40th Anniversary Report

1981-2021

40 years of supporting people living with Inherited Metabolic Disorders

Contents

2. An Introduction

4. The Beginning

6. 1980-1990: Individually rare, collectively common

14. 1990-2000: Growth and development

18. 2000-2010: Moving at pace in a changing world

21. 2010-2020: A connected world brings new opportunities

26. 2021 - A window of opportunity

30. Metabolic Support UK - Our future

31. Thank you to our sponsors

32. References

This report sets out the story of Metabolic Support UK in our first 40 years. It is a story of how one family made a difference for millions of others but also an insight into the rare disease sector more broadly - a sector full of passionate individuals challenging a system that leaves them out.

2022 will be a pivotal year for MSUK as we bring together 40 years of innovation and support with our forward thinking progressive plans to reset the tone for people living with Inherited Metabolic Disorders. Look out for our report 'Thoughts into Action' in early 2022.

I have the privilege of leading MSUK into the next 40 years. We will carry the spirit of our founders, Peter and Lesley Greene who began by handing out flyers in the street; delivering knowledge and power directly into the hands of people living with Inherited Metabolic Disorders.

Kirsty Hoyle Chief Executive Officer

Since we began in 1981, the landscape for people living with Inherited metabolic Diseases (IMD) has changed unrecognisably. Great progress has been made for rare patient communities however the needs of our communities remain.

Our 2030 strategy drives us forward into the next 40 years, building on the foundation of the last 40 years and establishing a strong structure moving forward. Focusing specifically on individual support, building communities, empowerment and advocacy for the IMD community in an interlinked approach. This requires open, transparent collaboration and excellence at every juncture.

Our 2030 strategy will ensure that MSUK remain not only current, but in the eye of the storm. IMDs, like other rare diseases, have long been considered an ‘orphan’, but as orphaned children do become independent adults, we must now accept both the responsibility and opportunity of adulthood. As we look back over 40 years of innovation and support and celebrate this major landmark, we also embrace the future, the new landscape and the emerging needs that we must anticipate and be ready to support.

I’m honoured to be part of the journey.

Dr Elin Haf Davies Chair of Board of Trustees

The beginning

Jennifer Rachel Greene was born on 8th December 1978. A happy baby, well-loved by her parents, Lesley and Peter, it quickly became clear that Jennifer was not gaining weight as expected for a child of her age and was vomiting a great deal. Trying to get help for their daughter, the family began the difficult journey to understand their daughter’s needs and eventually reach a diagnosis. This began with approaching Dr Robert Pugh, the family’s consultant paediatrician at their local hospital. Following several routine investigations for infants not gaining weight, such as gluten and wheat sensitivity, blood tests and x-rays that showed the reflux caused by vomiting, Dr Pugh realised ‘‘The penny dropped that this wasn’t a mechanical thing, that something else was driving this vomiting’’. It was suspected Jennifer had a metabolic disease and, eventually, Jennifer was diagnosed with cystinosis, a rare Inherited Metabolic Disorder (IMD) in April 1980.

Despite having a diagnosis, as the parents of a child with a rare condition in the early 1980’s, Peter and Lesley quickly discovered how difficult it was to access relevant support and advice. Lesley shares ‘‘We became extremely frustrated, and also very angry that we couldn’t find very much information on her condition’’. Although Dr Pugh and other medical professionals did strive to understand the rare condition, the general lack of support for people with IMD’s left Peter and Lesley with ’’a feeling of isolation’’.

‘The penny dropped that this wasn’t a mechanical thing, that something else was driving this vomiting’’

Dr Robert Pugh, MSUK Trustee

‘If I'd have thought that for the rest of our daughter's life we would just have to kneel down and pray...that would not be enough’’ Lesley Greene, MSUK founder

This experience galvanised the family, who wanted to find a way to support other people living with IMDs and, with the help of family, friends and a few key healthcare professionals, they founded the Research Trust for Metabolic Diseases in Children (RTMDC) in November 1981. The founding board aimed for RTMDC to promote research and be the world’s leading advocate and provider of bespoke support for those with rare metabolic diseases and their families.

Jennifer took this journey with her parents, supporting and championing the work of the charity during her life. Although Jennifer’s condition would ultimately be life-limiting, she lived a full life of ambition and achievements until her passing in 2007, aged 28. After receiving a kidney transplant, she went on to achieve a university degree and began teacher training in 2005. She also survived cancer twice following outstanding treatment and support from the NHS.

Metabolic Support UK is Jennifer’s legacy and the Greene family have ensured that, through setting up and supporting the charity, people in 2021 have somewhere to turn for support when navigating their journey with a rare inherited metabolic disorder. Metabolic Support UK has developed to become an indispensable network for patients and their families and will continue so to be.

Our founders’ successes can be observed through both Peter's Order of the British Empire OBE in 1994 and Lesley's appointment as Founder Director and later President of the Europe wide campaigning body EURORDIS as well as member and then Vice Chair of the Committee for Orphan Medicinal Products at the European Medicines Agency 2009-2018

1980-1990: Individually rare, collectively common

The Research Trust of Metabolic Diseases and Children (RTMDC) was established at a time when the rare disease landscape was relatively limited. Patients with rare diseases were underrepresented in the healthcare sector and faced an onerous diagnostic odyssey that is still a significant issue today. The individual needs of rare patients weren’t understood and there was also a lack of awareness of the collective public health burden of rare diseases due to their severity of symptoms, fatality and the number of people they affect.

RTMDC sought to increase awareness and knowledge across the UK but in the 1980’s there was little public access to the internet so quickly disseminating information was very difficult. So the Greenes started locally; they produced a leaflet detailing the charity’s ambitions - to support families and increase researchand simply starting handing them out in their neighbourhood. This is how they found their first family; a boy diagnosed with Hunter Syndrome (MPS 11) was just in the next street. This highlighted to Peter and Lesley how ‘’individually rare, collectively common’’ rare diseases are.

