Archive for August 2011
Researchers at the Stanford University School of Medicine recently announced that they have developed a computer program designed to find new uses for already approved drugs. As reported by Amy Dockser Marcus in The Wall Street Journal, researchers Atul Butte, Joel Dudley and Marina Sirota believe that their technology allows them to screen rapidly genomic databases in such a way that they can identify examples where a drug creates a change in gene activity opposite to the gene activity caused by a disease. Such an observation allows researchers to identify uses for drugs that they were not initially designed for.
At the outset, let me say that I firmly support all efforts to find new uses for drugs. And hopefully, this new approach will yield a breakthrough. But I am not convinced that this will be a bountiful source of new products.
It is interesting that whenever researchers look to repurpose old drugs for new uses, they always use sildenafil (tradename, Viagra) as their poster child, as it was serendipitously discovered as an agent to treat erectile dysfunction (ED), even though that wasn’t the specific use it was designed for. However, this discovery was not so accidental. Sildenafil was designed as a potent inhibitor of an enzyme known as PDE-5. The interest in PDE-5 inhibitors stemmed from the fact that inhibition of this enzyme should result in elevation of nitrous oxide (NO) in vascular tissue beds. NO is well known to be a vasodilator. Pfizer scientists hoped that by blocking PDE-5 in the heart vasculature, arteries would dilate and the result would be enhanced blood flow in patients with cardiac disease like congestive heart failure.
Sildenafil did, in fact, cause vasodilation. However, this vasodilation was first observed in the penis and not the heart. Instead of being a breakthough medication for heart disease, sildenafil became a major treatment for ED. So, yes, this was a biological consequence that was not initially envisioned. The key in all of this is that Pfizer scientists designed and synthesized a safe and effective PDE-5 inhibitor that could be tested in clinical trials to determine what the utility of such an agent would be. Sildenafil was, in fact, designed as a vasodilator. Its effects, however, were manifest in an organ other than the heart.
When a new mechanism is found to be effective in patients, scientists often explore where else such an agent may be of use. Pfizer researchers were also interested in learning whether sildenafil would cause vasodilation in other parts of the body. One theory was that the small arteries in the lung might also be sensitive to sildenafil’s effects. Patients with primary pulmonary hypertension (PHT) suffer from arterial constriction which is extremely debilitating, and people with this disorder have trouble breathing. Clinical trials showed that sildenafil was very effective in treating PHT, and it is marketed for this condition as Revatio.
Another example is Pfizer’s tofacitinib, an inhibitor of the enzyme JAK-3. This orally effective drug was initially designed to be used as an agent to prevent organ transplant rejection. However, when the impressive early clinical data first came in, researchers began to envision other uses for a drug that acted by this mechanism, including rheumatoid arthritis and psoriasis. Tofacitinib is now in late stage clinical trials for these and other indications.
These two examples illustrate two important points. The first is that, while serendipity is always appreciated in any research program, for any pharmaceutical research program to be successful, you need to have a safe compound which targets a specific biological process. Once in the clinic, you may find that the mechanism for which the drug was originally designed does not prove to be the optimum use for the new drug (there is also a downside to this – sometimes the new mechanism may have a mechanistically related side-effect that turns out to kill the drug). But you don’t go blindly into clinical trials with the hope that a PDE-5 inhibitor might do something beneficial in people. Rather, you must connect the mechanism to a biological effect.
The second point is that when a mechanistically exciting drug shows beneficial effects in a disease, the news spreads rapidly throughout a research organization. Scientists will share these results and then hypothesize where else such a compound may be effective. This leads to many other experiments to explore the new exciting finding and potentially, new uses for this drug in medicine.
The Stanford scientists have raised a lot of hopes that their new approach will uncover new uses for existing medications. Hopefully, they will have success. But casting a broad net with the hope of finding something new will be very challenging. As the understanding of the causes of diseases grows, and should a compound that would be expected to interact in this specific pathway already exist, chances are that the company that developed the drug is already onto this new potential use.
