Michael Vellard is a specialist in developing therapies for difficult to treat rare genetic diseases. Read the story behind his remarkable success.

Rare genetic diseases are tough to diagnose and develop treatments for. The increasing number of genomic databases should help this process significantly. But is there an ethical dilemma around allocation of time and funds towards a disease that might only affect a tiny part of the population?

With more drug developers looking into rare diseases, are we seeing a potentially dangerous shift towards prohibitively expensive treatment? Michael Vellard, has dedicated his career to curing these conditions, and is in no doubt about the social benefit of his work. He took the time to speak to us about his motivations, and how genomics is already helping drug development.


Michael Vellard

Michael Vellard, VP Research, Ultragenyx

There are many personal stories that inspire genomic research. People see the potential benefit and the gaps they can fill, but a lot of the time it’s the experience of friends and family members with genetic diseases that drive people in the field. What is it that first got you interested in genomic research, and ultimately led you to work at Ultragenyx?

My niece was diagnosed with Cystinosis when she was only one year old. It’s a disease that breaks up the kidneys early on in life, so that they can’t keep and absorb minerals. Kid’s with Cystinosis have to drink a lot, and are deficient in a lot of different minerals. So, often there is kidney failure early in life if they don’t get a transplant.

At the time of the diagnosis I was already studying biology, so I decided I would try work in these diseases because nothing was really known about them. Even the gene wasn’t known at the time. After I completed my PhD, I was fortunate enough to get grants to do my research wherever I wanted. So I tried to find labs that were working on Cystinosis, which led me to UCLA. The goal of my post-doctoral work there was to find and clone the gene responsible for Cystinosis. I tried that for two years, but I wasn’t successful. That was relatively hard for me, as you can imagine. From that, I took a few years of sabbatical.

After a few years out, I went back to research because I knew that I definitely wanted to do something in those rare genetic diseases. One of my colleagues whom I met at UCLA happened to create a company that was doing exactly this; working on a rare genetic disease. The company was called BioMarin Pharmaceutical. So I ended my sabbatical, went to work at BioMarin Pharmaceutical and stayed there for 14 years. I was excited by what we were doing. It was what I wanted; to find cures for those diseases. Through those 14 years, and in the year and a half since I joined Ultragenyx, that’s pretty much what I’ve been doing.

For me, my niece was, and still is, my motivation. In my field, a lot of people are like me, with a strong personal motivation.


Rare diseases are a group that is often overlooked due to the relatively small market size. Value based pricing schemes have tried to make it a more lucrative prize. To what extent is there an ethical duty to research therapies for these diseases?

There is definitely an ethical obligation, at least for me. First of all, for a lot of rare genetic diseases there is often a known treatment. So not developing this treatment because of commercial pressures, just completely blows my mind. You can develop the treatment, save kids, facilitate their lives, and to just say “no I won’t do it because I might not make money and I’m taking too much of a risk”? No. There is no doubt in my mind that I have an ethical obligation to pursue those treatments, because I know how to do it.

I’ve always been interested in HIV. One of the things that has been fascinating me from the start is knowing that some people were immune from the disease. Now six or seven years ago, people have found that it was one gene that was giving immunity. In fact, the discovery of this gene has been helpful in developing some of the HIV treatments that people are talking about today. In Ebola, people have done the same kind of thing. They found that some people were immune to the virus, and have found which gene contributed to that resistance. It’s possible that in a few years, a treatment for Ebola might come from this. But the resistance gene is the same gene that is involved in a lysosomal disease I used to work on, NPC1. For me the circle is closed somehow. Working on rare genetic diseases could also have an impact on something a lot more common, like Ebola. Ethically, I feel good about working on rare genetic diseases.


Was there anything else that has really surprised you through your involvement within the industry?

It’s really that money issue. For some of the bigger companies it’s really just about how much money they can make, rather than whether or not they can develop a treatment or not. That really surprised me at the time. But this is something that’s actually reversing now. Big companies are definitely more interested in some of these niches. People are seeing that they can make money even in some of those very, very, small markets. Before, it was all about big blockbusters for billions of people, but now the market is changing to something more individualistic.


In the cases of rare genetic diseases, advocacy groups can often be an integral source of support for patients, and their families. How important is it to involve them in your work?

For us, it’s extremely important for a few different reasons. One big reason is because it’s these groups that will let us know exactly what the patients are suffering from, and what is most important to them that needs to change in their lives. This helps us in organising clinical trials, knowing what we need to change and even at the level of the FDA. We can show them that we’re doing something relevant to help these patients’ lives. It’s extremely important for us to know exactly what the patients need. For me, that’s the biggest benefit of working with advocacy groups.

Secondly, for the patient, the advocacy group can be a very good in-between with the company. And they can also help those dialogues with the FDA and the EMEA, putting a lot of pressure on them to change the regulations around drug development for specific diseases. This helps us a lot in cases where the regulators may not know much about a condition, and helps us get approval and set up clinical trials.

Advocacy groups are also a really good place to start databases, and registries, to track the natural history of the disease. This is something that is extremely important for clinical trials. When we have natural history we know what we are going up against and we can compare the treatment against the normal evolution of the disease. These kinds of controls are extremely important to the FDA.


Genome databases have the potential to be extremely powerful research tools. What is the biggest benefit likely to be for drug developers?

