“Developing the next blood pressure tablet is a noble pursuit, but there are lots of blood pressure tablets, right, so it is not particularly compelling,” says Joe Wiley. He is explaining what it was that first attracted him to the pursuit of drugs to treat rare diseases.
“But setting up a company that has the potential to develop the first ever treatment for a rare disease like we have just done for epidermolysis bullosa (EB), now that’s really compelling.”
EB is one of about 7,000 rare diseases. Of these, just 10 per cent have any treatment available. Until now, EB was one of the 90 per cent whose patients simply have no therapy options. But not any more, at least in Europe. Wiley’s Amryt Pharma has just secured approval from the EU regulator, the European Medicines Agency (EMA), for its drug called Filsuvez.
EB is, in Wiley’s words, an “awful disease”. Also known as “butterfly skin” disease, it is a genetic condition in which skin blisters at the slightest touch — even something as routine as pulling on a sock potentially. It can affect anywhere in the body, with the exception of the brain, according to support group, Debra Ireland.
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“It’s akin to falling off your bike and sliding along the tarmac and you remember hurting your knees and elbows and how sore it is when you do that,” Wiley says. “And that’s because your nerve endings are underneath your skin so anything that does that gives you a painful injury.
“And that’s what these kids have all the time. They need opiates to get through dressing changes because as the bandages are taken off the skin comes off with them, so it is truly awful.”
Most patients are children, in large part because a particularly aggressive form of skin cancer afflicts many patients in early adulthood. In Ireland, there are about 300 patients, of whom about 90 have the two more severe forms of the disease for which Amryt’s drug has been sanctioned.
For a small Irish pharmaceutical firm, founded only seven years ago to deliver a first therapy for this group of patients is a major success for Amryt, and Wiley is justifiably proud of the achievement.
“It is a massive undertaking; it is very costly, it is high risk but we have been successful and we are so pleased for those EB patients who now have something. Our mantra is to bring hope to those in greatest need and that’s what we feel we have done with this approval.”
Amryt is a young company, founded in Dublin only in late 2015, by Wiley, a doctor, and Rory Nealon. From the outset, Wiley and Nealon were determined to be a commercial business rather than just a drug developer. And they decided to target rare diseases.
“We were a start-up in 2015, with just the two of us, and we had ambitions to become a global pharma company in rare diseases. In rare diseases you have small numbers of patients being treated by small numbers of physicians in a small number of centres, which means you can have a commensurately small commercial footprint and address the market opportunity.”
In a previous role with venture capital firm Sofinnova, Wiley had been responsible for keeping tabs on drug development in Europe. In Germany, he came across a company called Birken that had developed a gel.
“What was really interesting about it was that they had data on this rare disease, EB,” he recalls. But the Birken team was pursuing other targets for the gel, such as in the treatment of burns. “The team they had was not backable” from a Sofinnova viewpoint, he says. “But when I was setting up my own company, I approached them and we agreed a deal to buy them.”
It wasn’t as easy as that sounds.
“At the time, we had raised the princely sum of €1 million from small investors with an ambition to buy pharmaceutical companies, so that was not without its challenges,” Wiley says. “But we had identified this company and we struck a deal with their billionaire owner at the time.”
Essentially, the transaction was a reverse takeover, which saw the nascent business listing on the London AIM market and the Birken investors taking a stake in the business. Amryt immediately focused the Birken gel product exclusively on EB, setting up the biggest study to date in this area.
“In rare diseases there are lots and lots of issues with clinical trials. Because they are rare, finding patients to study is difficult, and we were doing a study of over 230 patients. That doesn’t sound like a lot but we had to go to 58 sites in 28 countries to run that study,” Wiley says.
“Even getting in a taxi and sitting on the seat can rip their skin off so actually to get them to come into a clinical study is very challenging. So it took a long time to recruit and that’s why we had to go to so many different sites in so many countries. It was a massive undertaking, its actually why the Germans didn’t do it. It was a huge, huge undertaking but we felt that the data was compelling.
“And, in particular, there was nothing [for these patients]. These are mostly children with this disease because unfortunately they die with the disease either before adulthood or in adulthood and these children had nothing.
“We felt there was a good chance we could be successful and we have proved that with this approval.” The Birken team, Wiley reveals, will now get a significant milestone payment — “a €10 million milestone because it has got approved, so they have done very well as well,” he says.
Drug development is not a cheap business. The average cost of getting a drug approved is more than $1 billion. “That doesn’t mean it costs a billion dollars to get a drug approved,” Wiley clarifies. “It means that, because the attrition rate — the failure rate — is so high, that if you look at per drug approved, what does it cost to get there, it is over a billion dollars.”
After drug discovery, there is a long process on “bench” development and then preclinical studies in animals to ensure the drug is safe before it can be assessed on humans. Wiley says the average time from “bench to bed” — ie, human trials — is about 14 years. And of 10,000 or so drugs discovered, only one ever makes it that far.
“And when you get into the clinic, only about 6 per cent of those drugs ever get approved and there is the cost involved in doing that programme as well,” he says.
Fortunately, Birken had done much of the early development and studies on what has become Filsuvez, so Amryt could focus on the Phase III trials in EB patients. He reckons its development has cost more than $100 million (€98m).
