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Cardiovascular Disease

PCSK9 at the FDA

So an FDA advisory committee met yesterday to consider the PCSK9 antibody from Regeneron and Sanofi, and today it’s the turn of Amgen’s candidate. These, as anyone with even a passing interest in cardiovascular medicine will know, are potential gigantic blockbusters and advances in the field, promising to lower LDL across a huge swath of the patient population. The question, though, is clinical outcomes – the big question is always clinical outcomes. Does lowering LDL via this mechanism lead to lower CV mortality, fewer heart attacks, etc.? By now, we have such data for statin therapy, and it does indeed seem to provide those benefits. Those numbers take years to generate, though, and although these studies are underway, the various PCSK9 developers would much rather not wait another two or three years for them to report, in much the same way that you or I would rather not spend that time dangling by our feet. So everyone is looking for a way to get these drugs onto the market.
Sanofi and Regeneron are looking to target patients who have a genetic predisposition to high LDL levels, and a larger group who are intolerant to statin therapy. The FDA committee was fine with the first plan, but not wildly enthusiastic about the second one. One worry they seemed to have was sending a “ditch your statins” message, which they don’t want to do.

A whole generation of well-known statins, now cheap and easily available, has emerged with proven cardiovascular benefits for patients. Other LDL drugs, though, turned out to be controversial failures on CV outcomes. The FDA is fretting that an approval based on the LDL surrogate leaves it with no authority to demand a cardiovascular study. And regulators are alarmed over the impact these new drugs could have on statins, even though there are no proven CV advantages.

That’s from this FierceBiotech piece, written before the committee meeting. Here’s their take afterwards. Matthew Herper has an analyst who thinks that many statin-intolerant patients will go onto the new therapies, no matter what the label might way. We’ll see. No PCSK9 antibody is going to reach its full market potential until the outcomes data arrive – that much has been clear for a long time. But now the companies (and their investors) are wondering about what they’ll be able to realize before that happens.

23 comments on “PCSK9 at the FDA”

  1. Anon says:

    Another drug family that will provide marginal benefits to mainly rich people (we already have statins) while providing millions to shareholders and executives…How about focusing on Alzheimer’s disease or infectious diseases instead? No wonder the drug industry gets so much flak…

  2. Hap says:

    Statins don’t work for everyone, though, and have significant side effects in some people (rhabdomyolysis). People have spent lots on Alzheimer’s but given that its mechanism is still unknown and the trials will take years to gather evidence of effect, drugs for it are far more likely to be for wealthy people at first than these. Infectious diseases haven’t made a whole lot of money for anyone, and if you figure your job is to make money, you’re not going to work there, particularly on drugs for the diseases that would most help. Of course, one might have said this about AIDS and hepatitis C, too, so something could happen.
    I would assume that insurers would have something to say about whether people would be dropping statins for PSK9 inhibitors – expensive compounds unlikely to be generic for a long time that require a doctor for administration (I think) would seem to trigger all of their red flags, at least in cases where statins would work. Where they don’t, though, insurance companies would have little leverage, and heart attacks are expensive, too.

  3. Biotech Capitalist says:

    @1 Anon, atherosclerotic cardiovascular disease is the leading cause of human morbidity and mortality in the world even in the presence of safe, effective and cheap statins (which @2 do lower LDL without adverse effects for 95% of patients). How can a person reasonably say there is not unmet medical need here?

  4. Ounce of prevention says:

    These are interesting and potential very effective new drugs.
    This is a good time, however, to remind ourselves that the underlying issue here is that most US citizens do not eat healthy and do not get enough physical activity.
    Adding both to our daily regimens would obviate, or at least reduce, our need for these medications.

  5. Biotech Capitalist says:

    @4 Widespread healthy diet and exercise would boost US GDP ~3%

  6. Anonymous says:

    @4 Nah, I can’t tell you the number of vegetarians I know with bad LDL.

  7. Magrinho says:

    I am middle-aged, obese, do not exercise and eat poorly.
    Meet my medical needs!
    First world problems.

  8. Anonymous says:

    Anyone knows why FDA is tougher on LDL-lowering drugs than glucose-lowing drugs in terms of outcome benefit (not just safety) requirement?

  9. Hap says:

    Atul Gawande’s article on bariatric surgery in Complications noted that the surgery was pretty much the only long-term effective weight loss option – almost all diets don’t work (people gain the weight back over time, in nearly all cases). So while it would be nice if people ate better and exercised more, the fact is that they don’t and won’t. (Also, food has a relative to the Engineer’s Triangle – it can taste good, be healthy, fast, or cheap, but rarely more than two of those options, and sometimes three.) A “treatment” that is predicated on behavior that doesn’t happen in the real world isn’t a treatment. Hence, the emphasis on medical options and reduced calorie foods – if you can’t change the behavior, then something else has to give.