In the field of rare diseases, it’s often very hard to diagnose patients and to know how many actually exist. So the question of number is relatively important. From a business perspective, it’s useful to know the potential size of your market. So as genome databases become more popular, we should be able to have a much more accurate idea of how many patients there are likely to be for specific diseases.

The relationship between the mutations that a patient might have and the pathology of the disease is also very important. So from a treatment point of view, genome databases will also help to adapt treatments to the patients much more effectively. For me, those are the two big benefits; identification of the patient and more effective treatment. Particularly, if you can start to identify patients at birth, so that your treatment can be even more effective.


Here in the UK the 100,000 Genomes Project is specifically looking at rare diseases as well as cancer. Even so, the nature of rare diseases is such that the relevant sample size for each rare disease is likely to be small. Do you think genome database building is going to increase dramatically over the coming years? Will integrating results from different databases significantly improve our understanding of diseases with individually small sample sizes?

The 100,000 Genomes Project is very interesting. I think this kind of project is definitely going to become more and more popular with the price of whole genome sequencing going down so quickly. For the rare genetic diseases, it’s pretty much the only way we will be able to really detect those patients. It’s really a question of numbers because these are so rare. So we really need to try to sequence everyone to be able to have an idea of the frequency of those specific mutations. So I think we will get more of these databases, and once we have a systematic process for sequencing the population, it will dramatically help in rare diseases.


How easy is it to integrate genomic information into projects already deep into development?

We’re already doing it now. In my job, for one of the diseases I’m working on, we’ve created a program of genotypic identification of the patient. We pay for the genotyping because we want to make sure that they have the disease we think they have, and we also really want to know which mutation they have. That really helps us adapt the treatment for those specific mutations. In rare diseases there are a lot of very different mutations with a lot of different outcomes. So at our level, that’s extremely important information for us to know.


Specifically in cases of rare diseases, keeping patient data truly anonymous can be difficult. How do you balance patient privacy with the potential benefit to research?

A lot of people are working on how to make these databases private. TREAT-NMD, have a program where they are working on a database that ensures the patients privacy while also allowing for information to be disseminated to researchers and patients. It’s extremely difficult, but there are a lot of groups doing this. I think genomic databases are extremely important resources that scientists need open access to, but it is also very important that we protect people’s identities.


You recently had your own molecule approved this year. This is one that you’ve managed to develop from bench side all the way through to bedside. How does it feel to take something through that whole journey?

The feeling is definitely an amazing feeling! Without a doubt! It was tough though. The disease I worked on was Morquio A Syndrome, which is another lysosomal disease. I started work on it about ten years ago, and it kept going back and forth. The disease itself had some challenges. Some people thought it wasn’t treatable because it has to do with bone and cartilage. Cartilage is a very hard thing to treat because it is so poorly vascularised. So a lot of people were thinking “let’s give up on this disease”, because it’s too hard and too risky. But I didn’t! I tried to demonstrate, step-by-step, that it was possible. After a lot of ups and downs, I was lucky enough to feel the experience of being approved by the FDA and EMEA.


Are there any moments throughout the development and testing that really stood out as highlights for you, or people who played a pivotal road in helping you get the molecule all the way through?

Definitely. I remember very well, early on in the process, I was visited by a young kid who had the disease, Ian Michael Smith. He’s an extremely small guy, with all the symptoms of a Morquio A Syndrome sufferer. At one point, they used to call the disease ‘Gargoyle Disease’, so that gives you an idea of how deforming it can be. But this kid was so full of life, and so bright. In fact he went through to MIT, and is an engineer not far from here in Oakland now. The brain is completely normal, but he faces a lot of challenges. He’s in a wheelchair, has hearing difficulties, he’s 4ft tall at the very most. He has a lot of deformities, but he’s an amazing kid. For me, this visit really drove me on. From the start, I was really pushing the research up against a lot of people who really didn’t believe in it, so I needed a lot of motivation. Meeting Ian Michael Smith, seeing his perspective and enthusiasm for life, was a big part of that for me. It was important for me know that if I could do something, then I had to try to do it.


Is there anything you would have done differently with the benefit of hindsight?

To panic less when I had bad results and had to fight people! I would have liked to have been more relaxed. But I was a passionate guy with a mission, so I pushed and carried the stress. I guess I would have liked to have been a bit more relaxed, but I don’t know if the results would have been the same though.


How do you think healthcare is going to change over the next 10 years?

There are good and bad aspects to this. On the good side, I think it will become more and more individualised. Genomics will be a big part of this, enabling those kinds of personalised treatments. Rare diseases are already a part of this trend to get more and more individualistic, and it’s also happening in cancer. But will we have the luxury to do this? It costs more and more money, the more personalised a treatment is. So I don’t know if we’ll actually be able to afford those kinds of treatments. So it will most likely be a situation where we have more and more treatments, but they’ll also be more and more expensive.


As with the recently announced Glybera price tag?

Yes. Although gene therapy is another issue, but most likely that is the kind of pricing we’re looking at. For me working in rare diseases, I think the drugs I worked on are in the world’s top 10 most expensive drugs in the world. The question I ask is whether it is ethical to pay millions a year on one child, or should we spend that same amount somewhere else and ignore that one child? I don’t know… There’s a definite ethical question there. If we only have a certain amount of funding to distribute, then there will be some very hard choices to make.


Congratulations again on getting your approval, and thank you for sharing your story with is. Is there anything else you’d like to say to our readers?

For me, my story is really about following your gut and your motivations somehow. That’s what drove me.

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