Alongside finding and bringing together patients, the Greenes needed allies in the medical profession to grow the charity. Their first supporter, their daughter’s consultant paediatrician Dr Robert Pugh, introduced Peter and Lesley to Dr Imdadali Badruddin Sardharwalla, an influential healthcare professional as Head of the Willink Metabolic Unit at Saint Mary’s Hospital, Manchester and a member of the Society for the Study of Inborn Errors of Metabolism (SSIEM). Through this connection, the charity was also introduced to the President of the SSIEM, Dr George Marcus Komrower, who became RTMDC's first President and helped to develop its specialist Medical Advisory Board

Key Milestones

The Research Trust of Metabolic Diseases and Children was formed in November 1981.

RTMDC successfully campaigned (with others) for new-born screening to be expanded beyond hypothyroidism and phenylketonuria.

The Orphan Drug Act was introduced in 1983, leading to the first orphan drug approval in the USA paving the way for Europe's orphan regulation 16 years later.

These crucial introductions helped the Greenes to bring together a group of influential professionals who formed the charity’s inaugural medical advisory board. The board supervised the charity’s information leaflets, spoke at conferences and acted as research assessors. This early development for the charity highlights the significance of collaboration in promoting the rare disease community; it is vital to work together to share expertise.

As the family worked at progressing the charity, the wider rare disease landscape was changing. The SSIEM launched the Journal of Inherited Metabolic Disease in 1978 in order to provide invaluable information regarding specific topics in the field of inborn errors. This was fortuitous timing for the RTMDC; the SSIEM became an important driver for increasing awareness of the charity. Through this connection medical professionals began referring families to RTMDC, trusting in its growing reputation for a strong commitment to care and support

In 1982 the charity was slowly building a presence in the medical and local communities when a media opportunity created a step change. Through their local connections the Greenes secured an appearance on Songs of Praise in their local church, Saint Mary’s Church in Nantwich. Lesley was interviewed on this hugely popular tv show and talked passionately about Jennifer and rare disease sharing that ‘‘not only was information not reaching parents of children with rare diseases but information was not in fact reaching doctors either’’. The exposure from this interview created a swell of interest, financial donations and other opportunities; the popular Radio 4 presenter Roy Hudd saw the piece and as a result released a Radio 4 charity appeal for a friend whose granddaughter had a metabolic disease.

‘‘Not only was information not reaching parents of children with rare diseases but information was not in fact reaching doctors either’’

Lesley Greene speaking on Songs of Praise, 1982

The increased attention on the charity brought challenges; there were those who were worried that incorrect information or false hope would be given to already frustrated families. Some suggested that the Greenes should focus on supporting families rather than aiming to actively support the research of rare diseases. Others were concerned that as RTMDC was established as an umbrella organisation for all IMD patients, not as a condition-specific support group, they may not be best placed to represent the needs of specific patient communities. One consultant expressed his concerns that the charity would encroach on the diabetic community which highlights how rare diseases were, and still are, fighting for attention in an already saturated landscape

RTMDC responded to these concerns by putting collaboration at the heart of their work and worked closely with these smaller cohorts of families. Collaboration during this time was very important for the benefit of all; the organisation Contact a Family began a directory in order to direct families to RTMDC and other similar organisations. RTMDC also built its own capacity to support patient communities; we provided grants to patients who wished to set up their own charity and patient advocacy group. One example of this model of engagement includes Niemann-Pick who are now a well-established and successful patient group.

Niemann-Pick UK - Collaboration at the heart of patient communities

Niemann-Pick UK (NPUK) is a charitable organisation dedicated to making a positive difference to the lives of those affected by the ultra-rare group of conditions, known as Niemann-Pick diseases. The origins of NPUK are similar to that of so many other rare disease organisations…just a small group of passionate and determined families, joining together to support one another and to make a positive difference for others.

A year after their family’s diagnosis, parent Susan Green picked up a leaflet about the Research Trust for Metabolic Diseases in Children (RTMDC, now known as Metabolic Support UK). This chance connection and the subsequent support offered by RTMDC facilitated the formation of NPUK. In 1991, at Susan’s request, a ‘Niemann-Pick Disease’ satellite seminar was held at the RTMDC annual conference at the University of Keele, and attended by 10 families. This was the first time each of the families had met another living with Niemann-Pick disease and the experience inspired them to meet again and form a parent support group.

From 1991 to 1993 the Niemann-Pick parent support group went from strength to strength in a world that looks a lot different to that of today (i e no emails or websites!), establishing a newsletter and being listed in the Contact a Family directory In 1993, support from RTMDC enabled NPUK to form a management committee, creating the RTMDC Niemann-Pick Disease Group

From 1993 to 1996 the RTMDC Niemann-Pick Disease Group worked tirelessly to raise awareness and engage key stakeholders. The group had many successful outcomes including; recruitment of a medical advisor, circulation of the very first information leaflet, international collaboration and research and facilitating the development of a Clinical Centre for NiemannPick Disease at the Willink Biochemical Genetics Unit of the Royal Manchester Children’s Hospital

In 1996 the Group became independent and was granted charitable status as the “Niemann-Pick Disease Group UK” In 1999 they employed a dedicated Clinical Nurse Specialist for Niemann-Pick Diseases, providing an invaluable lifeline to affected families

In 2002 Niemann-Pick Disease Group UK began working on the development of an international network of NPD patient organisations which led to the formation of International Niemann-Pick Disease Alliance in 2009, which now has 23 member groups from 17 countries. In 2013, following a successful application for EU funding, they helped to create the International Niemann-Pick Disease Registry.

In 2016 Niemann-Pick Disease Group UK rebranded to the widely recognised Niemann-Pick UK (NPUK), in celebration of their 25th anniversary. Since the very first gathering in 1991, NPUK has grown from strength to strength, today supporting over 140 patients and their family members, through a 7-strong staff team, and have contributed to the research and development of treatments and therapies for people living with Niemann-Pick disease. Now celebrating their 30th year, NPUK’s journey demonstrates the power of collaborative working and determination that enables rare disease organisations to successfully form and grow.

