Great NYT Story — On Injectible Biologic Candidates — Promising To Revolutionalize LDL Management

As it’s a rather quiet news week at Whitehouse Station, I’ll point the readership to an older discussion we had here — brought back to top of mind, by this fine article from Gina Kolata, writing for The New York Times, this morning.

It’s a fast-paced, breezy plain-English, but scientifically accurate, read through — of the exciting race to create a biologic (i.e., grown inside living cells) agent that mimmicks an exceedingly rare, and exceedingly beneficial, genetic mutation which makes certain people almost immune to heart disease. That mutation, it turns out, was discovered because someone noticed the racial differences in otherwise similar populations, related to LDL levels. But I am getting ahead of myself.

Do go read it all, but here’s a bit:

. . . .She was a 32-year-old aerobics instructor from a Dallas suburb — healthy, college educated, with two young children. Nothing out of the ordinary, except one thing.

Her cholesterol was astoundingly low. Her low-density lipoprotein, or LDL, the form that promotes heart disease, was 14, a level unheard-of in healthy adults whose normal level is over 100.

The reason was a rare gene mutation she had inherited from both her mother and her father. Only one other person, a young, healthy Zimbabwean woman whose LDL cholesterol was 15, has ever been found with the same double dose of the mutation. . . .

And so, this sleuthing for a drug/biologic to mimmick the beneficial LDL mutation story reminded me of a discussion we had, when Sen. John McCain was running for President (in the Spring of 2008) — and lower LDL via a “gut mechanism” was being shown likely to be little more than an “extremely-expensive placebo” (Vytorin®/Zetia®), day by day. Back then, we all expected that IMPROVE-IT might well settle the question, definitively — and be published by 2012. We now expect IMPROVE-IT results some time after 2014.

To be clear — I do think the biologics’ approach to LDL lowering has a very good chance of being wildly-successful in improving outcomes — reducing heart attack risks. This is so because the mechanism each biologic employs (i.e., not a gut mechanism) is so different. If these biologics reach market before 2015, whatever IMPROVE-IT shows will become largely a footnote — it will all have been leap-frogged, by advancing science.

So while the question is still open — I’ll rerun that 2008 piece here — enjoy:

[UPDATED — 05.26.08 Noon: Mike Huckman, of CNBC, just linked my blog — presumably for the goofy graphic, below, right. Very cool. Here is the actual post-page of mine, to which he linked.]

Over the long Holiday weekend, once Ed at Pharmalot noticed the above change-in-meds in a news report of the Senator’s recently-released health records, we had some fun with graphics — creating a “collectible” campaign button for the above presidential-hopeful [click small version, at right, to view full-sized image]. Then, rather unexpectedly, a more serious discussion evolved in our comment-box. We highlight it here — and hope that it will continue.

Thanks thus go to the Anonymous Commenter, below. My thoughts are in dark-blue, the Anonymous Commenter’s are in dark orange [all as in the original, save the clean-up of a few obvious typos on my part]:

Anonymous said…
Yes, humorous. What about the idea around “getting the patient to goal?” If the Senator’s LDL has elevated up to 123 from the 80’s, the Vytorin was working and now the Zocor can not do the job. We are without the Senator’s complete medical status and cannot determine what other major risk factors might be present. (McCain’s age counts as one risk factor. What is his HDL? Does he have a family Hx of heart disease?) Using the word “acceptable” is only relative; some physicians are more aggressive and some are not. Many physicians treat all their patients to an LDL goal of less than 100.

I would prefer to rely on the more than 25 years of evidence that there is a clear relationship between lower LDL and fewer cardiac events – 4S, HPS, WOSCPS, ASCAP, POSCH, etc. Until the NCEP changes elevated LDL cholesterol as the primary target of therapy, chances are better that a smaller LDL number is a better number. We are starting to see patients who insisted on being removed from Zetia who are no longer at goal. Many are rethinking that original decision because their Vytorin was working and there are no safety issues in the Enhance trial. In spite of Enhance being handled poorly, it is only a piece of the pie – a bit of information in the long continuum of understanding how a drug behaves.