Now comes the tricky bit. The EMA might have approved the drug but Amryt will still have to hammer out reimbursement agreements with each of the 27 EU member states. It’s a drawn-out process that takes time and it’s one where the odds are always against drugs for rare diseases. Mostly it is national health services that are picking up the tab and, as we hear regularly from the Health Service Executive, resources are permanently under pressure. Drugs go through a “value for money” exercise to determine if they are worth investing in for patients in each country. The formula used for this is standard and that is an issue for developers of drugs to treat rare diseases.
In Ireland, the sticking point almost always is cost. Assessments of new drugs regularly determine that they are not worth using at the price being sought by pharma companies. What generally follows is an extended period of negotiation over price in the context of the annual HSE medicines budget. Wiley won’t be drawn on price, a commercially sensitive subject and, as a publicly-listed business, not one about which he can talk about outside of a general market announcement.
“The problem in rare diseases is in the name — it is rare — so using the same methodology and metrics to assess a rare disease product is flawed,” Wiley argues. “They are tiny numbers and to use the same metrics to assess reimbursement for five people in the population versus a common disease where you are going to have thousands and thousands [of patients] is an unfair playing field and therefore it is discrimination because patients do not get access and that is wrong.”
A rare disease is one that afflicts fewer than 200,000 patients in the US market of 300 million; an ultra-rare disease is one where there are just 50,000 — or just 167 per million of population. In Amryt’s case, two of its three existing commercial drugs treat diseases where there is just one patient per million, so 300 in the US and just five in Ireland, for example.
Even with Filsuvez, there are just 90 Irish patients who could benefit — or 18 per million of population — but, for that group, the benefit could be life changing, the company argues.
The company expects patients in Germany will be the first to receive supplies of the new drug as soon as September. The Birken acquisition brought with it a manufacturing plant outside Stuttgart so Amryt will make its own supplies of the gel before outsourcing the finishing and packaging.
When — or even if — Irish patients will receive the drug remains unclear. A study last year measured how fast European countries approved 152 drugs that came to market between 2016 and 2019. Only 35 per cent of the drugs were approved in Ireland at all by 2021, the lowest among western European states. And, on average, the process took 477 days. In western Europe, only France and Portugal took longer.
Meantime, Amryt faces other challenges. Filsuvez might have been approved in Europe but the Americans have been more sceptical, with the FDA — the US drugs regulator — seeking further supporting evidence. That news knocked almost a quarter off the company’s share price when it was delivered back in February. The share price recovered somewhat, since then, but it remains just 10 per cent above its 2022 nadir and 35 per cent off the level it was trading at back at the start of the year.
The day after it announced the European approval of the drug, Amryt said it would challenge the FDA decision; filing a formal dispute resolution request for the drug with the FDA.
“I will say I think the way the EMA conducted the review was better. They sought and got the input from the experts in the EB field. The problem with rare diseases is that you are educating the agencies because they do not know what this is.
“The EMA did the right thing in our view ... The FDA chose not to do that and we think that was a mistake.
“This particular division — dermatology and dentistry — they are not used to reviewing a rare-disease product. We feel that with the body of data that we have, really they have made a mistake.
“This is a process for exactly this issue — where you are in scientific dispute — that you can basically appeal above the division by going higher into the agency and you make your case there and that is what we are doing.”
He is hopeful that the process will take months, rather than years. If Amryt is successful, he says he does not expect a massive delay for the roll-out of the therapy in the key US market.
Amryt already has 300 staff and a distribution network across North America and, it says, globally, with the exception of Asia Pacific which is “an area of focus for us moving forward”. This is as a result of the acquisition of two Boston rare-disease businesses in recent years, each of which has delivered a commercially available drug.
“We are a global business now. After Birken, we inlicensed the European rights to a drug from a US company firm Aegerion in December 2016. That was our first commercial asset.” The drug, Lomitapide, reduces high cholesterol levels caused by a genetic disorder
“We then went and bought that company out in 2019 ... and that gave us global rights to two commercial assets”, including Metreleptin, used to treat a condition that causes sufferers problems with the way their body stores fat
“We have done extremely well with that, we have grown that 20 per cent year over year even through the pandemic, so that has been really, really great.”
Last August, Amryt bought Chiasma, whose Mycapssa drug treats a condition that causes gigantism.
So what next?
“Our business model is that we acquire, develop and commercialise and we will continue to do that,” Wiley says.
“We have significant runway with our four existing drugs. We will do $260-$270 million this year, if you look at the analysts who follow us, that doubles or more over the coming years.”
And the outlook for Filsuvez?
“We’re not allowed give projections under SEC rules,” he says. However, analyst estimates range from peak annual sales of $300 million to $450 million.”
C.V.
Name: Joe Wiley
Age: 51
Position: Cofounder and chief executive Amryt Pharma
Family: Married to Niamh, a psychiatrist, they have three children; twins Portia and Luca, and younger sister Athena.
Interests: “I’m a hacker at golf, a happy hacker. I like to play. And I took up tennis a few years ago.”
Something you might expect: Wiley’s immediate focus is on persuading the FDA that the drug should be approved for American patients and agreeing reimbursement with European health authorities.
Something that might surprise: The company name is personal. Wiley’s middle name is Amrit — a legacy of his aunt’s Malaysian husband. It’s Sanskrit and means “a healing elixir from the gods”. “We thought wouldn’t that be a cool name for the company when we were buying Birken,” Wiley says, though the “i” had to be tweaked to a “y” so as not to clash with the trademark of an Indian firm.
