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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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March 10, 2011

Benlysta for Lupus

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Posted by Derek

Congratulations to Human Genome Science (and their partners, GSK) for getting the first new lupus drug in 50 years through to approval. It has not been an easy road for Benlysta (belimumab), to put it lightly. Back in 2005, for example, the drug missed its endpoints in Phase II, and things didn't look good.

Further work in the clinic did eventually show a benefit for the antibody, which goes after the B-lymphocyte stimulator protein. But it's not a home run. The FDA advisory committee cleared the drug, but expressed concerns about how effective it really is. The placebo response rate in the trials was rather high, reflecting the difficult clinical presentation of lupus, and that certainly cut into the significance of the final numbers.

But in the end, it does seem to help, and there's been nothing else for so long, and thus approval. How long did all this take? HGS announced that they were starting work in the area back in 2000, a different world compared to today (and especially for them; just look at the long-term stock charts). Did it cost $43 million to develop, as we've been assured is a good estimate for such things? Are you kidding?

Comments (21) + TrackBacks (0) | Category:


COMMENTS

1. Morten G on March 10, 2011 11:29 AM writes...

How does it compare to other strategies, such as cutting grains and dairy?

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2. anchor on March 10, 2011 12:16 PM writes...

Yearly cost for the administration of the drug/patient... upward of $30,000.

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3. Anonymous on March 10, 2011 12:22 PM writes...

This drug had marginal benefit in trials that were sponsored/controlled by a company with no products that was absolutely desperate for a drug. I think we can assume that they would do roughly ANYTHING to get this drug approved, so I think its safe to assume that this drug has ZERO efficacy.

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4. emjeff on March 10, 2011 12:58 PM writes...

#3: if you had lupus, I bet you would feel differently.

Why would anyone think that this drug is a "home run"? (whatever that means). Medicine progresses on incremental benefits. In cancer therapy, for example, you see incremental benefits of new therapies over old of 1-6 months and people scoff. But in 10 years, you have advanced the landscape significantly.

In the case of SLE, where therapy has been stuck in the 1950s, this is a real benefit. OK, it doesn't work in everyone, and there are some ethnic issues that need further exploration. But, if you hold out for a cure, you will be waiting a very long time...

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5. Anonymous on March 10, 2011 1:34 PM writes...

Wait, wait, wait. I read a Slate article just the other day that said there weren't any drugs in the pipeline. How can this be?

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6. Gregory House on March 10, 2011 7:20 PM writes...

It's not lupus.

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7. Forget About IT on March 11, 2011 6:58 AM writes...

@3 @5 @6 ... lets only make informed comments please

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8. Still Scared of Dinosaurs on March 11, 2011 8:09 AM writes...

SLE has messy, messy endpoints which tend to weaken the power to detect differences. Combined with a disease with few really good alternative therapies and you often get higher than expected placebo response rates.

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9. Anonymous on March 11, 2011 11:32 AM writes...

I stand by my educated guess that this drug has ZERO efficacy and the marginal positive data in the trial is based on data massage/maneuver. I do not trust these HGS guys - desperation makes companies act in untoward ways. I BET that when an academic-based clinical trial is done (ie. study design/data analysis not controlled by the company), the trial shows ZERO efficacy. When that happens, you guys will owe me $50.

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10. drug_hunter on March 11, 2011 12:09 PM writes...

#9 Anonymous - I think you're mostly right: my guess is that the academic trial will find that only a small subset of patients do significantly benefit, and eventually we'll figure out why (e.g. subtle differences in B-cell signaling or JAK/STAT signaling or whatever). And then do I get the $50?

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11. Anonymous on March 11, 2011 12:57 PM writes...

Ok, I'm a scientist and regulatory affairs professional but I'm going to put on my patient advocate hat on for this..........

If you have Lupus and are in that small subset where this drug has benefit then I would say who cares about the economic/marginal benefit arguement especially if there is a sub-group that benefits. Patients who do not have any viable treatment have something that may help and the benefit/risk profile is at the very least acceptable based on the current study design.

Discuss...............

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12. Anonymous on March 11, 2011 1:11 PM writes...

@11

If a drug appears to be no better than placebo, it is not possible to pull out a group of patients (say, white people, or whatever) and say that the drug was effective in this subset. One can generate a hypothesis this way and then test it in a later study. Retrospective grouping in this way is not scientifically meaningful, since it leads to the following types of conclusions - "Despite not showing statistically significant benefit in the study population as a whole, the drug showed clear efficacy in patients that lived on a street with the letter "p" in the street name." Such grouping may work out retrospectively, but will almost always fail prospectively. So, my argument is that statements to the effect of "While not showing statistically significant efficacy against the patient population as a whole, a fraction of patients did benefit" is marketing drivel, not science.

If I BELIEVED that the drug showed efficacy, I would be on board with it REGARDLESS of price. For me, its not cost/benefit. I simply believe there is no benefit FOR ANYONE.

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13. SteveH on March 11, 2011 2:00 PM writes...

@ #9 Anonymous - I'm confident the FDA's statistical analysis of the clinical trial data showed what was noted above - a weak but significant efficacy result (probably barely significant). I hope there wasn't any massage of the data, though it has happened in the past (I'm lookin' at YOU , GSK).

