(Update 12/04 – This breaking news blog entry is moved to the top as the blogosphere continues to react.)
More on this HDL-raising drug’s stunning collapse. There’s talk Pfizer stock will drop to $20. I’m disappointed myself, since there is no reliable way to raise HDL, save for niacin and fibrates. I thought they were idiots not to test it alone, but only in conjunction with Lipitor. Was it the combination of the two that lead to the increased deaths? We’ll never know now.
Clinical Cases and Images:
“We are back to square one — there is no highly effective pharmacological treatment for low HDL apart from Niacin which usefulness is limited by unpleasant side effects (flushing) and poor glucose control in diabetic patients.”
Dr. Wes:
“As painful as it must have been, Pfizer did the right thing. They will feel the sting in their stock price over the short term, but in the long term, they saved many more lives with their bold decision and will survive to develop another blockbuster drug another day.”
Derek Lowe:
“This is a complete clinical disaster: the world’s largest drug company just ditched their potential biggest drug. And this comes two days after a press conference where they talked about how they were planning to submit it for approval within months. Development of torcetrapib, the cholesteryl-ester transfer protein inhibitor designed to raise HDL levels, has been halted. Last week, that sentence would have been the subject of nightmares at Pfizer, but now it’s the top of the news. No alarm clock buzz will make it go away. If you’re looking for an example of just how difficult drug development is, look no more.”
John Mack:
“Back in mid-October, Pfizer Chief Executive Jeffrey Kindler, at a Wall Street analyst meeting, softened Pfizer’s message on torcetrapib’s chances for early and resounding success. At that time, everyone was focused on the worry was over the discovery that torcetrapib raised systolic blood pressure an average of three to four millimeters of mercury.
Would a few millimeters prevent the risk-adverse FDA from approving the drug no matter what the benefits or did Mr. Kindler know something his medical consultants and chief medical officer did not know?”
Peter Rost, gleefully taking the opportunity to kick Pfizer when it’s down:
“Of course, in the drug industry, bad stuff happens. But in this particular case, the whole scientific world had been worried about the fact that torcetrapib raises blood pressure. Not a good thing for a cardiovascular drug. But that didn’t stop the Pfizer executives from hyping torcetrapib. Until it turned out that “one of the most important developments in our generation” was really a killer drug””quite literally.
And this is what makes Pfizer”˜s CEO Mr. Kindler and Pfizer’s research chief Dr. LaMattina officially the most clueless executives in the drug business.”
Carlos Velez:
“I wonder if Pfizer is literally giving up on torcetrapib completely, or will they develop this for a high risk population? My guess is that Pfizer will give up completely, and not want to risk Baycol-like lawsuits.”
Update 12/04 -
Matthew Holt:
“But beyond that it is also a pointer that some of the easy “targets” such as heart disease and diabetes may be nearing their natural limits for medication therapy, and that lifestyle changes, the old “diet and exercise” may really be the best way to deal with them””allied of course with the generics which were the blockbusters of yesteryear. Almost all the growth in the drug business in the last few years seems to be in niche and very expensive biologics for virtually orphan diseases.”
Molecule of the Day:
“Torcetrapib wasn’t the only in-pipeline CETP inhibitor (in fact, Pfizer has others), but this is going to make everyone take a long, hard look at the class.”
Steven Nissen, M.D. via the NY Times:
“This drug, if it worked, would probably have been the largest-selling pharmaceutical in history.”
Classically Liberal:
“And if it had worked, and was the largest selling drug in history, then Pfizer would have been constantly attacked for their greed and excessive profits. Will any activists now lament the $1 billion lost? . . .
. . . Anti-market “activists” frequently demand that profits for companies like Pfizer be “limited”. Yet there is no way to limit losses. And more drugs fail than succeed. For every one drug that goes to market thousands are shelved. And of those that do go to market only 30 percent cover their costs.”
