A Smart Drug Company? Holy Crap!

This week's Business Week cover story features Novartis, apparently the one drug company not as dumb as Detroit. The good news is that smart management there may provide a new model for badly needed new drug development. The bad news is that none of these drugs are likely to be psychiatric meds.

Novartis is the one drug company headed by a medical doctor, Don Vasella (pictured here). The others are dominated by lawyers and accountants and marketers who fail to appreciate science and who have forgotten who their true customers are. According to Business Week:

"Most big drugmakers shower their research and development funds on diseases such as cancer or depression, where huge potential markets beckon despite a deficit of scientific understanding. In recent years this approach has led to high rates of failure when drugs are tested in clinical trials."

In contrast, seven years ago, Novartis embarked on a policy of pushing drugs through testing and development only if they were backed by proven science. It didn't matter that the particular diseases the drugs treated were rare. In the words of Dr Vasella: "If you are guided purely by financial estimates and not the science, you end up wasting time and money."

Novartis' Gleevec was initially approved for a rare blood cancer that strikes just a few thousand people a year, but has since proved effective against six other diseases. Last year, the drug pulled in $3.7 billion in sales.

The idea is that although there are 24,000 genes in the human genome, there are only a few dozen pathways that are shared by virtually all diseases. The trick is to track down all the links in a pathway, then locate the key signals that switch genes on and off.

In the development phase at Novartis is a drug to treat a rare inflammatory disorder called Muckle-Wells syndrome, involving a single gene variation that may be implicated in other illnesses. Thus, the rare diseases may shed light on a host of other illnesses and hold the key to future drug discovery.

Here's where the drug industry's blockbuster/me-too mentality has left us, according to Business Week:

Experts say drug companies have exhausted the easy targets. With patents on many older blockbusters starting to expire, the industry is poised to lose an estimated $140 billion in sales to generic competition over the next five years. Those revenue sources must be replaced.

Despite multibillion-dollar research budgets, none of the top companies has a wealth of promising compounds in its development pipeline. The industry also faces regulators more vigilant than ever about safety, and health insurers starting to balk at covering costly drugs that bring only modest benefits.

Dr Vasella shook things up when he moved Novartis' main global research operation from Basel, Switzerland to Cambridge, MA, and got a Harvard cardiologist to run it, with a brief to turn things upside down. Under the new order, scientists stared calling the shots rather than executives in sales and marketing.

The men and women in suits fought back hard, but ultimately more than a thousand sales and marketing execs were purged and medically trained scientists brought on board.

Here's the catch: Our current scientific understanding of mental illness would not meet Novartis' rigorous standards for green-lighting new drug development. According to its 2008 Annual Report: "Diseases affecting the brain and central nervous system pose exceptional hurdles in drug discovery."

All our current psychiatric meds are the result of serendipitous discovery, based on old technologies. They get some of the people somewhat better some of the time, and we have no idea why. The drug industry made vast sums of money essentially putting old pills in new bottles. That era is just about over.

The new era would involve finding the precise illness pathways that cause specific mental illness symptoms and figuring out which gene variations are involved. Forget about a treatment for all of depression. Rather, it might be more productive to uncover the underlying mechanisms to, say, lack of motivation. Maybe only a small percentage of depressions involve lack of motivation. But maybe such a drug would get a lot of these people a lot better a lot of the time.

Maybe, also, this motivation drug would help with other diseases and conditions that involve lack of motivation, such as various neurological ills. Maybe also various fatigue ills, and maybe even the flat affect symptoms of schizophrenia.

And maybe the best way of testing the drug would be to first try it on some really rare disease that only two people in the world know anything about, and then branch out.

Would your typical drug company be interested? No way.

Might Novartis be interested? You bet, assuming the science is sound. A ray of hope ...

Related Blog Pieces

It's Official: Pharma is Dead to Us

Pharma and Biotech: No Practical Solution Yet

Tooting from San Francisco - I

Today, Monday, 4 AM: What the hell am I doing wide awake this time in the morning? Let’s pick up from where I left off yesterday.

Yesterday, Sunday, 1 PM: I touch down at San Francisco Airport, collect my bag, and take the BART into town. My hotel is a fleabag in a colorful part of town within walking distance of the Muscone Center where the American Psychiatric Association annual meeting is taking place.

