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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

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« We Won't Stay Off The Radar Screen For Long, Y'Know | Main | Roche / Genentech: So There is a Deadline »

February 9, 2009

Maribavir, Ouch

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Posted by Derek

Viropharma has announced that their Phase III trial of maribavir, a compound targeting cytomegalovirus, failed big-time. Well, they didn't used the term "big-time", but they might as well have. The treatment group (patients with recent bone marrow transplants) showed no difference in CMV infection rates compared to placebo. This is especially disappointing, considering that the compound looked pretty good in Phase II. That's a useful lesson in the difference between Phase II and the real world.

The company has been through this before. Back in the late 1990s, they were working on another antiviral, Pleconaril, that in those heady days caused their stock to shoot up well over $50/share. Some people had gotten it into their heads that the stuff was going to cure the common cold and who knows what else besides. In the spring of 2000, the bad news came in that the drug would do nothing of the kind. I was short the stock at that point, and I've long wished that I had a videotape of me trying to call my broker after I saw the stock quote that morning. I kept missing the buttons on the phone; it was pretty entertaining.

Maribavir isn't one of VPHM's own creations, actually - they licensed it from GSK, and it's a good ol' nucleoside analog in the tradition of many antivirals. But that's a tough area to work in, and today's bad news is just more proof.

Comments (12) + TrackBacks (0) | Category: Clinical Trials | Infectious Diseases


COMMENTS

1. HelicalZz on February 9, 2009 2:08 PM writes...

Was there supposed to be a URL linked at the end?

Zz

Permalink to Comment

2. Hap on February 9, 2009 3:39 PM writes...

1) Wouldn't have being short on Viropharma at that point be a good thing?

2) Why do Phase II trials differ so significantly from Phase III trials?

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3. Anonymous on February 9, 2009 4:18 PM writes...

Hap,

I think he means that he wanted to call his broker to buy back stock to complete the short before the stock price jumped back up.

As for II vs III. Phase II can be more of a case study type thing with a selected patient group (in this case it seems the selected group responded well.) But phase III trials are randomized patient populations. You could select in II the 10% population the drug works on and in phase III you get all cases so the drug only shows 10% effectiveness. Mind that some phase II trails have been set up with more randomized patient populations and in these cases II and III do closely mirror one another.

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4. Anonymous on February 9, 2009 5:34 PM writes...

#3: Could you explain if it is possible to select the same population for both phase II and III?

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5. #3 on February 9, 2009 7:49 PM writes...

#4

(disclaimer:i've never worked on the side of the industry that actually picks the trial population so someone correct me if I'm wrong here)

Usually phase II is a smaller trial 30-500 ppl, phase III is 300-5000. Phase II generally tries to show crude effectiveness and refine dosage. Phase III is a broader study and tries to mimic the effectiveness against general patient population. So..they could have they could have the same population if both phases are random samples. If I'm treating disease X with types A,B and C, B of which being the most common form and C is most deadly.
case 1: Phase II as disease X type B, phase III type ABC. (different populations-sameish outcome since type B is the majority)
case 2: Phase II type ABC. phase III type ABC (same populations-same outcome)
but you can imagine case 3: Phase II disease X type C (10% of population but the most difficult to treat one, so if it works here it should work against other 2) Phase III all types. But oh no my drug only works on type C. So in phase III you only show efficacy among 10% of the population.

Again I'm only stating possibilities here. Hope that clarifies.

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6. Anonymous on February 9, 2009 8:58 PM writes...

Thank you very much for the clarification.

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7. pfizerite on February 10, 2009 1:46 AM writes...

Another problem with cerry picking your phase III study would be that the drug would be label only for those patients showing the same genotype or conditions as the selected population.

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8. MTK on February 10, 2009 9:47 AM writes...

#3. randomized only means that the patients recruited and accepted in the trial are randomized into the appropriate arms of the study, not that patients are chosen for the study at random. All trials, no matter the phase, have predefined patient populations. Those populations are set by what type of labeling you are trying to support.

The important thing to remember is that first the market and labeling goal is determined, then the trial is designed and executed. A development plan strategy is generally formulated backwards, much like a retrosynthetic analysis.

a) What is the market we are aiming for?
b) What is the labeling we need to obtain?
c) What is the Phase III study we need to support that labeling?
d) What are the go/no go criteria in determining whether we should go forward to Phase III?
e) What are the Phase II studies needed to answer the go/no go criteria?
f) etc.

You get the point.

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9. sceptical on February 16, 2009 1:42 PM writes...

The phase II “looked pretty good” is a fair comment. They showed the drug was active not effective. They did this using prevention of CMV infection at 100 days as the primary endpoint (CMV pp65 antigenemia) in a study of just over 100 patients. There was no clear dose response nor do they appear to know what plasma level of drug is effective. There were just 3 cases of CMV disease. All were in the placebo group but because of the sample size the difference was not significant. They then initiate a phase III study using what they think is the best dose and change the primary endpoint to CMV disease. This is an important end point, as disease may well lead to graft failure. However, the drug had not shown any benefit over placebo in disease prevention in phase II. Going to phase III with uncertainty over the dose and changing the end point is always risky. Sometimes you win but more often you lose.

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10. regroupement credit on September 4, 2011 10:13 PM writes...

great article, thank you for this information.

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11. Jaye Clauss on December 28, 2011 5:42 PM writes...

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12. Stanley on February 27, 2013 12:39 AM writes...

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