Major depression is a serious disease. In 2005, The New England Journal of Medicine (NEJM) published Dr. J. John Mann’s excellent review “The Medical Management of Depression.” In this piece, Dr. Mann states: “major depressive disorder accounts for 4.4% of the global disease burden, a contribution similar to that of ischemic heart disease…” Equally concerning is that: “Patients who have diabetes, epilepsy, or ischaemic heart disease with concomitant major depression have poorer outcomes than do those without depression.”
One would think, therefore, that those concerned with medical care would be grateful for the availability of drugs to treat depression. Yet, there are many who challenge the value and the need for antidepressants. Dr. John Abramson, author of Overdosed America and my verbal sparring partner on The Dr. Oz Show, says the following in his book: “…new antidepressants were found to be not even 10% more effective than placebos: symptoms of depression improved by 30.9% in the people who took placebos and by 40.7% of people who took the newer antidepressants.” Dr. Abramson’s implication is that these drugs offer little value over sugar pills.
Dr. Marcia Angell, a noted pharmaceutical industry critic and a former editor of the NEJM, has also expressed a number of concerns about antidepressants, not the least of which is that drug companies rarely publish negative data on these drugs. In her article “The Epidemic of Mental Illness – Why?” which appeared in the June 23rd edition of The New York Review of Books, Dr. Angell states the following:
“When drug companies seek approval from the FDA to market a new drug, they must submit to the agency all clinical trials they have sponsored… If two trials show that the drug is more effective than a placebo, the drug is generally approved. But companies may sponsor as many trials as they like, most of which could be negative – that is, fail to show effectiveness… For obvious reasons, drug companies make very sure that their positive studies are published in medical journals and doctors know about them, while the negative ones often languish unseen within the FDA…”
Factually speaking, Dr. Abramson and Dr. Angell are correct. Antidepressant drug trials usually show only modest superiority of the experimental drug over the placebo. And yes, drug trials where there is no difference in the efficacy of the drug vs. the placebo normally aren’t published. However, such statements don’t tell the whole story in the battle to treat psychiatric disorders.
In doing clinical studies, there are some medical areas where it is easy to measure whether a drug is working or not. If you have a new antibacterial to treat an infection, you can take blood samples to measure the effect that the drug is having on the eradication of the bacteria from the patient. Similarly, with a drug to treat high blood pressure, you can treat a patient with a new drug and take real-time blood pressure measurements to quantify the drug’s effects.
Psychiatric diseases are different. In clinical studies, patients are given a standardized test, such as the Hamilton Rating Scale for Depression (HRSD), which involves answering a variety of questions about a patient’s mood, anxiety, ability to sleep, etc. The patients are then randomized to receive either the placebo or the test drug. Each week, the patient returns and is seen by the psychiatrist to determine if any improvements are evident. Generally, these studies last for about two months. Such studies are notorious for the high efficacy response rates seen in patients who turn out to be taking the placebo. In an excellent 2002 NEJM paper on this subject, “Placebo Response in Depression Studies” by Timothy Walsh, Stuart Seidman, Robyn Sysko and Madelyn Gould, analysis of 75 clinical trials showed that the response to the placebo across the trials ranged from 10% to more than 50%. While the authors couldn’t point to one definitive reason why such high placebo rates occur, they offered a few possibilities:
1) patients in these trials, whether on the placebo or on the drug, are usually allowed to take sedatives and anti-anxiety medication, so the placebo responses encompasses the effects of these drugs;
2) the weekly physician visits contribute to the patient’s great sense of improvement;
3) it’s likely that these studies included patients with milder, briefer, and more responsive forms of depression thereby enhancing the chances of either the placebo or the drug being effective.
