stating that the UK would be a Tier 1 early launch country over the next three years.

The promise for people with rare diseases was even more exciting, with over one-third of the new medicines launches planned in the UK being for orphan or ultra-orphan medicines.

Headlines for breakthrough rare disease medicines, such as the triple therapy for the cystic fibrosis gene therapy, Zolgensma, which NICE ruled had an ‘exceptional impact’ for babies with severe spinal muscular atrophy (SMA), majored on deals and list price.11,12Little was reported about the time the negotiations took, and the number of other promising orphan medicines that didn’t make it over the line with either NICE or NHS England, due to the unique challenges orphan medicines face in research and data generation. Consequently, over the last five years, patients living with rare diseases in the UK and their carers have been dissatisfied with the medicines approval processes for rare disease treatments, according to a survey of this community by the Genetic Alliance and Alexion. 13 Typically, patients believe the UK processes are unfair on those living with a rare disease, and the system is both too slow, and not resourced for rare diseases.

Narrow eligibility requirements for the Highly Specialised Technology (HST) programme means that many treatments can struggle to secure approval from NICE for routine use on the NHS. In most cases, those that do secure approval often see their use restricted to certain subpopulations of their licence. The result is that patients in the top five European countries, such as Germany, Italy, and France, have better access to medicines than counterparts in England. Yet, England is ahead of most European countries, including Scotland, and restrictions to medicines might be valid given the evidence available.14

However, steps are being taken by Government and the NHS to reduce these inequalities, through initiatives such as the review of NICE’s methods and processes, the implementation of the Rare Disease Framework, and development of the Innovative Licensing and Access Pathway (ILAP). Former Minister for Innovation, Baroness Nicola Blackwood – who herself suffers from a rare disease and endured her own diagnostic odyssey – set up the Accelerated Access Collaborative and launched the NICE methods review and the Commercial Framework, announcing the new £500m Innovative Medicines Fund as part of the 2019 Conservative manifesto.

The IMF will seek to expand on the existing Cancer Drugs Fund (CDF) for the purpose of improving access to rare disease treatments, among others. This is an important step. No single initiative can solve the access to treatment challenges facing patients and their carers in England, but the IMF can address the fundamental issue of data uncertainty for rare disease treatments at the time of their first assessment by NICE.

The IMF could be a catalyst for improving access to orphan medicines. However, it is important to note that it should not be seen as a bypass for improvements to these medicines being approved for routine commissioning. IMF should ensure that system challenges, such as biomarker testing at the seven regional Genomic Laboratory hubs, do not further delay patients with life threatening diseases with access at a local level to these nationally approved innovations.

In March 2021, Alexion and AstraZeneca rare disease commissioned IQVIA to work with the rare disease community and thought leaders in the UK medicines access policy, on the development of a white paper. This was launched in September 2021 – The Innovative Medicines fund – acatalyst for access to rare disease treatments.15

The paper is designed to:

The paper makes a series of recommendations for consideration by those finalising the IMF, to ensure that orphan medicines take their rightful place in it.

Recommendation 1: Ambition To drive access for patients, rare disease medicines must have the same opportunity for IMF-funded access as a medicine for any other disease.

Recommendation 2: Entry and exit criteria The IMF must have clear but flexible entry and exit criteria that can accommodate rare disease medicines, as well as other medicines.

Recommendation 3: Funding IMF funding should not be ringfenced by disease area or medicine type, and must not operate on a ‘first-come, first-served’ basis.

Recommendation 4:The IMF should have a flexible budget linked to horizon scanning.

Recommendation 5:Funding for the IMF should be tabled as part of negotiations on the 2024 Voluntary Scheme for Branded Medicines Pricing and Access (VPAS).

Recommendation 6: Data collection The IMF should allow for bespoke data collection, taking a medicine-bymedicine approach to outcomes, data sources and the time required. The IMF must recognise the complexity and difficulty of evidence generation in rare diseases.

Recommendation 7: Governance An external IMF multi-stakeholder group should be formed, reporting annually on IMF performance using Key Performance Indicators (KPIs) broken down by disease and orphan status.

Recommendation 8: The IMF must be aligned with the evolving access landscape, including initiatives such as the ILAP, NICE Methods and Processes Review and UK Rare Diseases Framework.

The four UK nations should hold discussions to leverage lessons from the IMF – and their own funds – and explore the scope to increase the value of the evidence generated. The four UK nations should also work together to ensure access to innovative medicines, including rare disease medicines, is equitable across the UK.

RARE DISEASES AND GENETIC RESEARCH

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. 1

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.

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.

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.

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.

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.2The 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. 3 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.

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.4 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.