EDITORIAL COMMENTARY

August 1, 2008

As many of you know, and believe me, I am not patting myself on the back, I was an early opponent of Tysabri and was early in predicting the removal of Tysabri from the market in 2005.

As many of you also know, I was vehemently opposed to the FDA's decision to approve Tysabri, for re-introduction in the U.S., even with the so-called "black box label." The fact that European drug agencies had approved the drug for the treatment of multiple sclerosis (MS) did not provide me any comfort.

Please, please, take note of the following press release from Biogen-Idec and Elan, manufactures/marketers of Tysabri:

http://www.bloomberg.com/apps/news?pid=conewsstory&refer=conews&tkr=BIIB:US&sid=a40u7vb1OLaw

In short, progressive multifocal leukoencephalopathy has now been found among a small number - very small at this point - of patients taking the drug for MS. Many prominent neurologists - many whom I deeply respect - have been supporters of this "treatment." Again, despite this, I have remained adamantly opposed to the use of this drug.

Why? I am sorry. But the risk of developing a deadly brain virus, even if the manufacturers quantify the risk at very low percentages, just seems a bit too HIGH for me relative to a) the fact that MS, itself, is not deadly, and b) there are other options. AND, while those options are not yet perfect, there are several new drugs in late stage clinical trials, including oral medications, that so far are proving far more effective in treating MS.

Biogen-Idec and Elan state that they have no intention of voluntarily pulling Tysabri from the market - once again.

As the news report from Bloomberg, a major business news sources, reports, the companies still plan to have 100,000 people on Tysabri by 2010. However, as of today, the stock market has made the assumption, by dropping the prices of the stocks, that the market for Tysabri will soon evaporate. As, in my humble opinion, it should.

For far too long, people with MS and others diseases, have been used as a guinea pig population, with the FDA permitting companies to rush new compounds to market. There is a trade-off here. I understand that. People want treatments. They want effective treatments. Many people that suffer from diseases such as MS want new treatments because they feel increasingly feel frustrated - and rightly so (being one of them) - with the persistent march of their illnesses and the negative impacts on the quality of their lives.

I understand all of that. I also understand that two pharmaceutical companies, Merck and Pfizer, that have performed clinical trials on very inexpensive drugs - statins - for the potential treatment of MS, seem to have no interest in pursuing the MS market with those soon-to-be off patent protection Pfizer's Lipitor), or already off patent protection (in the case of Merck's Zocor/simvastatin) drugs. After all, the MS market is far more lucrative if you can offer a new drug for $2,000 - $4,000 monthly instead of $23 - $100 a month. Keep in mind, in the U.S., there are only about 400,000 known cases of MS. So it's not a huge market.

I hope that you can take time to pass this Tysabri news on to people that may be interested.

Let me see. The possibility of death vs. living with MS. For me, however small the risk of progressive multifocal leukoencephalopathy, I will happily live with MS.

Sincerely,

Cary J. Polevoy

A Risk in Cholesterol Drugs Is Detected, but Is It Real?

DOCTOR'S DILEMMA

Data Crunching Hints At Tie to Lou Gehrig's; FDA Isn't Concerned
By AVERY JOHNSON
July 3, 2007

As he examined data on a computer one day last fall, drug-safety reviewer Ralph Edwards saw something that concerned him: Of 172 people in his database who developed Lou Gehrig's disease or something similar while taking prescription medicines, 40 had been on statins, the huge-selling cholesterol drugs.

Dr. Edwards, director of the World Health Organization's drug-monitoring center, has amassed about four million reports of medical problems experienced by people taking prescription drugs. His job is to sift through these so-called adverse events, looking for "signals" of potential side effects.

The number of Lou Gehrig's cases associated with statins struck Dr. Edwards as high. He would have expected a number in the single digits, judging from how often other drugs in the database were linked to the disease. Still, the analysis didn't prove anything. Dr. Edwards hesitated to publicize his finding, wary of creating a drug scare and mindful that statins have been shown to reduce heart attacks significantly.

INTERVIEW


Read excerpts from Dr. Edwards's conversations with The Wall Street Journal.
It's an increasingly common dilemma nowadays. Sophisticated software allows health authorities to troll through huge databases looking for possible drug dangers. The data mining can detect rare side effects that didn't show up in clinical trials. But it can also raise false alarms and force regulators to divert time and money from more pressing dangers.

"People reach different judgments on when to shout and when not to shout," says Robert Temple, medical director at the Food and Drug Administration division that evaluates drugs. "It's the hardest single thing -- the value and danger to screaming early."

The issue is likely to grow as regulators expand access to their databases. The FDA and other national drug regulators used to keep a tight lid on the adverse-event reports they collected, but now the WHO can freely disseminate them. Also, since 2004, the FDA has posted its quarterly data files on the Internet, and anyone can download them free of charge. Some companies have started offering software to crunch the data for side-effect patterns.