RTMDC are proud and honoured to be a part of the Niemann-Pick UK heritage and are researching different models of support to enable patient communities to realise the growth, development and achievements evidenced by Niemann-Pick UK.

“The benefits of effective collaboration in rare patient communities such as ours cannot be overstated. The early support and guidance provided by RTMDC was invaluable to our development as a patient organisation and has enabled us to go on to achieve much on behalf of our patient community, not just here in the UK but globally.”

Toni Mathieson, CEO

The charity needed national growth and awareness to ensure it was finding families across the UK. Engaging with parliamentarians was an important step in securing the reputation of the charity and the Greene’s local MP, Gwyneth Dunwoody, sponsored the charity’s first presentation and exhibition in the House of Commons in 1986. This event introduced the charity to influential ministers from the Department of Health and paved the way for multiple years of grants from RTMDC using Section 64 of the Health and Services Act 1968.

During this increased focus on rare conditions, the USA Orphan Drug Act was introduced in 1983, allowing incentives for pharmaceutical companies developing treatments for rare diseases. The Federal Drug Agency (FDA), the USA’s governing body for drugs, approved the first orphan drug in 1983. This paved the way for Europe sixteen years later with the European Parliament adopting the Orphan Regulation (EC) No 141/2000 in December 1999.

As we continued to grow, a crucial development was taking place in diagnosing and finding IMD patients: newborn screening. In the 1980’s new-born screening expanded to include Tandem Mass Spectrometry (TMS). TMS made it possible to increase the range of detectable congenital metabolic diseases. One of these diseases, Medium Chain Acyl CoA Dehydrogenase Deficiency (MCADD) has life-limiting effects that can be profoundly lessened or prevented if diagnosed early.

Knowing that TMS identified MCADD, and over 50 other inborn errors of metabolism at infancy in a single sample, the MCADD patient community pushed for the adoption of this technology. RTMDC was greatly involved in advocating for this technology and so this development was a key campaign win for the charity.

Thomas and the impact of new-born screening

Soon after little Thomas was born, his heel prick test showed that he had MCADD Although a difficult time, his parents Kate and Dab found that this early diagnosis meant Thomas was immediately referred to the specialist metabolic team at Manchester Children’s Hospital. Thomas’s condition could have been fatal, but this early diagnosis and appropriate condition management meant that, and although his condition has resulted in several hospital admissions, he is a thriving toddler.

‘MCADD is such a serious condition if not managed correctly Luckily for Thomas, and us, it was picked up within his first few days and we were able to get into a good feeding routine… We know how lucky we are to have him, because we got the diagnosis of MCADD early That little heel prick test resulted in him being here today.' Kate Jenkins, Thomas’s mum

Thank you to our fundraisers!

One of the crucial elements to the growth of our organisation throughout the past 40 years has been the unwavering support of our families in their efforts to donate much-needed funds. For 40 years you have cooked, cycled, jived and ran (many, many miles) for us and your efforts have a direct impact on all our IMD community.

Claire's family and their on-going support

Claire Rivett was diagnosed with Gaucher’s Type 2 Disease and her parents, Mike and Fiona, were introduced to RTMDC by Claire’s consultant Sadly Claire passed away in 1991 but her parents remained connected to RTMDC, sharing that we had been a helpful support throughout Claire’s life. Since that time Mike and Fiona have been passionate fundraisers for the charity, with their first event in 1993 seeing Mike cycling 225 miles from London to Stockport Nearly 20 years later and the Rivetts continue to raise an astounding amount of money and have created an inclusive community of likeminded, enthusiastic individuals who get involved. Their most recent event in May 2021 was the ‘Mileage Challenge’. Thank you, from all of us.

1990-2000: Growth and development

The 1990’s began with political movements attempting to refocus healthcare services in an attempt to be more patient-focused. The Patient’s Charter, introduced in 1991 by John Major, was an attempt to revolutionise public services. The charter outlined rights and expectations for patients to ensure improved standards in their local medical services; the Welsh Charter wanted patients ‘to help choose care and treatment appropriate to you’. (Department of Health, 1991). However, there were criticisms over the leniency of waiting times as this assumed that everyone had the same privilege of holding out until treatment was available to them.

Moreover, each Charter included a section that told patients how they can help themselves, with the Welsh Charter including ‘Try to be well informed about your health or condition. Ask questions so you can make decisions based on a better knowledge and understanding’ (ibid). Of course, this is not always possible for those with rare diseases, and so some felt the Charter fell short of understanding the needs of rare communities.

Other changes during this decade impacted the rare disease community. The devolution of powers, beginning with Scotland and Wales in 1997 and Northern Ireland in 1998, meant those governments could make the majority of decisions relevant to their health and social care services. This allowed for different approaches to diagnoses, treatments and care options to be fostered, whilst still maintaining the same NHS standards throughout the United Kingdom.

Key Milestones

At its 10th Anniversary in 1991 RTMDC launched its pioneering model of residential conferences

RTMDC were instrumental in the founding of EURORDIS in 1997

EURORDIS successfully pushed for European orphan drug regulation, resulting in the Orphan Drug Regulation in 1999.

RTMDC changes name to Children Living with Inherited Metabolic Disorders (CLIMB)

In 1999, the National Institute for Clinical Excellence was established

Soon after, in 1999, the National Institute for Clinical Excellence (NICE) was established. Now known as the National Institute for Health and Care Excellence its focus was on producing evidence-based evaluations of health technologies, clinical practice, and guidance for public sector workers and social care services. This new organisation gave rare patients a stronger voice as NICE gathered evidence from stakeholders, including patient organisations such as RTMDC, to inform their work in evaluating the clinical and cost-effectiveness of treatments.

