Discussing Shire's Rare Disease Pipeline with Hartmann Wellhoefer, M.D.

Hartmann Wellhoefer, M.D., head of medical affairs at Shire, sits down with Rare Disease Report at the 14th Annual WORLDSymposium to discuss the company's recent data for lysosomal storage diseases.

Wellhoefer: Shire, as a company, is very much strategically committed to the rare disease space. We have - as a company - a couple of years ago, made a strategic decision to very much focus on rare diseases and orphan drugs and the rare genetic disorders, mainly. That led to a very good clinical pipeline that we currently have. We have about 40 drugs or so in clinical development and three-fourths of these 40 drugs are actually for rare diseases. These are orphan drugs.

When you ask about the challenges of rare diseases in terms of clinical trials, one of the big issues we are having is, because rare diseases mean the patients are rare, it’s very difficult to find patients; particularly for diseases where no treatment yet exists. Even for diseases where treatment exists, it’s difficult to find patients. So, you need to go sometimes into countries where you typically would not go, namely outside the U.S. or Europe. That’s one issue, and the other issue is from a clinical development perspective; typically in rare diseases, you don’t have good data and good knowledge about the natural history of the disease because these data are normally not typically collected. Maybe some centers of excellence have these type of data, but they might not be complete enough so you go very much into unchartered territory in these diseases.

Quite often you don’t know what is the appropriate endpoint you need to pick. Take Fabry disease as an example: we are in Fabry disease for more than 20 years now, but to date, there is still no good biomarker existing for Fabry disease. We really don’t know what is the right clinical endpoint where you would power and focus your clinical trial program on it. Is it pain? Is it renal function? Those are just examples for that.

And then it is the variability of the disease. Although genetic disease are typically monogenetic diseases, so you would assume they are fairly homogenous in terms of their picture or phenotype, in most of these diseases you have a great variability of the phenotype of the disease. So, you might have very early onset of the disease where you very early get very severe course of the disease. A lot of symptoms can cause the children deteriorate quite quickly. Then, you have late onset phenotypes where in adulthood or even late in life you see problems. MLD (metachromative leukodystrophy) is an example for that where you have early forms of the disease that very rapidly show cognitive decline or impaired motor functions and then you need to decide. What is the type of phenotype that you target for your clinical development program and then what is the endpoint? Do you focus on neurocognitive decline or neurocognitive symptoms? Behavioral symptoms or on motor symptoms? Or you have a biomarker? That’s one of the many challenges.

You need to have an agreement with the regulatory authorities and that’s not the end of the story; it goes further because nowadays even in rare diseases, in orphan drugs, there are clear access hurdles in terms of reimbursement, the health authorities, the healthcare systems around the globe ask 'what’s the evidence that support your pricing and how do you justify the cost associated with your compound?' So, you need to think about what is the benefit that you bring. What is the value you put on a kid’s life that will have less cognitive decline or less behavioral issues? What’s the value to society? So, these are questions we need to tackle and find answers.

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