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Why a ‘miracle’ drug exists but you can’t have it yet

It’s supposedly getting easier for innovative drugs for rare diseases like Duchenne muscular dystrophy to reach the market. So why is hesitancy still proving devastating to desperate families?

Had it begun five years earlier, Leo Le Gal's story would have followed a depressingly familiar pattern. Aged somewhere between 8 and 11, Leo would lose the ability to walk and go into a wheelchair. In his teens, he'd progressively lose the use of his arms and with them, his independence. And eventually, some time between the ages of 21 and 30, his heart and lungs would give out, causing him to suffocate. But today there is a tantalising hope.

Leo's parents, Ruth and Damien, got him onto a clinical trial for a drug that promises a reprieve. It's one of three drugs that are trying a totally new approach: directly treating the genetic problem that causes his disease, Duchenne muscular dystrophy (DMD), rather than simply treating its symptoms. Trials like Leo's have sent parents scrambling to get their sons on them and have brought the drugs to the threshold of widespread availability. Yet if he weren't already involved, the drug would probably remain out of reach for him, as it is for most of the 250,000 boys with DMD worldwide.


Leo's condition occurs because he's a boy. As a woman, his mother has two X chromosomes, but one has a flaw in the gene carrying instructions for making a protein called dystrophin. Dystrophin sits inside muscle fibre cells and normally helps to hold them together, but the gene for its creation is one of the longest we have and is therefore susceptible to random mutations.

As a boy, Leo inherits one of Ruth's X chromosomes and pairs it with his father Damien's Y chromosome. Ruth – with her two X chromosomes ­– is unaffected by her faulty dystrophin gene because she has a spare; Leo, who has inherited the flawed gene, has no backup. This pattern means that usually only boys have DMD.

The long dystrophin gene makes a large, complex protein that would be unable to get into muscle fibre cells from the outside, meaning the protein itself can't be a treatment. Instead, steroids have long been the main therapy, boosting what muscle remains and providing better breathing and a healthier heart. But steroids come with a long list of side-effects, making them despised by the Le Gals and other DMD families.

The most obvious side-effect is a round-shaped face, caused by a build-up of the hormone cortisol that encourages fat deposits there and elsewhere throughout the body. The other side-effects include osteoporosis, which gives boys extremely weak bones, and cataracts. In addition, steroid treatment only slows the progressive muscle wasting. When their breathing muscles get too weak, boys with DMD go on ventilation machines, which can add at least ten years to their lives.

By the time Leo's DMD was confirmed in 2011, the New Jersey-based company PTC Therapeutics had already been testing a drug treatment in boys for nearly six years. When testing whether DMD drugs work, the most important measurement is currently how far recipients can walk in six minutes. In one trial, conducted between February 2008 and December 2009, boys given one dosage for 48 weeks could walk 31 metres further on average than others who'd been on an inactive placebo for the same time. "In the patients who were walking less than 350 m, we saw a greater than 68 m difference in change in distance walked versus placebo," says the CEO of PTC, Stuart Peltz. "That is one of the largest changes ever seen in the six-minute walk test in a clinical trial."

Yet these results were at first considered a failure. They hadn't passed the 'statistical significance' test used to ensure apparent drug effects aren't chance improvements. Government regulators like the European Medical Agency (EMA) and US Food and Drug Administration (FDA) normally demand statistically significant results before they allow drugs to be sold. Consequently, the boys on the trial had to stop treatment, sending shockwaves through the patient community via the internet. "It was a desperate situation for parents because their children had seen a benefit, and then it had been stopped," Ruth recalls. PTC also paid a price soon after, losing its DMD partnership with a larger drug firm, Genzyme, in September 2011.

But PTC didn't give up. In June 2012, it once again began giving its drug to people who had been on the 2008/09 trial. The boys got continued access to the therapy, while the company would get long-term data to help clear up previous safety concerns. Keenly watching PTC's progress, Ruth and Damien heard that the company had another, larger, trial planned, but to get on it Leo – then aged seven – had to be able to walk 150 m.