As these government policy developments opened new avenues of influence for RTMDC, so did a relationship with pharmaceutical companies. In the 1990’s RTMDC worked with pharmaceutical companies to try to galvanise drug regulation in Europe and in 1997 EURORDIS was formed. EURORDIS, an alliance of rare patient organisations, became a powerful influence in advocating for and establishing the European Orphan Drug Regulation. Unlike the American Orphan Drug Act, the EU regulation required a committee to include three patient representatives at any given time – a huge step forward in centering the patient voice.

This regulation acknowledged the inherent inequality of treatment for patients with rare conditions and resulted in several key components being added to the European Union’s Orphan Medicinal Products framework. These included creating the Committee for Orphan Medicinal Products (COMP) at the European Medicines Agency (EMA) who were made responsible, with the ultimate endorsement by the European Commission, for the scientific approval of orphan drugs and creating incentives.

These measures aimed to increase the likelihood of pharmaceutical companies producing orphan drugs by offering a 10-year market inclusivity with tax credits. Since the legislation was passed, the number of treatments for rare diseases has risen from 10 to over 400 (Stephens and Blazynski, 2014). In the 1990’s the boost of ‘blockbuster drugs’ - drugs that created over $1 billion annually for their manufacturer caused further difficulty in promoting for the development of orphan drugs. The profit that pharmaceutical companies would lose out on should they fund orphan drugs made it difficult to encourage them to do so.

The beginning of the decade was an interesting time for RTMDC as Hollywood called! In the late 1980s, RTMDC were connected to Lorenzo Odone an American boy diagnosed with a condition called adrenoleukodystrophy. Lorenzo had been given a life-limiting prognosis but his parents, like Lesley and Peter, refused to sit back and accept just waiting for their child's death. Instigated by the family’s own research Lorenzo underwent a clinical trial of an oil (consisting of erucic acid and oleic acid) thought to slow progression of the disease.

Across in the UK, RTMDC funded and supported research at Birmingham University into leukodystrophy and this oil treatment - that eventually became known as Lorenzo’s oil. Universal Pictures contacted RTMDC who brokered a relationship with Lorenzo’s family, leading to the production of the 1992 film ‘Lorenzo’s Oil’. RTMDC were also invited to the premiere, and interviewed by multiple news outlets, allowing for a great amount of publicity for the rare disease community.

‘’It was not until I was writing the music for ‘Lorenzo’ in 1996 that I began to appreciate the devastating impact that metabolic diseases, such as ALD, have on children and their families, there is the desperate search for answers and treatments; the frustrations felt by researchers looking for cures...Climb has helped thousands of families through the period of devastation and isolation that was so graphically shown in the film ‘Lorenzo’s Oil’. The charity is to be congratulated for its commitment and dedication to a cause that is so vital for so many. Unfortunately, it is also a cause that attracts far less publicity than it deserves, because of the rare nature of all these metabolic diseases.’’

Phil Collins, Musician

As the rare disease landscape changed, we responded and at the end of the 1990’s it was agreed that our original name, Research Trust for Metabolic Diseases in Children would be changed to Children Living with Inherited Metabolic Disorders (CLIMB). This reflected our growing role in supporting patients and families as medical services began offering a wider range of life-changing approaches, alongside funding important research into these treatments.

CLIMB would grow the work of RTMDC providing essential support, and in some cases financial help, for disease specific groups as we remained the home organisation for all IMDs. We continued forming a growing network of medical experts in order to develop patient information and provided grants for early-stage lab research.

CLIMB Achievements 1981 -2002

Grew from supporting 1 to over 500 inherited metabolic disorders

Published 600 disease specific information packs

Supported over 1500 families

Delivered 22 national conferences

4 Services of Celebration

Designed and delivered a range of projects including social welfare and a befriender network

2000-2010: Moving at pace in a changing world

In the 2000s, the dramatically increased use of the internet was one of the most significant developments for all rare patients, and wider society. In 1998, six million people in the UK had access to the internet either at home or work (Nuffield Trust, 2021); by 2005 over 50% of Britain’s households had internet access (Belam, 2015). By 2000, the National Health Service, Department of Health and the British Medical Association all had websites to publish documents and reports.

The explosion of information now at the fingertips of millions across the world allowed for those with rare diseases to undertake their own research and provided a space for families to begin connecting and sharing ideas from across the globe. This vast amount of sudden, unorganised information would require hours of frustrating research which is often not an option for those with confusing, already timeconsuming diagnoses. Against this backdrop of digital revolution developing an online presence was an important advancement for CLIMB and we launched our website in 2000.

In the early 2000's CLIMB also developed a business arm to the charity known as the National Information Centre for Metabolic Diseases, allowing us to access grants used to expand our support services, meaning our staff members reached 12 in this period.

Key Milestones

CLIMB launches website in 2000

The expansion of the internet provided a space for families to begin connecting and sharing ideas from across the globe.

The introduction of Foundation Trusts in 2004 meant local areas were able to choose to use their funding to expand their relationship with the rare disease community.

Our annual conferences were a real driver in connecting patients and healthcare specialists. and we were the first organisation to ensure the patient voice was influential during these conferences; the programmes would feature both scientific-focused and patient needs sessions such as stress and grief management. Our successful conferences rotated across the the country, offering a more localised and accessible opportunity for families.

During our 25th anniversary conference in 2006, ‘Back to the Future’, we had support from 25 high profile supporters including Purple Ronnie (now known as Edward Monkton) and Phil Collins who also wrote the music for ‘Lorenzo’s Oil’, all offered messages of encouragement and donated items to auction at our conference.

''Arriving at the Hilton...I began to wonder my reasoning for coming. After all my son had recently died and I could step back from metabolic disease and 'get back to normal'. (However) I was glad I decided to come. I met some of my closest friends and we have grown, learnt, lobbied, fought and cried together...confident that we understand each other. Some of the most respected scientists and clinicians in the world (attend)...and over dinner (there is) an exchange of information between experts on both sides of the experience, the families and the professionals ''

Jackie Ford, rare parent, in an article about our 2001 conference for Climb magazine

CLIMB was now helping families everyday through our support services, running an advice line and offering one to one support. Alongside these day-to-day interventions the team were also working in the policy space to push for wider reform. CLIMB’s founder, Lesley Greene, was elected as a founder director of EURORDIS during this time and acted as its President between 2001-2003.