Adverse-event reports are a major way to identify side effects after a drug is on the market, but the data can be flawed or misleading. The reports can be turned in by anyone -- patients, doctors, even plaintiffs' lawyers. Media coverage or Internet postings claiming dangers in a particular drug may lead doctors and consumers to report more problems with that drug. Meanwhile, many problems never get reported.


Determining causation is another issue. If people taking a drug are older or more overweight than usual, an adverse-events database may show more links to heart attacks. That wouldn't necessarily point to any problem with the drug -- it would just reflect the less-healthy state of the people taking it.

Clinical trials in which patients randomly receive either a drug or a placebo are usually the best way to identify side effects, because any significant difference between the two groups is likely to be a result of the drug. However, trials are often too small or too short to identify unusual side effects, and they don't necessarily reflect how patients take a drug in the real world.

Drug Monitoring

The WHO, a United Nations body, set up its collaborating center for drug monitoring in 1968 after the thalidomide scandal, in which pregnant women who took the medicine for morning sickness gave birth to children with stunted limbs and other malformities. Now based in the Swedish university town of Uppsala, the center pools adverse events from 83 countries, including the U.S.

Dr. Edwards, a 64-year-old Briton with a background in internal medicine and clinical pharmacology, took the center's helm in 1990. His first experience with puzzling side effects came during a stint at the University of Zimbabwe almost 30 years ago. There, he noticed some patients with a rare skin condition, and tracked down some antibiotics they were taking as the cause.

In the mid-1990s, Dr. Edwards's team developed a software program to mine data with the help of artificial-intelligence Ph.D.'s from a local university. The software made it easier to analyze adverse events for one drug in the context of all event reports and fish out signals of problems.

At first, Dr. Edwards needed permission to publish from the national drug regulators on whose data he relied. Then, at a conference in Hong Kong in 2002, national drug agencies including the FDA loosened their grip, allowing the WHO to publish without permission. Dr. Edwards also received the right to share his data with anyone who requested it, he says.


He gets about 200,000 new adverse-event reports and pinpoints about 60 serious signals a year. Usually he notifies national health authorities and goes no further. Only rarely does he publish his concern. One such case involved babies getting withdrawal symptoms when their mothers took certain antidepressants. That report appeared in 2005 in the Lancet.

Last fall, Dr. Edwards decided to see what his database could tell him about statins and Lou Gehrig's disease, known medically as amyotrophic lateral sclerosis or ALS. The progressive neurodegenerative disease is almost always fatal. He had heard from an American doctor about an ALS-like case that was seemingly related to statins. Dr. Edwards himself had a friend who developed another serious nerve disease, called peripheral neuropathy, after taking a statin.

With a few clicks, Dr. Edwards came upon the 40 cases of ALS in people taking statins, and his software told him the number was much higher than expected.

DATA DEBATE

• The Issue: An analysis by a drug-monitoring group suggests a link between cholesterol-lowering statins and Lou Gehrig's disease, but U.S. regulators say they don't believe there's a risk.
• The Background: Scientists are increasingly using data-mining software to sift through reports of adverse events involving drugs.
• What's Next: More studies to figure out what's happening.
Reviewing scientific literature, Dr. Edwards came up with a theory about the cases. All statins carry a warning on their label about a rare disorder that causes muscle pain or weakness, a long-known side effect of the drugs. More recently, studies have linked statins to peripheral neuropathy. Dr. Edwards speculated these diseases and ALS might be connected, since they involve some kind of neuromuscular degeneration, and he thought all might be triggered by statins in unusual instances.

Yet Dr. Edwards also learned that pharmaceutical companies and other researchers are studying statins as potential treatments for brain or nervous-system diseases such as Alzheimer's, multiple sclerosis and even ALS. Some believe the anti-inflammatory effects of statins may be useful in these diseases.

As Dr. Edwards reflected on whether to publish his findings, one point weighed heavily. ALS is rare -- it strikes about five in 100,000 people and affects some 350,000 people world-wide. By contrast, heart attacks are a leading cause of death, and statins have helped millions of people reduce their heart risk. Dr. Edwards didn't want to raise unwarranted fears about drugs whose value is well-documented.

"We were on the horns of a dilemma and it wasn't easy to resolve," Dr. Edwards says.

Behind the scenes at the FDA, officials were facing a similar dilemma. Ana Szarfman, an agency official who pioneered statistical analyses of adverse events, had noticed the ALS-statin signal in March 2006, about six months before it caught Dr. Edwards's attention. She was using the FDA's database, which overlaps with the WHO's but isn't identical. The FDA says that through the end of last year, about one-third of the ALS adverse-event reports in its database -- 99 of 298 -- involved people on statins.