Given that they live in southwest England, they might have enrolled Leo onto the arm that was due to start in London in December 2013. However, they knew that if they waited until December he'd never make it. Instead they pushed to get Leo onto an arm conducted in Boston, Massachusetts, starting in August.

In Boston, Ruth and Damien sat outside the room in which Leo was being tested. "That was very nerve-wracking," Ruth tells me, with Leo sat behind her, brandishing a raygun made from old plastic milk bottles. "We said to Leo, very clearly, 'Just do as much as you can, and if you can't do it, don't worry – mummy and daddy will find a different way to get you the medicine.' Then we sat in the corridor, just praying that he was going to do it."

Thankfully, Leo was just able to walk his 150 m and got accepted onto the trial. Since then he's been taking his medicine as vanilla-flavoured powder mixed with milk and water three times a day, flying to Boston every eight weeks so the scientists can check his progress.

To make proteins like dystrophin, our bodies rely on machinery that assembles them from amino acid building blocks. That machinery carefully follows a set of genetic instructions, adding block after block until the protein is complete. DMD mutations are therefore like a misprint in the middle of the instructions. Leo's nonsense mutation, which he shares with around one in eight DMD boys, switches an instruction to add another block for one that simply says 'stop'. That leaves him with an incomplete and ineffective protein that quickly breaks down.

PTC's drug is designed to tell the protein-building machinery to carry on past the nonsense stop message to make a full-length, functional protein. "Dystrophin restoration on its own does not increase muscle strength or mass," says Peltz. "You have to increase muscle fibres to do that. When kids are five or six years old, they still have a significant amount of stem cells, a lot of capability to regenerate muscle. Add dystrophin and that's how at that early age you're probably capable of seeing some increase in strength."

Despite its earlier setback, PTC persuaded the EMA to consider granting approval based on data from the same 'failed' trial. At first, the outcome was also disappointing: in January 2014 the EMA turned PTC's application down. But, after PTC asked it to reconsider, just four months later it recommended conditional approval (a one-year, renewable licence allowing a company to market a new drug while further studies continue), on the grounds that "the benefits…outweigh its risks". Boys in Europe are beginning to get the drugs through normal routes, on the condition that the results of the trial that Leo is now on make the case for it stronger.

There are further constraints: it's only for boys above the age of five, and only those who can still walk. If that becomes the only group in the UK able to get it, it will mean more agonising delays for the Le Gals, because Leo is unlikely to be eligible – he's now nine years old and has reached the point where he can only take a few steps, with help.

"We've seen quite a lot of deterioration in his walking, so we believe he's getting a placebo," says Ruth. "For us it's very hard because this medication has been sitting on the shelf since the day he was diagnosed. And that just makes us want to scream."


Three long biopsy scars on his bicep, a coin-sized infusion port implanted beneath the skin in his chest, and more air miles than most 12-year-olds: this is part of the price Max Leclaire has paid for halting and seemingly reversing the deadly creep of DMD through his body.

"After about 16 weeks he started getting better, and that made everything that we were doing completely worth it," says Max's mother, Jenn McNary. Moon-faced and shy, Max walks in on our Skype call, politely says a few words, and walks off again. "He is no longer using a wheelchair at all. He's just started learning how to pedal a bicycle, although I'm very careful about him getting hurt."

Max is missing a chunk of DNA, known as an exon, containing some of the instructions for dystrophin. Our protein-building machinery can just carry on if whole steps are missing; this makes the short but partly functional dystrophin seen in Becker's muscular dystrophy, a milder form than DMD. But the deletions in boys with DMD leave behind part of a step, which confuses the process and halts it altogether. There are 79 exons on the dystrophin gene, and Max's deletion is in number 52. One in five of all DMD boys have a deletion in this area, near exon 51.