The drug’s usefulness and the behavior of the executives continue to diverge. The issues of behavior continue to be troublesome but the issues around Vytorin are less so.

How about this question: If lower LDL is better for sick patients, why wouldn’t lower LDL be better for patients without heart disease, especially those that may be serving as president?

May 24, 2008 2:29 PM

condor said…
It is well to note that we share a sense of humor — that ought to serve us well, in our discussions.
Now, I think the crux of our disagreement will boil down to “Why that particular goal level (LDL number)?

I think it fair to say that for his advanced age, Senator McCain enjoys very robust cholesterol/heart health. Did you see his scores on the treadmill/stress test? Pretty impressive — for a guy his age.

That is the (very) good news.

Now, some clean-up, here: your “25 years of evidence” do not speak at all to gut-mechanism LDL lowering (the Vytorin/Zetia method). All that data is from statins, and earlier drugs (i.e. liver mechanisms).

Gut mechanisms” for LDL lowering may — emphasis may — simply change/lower the number, without any real benefit to mortality risks.

Because Sen. McCain is so relatively-healthy, this may be a smaller concern for his case, but aren’t you at all concerned that using Vytorin in all cases, aggressively, may lull patients into a false sense of security i.e., “my NUMBER is way low; that’s GREAT!” — so much so, that they stop eating a healthy diet, or stop exercising, and then suffer a cardiac event?

What if it just doesn’t work?

I think I would be concerned about that. What if Vytorin is like being “book smart” (a kid who tests really well on the ACT), but lacking “street-sense” — getting rolled all the time, for lack of common sense (out well after midnight, alone, in a tough neighborhood — one he doesn’t know, at all — in a dark alley, on foot)?

That is why we must wait until 2012, at the earliest, to know whether Vytorin is worth all the extra money, and all that (circa 2006) fanfare.

Thanks for the thoughtful, and thought-provoking, commentary.

Do stop back.

May 24, 2008 5:52 PM

Anonymous said…
Ah, yes, it certainly will. Humor me now.

LDL goals are carefully designed by a large group of experts. (Refer to the NCEP guidelines.) These goals are not advised without a great deal of evidence as well as taking risk of side effects into consideration. I am not alone in believing an “acceptable” LDL is not the best approach. I quote the press briefing for Senator McCain, “But several outside cardiologists not involved in Sen. McCain’s care said cholesterol tests and blood-pressure measurements also included in the records suggest his risk of having a heart attack in the next 10 years is at least 17% — and perhaps a little above 20% — and they recommend more-aggressive treatment than the senator is getting.”

There is substantial evidence that the more aggressive approach in lowering LDL produces a greater reduction in LDL and fewer cardiac events.

Back to basics: LDL can be lowered by a variety of strategies. The comment that “All that data is from statins, and earlier drugs.” is simply not correct.

1. Diet and exercise (life style changes) are frequently recommended for patients and can lower LDL.

2. Statins, Fibrates, Bile Acid Sequestrants, Nicotinic Acid and Cholesterol Absorption Inhibiors (Zetia and the gut mechanism) ALL lower LDL.

3. Ileal bypass lowers LDL as well. The POSCH study, not a statin study at all, demonstrates this effect. See the review:

In 838 patients followed for 9.7 years, the marked lipid modification achieved by partial ileal bypass in the POSCH trial led to demonstrable increases in the disease-free intervals for overall mortality, coronary heart disease mortality, coronary heart disease mortality and confirmed nonfatal myocardial infarction, and coronary intervention procedures. For the clinician and the patient, estimation of disease-free intervals may be more relevant than assessment of differences in incidence rates and risk ratios.

The POSCH findings in women support the aggressive treatment of hyperlipidemia in the general management of atherosclerosis in women.

Effective lowering of total cholesterol and low-density lipoprotein cholesterol in a postmyocardial infarction population significantly reduces atherosclerotic coronary heart disease (ACHD) mortality, ACHD mortality combined with a new confirmed nonfatal myocardial infarction, and the number of coronary artery bypass grafting and angioplasty procedures performed.

