Pharma’s Cutting Edge

In November 2007, Harris Interactive published their annual poll of Americans attitudes towards industrial regulation by government and the trustworthiness of industries.  I made the above chart using data from that poll.  It shows the percentage of people polled who believe that the referenced industry is generally trustworthy and honest.

As evidenced by the poll, despite being a nation supposedly undergirded by capitalist, free enterprise principles, we have a deep distrust of industry.  In 2007, 44% of us believed that none of 17 industries mentioned was generally honest and trustworthy.  Furthermore, our distrust of industry has been increasing.  In 2003, just 37% found none of the listed industries to be generally honest and trustworthy.  I’ll leave it to the politicial pundits to judge whether the current administration’s generally pro-industry policies are the cause of the recent, steady erosion of public trust (not that there was not a heck of a lot of trust to erode in 2003).

Let’s focus on our industry.  Pharmaceuticals, surprisingly–given the almost daily attacks in 2007 from Congress, insurers, presidential candidates, medical groups, and consumer advocates–fared relatively well in the public’s eyes.  Sure, the industry is trusted no more highly than car manufacturers or airlines, but it is more highly regarded than managed care providers and health insurers.  More than twice as many respondents trust pharma over managed care.  And pharma’s rep actually improved by four percentage points over 2006, one of only five industries to see an increase in its trustworthiness during that one year interval.

But let’s face it, despite the public not quite equating pharma with tobacco yet, it’s not the place to work it once was.  Back when I got into the business of pharma R&D in the mid-1990’s, it seemed like everyone was celebrating its achievements.  Wall Street loved us because of our lofty equity valuations based on robust growth prospects; politicians lauded us an example of US-led innovation success, and health advocates praised us for bringing much needed advancements to medical care in many previously underserved areas of medicine (think of SSRIs for depression as an example).  What happened to our rep since then holds many lessons for industry leaders, some of which I’ve offered in posts since I began blogging a few years ago.

Today, instead of offering some advice to a select few industry leaders who will never read nor heed it anyway, I thought instead that I would speak directly to the thousands of you who, like me, make no claims to and have no aspirations for such positions of power and responsibility.   

Call it viral PR.  Call it standing up for yourself.  However you think of it doesn’t matter.  What’s important is that each of us has a responsibility to make ourselves a part of the response to attacks on our work.   

We want to believe that we work in an industry whose R&D efforts are genuine, with lofty goals that include the alleviation of human suffering and improvements in the quality and span of life.  We want to believe that we help to market and sell our wares at the highest prices local markets can bear, because our R&D efforts are worthy of substantial at-risk investments that depend on the promise of generous financial returns.  We want to believe that all of our co-workers feel as we do. 

We are sickened by comparisons between pharma and tobacco or insurance companies.  We understand why many people mistrust us, but we hate it.  We don’t have thick skin, as PhRMA’s head Billy Tauzin, recently said in a WSJ interview.  We have the same delicate skin as everyone else in the healthcare professions who head to work each day feeling like they are making a positive impact on their local communities and maybe the rest of the world.

We, each of us, must defend our work if we believe in it.  It’s okay, no…it’s important, to be openly critical of specific policies espoused by our political leaders if we believe they are misguided.   But we must also resist denigrating our own well-intentioned efforts to fit in with conventional thinking.  Respond when people attack your work, and start by questioning their assumptions.

When asked how you justify spending valuable R&D funds on “me-too” drugs, first state that the term “me-too” is derisive and you don’t appreciate it.  Never use it yourself.  In other industries, we don’t think of follow-on innovations as “me-too;” we think of them as welcome competition that lower prices and offer more choices (of features, for example).  In pharma, such innovations are generally critically important to offering patients choices that increase the chances of finding a drug that works as intended without adverse effects.  Eventually, when the US government becomes the single largest direct negotiator of drug prices, follow-ons will also become more important as money-savers for consumers.  Sure, there will always be certain examples of follow-ons that proved to be of no incremental benefit (a couple of stereoselective enantioners come to mind), but these will be exceptions to the general rule.

After you’ve addressed faulty assumptions, dispel grand conspiracy theories that are used by industry enemies to paint pharma with the broad brushstroke of “evil-doers”.  People love a good conspiracy theory, and they are apt to assume that a grand conspiracy is the correct explanation for bad behavior evidenced by pharma (yes, like every financially motivated business, pharma has experienced its fair share of bad behavior).  Explain to them that a grand conspiracy isn’t necessary for a company’s bad behavior, even large-scale bad behavior.  It takes only a handful of bad actors in powerful positions to drive a large corporation to the dark side.  Look at Enron as a shining example.  Explain that you and the people in your circle of fellow researchers/marketers etc. are well-intentioned.  Explain that, for the most part, important decisions you have been involved with making came down on the side of doing the right thing, even when the right thing and the most highly profitable thing were not the same.  Admit that in your particular industry there is always a need to balance priorities between the need to get the most important drugs into the hands of the people who need them most and the need to sustain the expensive R&D engine that invents those drugs.  And admit that some individuals let greed be an equal priority.

After you’ve dispelled some faulty assumptions and grand conspiracies, don’t be afraid to tell people about achievements of a personal nature for which you can take pride.  Remember, keep it personal:  “I worked on a 50-person project team that helped to develop a follow-on drug for heart disease.  Because we knew that there was a similar drug already approved, we conducted a very large study measuring the effect of this drug compared with standard therapies to prevent deaths.  We coordinated the activities of over 100 clinical investigators and their patients from 17 different countries in this study.  It cost us over 100 million dollars to conduct it.  The good news was that it worked.  There were nearly a third fewer deaths seen after just five years of study.  Now, about a million people around the world use this drug every day.”  That same story with a different outcome, a failed trial, can be even more compelling to a skeptical audience.  Be as proud of your failed efforts as you are of your successful efforts.