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14. Still Scared of Dinosaurs on March 11, 2011 10:58 PM writes...

An academic trial confirming the results of an industry sponsored trial is huge. Take that to the bank.

One failing to replicate the results by failing to show a treatment effect doesn't mean much to me. Way too many academics are way too bad at designing and running trials. In terms of quality of execution the 75th percentile for academics is about equal to the 25th for industry.

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15. Stan Dundon on March 12, 2011 1:06 AM writes...

What other autoimmune sufferers might benefit? Gillian-Barre, CIDP?

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16. Anonymous on March 12, 2011 8:45 AM writes...

DONT EVER GIVE LUPUS PATIENTS FALSE HOPE! MY ELDEST DAUGHTER SUFFERED FROM LUPUS AND WE WERE CLUTCHING AT EVERY STRAW THAT WAS HELD OUT TO US ( AT TIMES AGAINST THE ADVICE OF HER PHYSICIAN. BUT AS THEY SAY; HOPE SPRINGS ETERNAL..) THIS FALSE HOPE WOULD GIVE US A TREMENDOUS BOOST JUST TO LATER DROP US IN THE DARK DUNGEONS OF DISPEAR.IN THE END (ON 17 SEPT. 2007) SHE LOST HER BATTLE AGAINST THIS ILLNESS AND MY WORLD CAME TUMBLING DOWN.KNOWING WHAT SHE WENT THROUGH, I ALWAYS HOPE AND PRAY THAT A CURE FOR LUPUS WILL BE FOUND.I WAS EXTREMELY HAPPY WHEN I HEARD THAT A CURE (BELYSTA) HAD BEEN FOUND.HOW DISAPPOINTING TO READ THAT; IT COULD ...IT MAY NOT... IT IS FOR ECONOMIC REASONS ONLY.

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17. Cellbio on March 13, 2011 11:09 AM writes...

Regarding responding subsets, isn't it just as likely the small delta over placebo is due to small but measurable differences in almost every treated patient, or isn't this more likely? I just finished a clinical trial biomarker discovery project where every single person involved spoke of the "responding subpopulation". I plotted the distribution of response, which illustrated that there is not an outlier group in the treated arms that pulls the mean or median towards response. Additionally, the tail of best response was made up of placebo treated individuals. Despite this, we aimed to discover biomarkers associated with response, that yes, more likely than not, will fail in a prospective analysis. Does anyone have insight into the distribution of response to Benlysta? A slightly shifted distribution can produce a statistically significant difference in mean disease score, but not much of reason for hope. However, if the disease score moves a bit, then maybe combo therapy is the next question to explore.

L. Jacobs. My sympathies. Most every drug discovery scientist I know is sincerely motivated by the real life pain and suffering that your daughter and your family have been through. Glad you are here on this blog, where truer words will be spoken than the news media and corporate hype which does serve to amplify potential benefits.

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18. Still Scared of Dinosaurs on March 15, 2011 8:34 AM writes...

Cellbio - very good questions. I'm guessing that if there aren't rumors of some magic subset out there they don't have much to go on.

From Derek's summary the trials showed higher than expected placebo response. That usually means that there is a lot more noise in the system than the trials were designed to handle. This leads me to believe that before I would chase subsets I would try to figure out how to tighten up the execution of the trial, restrict the trials to the right severity of disease, determine the right time points for analysis, etc., while measuring the potential biomarkers as accurately as possible. If you feel really confident about subsets you can stratify on them but I would not place my bets there yet.

Of course, an alternative for Benlysta is to say, "Hey, we've got an approval. Let the market figure out how to use it." Kind of depends on how much cash they have on hand to run trials.

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19. Cellbio on March 15, 2011 11:31 PM writes...

Still Scared,

I haven't been involved with a Lupus trial, but two other diseases with scoring systems that aggregate hard measures, like CRP levels, with soft measures, like a patient reported measures of disease severity (drawing a line across a line along a 10cm line indicating level of discomfort). With these, there is a lot of Placebo score to overcome with treatment. I just looked at data from one trial and split N Amer. and European sites, and saw significant placebo rate differences, amounting to half the magnitude of treatment effect. Trial site variance is another contributor to noise, and with more competition, trials are spread out in many more regions and sites. This trial I worked on had more trial sites than treated patients. Many failed to recruit a single patient, some recruited one or two, some 5-10.

Trial data variability is tough to control, but as you say, key before looking for other quick fixes.

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20. German on March 17, 2011 5:11 PM writes...

Thank God for this New Drug people who have Lupus like my self can probadly benfit from this drug.
There is still more out there like Stem cells, that can help other diseases to.

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21. Still Scared of Dinosaurs on March 19, 2011 4:29 PM writes...

Cellbio,

Personally the line crossing a line or Visual Analog(ue) Scale (VAS) doesnt't bug me that much because the numbers behave reasonably well. You want to see a horror show look at the EDSS, the standard measurement in MS. It's so bad you can't even define it algorithmically - there's always room for the MD to fudge it up or down half a point (on a 0-10 scale).

And lest we forget messay measures mean variable data which mean more patients which mean more time and money. But since everyone studying MS uses the same tool we're stuck with it.

But even with a perfect measure most chronic conditions should have a substantial placebo response as so many of them wax and wane. You just want more waners in the group receiving your treatment.

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