Rare Diseases - Q1 - Feb 2019

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DR JAYNE SPINK Rare disease patients are using their voices to bring about change. » p2

PROFESSOR RAFAEL YÁÑEZ Many of the conditions detectable in newborn screening, if left untreated, have serious effects. » p8

DR DARIA JULKOWSKA How creating a European ecosystem will accelerate research, diagnosis and development. » p12

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Time to refresh our approach to rare diseases One in 17 people will be affected by a rare disease at some point in their lifetime. At this moment, it is estimated that there are more people in the UK living with a rare disease than there are seniors living with dementia.

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his statistic may seem puzzling - until you reflect that, while individual rare diseases affect relatively small numbers of people, there are more than 6,000 rare diseases that will affect 3.5 million UK citizens. Lack of awareness of rare diseases has created an unmet health need on a scale larger than that for any individual common condition. It has starved rare disease research of funds and isolated patients and families, depriving them of access to information and support and access to speedy diagnosis, coordinated care and effective treatments.

This year, as Rare Disease UK campaign marks its 10th year, we are reflecting on a decade of progress that has grown out of, and been sustained by, increasing awareness. From a

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handful of voluntary groups, the campaign has grown to a community of over 300 organisations.

Patient involvement boosts understanding of rare diseases Rare disease patients are using their voices to bring about change; making vital and positive contributions to developments in research, policy and delivery of care. We now know more about the common issues faced by those with rare diseases. We know too, that for the majority of rare diseases, there remains much we need to improve.

More funding needed for research Rare disease research continues to

There are fewer than 200 proven medicines to treat rare diseases, only half of which are routinely available on the NHS.” claim a disproportionately small slice of the research funding pie. There are fewer than 200 proven medicines to treat rare diseases, only half of which are routinely available on the NHS. The NHS offers fewer than 100 specialised services tailored to the needs of patients diagnosed with specific rare diseases.

Genome medicine can improve personalisation of treatments With the advent of genomic medicine

DR JAYNE SPINK Chief Executive, Genetic Alliance UK Chair, Rare Disease UK

and the technological strides being made in research into treatments, there is the true prospect of transforming the experience of healthcare for rare disease patients.

This transformation will be a critical component in the delivery of a 21st century NHS with its promised focus on greater personalisation and prevention of declining health.

We can only truly achieve this transformation through raising awareness of rare diseases among the public, professionals, politicians, policy-makers and funders. A review and refresh of the UK Strategy for Rare Diseases - innovative on publication in 2013, but now rendered moribund in the face of progress and change - will be key.

Rare Disease Day celebrates what has been achieved so far History teaches us that the most noticeable problems are the ones that are likely to be addressed – or to put it another way that, ‘the squeaky wheel gets the oil’. Rare Disease Day is a day when we celebrate the progress we have made and campaign for the reforms that have yet to be made – the day when the voice of our community is heard across the world.

Read more at healthawareness.co.uk

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Are we on the cusp of a rare disease treatment revolution?

Continued innovation and collaboration are key if we are to see a major breakthrough in the treatment of rare diseases.

Byline: Kate Sharma

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ndividual rare diseases may impact just a handful of people.

Collectively, however, a large number of people - 30 million in the EU1 and 350 million worldwide2 have a rare disease. According to Dirk Moritz from Blue Matter Consulting, this makes it a huge public health issue.

“There are an estimated 7,000 rare diseases,” says Moritz. “Most are undiagnosed, and only about 5% have an approved treatment. Sadly, since most are of genetic origin, they manifest early and predominantly affect children.”

The sheer number of rare diseases, the complex nature of many, and the fact that patients are rare and spread across the globe, pose specific challenges to biopharmaceutical companies. These challenges must be overcome to support the millions of people living with these often lifethreatening conditions.

Finding patients is challenging The first step to finding a treatment is to understand as much about the condition as possible. With rare diseases, this can be immensely challenging, as the relatively few patients are typically dispersed globally and may present with different symptoms and levels of progression. Similarly, the specialist academics and medical professionals working on those diseases are scattered internationally. Except among a few experts, awareness of a given condition is generally low.

Getting a definitive diagnosis can take years.

“Companies must define the diagnostic criteria, search for and identify patients. If there are only a handful, it’s difficult,” continues Moritz. “For companies, developing rare disease treatments remains risky and challenging. The required

investment is high, and there’s no guarantee of success.”

I believe, in our lifetime, we will witness a complete transformation of the treatment of rare diseases.”

Government regulations and incentives for rare diseases have led to the development of new treatments. This has helped, but as Moritz points out, “We now have about 500 treatments for only 5% of all rare diseases.” Due to small patient numbers, prices are typically high with treatments often costing between US$300,000 and US$750,000 per year, according to the Rare Disease Report3. “It’s critical that rare disease companies demonstrate the value of novel treatments and evolve current payer models,” adds Moritz.

DIRK MORITZ, PhD Principal, Rare Diseases Blue Matter Consulting Breakthroughs in gene and cell therapy research in treating rare diseases The challenges are real, but not insurmountable. Moritz believes that innovation is key to driving development and that collaboration between companies and key rare disease players will make that happen. In recent years there have been huge developments and Moritz is excited about the future.

Decades of research into gene therapy are now paying dividends with recent breakthroughs for conditions such as spinal muscular atrophy (SMA), thalassemia, and rare eye diseases. Moritz cites more than 1,000 ongoing gene and cell therapy studies in development and expects to see some key regulatory approvals in 2019.

“Gene therapy potentially offers the promise of a cure,” he enthuses.

“It is clear that gene therapies work;

the key question now is whether companies can find a way to successfully commercialise them.

I believe, in our lifetime, we will witness a complete transformation of the treatment of rare diseases.”

Moritz is excited about the future, but points out that innovation mustn’t stop here. Novel thinking regarding not just research and development, but also commercial aspects of how therapies are provided to patients is essential to realise this promise.

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1: eurordis.org 2: globalgenes.org 3: www.raredr.com/news/orphan-pricing-2017

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Could artificial intelligence help treat rare diseases?

The healthcare industry has struggled to find therapies for rare diseases. Now, artificial intelligence and machine learning offer potential breakthroughs in treatments for patients.

Byline: Kate Sharma

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o date, the healthcare industry has had limited success in developing treatments for rare diseases. Reassessing their approach to drug discovery and development has opened the door to the use of artificial intelligence (AI) and machine learning (ML). AI and ML offer augmented approaches and healthcare is already using such technology to support diagnosis and optimising patient treatment in a number of settings.

“If you think of the digital data that we have access to now, and if AI and ML can be used together with human expertise to recognise associative patterns between disease pathophysiology, symptoms, targets, and drugs, the possibilities are enormous,” says Krishnan Nandabalan, CEO of InveniAI, who seek to transform access to innovation for healthcare and other industries.

The difference between AI and ML AI and ML are often spoken about MEDIAPLANET

in the same breath, but there are nuanced differences between the two. AI focuses on using computers to do jobs that are typically done by humans and accelerating the rate and accuracy with which they can be performed. ML, on the other hand, is really about developing algorithms and models that help identify patterns to predict outcomes.

Fewer patients with rare diseases means they are hard to research Nandabalan believes the applications of both AI and ML can go further than diagnostics, and that they hold particular promise for the development of treatments for rare diseases. “Only about 10% of drugs that make it to clinical trials are successful. For rare diseases it’s half or even a third of that,” he says. “The reason we have less success is the fact that there are fewer patients, so it’s much harder to gain the insights you need to develop treatments.”

Only about 10% of drugs that make it to clinical trials are successful.

For rare diseases it’s half or even a third of that.”

Without these key insights, issues of risk and safety become stumbling blocks. This is where AI and ML can help to bridge the gap. ML offers the capability to take data from a whole range of sources and uncover common threads, hidden connections and other patterns that give fresh insight into possible treatments and the impact they could have on patients.

Uncovering hidden connections and insights by using AI and ML While no drugs have come to market as a result of using AI and ML as yet, Nandabalan believes it’s only a matter of time. “As more and more data is being accumulated, AI and ML can

KRISHNAN NANDABALAN, PhD CEO and President, InveniAI Corporation uncover new insights,” he says.

