Inflated expectations

I have had my inflation paper published in Contract Pharma.
I have long believed vendor contracts in the pharma industry were ill-thought-out and overly generous to vendors, and recently finally got around to spelling out why.
I reckon the timing was nice of the Rupee crisis, since I have a bit of a go at INR weakness in the article.

Royalty Pharma, Elan, and the oil & gas industry analogy

http://mobile.bloomberg.com/photo/2013-04-15/royalty-pharma-raises-offer-for-elan-to-as-much-as-12-per-adr

I can see why Royalty Pharma is interested in Elan's rump (back story here about Elan spinning off their R&D as Prothena), because to my mind this is just a terminal-value play like a reverse bond (see http://en.m.wikipedia.org/wiki/Intangible_asset_finance). I view it (the Elan rump property) as like a single oil field that is of known volume and largely played out, and now they are pumping water in to get the last squirts for a few years (my favourite analogy, more and more, of the oil and gas industry for pharma).

Prothena on the other hand is their small exploration unit that only ever found the one elephant (http://en.m.wikipedia.org/wiki/Natalizumab - ok, maybe there were others). However, $100M as a price for the company, when they have $100M net cash and that's enough to run the exploration unit for a couple/few years, seems a reasonable wager.

The philosophical question Elan raises is why wouldn't any given pharma company split off their exploration unit, and run the existing products into the ground as a terminal-value runoff deal that throws off cash until nobody buys the products any more? I suppose one reason is that this sort of idea is the pinnacle (nadir) of pessimism about the company, surely. Ironically, I think our self-hatred/pessimism complex as an industry is bad enough for this type of thinking: exhibit 'A' for the prosecution is that Elan have already done what they've done.

The reason ExxonMobil and RD Shell aren't doing this themselves is presumably because they still believe in their own exploration ability. And, they know that oil exploration and production is so expensive and so risky that you almost need to have a giant production unit that throws off insane amounts of cash, to fund the expensive exploration and dry holes. The smooth and giant cash flows fund the extremely lumpy dry- and wet-hole business. This is of course precisely the business model of pharma over the last 100+ years. I think one of our main challenges is simply having the balls and the existential confidence to stay the course.

Doctor Copper

I have always liked the sight of fresh copper guttering and downspouts, Swiss-style. I would be interested in knowing what the lifespan is, and cost, relative to baser metals. Clearly the Swiss think the longevity and aesthetics of copper outweigh the cost. Also, the country enjoys low enough crime for theft presumably to be less of an issue.

The photo is at Bruderholz tram stop a short stroll from our house.

Last days at Roche

It will be my last day here soon!

Possible HIV vaccine progress

http://m.sciencemag.org/content/early/2013/03/29/science.1234150

A clever story here where these folks out of Seattle and elsewhere have gone one step better on the lead of a well-known antibody that some people infected with HIV produce. The antibody, VRC01, neutralises most virus variants, but researchers have struggled to coax normal people to produce the antibody, since the necessary B-cell germ line is not easily roused to manufacture this antibody. At least not by simply dosing people with the gp120 viral protein that this antibody targets.

[A little background/reminder is that gp120, an HIV protein, binds CD4, a receptor on human T cells. It is the attendant destruction of such CD4-positive (CD4+ in the lingo) cells that ruins one's immune system: hence [virally] Acquired ImmunoDeficiency Syndrome.]

This VRC01 antibody—which would be key to a vaccine if one could force the body to produce it—binds gp120, but somehow in a different manner than CD4 binds it. It also importantly binds gp120 independently of the various variations in shape of the viral "spike" and its surrounding envelope constituents, thus maintaining its effectiveness in spite of all the devious manifold variations that HIV constantly throws up due to mutating rapidly.

Now then, the above researchers have taken gp120 and whittled it down cleverly to the tiniest fragment they could achieve that still binds VRC01. This little fragment should in theory then be a potent little immunogen since there's not much to it other than the bit that should stimulate VRC01 production.

Seemingly just whittling it down wasn't enough: these folks then assembled the fragment into virus-like nanoparticles of 60 or so fragments, and those pseudo-virii apparently stimulate, in vitro, the right kind of B cell! So, bravo, and their next step is to try this in animals that have been engineered to produce human type antibodies.

Why Nanoparticles?

