Manos Perros, chief scientific officer of Antivirals at Pfizer, describes his decade-long journey developing a drug to treat HIV.
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Topic: CCR5 Manos Perros: CCR5 is a very interesting story and it is the first project on which I worked in HIV after I joined Pfizer. HIV is the virus that causes AIDS and it had been known for a number of years that in order for HIV to infect the white blood cells, which it ultimately kills, it needs to recognize the protein on the surface, very much in the same way that a key fits into a lock. That protein was called CD4. And everybody knew that there was a need for a second protein, to be used as a landing pad in a way, for the virus to attach itself. And the identity of a protein was discovered in 1996. This was a really exciting year. A number of labs within the space of weeks identified the molecular function, they identified the protein called CCR5, they worked out how the virus uses it. Also what made it particularly exciting was some epidemiology work which was published literally weeks after the protein was identified that same year. That showed that a number of humans have a genetic variation on that receptor which effectively wipes it from the surface of the white blood cells. And by doing that, that mutation rendered them resistant to HIV infection. So those subjects did not seem to be infectable by HIV. Over a decade since it’s discovery, there’s only a handful of what we call CCR5 homozygous who have been found to be infected by the virus. This was obviously really exciting because not only validates the target as one that, if you block, you could stop the virus from entering the cells, but also taught us that it would be relatively safe to do so with a small molecule drug, therefore giving us both confidence that it will work and that it will be safe, all in one experiment. What ensued is actually even more interesting because you would have thought that with this great idea, it would be relatively straightforward to discover drugs. Over a decade again, since this discovery, we are the only company that has managed to develop a drug and take it to the market. It was discovered only a few years after the discovery of the receptor, but it has taken over a decade to get through all the regulatory pools and to patients. An extremely rewarding experience to be seeing the project from start, from idea, to finish, but also a very enriching one. The initial idea was published and shared by a number of inventors and both academic and pharmaceutical companies who worked on it. And almost every pharma who had an interest in anti-HIV drugs invested in a CCR5 program. And after this first good idea, there had to be a number of other good decisions made for that program to result to a drug. This is where my job is really interesting, because the day to day discovery process, making the right decision every time is what gives us the edge, the competitive edge over other pharmas and other labs. It was extremely rewarding to see how our progress progressed when others were finding it more difficult to balance the right properties in the same molecule. Getting a molecule that works against CCR5 was easy. It was a matter of a couple of years. We had some pretty potent small molecules that would block the virus from entering the cell. But then it took another two years to get them to be safe, to get them to be stable, such that they could be given only once or twice a day, and to develop them into a form that would turn them into a drug. This is really where pharma has its main strength, bringing together all the disciplines, the knowledge, the skill that they acquired for scientific discovery to be turned into a life saving treatment. I will always remember the first data that came back from the patient clinical trials where patients who had run out of options, who had gone through two, three, or more lines of treatment and failed, that had the virus that was resistant to almost everything that was out there and were put on a regimen that contained Maraviroc, Over half of them responded to that treatment and suppre