The Perils of R&D in Well-Trodden Areas

To most working in pharmaceutical R&D, it became clear a decade ago that the era of novel anti-hypertensive research was coming to a close.  The blood pressure market was saturated with many safe and effective drugs, most of which were generic or soon to be so.  These treatments included diuretics, beta blockers, alpha blockers, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).  Thus, it was pretty surprising that Novartis pursued renin inhibition, yet another type of mechanism for blood pressure lowering.  This approach was not novel.   In fact, scientists had been working on trying to discover and develop novel renin inhibitors since the early 1980s.  For a variety of reasons, most companies had abandoned their efforts by 2000 as it was no longer clear that a renin inhibitor would have any benefit over existing therapies.

Thus, it was pretty surprising that Novartis continued in this field and brought aliskerin (sold as Tekturna or Rasilez) to market in 2007.  The fact that Novartis scientists were able to find such an agent after decades of research in an area where many had failed was remarkable.  Aliskerin was indeed a potent blood pressure lower.  It significantly lowered blood pressure for a full 24 hours when given as a single dose and added efficacy when dosed on top of other blood pressure medications.  But its blood pressure lowering effects weren’t dramatically better than existing therapies. Was aliskerin too late to market for it to be a commercial success?  Renin is an enzyme that initiates the first step in what is called the “renin-angiotensin (RAS) cascade” that ultimately produces the blood pressure regulating peptide angiotensin 2.  But the ACE inhibitors and ARBs both also target the RAS cascade, so many questioned whether aliskerin would offer meaningful advantages over existing agents.  Why would payers be willing to pay a premium price for a new unproven agent without superiority data?

Novartis tried to show the medical importance of aliskerin by conducting a number of long-term outcomes studies to demonstrate its advantages. One of these was called ALTITUDE (ALiskerin Trial In Type 2 Diabetics nEphropathy).  Novartis described the trial as follows:

“The placebo-controlled Phase 3 ALTITUDE study is the first trial to investigate Rasilez/Tekturna for more than one year in a specific population of patients with type 2 diabetes and renal impairment.  These patients are known to be at high risk of cardiovascular and renal events.  In the study, Rasilez/Tekturna was given in addition to optimal cardiovascular treatment including an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB).”

ALTITUDE was an events driven study involving 8,600 patients and it was monitored by an independent Data Safety Monitoring Board (DSMB).  Novartis was hoping to show that aliskerin, when added to conventional therapy, delayed heart and kidney complications in the type 2 diabetes population.  Basically, Novartis hoped that in addition to lowering blood pressure aliskerin would also have protective effects for organs like the kidney.  In studies like this, it is the role of the DSMB to monitor the progress of patients on a periodic basis in order to determine how well the novel treatment is working.

On December 20, Novartis announced that the DSMB recommended that the ALTITUDE study be halted.  To great surprise, they found that the trial arm that contained aliskerin after 18 – 24 months  resulted in an INCREASED incidence of non-fatal stokes, renal complications, hyperkalemia and hypotension in this high risk study population.  As a result, Novartis immediately halted promotion of aliskerin-based products for use in combination with ACE inhibitors or ARBs.  For some unknown reason, aliskerin doesn’t seem to have organ protective properties, but its use appears to cause unforeseen toxicities when given in combination with other blood pressure lowering medications.

This is a terrible result for Novartis and is likely to cause the demise of this drug.  Matthew Herper’s Forbes story on this event contained the following quote from Texas cardiologist Dr. John Osborne, who summarizes the situation that Novartis now faces:

“The Novartis hypertension franchise is now DOA, obviously.  Furthermore, this class of DRIs has died with the death of this drug… Furthermore, given this data, why would one use this molecule anyway?”

A few lessons can be drawn from this.

1)      Going after a new mechanism where there are already excellent treatments on the market is always very risky, especially when generics are already present or on the horizon.  This isn’t limited to anti-hypertensives.  For example, an area like LDL-cholesterol lowering is very well-served with statins.  Any new LDL-lowering agent would have to be very special for payers and physicians to accept it.  The same thing can be said for anti-histamines, anti-ulcer agents, etc.  R&D resources are best spent in areas of major medical need, where a new medicine can make a difference.

2)      If you still believe your new drug has something to offer patients, despite the fact that good medicines already exist in this therapeutic area, it behooves you to do key clinical studies before filing the NDA.  My guess is that, despite the fact that Novartis has generated income over the past 4 years with aliskerin, the R&D, manufacturing and launch costs for this drug were pretty high and not compensated for the sales to date.

3)      This type of result further supports conservatism by regulatory authorities.  I wouldn’t be surprised if the FDA uses this case as an example of why they want more Phase 3 studies carried out BEFORE approval in order to justify registration of a new drug in a therapeutic area already well served.

When a drug fails, it is not an event that impacts only one company.  Presumably, other R&D organizations will learn from this and design future clinical development programs appropriately.  For regulatory agencies, one would hope that this type of result won’t cause further conservatism and cause them to increase the demands placed upon companies charged with the discovery and development of new medicines.  Finally, this is another example that can be used to teach the critics of the drug industry that the work pharma does is challenging and highly risky – yet important to the health of us all.

A Holiday Gift From Merck’s Ken Frazier

These are quotes that a pharmaceutical R&D supporter like myself loves:

“The most sustainable strategy is innovation.”

“Science and translating science into medically important products has always been at the core of how (we) define ourselves in the world.”

“Science and innovation are in the DNA of the company.”

