Biotech Values

[DewDiligence]

Bristol’s Big Win (Ipilimumab)

[See the sidebar at the end of this post for a profile of researcher James Allison and his conjecture vis-à-vis Ipilimumab’s MoA.]

http://blogs.forbes.com/sciencebiz/2010/06/bristols-big-win/

›June 5, 2010
By Robert Langreth

The first day of the year's biggest cancer conference is turning into a big victory for Bristol-Myers Squibb as its immune-boosting drug delays death from melanoma, one of the hardest-to-treat tumors.

The medicine, ipilimumab, could be a big help to patients like Sharon Belvin. She was on death’s door a few years ago. Melanoma had spread all over her body and conventional treatments had failed. Then, in 2005, she the Bristol drug, ipilimumab. It worked--even as the drug failed to help numerous other patients. The 29-year-old remains cancer free today.

But [whether] ipilimumab helped the broader population of patients remained an open question--until today. In a huge win for Bristol-Myers Squibb, researchers presented data from a 700-patient trial showing that the drug improved survival in advanced melanoma patients. The data is being presented at the American Society of Clinical Oncology Meeting in Chicago and published in the New England Journal of Medicine [#msg-50941949]. It’s the first time a melanoma drug has been shown to extend survival, and it paves the way for marketing approval of the drug next year.

Few patients got responses as dramatic as Belvin. Overall, researchers reported that patients on ipilimumab lived 10 months, versus 6.4 months for patients in a control group who got a vaccine called gp100. Nearly half of the patients on ipilimumab were alive after one year [46% to be precise], versus one-fourth of the patients on the vaccine [#msg-50941842]. It causes inflammation in the skin and colon, which can be deadly in some cases.

“It is going to used by almost every oncologist [who treats melanoma] because it so darn easy to give, it has potentially long-lasting benefits, and we don’t have much else,” says Memorial Sloan-Kettering Cancer Center oncologist Jedd Wolchok. Adds Dana-Farber Cancer Institute oncologist Stephen Hodi, a lead investigator on the ipilimumab trial. “This is paradigm-shifting. It is hopefully the beginning of a new golden age of melanoma treatments.” Roche has a promising melanoma drug that works by a different mechanism.

Ipilimumab doesn’t try to kill or quell tumors directly, like most existing cancer treatments. Instead, it aims to rev up the immune system’s killer cells so they will infiltrate and kill tumor cells. It does so by turning off a protein called CTLA4 that acts as a brake to keep rampaging out of control. [See the MoA discussion in the sidebar at the end of this post.]

Researchers have high hopes that melanoma result will help pave the way for a new arsenal of cancer treatments that spur the immune system against cancer. But the ipilimumab data is the second clear success for immunotherapy after decades of murky results and outright failures. In April Dendreon’s prostate cancer vaccine snagged FDA approval.

“There has been a lot of controversy for a long time” over whether immune therapy for cancer works, says Dana Farber Cancer Institute oncologist Philip Kantoff. “Here we have two trials in two different diseases that validate the concept.” He adds: “You can just feel the change in the atmosphere.”

The advanced melanoma market is relatively modest, perhaps 7,000 patients a year. But Bristol has big plans for the drug. It is conducting a major trial to see if ipilimumab can help keep early-stage melanoma patients who have had their tumors surgically removed disease free. This is potentially a far larger market. It is also conducting a large trial in patients with advanced prostate cancer, another large market. The drug also shows promise in lung cancer, according to results of a mid-stage trial presented at the ASCO meeting. [The phase-2 results in NSCLC were modest—see #msg-50436537.]

Ipilimumab “should be usable against any type of cancer,” says Axel Hoos, the Bristol-Myers executive who led the ipilimumab testing. He predicts that immune therapies such as ipilimumab will eventually become a mainstay treatment for all sorts of tumors.

