The short life of Efalizumab (BRiTE) Phase-II Clinical Trial

In early April, I found out about a new phase-II clinical trial, called BRiTE, that tested Efalizumab as a possible honeymoon cure for type-1 diabetes. Efalizumab (tradename "RAPTIVA") is a product of Genentech and is already approved for use on psoriasis and rheumatoid arthritis, which are autoimmune diseases in some ways similar to type-1 diabetes. I was in the process of writing up the summary when the news turned bad.

Later in April, Genentech and the US FDA announced that Genentech was voluntarily withdrawing Efalizumab from the market. I assume that this will mark the end of the type-1 clinical trial as well. Genentech has received 3 reports of progressive multifocal leukoencephalopathy (PML) in people treated with RAPTIVA. This disease is caused by a virus and is almost always fatal (survivors are often brain damaged), and is very rare.

This is a cautionary story for our testing process for new treatments. As the US FDA has said:

Raptiva was approved for the treatment of moderate to severe plaque psoriasis in 2003. There were no cases of PML seen in the clinical trials that supported the approval of Raptiva. At the time of approval, a total of 2,764 patients had been treated with Raptiva. Of those 2,764 patients, 2400 had been treated for three months, 904 for six months, and 218 for one year or more.

Since the approval of Raptiva (efalizumab) in October 2003, the FDA has received reports of three confirmed cases and one possible case of progressive multifocal leukoencephalopathy (PML) in patients who were 47 to 73 years of age who were using Raptiva for the treatment of moderate to severe plaque psoriasis. Two of the patients with confirmed PML and one patient with possible PML died. All four patients were treated with Raptiva continuously for more than three years. None of the patients were receiving other treatments that suppress the immune system while taking Raptiva.

Notice that there is no discussion of clinical testing lasting longer than 2 years, and that the people who got PML had all been taking the drug for over 3 years. The testing that RAPTIVA got is pretty much the same testing that the various type-1 cures currently under development are getting.

And you may want to think back to the bravebuddies discussion of a few months ago ("Ask the FDA to better serve diabetes patients" and "COMMENT ON FDA PETITION", when people were complaining about extra testing that the FDA wanted to require to make sure drugs approved for diabetes did not cause heart problems. Those drugs were getting approved with less than 1 year of testing, and people were howling that the FDA wanted two years or maybe more!)

This is also something to remember if an immunity drug based cure becomes available. If one does we will all be asking ourselves the same question: should my child be first in line to get this cure? It's now been FDA approved, should I get it for my kid right now, or wait. And if I wait, how long? These are not going to be easy questions to answer.

My understanding is that Efalizumab lowers the autoimmunity by targeting a specific type of T-cells, called CD11a. Several other treatments for type-1 diabetes which are currently in clinical trials work by targeting specific types of T-cells, although I don't know of any other drug that targets CD11a cells specifically. ToleRx and MacroGenics both target CD3 cells, while Pescovitz's research targets CD20 cells, and Faustman is targeting certain CD8 cells.

Here is the Clinical Trial record for the type-1 test: http://www.clinicaltrials.gov/ct2/show/NCT00737763
And a press release of the withdrawal: http://www.raptiva.com/raptiva/index.jsp?p=Raptiva&fr=yfp-t-501&toggle=1&cop=mss&ei=UTF-8

Joshua Levy