Mutations near exon 51 are therefore the obvious first target for Sarepta Therapeutics in Cambridge, Massachusetts, the company making the drug Max is taking. Instead of targeting the protein manufacturing machinery, they paste a molecular patch onto the instructions being fed into it, ensuring that no confusing partial steps remain uncovered. The troublesome exon is simply skipped. Part of the protein is missed out, but a mostly normal chain is still made.

It may sound simple, but to do this Sarepta must painstakingly build DNA-like chains that can stick to the flawed genetic instructions. Every molecule of its drug has 30 segments, each containing just over 1.5 times as many atoms as PTC's drug. "This could be one of the more expensive drugs to produce in the history of our industry," says Chris Garabedian, Sarepta's CEO. Its size and composition also mean the drug can't be swallowed and has to be injected – in Max's case, via the chest port that feeds directly into his bloodstream.

That expense meant that when planning the trial Max started on in August 2011, Sarepta only had enough drug for a 12-person trial, with four getting placebo. "We knew it had to be the smartest designed small study in the history of Duchenne," Garabedian recalls. "We needed to select patients very carefully in order to show a potential drug effect."

"It was like trying out for a play," McNary remembers, but luckily for Max he fitted the bill of being neither too healthy nor too weak. A stay-at-home mum at the time, McNary flew with him and her baby daughter from their home in Vermont to Columbus, Ohio, every Tuesday, returning every Thursday. Meanwhile, her then-husband took care of the four other children who stayed at home – including Max's older brother Austin, who also suffers from DMD.

Where Max is the quiet video game player, Austin would confidently talk to me on his own, were he not exhausted and bed-ridden after summer camp. "Austin knows all the different things he wants to be," McNary says. "He needs to be about ten different professions, but he's talking about college, zoology, mechanical engineering. He's such a little entrepreneur already. He's talking about all the different things he wants to do. He wants to be rich, to make money."

Austin also desperately wants to be off steroids. "The biggest problem is osteoporosis – it's very severe," McNary says. "I broke his back just setting him in his wheelchair. They have back breaks on a regular basis. There isn't anything they can do; their bones are sort of powdery. It's a compression fracture, so there's no casting or anything as such. Austin often talks about how steroids are some of the worst drugs in the world, and they're OK for his use, but we can't get Max's drug, which has no side-effects. It's really frustrating."

Three years older than Max and therefore weaker, Austin wasn't eligible for the Sarepta trial, although he once had a rival drug injected into the skin of his belly. That drug originated from Prosensa in Leiden, the Netherlands, who are pursuing the same approach as Sarepta, albeit with a different molecule. But Austin was given it by the British pharmaceutical giant GlaxoSmithKline (GSK), who signed a deal with Prosensa in 2009 to take it into one of the largest DMD trial programmes ever.


GSK's resources could smash through any problems of supply and run trials in places exon-skipping drugs had never reached before. But – despite earlier promising, positive and statistically significant results – it couldn't translate that to the larger-scale trial outcome normally needed to get drugs to patients. In September 2013, on what Prosensa CEO Hans Schikan says DMD families call 'Black Friday', the companies had to announce that another trial had failed.

"When we had our Prosensa town hall meeting here and announced the result, some people started crying because they'd put years of energy and effort into it, and everything seemed to be on a roll," Schikan reveals. He adds that there were downsides in reaching for a larger trial, like bringing in countries with different standards of care, or with less experience in the tests used. "In one site, the six-minute walk test was done in a church because they didn't have a long enough corridor correct to the standards," he says. "If you have a 10,000-patient trial, all over the world, that's robust. To run a 186-patient trial in a rare disease in nearly 50 sites in almost 20 countries on five continents, in hindsight, I would say that's almost destined for failure."

As well as leading to the termination of the deal between GSK and Prosensa, the results also spoiled things for Sarepta, whose trials are delivering statistically significant outcomes. "In October 2012 we had what we believed was unprecedented data," Garabedian says. "We were getting pressure from the DMD community at that time, to do everything possible to get the FDA to approve the drug. We said we're not sure if the FDA would consider this for approval, so we're going to talk to them and ask the question."

