1. Marilyn Mann on May 20, 2009 4:00 PM writes...

If mipomersen is safe and effective, it would be an advance for homozygous FH patients, because otherwise they usually have to have LDL apheresis.

Another potential use of mipomersen is for lowering lipoprotein(a). See this study in mice:

http://circ.ahajournals.org/cgi/content/full/118/7/743

I am personally interested in this, because my husband's lipoprotein(a) is elevated. Also, my husband, daughter and MIL have heterozygous familial hypercholesterolemia (heFH) (my husband only has a mild case, i.e., incomplete penetrance).

I have some doubts about how big the need is for an additional drug for primary prevention in heFH patients, assuming they are not statin-intolerant. Statins are already very effective in heFH patients, as shown by this study published in BMJ last year by FH researchers based in the Netherlands:

http://www.bmj.com/cgi/content/full/337/nov11_1/a2423

Versmissen et al., Efficacy of statins in familial hypercholesterolemia: a long term cohort study, BMJ 2008;337:a2423

Of course, in people with heFH treatment needs to start early, so if someone isn't diagnosed until middle age I suppose you would try to reach a lower LDL target than otherwise, in which case you would probably need an add-on drug.

Or if someone with heFH already had heart disease, you would be shooting for a lower LDL target.

I guess my basic point is that even if someone has very high LDL (e.g., my 16-year-old daughter's is 250-270 when not on medication), you can still substantially lower their risk of premature heart disease with statins, especially if you start treating them in early adulthood.

Do you have any information on when Isis/Genzyme is going to start their outcomes study?

2. Chrispy on May 20, 2009 4:01 PM writes...

I think there are a lot of people (myself included) who are wondering HOW this drug works. It is hard to believe that it really works through antisense. If it did then it would be truly transformative. You've written a lot about the non-antisense effects of antisense treatments; it seems likely that there is some other mechanism.

3. adam on May 20, 2009 4:13 PM writes...

liver tox! danger danger!!!

4. Bob on May 20, 2009 5:21 PM writes...

Mipomersin?????

Can someone, anyone tell me how they end up naming these drugs. It's always a name on the fringe of pronounceability.

5. CMCguy on May 20, 2009 6:32 PM writes...

Bob I know the last part of the drug names are dictated by USAN conventions (in this case "ersin" I think) so companies try to tag the front with something that "easier" to say or perhaps spell but there are many rules/restrictions that make it difficult. Some places I have been had naming committees or contests while at others its decision of usually high up individual (CEO, Reg VP, Marketing VP). This becomes the generic name that often fades since most places do attempt to make the Trade name easier or more memorable.

6. George on May 20, 2009 8:22 PM writes...

There is no threat of liver toxins. The analysts completely missed the mark on this one. I will be loading up on these dips.

7. PottedPlant on May 20, 2009 10:48 PM writes...

I love ISIS....I go to the Head of the class with ISIS. ISIS is the best...its drugs will cure all diseases man has ever had or will have.

Live toxicity....yes, but that doesn't matter.......we have another antisense drug that cures liver cancer and liver toxicity too.

Go to the Head of the Class with ISIS.

A death to the "dream team"

Potted Plant

8. baby bird on May 21, 2009 2:37 AM writes...

@ Bob
quote:
"Mipomersin?????

Can someone, anyone tell me how they end up naming these drugs. It's always a name on the fringe of pronounceability."

there is a pretty cynical marketing strategy that gives drugs an almost unpronounceable name, that way people use the brand name, for an example oseltamivir vs tamiflu, and the profusion of x's and z's in drug names.
the idea is doctors can't pronounce the generic name so use the brand name and therefore buy the branded product

9. CMCguy on May 21, 2009 10:05 AM writes...

Bob I was incorrect as antisense oligonucleotides have the "rsin" as USAN stem. (USAN is part of AMA so in theory is MDs who select the generic name)

The "rules" linked below and even then a company only makes recommendation(s) that get approved.

http://www.ama-assn.org/ama/pub/about-ama/our-people/coalitions-consortiums/united-states-adopted-names-council/naming-guidelines.shtml

Guess the only saving grace is that in general the USAN name is better than attempting to use IUPAC type nomenclature on most molecules.

