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Lundbeck on the challenge of schizophrenia research

? Schizophrenia is a difficult syndrome to treat, in part because of its complexity.

? Innovation in the field is stymied by the inability to test new mechanisms in animals.

? Lundbeck's collaboration with Vanderbilt University could yield new medicines for the disease.

H. Lundbeck A/S Chief Medical Officer Doug Williamson spoke to S&P Global Market Intelligence about advances the Danish company is making in finding new treatments for schizophrenia and about a recent collaboration with Vanderbilt University in Nashville, Tenn. H. Lundbeck A/S is exclusively focused on finding and developing new medicines for diseases of the central nervous system, notably Alzheimer's, Parkinson's, schizophrenia and depression.

The following is an edited transcript of that conversation.

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Doug Williamson
Source: Lundbeck

S&P Global Market Intelligence: What causes schizophrenia?

Doug Williamson: Schizophrenia as a syndrome has a complex variety of underlying causes. It's not a simple one thing going on in the brain that causes this complex collection of symptoms, it's a number of different things going wrong. And to make it even worse, each individual sufferer of schizophrenia probably has different things going wrong. It is not like they all have the same complex variety of things going wrong, they all have different parts of it going wrong.

They result in a similar looking set of symptoms, we call it the same disease. Now, how do we know this? We know this because most of the drugs that we use currently have one mechanism of action – they block dopamine in the brain. And if that was the underlying cause, we'd have nailed it. Everyone would respond to that treatment. But they don't and individual patients vary from complete recovery to no response at all — and everything in between — to drugs with very similar mechanisms of action.

Is there a genetic component to the disease?

Yes. We know that because in twin studies, with identical twins, if one has the disease, there's about a 40% chance the other twin will get the disease — which of course is very high risk, but what that says is that there are hundreds of genes implicated in this disorder.

Why has there been so little innovation in medicines for schizophrenia?

Each gene basically codes for a protein — and if you're in drug development, the proteins you're more interested in are enzymes or receptors for transmitters that you can develop as a potential target for a novel drug candidate. The chemistry in our industry has really gotten very sophisticated over the last couple of decades, so they can pretty much develop a drug candidate for any new target they come up with. And there are plenty of targets, even in a complex disorder like schizophrenia, or especially in a complex disorder like schizophrenia.

Usually in drug development, you'd then screen those [drug candidates] in animal tests. But we don't have any animal models for schizophrenia. Now, there are animal models that are used in schizophrenia development, but they're really animal models of a particular mechanism of action, and most of the drugs have been drugs which block dopamine. So, there are animal models which will tell you, yes, this drug is blocking dopamine, but there's not an animal model of a complex syndrome like schizophrenia, and so these models have proven very unreliable in predicting a response in humans for novel mechanisms, for mechanisms which are outside of dopamine blocking.

What does that mean?

And so that means that the failure rate is much much higher than in other therapeutic areas, the cost then goes up, the amount of time it takes to bring candidates forward goes up — and really that's at the root cause of why development in this area has been so slow and so challenging. As we understand more about the human genome, we get more potential targets almost every day and we're very good at developing drug candidates for those particular targets. It's how complicated and expensive and slow the process of moving those drug candidates forward, and trying to predict which ones will be effective in patients, that's led to the slowness compared to other therapeutic areas.

What is it about this collaboration with Vanderbilt that makes you excited about the possibility of finding new treatments for schizophrenia?

In early development — at the point of identifying these novel targets and identifying novel drug candidates to screen against them — it would be extremely foolish and arrogant to think that you can do that alone, as one company. So part of our early strategy is that we're always out there looking for very early collaborations and opportunities to partner with other companies or with academic groups to take advantage of the fact that, although we have our own brilliant scientists working on developing novel drug candidates, we don't think we can do it alone.

Vanderbilt has been a leader in doing some of the work of target identification, identifying these targets and developing drug candidates even that used to be the sole domain of pharmaceutical companies. They identified this very promising looking candidate and so we wanted to partner with them in moving it forward toward clinical development. And the partnership itself is not just this molecule. We've entered into a partnership with them to collaborate on future compounds that they may come across or invent.

How would this compound work?

I am forbidden from describing the exact mechanism of action but I would tell you that it still works by affecting dopamine. Most current drugs block dopamine receptors — in fact, all current drugs block dopamine receptors in the brain. So it still works through the dopamine system but it modulates the release of dopamine rather than blocking it. And that's as much as I can say.