Drug Truths

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Consultants Might Have More Credibility If They Had Their Facts Right

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Big Pharma often finds itself Wall Street’s whipping boy.  Why?  Analysts are looking for immediate answers from an industry built on proving–and disproving–hypotheses.  Unfortunately, the result is often misguided analysis, as happened last week when the firm Oliver Wyman issued a white paper  entitled “Beyond the Shadow of a Drought – The Need for a New Mindset in Pharma R&D.”

Before last week, I had never heard of Oliver Wyman, which describes itself as follows:

“Oliver Wyman is a leading global management consulting firm that combines deep industry knowledge with specialized expertise in strategy operations, risk management, organizational transformation and leadership development.”

Given my history in this field, I was eager to read this paper as this is a topic close to my heart.  Wyman’s analysis, however, was disappointing as it, for the most part, rehashes a lot of what has been discussed by others over the past few years.  What really surprised me, though, was that a number of the Oliver Wyman “insights” were based on misinformation.  One of these purported insights that particularly stood out to me was Wyman’s take on Pfizer’s torcetrapib program.

In order to better understand how off-base Wyman’s white paper is, it’s important to understand torcetrapib’s history.

As most people know, statins have revolutionized the treatment of heart disease.  They act by lowering LDL, the so-called “bad cholesterol,” and multiple long-term studies have shown that these drugs, in combination with diet and exercise, can effectively reduce the potential of heart attacks and strokes in patients with heart disease.  But many researchers have believed that lowering LDL is only addressing part of the heart disease problem.  Intriguing data have built up over the years showing that if one could effectively raise HDL, also known as “good cholesterol,” further progress could be made in reducing heart disease.

The problem that scientists have faced in this field is that not a lot is known about raising HDL and so trying to accomplish this feat in the laboratory has proven quite challenging.  An exception involves the emerging biology around a protein known as “Cholesteryl-Ester Transfer Protein (CETP).”  Back in 1990, a report in The New England Journal of Medicine described a Japanese family who, due to a genetic defect, didn’t produce CETP and as a result had very high HDL levels and low incidence of cardiovascular disease.  Because of this observation, a number of companies, including Pfizer, sought to come up with an inhibitor of CETP to test in heart patients.  The rationale was pretty simple: by inhibiting CETP, the new drug would raise HDL thereby mimicking the situation in the Japanese family who were born without this protein.  Theoretically, the CETP inhibitor would reduce heart disease maybe as well as statins.  In a dream scenario, the combination of statins and CETP inhibitors would reverse heart disease, enhancing the quality of life of hundreds of millions of people.

Finding inhibitors of CETP proved to be very challenging and most companies gave up.  Pfizer almost did as well.  But through hard work, creativity and a bit of luck, the CETP inhibitor torcetrapib was found.  It successfully cleared preclinical toxicology studies and entered clinical trials in 1999, eight years after the discovery program began.  The initial clinical results were astonishing.  Patients on torcetrapib had increases of HDL of 100% or more – an unprecedented finding.  Even better, torcetrapib also caused a modest decrease in LDL; however, when torcetrapib was added to Lipitor (atorvastatin), not only was the HDL elevation maintained, but LDL drops of 40 – 60% were seen.  The lipid remodeling that was achieved with this combination had never been seen with any therapy.

The combination of torcetrapib and atorvastatin (T/A) became a major focus not just for Pfizer but for the entire cardiovascular field.  As the early clinical data for T/A emerged, other companies that had previously given up their efforts in looking for CETP inhibitors jumped back in the hunt.  But although T/A uniquely modified the lipid profile of patients with heart disease, its ultimate value was not yet established.  The long-term benefits of altering heart disease with CETP inhibition were still hypothetical.  Furthermore, at the end of the Phase 2 studies, it was found that T/A caused a small, but reproducible increase in blood pressure.  However, based on the known association between atherosclerosis, blood pressure and cardiovascular disease, the large increase in HDL was expected to provide benefits that would be far greater than any harm caused by the small blood pressure increase.  To prove this, Pfizer had to carry out an extensive Phase 3 program which included a multiple year study in patients with heart disease with the hope of showing that patients with heart disease fared better on T/A than they did with Lipitor (atorvastatin) alone.  This was a pretty high hurdle.  Pfizer wasn’t content to test T/A versus a placebo; rather, it chose to test T/A against Lipitor, the premier statin that had a successful track record in reducing cardiovascular disease.

