by Pharmaphorum | Nov 8, 2016 | Journals
After chairing a panel discussion at this year’s Cambridge Rare Disease Summit in late October, Paul Tunnah muses on the lessons that can be learned for the future of drug development from the collaboration and innovation in this space.
In late 2015 I had the pleasure of attending the inaugural Cambridge Rare Disease Summit in the UK, a new event effectively marking the launch of the Cambridge Rare Disease Network (CamRARE), which brings together all those local groups that have an interest in this area of medicine.
This year, I was flattered not only to be invited to attend again, but also to moderate a panel discussion as part of the proceedings, with free rein to position this as appropriate. It was clear to me that a good focus for this session would be a discussion on the parallels between rare disease research and the much broader evolution of personalised medicine.
The definition of a rare disease, in Europe, is one that affects less than five in every 10,000 people but, collectively, the prevalence of rare diseases is much higher, at around 5-10% of the population, depending on the country. In the UK, for example, around 3.5 million people have some form of rare disease, which, as the incoming chairman of CamRARE, Alastair Kent OBE, pointed out, is greater than the population of Wales!
To put this figure in perspective, it is estimated that there are fewer people – around 2.5 million – living with some form of cancer in the UK, collectively spanning the major tumour types (for example, breast, colorectal, lung and prostate) right down to cancers that are themselves defined as rare diseases. But, if you look within the major tumour types, you will find that, while the site of presentation is consistent, the genetic basis is extremely varied. In effect, these common diseases are, at the genetic level, collections of many rare diseases. Over time, we are learning that the same is true for many other areas, such as heart disease, diabetes and respiratory disorders.
This understanding has driven the rise of personalised medicine, targeting the genetic underpinnings of a disease, rather than its morphological presentation. While it is important to recognise that not all rare diseases are ‘genetic’, in the sense of being present from birth, it does drive interesting parallels between the two fields. So this was the focus for my panel, entitled ‘Riding the personalised medicine wave to accelerate progress in rare disease treatment’.
The four panellists collectively represented the nature of collaboration that you can see everywhere in rare disease research.
Dr David Pardoe, Head of Growth Projects at MRC Technology, talked about the work the charity is doing in funding novel research and, specifically, in joining the dots between academia, biotechnology, pharma companies and other charities. This is not just about connecting great science with commercial capabilities, but also about exploring new funding models, e.g. crowdfunding and societal impact investment to accelerate development of new treatments.
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Dr Birgitte Volck, Head of Rare Disease R&D for GlaxoSmithKline (GSK), reiterated the importance of collaboration and the important role that ‘big pharma’ plays in helping both smaller biotechs and academic researchers progress critical research to a stage where it can be of benefit to patients. Volck is in a prime position to understand this research ecosystem, having only recently joined GSK, after four years with Swedish Orphan Biovitrum (SOBI) and working for the ‘original biotech’, Amgen, prior to that.
Dr Richard Scott, Clinical Lead for Rare Disease at Genomics England, provided an update on the 100,000 Genomes Project and how important it is with regard to rare disease research. The huge investment in this project, which itself collaborates with multiple academic and commercial partners, will surely help to drive quicker diagnosis of known disorders and even identification of new rare diseases over time. Critically, the evidence base they are building is freely accessible for non-commercial research organisations (and within the bounds of data privacy).
Finally, it was a distinct pleasure to feature Emily Kramer-Golinkoff, the Founder of the US not-for-profit organisation Emily’s Entourage, on the panel. The only participant not to have the title ‘Dr’, Emily is more qualified than most medics on the challenges of living with a rare disease, having lived all her life with cystic fibrosis (CF). The work she has done with Emily’s Entourage, in raising millions of dollars of research funding, accelerating trials and building a groundswell of support and publicity, is inspirational and has even garnered the attention of the White House, as the US seeks to lead the world on ‘Precision Medicine’.
But one important point that Kramer-Golinkoff makes about more prevalent rare diseases like CF is that they are also, like many common disorders, collections of many different genetic subtypes. Novel therapies like ivacaftor are delivering real step-change for some CF patients by addressing the underlying cause of the disease, but only for the small proportion with the relevant genetic mutation. As with other genetically complex and diverse diseases, like breast cancer, it is important to keep pushing for novel therapies that will help all patients, not just the minority.