"In 2013, the first time we asked the question, they said they were open to a New Drug Application (NDA) and we began to prepare our submission," he says. "In November [after the GSK/Prosensa announcement] they changed their mind and indicated it was premature to submit an NDA, citing reasons related to our competitor's failed study, among others, not based on any new data from our drug."

"It's maddening, it really is," McNary fumes. "It was frustrating at 16 weeks, when I saw it start to work, and it was even more frustrating at 48 weeks when they had data to back that up. I really expected the FDA to just bend over backwards, reach out to this company and say 'Apply now, we want to approve your drug,' because this is an untreated illness.

"Austin is set to lose the ability to feed himself – his arms just aren't reaching up high enough. Every time he's starting to lose a skill, I wonder: if he had been on drug six months ago, would he have kept that? I think it's devastating for him too, to see how well Max is doing and wonder why it's our government [the FDA] standing in the way. It isn't research, it isn't money; it's simply the government being too cautious."


These struggles come at a time when it's supposed to be getting easier to bring drugs for rare diseases to patients. Each of these three leading drugs has been given the label 'orphan' by the FDA and EMA, thanks to their focus on a rare disease. That label gets their cases processed speedily, reduces the costs involved and gives drugmakers longer before other companies can bring generic versions of the same drug to market. The EMA also offers conditional authorisation – which PTC's drug is benefiting from – through which 1 in 20 drugs is now being approved by the regulator.

Conditional authorisation is used "where there is a great medical need," explains Spiros Vamvakas, head of the scientific advice office at the EMA. "Orphan products qualify for it as part of their designation." But drugs proceeding down this route must still provide convincing data to confirm that they're actually having a positive effect on their target disease to stay on the market: "The fact that the exon-skipping approach is a pharmacological Rolls-Royce has to be translated into clinical efficacy," says Vamvakas.

The EMA has also held 'open discussions' with DMD experts and families and brought charities and patient groups onto its scientific advisory groups for clinical trials. Perhaps inspired by these meetings, Vamvakas, an archetypal bespectacled, greying civil servant, makes the surprising admission that faced with a disease like DMD, he'd "try any drug for myself or family members I love". But, with a hint of regret, he stresses that the EMA's job is ensuring that all new drugs have a "scientific basis of proof" – and that inevitably takes time.

While the FDA doesn't have an exact equivalent to the conditional route, Sarepta's Garabedian calls the involvement the authority is giving their trials "incredible at all levels".

"[The FDA's] attention to this is significant," he says. But given that no one has ever tried to run trials like this before, he's not surprised the going hasn't been smooth. "This is a new genetic technology, being developed for a disease in which there are no current drugs like this approved. When you have that much uncertainty and newness, I think we often see a natural conservatism from regulators."

The close attention to DMD may now be set to pay off. The FDA has set out 'accelerated approval' pathways for both Sarepta and Prosensa's exon-skipping drugs. Prosensa has now started filing its updated evidence. Sarepta's plans to do similarly, however, has been put back to 'mid-year 2015' after the FDA asked for extra data.

The FDA pathway invites applications based on their existing data and also calls for further trials, which is good news for the so-far neglected majority of DMD sufferers. It's also a boost for boys with deletions on exons other than number 51, as the FDA says it will consider results from trials of drugs modified to skip them. Sarepta's efforts to collect more information include giving its exon 51 drug to boys previously excluded from the trials because they were too young or can't walk.

That move has meant that, after years of watching his brother Max benefit, Austin Leclaire now hopes to enrol in a study for the same drug. Likewise, Prosensa has committed to re-dose boys on its previous trials – including non-walkers given its drug just once, like Austin – and plans to extend this to many more.


People with DMD and their families who have suffered for so long would be justified in claiming part of this small victory for themselves. Organisation has emerged from frustration, and patient charities are now a powerful driving force, not only for regulatory change but also for drug research and development.