The Phase 3 program wasn’t cheap.  Overall, it was projected to cost $800 million.  But such an extensive and expensive plan was necessary.  Pfizer realized that even if this program was successful, T/A would be competing with generic statins such as simvastatin and eventually atorvastatin itself.  For physicians to be willing to prescribe T/A, for payers to be willing to pay for T/A,  and for patients to be willing to take T/A, the clinical program needed to show that it was a drug of clear value.

By now, most know of the result of the Phase 3 outcomes trial.  In late 2006, this study was halted by the Data Safety Monitoring Board (DSMB) responsible for overseeing the study.  The reason for halting the trial was an imbalance in all-cause mortality in the T/A patients as compared to those on atorvastatin.  In other words, T/A was not better than Lipitor alone; in fact, it was worse in reducing heart attacks and stroke.

This result stunned cardiologists around the world.  One of the more telling comments was from the renowned Dr. Steven Nissen of the Cleveland Clinic, who said: “These studies further demonstrate the great difficulty in developing therapies to disrupt the atherosclerotic disease process.”

So that’s the history.  Now here is the Oliver Wyman version of the story.

“Five years ago several companies—Pfizer, Merck, and Roche amongst others—were pursuing CETP inhibitors, an important new class of HDL-raising therapies.  Pfizer, with torcetrapib, was in the lead, and by combining the new agent with Lipitor, they had the opportunity to create an efficacy fortress and extend the significant value of their lipid therapy franchise.  But speed was of the essence if the combo was to launch before Lipitor lost exclusivity.  Despite having seen signals of increased hypertension in Phase II studies, Pfizer chose to move forward with a landmark 25,000-patient Phase III trial.  Unfortunately, the trial showed conclusively that torcetrapib increased cardiovascular events rather than reducing them.  In contrast to Pfizer, Merck chose to slow development of its CETP inhibitor, anacetrapib, to investigate the hypertension signal.  They proceeded only after they found that it appeared to be a torcetrapib-specific effect, and was not class-wide.  In results shared at the 2010 AHA, Merck showed that anacetrapib raises HDL by 138 percent, without the side effects of the Pfizer molecule.  What is this worth? Analyst (sic) currently project that anacetrapib will achieve peak sales ranging from $3 billion to $5 billion.”

Oliver Wyman uses this example to justify one of the tenets of its paper, which is, “speed kills” and that thoughtful, more deliberate clinical development processes are needed for pharmaceutical R&D to regain success.  Its analysts believe that rushing torcetrapib through clinical development was a mistake, that “overemphasizing speed leads to throwing good money after bad” and that it is “better to slow things down to get a perspective on a molecule.”  The implication is that Pfizer would have been far better off if it had taken the more thoughtful route used by Merck.  Unfortunately, Oliver Wyman doesn’t know what it is talking about.

As was stated above, it was generally believed that the dramatic HDL elevating effects of torcetrapib would be of far greater clinical importance than the relatively minor blood pressure elevating effects caused by torcetrapib.  Furthermore, the patients in this study were already on blood pressure lowering medications, thus their hypertension was being controlled.  This was not just Pfizer’s belief.  Some of the world’s leading cardiologists, like Dr. Nissen, were not only advising Pfizer on the torcetrapib program, but they were also carrying out the clinical trials.  Raising HDL was viewed as the “holy grail” in cardiovascular research.  Heart physicians around the world were anxiously awaiting the results from the torcetrapib studies.  It wasn’t a matter of going fast to maximize profits – this was state-of-the-art science.

When the torcetrapib trial was halted, everyone in the field was shocked.  Suddenly, the promise of CETP inhibition had evaporated.  Experts began to question whether raising HDL would have ANY benefit in patients with heart disease.  Merck, which had planned to launch their Phase 3 program at about the same time that Pfizer halted theirs, instead put their program on hold for a year as they tried to evaluate what to do.  Yes, anacetrapib didn’t raise blood pressure, but perhaps the CETP mechanism was flawed.   After a year of intense internal debate, Merck decided to go ahead with anacetrapib clinical studies, but in a slower fashion than they originally had planned.  Their first phase 3 trial, reported at the American Heart Association meeting in 2010, showed that anacetrapib can be safely administered to patients with heart disease for 18 months with dramatic HDL elevation and LDL lowering without undo consequences.  They are now running the crucial large scale Phase 3 outcomes study that, hopefully, will show that CETP inhibition can confer additional benefits in heart patients when compared to statin therapy alone.

But this remains a controversial field.  Interestingly, back in 2006, Pfizer had a compound with a similar profile to anacetrapib in Phase 2 studies when the torcetrapib results were found.  Clearly, Pfizer has chosen to get out of the CETP area of research and not advance this compound further, despite the sales projections, as quoted by Oliver Wyman, being made by analysts for the Merck compound.  Unfortunately, the torcetrapib results raised more questions than provided answers.  Perhaps the work being done by Merck and other companies will answer whether there is value in CETP inhibition.