Sunday, 3 PM: I pick up my media credentials at the conference, shake the sleep out of my system, and plot my next course of action. Nothing much going on, so I head out to the exhibit hall. Pharma’s out in force, but it is looking like their last hurrah. Conspicuously absent is GSK (Lamictal, Wellbutrin, Paxil), which pulled out a year or two ago, along with Abbott (Depakote) and Novartis (Tegretol). All their drugs, of course, are off-patent.

Bristol-Myers Squibb is there by virtue of Abilify, which is still on-patent, along with Astra-Zeneca, with its blockbuster Seroquel. Eli Lilly is no longer flying their Zyprexa and Prozac flags - they have set up their tent by virtue of Cymbalta. Other companies are looking tired trying to generate excitement over new versions of old products.

There is very little taste of the future in the exhibit hall. The biotech companies, with nothing to market, are nowhere in sight. Neuronetics, which recently obtained FDA approval to treat depression with an rTMS device, is basically showing off a new application of an old technology.

In short, for now, the party is over.

6:30 PM: I feel a desperate urge break Rip Van Winkle’s record. Nevertheless, I grab a seat at the grand ballroom of the Hilton Hotel, where Shire is sponsoring a dinner symposium on the pathophysiology of ADHD. This is the last year of industry-sponsored symposia at the APA. Reform is in the air, but the truth is Pharma has lost interest in staging these events. Over the years, as meds have gone off-patent, fewer and fewer of these events have been staged.

Industry-sponsored symposia are a mixed bag. Some of them come across as infomercials, but tonight’s presentation is outstanding. A panel of experts - mainly from Harvard - articulate the underlying biology to ADHD, both on the cellular level (namely what happens when a neuron fails to correctly process information that dopamine is supposed to be delivering) and on a systems level (such as when certain parts of the brain aren’t talking to each other).

Brain scan technology has revolutionized mental illness research. I’m seeing it in all fields - depression, stress, schizophrenia, bipolar, personality disorders, you name it, most of it having taken place in the last three or four years. Thanks to MRI technology, we can now see structural abnormalities in the brain compared to healthy subjects, as well as functional deficits. Example:

A slide of the anterior cingulate cortex goes up. The ACC plays a major role in modulating thoughts - in selecting relevant ones and filtering out irrelevant ones - and is wired into both the thinking cortical areas and primitive reacting limbic system. A series of superimposed markers represents the ADHD brain scan studies performed on this area of the brain. Significantly, the study results testing for an emotional response show activity in the bottom half of the ACC while the study results testing for cognitive response show activity at the top.

Many individuals with bipolar also display cognitive deficits, so what I am learning tonight is shedding light on my own illness.

This is why I am here, to listen to smart people who have dedicated their lives to improving mine. Five minutes into the first presentation and I am wide awake. Last week I got tied down in doing stories about idiots - people like Andy Behrman who have walked away with $400,000 by lying to us, people like Pat Risser who pushes an antipsychiatry agenda predicated on the belief that there is no science to support the concept of mental illness.

Those idiots are irrelevant, as are those who try to legitimize them. Before our very eyes, a picture of the brain at work is emerging, one that is displaying a dramatic interplay between genes, biology, environment, and symptoms/behaviors. This is the real story, the one we need to be paying attention to.

This is the story of the future, as in terms of new drug development. But it’s also the story of the here and now, as in putting recovery principles into practice.

9:15 PM: I’m back in my fleabag hotel, just one block from the Hilton. I flop onto the mattress and am asleep before my head hits the pillow.

Today, 4 AM: The reason I’m awake right now is obvious. I crashed three hours earlier than usual, and had a much sounder sleep. But later today my brain will demand a settling of accounts.

This morning I head out to hear the legendary Kenneth Kendler expound on psychiatric genetics, then the highly-acclaimed author Elyn Saks discuss her journey through madness. Later on, the DSM, new research, and other cool stuff. No way I can sleep through this ...

Pharma and Biotech: No Practical Solution Yet

I concluded my last blog piece on this downbeat note:

So, where are the new meds going to come from? Don't bank on Pharma. They got out of drug development - assuming they were ever in it - at least a decade ago. Hopefully, new players looking to make profits based on innovation will fill the vacuum.

In the meantime, it's as if Pharma doesn't exist. Those meds you are taking right now? Probably generic from generic suppliers. Get used to them - these will be your only choices for quite some time.

