Genomic advance lifts hopes of patients with rare diseases

by Andrew Ward

For decades, rare diseases were all but ignored by the pharmaceuticals industry. The science was difficult and the economics even harder. So it is testament to how much has changed that today, rare diseases — defined in Europe as a condition affecting fewer than 1 in 2,000 people — are among the hottest areas of drug development. A third of all medicines approved by the US Food and Drug Administration in the past five years have been for rare diseases — including a record 17 in 2014. Peter Saltonstall, president of the US patient group National Organization for Rare Disorders (Nord), says all the signs point to this momentum continuing. “We’re in a very exciting period of scientific and technological innovation.” This rush of R&D is delivering fresh growth to the pharmaceuticals industry — and raising new hope for patients previously stranded on the margins of medical science. While each is rare in its own right, the roughly 7,000 diseases that fall under the category collectively represent a formidable challenge. About 350m people globally have some kind of rare disorder — 10 times the number living with HIV.

They range from relatively well-known ailments such as cystic fibrosis and multiple myeloma to obscure ultra-rare conditions, including perinatal hypophosphatasia and dopamine-responsive dystonia. Less than 10 per cent have an effective treatment. This high unmet need has combined with three big trends to attract a surge of investment in rare disease R&D. First, and most important, are the scientific advances that have sprung from the decoding of the human genome a decade ago. This has made it possible to develop more personalised medicines targeted at specific genetic mutations. Such an approach has proved especially fruitful against rare diseases, because about 80 per cent of them are genetic in origin. To take one example, Kalydeco, made by US-based Vertex, targets various mutant genes associated with certain types of cystic fibrosis. “The genomics revolution has allowed us to understand rare diseases on a molecular level in a way that was not possible before,” says Jimmy Lin, founder of the Rare Genomics Institute, a US non-profit research network. These breakthroughs have been accompanied by a second driving force: digital technology. The ability to harvest and analyse large volumes of genomic data are accelerating the hunt for genetic markers of disease and, crucially, helping identify people with rare conditions who might previously have gone years without diagnosis. In the UK, for example, the government-backed 100,000 Genomes Project is building a database of DNA codes from patients with rare diseases and cancers — and their relatives — to aid diagnosis and research. Technology is also helping small, far-flung patient communities support the push for new treatments. Before the internet, their best hope of wider attention was for a doctor to write about their condition in a medical journal. Today, social media gives them a platform to share information and lobby drug companies and regulators for action. Yet none of these scientific or technological advances would have turned the tide without the third trend: a shift in the pharma business model away from one-size-fits-all “blockbusters” and towards high-priced niche treatments. For decades, the holy grail for pharmaceuticals companies was finding drugs for common conditions, where the large number of patients guaranteed multi-billion-dollar revenues. But a wave of patent expiries has forced the industry to look elsewhere for new drugs.

Regulators have encouraged the shift by creating incentives for companies to focus on so-called “orphan diseases” that lack an effective treatment — a category that includes most rare diseases. Fast-track approval processes have been introduced in the US and Europe to accelerate the path to market. This has made rare diseases increasingly attractive to developers, compared with the slow and costly large-scale clinical trials required of mainstream drugs. But perhaps the biggest commercial appeal is the high prices and margins commanded by rare disease therapies. Traditional blockbusters involve heavy expenditure and armies of sales reps competing against rival products, while rare disease medicines are typically the only product for their condition, and can be sold with minimal overheads via a few specialist medics. Companies justify high prices by the small number of patients from which to recoup costs — and the big medical benefit they often provide to patients. Alexion, a US-based rare disease specialist, for example, charges more than $400,000 per person per year for Soliris, a medicine for a kidney condition called atypical haemolytic-uremic syndrome. This allowed the company to generate $2.2bn of sales last year from its sole approved product, serving a total market of just a few hundred patients.

Returns such as these are attracting increasing interest from big pharma groups. In April, Bristol-Myers Squibb of the US agreed a partnership worth up to $1bn with a small Dutch company called UniQure, whose treatment for lipoprotein lipase deficiency has been dubbed the world’s most expensive therapy, at €780,000 a patient. Companies are confident that sky-high prices will be tolerable for health systems, because so few patients require treatment. However, as more drugs arrive, the collective burden is rising. They have achieved very high pricing while they have been a tiny proportion of the drugs bill, says Glyn Edwards, chief executive of Summit Therapeutics, a UK company developing a therapy for Duchenne muscular dystrophy. “But there is doubt about whether these prices are sustainable.” Fraught policy debates are under way in cash-strapped European health systems over how much public spending on rare diseases can be justified. Prevention and treatment of common conditions produce a larger collective benefit to society, but the principles of universal healthcare demand that people with unusual diseases should not be abandoned. Patient advocates such as Mr Saltonstall insist that the benefits of rare disease drugs will outweigh the costs. He says they are the leading edge of a wider shift towards personalised medicine that will eventually make health systems more efficient. “In the long run,” he says, “every disease will be rare.”