In 2009 Lesley also joined the Committee for Orphan Medical Products (COMP) at the European Medicines Agency (EMA) in order to continue advocating for the promotion of safe and effective drugs for patients with rare metabolic diseases. EURORDIS continued its contribution to the rare disease landscape and significant EU acts throughout the 2000s.

In 2009, the NHS Constitution (Department of Health 2009) was published, outlining a revised set of rights and responsibilities for both patients and staff that follow the principles and values of the NHS. Elements of this constitution particularly beneficial to patients with rare metabolic diseases include emphasising the right to receive drugs and treatments that have been approved by NICE, the right to expect local decisions to be made regarding the funding of other drugs that would be right for you, and the right to receive screening programmes. As we near the end of the decade the future looks brighter for rare patients

During this time there was a continuing focus on devolving powers from central government to local authorities in England and Wales. In 2004 Foundation Trusts were introduced, managed by local authorities, on the presumption that they would be able to be more responsive to the needs and wishes of local people. By creating stronger connections between local hospitals and communities, decisions and budgets would be able to represent what is needed.

The freedom this brought for local trusts brought positive results for the rare disease community. Guy’s and St Thomas’ NHS Foundation Trust set a precedent in 2017 when they launched their Rare Diseases Centre for adults and children. Due to their foundation trust status, they were able to choose to use their funding to expand their already highly established relationship with the rare disease community and patients were now able to attend all their appointments in one place and clinics ran more efficiently.

Other foundation trusts that followed include the University Hospitals Birmingham NHS Foundation Trust, Great Ormond Street Hospital for Children NHS Foundation Trust, and the Manchester University NHS Foundation Trust.

2010-2020: A connected world brings new opportunities

In 2003, the ground-breaking Human Genome Project published the complete genetic code of a human being, otherwise known as their genome. It then took 13 years of international collaboration in order to read the genome, resulting in the discovery that there were around 20,000 genes found within the human genome. By sequencing the entire human genome, a revolutionary understanding of the role of genes in health and disease would be unearthed, and so the 100,000 Genomes Project was announced in 2012 in the UK, a partnership between the National Health Service (NHS) and Genomics England. Focusing on patients with rare diseases and cancer, the aim was to sequence 100,000 whole genomes in order to enable new scientific discovery and medical insights.

Since completing the 100,000th sequence in 2018, 1 in 4 patients with an undiagnosed rare disease have now received a diagnosis for the first time (Department of Health and Social Care, 2021). That same year, the Health Secretary, Matt Hancock, announced that the project would be supported in its expansion to sequence 1 million whole genomes, with plans to expand this further to 5 million genomes in the following 5 years.

Key Milestones

Metabolic Support UK began its involvement in producing reports for NICE including advocating for drugs to begin the HST process

Metabolic Connect launched in 2019 expanding our community to include young people affected by IMD’s and siblings.

Metabolic Support UK encouraged the expansion of the new-born screening programme, resulting in four more inherited metabolic diseases being included in the analysis.

NICE’s HST program increased the threshold for cost-effectiveness allowing for a greater number of orphan drugs to be developed and produced on a greater scale.

The UK’s Strategy for Rare Diseases in 2013 aimed to improve the efficacy or coordination of care between the NHS healthcare services.

In 2012 the 100,000 Genomes Project was launched.

The introduction of European Reference Networks allowed for increased collaboration across Europe.

During this decade, the European Union introduced two significant expert groups to improve the rare disease landscape: the Commission Expert Group on Rare Diseases (2014-2016) and the European Union Committee of Experts on Rare Diseases (2010-2013). The latter included an agenda of new-born screening and orphan drugs and, with the cooperation of member state representatives, the European Commission, patients and other stakeholders, fostered exchanges of relevant experience, policies and practice. As a result, significant progress has been made across Europe, with 25 countries adopting either a national plan or strategy around rare disease.

The UK’s Strategy for Rare Diseases in 2013 purportedly recognised the importance of coordinating care between the NHS services so that care is effective, accessible and convenient to patients. However, between 2016 and 2017, the All Party Parliamentary Group (APPG) on Rare, Genetic and Undiagnosed Conditions held an inquiry into how effective the UK Strategy for Rare Diseases in England had been. The inquiry concluded that the strategy was not being effectively implemented in England; each Department of Health in the United Kingdom other than England had coordinated an implementation plan.

This lack of administration, according to the APPG inquiry, had meant many patients of rare diseases in England have not been able to access appropriate treatment or information about their condition. It is only following this report that an implementation plan was introduced in 2018 to document future commitments the Department of Health and Social Care in England will undertake to effectively execute the 51 commitments set out in the UK Strategy for rare diseases initially.

Against this background of inconsistency for rare patients in the UK, CLIMB continued to develop and grow and, in 2015/2016, with a new CEO, carried out a stakeholder wide consultation. We consulted with IMD patients and carers, IMD medical professionals, primary care practitioners, pharmaceutical industry, other rare disease Patient Advocacy Groups and specifically young people with IMDs.

The purpose of the consultation was to reconnect with our communities by asking three key questions.

Who are the communities we are trying to support?

What are their current needs and priorities?

What are the most important issues for them in the future?

The consultation concluded that large-scale reform was required in order to truly meet the needs of the communities we wanted to serve. The charity needed to take a more planned and proactive position to supporting the community and less of a reactive position.

As part of these changes, and to reflect that we supported a wider group than just children, CLIMB changed its name to Metabolic Support UK in 2016. Strengthening our Metabolic Support UK offer, we launched our family services sector in order to connect families directly, giving families greater knowledge and support using their own experiences, relaunched in 2019 to include young people as Metabolic Connect.