Significant differences in morbidity and mortality were preserved over a 5-year period following the trial.

Let’s return to the initial 25 years of evidence referenced, which DO speak strongly of the relationship of lower LDL (from MANY sources AND not limited to statin use only) to fewer events.

There is a Log-linear relationship between LDL-C levels and relative risk for CHD. This relationship is consistent with a large body of epidemiological data and with data available from clinical trials of LDL-lowering therapy. These data suggest that for every 30-mg/dl change in LDL-C, the relative risk for CHD is changed in proportion by about 30%. The relative risk is set at 1.0 for LDL-C =40 mg/dl.
Grundy SM, Cleeman JI, Bairey Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44:720-732.

As to a false sense of security, it is commonly agreed that life style changes are easier said than done. Even if they are executed perfectly, this strategy only lowers LDL by 10-20%. Patients commonly need 40% lowering or more.

Good street sense can be demonstrated by following the mountain of evidence pointing to the importance of lower LDL. It is reasonable to conclude that any strategy that lowers LDL will most likely result in fewer events. A variety of strategies can be implemented to achieve reduction in LDL including (but not limited to) “the gut mechanism”. It is simply naive to propose that Vytorin/Zetia “don’t work.”

Using appropriate Tx and combinations of strategies, including Vytorin and Zetia when indicated takes advantage of this evidence. Waiting until 2012 for additional confirmation will prove deleterious for some. There is enough evidence to adopt an aggressive strategy at the present. Lower LDL prolongs life, therefore I stand by the argument that Senator McCain, and you and I should not settle for an LDL above 100.

Thank you for your extensive research regarding these troubles of SP. The drugs created by scientists are not the source of SP difficulties. Instead continue to follow the money.

May 25, 2008 12:28 AM

condor said…
Thank you for this thoughtful discussion. Your points deserve a longer response — one which I will return to offer, after the Holiday weekend, here in America (circa Tuesday). I’ll likely post your very fine comments, and my responses as a new, headlined blog-post, then, okay?

For now — let me be more precise — as your insightful replies have revealed my muddy word-choices here.

Is there any study that shows an outcome benefit — in any population — for lowering LDL via a “gut mechanism“?

You and I both know the answer to that. The answer is “no“.

And you are right — I am not upset with most of the Schering scientists — it is their keepers, in K-1, I am disappointed with.

I did, in fact, “follow the money“, and I found that Vytorin costs between 3 and 10 times what generic statin-only-regimens cost.

That is plainly the fault — the shared fault — of Schering’s executive team, and the FDA (for approving a drug that shows no incremental “outcomes” benefit).

What I don’t get is how the Schering spin-meisters can convince themselves that they are serving the common good by overcharging for an in-the-best case (at present) “me, too!” product.

There is simply no evidence that the “gut mechanism” — Vytorin/Zetia’s — works to improve actual outcomes.
Follow the money, indeed — it leads to a marketing flim-flam.

May 25, 2008 7:54 AM

Anonymous said…

I propose the reason for your continued insistence that Vytorin/Zetia are a medical rip-off: We are offering these divergent views due to differing definitions of the word “outcomes”. We are approaching the word as if it has one meaning and we each are using a meaning that is learned from our own experiences. This careless handling of the word is akin to running fast and loose without agreement on basic vocabulary and definition.

Based on that wide chasm, you believe there is a “flim-flam” and I argue that bad behavior from executives aside, there is significant evidence that using Vytorin/Zetia does have merit.

Recent developments in medical program evaluations address the two primary concerns of cost and quality of care. Political concerns about the rate of increase in cost of medical care led to an intense interest in evaluating procedure- or treatment-specific costs in order to curtail them. However, there is a great danger that uninformed attempts to cut costs may, while achieving their goals, significantly sacrifice quality of care. Thus, it is essential that quality of care ought not be relegated to second place in deference to pure cost containment issues, but rather be given at least equal status.