Speaking of his company’s own research he continues: “We have already used AI and ML to uncover hidden connections between basic biological processes and pathophysiology that allowed us to identify existing drugs that can be used to treat common and rare diseases. For example, our technology identified BXCL701, a DPP8/9 and FAP inhibitor, as an immuno-oncology candidate that is expected to enter Phase Ib/II trials for treatmentemergent neuroendocrine prostate cancer (tNEPC), a rare hormonerefractory segment of prostate cancer.”

would also fall, which is so often a limiting factor in the development process and certainly a major setback for rare diseases where there are already limited therapeutic options.

While it can be easy to overhype technology, many believe AI and ML are the next step in the evolution of the drug discovery and development process.

Big pharmaceutical companies are investing in the technology and, with gathering momentum, all the signs suggest that big breakthroughs are just around the corner.

Treatment concept to approval can take 10 years At present it takes around 10 years to take a new treatment from concept through to approval. Nandabalan believes this time could be halved with the application of AI and ML, especially when repositioning drugs.

With a reduction in timescales costs

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AI: Accelerating the diagnosis of rare diseases IOLE PEZZUTO, PhD Scientific Communication Specialist, SOPHiA GENETICS

Data-Driven Medicine is a big step forward for rare diseases AN INDEPENDENT SUPPLEMENT BY MEDIAPLANET

“Serial referral” could be the title for the diagnostic journeys of some rare disease patients. Artificial intelligence (AI) now sets out to help to break this arduous cycle of referrals.

Byline: Tony Greenway

or many patients, a quick visit to the doctor’s office may not be enough, as the physician will likely need to do multiple tests to identify the cause of their symptoms. To use an analogy, if a tree surgeon has to diagnose a sick tree, they would look beyond the visible symptoms, such as the fallen leaves, and dig deeper to identify the root cause. Similarly, physicians need to dig deeper into the molecular architecture of their patients to find what is causing the disease.

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AI technologies continuously learn how to better pinpoint specific molecular markers associated with rare diseases and reach a clinicalgrade accuracy.”

AI technologies help to crack genomic data Artificial intelligence can help hospitals worldwide to go beyond patients’ observable symptoms and spot the invisible; the mutated sequence of DNA responsible for a disease.

AI enables the analysis of the large amount of complex data coming from a patient’s genomic profile to accurately detect and characterise potentially disease-causing mutations. Health professionals can leverage an extensive data pool, built on the knowledge of worldwide genomic experts and trusted external data sources.

AI technologies continuously learn how to better pinpoint specific molecular markers associated with rare diseases and reach a clinical-grade accuracy. But the capabilities do not stop there. In addition to the advanced analytical performance, leading technologies also offer efficient variant filtering strategies to make the interpretation process easier for clinicians. Therefore, among the daunting number of detected alterations harboured within an individual's genome, it is then possible to focus on and deeply explore only the variants of interest. As a result, patients can receive a more precise diagnosis in a shorter time frame.

A better tomorrow with Data-Driven Medicine “It is my strong belief that advanced technologies like SOPHiA are the key to unlocking the era of Data-Driven Medicine, where secure data pooling and knowledge sharing will be extremely valuable for patients. Using SOPHiA, data collected from a patient diagnosed with a rare genetic disease in London can help diagnose a patient in Sao Paulo who has the same genomic profile. By accelerating DataDriven Medicine adoption worldwide and maximising its impact, we can ensure that the data used to help patients today will also benefit the patients of tomorrow, thus contributing to make the global healthcare system more sustainable,” says Gioia Althoff, SVP Genomics at SOPHiA GENETICS. Read more at sophiagenetics.com

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LEWIS DARNELL Clinical Scientist and Deputy Quality Manager, Molecular Genetics Department, Nottingham University Hospitals NHS Trust

Rare disease diagnosis has been improved with the introduction of technologies such as genomics and artificial intelligence, which help clinicians analyse results more efficiently. t's impossible to overemphasise the importance of speedy diagnosis for anyone with a medical condition, says Lewis Darnell, Clinical Scientist and Deputy Quality Manager in the Molecular Genetics Department within Nottingham University Hospitals NHS Trust. Unfortunately, in the area of rare disease, this can take a long time. “Until recently, approximately 30% of patients who see a specialist geneticist will usually receive a quick diagnosis, but many wait much longer, and it has been estimated that up to 50% won't receive a diagnosis at all.”

Being stranded in medical limbo takes an unbearable emotional toll.

Parents of babies with rare diseases, for example, want a rapid diagnosis to relieve their worry and open up potential treatment options. “In my experience, people want to put a name to their condition — or their child's condition — as soon as possible,” says Darnell.

Fear of the unknown creates anxiety “An unnamed condition is an unknown condition, and fear of the unknown creates uncertainty and anxiety. For example, how might the condition progress? What other complications might arise? And if the patient is your child, how will you meet their future medical needs? How might you have to change your life in order to adapt to their condition? Or — frankly — how long will they live? It's an emotional tightrope.”

Rare diseases can cost families huge sums From a clinician’s point of view, it stands to reason that it's a lot easier to treat patients who have an easily recognised condition. “If doctors

Being stranded in medical limbo takes an unbearable emotional toll.

Parents of babies with rare diseases, for example, want a rapid diagnosis to relieve their worry and open up potential treatment options.” aren't sure what they are looking for, however, it means more hospital visits for patients, more monitoring and more tests,” says Darnell. “And that's not a good situation for either the patients or their loved ones.”

It can also be expensive, putting increased financial pressure on an already struggling health system.

Deep genome analysis is more efficient In recent years, however, research into rare diseases has been transformed by genome sequencing — the mapping of a person's entire genetic code. Before this science became available, clinicians could only test a few genes at a time, which was a lengthy process that often caused a delay in diagnosis. “But now genome sequencing allows us to gather information on nearly all of a patient's genes in a single test,” says Darnell. “That's been a big step forward.” It's also a more financially sustainable solution.

There is a limited number of scientists to analyse all data Even so, it did have a downside. As genome sequencing progressed, it began returning millions of genetic variations — or 'variants' — that might be responsible for causing a patient's condition. That's an unworkable amount of data for clinicians to study, particularly when only one or two variants might be the culprits. “Analysing that amount

of information is quite impractical because there is a limited number of Clinical Scientists in the country,” says Darnell. “We simply don't have the resources to look at thousands of variants individually.”

Artificial intelligence narrows the search Thankfully, new AI technology is now available, which allows these results to be analysed and filtered more efficiently. “This technology helps us work out where to direct our attention,” explains Darnell, who points out that Data-Driven Medicine is beginning to make a big difference to patients on long “diagnostic odysseys” (clinicianspeak for “length of time to diagnosis”). It's also taking pressure off medical professionals who would otherwise have to rely solely on their own expertise to explore next steps with regard to diagnosis and treatment when, understandably, their knowledge may be limited in some rare disease areas.

Genomics is still in its infancy “Genome-sequencing and AI technology applied to genomics is a hugely positive step for the world of medicine,” says Darnell. “I've been working in this field for around 12 years, but this type of technology has only become properly available to use in the NHS in the last few years, although it's not widespread.

Yet there's definitely a place for large-scale sequencing. For one thing, clinicians now have the chance to study the genetics of tens of thousands of people, and therefore develop a greater understanding of which genetic variations are normal, and which cause disease.”

Read more at healthawareness.co.uk

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This article was developed in collaboration with Actelion Pharmaceuticals UK who also provided funding. Contributors to this article did not receive payment for their involvement.

CREDIT: MALIJA

Time to act - Patients with PAH need earlier referral and diagnosis PROFESSOR DAVID KIELY Director, Sheffield Pulmonary Vascular Disease Unit

TESS JEWSON PAH Patient and Professional Musician

Diagnosis for pulmonary arterial hypertension (PAH) takes too long and the condition can often be misdiagnosed. We need to take another approach says a leading specialist.

Tess Jewson was just 17 when she was diagnosed with pulmonary arterial hypertension (PAH), but she’s refused to let this rare disease stop her living her life to the full.

“It's vital that diagnosis is improved for patients with pulmonary arterial hypertension (PAH).

It is a chronic and incurable heart and lung condition that affects some 3,000 people in the UK,” says Professor David Kiely, Director of the Sheffield Pulmonary Vascular Disease Unit.