Update #2, 12/04 -
Robert Centor:
“Withdrawing this drug is a victory for patients, although we mourn those who died prematurely participating in this study. These studies are a victory for careful research and independent monitoring boards.”
Jim “Mad Money” Cramer:
“Maybe they really are a bunch of jokers at Pfizer. Either that, or their timing is just nightmarish. I can’t believe that two days after the company discussed a new cholesterol drug at its analyst day that they scrap it.”
Update #3, 12/04 -
The Reflecting Pool:
“Why is this receiving such attention? Why do we worry about Pfizer’s health so much, when primary prevention trials – which could obviate the need for these heart drugs altogether – fail consistently? If we spent half of what Pfizer spent on R&D (or marketing for that matter) – we’d have lots to work with in primary prevention.
But no…that’s not our culture. Pfizer can turn psychogenic erectile dysfunction into a disease and then sell us costly medications for it. They can do anything.”
WSJ Law Blog:
“The legal community is already atwitter about whether litigation will ensue from torcetrapib’s demise. Says defense attorney Richard Scheff, a partner at Montgomery, McCracken, Walker & Rhoads: “You can bet there are very creative, smart plaintiffs’ lawyers who have their thinking caps on as you and I are talking right now.”
The company is unlikely to get hit with personal injury lawsuits because the patients took torcetrapib in clinical trials. According to Roger Morris, health group chair at Quarles & Brady, there’s some fairly standard language used in informed consent that typically absolves companies of liability in clinical trials at the negligence level or below. “They can still be liable for gross negligence or fraud,” Morris says, adding that this is rare.”
Related posts:
- RIP Torcetrapib
- Peter Rost piles on Pfizer
- Torcetrapib failed even worse than thought
- The FDA assault on quinine and guaifenesin
- Pfizer: Going to the dogs
- The numbers behind the torcetrapib decision
- Is the FDA killing research?
{ 11 comments }
CETP inhibition as a concept is not dead, and Pfizer has two other compounds under study. Like everything else, the compound has to work safely, and in the new HMO standard has to save lives not just improve statistical risk based on epidemiology. So if you have excesss deaths- causality of the deaths with torcetrapib will not be revealed I’m sure-you have to drop the compound. The hypothesis about HDL raising actually lowering CHD deaths (actual deaths not the risk of it) has not been proven yet with anything. CETP-inh as a method is not dead. Just ask Roche and Merck.
Ah, I was wondering why Pfizer just announced that it was cutting 20% of its sales force. That news coupled with the torcetrapib announcement now makes sense.
I to think that “easy “targets” such as heart disease and diabetes may be nearing their natural limits for medication therapy”. Many of the health problems today are over-medicated, and the positive results from things such as a healthy diet and daily exercise are overlooked and under-utilized.
Let’s just review some basic biochemical facts.Cholesterol has a hydrophobic end as well as a hydrophilic end. It is an essential component of cell membranes as it is “the bridge” between aqueous molecules and lipid molecules for holding them together. Cholesterol is insoluble in water and therefore also in blood. Cholesterol gets converted to cholesteryl ester and carried inside a surrounding covering of water (blood) soluble lipoprotein. CETP releases cholesteryl ester from LDL and HDL so that it can be used in cell membranes. Inhibiting CETP does two things…it stops cells from getting necessary cholesterol and you also now have a synthetic torcetrapib molecule (or any other toxic drug molecule) stuck to the non-functional CETP. The immune system now recognizes this complex as an antigen. Blocking this important transfer protein is the biochemical equivalent of cutting your telephone line or drilling holes in your boat. The immune system attacks the foreign synthetic drug molecule stuck to the CETP by oxidizing it which is the first stage of the immune response…the LDL particle is then immobilized on the vessel wall..it is attacked by monocytes which gobble it up. The monocytes pull the offending toxic LDL particle through the vascular endothelium and continue to attack it.If there is excess toxic material the monocytes burst releasing toxic material which is attacked again by other monocytes eventually leaving lots of dead cell debris in a pool of toxic chemical thus forming the plaque. You all know the rest of the story. The body can eventually