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Developing medicines for rare diseases requires an entirely different mindset, says John Crowley, chairman and CEO of rare disease company Amicus Therapeutics. "Developing drugs in rare diseases is very different from more prevalent disorders – the clinical studies are very small, you have different endpoints and biomarkers, different regulatory paradigms and different types of sales and marketing, plus the focus on the patient is intense. It takes a fundamentally different mindset than the one in bigger pharma companies."

For Crowley, it's all about following the science. "We describe Amicus as business led but science driven, and I have always believed that if you pursue great science and make a great medicine that trans-forms people's lives then the profits will follow."

After nearly 10 years, his vision was realised when the EMA approved Galafold, an innovative treatment for rare, inherited lysosomal storage disorder, Fabry disease. "This approval completes our transformation to a global, fully-integrated, commercial biotechnology company focused on rare and devastating diseases," says Crowley. "It is also a significant advancement in the field of precision genetic medicine and a tremendous milestone for the Fabry community."

People with Fabry disease have a deficiency with an enzyme due to a genetic mutation leading to the accumulation of a lipid called GL-3 in the tissues of certain organs. "It is a devastating disorder, life-limiting in terms of pain, fatigue, gastrointestinal symptoms, and people typically die of heart attacks, stroke, kidney failure," he says.

Galafold represents a new way of treating the disease, says Crowley, a departure from current treatment – enzyme replacement therapy. "ERT is a life-saving treatment but we believe our approach is a much more natural way of treating the disease. Rather than giving patients a bolus of replacement enzyme every 14 days by infusion – much of which is not properly targeted and only stays in the body for a day or so – our product promotes the creation of the enzyme all day every day, helping patients to live free of the symptoms of the disease."

The approval is a milestone in the fight against genetic diseases, he says. "The challenge in developing this new treatment was that we didn't have the resources to study all 800 mutations behind Fabry disease in the clinic. To overcome this, we studied a small subset of 50 mutations in the study and also developed an assay to predict which other mutations would also respond to treatment. We found a 100 percent correlation between our predictions and the patients who responded. 

"The EMA's approval covered 269 mutations, the first example we can find in genetic medicine. The European regulators went through an incredibly rigorous review of our data, so for them to have confidence to include all 269 mutations is pretty extraordinary," says Crowley.

The EMA also permitted Amicus to develop a website listing the mutations, including any new mutations. "New mutations are identified in the clinic practically every week and because we have the assay we can update the label on the website without having to go through the regulatory process each time. This is how I believe genetic medicine is going to evolve, which is why it is so important for us to fully understand the genetics of the disease and the responsiveness of medication to mutations."

Keeping it personal
Crowley's motivation to find new treatments for lysosomal storage disorders such as Fabry disease is a very personal one – his daughter and son have the related disorder Pompe disease.

"My family and I have been on this journey for 20 years. Megan was 15 months old and Patrick only seven days old when they were diagnosed, and we were told by doctors that nothing could be done, that they would only live a few years."

Pompe disease is a severe neurological disorder where the energy molecule glycogen accumulates inside the cells and leads to progressive muscle weakness, particularly in the heart, skeletal muscles, liver and nervous system.

"Very quickly my wife and I went from shock and denial to determination to do something to try to change the course of the disease," he says. "At first, we raised a little money for a not-for-profit but soon realised we needed to become entrepreneurs."

After a brief stint at Bristol-Myers Squibb, Crowley started a small biotech company using a home equity loan, which was later acquired by Genzyme. Crowley headed the Pompe development programme that resulted in the life-saving enzyme replacement therapy, Myozyme (alglucosidase alfa). However, as life-saving as ERT can be, it is no silver bullet, he says. "There are a number of deficiencies with Genzyme's ERT. We saw with our kids – and with many other patients – that they would improve for a while, plateau and then begin to decline."

The Amicus scientists decided to develop their own enzyme and to co-administer it with a chaperone drug that stabilises the enzyme in the blood, ensuring it reaches the muscle cells in a much more active form.
"With each of our drugs, the goal is to significantly improve a patient's life. We are now in clinical studies in Pompe patients and we're very hopeful it could be a profoundly different medicine," he says.

Patients in the bloodstream
For Crowley, a key component of the different mindset needed to work in rare diseases is a very close relationship with patients. "Companies need to realise a very simple point – you can talk directly to patients and still be a very compliant company, as long as you know all the rules and design a system to interact appropriately.

"One of the first people I hired when we set up Amicus was a head of patient advocacy, who then built a team of patient advocates who are our primary interface with the patient community. Patients are in the bloodstream of the company, even without any patients being in the room we consider their needs at every stage. It is about building the culture and understanding what makes a difference in patients' lives," he says.

When the team came to Europe to talk about its Pompe study, they talked to patients before the investigators. "We consulted with them first then, once we had a plan vetted by the doctors, we came back for their feedback. Patient involvement makes us a better company and makes for better programmes. Ten years ago, no companies had patient advocates; we did. Now, we are now the only company to have a chief patient advocate on the leadership team."

An early development was the creation of patient advisory boards. "Every company has scientific advisory boards but we have patient advisory boards with whom we share everything we know about our programmes – the good, the bad and the in-between. Originally, a couple of my board members were uncomfortable over the idea, especially around confidentiality but we have not had any problems, no tweets or Facebook posts, nothing. There is absolutely trust."

While it is important to talk to patients, it is even more important to listen, he says. "Only last month, we convened the board for Pompe disease and shared the data from the clinic. I'll share a personal story because my daughter asked to join the advisory board. She turned 18 last year and is a remarkably thoughtful young woman – although she lives in a wheelchair and is ventilator dependent, Pompe never affects the mind and she is smart and precocious."

The Amicus team discussed an upcoming study, including the clinical endpoints, then turned to the patients to ask them what factors were most important to them, says Crowley. "It is difficult to understand Megan as the disease has made talking difficult but she was able to make it clear that two things were important to her – the ability to breathe for one minute without her ventilator and to talk a little more clearly.

"Genzyme's medicine fixed her heart but the response in her other systems was more variable, and her dependence on the ventilator is the most hazardous part of the disease. Being able to breathe for a minute would be enough time for a nurse to reach her and re-intubate, so that is very important. Megan is just getting ready to go to college – when she said she wanted to talk more clearly, it was because it would be easier to make friends.

"Every patient has a different perspective so it is really important to get feedback from as many as possible. Hearing their stories always makes you think differently about the experience of living life with a disease like Pompe."