“Multiple new PAH treatments are available, which have dramatically improved survival rates,” he says. “Early diagnosis means greater opportunity to access these treatments, meaning better outcomes for patients.

“Unfortunately, diagnosis of PAH can take about two years and many people remain undiagnosed — a situation that is common in many other countries around the world and hasn't changed significantly over the last two to three decades.”

Music teacher, Tess Jewson, was just 17 when she was diagnosed with PAH. She had always suffered with asthma as a child but, during a night out with friends, began to feel dizzy and severely out of breath. After doctors ran a series of tests, Tess was told that a congenital heart condition had led to pulmonary hypertension (PH) with Eisenmenger syndrome — and that she might have only months to live. That was 11 years ago.

Tess says the medication she has been prescribed, the managed care she receives and the support from her family and friends have all helped change that dire prognosis.

She also thinks her positive mental attitude has made a difference. After her initial diagnosis and months of successful treatment, she was discharged from hospital. She packed her bags and went to university to study music. “I had a place at Southampton and nothing was going to stop me getting there,” she says.

Average survival is just 2-3 years if left untreated PAH — a rare form of pulmonary hypertension (PH) — narrows the small blood vessels that lead to the lungs, causing patients to struggle for breath. In some types, such as idiopathic PAH, average survival is just two to three years if left untreated.

The trouble is, breathlessness — the main symptom of PAH — also presents in many other common conditions, which means it's easy for patients to be misdiagnosed. “Our current approach to investigating breathlessness

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doesn't help identify rare conditions,” explains Professor Kiely. “So, we need to apply new and alternative approaches, including the use of artificial intelligence techniques that have the potential to identify those at greater risk of idiopathic PAH.” Importance of referral to specialist care Specialist management is essential for patients with PAH. When the condition is suspected it’s incredibly important that adult patients are referred to one of seven specialist pulmonary hypertension centres around the UK, with children referred to a specialist centre in London.

“These centres allow patients to receive a speedy diagnosis and begin – often complex – drug therapies,” says Professor Kiely.

“These centres have been big success stories and greatly increased the number of people receiving treatment.”

“Once patients have started treatment, it's important they are regularly monitored and assessed with a variety of different, usually non-invasive tests. That's why it's important patients are assessed in specialist centres where highly skilled, multi-professional teams are experienced in managing this challenging condition.”

I can’t work full-time because of PAH Even so, her life did drastically change. She had to give up the trumpet (“That was my main study — so having it taken away from me was terrible”) and after going out with friends she has to rest the next day.

She also isn't able to work full-time and says it can be frustrating that the public and even some clinicians don't know enough about the condition and how chronic it can be, especially as it’s an

invisible illness for many PAH patients.

"PHA UK offer great support" Despite these challenges, Tess is keen to allay the fears of anyone newly diagnosed with PAH. “There is very good support available,” she says. “I'd direct people to PHA UK — the Pulmonary Hypertension Association — in the first instance. Also, appropriate treatment and ongoing management of the condition with your healthcare team and support network can now help you live the life you want to live. Look at me: I'm still going strong. ” Don't let it hold you back. As I always say: “I don't live with pulmonary hypertension.

Pulmonary hypertension lives with me.”

Byline: Tony Greenway This Rare Disease Day Actelion is supporting a number of initiatives.

Check out any of the following hashtags to see what else is happening this #RareDiseaseDay #RareDiseaseDayChat #ShowYourRare #RareReality NOP 19/0447d February 2019

Read more at healthawareness.co.uk

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My road to recovery from Cushing’s disease

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aving suffered debilitating symptoms for years, Esther found a new lease of life after she was finally given the correct diagnosis.

I was 12 when I started to experience excruciating menstrual pains. The stomach cramps would cripple me, my face and neck would be covered with severe rashes.

I had severe hyperhidrosis (excessive sweating) from my scalp and face. I would drip endless buckets of sweat and there was no way to control it, but I carried on, trying to live a normal social and working life.

I was told my symptoms were due to stress In 2014, my hyperhidrosis worsened.

I developed asthma and hay-fever and I started to suffer from sleep

ESTHER FLORENCE Cushing’s Patient

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deprivation. I was told this was all probably down to stress.

By 2016, my life was at a standstill.

I felt like I was a prisoner to my hyperhidrosis and I was running on one to two hours’ sleep a night.

Reluctantly, and only out of naive desperation, I took sleeping pills that my GP recommended. I wanted to feel human, and not like a total zombie all the time because I wasn’t getting enough sleep. I was told I was obese and needed to change my lifestyle habits - eat well and exercise regularly.

I was doing all of that and more for years prior, yet I was getting worse.

Some medical professionals made me feel like I was exaggerating my symptoms.

I continued to push for answers because I so desperately missed doing all the things that made me happy. I tried to keep a positive mindset throughout it all.

Even though my body was failing me, I wasn’t going to allow my mind to fail me too.

I was misdiagnosed, and weight loss surgery was suggested After being referred to multiple specialists – dermatologists, hair and nail specialists, endocrinologists – I was misdiagnosed with polycystic ovary syndrome (PCOS). I was also referred to a weight management programme to be considered for bariatric surgery. I was petrified, as I didn’t want this type of surgery. I knew it

wasn’t my lack of control causing the weight gain. I was tired of feeling so lethargic all the time and ashamed of the way I looked.

In 2017 I was finally diagnosed with a life-threatening and rare condition called Cushing’s disease, following the discovery of a benign tumour on my pituitary gland. I felt an overwhelming sense of relief to finally have an answer.

Nothing could prepare me for the recovery journey A year has passed since my surgery and, while nothing could fully prepare me for the recovery journey, I am so grateful to have been given a second chance at life. I am proud of myself for not allowing the debilitating symptoms that follow after surgery to completely take a hold of my life.

I am currently trying a phased return to work and I am also looking to volunteer with local charities to help mentor vulnerable children and adults who have experienced trauma or any form of mental illness.

It’s important for me to add value and positivity to someone else’s life; to enable individuals to better deal with the demands and challenges of everyday life.

I will strive hard to spread awareness about Cushing’s disease and recommend anyone experiencing symptoms to check out The Pituitary Foundation, whose resources have helped me better understand and cope with my condition.

Read more at healthawareness.co.uk

No deal threat to rare disease collaboration NICK MEADE Director of Policy, Genetic Alliance UK

To date, many of the discussions around Brexit have been on the immediate risks of an outcome without a deal. However, there is another wave of consequences that follow with longer term impacts, arising because the UK and the EU do not have the opportunity to plan their future relationship in a transition period.

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ithout a transition period, we must start from scratch as a ‘third country’. Ongoing collaborations and initiatives that use EU infrastructure, funds or law will all have to stop, until a new basis for the UK’s relationship with the EU can be established and the specific terms

of collaborations and initiatives renegotiated. Signs are that this could take some considerable time.

European Reference Networks connect 20,000 HCPs across 26 countries European Reference Networks (ERNs) exist because of EU legislation and

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CREDIT: RAWPIXEL

use EU infrastructure. ERNs provide a new way for rare disease clinicians to collaborate across the EU - sharing information and expertise, and supporting each other with specific cases. This approach is crucial for growing expertise and improving best practice in the treatment of rare diseases.

Rare disease research relies on multinational collaboration Despite their number and diversity, rare diseases have in common that they tend to be complex and difficult to treat. The road to diagnosis can be lengthy and difficult. They have in common, too, the need for multinational collaboration in research - the sharing of expertise and infrastructure that delivers advances in treatment and hopes of a cure.

Rare disease care after Brexit There are more than 6,000 known rare diseases, and others yet to be identified. No single centre, no single country can provide the specialist expertise necessary to properly meet the needs of every patient with every rare disease. The best outcomes for patients depend upon collaboration across borders.

ERNs can provide for this collaboration, linking approximately 20,000 healthcare professionals in 300 centres of excellence, across 26 countries. ERNs are already delivering benefits to almost a million rare disease patients - and their future potential is enormous.

In 2017, the EU established 24 ERNs. UK NHS institutions are members of 23, and have played a pivotal role in the foundation of most.

The rare disease community cannot afford to lose the expertise of any one country. This will have a detrimental effect on patients living in both the EU 27 and also in the UK,” says Yann Le Cam, Chief Executive Officer of Eurordis.”