This decade saw the impact of our earlier successes; since the introduction of Tandem Mass Spectrometry (TMS) in the 1980’s, the number of patients in whom metabolic disorders are diagnosed by screening has doubled. Each year approximately 176 babies receive a positive diagnosis using the new-born screening programme (Metabolic Support UK, 2019).

The most recent expansion of conditions was driven by Metabolic Support UK, encouraging the launch of a one-year pilot study in 2012-2013 offering training to healthcare providers on the Expanded Newborn Screening Pilot. These efforts resulted in four new inherited metabolic disorders being included in the analysis. Currently, 6 out of the 9 conditions that TMS analyses for are inherited metabolic disorders, with the criteria and standards having been set and monitored by the National Screening Committee.

These criteria have made it especially difficult for any further metabolic disorders to be included in the analysis, with no new conditions being added since 2015 in England, despite other comparably highincome countries routinely screening for up to 50 conditions.

Metabolic Support UK remains on the NHS

Inherited Metabolic Disorders Screening Advisory Board and continues to support the developments in new-born screening and other diagnostic approaches for rare diseases. At the start of the decade we were invited to a Celebration of Newborn Screening in Parliament to celebrate being the primary innovator in extending new-born screening.

Screening matters - Eleanor

Just before she turned two Eleanor was diagnosed with GA1 following a distressing journey to diagnosis. Although Eleanor is now a sociable, artistic and sporty teenager who enjoys most foods despite her diagnosis, her mum Kate describes the impact of GA1 not being included in new-born screening:

‘‘I do think we would have benefited from new-born screening... I knew there was something wrong from the first day she was born but no-one would listen to me and it was a constant battle to convince anyone. We were extremely lucky that Eleanor survived going into a coma and that the outcome was as good as it was. If only we had known from the outset, we could have been aware of the potential issues we might face.’’

There were several key developments across the UK that provide a helpful background to understanding the needs of rare patients in this decade:

The Early Access to Medicines Scheme (EAMS) was launched in the UK in 2014 in order to give people, where there is a clear unmet need, early access to medicines still under clinical trials evaluation that did not yet have marketing authorisation. This has allowed for rare disease patients living with Duchenne Muscular Dystrophy, and haemophilia, to access life-changing treatments without having to wait several more years before a market is justified.

Highly Specialised Technologies (HST) Program has been operated by the National Institute for Health and Care Excellence (NICE) since 2017 and has increased the threshold for cost-effectiveness when reviewing orphan drugs, placing the value of health benefits in rare diseases up to 15 times higher than the equivalent benefits in common diseases. This means that more orphan drugs will be able to pass these criteria and begin their manufacture, but we might see increased prices from pharma companies to alleviate the limited market-to-profit ratio that come with funding orphan drugs. Throughout this period, Metabolic Support UK, alongside other patient organisations, have researched the experiences and opinions through patient interviews and focus groups to provide NICE with a detailed overview on whether a particular orphan drug should be escalated to the HST process.

Parliamentary Advocates for Rare Diseases network was launched in 2017 at the European Parliament in Brussels after ongoing efforts by EURORDIS to ensure European stakeholders are continually encouraged to tackle challenges and inequalities that those with rare diseases face. By bringing together members of the European Parliament, strong international and local action can be achieved, and future legislation will integrate the rare community into all relevant policies.

European Reference Networks (ERN) were launched by the European Commission in 2017 with the aim of increasing collaboration across Europe regarding rare diseases. There are now 24 networks specialising in different areas, ranging from rare bone disorders to metabolic disorders, facilitating strong networks of individual countries and over 900 health organisations to collaborate. Following the decision for the United Kingdom to withdraw from the European Union in 2016, Brexit, the United Kingdom and its healthcare providers can no longer participate in these networks.

Prior to Brexit, the UK led a quarter of all these networks and they were located here. There are concerns that the UK’s health providers will lose critical experts should these UK-based ERN’s relocate, and that the UK will become distanced from the developing rare disease landscape in Europe. Despite cutting ties with the UK the European Commission have expressed their hope to collaborate with UK-based clinicians and representatives from UK-based patient organisations, for the benefit of rare diseases, making it easier for individual countries and over 900 health organisations to research, and introduce up-to-date educational training programmes. Brexit’s impact on access to Orphan Medicines brings additional uncertainties, despite efforts by the Medicines and Healthcare products Regulatory Agency (MHRA), to create an innovative landing place for biotech and pharmaceutical companies.

2021 - A window of opportunity

As we look back at 40 years of change, innovation and determination, we are hopeful that in 2021 the changing policy landscape brings opportunities for the genuine advancement of rare patients’ needs. However, although the number of rare diseases has increased since the 1980’s, the issues experienced by the Greene's are still as real today and only a small proportion of diseases have clear diagnostic tests or effective treatments.

This year of our 40th anniversary, there is a window of opportunity as we see three major policy changes: UK Rare Diseases Framework, NICE Methods Framework and the MHRA’s Innovative Licensing and Access Pathway (ILAP).

The UK Rare Diseases Framework (January 2021) (6) recognises that as a collective, rare diseases are collectively common. This is vital as rare diseases can be severe, life-long and fatal conditions and through developing treatments for them we learn more about common conditions and how they can be treated. Rare helps us care; we learn more about how services and NHS delivery can be more innovative in the face of challenges presented by these sorts of diseases.

The framework’s four key priorities chime with our own: Helping patients get a final diagnosis faster Increasing awareness of rare diseases among healthcare professionals

Better coordination of care

Improving access to specialist care, treatments and drugs

While this is heartening, patient groups must keep vigilant and ensure there is meaningful change in these areas as evidenced by our own measures

1 in 17 people will be affected by a rare disease at some point in their lifetime in the UK

(Department of Health and Social Care, 2021)

We believe that it is in close co-ordination, and conversations, with all stakeholders as equals, that these priorities will be best achieved. Patients will obtain a final diagnosis faster if referred by clinicians to vital information and support through patient organisations. Collaboration with organisations such as Medics for Rare Diseases and the Cambridge Rare Disease Network will increase awareness among healthcare professionals. Patient groups also play an important role in better coordination of care including connecting families that can discuss and share experiences and treatments.

