Monday, 26 September 2011

Dans la merde

I’ve been meaning to write something on the state of Pharma ever since my good friend Anthony Nicholls posted What Is Really Killing Pharma back in April. Ant sees an industry that is rapidly abandoning its science base and he is less than complimentary about Pharma management:

‘One consequence of this shift from science to business in the pharma industry has been less and less appreciation for the realities—as opposed to the hype and hope—of drug discovery. This is reflected both in the quixotic choices made by pharma as to what to pursue and in the stunningly bad management of the core talent in drug discovery.’

Now I don’t happen to fully agree with Ant on the diagnosis and it is possible that the underwhelming management of Pharma is more a symptom of the underlying disease than a disease in its own right. However, I will make some comments on Pharma management before moving onto some of what I see to be the industry's real woes. One brutal assessment of the situation is that, if society has decided that discovery of new medicines is to be a commercial activity, we (as members of society) should not complain when pharmaceutical businesses behave like businesses. I don’t believe that it is actually necessary for a Pharma CEO to understand the science although it’s a bonus if they do. Given that the time to bring a drug from hypothesis to market is longer than the tenure of many CEOs, it’s much more important that they be prepared to take a long term view and understand how the different parts of the business fit (and function) together. The shareholders of the company need to find mechanisms to persuade their CEO take a long term view. The CEO needs to seek advice from people who are prepared to tell the truth and not sideline them when they do. Those managing the drug hunt must avoid becoming panacea-centric in their thinking and remember that, while technology is a good servant, it is a poor master.

We need to take a closer look at the industry to better understand Pharma’s woes. As many people know, bringing a drug to market takes a long time and is also very expensive. The industry is highly regulated and the cost to the regulators of accepting something that they shouldn’t have greatly exceeds that of rejecting something that they should have accepted. Since Pharma companies don’t usually see themselves as in the Generics business, they need a steady stream of new products in order to remain viable. Unfortunately, this stream has slowed to a trickle and it is perfectly reasonable to question whether Drug Discovery is still a commercially viable activity.

It is easy to blame management for the current state of the industry and I’ll be the first to admit that many CEOs appear to be poor value for their employers (the shareholders). However, the current state of pipelines also reflects unmet scientific challenges and one can argue that the frequently bizarre behavior of Pharma leaders reflects increasing desperation in their search for other solutions.

Generally, a Drug Discovery project starts with a hypothesis. Typically, this will take the form that interfering (drugs are usually inhibitory) with the action of a target or system of targets (e.g. a pathway) will result in a therapeutically beneficial effect. Testing these hypotheses is termed Target Validation (TV) and usually one will try to develop an animal model of the human disease before taking a drug into development. Let’s think about why a drug may fail to show efficacy in a Phase 2 clinical trial. One explanation is that there is no link between target and disease (another way of saying that the TV hypothesis is incorrect). However, it could also be that the target is still valid but the animal model is simply not predictive of the human disease. Needless to say, TV is challenging and even reproducing claims made in the scientific literature can be difficult (readers who are LinkedIn may also wish to check out the discussion in the Society of Laboratory Automation and Screening group entitled "Reliability of 'new drug target' claims called into question").

However, there is yet another reason that a drug can fail to show efficacy in Phase 2 and that’s poor pharmacokinetics (PK). Now many of you are probably thinking that I’m talking from the wrong end of my alimentary canal when I say this because everybody knows that Phase 1 is where PK failures happen. You run a Phase 1 clinical trial to check that levels of the drug will be sufficiently high to engage the target and this is most relevant when the target ‘sees’ the blood stream. However, when the target is intracellular or on the far side of the blood brain barrier, we know a lot less about the free (unbound) concentration of drug in the vicinity of the target. Now you’ll see the problem and I’ll leave it to you to decide whether we’re dealing with known unknowns or unknown unknowns. The blood levels look great but we have little idea about what’s happening where it really matters. For intracellular and CNS targets it can be argued that the Phase 1 trial is less complete than for targets such as cell surface receptors that are exposed to the drug circulating in plasma. How much less complete is anybody’s guess because measuring free concentrations of an arbitrary drug in cells is just not something that we can currently do, even in laboratory animals.

This is probably a good time to bring up the subject of toxicity and it’s worth mentioning that the point made about free concentration is also relevant to toxicity (and ‘polypharmacology’). Pretty much the worst thing that can happen to a drug is that idiosyncratic toxicity reveals itself when the drug is already on the market. Rare toxicity is fiendishly difficult to predict and its rareness means that you have to dose a large number of patients (who may also be taking other medication) in order to even observe it. The rareness of the toxicity means that the enrichment studies that are so popular with the virtual screening and QSAR communities are unlikely to shed much light on the toxicity. Choking in Phase 3 is certainly bad but you can always console yourself with the knowledge that it could have been even worse.

So what’s really killing Pharma? There’s no shortage of gutless and witless managers in Pharma and there would be huge benefits in ensuring that undiluted Darwinian principles applied freely to the Leadership Function (surely a strong candidate for oxymoron of the month) of the industry. Would this be enough to save Pharma from a dearth of well-validated targets? Or one bust too many in the Phase 3 Casino? What do you think?

Literature cited

Prinz, Schlange & Asadullah, Believe it or not: how much can we rely on published data on potential drug targets? Nat. Rev. Drug Discov. 2011, 10, 712-713. DOI


Bastard said...

Really? Phase I evaluates based on blood levels solely?
It would seem more prudent to radiolabel the compound and evaluate blood, urine, and feces (maybe sweat too, not sure if it is a significant elimination route - from my white t-shirts I would say that it is at least significant for bilirubin).

thedoctor said...

We need more non-competitve target validation (TV) studies - i.e. government funded alongside industry consortia - up to phase 2. Then when the competition starts, every pharma company will have a much lower chance of failure - i.e. it'll be purely about their molecule and not about the basic background biology. Everyone would benefit from such an arrangement - both pharma and society.

Dr. Teddy Z said...

I don't necessarily think it is the is Wall street that is demanding increases in rates or profitability that are unrealistic. Mgrs (and I have no love for them) are just doing their fiduciary best. Science is expensive, so it always get cut first. And the most expensive gets firstest.

Peter Kenny said...

Analysing urine and feces will give you information about the nature of clearance (e.g. is drug excreted unchanged in urine) and may highlight absorption issues. However, observing the form in which drug leaves the body won't tell you anything about free (unbound) concentrations in cells or on the far side of the blood brain barrier. Radiolabelling studies may provide information about tissue distribution of the drug. However these doen't measure the free concentration of the drug in cells of interest (e.g. tumor; intracellular parasite).

Peter Kenny said...

TV studies, non-competitive or otherwise, will still need to reproducible. The LinkedIn discussion that I referenced makes interestign reading. Funding will be a real issue and funding by an industrial consortium implies competition between members and non-members of the consortium. Also the people doing the TV may wish to capitalise on the knowledge that they have gained during the TV project. This may be a factor in the apparently poor reproducbility of published TV studies.

Something that needs to be taken account of if one wishes to increase the regulation of TV studies is that different Drug Discovery orqanisations have different levels of risk tolerance and some may be prepared to commit resource to less validated targets at an earlier stage.

Peter Kenny said...

The CEOs are in a tough position since investors only want honesty from their CEOs when the news is good. If one CEO tells it is, the investors will take their money to another one who paints a rosier picture. Honest politicians have a similar problem.