The perspectives represented by the above panellists in our discussion were reflected in all the presentations throughout the day, from scientists, charity leaders, medical professionals, patients and their families. These conversations and collaborations are also happening every day of the year for those working in the rare disease space.
For the sake of current and future patients, whether relating to a ‘rare disease’ or rare subtype of a more common disorder, it is important to listen to them, learn and adapt the way we do medical research. This type of collaboration and innovation is the future.
If you get chance to come along to next year’s Cambridge Rare Disease Summit I would recommend it and, in the meantime, stay well.
by eCancer | Sep 26, 2015 | Journals
It is no surprise that most effort in the pharmaceutical industry has been directed towards developing drugs for diseases that are common in affluent societies.
Drug discovery is in many cases an extremely expensive process with, on average, well over a billion dollars now spent on each licensed medicine.
Drug development for rare diseases is a particular challenge; not only are drugs for rare conditions expensive but small patient numbers can make it hard to set up statistically significant clinical trials.
The earliest drugs to be developed against cancer – cytotoxic chemotherapy drugs – targeted rapidly dividing cells, and so each could be used in many tumour types.
Second- and third-generation cancer drugs that target specific, dysregulated molecular mechanisms have the benefit of reduced side effects, but most will only be effective in a small patient population.
Developers of targeted cancer drugs can therefore face the same types of challenge as developers of drugs for other rare diseases.
The term ‘rare disease’ has been defined precisely, although this definition differs between jurisdictions.
In the US, a disease is classed as rare if it affects fewer than 200,000 individuals in that country, whereas the European Medicines Agency (EMA) defines a rare disease as one that affects no more than five in 10,000 people and is ‘life-threatening or chronically debilitating’.
Whichever definition is used, about 8,000 diseases are currently classified as ‘rare’ and this number is growing in particular through the discovery of new ultra-rare genetic lesions.
As there are so many rare diseases, a surprisingly high proportion of any population – some 30-40 million in the EU, for example – will be diagnosed with a disease in this category at any time.
About 80% of rare diseases have known genetic causes, and many of these are Mendelian diseases that are diagnosed early in life and can be severely life-limiting.
Some cancer predisposition syndromes, in which a mutation in a proto-oncogene or tumour suppressor gene greatly increases the risk of affected individuals developing one or more specific cancers, fall into this category.
These include Li-Fraumeni syndrome, which is caused by a germline mutation in the tumour suppressor p53 and in which the risk of developing invasive cancer before the age of 30 rises from 1% in the general population to about 50%.
Patients with inherited mutations in the BRCA genes have a greatly increased lifetime risk of developing several cancers, most notably breast and ovarian,
However, the basic definitions of ‘rare disease’ also encompass other cancer types, including some not generally thought of as uncommon.
Pancreatic cancer, for example, is the fifth most common cause of cancer death in the UK but still has an age-standardised prevalence of about 6 in 100,000, which fits very well within the European rare disease definition.
Both the EMA and the Food and Drug Administration (FDA) in the US designate candidate drugs for rare diseases as ‘orphan medicinal products’ and offer companies incentives to work on them.
Partly due to these incentives, the numbers of orphan drugs in clinical development have increased significantly in recent years.
However, most of these are still in Phase I or Phase II trials and there are no currently approved drug treatments for approximately 95% of the diseases designated as rare and eligible for support through orphan drug legislation.
There are more orphan drugs in development for specified cancer types than for any other broad class of disease.
Furthermore, as the detailed molecular landscape of cancer is elucidated, the orphan drug definition comes to encompass drugs for specific subtypes of even the commonest cancers that are defined through genetics or morphology.
Some of the 105 cancer drugs included in a list of orphan drugs in development published by the FDA in 2013 had been designated for subtypes of one of the commonest cancers – lung cancer – identified using gene or protein biomarkers.
These drugs should be licensed only with a companion diagnostic to ensure that they are given only to patients who can be expected to benefit.
Although progress is still slow, prospects for patients with a number of rare conditions, including rare cancers, are beginning to improve.
These improvements are being driven by genomics and allied technologies helped by orphan drug legislation and by the increasing involvement of the patients themselves.
In some cases, patients or their close relatives have become entrepreneurs, establishing foundations and pioneering research into the diseases that affect their families.