Dr. Szarfman was known at the FDA for her sleuthing into unexpected side effects, such as the odd link between a Parkinson's-disease medicine, Mirapex, and isolated cases of compulsive gambling. She also helped confirm in 2001 that Baycol, a Bayer AG statin later withdrawn from the market, was linked to an especially high number of muscle-disease cases.

Dr. Szarfman took the ALS signal seriously and considered publishing an article about it. But she held off while the FDA took a closer look. The agency didn't want to jump to any conclusions about a life-saving class of drugs, officials say. Unlike the WHO, the FDA has the ability to press drug companies for more information. That's what it did in this case, asking Pfizer and other statin makers for all their clinical-trial data.

Statin Trials

Taken together, the long-term statin trials involved 120,000 patients. The number of ALS cases came to 20, spread equally between statin takers and those on placebo.

"The result of the analysis was very reassuring," says Dr. Temple, who takes a statin himself. "I personally was relieved because I like my statins."

Dr. Temple says a close look at the FDA's adverse-event data suggested some reports might be unreliable. Slightly more than half of the adverse-event reports in the FDA's database about statins and ALS were submitted by consumers, which is unusual because doctors usually account for the lion's share. Also, some of the ALS cases were reported soon after the patients had started taking statins, raising doubts about whether the drug could have been the cause. Officials noted that the incidence of ALS in the general population hasn't risen since statins became popular.

The FDA plans to publish an academic paper about its statistical findings soon, says an agency official. But based on the analysis of clinical trials, it decided it didn't need to issue any caution about statins.

Dr. Edwards came to a different conclusion. He talked the issue over with his staff and P. Murali Doraiswamy, an expert in neurodegenerative diseases at Duke University who has done research on statins and the brain. Dr. Doraiswamy agreed that the ALS signal was worrisome and should be investigated.

After months of hesitation, Dr. Edwards came across a study by Greek researchers that helped make up his mind. Typically, ALS leads to death within three to five years, usually because the lungs fail when the neurons that send instructions to the respiratory system stop working. But in some rare cases, ALS-like symptoms could be halted or even reversed, the study said. Dr. Edwards decided his finding might help some patients prevent their disease from deteriorating. He wrote a paper and submitted it to two prestigious journals.

Both journals, the British Medical Journal and the Lancet, rejected it, he says. Fiona Godlee, the BMJ's editor, says she can't comment on specific papers, but she calls adverse events hard to interpret. "You only have a record of the people who developed problems, without knowing how many people took the drug and didn't develop problems," she says. The Lancet declined to comment.

Dr. Edwards pitched his paper to Drug Safety, a little-known journal based in New Zealand, which rushed it into print last month.

The paper acknowledges that some Internet sites have been discussing an ALS-statin link for at least a year, raising the possibility of skewed reporting of adverse events. But it notes that the number of events was also high earlier in the decade, before the majority of the Internet postings. The paper calls on patients using statins to talk to their doctor about stopping if they experience severe neuromuscular symptoms.

Pfizer, which brings in nearly $13 billion a year from Lipitor, says it too noticed the ALS signal last year in adverse-event reports, but concluded there was nothing to it after examining all its data. The company says Dr. Edwards has the right to publish what he found, but signals derived from adverse events can unnecessarily alarm the public and create needless headaches for drug companies.

Manfred Hauben, a Pfizer medical director, has long specialized in analyzing adverse events, and several years ago started using sophisticated software adopted by Pfizer. A math junkie who jokes that he suffers from an impulse-control disorder and stays awake at night studying statistics, Dr. Hauben says his enthusiasm for data mining has cooled.

He says with so many drugs and diseases, mere coincidence will create some worrisome-looking links. "Especially when you're looking for rare events, most positive results are going to be false positives," he says. Also, data mining presents "a lot of opportunities to retrofit an analysis to pre-existing expectations," he says. "Two different vendors' software can give two different results."

Prompting Research

Dr. Edwards says his paper is merely intended to prompt more research into the matter -- not cause millions of heart patients on statins to panic and stop the drugs.

But he hopes it will be useful to some patients. "Suppose you started to get symptoms and your doctor said, 'Now you have two years to live,' " he says. "Wouldn't you want to know that there's some possibility that the disease is linked to the drug so you could stop taking the drug?"

Dr. Edwards isn't persuaded by the clinical-trial data collected by the FDA. The signal wouldn't necessarily show up there, he says, because ALS is so rare.