Yann Le Cam CEO, Eurordis

That’s 40 UK centres of excellence, and 114 specialist units, caring for approximately 150,000 rare disease patients in the UK. The best and the brightest UK clinicians have indicated that they see their best possible future within

a specialist centre connected to an ERN. UK patients have played an important role in setting the terms of this collaboration, and regard our future participation as crucial for the future of rare disease care in the UK. Eurordis - the Voice of Rare Disease Patients in Europe - supports the UK’s continued involvement: “European Reference Networks are a landmark infrastructure that our community waited nearly 20 years for. Brexit threatens to destabilise this new infrastructure as UK expertise is one of the founding cornerstones of these networks.

“The rare disease community cannot afford to lose the expertise of any one country. This will have a detrimental effect on patients living in both the EU 27 and also in the UK,” says Yann Le Cam, Chief Executive Officer of Eurordis.

Show your support for UK access to research postBrexit The UK government has signalled that continued participation in ERNs will be a priority within a transition period with an overt statement in the draft withdrawal agreement. We need to show the European Union that this is a priority for the rest of the EU too - you and everyone else can do that by supporting our Protect ERNs campaign at protect-erns.eu.

We will take this clear message that the continuation of the UK’s participation in ERNs is a Europewide priority, to the EU, as soon as the transition phase begins… If, of course, we get one.

Read more at healthawareness.co.uk

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Newborn blood spot screening - UK stuck in 20th century PROFESSOR RAFAEL YÁÑEZ Chair, Genetic Alliance UK Professor of Advanced Therapy, Royal Holloway, University of London

What it means to be ‘rare’ — and how collaboration can help PROFESSOR TIMOTHY COX Director of Research, Honorary Consultant Physician and Emeritus Professor, University of Cambridge

In the UK, newborn babies are tested for nine diseases using a blood spot screening programme. That’s fewer than half the number tested in many European countries.

We need to do better to catch rare diseases earlier on.

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n the UK, we have been collecting spots of blood from the needle-pricked heels of newborns since the late 1960s.

Parents are accustomed to the notion that these small samples of blood will be used to test babies for fatal or disabling conditions as early as possible so that treatment can begin where disease is detected.

Many of the conditions detectable in newborn screening, if left untreated, have serious effects that may include intellectual, developmental and physical disability – and even death.

People assume as many conditions as possible are being tested.

The UK is stuck in the past compared with other developed countries The first condition to be introduced to the blood spot screening programme was phenylketonuria (PKU), a rare disease affecting around 1 in 10,000 newborns. The adverse impacts of this condition can largely be reduced or avoided by restricting a substance called phenylalanine, present in food protein. In the following 30

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years the only additional test to be officially recommended throughout the UK was that for congenital hypothyroidism.

Almost 60 years since blood spot screening was introduced, the UK has added just nine tests in total.

This glacial pace of change has left the UK out of step with other high-income countries. The USA screens for up to 60 diseases, and many European countries screen for between 25 and 40.

Infant deaths could be avoided with genome sequencing Newborn screening in the UK has undoubtedly saved and transformed thousands of lives. However, the process and criteria used by the UK National Screening Committee (UK NSC) to decide which tests should be included in newborn screening have not kept pace with medical science and social values.

The advent of genomic medicine and genome sequencing could widen the gap further, potentially allowing thousands of inborn differences to be

detected from a single spot of blood.

The impact of this screening inertia has resulted in entirely preventable infant deaths. For instance, in severe immunodeficiencies, only 40% of first siblings survive while, following tests, 90% of later siblings do. It has also resulted in significant disability and has robbed parents of reproductive choice.

Bringing the UK into the 21st century is morally imperative The ‘disease by disease’ approach taken by UK NSC will not serve us well. Medical science is delivering new and improved treatments with increasing efficiency. There is an ethical and moral imperative to ensure that this growth in knowledge and capability be harnessed for the benefit of our children and public health. It is time to shake off the shackles of inertia and think differently about newborn screening for rare diseases.

Read more at healthawareness.co.uk

Byline: Tony Greenway

Collaboration is a vital part of rare disease research, says one leading doctor. Teamwork has led to big breakthroughs in the past — and will lead to many more in the future.

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rofessor Timothy Cox — Director of Research, Honorary Consultant Physician Emeritus Professor of Medicine at the University of Cambridge — has always been fascinated by the field of rare disease research. And for good reason. “To be 'rare' is shocking for patients,” he says. “It means delayed diagnosis, alienation, and no-one knowing what to do or how to help you. You only have to look at the disabling effect of genetic disease in young children. That's a human tragedy. So (as a clinician) the thought that you might be able to put things right — and also that your research could extend treatment into other areas — is a powerful force.”

Professor Cox says, while not being a religious man, he is

evangelical about what can happen when researchers, pharmaceutical companies, the medical profession and patients work together for the greater good. Regional Rare Disease Networks — such as the CRDN in Cambridge — bring all the agencies together and also, importantly, local patients and their organisations.

Such collaborations can result in life-prolonging or even life-saving orphan drugs.

The strength of patient advocacy groups He's especially passionate about the power of patient advocacy groups, whose lobbying was partially responsible for the introduction of the European Orphan Drug Act in 2001 (“which made a massive difference to drug development”)

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Optimism, but challenges ahead for curing rare diseases Once, those born with cystic fibrosis would often not live into their teens.

Now they are living much longer.”

operation cannot be underestimated.

Yes, the different 'stakeholders' processes and rewards are different, but their goal is the same. Seeing that synergy develop has been the thrill of my professional lifetime.”

and whose vigour sparked major research breakthroughs into diseases such as cystic fibrosis.

Once, those born with cystic fibrosis would often not live into their teens.

Now they are living much longer.

“With cystic fibrosis, the assembly of specialist services has improved care and outcomes through best practice. Specialist services now able to advocate for access to the best molecular therapies,” says Professor Cox. “It is early days but the latest treatments hold enormous promise for prevention and indeed some reversal of the disease.”

Medical advances are made by the diligence of many individuals, says Professor Cox. “For example, take the scientist who discovered the cystic fibrosis gene. Then the scientists who worked on the protein identified by that gene and discovered what was going wrong with it. Then the screening team who screened thousands of random chemicals in the search for a treatment, and so on. The individual motivation and positivity that comes from such co-

Providing insight into more common conditions It has another benefit too. Research into rare diseases can also lead to important discoveries that may help the treatment or management of more common conditions. For example, Professor Cox cites how recent research found that the gene mutations involved in Gaucher disease — a rare genetic condition — are linked to the much more common Parkinson's disease. “The study of rare disease is full of scientific insight,” says Professor Cox. “You don't know where that insight will take you.”

Naturally, it is vital that this work continues, which is why it's so important to remember rare diseases all year round — not just on Rare Disease Day. “In a way, Rare Disease Day reminds us of what we haven't achieved,” says Professor Cox. “Although it also highlights what we are beginning to achieve in this complex and important field.”

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Read more at healthawareness.co.uk

DR SHEULI PORKESS Deputy Chief Scientific Officer, ABPI

When I hear about the experiences of people and families coping with rare diseases there are some all too common themes – strange and varied symptoms, and difficulties with diagnosis.

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ven if a condition is diagnosed, the reality is that there probably isn’t a treatment for it. The fact that only 5% of rare diseases have any licensed treatment options available drives our scientists to discover the treatments and cures people need.

But there have been some developments that mean the future is brighter.

Firstly, the announcement of the NHS Genomic Medicine Service in the NHS Plan was excellent news.

Unlocking the secrets of the genome will not only aid early diagnosis but should help us create much-needed new treatments and therapies.

We look forward to working with government and the NHS to help patients take full advantage of the opportunities genomics presents.

Tackling the challenges in medicine approval We have also made some progress towards unlocking the process for getting medicines approved for use in the NHS, which currently holds back treatments in this field. You

need a certain level of evidence and the right number of patients for clinical trials to create the data needed to prove that a medicine works. But, by the very nature of rare diseases, the patient numbers – and therefore the data needed – simply aren’t there in the same way as for other diseases.

This year, we will be working with NICE on a review of how medicines are assessed. This will hopefully lead to important changes in the assessment process for new medicines that will overcome this barrier and help us bring new treatments to rare disease patients.