An article by NY Times business journalist Lawrence Fisher appearing in the quarterly publication, The Milken Institute Review, provides the lowdown:

In theory, "biotech" is where the innovation is supposed to be coming from. As opposed to Pharma, which is rooted in ancient chemistry, biotech is all about sexy proteins and genes and stuff. These are your go-go companies founded by brainy people using smart-money venture capital. Think Genentech, Amgen, Gilead.

One catch: Take these three companies out of the mix "and the cumulative return on investment over the life of the sector was negative even before the financial markets' collapse."

In hindsight, it's easy to see why. It takes ten years to bring a new drug to market, but the way the game is set up investors need to see returns in five years. We're talking on average a billion-dollar stake in a high-risk crap shoot where nine out of ten compounds in development fail.

Not surprisingly, innovation-rich and cash-strapped biotech turned to innovation-poor and cash-rich Pharma. Unfortunately, the marriage didn't quite work out as planned. As Lawrence Fisher explains:

"Pharma ideally seeks companies with products on the market close to receiving approval. But most biotechs are risk years away from that goal, and those that are closest often come with substantial infrastructure and big employee bases that the majors neither need nor want."

Then, there's the matter of niche vs one-size-fits-all drugs. It's a question I have been asking virtually the entire ten years I have been writing on mental health, and I have yet to receive a satisfactory answer.

We know, for instance, that antidepressants work really well for about one-third of those who take them. But what about the other two-thirds? We need more flavors aimed at different palates. But Pharma is not set up for that. Plain vanilla spells blockbuster, their license to print money.

Biotech is all about the sophisticated niche meds we badly need. But who wants to roll the dice on a high-risk, low return product? Thus, when biotech meets Pharma worlds collide.

The two somehow need to figure out how to work together, most likely with government partnership. Foundation money and NIH grants are keeping the biotechs on a Ramen noodle diet for the time being, but this isn't going to last forever. Meanwhile, Pharma has run out of products, together with its license to print money.

And here we are, stuck with meds based on technologies that were considered new when Eisenhower was President.

It's Official: Pharma is Dead to Us

And on the pedestal these words appear:
`My name is Ozymandias, King of Kings:
Look on my works, ye mighty, and despair!'
Nothing beside remains. Round the decay
Of that colossal wreck, boundless and bare,
The lone and level sands stretch far away.
-Percy Bysshe Shelley

In My Top Ten Mental Health Stories that I posted here last week, I listed "The beginning of the end of drug companies." As I stated in my entry:

Everything seemed to happen at once: Patients and doctors seeing through the Pharma hype, blockbuster meds losing their patent protection, and no new meds coming out of the pipeline. No longer with any financial interest in influencing psychiatry, Pharma virtually backed out of the game. And with mega lost revenues from loss of patent protection, Pharma may lack the resources to ever get back in it.

Bottom line: Due to their arrogance and stupidity, Pharma fully deserves what's coming, but do we?

In short, how the mighty have fallen. Until just a short time ago, it seemed that Pharma would remain forever at the top of the mental health food chain. Technically, they still are, but we are clearly witnessing the beginning of the end.

I started to see the signs two or three years ago at the American Psychiatric Association's annual meetings. Certain manufacturers were not exhibiting, nor were they sponsoring symposia. The reason was clear: Their current stock of meds had gone off-patent, with no new ones on offer.

The handwriting turned up on the wall even earlier at DBSA conferences I attended. Gone were the frills, such as the canvas conference bags with the GSK logo and the ice cream breaks. A quick comparison of DBSA annual reports two years apart reveals an obvious stampede to the exits.

The DBSA 2005 report lists one $500,000-plus donor - Wyeth. The 2007 report lists none. Fortunately, over the same period, DBSA has been weaning itself off Pharma. What I'm seeing is a far more focused organization in a much better position to serve its constituents.

Psychiatry's make-over may prove far more dramatic and beneficial. Not too long ago, you couldn't throw a stone in the direction of a psychiatrist without it bouncing off at least 10 Pharma hacks. Their tentacles were everywhere: In research, in publishing, in professional education and continuing education, in universities, in hospitals, right into the very sanctity of the psychiatrist's office.

Now, on all fronts, they are disengaging. We are already beginning to see signs of reform in the profession. It's going to take time, but one hopes the final outcome translates into patients being able to take the word of their doctors at face value.

