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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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

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June 8, 2010

Ipilimumab (And Progress Against Cancer)

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Posted by Derek

This time last year, Medarex made all sorts of headlines with their antibody ipilimumab. A press release from the Mayo Clinic made it sound like a miracle cure for prostate cancer; the company's stock soared, and they were acquired not long afterwards by Bristol-Myers Squibb. I wrote about ipilimumab once, and I still get email from people asking me if I know how they can possibly get some for their relatives with cancer.

As Jim Edwards points out at Bnet, though, this week's ASCO meeting has results for the drug that are more in keeping with what we've come to expect. The antibody had real effects in metastatic melanoma patients, and that's a good thing, because that's a particularly hard situation to show anything useful. (And all too many melanoma patients present after the disease has already gone metastatic, for that matter). From the data that BMS presented, there appears to be no doubt that ipilimumab extended survival.

But it did so by three or four months, on average, with some serious adverse events in the treatment group. As I said yesterday, this is the sort of progress that we generally make in oncology, not the oh-my-God-the-cancer-disappeared sort that last year's press release had people thinking about. And again, you can look at this news in two different ways. On the one hand, showing real statistical efficacy against metastatic melanoma is impressive: pretty much everything else we've got does nothing at all. But on the other hand, well. . .three and a half months.

For some people, that's definitely going to be worth it, while for others, they (and their heirs) would be better off not spending the money. That's a very hard decision, one of the hardest, but it is a decision. And either people will make it for themselves, or someone will make it for them. Given the continued emphasis on bringing down the costs of modern medical care - which doesn't look to be going away any time soon - you have to expect that there will be times that governments and/or insurance carriers will say "No, not for that price." Expect? It already happens. But it'll happen more.

This does present a problem for drug discovery. As many commenters noted yesterday, these are the sorts of incremental improvements that can add up in oncology. We're unlikely to hit many miracle-cure home runs, so we have to add a few months here and a few months there, learning as we go, and coming back around with better ideas next time. This takes money - big stacks of it - and we in the industry are expecting people (and their insurance companies, and their governments) to pay up. What if they don't, or not so much?

One thing we could see is companies finding themselves caught out, developing drugs in anticipation of a pricing structure that won't materialize. And it's true that strong pricing pressure will likely slow down progress in the whole field - after all, we don't have any other cheaper ways to develop drugs yet. But that doesn't mean that it couldn't happen. If we want to forestall it, I think we should make clear how incremental and expensive most oncology work is likely to be, and to point out that if there are miracle cures out there, that we're probably not going to find any of them without going through a lot of not-so-miraculous ones first.

Comments (21) + TrackBacks (0) | Category: Cancer | Drug Prices


COMMENTS

1. Anonymous on June 8, 2010 7:29 AM writes...

ipilimumab

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2. Anon on June 8, 2010 7:32 AM writes...

ipilimumab

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3. john on June 8, 2010 7:47 AM writes...

Derek, the design of this trial was a little unusual, in that they used no placebo group. The arms were gp100, gp100+iplimumab, and iplimumab alone. Gp100 is apparently a melanoma antigen that has been used as an experimental vaccine.

A lot of the current thinking in the cancer vaccine area seems to be that the reason most vaccines have not worked is local immune suppression in the vicinity of the tumor. According to this line of reasoning, coadministration of compounds like iplimumab should eliminate this local immune suppression and provide activity.

I think this trial was planned around the idea that iplimumab+gp100 would be a "home run". Instead they ended up with iplimumab alone giving results similar to the combination, and gp100 alone giving results that were arguably worse than those obtained historically with placebo.

So they have a funny set of data to try to interpret. Furthermore, the failure of the iplimumab+gp100 to give better results than iplimumab alone seems to me to be a setback for the whole area of cancer vaccines. Maybe someone with knowledge of this area can comment on this?

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4. john on June 8, 2010 7:49 AM writes...

Oops, I got the name wrong too.

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5. partial agonist on June 8, 2010 8:02 AM writes...

Annon, for ethical reasons pII cancer trials typically have no true placebo group- there is a standard-of-care group. If (as is typical) the test drug is tried as an add-on to an approved therapy, the study arms are approved therapy+test drug and approved therapy (or approved therapies).

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6. partial agonist on June 8, 2010 8:07 AM writes...

Annon, for ethical reasons pII cancer trials typically have no true placebo group- there is a standard-of-care group. If (as is typical) the test drug is tried as an add-on to an approved therapy, the study arms are approved therapy+test drug and approved therapy (or approved therapies).

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7. John on June 8, 2010 8:08 AM writes...

PA, I understand but according to the WSJ article there is no standard of care for late stage melanoma, or at least not one containing gp100.

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8. nucleotide on June 8, 2010 8:15 AM writes...

Tough loss Derek, giving up seven runs in four innings against the D-backs last night...

Maybe you be a reliever in the bullpen instead of a start while working on your blog entries about the trends in the pharmaceutical industry.

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9. RandDChemist on June 8, 2010 9:41 AM writes...

#6 Not sure if it matters, but it was phase III. And the nature of the "placebo" was noted as odd in a few of the reports.

The NYT pieces that was posted a little while ago talks about a few months here and a few months there adding up, at least potentially if more treatments arise.

So a question is, are you buying time, or delaying the inevitable?