New agreement on medicine pricing Another positive development is the agreement of a new, voluntary scheme for medicines pricing with government. Under the agreement, the overall NHS bill for medicines will not rise by more than 2% in any of the next five years. The scheme is aimed at making sure that cost isn’t a barrier and the NHS can adopt new innovations as they are created –

which is good news for rare diseases and for medicines generally.

Increase in gene and cell therapy trials There are also some positive developments in research, with reports that cell and gene therapy clinical trials increased by 37% since 2017. We want to make sure the positive work of advanced therapy treatment centres continues to help drive this improvement further.

Industry is determined to help combat the fear and misery that rare diseases can cause to so many.

There’s a lot of work to do, and we know it must happen faster. It is also essential that we maintain close scientific collaboration with the EU, post-Brexit. But this year, we have seen some welcome steps towards the day when people with rare diseases can enjoy the same access to treatments as those with more common conditions.

Read more at healthawareness.co.uk

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Pioneering service to expand genetic testing GEMMA CHANDRATILLAKE Education and Training Lead, East of England Genomic Medicine Centre and Trustee, Cambridge Rare Disease Network

A ground-breaking new service is poised to transform diagnosis and care for people living with genetic rare diseases in England.

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he NHS Genomic Medicine Service, which was announced last September, will provide healthcare professionals with a directory of available genetic tests in a bid to speed up diagnosis and deliver more personalised medicine.

Patients will also be offered the opportunity to participate in a national programme of data collection and research that could inform future treatments and care pathways.

Gemma Chandratillake, Trustee of Cambridge Rare Disease Network, said access to this new technology currently varied across the country, and that this was compounded by a general lack of knowledge around genetic testing and rare diseases.

Cutting the diagnostic odyssey short “Because there is a lack of awareness of rare diseases, patients can spend a long time being passed from doctor to doctor before they get a diagnosis.

“People call it the diagnostic odyssey – the continuous frustration of going from medical appointment to medical appointment, but never really knowing what’s going on.”

The new service hopes to change all that.

Doctors will be able to look up a patient’s symptoms, and the directory will tell them which tests are needed. These will then be carried out at one of seven new genetic testing “hubs” across the country.

“We hope it will speed up diagnosis, because without a diagnosis it is difficult to let people know what to expect and also what the chance is for other children in the family to be affected.

Diagnosis unlocks things people need like education and support,” said Chandratillake.

100,000 Genome Project looked at DNA of 85,000 people The service has been made possible by the 100,000 Genome Project, which sequenced the DNA of more than 85,000 people. This huge

10 HEALTHAWARENESS.CO.UK

Because there is a lack of awareness of rare diseases, patients can spend a long time being passed from doctor to doctor before they get a diagnosis.” database of genetic information will now be expanded thanks to the option to participate in research made possible through the new genomic medicine service.

The possibilities are transformative, said Chandratillake, who is currently educating healthcare professionals on the new system in her role as Education and Training Lead at the East of England NHS Genomic Medicine Centre.

“By putting huge numbers of people together, you could identify genes that cause conditions no one even knew about before,” she said, adding that the small number of people living with any one rare disease often made it difficult to conduct meaningful clinical trials.

“In the future, researchers who want to do a clinical trial will be able to apply to access a ready-assembled cohort of participants.”

And as the service gathers more information on how genetic rare diseases affect people over time, it will inform standards of care.

The project will help families affected by rare diseases “In many cases, we don’t know the full range of a condition or what life looks like for families going forward. But this data will offer a better idea of the things to look out for, and how they can affect the patient journey.”

Ultimately, the service will help the NHS deliver quality care to the one in 17 people who lives with a rare disease, she concluded.

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Collecting data from patients to improve access to treatment SHEELA UPADHYAYA Associate Director, Highly Specialised Technology (HST) Programme and National Institute for Health and Care Excellence (NICE)

People with rare diseases can face many challenges on the – often long – road to accessing treatments. These challenges can make informed funding decisions very tough; in part due to limitations in the evidence for the treatment’s effectiveness.

T

hese evidence gaps are often difficult to quantify and decipher in a world that values scientific data over real-life, experiences. Managed access arrangements (MAAs) represent a way of enabling patient access to promising drugs while collecting data from their use in the real world. The data collected from patients help to address clinical uncertainties and mitigate some of the financial risk to the NHS. And the more insight, the higher the chances of better longterm commissioning decisions.

Multi-stakeholder approach across patients and healthcare professionals In order for an MAA to collect meaningful and robust data, a multi-stakeholder collaborative approach is necessary. All stakeholders play a vital role in developing and delivering the MAA by helping to define which data to collect, how to collect it and from whom.

Industry and the NHS are required to facilitate the collection of data agreed in the MAA, while clinicians and patient groups help to identify and overcome personal and practical challenges to data collection.

Practicalities of a data collection group In England, the National Institute for Health and Care Excellence (NICE) plays a role in overseeing the delivery of the agreement by ensuring the data outputs meet the needs of a future evaluation by NICE. NICE does this by assembling a Managed Access Oversight Committee (MAOC) for each MAA, consisting of representatives from the company, patient organisations, commissioning bodies and treatment centres.

This group operates under the chairmanship of NICE with the primary function of reviewing the progress of data collection and identifying operational challenges in implementing the terms of the arrangement, ensuring implementation issues are promptly resolved.

Who benefits from a managed access agreement?

These agreements offer an opportunity for patients with rare diseases to access new and innovative drugs that may deliver benefits to them and their families, in addition to

collecting real-world data to address gaps in the original evidence base. This set-up provides a win-win scenario for all stakeholders: • Patients who meet appropriate eligibility criterion can secure access to a treatment that would not routinely be available outside of managed access in England • Industry is able to collect data in a real-world setting that is applicable to a UK population • The NHS has some protection of the financial risk, as the agreement is time limited • NICE can reassess the technology with a fuller evidence base in the future These opportunities can only be explored when the NICE committee feel it is possible to collect further data to help close gaps in the presented evidence. The committee will ask itself: ‘Which data is missing?’; ‘Can it be collected?’ and ‘How much time will it take to achieve adequate data before it will consider if an MAA will be a good option to consider?’

Data from patients can be collected by questionnaire The data is collected mostly in the clinical setting but can be collected in other ways, e.g. by asking patients and/or their families to complete questionnaires about the impact the treatment is having on their quality of life.

At the end of the agreement, the collected data are incorporated into a new submission to NICE for re-evaluation to determine if the technology should be recommended to be provided routinely to eligible patients by the NHS. All stakeholders are made fully aware that the decision made by NICE at re-evaluation is the one the NHS will be mandated to implement.

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Taking trials to patients in rare disease clinical trials Byline: James Alder

Finding and retaining patients for a clinical trial is a problem all researchers will be aware of. Studies that put the patient’s welfare first are far more likely to succeed in that respect, as Helen Springford of Illingworth Research Group explains.

T

he use of off-site or ‘mobile’ research nursing within clinical trials is certainly not a new concept. That said, increasingly frequent use within clinical research points towards a more patient-centric general trend across clinical trials.

Taking the trial to the patient, with mobile research nurses able to perform many of the requisite tasks in the home or the patient’s school or workplace, can drastically reduce the levels of stress associated with travelling to the hospital for visits and can, as a result, improve the quantity of patients a study attracts.

Conducting trials visits at patients’ homes/schools/ workplaces Helen Springford of Illingworth Research Group is clear on the

benefits of conducting visits outside of a clinical environment for both those running clinical trials and patients.

“We see mobile research nurses take blood samples for pharmacokinetic sampling (measuring the movement of drugs throughout the body), administering intravenous drugs or even simple tasks like monitoring a patient taking an oral study medication.”

“These don’t need to be done in a clinic and, with rare diseases specifically – where your patients are, by the very nature of what they have, likely to be few and far between – finding research nurses near them makes the decision of whether or not to take part in a study a far simpler one.”

Ensuring a study does all it can

Make rare diseases matter.”

to lessen the impact on a patient’s and their family’s life can vastly improve both patient recruitment and retention in the long-term.

An Icelandic family needed to travel to Canada for trials; until trials mobilised “A family from Reykjavik in Iceland had two young boys with Duchenne Muscular Dystrophy (DMD - a rare genetic disorder),” Helen explains.

“They found out about a trial that could benefit them, the only problem being the site was based within a hospital in Calgary, Canada.”

