Drug Baron

February 19, 2012
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Avoiding the pain of the not-so-mystical placebo effect with the almost-magical run-in period

Nothing kills biotech companies like an active placebo.  More often than not the press release after a failed trial points the finger at a “surprisingly large placebo response” against which the active drug had little scope to excel.

It’s easy to assume that this placebo effect has its origins in some almost mystical neuropharmacology, where simply believing you are being treated with a powerful new drug is sufficient to induce a miraculous recovery – and as a result that there is little you can do to mitigate against the effect.

But in reality by far the largest proportion of the placebo effect originates from the design of our clinical trials, and can be readily neutralised by careful adherence to a few simple principles.  The first step to eliminating the avoidable failure that comes from high placebo response rates is to recognise that it’s not in the lap of the gods – but in the hands of your Chief Medical Officer.   All you need is the almost-magical power of a run-in period.

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January 30, 2012
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Targeting tumour metabolism: the next land grab?

The sale of Avila to Celgene may mark the pinnacle of the market for kinase inhibitors in cancer.  Where might early stage drug discoverers in cancer start looking now if they want to create successes like Avila in five to eight years time?

Excitement for different kinds of therapeutic target in cancer goes in waves – and with cancer by far and away the leading indication for biotechs (judged by the number of molecules in development), predicting the “next big thing” is an important and valuable skill for early stage investors. What comes next after kinase inhibitors and epigenetic modulators?

With anti-infectives, all therapeutic strategies rely, in some way or another, on exploiting the (often subtle) differences between pathogen and host.  So too with cancer – only the differences tend to be an order of magnitude smaller.   It has been known for a long time that different metabolic pathways dominate in cancer cells, but recent research has focused on a couple of key metabolic “switches” that might be different enough from normal cells to represent viable therapeutic targets.

Will these metabolic switches prove to be effective new targets, particularly in combination with other strategies that deprive tumours of their blood supply and so make them more reliant on anaerobic metabolism?  Its too early to tell, but the science has moved far enough forward now to make it worth renting a few square metres of this virgin new territory just in case metabolic inhibitors become the focus of the next big “land grab” in cancer.

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January 23, 2012
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Merck’s $800M bet on Sir Austin Bradford Hill

Why Merck’s CETP Inhibitor programme is such a huge gamble – and why DrugBaron fears the odds are stacked against them.

Few programmes in the pharmaceutical industry were born with such optimism as the search for CETP inhibitors.  Decades of epidemiology had already pointed to the importance of HDL-cholesterol (the so-called “good cholesterol”) as a predictor of future risk of heart disease, but no-one really knew how they might raise HDL with a drug.  That changed in 1990, with a New England Journal of Medicine paper describing a Japanese family with a mutation in the CETP gene that abolished CETP expression and dramatically raised HDL.

Despite challenges finding a CETP inhibitor, Pfizer eventually got a CETP inhibitor, torcetrapib, into the clinic and the results were astounding: not only was HDL-cholesterol doubled, but LDL-cholesterol (the “bad cholesterol” lowered by statins) was reduced.  Against this background, the dramatic failure of the resulting Phase III trial of torcetrapib in 2006 hit the cardiovascular field like an earthquake.   Not only was torcetrapib ineffective, it actually increased heart attacks and strokes.

After years of soul-searching, Merck, who were following behind with anacetrapib, decided to continue development.  Their assessment was simple: the rationale for HDL elevation was so good that their had to be another explanation for the failure of torcetrapib.  That something, perhaps, was the hypertensive effect of the Pfizer molecule that wasn’t a class-wide liability.   Since hypertension is associated with increased risk of cardiovascular events, surely their clean CETP Inhibitor would reveal the benefits of HDL elevation?

The Phase 3 trials are running now to answer the question.  DrugBaron, though, predicts more disappointment when the final results are published.

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