Drug Baron

December 4, 2012
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What price an orphan this Christmas?

Tiny Tim wasn’t the only orphan to suffer a miserable Christmas at the hands of a merciless Scrooge.  The same fate awaits so-called orphan disease patients in the UK.  This year, it’s the turn of around 400 cystic fibrosis patients, who cannot access newly-approved Kalydeco on the supposedly comprehensive National Health Service (NHS).

Its easy to imagine the sadness of children from poor families pressing their nose against the glass of the toy shop window decked out with dazzling presents for Christmas, knowing these delights will be denied them but not their school friends.  How much worse must it be knowing there is a drug that could dramatically reverse your chronic illness, but being told you cannot have any?

Yet that is exactly what is happening, not for the poor children on the block but in the world’s seventh largest economy.

On the face of it, the cause of this wholly unacceptable state of affairs is the ‘scandal’ of drug pricing.  Vertex, makers of Kalydeco, want $294,000 for a year’s treatment.

“Can it be right for the NHS to offer free IVF to infertile couples while denying Kalydeco to CF sufferers?” @sciencescanner on Twitter

But actually, the ultimate cause is the myth we (in the UK) continue to perpetuate that its possible to offer comprehensive healthcare to all, free at the point of use.  While the development of new drugs is funded almost entirely with private capital, yet healthcare is delivered from the public purse there will always be a mismatch – with companies developing drugs no-one can afford to use.

What is urgently needed is a proper debate about healthcare priorities – a debate that is stifled by the increasingly hollow assertion that the state can cover all your healthcare needs.

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November 27, 2012
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Healthcare-omics: why we should close down every angiography suite and hand out free statins to everyone

Billions are spent discovering new medicines every year – even with the knowledge that most projects (and even many vastly expensive Phase 3 trials) will fail.  But the aim is noble, the prize for success high, and despite debatable return on capital, pharmaceutical R&D has grown exponentially over the last three decades.

The presumption behind this is that we need new medicines to improve clinical outcomes for patients.  This, in turn, assumes that we make something approaching the best use of the medicine cabinet we already have.

Is there any evidence that we do that?  After all, clinical trial evidence addresses only very narrow questions – did a particular group of patients do better when treated with a drug compared to standard of care, for example.  But that provides no information about whether the group that should receive the drug should be bigger, smaller or altogether different, either from a clinical outcome perspective or a cost-effectiveness perspective.

Even the added layer of cost-effectiveness assessment added by bodies such as NICE and IQWIG in Europe or the payors in the US asks a broader question only in so far as it compares different medicines with the focus on cost to benefit, but it can still only work with the available clinical trial evidence.

The problem is simple: complexity.  Treating any disease is a complex process.  And complex means more than just difficult to understand: complex is also a technical term for a system whose behavior cannot be predicted from the behavior of its sub-processes.  In other words, you cannot work out the best way to treat people with a particular disease by optimizing individually the diagnostic and therapeutic components of that treatment.

Put simply, the reductionist approach of clinical trials means we have, for the most part, no idea how efficiently we use the medicines we already have.

“There is a presumption that no ‘mere mathematician’ armed with the same computer models that revolutionized financial markets and manufacturing industries alike could possibly know better than even a humble primary care physician as to how to treat your grandmother”

And when we dig a little deeper, the information that is available suggests precisely the opposite.  That we are strikingly inefficient at using the tools available today from both and outcome and cost perspective.

DrugBaron draws a parallel between the complexity of the human organism and that of the healthcare system, and asks whether the tools of systems biology could and should be applied to healthcare delivery.  The results from such a paradigm shift could be dramatically improved clinical outcomes from a lower healthcare spend – something new research consistently has failed to deliver.

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October 29, 2012
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Bardoxolone and BG-12: A Tale of Two CITIEs (Covalently-Interacting Therapeutic IntErventions!)

Until 18th October, bardoxolone methyl (Abbott/Reata) and BG-12 (Biogen) had two things in common: the nrf2 transcription factor complex as their molecular target; and their candidacy for blockbuster status.

Then Reata halted clinical development of bardoxolone, following an excess of unspecified serious adverse events and mortality among the treated patients in the Phase 3 BEACON trial in chronic kidney disease.

Almost simultaneously, the FDA paused for breath in their assessment of BG-12, delaying a decision on approval – although Biogen argue that the delay is unrelated to the sudden collapse of the bardoxolone programme.

Should Biogen shareholders be concerned?  Is this the end of the road for nrf2 activators?

Ironically, the presumed similarity of mechanism is also less certain than has often been assumed.  Both compounds can react covalent with nrf2 and modulate its activity, but the extent to which nrf2 is central to the beneficial effects or the adverse events seen with bardoxolone is an open question.

If the data with BG-12 supported approval before the Reata announcement then nothing should change.  And nrf2 remains an attractive target for non-covalent modulators – both bardoxolone and BG-12 suggest, but don’t yet prove, that this pathway is an important one in a range of disease processes.

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