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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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March 28, 2005

Targretin's Troubles

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Posted by Derek

More pre-ASCO-meeting oncology trial news, this time from Ligand: their Targretin (bexarotene) failed all its endpoints for lung cancer. Two Phase III trials both came up empty for a survival benefit, sending the stock down a good 25% or so. (As you can imagine from that cliff dive, Targretin is a big part of Ligand's fortunes.)

And it must have been a rough place to work for the last year or so. Last spring, the mood was a lot more festive - see this story from the San Diego media. Let's take a painful trip back in the time machine:

"Three separate studies showed that combining Ligand's Targretin with the widely used Taxol (paclitaxel) prevented or reversed acquired tumor cell resistance to Taxol in non-small cell lung cancer (NSCLC) and advanced human breast cancer cell lines. . .In the Ligand studies of NSCLC and breast cancer cell lines, when Targretin was combined or used concurrently with the chemotherapy, it resulted in superior reduction of tumor growth than did chemotherapy alone. . .Earlier this month, the biotechnology firm reported its first quarterly profit ever. Ligand shares (Nasdaq: LGND) gained $1.40, or 7.3 percent, to close at $20.56 today after notching a 52-week high of $20.85 during intraday trading. The firm has a market cap of $1.51 billion. Trading was heavy, nearly triple the average daily volume of 1.5 million shares. The stock has more than tripled in price in the past year, after hitting a 52-week low of $6.20 on March 31, 2003."

Contrast that to the company's home page today, whose downer headlines are "Targretin Fails to Meet Primary or Secondary Endpoints in Pivotal Trials" and "Ligand Announces Delay in Filing of 10-K". And the stock has round-tripped back to the six-dollar price. How did this happen?

Well, Targretin an interesting and risky drug, in an interesting and risky therapeutic area. It's an activator of the RXR nuclear receptor, which is at a huge multilane intersection (PDF file) of gene expression pathways. I've worked in this area myself, and it's an exciting mess. There are surely thousands of genes whose expression levels can be sent up or down by changes in RXR, and it's a safe bet that we don't know what many of them are. While we're at it, it's a safe bet that we don't understand a lot of crucial things even about the ones we've heard of. It's a real monkeywrench of a drug, which puts it in the same position as many other oncology therapies.

The drug was approved several years ago as a second-line therapy for small indications like cutaneous T-cell lymphoma, and since then Ligand has been trying to break it through into the larger markets like lung cancer. They still have a number of other combination trials going on, as they should, but these results have to hurt. In today's press release, you find only the echoes of last spring, phrased in the saddest verb tense there is:

"The initial daily dose of Targretin in both trials was similar to that used in prior phase II studies in which a positive trend in survival had been observed. . ."

Comments (1) + TrackBacks (0) | Category: Cancer


1. jim h on March 29, 2005 1:40 PM writes...

Any thoughts on whether this week's (and last week's) oral cancer drug failures are due to variability in PK? A small Tarceva clinical study showed 30-fold variability in AUC, so the true population number is probably 60-70 fold. As we know, that drug barely squeeks by, and having patients that get no exposure is not good for the efficacy tally.

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