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.