repair this mess given the chance. The same applies to any medication. ..it has to be disposed of. If there is too much…the body can’t cope in trying to contain the toxic material which leads to plaque formation. It simply does not make sense to block CETP. This pharmaceutical arrogance misleads everybody. There is no such thing as “good” or “bad” cholesterol. Cholesterol does not cause heart disease. (See http://www.thincs.org and http://www.statinalert.org) Diet has absolutely nothing to do with causing heart disease and saturated fat is better for you than poly-unsaturated fat. Statins can cause cardiomyopathy among many other side effects by blocking Co Enzyme Q10. Eggs are very healthy and contain the most cholesterol of any food known. The world has been conned by corporate fascism and political lobbying because they have manipulated science for their own financial gain instead of sticking to scientific fact for the good of humanity. Millions of people have been killed by well intentioned doctors prescribing toxic medication. The “guidelines” are written by pharmaceutical “whores” and do not reflect the truth. Your cholesterol level has a genetic set point and whatever your level is is right for you. See Wikipedia and enter SREBP (Sterol Regulatory Element Binding Protein). Eat good food,exercise,stop smoking and avoid drugs for optimal heart health.Ignore DTCA ads. on the media. Avoid trans-fats fats which also can make your cell walls leaky and cause Type 2 Diabetes according to some. Suggest also that you sell all your pharmaceutical shares immediately so that we don’t have to listen to their lies anymore and start living healthier lives as is our God given right! Stuff the share-holders!
As a participant in the Torcetrapib study and a user of the actual drug I am deeply saddened by the outcome of the study. What also appals me are the comments concerning putting Pfizer in its place due to its greed etc. As a victom of a heart attack, high blood pressure, and a 5 way bypass I felt that this drug would help me to continue my life by helping raise my HDL. Through diet and lifestyle changes I have managed to lower my cholesterol level, lower my triglycerides, lower my LDL and everyother item that I have been told to do. The only thing that I had no effect was a HDL level of 28. I want to thank P
I also was participant in the study. It helped raise my HDL significantly. Wht concerns me about Pfizer is that it was at the vey least over a month after they knew of the dangers before they pulled the drug. To me that implies that they did not care about their volunteers.
I also was a participant in the study and feel like I’ve been given a time-bomb.(I just had a blood test and my HDL is 89, so my guess is that I was taking the drug) Three questions: (1) How could Pfizer (or those running the study) not have known one, three or even six months before December 2 of the incresed mortality rate? Thirty people could n0t have died in November. (2) Will Pfizer (or someone) keep following those in the study to see what happens to the mortality rate after December 2(failure to do so seems highly irresponsible)? and (3) Who (aside from prisoners) would agree to paticipate in another clinical study of this kind of drug?
Two points:
Anon 0158-Most clinical trial protocols have very specific guidelines on if/when data can be examined for a trial in progress. Imagine for a moment that instead at the end of each day they ran the stats to see if they had reached their adverse events threshold. It isn’t so inconceivable that in the first month or two, by pure chance, there are excess deaths in the medicated group. In the extreme case, if you checked every day and by chance 1 person in the medicated group died before anyone in the control did, then would you stop the trial because there were infinity % excess deaths in the experimental arm?
Given that they only exceeded death threshold by 2 deaths, they were probably just under threshold at the last in-trial data analysis point.
Kevin-
You said (I think it was you, might have been a quote …) that you thought Pfizer was stupid to test combination therapy vs lipitor instead of mono tx vs placebo.
I suspect that they couldn’t find an IRB that would approve that design. I don’t know off hand, but how big a market is there for people needing only to raise their HDL without lowering LDL? Presumably in order to recruit enough subjects they would have needed people with elevated LDL and the ethics panel would never have approved a protocol that had a placebo control arm when those people definitely needed a statin.
Finding patients with low HDL, <60 mg/dl, would be relatively easy.