The Rare Diseases Framework acknowledges that parents of children with rare conditions face additional burdens and seeks to minimise this using technology and digital tools, using the lessons learned from the Coviid-19 pandemic, to access to specialist care treatments and drugs. The framework acknowledges the importance of the patient voice in this process; MSUK and others have been active for many years with orphan drugs and campaigning on the importance of pushing for new drugs and technologies and treatments.

All four nations in the UK have agreed to publish action plans for the framework within two years – the patient voice is essential in these action plans so we must work together to support this.

We welcome the NICE Methods Framework proposal which includes a severity modifier and considers severity of disease not just the years of life someone can gain through treatment. Our rare community need to know that policymakers understand that treatments for severe, life-long conditions are highly important irrespective of the numbers of people affected by any one disease. Rare communities’ needs should be weighted appropriately where budgetary restrictions throw up conflicts around investing in a common or rare treatment - 100 hip replacements or just one gene therapy for a metabolic disease? Our found, Peter Greene says ''Our argument would always be if a person with a particular condition can have gene therapy… that means they don’t have to go to hospital admissions and they don’t need to have physiotherapy and endless therapy and they can become working members of society.''

NICE’s proposal to explore health inequalities through health technology evaluations and the plans for a formal modifier is good news. We hope this modifier will present the challenges faced by those living with rare conditions and allow these challenges to be more formally considered during the evaluation process.

But it is vital that NICE recognises all sources of inequalities including the socioeconomic disadvantage. Rare disease patient groups are doing a lot of work in this area and many are advanced in their research and activities, so we hope to see an open door at NICE enabling genuine collaboration.

We need tangible deliverables – how exactly will NICE work with patient organisations and consider our evidence, alongside academic discussions, during the collation of Real-World Evidence and unmet needs?

‘’Our argument would always be if a person with a particular condition can have gene therapy… that means they don’t have to go to hospital admissions and they don’t need to have physiotherapy and endless therapy and they can become working members of society’’

Peter Greene, MSUK Founder

The Innovative Licensing and Access Pathways (ILAP) was launched in January 2021 to speed up development and access to innovative medicines in the UK post-Brexit. We have already witnessed researchers, scientists and regulatory agencies pack a 10 year drug development process into 12 months, in the form of the Covid-19 vaccine. Therefore we can set our expectations high and anticipate a reduction in the time taken to develop and bring essential and innovative treatments to market.

We must be mindful that promises of change without meaningful implementation do not help rare communities but instead serve as cat toys, meaning we take our eye off the ball. In 2018, NHS England introduced a requirement for providers of specialised services to give every patient with a rare disease an alert card (as part of the 2013 strategy for rare diseases) to include information about their disease, any particular treatments of their rare disease that needs to be taken into account, details how to contact an individual expert in that patient’s care.

This would mean that information and details can be accurately passed on to medical professional removing poor communication. However, a lack of knowledge and awareness about this alert card means that three years after this commitment, little has happened

COVID-19 Our communities are still reeling from the on-going effects of the Covid-19 pandemic. We are concerned about the long term impact the pandemic will have on the number of patients diagnosed, access to treatment, access to care, and a potential economic down turn for individuals and society as a whole.

MSUK responded with alacrity and care for its communities, our MSUK Covid 19 impact report showed that 52% of people living with IMD’s who should have had a shielding letter did not. We saw a 95% increase in incoming enquiries from 2019 to 2020, with 41% of these families not previously known to us, highlighting how patient organisations are absolutely vital in providing information and comfort in difficult times.

There are some bright spots on the horizon, later this year the Rare Conditions Centre is to be launched at Manchester University NHS Foundation Trust. Alongside other rare disease centres across the country, this will improve training and education in rare conditions, develop research and patient trials, and encourage other Foundation Trusts to do the same.

We have also witnessed positive developments on a wider European scale with the third committee of the United Nations adopting the UN resolution on addressing the challenges of persons living with a rare disease and their families. In November 2021, members of the European Parliament debated rare diseases during a plenary session, calling on the European Commission for Europe’s Action plan for Rare Diseases.

Metabolic Support UK - Our future

Patient groups have strong voices, valuable evidence and unrivalled community access – but we can be fragmented in our approach, to our detriment. MSUK will be focusing on strong, connected collaboration and campaigning with our sector colleagues in the coming years. We are the first line of defence for people living with IMD’s and, alongside developing our own services, want to strengthen our capacity to support and nurture disease specific patient groups.

MSUK will focus on stepping fully into our identity as a trusted and respected umbrella organisation, bringing our sector colleagues together so that our responses to this current ‘window of opportunity’ are cohesive, data and evidence based and harder to dismiss.

We will be focusing on developing our capacity to make use of digital technology to generate better patient evidence and data in order to improve advocacy effort. Evidenced based advocacy is key on an individual disease level and for wider policy influencing.

A key part of our work will be gathering and analysing data and other evidence to demonstrate the impact of changes to the NICE methods review, the UK Rare Diseases Framework and the implementation of the innovative medicines fund. What is the impact on patients and their access to treatments - do these things work in practice?

We support all people living with IMD’s and their communities but we will move forward with a particular focus on underrepresented groups such as people with ultra rare diseases and young people. Most evidence for young people comes from adults and we want to explore other developments in this area.

Our 2021 'Rare Thinking Festival' aims to galvanize people living with IMD's into being experts not only in their medical conditions, but their rights and how to fight for them. There is an unmet need in the rare disease sector for progressive, informed activism and MSUK will lead the way in placing power in the hands of our people.

