December 7, 2021

I, Science

The science magazine of Imperial College

Drugs that treat rare diseases are riding a wave of financial and clinical success. But why should that be? And should we be pleased?

In the autumn of 2012, a paper was published in the journal ACS Nano that proposed a model for understanding how a rare condition called argyria comes about. The condition is caused by chronic exposure to silver salts and is particularly nasty, as it turns the skin a distressing blue colour. It characteristically occurs in the few people who ill-advisedly guzzle down ‘health tonics’ containing colloidal silver.

The new work was motivated by worries over the environmental fate of silver nanoparticles. These are now ubiquitous in modern life – found in everything from bandages to cleaning sprays – due to their antimicrobial properties. The new information about argyria was a happy bonus for the researchers. Since so few people suffer from the condition, it would be hard to imagine a funding body or pharmaceutical company ever investing in a full-scale search to find a treatment. To put it in terms of crude economics, the tiny size of the client base would make it a bad business move.

snakeBut surprisingly, so-called ‘orphan drugs’ – formulations that treat uncommon medical conditions, from rare genetic diseases to bites from obscure species of snake – are riding a wave of financial and clinical success at the moment.

According to a report by Thomson Reuters, the compound annual growth rate of orphan drugs increased by 25.8% between 2001 and 2010. Sounds like a lot? It really is, especially given the huge problems that the industry faces in general: in that same period, the non-orphan drug market contracted by 20.1%.

So why the disparity? One reason is the way drugs are licensed. In most cases a pharmaceutical drug can be patented for a set number of years (this varies depending on country of sale, among other factors). During that time the developer has exclusive rights to the active ingredients – the drug molecules – they have developed. But from day one their competitors can start working out how to make the same molecule more cheaply and efficiently. That means that soon after the patent expires, usually 10 years or so, the market will be flooded with ‘generic’ competition: the same drug sold under another name by a competitor. In some ways that’s great; cheaper drugs that have stood the test of time sound attractive. But in practice it means there is wariness from drug giants about how much to invest in researching a drug. If they begin to think they can’t recoup burgeoning levels of investment in the first 10 years, they are prone to pull out.

Pfizer, a large drug company, developed a cholesterol-lowering drug called Lipitor – the most profitable drug ever – some time ago. But it began facing competition from generic copies in November 2011. Even before then, the company had been cutting costs by closing offices and research centres around the world. In August 2012 they announced they would be pulling the plug on most of their research into Alzheimer’s disease. One of their clinical trials had failed, and the company evidently decided the cost–benefit ratio didn’t make sense anymore.

Orphan drugs are attractive to pharmaceutical and biotech companies since they have added protection from generic drugs plus a host of other financial bonuses attached to them. It all started in 1983 when the US introduced the Orphan Drug Act. Similar acts were passed in Australia and Singapore in the 90s, and finally one in Europe in 2000. These acts provided tax incentives to orphan drug manufacturers. But more than that, they offered ‘marketing exclusivity’ on top of the patent system, which in practice prevents the drugs from being copied for longer. The acts also mean that in some cases drugs only need to undergo shorter and smaller than average clinical trials. Applications for state approval can be fast-tracked too.

There are, of course, some difficulties with orphan drugs. For instance, it may be more difficult to find patients to participate in clinical trials – there are fewer of them, and they are spread out across countries – so organising logistics is not easy.

But this doesn’t seem to be putting companies off. The Reuters report says that, in 2010, the industry’s most expensive drug, Soliris, brought in a total of $541 million in total sales. Only between 4000 and 6000 people have the disease it treats – paroxysmal nocturnal haemoglobinuria, a rare and life-threatening blood disease – but the drug costs more than $409,000 per year so the money soon adds up.

Not only do patients pay more for orphan drugs, but they jump at the chance to do so. Most non-orphan drugs have some sort of lag time before the public get used to them and start using them. But patients who have a life-threatening disease with only one treatment option are understandably desperate.

So should we be optimistic about the future of orphan drugs? We’ve seen evidence of government legislation prompting research into drugs for people who would otherwise have been overlooked. That’s a reason to celebrate; there are drugs where before there was despair.

But at what price? We would be naïve to think that pharmaceutical companies champion orphans for reasons other than because they turn a good profit. None of the individual scientists are bad, or immoral, it’s just that the money for drug research and development must come from somewhere. So of course we should be pleased that orphan drugs are taking off. But we shouldn’t forget that 5.4 million people in the United States are living with Alzheimer’s. They may not be orphans, but they’re still worth caring about.

Image from Texas Parks and Wildlife website.