ULTRA-RARE DISEASES

Manjinder Bains:Many rare diseases will never be encountered by a clinician in their whole career. Because of this, awareness and understanding of specific rare diseases is generally low amongst the majority of healthcare professionals (HCPs). With as many as 7,000 known rare diseases, diverse and often-complex in nature, reaching a correct diagnosis can be a long and arduous journey. It is not uncommon for a diagnosis to take over five years, with some patients experiencing delays significantly longer.

Within this period of uncertainty, patients often face a myriad physical, practical, and mental health challenges. While clinicians will do their best to understand and manage the unexplained symptoms their patient is experiencing, a reality is that the person in question may not be receiving the treatment they need. The consequences of this can range from the worsening of their disease and symptoms to an increased likelihood of irreversible damage or even shorter life expectancy.

When an HCP does not see an improvement and the diagnosis remains elusive, the common solution is to seek greater expertise and refer patients elsewhere. In fact, in the UK, patients with a rare disease see, on average, eight clinicians, including four specialists, before a diagnosis. The patient and their family will have to deal with numerous appointments, tests, and misdiagnoses, which can severely impact the patient’s life – from missing school or time off work to being unable to cope with much else beyond their condition – often with no end point in sight.

We believe in the importance of supporting HCPs, and most importantly patients, to help overcome obstacles to rare disease diagnosis.

For the patient at the centre of these diagnostic pathways, the journey begins at symptom onset where their first port of call is most often their GP. While it is not feasible to expect a clinician to be familiar with even a fraction of the possible rare diseases, novel technological approaches can support GPs by flagging risk factors and symptom combinations that might be indicative of ultra-rare diseases. By partnering with health technology companies providing these services, Ipsen hopes to improve intervention at the earliest possible point in the diagnostic pathway.

Moving forward, the industry must work closely with the NHS, patient advocacy groups (PAGs), and patients to better define diagnostic pathways, leveraging research, real world data, and patient experience to optimise these processes.

While the specific causes of many rare diseases remain undetermined, a significant number are known to result from genetic abnormalities. Over the past 20 years, huge advances in genomics and health technology have opened the door to new research possibilities, helping us to better understand risk factors associated with certain rare diseases and how their early presentation differs from patient to patient. We now need to bridge the gap between research and clinics, and support HCPs in spotting early manifestations of these conditions.

As a step towards this, Ipsen is working with health technology company Mendelian to equip clinicians with a tool to assist in the early detection of NETs. Mendelian’s MendelScan tool can flag patients that are suspected of having a rare disease, including suggesting investigation into NETs. The scanning algorithm does this by searching electronic health records for indicators of rare diseases and associated clinical patterns.

Genetic testing is also important, and not only plays a role in understanding the causes of rare disease, but can also be utilised in diagnostics. Last September, the UK Government set out a 10-year strategy to create the most advanced genomic healthcare system in the world, building on the success of the 100,000 Genome Project and the ongoing UK Biobank, amongst other genomic research programmes. As part of their plan, the government will aim to roll-out whole genome sequencing to patients with a suspected rare disease, which could be instrumental in achieving earlier diagnosis of these conditions.

Historically, small patient populations have presented cross-sectional challenges when it comes to rare disease, from difficulties in recruiting for clinical trials, to a lack of investment and limited patient voice. There have also been significant challenges in showing the value of therapies using conventional models of cost-effectiveness. However, changes to the way in which new drugs are tested and evaluated means the pharmaceutical industry has been able to better utilise real-world data and patient insight. This has helped to remove some of the barriers to bringing new therapies to market, and allowed us to generate important debate about the provision of care for those impacted by rare conditions.

While rare individually, collectively, rare diseases affect 1 in 17 people, meaning there is a massive community of people that could benefit from improved standard of care. This can often be achieved in a realistic and practical way: creating more specialist centres, increasing homecare provision, and providing more support for caregivers.

As with all disease areas, patient organisations play a crucial role in providing information and support to patients and their surrounding networks. At Ipsen, whenever possible, we partner with these dedicated groups to help raise vital awareness, and provide information and support to rare disease communities.

While there are the obvious physical impacts of living with either a diagnosed or undiagnosed rare disease, there is also a huge psychological toll on the patient and their support network. Dealing with a disease diagnosis can be a confusing and daunting time, and while this is true for many conditions, emotions can be heightened with rare diseases. Unfortunately, due to the limited awareness of these conditions, there are often fewer resources and support services available to both the patient and their loved ones. Sadly, this has been exacerbated by COVID-19, which made people less able to connect with those around them and access external support.

Ultimately, the most important factor to consider is the quality of life attained by the patient living with the rare disease. Too often, the focus is only on whether treatment is reducing symptoms and prolonging life. However, the impact of treatment on the overall quality of life (QoL), and the ability for a patient to participate in work, socialising, and other aspects of their lives, should be considered as equally, if not more, important.

The changes being implemented by National Institute of Health and Care Excellence (NICE) to their health technology appraisals, following their recent methods review, are a positive step towards better factoring in QoL, when considering the value proposition of novel or innovative therapeutics.

Rare diseases as a whole encompass a broad spectrum of therapy areas and affect a multitude of bodily systems, so there are often learnings from our research into rare diseases that can be applied more generally, providing insight on disease drivers, genetic predispositions, disease pathology and inheritance patterns. In particular, genomics is a fantastic tool for understanding disease and medicine, and we are now able to utilise the capabilities of technology to store this data and build an increasingly clearer picture of health and disease. While health technology software is currently being utilised to scan for rare diseases, as this bank of genomic data, along with stored clinical patterns and symptom presentations expands, it may become possible for these approaches to aid clinicians in the earlier diagnosis of more common diseases.

The most important change is that there has simply been a much greater focus in the last 15 years on FOP as a disease. Prior to this, awareness and understanding of FOP was relatively low. This change is, of course, positive in terms of the impact on those patients living with FOP – ultimately more understanding of the disease and burden of illness leads to greater drive to investigate and develop treatments to improve outcomes.

The other key change that has happened is that the importance of early diagnosis has been brought to the forefront of FOP management. The fact that we now have a genetic marker to support that all-important diagnosis is crucial for many patients and their families.

As with other therapy areas (and especially in the case of rare diseases) patientcentricity needs to be kept front of mind. It is understandable that rare disease patients may sometimes feel ‘forgotten about’ or ‘left behind’. A feeling of being alone is understandable when a patient may have never met anyone else with their condition.

There is also merit in mentioning the importance of creating a focus on rare diseases for policy makers. Any approval and reimbursement processes need to be agile and adaptable as, simply put, it is a challenge to demonstrate the value of rare disease therapies using conventional models of cost-effectiveness. I am pleased to say that these processes are adapting and making better use of real-world evidence and patient insights to demonstrate value.

The most important takeaway is the plight of truly understanding rare diseases, and the importance of improving outcomes for those that live with them – be that treatments, homecare, support with mental health, or anything else that affects their overall QoL.

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.