Thus, it is well-established that there are high placebo efficacy rates in clinical trials in psychiatric disorders. As a result, studies where the efficacy of the placebo is equal to that of the drug being tested are rarely published. It is not that companies are hiding data. Rather, such a result is of little interest. Most skilled in the science behind the results realize that seeing the benefit of a placebo over an experimental drug is a hazard of this type of study. However, it is big news when a new antidepressant does, in fact, show statistically significant efficacy over the placebo. This instance is deemed very important by the scientific community and, therefore, medical journals are very willing to publish such results. In other words, there is a very simple explanation to Dr. Angell’s concern.
Dr. Abramson and Dr. Angell’s position that companies try to bury negative data is simply not true. For almost a decade, the US National Institutes of Health has logged and published the results of EVERY federally and privately supported clinical trial on the website http://clinicaltrials.gov. When each trial is completed, the sponsoring organization is required to summarize its results for all to see – favorable or unfavorable.
Still, Dr. Angell’s article has spurred a tremendous debate not just in New York Review of Books, but also in places like The New York Times (NYT). On July 9th, the NYT published an opinion piece by Dr. Peter Kramer titled, “In Defense of Antidepressants.” Kramer, a clinical professor of psychiatry at Brown, provided a spirited defense of the current methodology in treatment paradigms. As one would expect, the debate continued a week later with a number of letters to the NYT not just from Dr. Angell, but also from a number of heads of important psychiatric associations as well as psychiatry professors from major universities. However, the letters that made the biggest impression on me were the ones from actual patients. One in particular stood out.
“As a professional ethicist, I share… concerns about the medical-pharmaceutical complex and how the obsession with ever-greater profits can hinder, not promote, ethically intelligent patient care. But, as someone who has been using antidepressants successfully for many years, I can say from experience that some of that concern is misplaced. My life is richer and infinitely more satisfying because of this medication. I offer my profound gratitude to the dedicated researchers and conscientious clinicians who have made this possible.”
These are important drugs. They add value to society. Yes, they need to be prescribed appropriately. But to impugn the motives of the people and companies working to discover drugs to ease the pain of depression or the psychiatrists and physicians who prescribe them is irresponsible.
Nature Reviews Drug Discovery recently ran an opinion piece by me titled: “The impact of mergers on pharmaceutical R&D.” My interest in publishing this piece was to show that mergers are one of the major factors in the decrease in productivity for the pharmaceutical industry. My views on this hot-button issue generated a lot of discussion in the press and on the web; not surprisingly, some of the comments were unfavorable. One in particular used a quote of mine from 2004 to challenge my current views. The author felt that the opinion I expressed in Nature Reviews Drug Discovery was inconsistent with my previous views as stated in my quote below:
“I’m a big believer in size… When you are a smaller company, as we were 27 years ago when I started, you don’t necessarily have the resources to invest in things outside your immediate expertise. But as we’ve gotten bigger and become more resource rich, we’ve been able to expand.”
Actually, I am still a believer in size and stand by this quote today.
Twenty years ago, Pfizer’s entire R&D budget amounted to $627 million (in contrast to $9.4 billion in 2010). In those days, we were limited in what therapeutic areas we could work in as we couldn’t spread ourselves too thinly. For example, this meant not doing research on statins – an area we entered in 1997 when we did a co-marketing deal for Lipitor with Warner-Lambert – or not putting a big effort in areas like cancer and AIDS. This all changed as Pfizer’s revenues grew dramatically in the 1990s from $5.8 billion to almost $27 billion and, in parallel, the R&D budget grew to $4 billion. During this time frame, we were able to add resources to work in key research areas like cancer, immunology, addiction and pain. We were also able to invest in new equipment and technologies to enhance our research capabilities. This growth was done in a measured and systematic manner. All of these investments helped to build the current late stage pipeline now touted by Pfizer CEO, Ian Read.