These sentiments don’t come from the head of a biotech company or a scientist who is the CEO of a pharmaceutical company like John Lechleiter at Lilly.  Rather, they come from Ken Frazier, Merck’s first-year CEO, a lawyer by training.  As reported by Christopher Weaver, Frazier defended his commitment at a recent breakfast hosted by The Wall Street Journal.  Frazier’s views, unfortunately,  aren’t embraced by Wall Street.  Merck’s stock has stagnated in Frazier’s first year whereas that of Pfizer has increased by about 25%, partially as a result of the latter’s commitment to slash its R&D budget.

Frazier has not been rash in crafting Merck’s research budget.  In fact, the combined R&D budget for Merck and its acquired company, Schering-Plough, was $8.6 billion in 2009.  If Merck not only kept this budget but rather increased it by 5% annually, it would project out to be almost $10 billion in 2012.  Instead, Frazier is planning on a spending about $8 billion on R&D in 2012 – still a hefty amount but meeting that goal requires cuts to the new combined R&D organization.  Nevertheless, Frazier is finding himself defending this spending to Wall Street critics.  His response?

“What we are really trying to do is run the company to create sustainable long-term value for our shareholders… The problem with R&D is that it’s not always consistent.  It’s not like engineering where you can incrementally innovate and make another version of the iPhone… If you look in the past, there have been other fallow periods for R&D, but over the long-term, science has always made progress.”

There are tremendous medical needs now facing people around the globe.  Alzheimer’s Disease (AD) is a problem that is getting worse as the population ages.  The societal costs are enormous.  There are a number of compounds that are in clinical development that are hoped to slow or even reverse AD.  The problem is that these clinical trials are long and expensive to run.  The same can be said for the clinical trials needed to discover and develop new treatments for many other diseases such as obesity, diabetes, heart disease and osteoporosis.  Gone are the days when one can simply show that a compound stops bone loss in an osteopenic woman.  Instead, long-term studies are needed to show that such a drug reduces fractures in this population.  Physicians, payers and regulatory agencies are requiring these types of studies before justifying prescribing such new medicines to patients.

Big pharmaceutical companies are the only organizations with the resources and talent to do this.  But substantial R&D budgets are required to capitalize on the exciting new opportunities being uncovered by genomics.  One can argue that the Mercks of the world are serving the national interest by making these large investments because, if they don’t do these studies, no one else will.  So kudos to Ken Frazier for having the courage to stand up to the R&D naysayers.  Perhaps his commitment to R&D will return Merck to the status of the World’s Most Admired company, a title they owned in the late 1980s.

Consultants Might Have More Credibility If They Had Their Facts Right

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.

Diet and Exercise Are Important – But Often Insufficient

The stories are heartwarming.  A person is vastly overweight and finally decides to do something about it.  Through determination, hard work and a newfound discipline, this person loses 25, 50 or even 100 pounds, thereby changing his or her life.  Perhaps it is a woman who wants to have a child and is told that bearing a child would be life-threatening if she didn’t lose a significant amount of weight.  Perhaps it’s a man who has been ridiculed all his life who decides that he is tired of the verbal abuse.  You may have seen these scenarios played out on Dr. Oz or Oprah, or perhaps on the reality show, The Biggest Loser.  Seeing the changes in these people’s lives after such a physical transformation can be inspiring.

I am a big supporter of diet and exercise.  I once heard a doctor say that if you can somehow put the benefits of exercise in a pill, you’d have a wonder drug.  Yet, despite the obvious benefits and the importance of diet and exercise, recent studies suggest that for the majority of the obese population, just diet and exercise won’t be enough.

If you are worried about the obesity epidemic in the US, two recent New England Journal of Medicine articles might further concern you.  One is entitled “Comparative Effectiveness of Weight-Loss Interventions in Clinical Practice” (NEJM, 365;21, 1959 – 1968, November 24, 2011) and the other is  “A Two-Year Randomized Trial of Obesity Treatment in Primary Care Practice” (same issue, 1969 – 1979).  Essentially, these papers are similar in that they look at the effectiveness of different interventions in primary care practices by physicians who were trying to help their obese patients gain better control of their health.   On average, the patients in these studies had a body mass index (BMI)  of about 35 ( e.g., a height of 5’7” and a weight of 220 pounds) and had at least one cardiovascular risk factor (high blood pressure, plasma glucose, or cholesterol).  Both studies had control groups who received usual physician care.  In the behavioral intervention study, besides the control group, one group received additional face-to-face counseling and the other group received advice remotely (telephonic or email).  In the obesity treatment study, the control group was compared to those who received monthly lifestyle counseling and another group who received enhanced counseling plus meal replacements and weight-loss medications.

The good news is that in both studies, those patients who were getting enhanced treatment, be it extra counseling on behaviors, more frequent sessions with their doctors or physician assistants, or enhanced life-style counseling, all had sustained statistically significant weight-loss after two years.  The amount of weight loss wasn’t trivial – it was on the order of 5%.  Even if the counseling was done remotely, the results were meaningful.  Thus, extra time spent by primary care physicians and their associates can make a difference in helping their patients lose weight.

But the disappointing news is that even with the loss of 5% of body weight, these patients are still obese.  For the aforementioned person who loses 5% from their 220 pound frame, their new weight is 209 pounds and their BMI is 34 – still well in the obese range.  When you consider that the Center for Disease Control statistics for 2010 show that there are now 12 states where more than 30% of the adult population is obese, the loss of 5% body weight is just a small step to where we must get to in order to improve the nation’s health.

Obesity is a disease and its impact on the future health of the US cannot be trivialized.  Lifestyle changes are very important and can’t be minimized.  But for millions of Americans, this isn’t nearly enough.  Undoubtedly, the future for obesity treatment will necessitate a three-pronged effort that includes diet/exercise, life-style changes and new drugs.  For the latter, both the FDA and the pharmaceutical industry need to work together to help find safe and effective treatments to enhance a physician’s armamentarium to deal with this problem.