One might ask: why the virus-like nanoparticle? I can only guess that this gives the collection of viral epitopes some biological plausibility to the B cells in charge of deciding whether to commit to production of antibody. You will frequently see cartoon models of antibody functioning, or cell receptor binding, that depict human cells as giant spheres, and proteins binding to receptors in a binary fashion as keys bind to a lock. But no doubt, this is a crude oversimplification. I can well imagine that one viral antigen fragment might not get a germ-line B-cell "excited", but a nanoparticle resembling a virus particle might interact differently with the surface of the cell recognising it. Perhaps the recognising cell wraps around it in a sort of pocketed embrace, and multiple receptors interact with the particle and realise it's a viroid. A sort of cellular version of the blind-men-and-the-elephant [weak] "joke".

I am just speculating above, but this could be a case of an intelligent breakthrough being based at least in part on a rejection of the cartoonish idea that human cells are spheres, and protein-protein interactions occur in separate, standalone binary fashion like a field full of independent padlocks and keys.

Plant expression of therapeutic proteins

What do you think of this? Butler presentation on plant-based protein expression coming of age.

It was news to me that this is possible (it looks like tobacco spp is the plant in question). And they cover how the plant glycosylation makes this crap for ADCC and the like, but that the glycosylation can be "humanised". Don't ask me how you do that, but I guess it's in vitro, post-purification chemical modification of the Ab? Or is it actually possible to tweak glycosylation by genetic modification of the organism producing the protein? I don't remember how all that works: endoplasmic reticulum blah blah blah.

It's possible that camel antibodies or camel-antibody fragments (http://en.wikipedia.org/wiki/Single-domain_antibody), with their easier folding, simpler structure, greater stability, etc, would actually be even far better candidates for plant expression than other antibodies and proteins. For example, it's possible that whatever relatively harsh extraction techniques are needed to get the Abs out of the plant mush are less likely to denature the camelbodies than other Abs. So it's possible you get both greater yield in the plant, from ease of expression and folding, and also greater yield out the other end of the purification process.

My other question would be is it possible to use another plant species that does a sort of compartmentalisation of tissues. For example, if it's possible to get corn plants to express a given protein at high volume into the corn kernels/fruit, then wouldn't it possibly be easier to harvest the protein, if you only have to purify it out of a fruit-like tissue (with hopefully simple biochemistry e.g. mostly starch) and can throw away at the beginning all the green stuff?

This is the back side of the Bundesbahnli pub we sometimes grab a beer at after work (it is right near the Roche Hochstrasse office).

"Translational" medicine

The current buzzword of ‘translational medicine’, as near as I can tell seems to mean trying to insert research cycles as close to the bedside as possible, perhaps even literally as in seeing what happens in a patient, running back to the lab, and then altering treatment based on that running back and forth and scrutiny of results.

That all seems eminently sensible enough when it comes to clinical practice (though it seems so obvious that surely it is how doctors already practice medicine, ever since that mediaeval pervert doctor was tasting people’s urine to see if they had diabetes [mellitus: mmmm yummy, tastes like hunny]) but for clinical development it seems to have limited application, except for perhaps a big exception for critical diseases that involve treatment resistance. I can easily see how with HIV treatment or cancers of known resistance-pathway how you would keep tinkering the treatment as resistance in the patient comes up. But again that seems obvious, and again it is so difficult in practice, to get that through regulatory agencies, that the ideal of trying all sorts of investigational drugs in a row, based on the disease morphotype and resistance profile of the moment, seems a long way off.

I dislike “translational medicine” as a buzzword almost as much as I dislike “biomarker”. Biomarker is all over the industry, but my favourite jibe in response is that dogsh1t is a biomarker, or more palatably, leaves falling off trees is a biomarker of Fall. But, importantly, who cares? When we say biomarker we really just mean surely any molecule of biological origin that is of interest to somebody for some reason. Surely that is close to meaningless as a concept.


We are just watching How To Survive A Plague (http://en.wikipedia.org/wiki/How_to_Survive_a_Plague) which takes me back to my coop job days doing HIV work at St Pauls. Those days still seem like a model of how to keep pressure on regulators to speed up approvals where a disease is undertreated and deadly.

