November 28, 2021

I, Science

The science magazine of Imperial College

Are rare diseases actually rare? How much time and money should pharma companies invest in developing drugs for these?...


Fibrodysplasia ossificans progressiva. Fabry’s disease. Alkaptonuria.

Ever heard of these diseases? You’re probably shaking your head. That’s because they’re rare. Very rare.

But the great paradox of rare diseases is that, collectively, they’re very common.

The definition of a rare disease depends on where you are in the world, but if you’re on UK soil, a rare disease affects less than 1 in 2000 of us. This definition gives about 7,000 rare diseases – so there’s a relatively high chance you or I will be affected by one. In fact, Rare Disease UK highlights that 1 in 17 of us will be affected by a rare disease at some point in our lives, which amounts to about 3.5 million people in the UK. Rare diseases are therefore not rare – something which the UK Department of Health recognised in its new UK Rare Disease Strategy released last month.

And what’s more, rare diseases are becoming even more common. With dramatic improvements being made in genetic research, we are uncovering new disease patterns that we didn’t understand before. Rare diseases therefore represent a significant, and increasing, burden on health around the world.

And where there’s significant morbidity, there’s significant opportunity.

Rare diseases are called ‘orphan diseases’ because they had traditionally been neglected (or ‘orphaned’) by pharmaceutical companies. Drug development is a very expensive business, with costs running up to hundreds of millions and into billions, so pharmaceutical companies want to be sure they’ll make their money back, and more. That makes business sense, right? Why would a pharmaceutical company fund the development of a drug for only a handful of patients? You don’t need a diploma in healthcare economics to see that it would make more sense to develop a drug for a more common disease.

Or would it? In the early 1980s, the US government did something that transformed the way pharmaceutical companies approached rare diseases. They implemented the 1983 Orphan Drug Act, which provided incentives for pharmaceutical companies to develop drugs specifically for diseases that only affect a few of us. The idea caught on around the world, with the European Parliament finally adopting similar legislation in 1999. So, what do the pharmaceutical companies get from the deal? In the EU, developers get a generous market exclusivity of 10 years, a reduction in the various application fees, and even grants to support research and development.

But it’s not just these incentives that are raising a few eyebrows. It’s also the eye-watering prices that some of these orphan drugs can command when they do eventually make it to market. What’s the price of paracetamol? About 20p? What’s the price of the most expensive drugs in the world? $409,000 per patient, per year. That’s the price, according to Forbes magazine , of Soliris, a monoclonal antibody used to treat the ultra-rare life-threatening blood disorder paroxysmal nocturnal haemoglobinuria. Since then, Soliris has also been approved in various countries for another ultra-rare disease, atypical haemolytic uraemic syndrome. Other drugs in the hundreds-of-thousands-of-dollars bracket include a treatment for short bowel syndrome; a rare and specific form of cystic fibrosis; Gaucher’s disease; and homozygous familial hypercholesterolaemia.

Of course, these high prices can – and have to be – justifiable, otherwise no healthcare system or insurer would pay for them. The area of pricing is a central area of debate in the orphan drug market at the moment, but it is a quagmire which is too complex to enter now. The key question that arises for this discussion, however, is whether prices in the rare disease industry are sustainable.

What’s really interesting to look at, though, is how the orphan drug industry is pushing the boundaries of medical science in all directions. My last blog post discussed antibody-drug conjugates (ADCs), ingenious ‘smart-bomb’ drugs that are at the forefront of today’s cancer research and drug development. And what was the first ever ADC to be approved? Yep, you guessed it, an orphan drug for the treatment of acute myeloid leukaemia, a rare blood cancer. And what about the second ADC ever? Yes, you got it, an orphan drug for two rare forms of lymphoma. There are other orphan drug ADCs for rare diseases in clinical trials, including one of small-cell lung cancer, one for mesothelioma, and another for a rare type of leukaemia.

Alongside ADCs, another burgeoning field of revolutionary medical science is personalized medicine, where medical treatments are tailored to individuals according to their genetic information. Recent developments in genomics means we are learning the tools to give the right patient the right drug at the right dose at the right time. Since 80% of rare diseases have a genetic origin, and genetics is central to personalized medicine, it follows that the rare disease industry is going to soak personalized medicine up like a sponge. Look at cystic fibrosis (CF), for example. The genetic mutation medical undergraduates all learn about is called delta508. But there are several genetic mutations that cause CF, including a mutation in G551D. This specific mutation accounts for just 4% of all cases of CF, which you might imagine doesn’t account for many CF sufferers at all. But there is a drug, albeit rather an expensive one ( Xconomy reports $307,000/year), called Kalydeco, which is designed for use in this exact patient subpopulation. There are other examples of personalized medicine in the orphan drug industry, including drugs for a type of skin cancer with a particular genetic mutation.

The rare disease industry does raise some interesting ethical questions. If one argued for “the greater good”, in a sector where money is finite, it would be better to treat 50 patients with a common disease than 1 patient with a rare disease. On the flip side, why should a patient be excluded from treatment simply because their condition is rare? What do you think?


IMAGE: Wikicommons