With frequent visits over eight weeks, participation would have meant either staying in Canada or travelling back and forth – neither being an option for the family.

Conducting a portion of the visits at

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Spinal muscular atrophy treatment must become accessible Scotland’s ultra-orphan pathway for drug appraisals is something England should be aiming for.

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ew treatment, nusinersen, has been shown to slow down the progress of the devastating and sometimes fatal condition – spinal muscular atrophy. Now widely available in Europe and with NHS Scotland likely to offer full access from April 1st, even children with the most severe form of the condition cannot yet receive this treatment in England, Wales or Northern Ireland.

As a matter of urgency, we need access to this treatment to become possible. We also want to see a future alignment of England’s drug appraisal route with the new Scottish ‘ultra-orphan pathway’, which is so much better suited to medicines for rare conditions.

Make rare diseases matter.

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HELEN SPRINGFORD Vice President Strategic Development, Illingworth Research Group

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the family home in Iceland through off-site research nurses meant the boys could take part in the study.

Another of Helen’s stories really brings home how important flexibility is becoming to patients when making a tough decision on whether or not to participate in a trial.

Knowing it would be her last Christmas, this patient wanted to be at home “One terminally ill patient told me that she was desperate to perform her yearly ritual of making the Christmas puddings for her children on what she knew would be her last Christmas with them. Had it not been possible for the visits to take place at her home, taking part would have left her too exhausted to be a part of the study

and achieve the things she wanted to with her remaining time.”

The study of rare diseases poses many challenges, yet engaging patients through clinical trials that are designed to lessen the negative impact on their lives seems to be a way to alleviate one of the more pressing ones – finding patients and retaining them.

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Read more at illingworthresearch.com or email at helen.springford@illingworthresearch.com

Enzyme replacement therapy approved for UK clinical trials DR BRIDGET BAX Reader in Rare Diseases, St George’s, University of London

R

esearchers at St George’s University of London are developing an enzyme replacement therapy for MNGIE (mitochondrial neurogastrointestinal encephalomyopathy), a progressive disorder where patients die at an average age of 35 years.

Patients with MNGIE have a defect in the gene that codes for the enzyme, thymidine phosphorylase and results in affected individuals producing insufficient enzyme.

Thymidine phosphorylase is required for the normal metabolism of substances called thymidine and deoxyuridine. In its absence, these accumulate to toxic levels in the body, causing damage to the mitochondria, which are the powerhouses of the cell. Tissues that are heavily dependent on energy, such as muscle, the gastrointestinal system and nervous system are severely affected.

The St George’s team, led by Dr Bridget Bax (with Drs Michelle Levene and Niranjanan Nirmalananthan) are investigating the effectiveness of using the patient's own red blood cells (erythrocytes) as a vehicle to carry the missing thymidine phosphorylase in the blood circulation. The erythrocytes provide a

protected environment in which the enzyme can function. The encapsulated enzyme reduces the levels of toxic metabolites in the blood, relieving the nervous system and muscle of their damaging effects.

Data obtained from the compassionate use of erythrocyte encapsulated thymidine phosphorylase (EE-TP) in patients with MNGIE showed that a reduction in blood thymidine and deoxyuridine levels can be causally linked to clinical benefit. EE-TP has been approved by the Medicines and Healthcare products Regulatory Agency (MHRA), clearing the way for patient clinical trials to begin this year. The team are now applying for approval to extend trials to other countries.

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Specific herbal extracts for medical research: milk thistle and oncology DR JOAQUIM BOSCH Co-author of the studies and Head of the Lung Cancer Unit, Catalan Institute of Oncology (ICO)-IDIBGI in Girona Byline: Tony Greenway

New research suggests that a silibinin-rich extract of the milk thistle plant fruits (known to support liver health) may also be beneficial to patients with brain metastasis1,2.

M

ilk thistle is an extraordinary looking plant: spiky, spiny and usually adorned with a vibrant, red-purple flower.

Now, research suggests that it may have extraordinary anti-cancer properties too.

The active constituent of milk thistle is silymarin, the key component of which is silibinin. Since 1971, Euromed — a leading producer of pharmaceutical standardised herbal extracts — has been precisely extracting silymarin (and other botanical compounds) for the pharmaceutical and nutraceutical industries.

Initial research shows promise for HIV-positive subjects Milk thistle has long-been popular as a natural treatment to support liver health, with extensive clinical trials and scientific studies demonstrating its healthy liver function properties. Now, scientists are examining the efficacy of Euromed’s milk thistle extract in other areas of medicine.

For instance, preliminary research at the University of Washington, supported by the National Center for Complementary and Integrative Health, suggests that the company’s milk thistle extract elicits anti-inflammatory and immunoregulatory activity in human immune cells, including in cells obtained from HIV-positive subjects3.

Difficulty of treating patients with brain metastasis Then, recently, more research was published1,2, indicating that this specific extract standardised in silibinin may even be beneficial to patients with brain metastasis. “Brain metastasis is a major challenge in the field of oncology,” explains Dr Joaquim Bosch, coauthor of the studies and Head of the Lung Cancer Unit at Catalan Institute of Oncology (ICO)-IDIBGI in Girona. “It depends on the type of cancer a patient has, but it is estimated that around 10% develop brain metastasis, which worsens their prognosis significantly. It is also very difficult to treat, so we need to find a new therapeutic concept for brain metastasis.”

Milk thistle could help cancer patients in the future Dr Bosch’s research offers hope that this may be possible in the future. Silibinin is a direct inhibitor of pSTAT34, a protein constitutively activated in many different types of cancer that has a prominent role in mediating resistance to conventional chemo-/ radio-therapies and modern targeted drugs; and Dr Bosch found that administering it to brain metastasis patients reduced lesions without causing any adverse effects. Further research must now be conducted before silibinin can be used in clinical practice.

Several milk thistle preparations are available in the market; but these can differ due to agricultural and production methods — which may also result in variations of silymarin and silibinin.

So not all extracts are equivalent, warns Dr Bosch. “Euromed’s pharmaceutical-grade formulation of milk thistle fruit extract has optimal release rate and absorbability.

This can help overcome the Sponsored by limitations of oral administration of silibinin to cancer patients.”

Read more at euromed.es

1: Bosch-Barrera J, et al. Oncotarget. 2016 May 31;7(22):32006-14 2: Priego N, et al. Nature Medicine. 2018 Jul;24(7):1024-1035 3: Lovelace ES et al. PloS One. Published online February 3, 2017 4: Verdura S, et al.

Food and Chemical Toxicology. 2018 Jun;116(Pt B):161-172

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Why working together will turbo-charge rare disease research DR DARIA JULKOWSKA Assistant Director, Multi-Organisation Thematic Institute for Genetics Genomics & Bioinformatics, INSERM, the French National Institute of Health and Medical Research

For years, rare disease research was — and partially still is — fragmented in Europe. Now, a new programme plans to pull all the different strands together to improve innovation from “bench to bedside.”

Byline: Tony Greenway

Patients can sometimes wait 15 years to be diagnosed... We want them to receive diagnosis within one year of medical attention.”

“Close collaboration, joined-up thinking and knowledge-sharing.

These are the best ways to improve research into rare diseases and so help clinicians achieve better outcomes for patients,” says Dr Daria Julkowska, Assistant Director of the Multi-Organisation Thematic Institute for Genetics, Genomics & Bioinformatics at INSERM, the French National Institute of Health and Medical Research.

Research in Europe was — and partially still is — fragmented; but efforts to make it more collaborative started around 20 years ago and are still ongoing. Now, a new European programme has been launched to build on previous achievements, pull the different strands together, scale them up and create a comprehensive environment. Called the European Joint Programme on Rare Diseases (EJP RD), it was launched in January and is a five-year initiative co-financed by the European Commission and EU member states, which brings together 130 institutions from 34 countries under one umbrella. Dr Julkowska — who serves as EJP RD Coordinator — hopes the programme will be a turning point for European rare

disease research. It certainly needs to be. As the European Commission notes, rare diseases “affect or will affect an estimated 30 million people in the European Union.”

Faster innovation through knowledge-sharing “EJP RD is a programme that will be creating a European ecosystem to accelerate the research, diagnosis and development of treatment for rare diseases,” explains Dr Julkowska. “The idea is to bring together the majority of stakeholders — including research institutes, clinicians, university hospitals, funders and patients — to ensure the implementation of a comprehensive and cohesive research and innovation 'bench to bedside' pipeline.”