Rare diseases are a largely alien world for big pharmaceutical companies, so the science behind new treatments must be plucked from university labs and developed. Sarepta's drug emerged from the University of Western Australia, Prosensa's is from the University of Leiden, and PTC's came from CEO Stuart Peltz's time as a professor at Rutgers University. In developing these discoveries, the companies bank on strong financial support from charities – an asset that makes them better able to face the challenges they have than conventional small drugmakers. "We see a lot of support from patient organisations, which is unique to the rare disease world," Prosensa's Schikan underlines.

Charities are increasingly taking an even more direct role. For example, McNary is now the director of outreach and advocacy at the Jett Foundation, which raises awareness and funds for DMD within the Duchenne Alliance. The role gives her the flexibility needed to care for her family, while the money the Foundation raises goes towards the research grants that the Alliance makes through its 'Duchenne Dashboard' platform. "You have a researcher that has this really great idea and needs $50,000 or $100,000," McNary says. "We can fund that seed money, and eventually they'll get to a place where they get other funding for the development or a pharmaceutical company will pick it up. But often there just isn't enough money to start that basic, beginning research on something that looks particularly good."

This approach is also helping push a prospect that's exciting the entire DMD community, because it could treat every single boy. In the 1990s, Kay Davies at the University of Oxford discovered we have a backup genetic sequence for dystrophin. The slightly shorter protein it encodes, known as utrophin, goes into unborn babies' muscles, but we stop making it and start producing dystrophin when we're born. Davies co-founded a company called Summit that has already run early trials on a drug designed to restart utrophin production, aided by funds from Australian charity Save our Sons, among others. Davies is also getting money from the UK's Muscular Dystrophy Campaign to look for even more powerful alternatives.

Davies hopes that if this approach is successful it can be used together with the drugs nearing approval, each drug enhancing the other's effect. And regardless of the success of any individual treatment, she points out that the progress currently being made is unprecedented in her 30 years working on DMD.

"Even five years ago I used to stand up and say 'I still think a therapy's a long way off'. Now, I would say therapy for a certain group of patients is almost here," says Davies. "It may not be a huge improvement, but it will be some improvement. I think progress will continue to be reasonably quick – not quick enough for some of the patients, but the accelerated progress that we've seen over the past five years is likely to continue."

That progress is embodied by PTC's drug, which doctors can already give to patients outside of trial settings in countries like Turkey, France and Spain. In the UK, where Leo Le Gal lives, the government is set to decide whether to cover the costs by the end of December 2014, which would mean it might reach eligible boys by summer 2015. PTC is yet to negotiate a price in the UK, but Peltz told me to look at prices for other drugs for rare diseases, which are typically $200,000–$400,000 per year. For diseases like cystic fibrosis health systems have been unsure that level is affordable, but Peltz believes it will be for DMD. "We're not doing our job if we can't convince payers of the benefit to patients," he says.

Since I visited the Le Gals, Leo has finished the first 48-week trial of the PTC drug and has gone onto a two-year extension study where he definitely gets the real drug. "As soon as Leo tried it, he said 'Ooh, that tastes different'," says Ruth. "We've definitely seen a change; he seems to have stabilised. But what's going to happen in two years, we don't know."

Despite his young age, Leo is a great example of the steely determination and optimism that has delivered fragile hope. As we chat in his living room, he uses his arms to haul himself over to the sofa and up onto it to sit next to me. He tells me that compared to walking, his wheelchair is "more fun, in a way".

"He loves his powered wheelchair," Ruth laughs. "It's brilliant– he ties a rope on the back and ties it to his friends' scooters and tows them around. He tries to charge them 10p a ride. He has a fantastic time, whizzing around the green, getting up to all sorts of shenanigans.

"I do get upset at sports day, when I see all the other children running. And he says 'Mum, man up, for goodness' sake'. I get upset and he says 'stop moaning'. So we'd better stop moaning."

This article was originally published on Mosaic Science.