But in the current business environment, size plays a more crucial factor. The hurdles in bringing a new medicine to market are higher, and more expensive, than ever. Many new medicines now need to show not just an efficacy which is superior to existing therapies but also long-term safety in patients. These studies are expensive. For example, at the behest of the FDA, Pfizer is funding a study known as “PRECISION,” which is designed to compare the safety and efficacy of Celebrex with ibuprofen and naproxen in arthritis patients with cardiovascular disease. This one study will end up costing somewhere between $250 – 300 million. Nothing like this could ever have been contemplated 20 years ago – it would have consumed most of the R&D budget.
Size, therefore, has its advantages. My concern is, however, how a company grows. A company needs to be cognizant of the effects sudden growth has on its pipeline and science base. A company needs to grow at a reasonable pace; in other words, growth needs to be done responsibly and not as an attempt to meet a bottom line. In the combination of Squibb with Bristol-Myers, the two companies were “fused.” There weren’t major cuts made. True, this type of merger causes disruptions as outlined in my opinion piece, but they aren’t necessarily fatal, particularly if it is a onetime event. However, mergers of “synergies” where research sites are closed, thousands of scientists are fired, and pipelines are pared are devastating to a research organization. Such mergers eliminate, and perhaps lessen, the value that the new size theoretically brings.
If you want a merger to work, you need to ensure it doesn’t damage the R&D foundation of the company.
On August 10th, the Wall Street Journal published a letter to the editor entitled, “The FDA Isn’t as Innovative as It Likes To Think It Is,” in which Skyline Ventures Founder, Dr. John Freund, lashed out at the FDA. Specifically, he challenged the view espoused in Margaret Hamburg’s WSJ Op-Ed piece: “America’s Innovative Agency: The FDA.” The FDA’s self-anointed role incenses Freund, who wrote:
“The FDA has tightened up the requirements for approving new drugs for adult-onset diabetes, a disease that affects approximately 25 million Americans. The result is that performing the clinical trials for a new diabetes drug is so long and costly that no venture capital firm will finance a new diabetes drug.”
He also has doubts about the FDA’s desire to approve new drugs to treat obesity, writing, “In the past year, the FDA rejected three separate drugs to treat obesity, including one for which the FDA’s own advisory panel recommended approval. As a result, no venture capital firm will now finance a new effort to develop a drug for the obesity epidemic.”
Despite the fact that I am a “Big Pharma” veteran, I am on the side of the FDA on this one.
First of all, the relatively conservative position taken by the FDA in obesity and diabetes is not unique to these therapeutic areas. In fact, it is seen in new drugs for cancer, osteoporosis and heart disease. No longer will the FDA approve a drug for obesity based solely on its ability to induce weight loss. Similarly, the FDA wants to see more than blood sugar lowering before approving a drug for diabetes. While both are meaningful markers for improving the respective disease condition, the FDA also wants to see outcome studies, that is, two to three year long studies showing that the weight loss or lowering of blood sugar actually correlates to a reduction in heart attacks and strokes, the unfortunate end results for diabetes/obesity.
Why is the FDA asking for long-term data? Won’t weight loss and/or blood sugar lowering automatically result in enhanced survival? Surprisingly, the answer is no. A recent case-in-point was the widely prescribed anti-diabetic agent, Avandia. This drug was approved on the basis of its impressive blood sugar lowering ability. However, and to the surprise of many, this drug DID NOT reduce adverse cardiovascular events in long-term studies conducted after it was approved for sale. In other words, lowering blood sugar had no impact on the ultimate desired outcome.
In the case for weight loss agents, the FDA’s rationale is likely different. A true weight-loss drug is going to be widely prescribed and theoretically could become one of the biggest drugs in history. With the likelihood of such broad usage, long-term safety of such a drug needs to be shown before unleashing it on the public. This position is best supported by the diet drug phen-fen, which causes modest weight loss, but which is associated with severe cardiac damage on prolonged use.