To operate effectively, EJP RD activities have been built on a number of 'pillars'. These include the development of a virtual platform for rare disease information “encompassing research data, samples, tools and standards to support and accelerate rare diseases research;” and capacity building and empowerment to raise “the level of knowledge and know-how within the rare diseases research and care community.”

Diagnosis can take 15 years EJP RD wants to strongly contribute to the three 10-year goals established by the IRDiRC (International Rare Diseases Research Consortium).

“Firstly, patients suspected of having a rare disease can sometimes

wait 15 years to be diagnosed,” says Dr Julkowska. “We want them to receive diagnosis within one year of medical attention. If no diagnosis is forthcoming, they should then enter a globally-coordinated diagnostic and research pipeline.”

1,000 new therapies for conditions with no current treatment Secondly, the EJP RD aims to contribute to the goal of developing 1,000 new therapies for rare diseases, with a particular focus on those conditions where no therapeutic treatment is currently available.

“This objective is very ambitious,” admits Dr Julkowska. “It cannot be achieved unless all stakeholders work together.” EJP RD also wants to play its part in the third IRDiRC objective: to develop methodologies that will measure the impact of diagnoses and therapies on rare disease patients.

For Dr Julkowska, one measure of success will be if EJP RD establishes itself as the first port of call for patients, clinicians or researchers looking for the most up-to-date rare disease information, tools and support. “They might want data to help set up a clinical trial or undertake a specific research project,” she says. “Whatever it is, they will be able to find all relevant information and support within our programme.”

Read more at healthawareness.co.uk MEDIAPLANET

Regulators and payers are ready to talk about orphan drugs

DANIELE SEVERI BRUNI Vice President, Market Access, Two Labs

Securing market access for orphan drugs is littered with challenges, but early collaboration between manufacturers, regulators and payers is the key to overcoming the obstacles.

D

aniele Severi Bruni, Vice President of Market Access at Two Labs (formerly MKO Global Partners), believes there is an appetite for overcoming the challenges of bringing expensive, yet potentially transformative, therapies to market.

“The manufacturers and the scientific community are not the only ones who are excited for cell and gene therapies.

“Others in the industry, like payers and regulators share the same excitement. They know patients with these diseases suffer and that the impact on families and society is enormous,” he says.

Payers simply have limited resources and, in providing funding for any drug, they must rely on robust evidence of its efficacy and safety.

Unfortunately, in orphan drugs, randomised, controlled trials in large patient populations are all but impossible, meaning data on how they work in the real world is limited. This problem is accentuated by new technologies, such as gene and cell therapy. With these technologies, a large upfront cost

is necessary, however the benefit is realised over time.

Huge sums of money for a small group of people It is on this basis that payers are being asked to allocate huge sums of public money to a relatively small proportion of the population for technology whose actual value is uncertain in the real world.

Daniele says: “I believe, in the end, all these drugs will be paid for, but it might be that it takes a very long time to negotiate the price and access conditions.

“In the meantime, you have all these patients with high, unmet needs who are suffering or even dying from rare diseases.”

Manufacturers and agencies must collaborate The solution is manufacturers taking payers’ decision-making process into account and working with HTAs and regulatory agencies “to find a solution that suits everyone”.

Managed access agreements or innovative pricing contracts, which Daniele compared to offering a

warranty or insurance policy on the treatments, could be based on any number of models. Outcome-based pricing and staggered reimbursement schemes are just two examples.

Mechanisms to reduce or dilute the financial burden over time and increase payers’ confidence in what they are paying for exist and should be embraced early on. These mechanisms do not only involve payers and manufacturers, but they should also leverage a partnership with regulatory agencies to ensure a flexible but robust evidence generation process.

For example, the European Medicines Agency’s (EMA) new Adaptive Pathways Programme allows for staged conditional approvals, which could be then linked to some conditional or innovative payment mechanisms. Similarly, the EMA also offers joint consultations with EUnetHTA to manufacturers. These approaches allow pharmaceutical companies to gather the information they need to design their evidence development plan in a way that works for both regulators and HTAs and helps payers understand the challenges that manufacturers face.

Daniele says: “This is potentially very advantageous for all parties involved, including orphan drug manufacturers, because it gives them the opportunity to get early advice and understand what needs to be done to secure approval”.

Reducing the perceived risk Early collaboration with payers and regulatory agencies is important not only to define a reasonable evidence generation programme, they are also fundamental in thinking how to derisk these innovative technologies for payers.

“While innovative access agreements or innovative payment mechanisms are the potential solution, with many such agreements, the “devil is in the detail”.

He added: “The biggest risk for manufacturers is moving from a risksharing to a risk-taking arrangement.

Innovative access agreements and innovative payment mechanisms must be designed in parallel with the evidence generation plan and discussed with payers early on. This will ensure that the manufacturer is able to provide an adequate level

of insurance for payers, without taking on board the entire risk. These contracts need to reflect the actual value of the therapeutic intervention and, most importantly, they need to be financially sustainable for the manufacturer.

“Ultimately, bringing this technology to the market requires much more planning and much earlier on than for traditional drugs. However, good planning and a collaborative approach will benefit everyone: manufacturers, regulatory agencies, payers and, most importantly, people living with rare diseases.

Sponsored by

If you are a manufacturer working on a rare disease drug and want to learn more about finding a solution that works for payers, please contact Daniele Severi Bruni at daniele.bruni@twolabs.com or visit www.twolabs.com to learn more.

A new era in rare disease therapy – but how can we make sure patients get access?

Patients with rare diseases are often desperate for new therapies — yet lengthy discussions with health service providers about ‘cost-effectiveness’ can often be a barrier to drug access.

Byline: Tony Greenway

I

n his 17 years at the sharp end of innovative drug development, Brendan Martin — VP and General Manager, UK & Ireland, Alnylam Pharmaceuticals — has seen a significant, positive breakthrough in rare disease medicines. Ten years ago, he notes, there were around eight orphan drugs (developed to treat rare disorders) in Europe. “But today there are more than 150 of them. In the US, there are between 200 and 300 orphan drugs. These are not medicines that exist simply as ideas on paper or which are still in development but rather drugs that have been approved.”

Supporting research in rare diseases is essential For patients or family members impacted by a rare disease, research into new treatments is so important.

Patients with some rare diseases have had limited or no treatment options – ever.

New, innovative medicines being developed are frequently lifeMEDIAPLANET

changing and, in some cases, lifesaving. Many rare diseases also have a genetic component, and the impact of this research means hope for future generations of an individual family.

Benefits are being seen today and there is real optimism for the future. However, drug development challenges in this space are considerable, the costs are enormous and the risks are huge, both for the drugs companies and their financial backers.

High-risk innovation requires new approaches to access “For established companies, it's estimated that every new drug costs about $2billion to develop,” explains Martin. “The costs for a start-up company, who also needs to build an infrastructure to bring that drug to patients, will be closer to $5 billion. That's an enormous amount of money to put at risk.” Especially when you consider that around 90% of drugs that reach Clinical Phase

1 fail and never get to Phase 3; and, Martin points out, of those drugs that do make it to market, around only 30% will recoup their research and development costs.

Both pharmaceutical companies and health services want to see these treatments benefitting patients and carers. But in an area where scientific advances are evolving so quickly, how we assess and make these medicines available needs to match that evolution. If not, the result means delays for patients who, in some cases, may not have time to wait.

Assessing the full value of a medicine is a shared responsibility “The industry has a responsibility to create drugs that are safe and effective,” says Martin. “While neither of these are simple to do, establishing that a medicine is effective usually takes a shorter amount of time than being able to demonstrate that it has a manageable and acceptable risk-

BRENDAN MARTIN VP and General Manager, UK & Ireland, Alnylam Pharmaceuticals

benefit profile.

New medicines may also have other, indirect benefits for society that have not typically been measured, such as the ability to go back to work, impact on carers, a reduced burden on health services and opening the door to further discovery.

There is another significant barrier to progress, however. A financial one.

“This is something that, quite rightly, frustrates patients with rare diseases and their families,” says Martin.