“Parent entrepreneur” Nick Sireau, who set up the AKU Society to support families affected by the disease that affects his sons, alkaptonuria, was one of the co-founders of the Cambridge Rare Disease Network.
The Cambridge Rare Disease Network in the UK was co-founded by one such ‘parent entrepreneur’, Dr Nick Sireau, who set, and to help with research towards its cure.
This network brings together all those with an interest in rare disease in the Cambridge (UK) area – researchers, entrepreneurs, activists, policy-makers, the media, patients and their families – to discuss shared interests and initiatives.
The network’s inaugural Rare Disease Summit, held in September 2015, featured keynote lectures by another parent entrepreneur, Matt Might, and a moving address given over a video link by perhaps the best-known rare disease patient of all: Cambridge’s Professor Stephen Hawking.
Sir Greg Winter, a pioneer of monoclonal antibody technology and founder of Cambridge Antibody Technology (now part of AstraZeneca) gave the other keynote lecture.
Winter explained that six of the 10 best-selling therapeutic drugs in 2014 were antibodies, and three of these – Avastin, Herceptin and Rituxab – are prescribed for cancer.
The success of these drugs comes despite the fact that antibodies tend to be expensive to manufacture and that the patient populations are not particularly large.
The most expensive drug in the world – Soliris (ecolizumab), with an annual price tag of $600,000 – is a monoclonal antibody that is used to treat two ultra-rare blood clotting disorders.
Winter recently founded another biotech company, Bicycle Therapeutics, to develop highly constrained bicyclic peptide drugs (‘bicycles’) which would have the same high affinity as antibodies but would be smaller, easier to work with and cheaper to produce.
A bicyclic peptide conjugated with a toxin has already been shown to be highly effective in a mouse model of sarcoma.
Several other speakers discussed developments in drug discovery for rare cancers and cancer subtypes.
Steve Jackson of the Wellcome Trust/Cancer Research UK Gurdon Institute in Cambridge described how the principle of ‘synthetic lethality’ has been exploited to develop drugs to selectively kill tumour cells, and how related principles might be used to alleviate genetic diseases.
Jackson explained how genetic defects in the genes BRCA1 or BRCA2 disable a specific DNA repair pathway.
Cancer cells in which one of these genes has been lost are highly dependent on a separate pathway for DNA repair, and blocking this pathway using an inhibitor of the enzyme poly-ADP ribose polymerase (PARP) will kill such cancer cells but not the patient’s normal cells.
PARP inhibitors are thus selectively toxic to tumour cells with this genetic profile and can therefore be relatively free of side effects.
Jackson was the scientific founder of the biotech company KuDOS which, through its acquisition by Astra Zeneca, has now taken three drugs into the clinic.
The most advanced of these, olaparib, has been licensed in the USA and the EU for advanced ovarian cancer with BRCA mutations and is in advanced trials in various other cancer types.
The Cambridge Rare Disease Network is only one sign of the growing importance of collaborations between patients and professionals in the rare disease community.
Patient communities are being formed online for some of the rarest diseases of all, where only a handful of families worldwide are known to be affected.
Nevertheless, each of these communities is very small, and they can be most effective when they join together in umbrella organisations such as Eurordis, known as ‘the voice of rare disease patients in Europe’.
Patientslikeme is an online community or in which patients with a wide range of rare and common conditions come together to discuss their disease and its treatment.
Its membership currently encompasses over 2,500 conditions including many cancers; members share data on their conditions, treatments and side effects with each other and the research community.
Many patients choose to share and donate data on their conditions via the ‘Data for Good’ research platform, and data from Patients Like Me participants has so far been used in over 60 publications.
Many cancer patients have become involved in this initiative.
“I owe other patients my experiences… and doctors and researchers need my data” explains one renal cell cancer patient in a video posted on the site.
As we understand more about cancer as a genetic disease, for example, the sequencing of 25,000 cancer patients’ genomes through Genomics England’s 100,000 Genomes Project, we will become even more aware of genetic differences between and within tumours.
We may come to treat every patient’s cancer as a rare, if not a unique disease, so the insights now shared by the rare disease community will become even more important for oncology.
Research publication
100,000 Genomes Project - Genetic Alliance UK (Rare Disease UK)
Vasculitis Rare Disease Working Group Meeting April 18th 2012
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