Sheila O'Donovan, a 62-year-old retired journalist who lives in Delray Beach, Fla., wishes the signal had been publicized sooner. Ms. O'Donovan was on Lipitor when she started losing control of her right thumb in 2005. Soon, she was limping and slurring her words. After going off the drug in April of last year, she suddenly felt "brighter," her muscle cramps stopped and she was able to swallow more easily, she wrote in an email. But the improvement was short-lived. Her neurologist diagnosed her with ALS last September and she's gone downhill since. Her voice is now almost gone and she needs a wheelchair to get around.

More evidence could be available in a year or two. Beatrice Golomb, an associate professor of medicine at the University of California, San Diego, is analyzing case reports of people who developed ALS-like symptoms after taking statins. And researchers at Stanford University are looking at patient records in Northern California kept by Kaiser Permanente, a big health-maintenance organization, to see whether people who developed ALS were more likely than control subjects to have used statins.

Write to Avery Johnson at avery.johnson@wsj.com

Lipitor (atorvastatin) As A Treatment For Spinal Cord Injuries Following Trauma

In a multidisciplinary investigation led by Inderjit Singh, Ph.D, a breakthrough has been made in relation to the treatment of spinal cord injuries (SCI). Set for publication in the April issue of the Journal of Neurochemistry (101, 182-200), the study investigates the efficacy of atorvastatin (AT), commonly known as Lipitor, as a treatment for spinal cord injuries following trauma. The report demonstrates, for the first time, that by using AT in treating spinal cord injuries after they have occurred, animal models with hind-limb paralysis showed significant functional recovery and less secondary tissue damage. Importantly, scientists discovered that AT also protects the cells responsible for producing myelin in the spinal cord, a substance which maintains normal function by insulating nerve fibers that carry signals through the spinal cord. Therefore, this discovery of post-injury AT treatment may be extremely valuable in preserving neurological function and walking following spinal cord injuries.

Singh is a Pediatrics distinguished university professor, Division of Developmental Neurogenetics director and Darby Children's Research Institute scientific director.

Spinal cord injury is a major cause of disability, and the current therapy with high dose steroids offers little benefit. Statins, including AT, belong to a class of drugs that are known to affect numerous cellular processes. Experimental investigations and clinical trials in patients have established the neuroprotective efficacy of statin treatment in multiple sclerosis, Alzheimer's disease, stroke and spinal cord injuries.

"These exciting findings suggest that AT shelters myelin producing cells and neurons during the inflammatory storm produced by trauma, and that when the storm has passed that such cells resume myelin production," said DCRI executive director, neurologist and neuroscientist Bernard Maria, M.D. "It opens up a new paradigm for treatment of spinal cord injury by preserving the integrity of progenitor cells that would otherwise have died off."

It is now accepted that the site, nature, and duration of secondary inflammations occurring immediately after a spinal cord injury determine the extent of functional loss or paralysis, and early reduction of these events is shown to minimize functional loss and enhance recovery. As a result, anti-inflammatory and neuroprotective agents, including statins, are the favored first line of defense as therapeutic agents in spinal cord injuries.

Singh said, "I am blessed to be leading a team of talented investigators who do pioneering work to delineate the mysteries of nature to develop novel treatments for neurological disorders. I'm especially proud of the pioneering work performed in the Darby Children's Research Institute to protect the brain stem cells for regeneration in various disease processes, such as multiple sclerosis and spinal cord injury. Presently, these drugs are being evaluated for therapy in inflammatory neurological disorders."

Neurodegeneration post-injury is evident in the form of white matter destruction that includes loss of tissue viability, degeneration of severed axons and myelin destruction. AT treatment post-SCI reduced these processes. Furthermore, AT treatment prevented apoptotic neuronal loss. This is of critical value in spinal cord injuries, as neuroprotective treatments after injury have the potential to lead to improved functional recovery and only a few residual axons (5-10%) are needed to achieve significant functional recovery.

While considering regenerative approaches, depending on the nature and extent of injury, it is likely that AT by itself or maybe in combination with other therapeutic approaches, such as stem cell transplantation, could prove beneficial and augment functional recovery. As immune suppression has been found beneficial for survival of transplanted cells, it is likely that anti-inflammatory actions of post-injury AT treatment could compliment cell grafting by creating a growth supportive environment to augment survival and differentiation of these cells to enhance the reparative process.

Emphasizing the therapeutic potential of post-injury AT treatment in spinal cord injuries, the investigation also strengthens the idea of long-term benefits that include reduction of secondary pathology through suppression of inflammation, Wallerian degeneration, gliosis, and most importantly - neuronal apoptosis.

This study is only the beginning of an endeavor to uncover the extensive potential of AT in treating spinal cord injuries as the various facets of this drug need to be carefully examined to more precisely determine the clinical effects of statins, the differential potency of statins, and to evaluate whether combination therapy might be more effective than monotherapy. However, due to the long-established human safety of statins, this report is likely to have positive clinical implications for spinal cord treatment.

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