The next decade will see MSUK lead with our 2030 strategy, focusing on remaining current, at the forefront, data driven and compassionate in all that we do. In Spring 2022 we will be launching our ‘Thoughts into Action’ report, setting out the state of the nation for people living with Inherited Metabolic Disorders and their communities, and our plans for change.

''There is an unmet need in the rare disease sector for progressive, informed activism. MSUK will lead the way in placing power in the hands of our people''

Kirsty Hoyle, CEO,MSUK

Thank you to our sponsors!

References

Belam, M., 2015. Timeline of .uk internet usage. [online] Medium. Available at: https://medium.com/30-stories-of-uk/timeline-of-uk-internet-usage-93b705c78891.

Commission of the European Communities, 2008. COMMUNICATION FROM THE COMMISSION TO THE EUROPEAN PARLIAMENT, THE COUNCIL, THE EUROPEAN ECONOMIC AND SOCIAL COMMITTEE AND THE COMMITTEE OF THE REGIONS on Rare Diseases: Europe's challenges.

Department of Health and Social Care, 2021. The UK Rare Diseases Framework. Department of Health, 1991. Patient's Charter. London: HMSO.

European Commission, 2014. Implementation report on the Commission Communication on Rare Diseases: Europe's challenges [COM(2008) 679 final] and Council Recommendation of 8 June 2009 on an action in the field of rare diseases (2009/C 151/02). Brussels.

Metabolic Support UK. 2019. Newborn Screening - Metabolic Support UK. [online]

Available at: <https://www.metabolicsupportuk.org/newborn-screening/>.

National Health Service, 2010. Quality and Outcomes Framework - 2009-10. Regulation (EC) No 141/2000 of the European Parliament and of the Council of December 16, 1999 on orphan medicinal products (1999), Official Journal of the European Communities, vol. 43 L18

Stephens, J. and Blazynski, C., 2014. Rare disease landscape: will the blockbuster model be replaced?. [online] Available at: https://pharmaintelligence.informa.com/~/media/Informa-ShopWindow/Pharma/Files/PDFs/whitepapers/Dec-2013-Rare-Disease-Landscape_JonathanStephens-Christine-Blazynski_11-2016.pdf

The Council of the European Union, 2009. COUNCIL RECOMMENDATION of 8 June 2009 on an action in the field of rare diseases. The Nuffield Trust. 2021. 1998–2007: Labour's decade. [online] Available at: <https://www.nuffieldtrust.org.uk/chapter/1998-2007-labour-s-decade#ethics-and-patientparticipation>.

US Food and Drug Administration, 1983. Orphan Drug Act.

List of picture references

Page 1 (woman and man) MSUK family

(boy in hospital bed) MSUK family

(baby with bee toy) MSUK family

(group of people at fundraising event) MSUK family

(people dancing at a celebration) MSUK family

(two boys looking at each other) MSUK family

(woman and man on carousel) MSUK family

(man outside of MSUK office) MSUK family

(two men in MSUK marathon outfits) MSUK family (baby and father) MSUK family

(two girls hugging) MSUK family

(baby boy) MSUK family

Page 2

Kirsty Hoyle, Chief Executive Officer

Dr Elin Haf Davies, Chair of Board of Trustees

Page 3

(close up of an RTMDC leaflet) The Research Trust for Metabolic Diseases in Children

Page 4

(summer family photo) The Greene Family - Jennifer, Becky, Lesley and Peter (Jennifer’s graduation photo) Jennifer’s graduation- Beki, (unknown), Jennifer Greene, Lesley Greene, Peter Greene

Page 5 (baby boy) MSUK family

Page 6

(Jen as a child) Jennifer Greene on Songs of Praise Peter Greene on Songs of Praise Lesley Greene on Songs of Praise

Page 7 (past conference) Lesley Greene handing out sandwiches (past conference) MSUK family at a conference (office) RTMDC Office

Page 9

(group of people at a fundraising event) Mike and Fiona Rivett’s fundraising event, the ‘figure of eight challenge' 2008

Page 10 (baby with MCADD bib) MSUK family (baby with bee toy) MSUK family (two girls hugging) MSUK family (girl and boy interacting) MSUK family (baby on sofa) MSUK family

(two boys looking at each other) MSUK family

Page 11

(father and baby) MSUK family

Kate Jenkins with Thomas as an infant

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MSUK fundraising update page (men with bicycles) Mike Rivett and his neighbour on their 1993 London to Stockport cycling event (police officer and woman) the Liverpool to Stockport, ‘the Mersey Walk’ fundraising event (group of people at a fundraising event) Mike and Fiona Rivett’s fundraising event, the ‘figure of eight challenge, 2008

Page 14 (family picture) MSUK family

Page 15 (film poster) Lorenzo’s Oil movie poster 1992

Page 16 CLIMB logo (group of people) MSUK family fundraising event

Page 18 (past conference) MSUK family at a conference (typed message and purple Ronnie) A message of congratulations and encouragement from Purple Ronnie, 2006 (aka Edward Monkton)

Page 19

( father and daughter with Minnie mouse ears) MSUK family

Page 21 (two women with Great Ormond Street Hospital sign) Dr Elin Haf Davies and Herdip (marathon runner fundraising) MSUK family

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Climb Update front page volume 6 no 5, June 2015 MSUK banner

Page 23 (girl and dog) Eleanor

Page 26 (sponsors) Arcturus Therapeutics

Kyowa Kirin

Alexion AstraZeneca Rare Disease

Nutricia Metabolics

Agios

PTC Therapeutics

Aeglea Sanofi

Chiesi

Ultragenyx Hemoshear Therapeutics

Page 28 (boy in green toy car) MSUK family (two women at the end of a fundraising challenge) MSUK family (man holding marathon medal) MSUK family (person climbing rock face) MSUK family (marathon MSUK outfit) MSUK family (two women at the start of a fundraising challenge) MSUK family

This report is dedicated to Jennifer Greene and to all people living with Inherited Metabolic Disorders and their communities