In other news we have the Glivec decision in India. In the mainstream media all the details seem to have been left out in terms of what the real dispute is here with the patent, and the compound and its formulation as this beta-crystalline variant. The Indian court’s finding that the different crystalline polymorph is no different in efficacy and looks like “evergreening” seems fair enough, in my view.http://pipeline.corante.com/archives/2013/04/01/novartis_loses_the_glivec_patent_fight_in_india.php


At the risk of overloading you with URLs, you have this story on the same (excellent BTW) blog:http://pipeline.corante.com/archives/2013/04/02/tecfideras_price.php One is reminded of the story of AZT in the movie above. AZT was just pulled off the shelf, and as we know it hardly works for HIV anyway, with resistance developing in a matter of weeks if I am not wrong. But Burroughs Wellcome still cheekily charged $10,000 a year for it presumably as they had the patent still. But the blogger is at least circumspect about these things – it’s not so simple as a straight ripoff, since companies have to try to maximise the price they get for their patented products.

Pistorius gag compilation

...with thanks to Aaron Murray and Aravind Velagapudi:

Oscar Pistorius Olympic Guilt?

We are now well into the first leg of legal arguments where Oscar Pistorius, once hailed as “the King of Spring”, is now, by many, being considered more “Prince of Darkness”. He stands trial for the callus murder of Reeva Steenkamp.

His defense team are claiming mistaken identity and self-defense; the prosecution say this is a step too far!

The prosecution team are adamant that they have found his Achilles heel: the alleged stance he takes on his movements on that night. They are not tip-toeing around his obvious disability, they claim he strapped on in his prosthetic legs "flex-foot cheetah" before shooting his load through the door of the bathroom, killing his girlfriend. He is rumoured to have used a sawn-off weapon.

From the dock he appeared soulless with lack of remorse. Neighbors have testified that they heard arguments on that fateful night. Reeva told him he was “Half a man” and she was the “one doing all the leg-work in the relationship”. He was said to be too needy and at times everyone was walking on eggshells as he pumped his body full of steroids and testosterone, sprinting ever-closer to chaos.

The forensics team were stumped as no foot-prints were present at the scene, only his strap-ons.

He awoke to the assumption that something sinister was afoot. Attempting to have the perpetrator toe the line, he decided to nail them with lethal force. The sound of 4 starting pistols echoed through the luxurious home as he came within 2 feet of the bathroom door, shooting his load without warning through the door, killing his girlfriend, whom with he was earlier watching "Footloose", instantly.

His defense team are calling in character witnesses, claiming here is a man of good standing, never before putting a foot wrong, always treading carefully and ever-leaping to the aid of others. One of the main witnesses is a lady known as Ula, a childhood friend. The Prosecution have referred to her (off camera) as “fib Ula” and are set on discrediting her in Court. Another, known to the Court as “Tibi”, a street performer and an acrobatic juggling stilt walking clown is striving for freedom on behalf of his Olympic Gold Friend. Many see it as a steep climb, to many hurdles in the path to victory and vindication.

More information has come to light about the relationship he had with Ms Steenkamp. There had been no sexual intimacy for some time. Some said that Oscar never got his leg over at all, whilst others claim he came up short in the bedroom and if he didn’t pull his socks up, Reeva would surely walk away altogether.

Bail has been denied until verdict, and although the judge made no mention of Oscar being a flight risk, it is clear a man of his resources could do a runner. Otherwise he may have been released on his own reclognisance.

His defense are well funded and almost 2 million has been stumped up for what will be a marathon case. Meanwhile, Oscar has found religion in the form of Shinto and asks that any man or woman walk a mile in his shoes before casting judgment. He says he is contrite, and before stumbling upon Shinto, he was a practicing Catholic and made the trek often to confession. The prosecution are looking for their 2Lbs of flesh and will cost the state an arm and a leg as the best and brightest in African Law are set on crippling Pistorius once and for all.

Nothing will heal the wounds left by this tragic loss of life. The prosecution are intent on cutting the legs from under him with surgical precision when he takes the stand for closing arguments. This is one ordeal that he will not walk away from and some say this will be his last stand. Supporters, however, are expecting him to cross the finish line unscathed and are already arranging a knees-up. But bookmakers handicap his odds of getting off as quite low.

Noah Legi, Reporting for Sprint magazine.