I know what you're thinking: With Pharma gone, where are all the new meds going to come from? Let's define "new," namely something that is not an updated version of an old technology. By this criteria, Pharma has not come up with a new psychiatric med in the last 50 years. To give you one example: J&J's Invega is Son of Risperdal which in turn is based on the ancient Haldol.

It's as if the people running Detroit have been moonlighting as Pharma CEOs.

So, where are the new meds going to come from? Don't bank on Pharma. They got out of drug development - assuming they were ever in it - at least a decade ago. Hopefully, new players looking to make profits based on innovation will fill the vacuum.

In the meantime, it's as if Pharma doesn't exist. Those meds you are taking right now? Probably generic from generic suppliers. Get used to them - these will be your only choices for quite some time.

What's Wrong with Pharma? They Don't Listen to Their Customers

In my last blog piece, I presented a simplified overview of the appalling Pharma management practices that have resulted in no truly new psychiatric meds on the market in more than 50 years, with no replacement drugs on tap that they can even pretend to call new.

What went wrong? Lots of things. But it all boils down to this one cardinal sin: Pharma never listened to its customers.

My background as a finance/business journalist has given me considerable insight into this. Back in the late eighties, when I lived in Australia, I co-wrote a book with a prominent businessperson there, entitled "The Customer," which went to number two on the best-seller list.

It's all about organizing your business around the customer. If management isn't directly serving the customer, then they need to be serving the people serving the customer. It's amazing how entire industries get this principle wrong. Detroit, for instance, has always dictated the terms of the customer relationship. Marketing, to them, is about conditioning us into acceptance rather than finding out what we want.

Look at where Detroit is now.

Detroit, at least, pretends to listen to the customer. Pharma? Let me tell you a story:

Two years ago, I was at a book launch on the east coast. I grabbed some finger food and started up a conversation with a pharmacology expert from Bristol-Myers Squibb.

"Maybe you can enlighten me," I opened. I had been doing some research into dopamine and had pretty well concluded that stimulants and antipsychotics amounted to "dumb" dopamine meds.

We needed "smart" dopamine meds. Surely, Bristol-Myers Squibb was aware of the situation. Surely, such a drug was at least on their radar screens, if not their drawing boards.

(For background on the issue, please see For Discussion: Dopamine Cocktail.)

We actually have a smart dopamine med, the man informed me. "Aripiprozole."

Surely, he misunderstood. Nothing against Aripiprozole (Abilify), but it's been on the market for years. I was looking into the future. I realized he wasn't in a position to disclose any company trade secrets, but he could at least fill me in on some general principles, namely: Where were the next new meds going to come from?

I'm a customer. I have a right to ask.

It was if the man hadn't heard me. Once again, he started talking about aripiprozole, undoubtedly the exact same pitch he gives to psychiatrists. For years, BMS has been telling doctors that aripiprozole is a "Goldilocks" drug - not too much dopamine, not too little, just right.

Stop trying to sell me something. I'm a journalist. I've heard it all before.

Again, I tried to get the conversation back on track. Again, the man tied to shove his stupid drug down my throat. It never occurred to him to ask me why I was so interested in a "smart" dopamine med in the first place.

Were there special challenges I faced that a smart dopamine med might address? he could have asked.

Was there anything about my illness that he needed to know, that he wasn't finding out about from psychiatrists? If a "magic bullet" were to come on the market tomorrow, how would this affect my life? What impact would a safer and more effective med have on my compliance?

Believe it or not, this man could have learned a lot from me. So could BMS and their competitors. Let me assure you, no one in the entire drug industry has even bothered to ask. I'm a patient author and advocate, so if they're not interested in me then I know they are not interested in you, either.

Actually, BMS did bring a patient author on board, Andy Behrman, author of "Electroboy," but in the capacity as a spokesperson - a grateful patient - for Abilify. The arrangement worked fine until the drug pooped out and Andy went public. Then all hell broke loose. (Never piss off a writer: Andy has a tell-all book coming out.)

So what happens to companies not interested in listening to their customers? We know the answer. The evidence is there. Detroit, Wall Street, Pharma ...

"How deserted lies the city," says Lamentations, "once so full of people!"

It's tempting to say, "good riddance," but if Pharma goes down, what becomes of us?