The same is true for new drugs in other classes. Studies have shown that just because a drug shrinks the size of a tumor doesn’t mean it enhances survival. Or, if a compound stabilizes bone formation, it may not prevent fractures. And there are a number of studies that show that raising HDL, the good cholesterol, doesn’t reduce heart attacks. Faced with this situation, the FDA has done the logical thing – it wants outcome studies to justify approval for drugs that will need to be used by patients for decades.
The assertion that Dr. Freund makes that “no venture capital firm will now finance a new effort to develop a drug” for diabetes and obesity is not true. Catabasis, a biotech company in Cambridge, MA, recently raised almost $30 million from VCs to support their exciting new approach to diabetes. And Gelesis, a company that has been formed by PureTech Ventures (where I am a Senior Partner), is focused on obesity and has also recently raised funds to support its R&D program. Despite this admittedly tough regulatory environment, good ideas are still garnering investments.
There is a positive aspect to all of this. If a compound can successfully clear these hurdles, it will be a blockbuster. The manufacturer will be able to say that its new compound not only causes weight loss, but it also reduces heart attacks and strokes. The same would be true for a diabetes drug that reduces cardiovascular events as well. Without question, the FDA’s regulations benefit everyone involved.
If you have friends or relatives with Alzheimer’s Disease (AD), you are undoubtedly hoping that some breakthrough will be made that will alleviate or even reverse this disease in your loved one. Unfortunately, recent reports might dampen your hopes that a breakthrough is right around the corner. The good news is that great progress has been made in understanding the root cause of this disease. We now know that AD is caused by the build-up of proteins into clusters that clog up nerve cells in the brain. These “plaques” break down nerve cells which results in a decrease in the ability of these cells to function, leading to the familiar AD symptoms of memory loss and an erosion of cognitive skills.
These insights have led researchers to design drugs that prevent the buildup of these plaques. This has not been trivial to do. Over the last 20 years, great work has been done to understand the multiple mechanisms on how these plaques form, develop genetically modified mice that mimic the human condition of AD, and design and synthesize compounds that could block or reverse this process in the human brain. In short, scientists are doing everything they can to try to cure the disease. A number of companies like Lilly, BMS, J&J and Pfizer have compounds in late-stage development in AD patients and the much-anticipated clinical trial data is starting to read out. But despite the knowledge of AD’s cause and the multi-tiered approach to finding a cure, early results have been discouraging.
Interestingly, this is the same place that cancer research found itself in the 1990s. At that time, a great deal of knowledge had been accrued on the genetic basis of tumor formation. The biopharmaceutical industry simultaneously created compounds to test these theories in clinical trials. These trials answered a lot of questions, disproved some theories and supported others. Eventually, this cutting edge research led to the new drugs that have been introduced in the last few years. Research in AD seems to now be in that stage.
Lilly has led the field in an area of research known as gamma secretase inhibitors. Lilly hoped its lead compound, semagacestat, would inhibit the enzyme which is believed to contribute to buildup of the amyloid protein, which in turn, forms clumps in the brain and causes AD. It was hoped that testing this compound in AD patients would slow or reverse the progress of AD. Unfortunately, Lilly halted the phase 3 trial for this compound as it led to a WORSENING of cognitive function compared to placebo in the AD patients in the study.
Was the Lilly compound flawed in some way? Or is the flaw in the hypothesis that a gamma secretase inhibitor should be of value in treating AD? That answer is not clear. More data will emerge from the study that BMS is doing with its gamma secretase inhibitor which they feel is superior to semagacestat. Will this compound behave similarly? Perhaps. But this is the nature of trying to discover a drug to treat such a difficult disease.