The theory and practice of measuring quality of care has evolved over time. The recent evaluative history of quality has centered on the assessment of patient outcomes, appealing to the last of the sequence of structure, process and outcome as originally proposed by Donabedian (1966). It has been recognized that evaluating only structure or process in health care delivery falls short of the ultimate measure of interest–patient outcomes. While structure and process are not irrelevant for evaluating health care systems and technologies, neither are they sufficient. Measuring patient outcomes is paramount.

Theoretical and conceptual research in pharmaceutical outcomes evaluation is focused on the relationships between biological parameters, clinical manifestations and health outcomes and the relevance of each of these levels of measurement for economic evaluations. Moreover, structure and dependence of each of these levels of outcomes is a fruitful area for conceptual development so you come by your bias honestly.

You might consider an in depth review of the FDA process for new drug approval, interviews with study designers or pharmacists to understand their definition of what different types of “outcomes” are possible. In this way you might narrow your complaint to a single interpretation of the word’s meaning.

Traditionally, medical “outcomes” refer to mortality and morbidity. From your comments, “outcomes” might mean patient outcomes, patient cost satisfaction, short term outcomes or a variety of other interpretations.

Using your perceived definition of “outcomes”, the Enhance trial had none but the Sands trial has. Neither are powered for or provide “Outcomes” in the traditional sense.

Before we can advance, you must “see” that the discussion should be narrowed by further and more specifically defining “outcomes”. There is a whole field of emerging study around this topic.

The development of more precise models and more efficient methods for assigning dollar values for changes in disease status and treatment processes are also needed to establish cost profiles for various treatment protocols. This costing research requires a detailed understanding of the clinical course of the disease, methodological issues and the potential clinical manifestations of the treatment regimen.

I remain interested in your evaluation of these problems. I remain steadfast in my belief that Vytorin and Zetia are clearly NOT “me too” products and are worth a premium as well. Over time, we most likely will converge on these issues.

May 25, 2008 11:43 AM
condor said…
I think you are right. We have not yet agreed about the word “outcomes” — in this context. Here is what I mean, when I refer to “outcomes“:

Improved outcomes would mean, to my way of thinking, a reduced rate of mortality, or reduced rate of cardiac events, all as compared to a “statins-only” regimen, in similarly-situated patients.

That is what IMPROVE-IT is, ostensibly, looking at. So, I guess we wait until 2012.

As to the POSCH study — lowered LDL via a liver mechanism [note that POSCH also relied on “. . . .an indirect cholesterol drain from increased hepatic conversion of body cholesterol stores to bile acids to replenish the depleted bile-acid reservoir. . . .” — a liver-draning mechanism, that!], IMO, does not equal lowered LDL via a gut mechanism — that much may safely be inferred from the ENHANCE study [non-] results. Else, why would we not have seen statistically-significant improvement in Vytorin patients, vis-a-vis statins-only patients. Remember here that — contrary to the companies’ claims — Dr. Bots declared the data were “fine. . . . no better, and no worse. . . .” than comparable sets of data measured the same way. So it will not advance the discussion, between the two of us, to suggest that ENHANCE is simply a case of bad measurements/faulty data.
I await your relpy. Thank you for the wisdom of your commentary, here.
May 26, 2008 11:14 AM
Anonymous said…
72 comments from the WSJ blog emphasize the practice of medicine as one of both art and science. “We must carefully evaluate cardiovascular risk and follow evidence based guidelines to HELP prevent heart disease”, as Dr. Cannon suggests. The POSCH study was quoted to remind that cholesterol can be reduced by a variety of methods, even surgery. I can not see where Enhance was suggested to be “simply a case of bad measurements/faulty data.” This game is one of chance. In making a move, it is useful to look at evidence and trends, individualize the approach and make a calculated decision on Tx. It is complicated and reminds us that we are doing our best without knowing all of the answers, even if one chooses to “wait” until 2012.

May 28, 2008 12:10 AM

condor said…
It could be that WSJ commenters have a little more skin in the game than some of those at the general health-care blogs, but we certainly agree as to that last sentence: “. . . .It is complicated and reminds us that we are doing our best without knowing all of the answers, even if one chooses to “wait” until 2012.”
May 28, 2008 4:10 AM


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