The Oliver Wyman paper implies that rapid execution of clinical programs is done in a heedless and reckless fashion, and that is a fatal flaw which is contributing to the lack of Big Pharma success.  This is absurd.   I am not so naïve to think that being first to market is not factored into a company’s decision-making process.  But this is true for any company in any industry.  Oliver Wyman’s implications are misguided, at best, and seem to be based upon uninformed research that relies more upon popular opinion than on actual data.  Oliver Wyman is only the most recent offender.  Misinformed analysts have long heralded the death of Big Pharma.  Why?  Most of Wall Street’s doomsday scenarios are attributed to a lack of understanding about what actually happens in labs.  Ours is an industry in which we are tasked with proving scientific hypotheses, a challenge that is more often frustrating than it is gratifying.  The scientific aspect of what we do is so interwoven with Big Pharma’s economic concerns that there exists a tenuous relationship between scientists needing years to prove theory and analysts demanding results.  That there would be confusion and frustration is unavoidable.  What is avoidable, however, is the perpetration of misinformation by analysts unwilling or unable to do the necessary research to provide accurate insight.


Written by johnlamattina

December 13, 2011 at 1:10 pm

Posted in Uncategorized

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4 Responses

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  1. The OW white paper offers a mix of rehashes, as you mention, and an apparent emphasis on hindsight as a planning tool – knowing what the results of a study will be certainly should make for improved decisions in the planning process. If, on the other hand, individual companies moved aggressively toward ‘differentiation and focus’ as recommended in the white paper…well, one would hate to hear the criticism for any company choosing an area that turns out to be more intractable than their competitors’ choices…

    Roger Frechette

    December 13, 2011 at 4:29 pm

  2. Even hindsight seems not to have educated all involved – we don’t yet know why torcetrapib failed in the hard-outcome Ph3. It is FAR too simplistic to assume it was due to the small elevation in blood pressure. At least as likely is the possibility that HDL is not the “killer” biomarker for CHD that it is often assumed to be.

    The problem is that HDL is an incredibly stable parameter (that is, shows very little temporal variability within an individual). Spot measures of HDL are therefore much more strongly associated with a chronic disease like HDL than, for example, very unstable measures such as triglyceride. Since HDL is correlated with many other lipid parameters (positively or negatively), HDL emerges as the most powerful spot measure to predict CHD status.

    But predicting CHD status is NOT the same as being causally associated. There is currently no evidence that low HDL itself causes CHD, or that elevating it therapeutically will reduce CHD.

    Indeed, the torcetrapib Ph3 data would suggest precisely the opposite.

    So even with the wonderful benefit of hindsight, Merck may still have gambled and lost with anacetrapib. If, as DrugBaron (http://www.tcpinnovations.com/drugbaron/) suspects, HDL is a correlative not causative marker of CHD, then the hard end-point anacetrapib trial now running will have as disappointing outcome as Pfizer’s efforts. In any event, they are unlikely to demonstrate additive benefit over now-generic Lipitor.

    Oliver Wyman’s worst error, then, is not to accuse Pfizer of killing their CETP programme with too much haste, but to be counting Merck’s chickens well before they have hatched. We don’t yet know if any CETP inhibitios will ever have any place in the cardiovascular medicine cabinet, so its certainly not time to start claiming 20/20 vision.

    • David,
      I cannot argue with your points – they are good ones. I am not sure that Merck, regardless of the outcome of the anacetrapib studies, will really answer the CETP/HDL question. Because anacetrapib doesn’t raise blood pressure, Merck is able to dose it higher and see higher HDL increases than Pfizer was able to get with torcetrapib. Thus, a favorable outcome with anacetrapib may mean that you need to raise HDL levels VERY significantly in order to improve CV outcomes over stain therapy alone.
      However, anacetrapib also causes a greater decrease in LDL above statins. I believe that the NEJM showed that patients on anacetrapib plus atorvastatin were getting their LDL levels on average into the 60- 70 mg/dL range, which I think is pretty exciting in its own right. A positive outcome from the anacetrapib trial might be due to its LDL effects and nothing to do with HDL.
      If anacetrpib doesn’t work, then the CETP mechanism is dead, but I am not sure how much light it sheds on the protective role of HDL elevation.
      Either way, I am looking to see Merck publish the data on this trial in a few years. Thanks for your comments.
      – John


      December 17, 2011 at 5:41 pm

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