Another way to attack AD is to try to administer an antibody which can bind to the deposited amyloid and clear it out of the brain. Such an antibody is bapineuzumab, which is being developed by both Pfizer and J&J. Unfortunately, this antibody caused vasogenic edema – brain swelling – in AD patients. Initially, this caused a lot of worry and called this mechanism into question as well. However, subsequent studies are suggesting that such swelling MAY be an indication that the drug is working and that, theoretically, the swelling is a result of blood vessels becoming leaky when ridding the brain of the amyloid protein. Is this a side-effect or an indication of efficacy? Obviously, more studies are needed. The FDA is working closely with those running these studies to help find the answers without jeopardizing patient safety. This is yet another example of how progress is made – not necessarily with a major “aha moment,” but rather with key experiments pointing you in one direction or away from another.
There are other issues that researchers are trying to navigate. Most of the drugs in clinical trials are in patients with well-established disease. Perhaps their disease has progressed too far for any compound to show cognitive benefits. Thus, maybe trials should be done in patients for whom disease is at the earliest stages. The downside to this practice is that to see a significant effect, the trials will likely need to be of a multi-year duration, which are costly and challenging to do.
With new treatments for AD years in the future, are there steps that people who are at risk of getting AD can take? A recent NY Times article (July 26) by Pam Belluck called “Grasping for Any Way To Prevent Alzheimer’s” tried to address this. People have touted all sorts of prevention paradigms: weight loss, dietary supplements, and physical activity among them. Unfortunately, an NIH panel recently concluded that none of these has proven to be effective. The issue again stems from the fact that this is a disease that is decades in the making. Studies of any kind to prove that a new treatment or regimen is effective takes years of study and research.
Before you get too depressed by this, remember that this is the same situation scientists faced in coming up with new treatments for cancer decades ago. However, the explosion in new cancer drugs is rooted in the R&D done back then. The same process is occurring now in AD. Tremendous breakthroughs in science are occurring. It is just going to take a lot more work to cure this disease.
Medicare Part D refers to the prescription drug benefit that went into law in January 2006. Basically, it provides for prescription drug coverage for everyone on Medicare. Clearly, this law was intended to bring medicines to people who previously couldn’t afford them and, in doing so, improve their quality of life.
Opponents of Medicare Part D feared that the costs would be prohibitive and drive up the overall healthcare costs of the nation. Proponents argued that enacting Part D was the right thing to do and that we as a nation were obligated to provide medicines to all who needed them.
Not many people banked on the possibility that such access to medicines might actually save money.
Last week, an article in the Journal of the American Medical Association (July 27, 2011) by J. Michael McWilliams, Alan Zaslavsky and Haiden Huskamp of Harvard Medical School showed that this may indeed be the case. Using survey data from the Health and Retirement Study, they compared non-drug medical spending for 6001 elderly adults (aged 65 and over) for those with limited drug coverage to those who had generous drug benefits before and after the implementation of Medicare Part D. What they found was extremely encouraging. Those with limited prior drug coverage had significant reductions in non-drug medical spending after benefiting from Medicare Part D. These reductions were specifically attributed to reduced use of skilled nursing facilities, less spending on physician services and reduced inpatient services. The amount of actual savings was estimated to be $306 per patient per quarter. In other words, greater access to medicines improved patients’ health, thereby saving downstream healthcare costs.
This really shouldn’t be a surprise. There are a number of studies where the introduction of new medicines has proven to have had major economic benefits. One of the best examples occurred in the treatment of AIDS in the late ’90s. Prior to the introduction of the “triple therapy” (highly active antiretroviral therapy or HAART), the overall per patient cost to treat AIDS patients amounted to roughly $1800 annually, of which $604 was due to drugs. Triple therapy was far more expensive at $821 per patient. But the overall cost to the healthcare system for AIDS patients on triple therapy dropped to $1521 per patient annually. More significantly, triple therapy cut mortality by 75%.
The debate about increasing healthcare costs will continue to rage over the coming years as the Federal and States’ budgets get tighter. It is important to remember in these debates that effective use of medicines and broad access to them not only improves the quality of one’s life, it also reduces overall costs to the nation’s doctor bills.