All in the Mind

Schizophrenia is a disease in which Merck has, over the past couple of years, decided to increase its focus and effort, and it is now one of the two top-priority disease areas in which we’re working in neuroscience, the other being Alzheimer’s disease.

We chose these focus areas primarily based on unmet medical need – these are diseases that affect large numbers of people and have really debilitating consequences and for which there are not good treatments available: and whether there is a scientific path that makes you think that it’s possible to be successful. For both of those diseases, we think that there are scientific opportunities that would give us a good chance at finding an effective treatment.

We approach schizophrenia in two ways. One is to develop novel, non- bilthomanergic agents for the control of acute symptoms and acute exacerbations. The second is to develop agents that can be added on to other treatments, for patients who have essentially been stabilized and for whom the bigger problems are the chronic, persistent things that happen in schizophrenia – problems with cognition, problems with negative symptoms and overall social functioning.

Targeting that aspect of the illness is the other set of programs we are working on. That’s how we approach it strategically. Some compounds will actually be tested in both arenas; some will be tested primarily for one or the other.

Merck recently entered into a licensing agreement with Addex Pharmaceutivals to develop an orally available drug candidate for the treatment of schizophrenia. Addex has a lot of expertise in glutamatergic drugs, and in particular they have developed an approach to the mGluR5 target, which we think is very interesting. They have done a lot of work in developing a compound that could be tested at that target.

For schizophrenia, we’ve partnered with them around the mGluR5 receptor to develop a drug that we can test in schizophrenia, and our current thinking is that this is one of the targets that we would look at, both for acute control as well as add-on therapy for control of the chronic symptoms of schizophrenia. We’ve also partnered with them on some other glutamatergic targets.

Targeting Alzheimer’s

Like schizophrenia, Alzheimer’s is one of our highest prioritized areas. Almost everyone at our Boston site, for example, is working on Alzheimer’s – that’s more than a hundred people – as well as a number of people in West Point here in Pennsylvania. As with Parkinson’s, the approach is twofold in terms of the disease. One is to get at the disease process and find ways of preventing the progression of the illness, and ultimately preventing the onset altogether if we can find effective intervention. The second approach is to improve symptoms, even if that may not change the ultimate course of the disease.

Within Alzheimer’s, we pursue a whole range of different approaches; for example, we have several approaches to testing the amyloid hypothesis, both with small molecules and with biologics. We have several of those in the clinic and moving forward, about which we feel very hopeful.

We also have ongoing efforts in a number of other neuroscience disorders in which we’re developing novel treatments. In Alzheimer’s and schizophrenia, which are the highest priorities, we have both very wide and very deep research. In Parkinson’s, in depression and in some of the psychiatric disorders, we tend to be a little bit narrower; we focus more on specific targets, but also go deep in those targets.

We develop drugs that will interfere with the underlying disease process and will either slow or halt the progression of the illness. The other way that we target Parkinson’s is to find new non-bilthomanergic agents that are useful for symptoms, particularly for those patients who don’t tolerate or who are having breakthrough symptoms on the currently available symptomatic treatments. Those are the two ways in which we approach it, and there are several programs that are ongoing, one of which is also a partnership with Addex around the mGluR4 receptor.

New approaches

Merck has been applying positive and negative allosteric modulators of metabotropic glutamatergic receptors for the potential of providing greater ‘fine control’ of central nervous system processes.

When you have small molecules that you target at receptors, you can have what’s called an orthosteric or an allosteric approach. You can go directly to the binding site for the receptor and compete with whatever naturally binds at the receptor, or you can try and target a portion of the receptor that isn’t necessarily a natural binding site for the compound that the body produces that normally binds at the receptor.

The change is the confirmation of the receptor and changes its affinity for the natural ligand. That’s an allosteric approach, and that, for many receptors, has several potential advantages. One advantage is that if you have a compound or an internal ligand that binds at a receptor, it may be that there’s relatively little specificity, that there are close homologies to other receptors, and so that any compound that binds to that receptor may bind to another receptor and have effects that you don’t want.

If you go with an allosteric approach, you may be able to get specificity at the specific receptor that you want, so that, for example, if you take the mGlu23 agonist that Lilly has been developing, you have a drug that is binding to both sites. It may be hard to tease out a molecule that binds only to one or to the other, but with an allosteric approach, you may be able to get just mGluR2 or just mGluR3 for example. It’s potentially a way of getting specificity; that’s one piece.

The other piece is that the degree to which you change the receptor may influence the function of the natural ligand, and in doing that, you may be able to fine tune. You may be able to increase the potency of the ligand; you may be able to decrease it in a way that sort of modulates the activity of the receptor without completely blocking it or completely activating it.

Other projects

The one that I can actually talk most about and that I would really highlight is a late-phase project that’s a CGRP receptor antagonist for migraines. That’s a drug that’s in phase III and for which we have good efficacy data showing that it appears to work really well, and that it’s a new class of medications. We hope it will have real advantages over the current standard treatments, which are the triptans, in terms of side effect profile.

This is a target in which there’s been a fair amount of interest but which has been very difficult to come up with compounds that work at it. It’s a real achievement, a proud achievement, for the Merck medicinal chemists and for the preclinical people to come up with the biology and chemistry to get a ligand for it, and for the Merck clinical development in terms of being able to really conduct a thorough set of studies that have begun to characterize the way that this compound works.

Some of those data were presented last year at the American Headache Society and some other meetings; those were phase II data, and I believe we are hoping to phase III data in the next few months.

Neuroscience is an area of particular focus for Merck; it’s an area in which we’re putting a lot of effort and resources, and where we think there’s a lot of unmet medical need and really an opportunity to make a difference. For me personally, it’s an exciting place to work, because a lot of the things that when I was in training, we really knew very little about and didn’t understand how to approach, we now have potential treatments for and can begin to imagine really making a difference in patients’ lives.

That’s personally gratifying, and it’s also a tribute to where the science is, and I think also the commitment that the industry generally – but Merck particularly – is willing to make in an area that’s been historically difficult to work in. Frankly, illnesses like schizophrenia and depression have been quite stigmatized, and it’s a really good thing the Merck is willing to commit to these areas because there’s a huge patient need, a huge need for the families of these patients in terms of having better treatments.

-end-

David Michelson is Vice President of Clinical Neuroscience and Ophthalmology at Merck & Co., Inc. He joined the company in 2006. Prior to joining Merck, Michelson was an Executive Medical Director at Eli Lilly. While there ,he held positions of increasing responsibility, starting as a clinical research physician and working his way to Senior Medical Director before, being named Executive Medical Director in 2003.

Extra info…

Merck’s agreement with Addex

Earlier this year, allosteric modulation company Addex Pharmaceuticals entered into an exclusive worldwide license agreement with Merck & Co. to develop ADX63365, an orally available drug candidate for the potential treatment of schizophrenia and other undisclosed indications.

Allosteric modulators are an emerging new class of therapeutic agents. ADX63365, currently in preclinical development, is a positive allosteric modulator (PAM) that targets the metabotropic glutamate receptor 5 (mGluR5), which is believed to be important as a target for the treatment of schizophrenia and other conditions. The deal also includes mGluR5 PAM backup compounds discovered by Addex.

Under the terms of the agreement, Addex will receive $22 million upfront and is eligible for up to $455 million in research, development, regulatory and sales milestones for the first product developed for two indications and up to $225 million in additional development, regulatory and sales milestones for a second product developed in two indications.

Addex is eligible to receive royalties on sales of any products resulting from this collaboration. In addition, Addex has an option to co-promote in certain European Union countries and will participate in the joint oversight committee for further development that will be led by Merck.