If things play out that way, Bristol-Myers Squibb has a head start. It has been one of the first large drug companies to move into cancer immunotherapy in a big way, with its $2.4 billion purchase of Medarex last year. The purchase gave access several other cancer immunotherapy drugs that are in early testing [see the graphic in #msg-47473034]. Other big companies working on cancer immune therapy include GlaxoSmithKline, which has a lung cancer vaccine. Pfizer is testing a drug similar to ipilimumab called tremelimumab.

Ipilimumab can also stimulate the body to attack healthy tissue, causing skin rashes and sometimes-severe colon inflammation. In the big melanoma trial, a few of the patients died who got ipilimumab died from drug-related complications.

As for Sharon Belvin, the drug has kept her well long enough to have two children, ages 2.5 years and 7 months. But what makes her different from so many other patients is unclear. She now leads a quiet life in North Carolina with her husband. “It is absolutely amazing that something that was such a big part of my life will be part of someone else’s life as well,” she says.

Bristol-Myers got other good news today: Its leukemia drug, Sprycel, now used in patients who have failed Novartis’s Gleevec, beat Gleevec in a big study [#msg-50942144]. The finding sets up a potential three-way marketing war between Gleevec, Sprycel and Novartis’s own second-generation leukemia drug, Tasigna. Tasigna is also presenting data at the meeting, showing it is better than Gleevec when used as initial treatment [#msg-50942189].


[SIDEBAR]

http://blogs.forbes.com/sciencebiz/2010/06/the-man-behind-bristols-bold-cancer-drug/

The Man Behind Bristol's Bold Cancer Drug

Bristol-Myers Squibb's new melanoma treatment could be the biggest win in cancer-drug development this year if results to be presented June 5 are positive. It could pave the way for a whole new type of medicine that fights cancer using the immune system. And it all tracks back to one researcher.

James Allison, a soft-spoken 61-year-old immunologist at Memorial Sloan-Kettering Cancer Center, is the man behind this approach. Twenty years ago at the University of California, Berkeley he chose to study how an obscure protein called CTLA4 impacted immune system cells. Most researchers at the time assumed that it helped activate the immune system. But he showed it did the opposite acting as a brake to prevent the immune system from running wild.

"As soon as I got the result, I had this idea that if we blocked it we could get enhanced immune response to tumors," says Allison. "The idea was that this could work for any type of cancer."

So Allison made an antibody to CTLA4 and had a trainee test it on cancer-ridden mice. The results were startling.

"We cured essentially all the mice in the first experiment. We went, "Wow, we have never done that before." The findings were published in Science. The approach was patented by the University of California and eventually licensed to the biotech firm Medarex, which made a human form of the CTLA4 antibody and brought it into trials. Medarex was bought by Bristol-Myers last year for $2.4 billion. Pfizer also is testing its own antibody against CTLA4, called tremelimumab.

Over the years, Allison went on to show how anti-CTLA4 drugs could work against numerous tumors in lab animals. It appears to be particularly effective when combined with radiation. The radiation kills some cancer cells and jump-starts and immune response, and the CTLA4 antibody keeps the immune response going and going. Still, skepticism about the approach persisted for years. "It was kind of mixed reaction. Some people thought immune-based therapies were useful, but others thought it was a pipe dream and it would never work."

One issue seen in early trials is the drug’s tendency to produce spectacular, long-lasting tumor shrinkage in a small minority of melanoma patients [see the photos in #msg-47415590], even as tumors don't shrink or keep growing in most patients. Some researchers have proposed there might be a genetic basis to this.

Allison thinks the explanation is far simpler. He likens giving the drug to removing the parking break on a car parked on a flat street. The immune system still needs a push to get it going, but once it gets going the drug assures a violent attack happens. "My feeling is you have to have some tumor destruction or inflammation when the antibody is there" in order to stimulate the immune system against the tumor. "That is not necessarily going on all the time. So you just give the drug a while and hope it happens."

He believes doctors will be able to get better results when they start combining immune-boosting agents. Other companies like Dendreon and GlaxoSmithKline are also working on immune boosters.

Allison will get some royalties from the University of California if the drug is approved. He says: "It feels good to have done something that actually helps people."‹