RE: 40 year old data, Framingham Study, the most common lipid [cholesterol] defect is NOT elevted LDL. It is low HDL. If you use a directly measured lipid panel with ALL the lipid fractions [as they did in the Framingham, ultracentrifuge / Beta-quantification ] vs. a Friedewald calculation / “Guesstimate” based lipid panel,.. as was known then [~40 years ago] is well known now. The Vertical Auto Profile, the VAP test, is a modern, high-volume commercial version of Beta-Quant.The MOST frequently observed lipid defect in ALL of the tested population for the year 2002, was LOW HDL2. The prevalence was ~74%. Far exceeding LDL > 130 mg/dL or even 100. ISOLTED Low HDL2, the ONLY lipid defect on the panel, was found in 30% of those tested. Nearly 1/3rdof the tested population. In the Framingham Study, traditional lipid factors [A Friedewald calculated LDL, total cholesterol/TC, triglycerides/TGs and HDL] accounted for only 40% of premature CAD. 75% of patients with an MI, Myocardial Infarction / heart attack, have “normal” levels of LDL and HDL. 80% of patients in the Framingham who experienced an MI or a stroke had ‘traditional’ lipid levels IDENTICAL to those patients who were event-free.
The fractions & ratios of the totals RE: TC/HDL being the most accurate, are far more specific at identifying risk of CAD, as well as predicting events. The single most powerful predictor of risk for CAD & vascualr events is NOT LDL, but using Beta-Quant [or the inexpensive commercial version, the VAP] it has been found to be the large buoyant fraction of HDL,.. HDL2 or HDL2b. Food for thought. Niacin @ 1 gm/day increases HDL2 / HDL2b by 113% at the 1st year,.. and continues its increase for up to 3 years. 2 gms/day increases HDL2 or HDL2b by 189% at the 1st year. The flush is transient, and when put in the hands of an EXPERIENCED clinician [>30% of his/her dyslipidemic patients on at last 1 gm/day of niacin] it is not that difficult. The lost art form is key: Patient education. 5 minutes at the initiation of therapy. 3 TBS applesauce,.. followed by washing the niacin down with 3-4 z water containing one dissolved Alka-Seltzer tablet [325 mg ASA aqueous]. Worked for Dr Wm Castelli of the landmark Framingham study 40 years ago & still works today. 50 years of safety, efficacy, regression of CAD, reduction of mortality & outcomes data [MI & stroke]. The short memory , or selective memory currently witnessed in medicine re: niacin is rather frightening. See Dr Bradley Bale`s video on Google. 3800 patients at risk followed for 10 years. 25% had already been cath`ed / PTCA or had a CABG, open heart sx. Only one MI & no deaths. TEN YEARS.
89% on statins and 66% on niacin. The future is already here,.. and has been for 40 years. Isn`t it time we mandated training for the SUCCESSFUL administration of prescription niacin ?? Not enough Big-Pharma $$$ to fund this ??
Ad infinitum, ad nauseum.
SDMc
Epidemiological studies have already shown that people with CETP deficiency have increased incidence of coronary heart disease. See Zhong et al. (1996) J. Clin. Invest. 97:2917-2923, “Increased Coronary Heart Disease in Japanese-American Men with Mutation in the Cholesteryl Ester Transfer Protein Gene Despite Increased HDL Levels” (full text available). In that study the people with CETP deficiecy had 35% less CETP activity, 10% elevated HDL, and 1.4-fold greater risk for coronary heart disease. Given that CETP enables the flow of cholesterol from the peripheral tissues (including cholesterol deposits in arteries) to the liver, it makes sense that inhibiting this process should be deleterious. It is not the amount of HDL that is relevant but the flow of cholesterol from the periphery to the liver, that is normally mediated by HDL. Evidently, the HDL particles whose concentration rises when CETP is inhibited or deficient are different from the normal mix of HDL particles that exist in normal physiology. I am surprized that Pfizer decision makers subscribed to the simple view that high HDL is good, no matter what type of HDL and at what physiological cost.
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