NEJM paper: http://www.nejm.org/doi/full/10.1056/NEJMoa1201248
Immune Reversal: How A Pfizer AIDS That Disappointed Investors Drug Might Help Transplant Patients
A Pfizer drug that failed to thrive as a treatment for HIV may now present a great hope for a deadly consequence of the bone marrow transplants used to treat blood cancers such as leukemia, myeloma, and lymphoma, according to a small study of 38 patients published this evening in the New England Journal of Medicine.
Transplants of stem cells found in the bone marrow can treat and even cure these cancers. Cells from a donor, often a family member, are injected into the patient after their own bone marrow has been wiped out. The result is that the patient has a new immune system that can attack cancer cells.
But sometimes – in fact, all too frequently – that new immune system attacks the patient, too. This occurs at least 30% of patients where the stem cells are “matched,” coming from a family member, and at least 50% when they are not. The main step to prevent this internal attack, called graft versus host disease, is giving the patient medicines to suppress the immune system, increasing the risk of infection.
Ran Rashef, an assistant professor of medicine in the blood and bone marrow transplant program at the University of Pennsylvania, thought there might be a better way. Instead of just shutting down immune system cells like white blood cells, why not tell them where not to go? These cells “don’t just wander around randomly into tissues and the blood stream,” he says. “There is a very well orchestrated process.”
The key to that process, earlier studies had shown, was the C-C-chemokine receptor type 5 (CCR5), a cellular switch on the surface of white blood cells that detects chemical signals coming from damaged cells. Blocking CCR5, Rashef thought, might prevent graft-versus-host disease. Luckily, the Pfizer drug, Selzentry, was already on the market. Pfizer provided the drug for his study and helped fund the clinical trial.
Rashef expected mainly to be able to see that the CCR5 inhibitor was affecting the movement of white blood cells. But the results were incredibly encouraging. Instead of the a third or more of the patients having graft-versus-host disease, only about 15% did – far fewer than expected, and a sign that the medicine may be extremely effective. “We were surprised we got some good efficacy for the study,” he says. “This was a pilot study that went wild.” Still, he emphasizes, larger clinical trials will need to be done to confirm the result. A Pfizer spokeswoman adds: “These findings are preliminary and it is too early to speculate on any future plans.”
Selzentry was approved in 2007 as a treatment for HIV patients whose HIV had entered their cells using CCR5 as a gateway. At the time, industry analysts expected Selzentry would generate $500 million in annual sales in 2011. In 2010, it generated only $128 million, far short of those expectations and far less than other AIDS medicines such as Merck‘s $1.1 billion Isentress and Gilead’s $6 billion HIV drug franchise.
If the results pan out, it will be one of the best examples yet of an idea known as drug rediscovery. One of the potentially big results from research emerging from the study of human genetics, this is the idea that existing drugs could treat new diseases. In some case, as with Merck’s Cozaar, which has shown promise against Marfan syndrome, a hereditary disorder, this can mean a relatively cheap medicine can help a population of people who were not thought of as large enough to warrant a big pharmaceutical research effort.
But the idea of “rediscovering” a drug can also create business challenges, because drugs are priced based on the diseases they treat. In one case, Celgenedramatically raised the price of thalidomide after it was found to be effective not just against complications of HIV and leprosy, but the blood cancer multiple myeloma. If Selzentry is effective against graft versus host disease, Pfizer might have reason to try a similar approach. The U.S. patent on Selzentry lasts at least until the end of 2019.