Vytorin And Zetia For Children? Not Yet, But…
14 CommentsBy Ed Silverman // March 18th, 2008 // 7:53 am
The FDA has granted pediatric exclusivity. Of course, this doesn’t mean the pill has been given a green light for kids. Besides, it’s not the right time. You may recall that the controversial Enhance trial found that the cholesterol pill failed to show any benefit over the much cheaper Zocor in reducing plaque in the carotid artery, and even showed a statistically insignificant buildup, although it did a better job of lowering LDL. The results created a debate about the merits of using Vyotrin, which includes Schering-Plough’s Zetia and Merck’s Zocor.
Nonetheless, Schering-Plough disclosed in a filing with the Securities and Exchange Commission that the exclusivity will add six months to the patents on Vytorin and Zetia. The composition of matter patents will now expire on April 25, 2017. This should give Schering-Plough and Merck, its joint partner in the cholesterol market, plenty of time to get past the controversy and develop a plan to treat children with high cholesterol.
Of course, given that scrips are way down, perhaps marketing to kids will start sooner than we think. Vytorin and Zetia scrips fell precipitously in February, according to IMS Health data cited in the SEC filing. Vytorin dropped nearly 13 percent, to nearly 1.6 million scrips and Zetia was off by 13.7 percent, to about 1.18 million. Wall Street analysts, however, believe the controversy over the Enhance results may diminish at the American College of Cardiology meeting later this month, when the full data is discussed in detail.
UPDATE: A Schering-Plough spokesman wrote us on Wed., March 19, to say that “the pediatric abstract for Study PO2579 will be presented by John Kastelein at the annual meeting of the European Atherosclerosis Society (EAS), Istanbul, Turkey, April 26-29, 2008. The manuscript has been submitted to JACC and is pending review and publication.”
Nathan
I’m sure this post was largely “tongue-in-cheek”, but in all seriousness I happened to run across an article this morning about a rare genetic disorder (called Progeria) that results in accelerated aging. Kids diagnosed with Progeria typically die by age 13 of heart disease. Marketing a drug like Vytorin or Zetia to kids like these is no laughing matter. It may add a few precious years to their lives.
Ed Silverman
Hi Nathan,
Largely tongue and cheek, yes, given the circumstances surrounding the drugs, the companies and their clinical trial. This was written from the perspective of looking at a pair of companies that could use a bit of a sales boost. The timing, as it so happens, is serendipitous.
Of course, this shouldn’t diminish the possibility that Vytorin or Zetia would not be helpful to some children some day. And I didn’t intend to suggest that. I don’t think I did.
Thanks for the info,
ed
Jack2
Plus familial hypercholesterolemia.
To get pediatric exclusivity do you just need to test the drug in kids for your original indication, or do you need to test it and win approval?
MKM
My 14-year-old daughter has heterozygous familial hypercholesterolemia (heFH), and I can tell you that ezetimibe is already being used in kids. My daughter used to be on it. Now she’s on a statin, and her cardiologist wanted to add ezetimibe, but I would not consent. I note that the AHA guidelines for kids with high-risk lipid abnormalities (published in Circulation last year) advocate using statins as first line treatment.
In addition, statins have been shown to prevent or slow the development of atherosclerosis in teenagers with heFH. Ezetimibe has only been shown to lower LDL. Not to mention that we have outcomes data in adults with statins, which we don’t have with ezetimibe.
Most of the patients in the ENHANCE trial had normal IMT, because they had been on high-dose statins. IMO, that shows that we don’t really need an add-on drug for people with heFH.
I also note that kids with heFH have endothelial dysfunction. Statins have shown to improve endothelial dysfunction. Ezetimibe has no such effect.
Marilyn Mann
CV MD
All this means is that the companies have performed the FDA-required work in pediatric patients and that short-term use is effective and safe for lowering cholesterol. The companies make an agreement with the FDA as to what needs to be done and then they do it. Because they do it, they get 6 months of extra exclusivity for their patent-protected product. It is a program that generates some additional data in kids and makes good business sense.
MKM
CV MD: I agree it makes good business sense, but the additional data they generated through conducting a trial in adolescents with heterozygous familial hypercholesterolemia seems worthless. The record on clinicaltrials.gov does not say, but I assume they were only looking at LDL. We already know ezetimibe lowers LDL, so how does that help us? Plus, I have not seen any announcement of the results. It is possible they plan to publish them (the trial was completed in June 2007).
Marilyn
Jack2
MKM: I presume they will at least present this data as a poster somewhere (if they haven’t already), and probably publish it. For a trial that ends in June 2007 to not be published yet is not unusual.
And you’re assuming because the drug lowers LDL in kids it will lower it in adults. Probably, but no one knows for sure until they do it. Also, the data will probably better inform dosing in pediatric patients and tolerability expectations.
CVMD: So they get exclusivity as long as they do the appropriate trial - not whether the drug works or not. Correct? (that’s how I think it should be)
MKM
Jack2
We know ezetimibe lowers LDL in adults. What we don’t know is whether it prevents heart attacks and strokes.
Marilyn
Nathan
Jack2,
You are correct. The pivotal question is whether the trial has been done in compliance with the FDA request. It has nothing to do with the outcome of the trial. Here’s a quote from the FDA web site: (see
http://www.fda.gov/cder/pediatric/faqs.htm)
“Q9. For approved drugs, must FDA approve a supplemental application before pediatric exclusivity is granted?
A9. No. The granting of exclusivity is not connected to approval; the pivotal factor is whether the applicant complied with the terms of the Written Request.”
BDM
The pediatric studies are mandated and conducted under the “Written Request” received from the FDA. They are usually more about safety than efficacy because patients younger than 18 years of age may have age-specific safety concerns and handle the drug differently than older pateints. Hence, safety and pharmacokinetics are very important results coming out of these studies. As a reward for doing the studies, the companies get 6 more months of exclusivity on the market. As they did th studies in HeFH, they may try to obtain an indication for the use of their drugs in this more difficult type of hypercholesterolemia.
Jack2
Thanks Nathan.
MKM: But you didn’t know it lowered it in kids. Also, to get pediatric exclusivity the company must pursue a trial similar to the one it pursued to get original market approval - just in a pediatric patients. This trial should not be connected to the Enhance trial.
MKM
Jack2
I don’t care whether it lowers LDL in kids or not. I care whether it prevents atherosclerosis, heart attacks and strokes.
We don’t need ezetimibe for kids with heFH because statins do the job. Witness the patients in ENHANCE, whose arteries were mostly normal, due to having been treated with statins.
Given that there is substantial uncertainty with respect to ezetimibe’s efficacy, there is no reason to give it to kids, except perhaps in rare cases.
Marilyn
Nathan
MKM,
I think you are missing the point. So far as I can tell, no one has claimed that ezetimibe is benificial for kids. The only thing we know is that SP and/or Merck has filed for pediatric exclusivity. They are allowed (and encouraged) to do so whether or not the drug is ultimately proved to be benificial for the pediatric population. Filing for pediatric exclusivity DOES NOT mean that the company is claiming that the drug is benificial for the pediatric population.
MKM
I would assume the FDA has some discretion as to whether or not to approve such an application. However, I have not studied the issue and it seems pointless to argue the point.
Here is some research comparing ezetimibe with a statin:
Landmesser et al., Simvastatin Versus Ezetimibe: Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans, Circulation. 2005;111:2356-2363.
http://www.circ.ahajournals.org/cgi/content/abstract/111/18/2356
Marilyn