Drug Baron

March 3, 2014
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Medicalizing biomarkers – the sure-fire road to commercial success

Creating new drugs is a process fraught with risk.   The risk involved with discovery and early development is obvious, but increasingly the greatest risk lies at the very end of the process: winning a decent market for your approved product.

But history teaches us there is a sure-fire trick to eliminate a large portion of both the technical and commercial risk from drug development.  A trick that has arguably yielded more blockbusters than any other approach: medicalizing biomarkers.

For sure, only a handful of biomarkers have undergone this transition – from something diagnostic to a target for intervention – but those that have, have yielded eye-watering drug sales.  Drugs to treat elevated LDL-cholesterol (such as Lipitor™ atorvastatin), elevated blood pressure (such as Diovan™ valsartan and other angiotensin receptor antagonists) or elevated fasting glucose (such as insulin and more recently GLP-1 agonists) have garnered countless billions in sales over the last two decades.

The industry will always push the boundaries to justify adoption of new biomarkers as therapeutic targets in their own right

The reason for their success is obvious: unlike complex disease phenotypes, its trivial (and usually very cheap) to identify the significant portion of the population with the elevated biomarker.  Its also straightforward to demonstrate, during clinical development, the impact of the treatment on the biomarker.  So the development risks are much lower than for drugs where unambiguous demonstration of impact on a complex clinical phenotype is required.

And the commercial risk is lower too.  Provided the link between the biomarker and disease is well-accepted, medical practioners, payers and patients alike are keen to embrace prevention rather than treatment when the disease itself manifests (perhaps much) later.

To the chagrin of the pharmaceutical industry, there are but a handful of such mother lodes to mine.  Hypercholesterolemia, hypertension and hyperglycemia are the only diagnostic measures that are universally accepted to justify intervention in the absence of any clinical symptoms.

Not surprisingly, therefore, we see a drive from the industry to expand the list – with elevated triglycerides and low testosterone in the vanguard.  After all, once regulators, doctors or even patients can be persuaded that a new biomarker requires treatment in the absence of symptoms, it would open up a brand new treasure chest.

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February 11, 2014
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The all new, good old-fashioned, solution to the “replication crisis” in science

As the number of reports highlighting the difficulty replicating academic studies proliferate, the clamour for better frameworks to ensure the repeatability of published science is becoming deafening.

But is replication the incomparable paragon it is held up to be? Should the scientific community be wasting resources doing the same things over and over again, rather than exploring new avenues?

At first sight, it seems obvious that shoring up important conclusions by independent replication is a good thing.  After all, if (for example) costly drug development activities are initiated on the basis of flawed experimental data, then the investment will be wasted.

But there is a problem with replication.  When the first two attempts at the same experiment yield different results, who was correct?  Without a large number of replicates, the true answer remains unknown.  And there is also an alternative approach: weight-of-evidence.  By looking at related questions, its possible to determine how likely the original experimental result is to be accurate.

Seeking consistency with neighbouring questions, rather than strict replication, has another important advantage too: it tests whether an observation is generalizable rather than simply true.  If a finding applies only under the strict conditions of the original experiment, it is very unlikely to be a useful conclusion at all.

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January 23, 2014
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Even odds-on favourites can lose: lessons from the Prosensa story

With the details from the DEMAND-III study, the full extent of the failure of Prosensa’s exon-skipping drug drisapersen to arrest progression of Duchenne Muscular Dystrophy (DMD) has become clear.

There are few grounds for optimism among the plethora of secondary end-points, no trends, not even a statistically significant post hoc sub-group analysis.  Only pages and pages of convincingly negative data.

While its obviously a relief that concerns about liver toxicities proved unfounded – the treatment was very safe – the safety profile is unlikely to be much consolation for such a convincing lack of efficacy.

But clear-cut as the data is, it leaves one very important question entirely unanswered: was the failure due to insufficient dystrophin production, or – more worryingly – because successfully elevating dystrophin is much less effective than has been assumed?

There are also lessons to be learned beyond DMD: the infinite subtlety of biology means that no phase 3 study is a “slam dunk” – failure lurks round every corner, even in the most unexpected of places.  Public market investors, in particular, can pump up asset valuations on an over-optimistic assessment of early clinical data (as the recent Intercept episode illustrates).  The chastening experience at Prosensa should serve as a warning that translating promise and potential into regulatory approval and sales is often more difficult than it first appears.

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