Source: www.nj.com/
Author: Susan Todd/The Star-Ledger

Jean-Jacques Garaud, who heads Roche’s pharmaceutical research and early development efforts in Switzerland, visited the drugmaker’s Nutley campus in mid-December and spent some time speaking with The Star-Ledger about the company’s efforts in the laboratory.

The talk with Garaud provided a rare glimpse of the giant Swiss drugmaker’s early-stage pipeline and highlighted the heavy bets it’s making on personalized medicine (drugs that are tailored to treat individuals whose genes or enzymes show specific biological signs of disease).

If the strategy succeeds, Roche could eventually push out some breakthrough drugs for cancer, Alzheimer’s disease and depression.

Garaud, a French-American who joined Roche five years ago, also opened up about a discovery made in Nutley that may represent a novel cancer treatment and the high hopes behind a project with the promise of altering the lives of individuals born with a syndrome that causes mental retardation.

During the interview, Garaud talked about some medicines so early in development that they are still referred to by strange-sounding laboratory names.

Q. Where do things stand with gantenerumab, the monoclonal antibody Roche is developing as a treatment for Alzheimer’s disease?
A. This is in phase 2 and this is testing a patient population in the early stages of the disease or suffering from mild cognitive impairment. We believe this particular type of intervention may be more beneficial when it happens early in the disease so that it delays progression.

This antibody targets the abnormal material called amyloid that deposits in the brain.
The antibody prevents the deposits and it is supposed to put away (eliminate) the material. We have actually demonstrated that in some of the patients. The point now is to demonstrate the next step.

There is big potential (in Alzheimer’s) and we are looking at different hypotheses. There are other things that are much more upstream (in even earlier stages of development) that we are looking at, but I’m not going to talk about those because it’s a bit proprietary.

Q. Can you highlight some of most interesting prospects that Roche has in early-stage development?
A. One of the more interesting prospects, which may move into phase 3 next year, is a monoclonal antibody against EGFR — epidermal growth factor receptor, a protein involved in the division of cells. There are already monoclonal antibodies targeting EGFR for colorectal cancer, head and neck cancer and non-small-cell lung carcinoma but they have limited action on KRAS, a certain type of mutation in the cancer cells.

We have engineered our antibody in a way that it is more potent and it may kill more of the cancer cells regardless of the mutation. We believe it will have stronger activity against the three cancers I mentioned. The signals we have seen have to be translated into survivor advantage, and that won’t be known until the end of next year.
If it turns out to be a me-too product, we will not continue developing it. That’s one of the things we are trying to do systematically, have products that are differentiated so we bring an advantage.

Q. Every pharmaceutical company is saying it wants to differentiate. What is Roche’s strategy for making drugs that offer some advantage over existing medicines?
A. There is one unique feature to us. We are focusing heavily on personalized health care. We believe that for us to bring medicines that are innovative and successful, the product is going to have to prove it is very beneficial.

How do you do that? By targeting the patient population that is more likely to respond to the treatment. It means that all the tools born out of the life sciences revolution, we bring them to the table to understand the viability of a given disease and the potential markers that will indicate a subpopulation (of patients) is more likely to respond. So when you run the clinical trials as early as possible, you identify whether you have the potential to be effective.

Q. Why is it a better approach?
A. The previous concept was mass treatment. Some 50 to 60 percent of the patients were likely to benefit from the drug, but maybe 40 to 50 percent of those treated would not fully benefit from the treatment.

Understanding why is leading to medicines that are more targeted. Take the example of Zelboraf, which was recently approved for melanoma. For 20 years we were using the same drugs for the management of metastatic melanoma. They were used with limited success. So a few years ago, scientists discovered that 40 to 50 percent of those with melanoma had one mutation on an enzyme that was driving the cancer. If we had a drug that was specifically targeting that enzyme, we could actually block the evolution of the cancer.

In the clinical tests, we tested only patients with the mutations and identified very quickly that (Zelboraf) was active. This was a drug that had one of the fastest developments in history. In a few years, we moved from phase one to the launch of the drug in the U.S. I think it started when I joined Roche, which was five years ago. That was very quick.

Of course, it doesn’t always work that way. When it does, it shows that deepening the understanding of the biology of the disease may lead to better medicines. Eighty percent of our projects have a biomarker-personalized health care strategy.

Q. Are there any interesting products in the pipeline that have come out of the laboratories in Nutley?
A. Let’s talk about MDN2 because it is specific to Nutley. There is something called apoptosis, which is programmed cell death. Cancer cells have a way of escaping that so they don’t die. They multiply without dying. The programmed cell death that should occur when an abnormal cell is made is not working anymore. The Nutley scientists have identified one of the reasons this occurs.

They have also also identified a family of molecules that, in tinkering with that survival mechanism, allows the cancer cell to die. The family of molecules is called the nutlins — from Nutley. The target is MDN2, a protein that sticks to another protein/molecule called P53 that is the driver of apoptosis. When MDN2 sticks to P53, there is no cell death.
Cancer cells have developed a skill to produce more and more MDN2 so that they won’t die. The nutlins can prevent that from happening. They block the interplay between MDN2 and P53 so that P53 can do the job of launching the death of the cell. It’s an example of good science, and we are far ahead of the competition on that one.

Q. What excites you most in the company’s early stage pipeline?
A. It’s something we call mglu-R5 — the drug’s lab name. It’s an inhibitor of the metabotropic glutamate receptor. (The receptor is involved in normal brain activity and becomes disrupted by neuropathological conditions.) The drug may have two avenues of exploration, one in difficult-to-treat depression and one is in a form of mental retardation called Fragile X Syndrome. (The syndrome is one of the most common inherited forms of mental retardation in boys.) This is the part that is more interesting because it is one of the potential, new avenues for treating neuro-developmental disorders, whether it’s schizophrenia or autism or mental retardation.

More and more, there is a deeper understanding of the biology of these conditions and there is a possibility that we’ll start to see a possible therapeutic intervention. Forever we have believed we could not actually recuperate the cognitive loss, but we are learning there is really a high level of plasticity of the neurons and it is possible to learn what you haven’t been able to learn.
What we have to do first is check whether if we intervene at the adult age we can bring back some cognition ability. It is an area that has been ignored because we believed it was not reachable.