“Because, in many cases the science is solved, and the drug is approved; but discussions around cost-effectiveness can delay access for two, three or four years.

“We are encouraged by the emerging trend of health services in a number of European countries working with industry and patient organisations to find better ways of providing early access to innovative new medicines. These health services are working to continually assess the clinical and cost-effectiveness of medicines once they are available,

addressing any uncertainties using real-world experience.

Collaboration is a crucial element of evolving the national processes that are in place to make medicines available in rare diseases. The collective goal is to improve patients’ lives, while discussions over price and cost-effectiveness take place, but without people missing out.

Rare Disease Day is another important reminder that there is so much positive change happening – but that everybody across the community has a role to play in ensuring that everyone who could potentially benefit from these advances has the chance to do so.”

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TTR02-UKI-00003-022019 Date of preparation: February 2019

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It’s a cruel and extremely rare disease — there are fewer than 100 cases worldwide. There is no known cause and no cure. Children with ROHHAD are not expected to reach adulthood.”

Hypoparathyroidism; rare, incurable and often caused by surgery LIZ GLENISTER CEO, Hypopara UK

Hypoparathyroidism severely impacts quality of life and is associated with renal failure and an increased risk of death.

L Robert Downey Junior joins Aaron, his sister, Lauren, his mum, Elisabeth, and his dad, Ian are co-founders of the ROHHAD Association.

Why Iron Man is helping Aaron battle his rare, terminal disease ELISABETH HUNTER Co-Founder and Chairwoman, ROHHAD Association Byline: Tony Greenway

When young Marvel fan, Aaron Hunter, was diagnosed with a rare childhood disease, he asked Iron Man to help him raise funds for research. Superstar Robert Downey Jr returned his call...

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hen he was five years old, Aaron Hunter was diagnosed with ROHHAD — or Rapid Onset Obesity, with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation — a life-limiting condition that mainly affects children, causing them to gain weight and experience breathing difficulties and other problems.

It's a cruel and extremely rare disease — there are fewer than 100 cases worldwide. There is no known cause and no cure. Children with ROHHAD are not expected to reach adulthood.

Weight gain and breathing problems are symptoms of ROHHAD “ROHHAD is very challenging to live with,” says Aaron's mum, Elisabeth Hunter.” Aaron is ventilated at night and sometimes during the day; he needs care 24/7. He can't maintain his body temperature and his heart rate is now falling dangerously low at times, so he may need a pacemaker soon.” Most recently, he needed an operation to remove his colon.

With no government support, Aaron’s family decided to set up their own ROHHAD charity After Aaron received his diagnosis — which took two years — Aaron, Elisabeth, his dad, Ian, and sister, Lauren, were devastated. They also decided to do something to raise funds for vital research.

“Because it's so rare, ROHHAD doesn't qualify for government funding or support from major charities,” says Elisabeth. “Yet we know there are consultants in the UK, Italy and America who are keen to understand this disease and improve patients' quality of life.”

So, four years ago, the Hunters launched the ROHHAD Association, an organisation that

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is funded entirely by donations. The charity also unites families around the world who are affected by the condition, offering them online support.

Aaron’s wish came true when Iron Man (Robert Downey Jr) got involved Aaron is keen to raise as much money as possible to help his friends with the disease and, last year, even got Iron Man star, Robert Downey Jr, involved in the cause. “He sent Mr Downey Jr a video asking for help to raise awareness — with the hashtag #AaronNeedsIronMan — which went viral,” remembers Elisabeth. Mr Downey Jr was so touched that he answered Aaron’s plea to help his special friends.

Aaron and Robert have since become firm friends and have started a ROHHAD fundraising campaign on social media, where the Hollywood A-lister jumped in a muddy puddle and then challenged his fellow Avengers stars to do the same.

Thanks to initiatives such as this, the ROHHAD Association will be donating £275,000 to ROHHAD research this year; but more — much more — is needed. Aaron is hopeful that many more people will get involved and help.

Perhaps Robert Downey Jr — who calls Aaron “a force of nature” — put it best. In one tweet calling for fundraising action Sponsored by he wrote: “I may play Iron Man, but Aaron is the true hero.”

iz Glenister, CEO of Hypopara UK, says: “Around 75% of our membership has postsurgical hypoparathyroidism (PoSH), mostly due to thyroidectomy. Surgical removal of parathyroid glands is occasionally necessary but is more often accidental, and can cause this rare condition. People go into hospital with one condition and come out with another which is incurable, life-threatening and very difficult to manage.”

There is an urgent need to improve surgical outcomes, and for more research on monitoring and treatment, which are currently inadequate.

The BAETS audit recorded a gradual decrease in the annual incidence of long-term PoSH (now 6.5%) but it remains an under-reported complication.

Hypopara UK works with top endocrine surgeons to improve this. “PoSH is a serious condition that is generally not well understood.

Our specialist advisors recognise the need for a change in practice and attitudes and are dedicated to furthering education and research.”

Consultant Endocrine Surgeon, Radu Mihai from Oxford University, found that PoSH had a severe impact on quality of life and led to frequent returns to A&E. Tom Kurzawinski, a Consultant

Endocrine Surgeon at UCL is currently developing a simple point-of-care, home tester for patients to test their calcium levels. This year, Consultant Endocrine Surgeon, Saba Balasubramanian from the University of Sheffield will trial an intraoperative imaging device.

“Living with PoSH can be very distressing so this research gives us hope. For the newly diagnosed, it is a difficult journey towards acceptance but patients are encouraged to know that they are being heard and keen to get involved in studies that may improve their lives.”

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Read more at hypopara.org.uk

PSP and CBD could hold clues for other neurological conditions ANDREW SYMONS Chief Executive, PSPA

PSP and CBD are progressive neurological diseases affecting around 6,000 adults in the UK. Caused by the death of nerve cells in the brain, they leave people unable to balance, walk, talk, eat, swallow, drink and see.

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SP and CBD are associated with an overproduction of a protein called tau in parts of the brain. Tau is also associated with Alzheimer’s and Parkinson’s diseases.

The rapid progression of PSP and CBD make the conditions ideal testbeds for new therapies that target tau, and researchers believe it could play an important role in the development of treatments for other progressive neurological conditions.

Celebrating our 25th birthday during 2019, PSPA continues to fund research that is paving the way for new drug trials. PSPA’s PROSPECT study is the world’s largest study into PSP & CBD disease progression, conducted in a network of national centres over a period of five to eight years. Our researchers collect regular biological samples, brain images, and detailed cognitive and motor data from people affected by the conditions. This data will lead to the

development of an accurate disease model that should provide an invaluable benchmark for future clinical trials.

Researchers strongly believe the accelerating pace of research into PSP and CBD will lead to effective treatments in the future. To support our UK-wide PROSPECT study, and be part of the global effort to target tau and develop treatments for PSP and CBD – as well as other tau related neuro degenerative diseases - please visit pspassociation.org.uk/research

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How NAIT changed our lives forever

During my pregnancy, I was treated like every other expectant mum and everything was normal, or so we thought. At exactly 40 weeks I went into labour but ended up having to have an emergency C-section. Isabelle was born a healthy 6lb 11oz.

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ver the next few is a happy, determined Treatment for NAIT weeks, however, little girl and is making works. It should be we began progress constantly. noticing things weren’t screened for in every pregnancy After our NAIT right. After some tests and treated.” diagnosis I found it was discovered that Naitbabies. Here I Isabelle had suffered a huge bleed in her brain learned about treatment. With support from and would be disabled for life. When she was a Naitbabies and my doctors we decided to year old, we were tested for the platelet disorder, have another child. During this pregnancy ‘Neonatal alloimmune thrombocytopenia’ I received weekly IVIG infusions and daily (NAIT). The results came back positive. My steroids. Daniel was born healthy via planned partner and I were incompatible with our C-section at 32 weeks with a normal platelet platelets and this caused my body to fight count of 275k. He is now a happy, boisterous against my own baby. NAIT had caused her 4-year-old. brain damage and the tests showed it would do Treatment for NAIT works. It should be the same in every future pregnancy. screened for in every pregnancy and treated.

Isabelle is 7-years-old now. She is severely poor-sighted, has cerebral palsy, epilepsy and Read more at is tube fed. She attends a special school and is naitbabies.org slowly learning to walk. Despite all this she

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