10. Hap on May 21, 2009 2:12 PM writes...

They probably couldn't fit the structure on the label, let alone the systematic name. Would the drug company get a dispensation if they had to use the IUPAC name and couldn't fit it on the label?

11. brian on May 22, 2009 2:04 AM writes...

Hi Derek,

Its wonderful that ISIS has clinically demonstrated that they can partially block ApoB production using anti-sense. And that this, in turn, lowers serum LDL. Great proof of concept.

But, before we load up on ISIS stock, please keep in mind that LDL levels are still a surrogate measure for all the clinically proven benefits of taking statins (and, yes, more evidence mounts regarding reduction of cancer risk and (!?!) erectile disfunction.) There is still slim to no clinical evidence of any such benefits for other classes of LDL lowering drugs.

Frankly, I would be strongly against ANY approvals for this indication with novel mechanisms based solely on surrogate measures. ISIS should be required to demonstrate actual risk reductions, and that will be costly, take time, and may, in fact, fail.

However, I am slightly more optimistic about this drug than, say, Zetia, because of its mode of action. By blocking the expression of ApoB, it may still have the effect of surpressing the HMG-CoA reductase pathway in liver cells (as the products of that pathway will therefore accumulate and inhibit it.) But not in the rest of the body, and probably not in exactly the same way as a statin.

But I have not seen any of the data, so I cannot say. Frankly, without actual clinical trials looking at the right endpoints, we just won't know what benefits (or risks) this class of drug will actually have. Sorry.

12. Marilyn Mann on May 22, 2009 8:51 AM writes...

Agreed on the need for a study with clinical endpoints before we know the risks and benefits of mipomersen. My understanding is that the FDA has told the sponsors that such a study will need to be completed before approval can be sought for indications other than homozygous FH.

http://www.sec.gov/Archives/edgar/data/874015/000110465908026744/a08-12569_1ex99d1.htm

13. brian on May 26, 2009 1:30 AM writes...

FH patients are perhaps the only group where elevated serum LDL might actually be an indication rather than a surrogate measure of risk. Especially in the case of homozygous FH, where heroic measures to lower it by any means possible are justified.

In these patients, the condition is almost analogous to gout, in that cholesterol literally precipitates out of the body (I.e. Xanthomas, see http://www.londonideas.org/internet/FHCascade/FH.htm)

I agree that these folks should have access to ANY drug which lowers their cholesterol, has relatively good safety profile and which can be used as an add on therapy to statins (which should still be the primary drug of choice, given the overwhelming clinical evidence demonstrating its safety and efficacy to date.)

14. Marilyn Mann on May 27, 2009 12:32 PM writes...

Hi Brian,

Since you bring up xanthomas, you might be interested in this recent study by (who else?) some of the FH experts in the Netherlands:

Differences in characteristics and risk of cardiovascular disease in familial hypercholesterolemia patients with and without tendon xanthomas: A systematic review and meta-analysis

Oosterveer et al., Differences in characteristics and risk of cardiovascular disease in familial hypercholesterolemia patients with and without tendon xanthomas: A systematic review and meta-analysis. Atherosclerosis article in press.

The study is of heterozygous FH patients with a genetically confirmation of an LDL receptor mutation. Age, male gender, LDL-cholesterol and triglyceride level were associated with the presence of xanthomas (p

Another genetic disease associated with xanthomas is sitosterolemia, which is fortunately very rare. In sitosterolemia, plant sterols build up in the bloodstream to very high levels, due to mutations in the genes for the ABCG5 and ABCG8 transporters.

Sorry Derek for getting a little off-topic.

15. Marilyn Mann on May 27, 2009 12:38 PM writes...

Part of my comment seems to have disappeared. It should read: p

16. Marilyn Mann on May 27, 2009 12:43 PM writes...

Trying again.

p less than 0.05 for age, male gender, LDL-C, and TG. Xanthomas were associated with a 3.2 times higher risk of CVD, p less than 0.01.