One of the issues noted in oncology in a Newsweek feature (from several months ago) on why there has not been better progress is that researchers who get funded are the ones looking for the home runs. Not the singles. The "sexy" science gets funded.

Progress is usually incremental. It's usually not pretty. It's not what anyone wants for cancer treatment, but it is reality.

The echo chambers around the so-called "death panels" seriously damaged a much-needed discussion in the US around end-of-life decisions. If people had good, honest discussions with caregivers, then they have a better opportunity to make sensible decisions that enhance their quality of life. Pallative care was set back by the rhetoric.

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10. Anonymous on June 8, 2010 11:12 AM writes...

Like most other emerging oncology drugs it's a matter of identifying likely responders with a good biomarker. Unfortunately, there are not yet any clear biomarkers of likely response with this antibody. Find one and you'll see a significantly higher EFS rate in a subset of patients and you can spare those that won't benefit (and the overall cost burden to healthcare).

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11. Nathan on June 8, 2010 12:39 PM writes...

Derek,
Sorry if this was pointed out already in the previous discussion, but it MUST be remembered that the 3-4 month life extension observed for many of these drugs is the MEDIAN life extension. A small number of patients go into full remission and continue living for many years. THIS is the bet that people are taking when they pay lots of money -- they aren't hoping to be the "median" patient. They are hoping to be the "top 10% responding" patient.

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12. Alex on June 8, 2010 1:53 PM writes...

@Nathan:
That is exactly the thought I also had. In the same vein, I'd be very interested in the standard deviation for those few months.

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13. barry on June 8, 2010 2:35 PM writes...

Roy Vagelos (formerly head of Merck Research) spoke at a med. chem. conference in 2005. He's no fan of governmental regulation, but it was clear to him that if Pharma focuses on hugely expensive treatments that deliver only modest extensions in the time spent dying, Congress will feel forced to act.
Our current profit-driven Pharma industry has delivered some great successes over the past century. With scant exceptions (gleevec*...) they emerged because the guys in the suits thought that the research would eventually/occasionally produce a profitable product. That profit depends critically on what the patients and the the insurers will pay. If we get real Health Care reform in this country some day, we may find that that limit excludes a lot of potential drugs (mAbs?) with high cost-of-goods.
Barry

*Gleevec has the distinction of keeping its "orphan drug" status even as it became a billion-dollar-a-year seller for Novartis, but the clinical trial were undertaken with the expectation that the CML patients could never pay back the costs

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14. John on June 8, 2010 3:57 PM writes...

Nathan and Alex, the prescribing info for most anticancer drugs include Kaplan-Meier curves that bear on your question. If you take a look at the sheet for Gemzar, for example, you get the impression that there may be a slight increase in the number of long term survivors of NSCLC, as indicated by a flattening of the curve at 24 months of observation. Unfortunately, this does not seem to be the case for ovarian or pancreatic cancer. Unfortunately,most trials do not seem to follow the patients out long enough to address this question with any real certainty.

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15. Jonadab the Unsightly One on June 8, 2010 5:29 PM writes...

Three and a half months might be viewed as a worthwhile, if disappointing, prognosis improvement, at least for people with bags of money to burn, if the side effects were livable...

But you said "some serious adverse events in the treatment group". That would be moderately scary wording anyhow, but in the context of cancer treatments in particular, where the bar for side effects is so high, it conjures up positively horrifying visions of miserable patients pleading and begging (with the doctors and/or their family) to have the treatment discontinued.

I could see putting up with "serious adverse events" if it introduced the possibility of long-term remission, but for an extra three or four months? Even if the drug were free, that seems like a pretty lousy deal to me. Are people really that desperate to prolong the inevitable even for just a few more weeks?

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16. Fabien on June 8, 2010 6:40 PM writes...

Can we find a middle ground here with Pharma getting full price for 10-12 years and then generics/biogenerics being discounted 80-90% vs the original drug?

Modifying laws to favor the rapid introduction of generics and biogenerics could ease a lot of the pricing pressure while making innovation worthwhile... Win-win, no?

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17. Anonymous on June 8, 2010 7:29 PM writes...

To Nathan's point: A video highlighting a couple of excellent outcomes.

http://www.hulu.com/watch/154618/nbc-nightly-news-with-brian-williams-new-drugs-offer-hope-for-battling-cancer

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18. dvrvm on June 9, 2010 11:02 PM writes...

@Fabien: how so? How will less time to make money on a drug for a big company make innovation worthwhile?

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19. Andrew Johnson on March 1, 2012 2:09 PM writes...

I have CRPC metastatic disease and am non-symptomatic. I received two infusions of Ipilumimab in a double blind Phase III trial. The first treatment had no effect. My PSA went from 16 to 25. After the second infusion, I experienced unrelenting severe headache within a day that lasted a couple of weeks with no relief until treated with a strong dose of prednisone. The headache went away but a month later I was hit by extreme (and I mean extreme) diarrhea that lasted a couple of months until successfully treated by a GI doc. I also felt a general feeling of malaise that lasted about two months. However my PSA went to less than .1 and has stayed there for the last 4 months. A bone scan showed a large decrease in activity consistent with the drop in PSA.
I feel great now so I think it was worth it, though I didn't feel that way when I felt so bad.

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