Worse Than Useless

About: AbbVie Inc. (ABBV)
by: Derek Lowe

Time for another look at AbbVie's (NYSE:ABBV) work on Rova-T (an antibody-drug conjugate targeting the tumor antigen DLL3), and for some hard thoughts about what drug development is really like. The last time I wrote about this program, things didn't look good. Now they look even worse. A Phase III trial of the drug has been halted because the treatment group is showing higher mortality than the standard-of-care control group.

AbbVie bought Stemcentrx for nearly six billion dollars (cash, not biobucks!) in a deal that I characterized as "either very smart or very stupid" in order to get their hands on this therapy and its follow-ups, and right now it looks like that entire investment is in danger of being a lost cause that will never be recovered. But let's step into the time machine. We don't have to charge up the batteries very much, because we're just going to go back to 2015. That's when the first clinical results for Rova-T were reported. The paper called it a "promising first-in-class" treatment. Now we move up to 2016, and trial results in small-cell lung cancer. That was not as impressive a showing, but still characterized as "encouraging", with "manageable toxicity". If you go back to March of this year, the further results made it look like the compound was, at best, only about as good as the standard of care, and a vast amount of money was trimmed off AbbVie's market capitalization. In June, the company presented an even more thorough look at the data, which made the entire program look like it wasn't even as good as currently available therapies, and thus nearly pointless.

And now it's gone past pointless to dangerous. This drug has, within the space of three years, gone from looking as if it would save lives to being statistically proven to accelerate death. And here's the key thing to realize: this is not some weird outlier. Sure, AbbVie paid a lot of money for this, and they probably should have waited to see some more clinical data before jumping in. And sure, Stemcentrx has the whole Peter-Thiel-Silicon-Valley history behind it. And it's also tied into the whole complicated story of cancer stem cells. But those (interesting as they are by themselves) are honestly side issues, and they don't really have that much to do with the clinical success of Rova-T. This story is not worth paying attention to because it's so different - it's worth paying attention to because it happens all the damn time.

It really does. It's a constant feature of drug development that things look much better in the earlier trials than the later ones. That's because the early trials involve carefully selected patients, but it's especially because the early trials are very small. Unless you're dealing with a massive, epochal throw-away-your-crutches effect size, human biology is complex enough to make small trials only very crude indicators. Signs of success are only that - signs. You need to go into more patients, of more varied types and in more varied situations, more times. Every time. There is no substitute for large, well-controlled, well-designed human trials. No one likes to hear that, because everyone's heard it before, and because it's not exciting and new and holds out no promise for huge accelerated money-saving breakthroughs. But it's true.

If you're a biopharma investor, you need to constantly remind yourself of that. If you're a reporter, you need to do the same. And if you're a potential patient waiting on such a new therapy, it's very hard news to be reminded of this, but reality is preferable and this is reality. In the clinic, most drugs fail. They don't all fail in the brutal Greek-tragedy way that Rova-T is failing, but most drugs fail.

And finally, if you're an advocate for getting the FDA out of the way by whatever way you want to call it, because you're convinced that it's some sort of big slow roadblock to life-saving drugs reaching needy patients, I have something to say to you: Rova-T. It was new, it was promising, it was exciting, it was first-in-class, its toxicity was manageable, its early results were compelling, and a big drug company thought it was worth six billion dollars in cash upfront. You would have given it to all those needy patients right then, back in 2016. Wouldn't you? And killed them faster.

Disclosure: None