  10. Biotech Capitalist says:

    @9 Hap, I bet if Americans shared in the cost of their healthcare more directly then they would change their behavior. Or not, in which case it would not matter since they would be paying for it.

  11. Hap says:

    I don’t believe his conclusion was limited to the US, so I suspect not. If it was limited to US experience, however, since most people in the US do share substantially in the cost of their healthcare anyway (employer-supported health care has significantly increased employee contributions, and everyone else has to get insurance somewhere), I don’t think it holds in that case either (or you’d expect people to be getting healthier soon, and see more food options and things for doing so, and I don’t think that’s happening).

  12. NMH says:

    People can’t break their addiction to tasty food to save their lives–literally. Would think that there would be great chemistry jobs in the food industry, but these days it may not be unlike working for Pfizer or General Dynamics in the 1970’s when they made missles…your selling yourself to institutional evil.

  13. Kyle S says:

    As an informative tangent on the problem of obesity, health, and causes, this NYTimes magazine piece details just how the convenience food industry uses its knowledge of human nature to create foods that are ever more alluring. Big reason behind the obesity/diabetes/CVD problems we’re seeing today. Change the environment, change the GxE interactions, get new phenotypes.

  14. Food babe says:

    Currently patients do not realize the cost of their therapies and doctor visits and hospitalizations. Once the fat ones realize the burden they impose on medicare, medicaid — they are likely to change habits.
    patients (wiith BMI > 25) should be forced to file insurance claims and deal with insurance companies on their own. That ought to have enormous benefit !

  15. Luke says:

    Fecal bacteriotheraphy is providing an interesting new potential avenue to weight loss as well

  16. Virgil says:

    Something that is going to have a huge impact on the statins/PSCK9 “choice” is delivery route – oral for statins versus injections for the antibodies. Most folks would opt for the pill any day of the week. The only ones who might go for the injection are the insulin dependent diabetics who are doing the needle anyway.

  17. Anonymous says:

    @6 Anonymous. Of course vegetarians can have bad LDL levels. High carbohydrate intake wreaks havoc on cholesterol levels, particularly with certain genetic factors.
    @8 Anonymous. Outcome benefit (not dying from a heart attack) for non-statin cholesterol modifying drugs is actually not as clear cut as reducing diabetic symptoms is for glucose lowering drugs. LDL levels are more of a biomarker more than a disease pathology.

  18. NMH says:

    @17: I went vegetarian and my LDL plummeted to very low levels, and I feel a heck of a lot better. Probably would happen to most people, I suspect, but not all. The meat and dairy industry, and their useful idiot/shill Gary Taubes has successfully brainwashed most into thinking high veg is high carb which wont work.

  19. Anonymous says:

    @NMH. I think there is probably far too much generalization going on, which had led the U.S. to its current terrible situation. Nutrient balance is not one size fits all, but the media are all too happy to promote the next “miracle weight loss trick” (Thanks Dr. Oz). Unfortunately every individual needs to identify the diet that works best for them AND they can maintain. For me that meant no grains and healthy fats and I lost a lot of weight. On the same regimen my wife actually gained weight.
    I don’t think the meat and dairy industry are conspiring to brain wash people into thinking vegetarian diets are high carb, nor that Gary Taubes is specifically shilling for them. He found a diet that worked for him, and it’s not for everyone although he thinks it is. He’s overtly aggressive to the vegan crowd, so I can understand why someone would take offense. There is still truth in that some vegetarians eat way too many carbs and wonder why they can’t lose weight.
    On the other hand, the snack food industry, as mentioned by #13 is conspiring to addict people to their foods and trying to convince mothers that fruit roll-ups are healthy. They take out whatever is trendy (fat, sugar, gluten) for marketing reasons.

  20. NMH says:

    @19- Agreed and well reasoned. I had too much coffee this morning.
    However, I just wish everybody who is unhappy about their weight could get vegetarianism a try for about three months just to see if it works. If it does not, try something else.

  21. LeeH says:

    The data I’ve seen for the effect of lowered LDL and trigylcerides on mortality and the probability of a future MI is quite different for people who have already experienced an MI compared to those that haven’t. From that data, it’s clear that the effect of statins in cases where people have already experienced an MI is pretty clear. Not so much for those that have not previously experienced an MI.

  22. HFM says:

    @17-20: I’m eagerly awaiting the NuSI trial comparing the Ornish and Atkins diets head-to-head. My guess is that both will improve health outcomes; if nothing else, they both restrict sugar and processed junk food.
    My own diet is 80% fat, mostly saturated. I tried it out of desperation (because I was a fat, sad pile of autoimmune diseases), and it worked. And my lipid profile is so clean it squeaks. But I have quality fat-burning genes, I guess.
    It’ll be fascinating to see how much matching of individuals to diets we really can do. There’s inter-personal variation, clearly.

  23. Dolph says:

    In this case you are too stupid to read data!
    The relative benefit in primary prevention with statins is significantly LARGER than in secondary prevention, and this is hardly surprising…

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