I guess that’s enough pontificating for today.  I leave it you to contemplate other ways to infect people with your enthusiasm for your job, assuming you still have some left.

This is destined to be one of the key HIV papers of this decade, if not longer.

–Robert Gallo

I’m a real fan of unconventional thinking and scientists who are unafraid of venturing outside of their comfort zones.  So, when I read the story of the discovery of new potential drug targets against HIV in Science recently, I was thrilled.  I believe the full article behind the news piece requires a subscription; if you have one it’s worth at least a quick read-through.

Stephen Elledge is a pioneer in the use of “forward genetics” to screen for host factors that influence (suppress and or promote) the malignant phenotype (see this for an example of his group’s creative scientific approach).  In Elledge’s brand of forward genetics applied to cancer target screening, he and his team apply massive pools of interfering RNA to cells of various types to determine whether blocking endogenous gene transcription modulates the malignant cell phenotype. 

In the recent Science paper, Elledge and his collaborators used the same approach with a foreign invader–HIV.  I don’t know whose idea that was, but it was brilliant, and I give Elledge lots of credit for not shying away from a complex, costly, time-consuming HIV study despite his previous lack of experience working with the virus.  In short, the labs grew transformed epithelial cells (HeLa) transfected with some 21,000 pools of siRNAs in pools of 4 siRNAs per gene (i.e. siRNAs against all expressed human genes with transcription-suppresion redundancy to help gaurd against false positives and negatives) and then infected the cells with HIV-1.  When HIV-1 was able to replicate despite host-gene transcription inhibition, the scientists could conclude that the host gene probably wasn’t important for HIV replication, but if HIV replication was disrupted, they could surmise that a host protein involved in HIV replication had been discovered.  As you’ll read, the group found 273 host proteins that HIV relies upon for replication, only 36 of which had been previously discovered, thus explaining how HIV is able to so effectively parasitize its human hosts despite having a genome of just 9000 RNA bases.

As this is a scientific paper, the authors themselves have respectfully avoided aggrandizing this work and their screening approach in general, but this type of study is potentially very clinically relevant in the near-should be a more fruitful strategy to eliminate the virus from the body.  This is because HIV can easily mutate in the face of selection pressure from drugs targeting its own proteins, but it will be much harder for HIV to mutate to circumvent a blockade of a host target (or two) that it requires for reproduction. 

The accompanying news story expresses some skepticism from a Novartis researcher regarding the ease of discovering drugs targeting HDFs and the willingness of pharma to fund such work.  I frankly can’t understand such skepticism, but perhaps the story excerpted the interview in order to provide a bit of contrast to the enthusiasm from Dr. Gallo that opened the piece.  Yes, the HDFs are mostly internal cellular targets, and yes, they probably have some important roles to play in normal host functions, but let’s remember that we already use lots of drugs that fit this description, particularly in oncology, and although side effects are common, so are benefits.  As for pharma funding the work needed to capitalize on this work, let’s remember that it’s one thing to gauge the suits’ interests in the face of established pathway opportunities, and it’s quite another to anticipate their interest in the face of potential therapeutic breakthroughs with large commercial potential.   In my mind, this is a must-do opportunity for any company with virology capabilities and experience.  From a platform perspective, I’d be surprised if most large discovery outfits aren’t already taking advantage of genome-wide functional screening to identify the host factors enabling invaders to live at our expense, whether those invaders be infectious organisms or our own cells gone awry.

Results from ENHANCE are now available.  I don’t think anyone is terribly surprised, given the delay in reporting the results, that addition of ezitimibe to simvasatin (i.e. Vytorin) did not have a sigificant impact on carotid intimal media thickness compared with simvastatin (Zocor) alone in subjects with heterozygous familial hypercholesterolemia (a disorder of LDL receptors that affects about 1 in 500 people globally). 

See my prior post on the implications of ENHANCE for most current Zetia users.  As I indicated previously, these results will likely have very little impact on prescribing of Vytorin or Zetia, despite pronouncements to the contrary yesterday, primarily from Steve Nissen of the Cleveland Clinic.  Dr. Nissen apparently gave lots of interviews yesterday, saying things like:

This wraps it up…That’s all there is. There just isn’t any evidence that adding ezetimibe to simvastatin produces any advantage.

to the Washington Post.

Of course that isn’t all there is.  One trial with an iffy surrogate endpoint in a highly selected population does not a definitive treatment recommendation make (said Master Yoda).

Since my last post, I was happy to learn about another trial of Vytorin underway, one with a hard outcome.  The IMPROVE-IT trial, sponsored by Merck and Schering-Plough, is a randomized, active-control, double-blind study of subjects with stabilized high-risk acute coronary syndrome. The primary objective in IMPROVE-IT is to evaluate the clinical benefit of Vytorin 10/40mg compared with Simvastatin 40 mg alone, where clinical benefit is the reduction in the risk of the occurrence of a composite endpoint of CV death, major coronary events, and stroke.  Nice.  Now enroll this sucker.

I’m not stopping my Zetia because of ENHANCE, and I’m confident that most other users of Zetia and Vytorin will not either.  Once the ENHANCE dust settles, it’ll be clear that ezitimibe remains our first best hope for atherosclerosis therapy beyond statins, at least until a definitive study demonstrates otherwise.

Disclosures:  I have no financial ties to Merck or Schering-Plough.