Note: I’m not affiliated with Loyal or any other longevity organization, I’m going off the same outside information as the author.
I think there’s a substantial chance that this criticism is misguided. A couple points:
The term “efficacy nod” is a little confusing, the FDA term is “reasonable expectation of effectiveness”, which makes more sense to me, it sounds like the drug has enough promise that the FDA thinks its worth continuing testing. They may not have actual effectiveness data yet, just evidence that it’s safe and a reasonable explanation for why it might work.
It’s surprising, to say the least, to see a company go from zero information to efficacy nod, because, well, what are you basing your efficacy on?
I don’t know what the standard practices are for releasing trial data, especially for an initial trial like this. Are we sure this isn’t standard practice? Even if it isn’t, I don’t think this is sufficient to assume that Loyal is being disingenuous.
They then looked at healthy pet dogs, and found that big dogs had higher levels of IGF-1, which is one of the reasons they’re big. Small dogs had lower levels of IGF-1. Small dogs, as we all know, live longer than big dogs. Therefore, Loyal said, our IGF-1 inhibitor will extend the life of dogs. Needless to say, this is bad science. Really bad science.
Take the outside view here, both Loyal and the FDA have veterinarians who seem to think that the drug is promising.
I also think there’s a reasonable argument to be made for an IGF-1 inhibitor in large-breed dogs. Large breed dogs often die of heart disease which is often due to dilated cardiomyopathy (heart becomes enlarged and can’t pump blood effectively). This enlargement can come from hypertrophic cardiomyopathy (overgrowth of the heart muscle). I don’t know if it’s known why large breed dogs have hypertrophic cardiomyopathy, but maybe IGF-1 makes the heart muscle grow over a dog’s lifetime which would suggest that an IGF-1 inhibitor is worth trying. It’s also suggestive that diabetes is a risk-factor for cardiomegaly (enlarged heart).
With this in mind, we can answer the next point:
And, even if they did, there’s no reason to believe that lowering levels of IGF-1 would reverse any of the “damage” caused by high levels of IGF-1! The big dogs will still be big!
So my theory says that high IGF-1 over a lifetime progressively increases the size of the heart muscle until you get dilated cardiomyopathy. Stopping IGF-1 even in middle age might help. We can falsify this theory by checking if large breed dogs show heart enlargement over their lifetime (instead of growth stopping after puberty like it should). Why would heart muscle keep growing while nothing else does? I’m not sure.
Now we can turn to the question: do large breed dogs actually have elevated IGF-1?
Looking at your first figure, the answer seems to be yes! There’s a straightforward correlation between bodyweight and IGF-1 concentration, the slope would likely be higher without the 3 outliers on the right. Notice also that the sample doesn’t have many large breed dogs (great danes weigh 110-180 lbs). I would guess that those 3 dogs are large breed dogs, and they do in fact have IGF-1 levels higher than most of the dogs in the sample.
Now lets turn to the second plot, we see that IGF-1 concentration decreases with age. Remember that there is survivorship bias at higher ages, large breed dogs with higher IGF-1 will die at around 72 months while chihuahuas will live over 150 months. Declining IGF-1 with age is exactly what we should see if we expected IGF-1 to correlate with longevity! The plot supports the theory that IGF-1 is important for aging, you can’t cherry-pick outliers and ignore the overall relationship in the plot.
oh, did I forget to mention that IGF-1 inhibitors have existed for humans for decades, and they have zero evidence of being longevity drugs?
I’m no expert, but I think there’s interest in IGF-1 inhibitors for longevity. To quote Sarah Constantin:
There’s a _lot _of evidence that the IGF/insulin signaling/growth hormone metabolic pathway is associated with aging and short lifespan, and that inhibiting genes on that pathway results in longer lifespan. IGF-receptor-inhibiting or growth-hormone-inhibiting drugs could be studied for longevity, but haven’t yet.
I would guess this is one of the reasons Loyal had an interest in IGF-1 inhibitors from the outset.
IGF-1 inhibitors can causelow levels of blood platelets, elevated liver enzymes, and hyperglycemia
The dose makes the poison! Every drug has negative effects at a high enough dose, the trials will determine if these actually arise at the dose they are using.
I’m no expert, but this evidence doesn’t seem sufficient to stop research on this drug. Will it prove safe or effective? Will it also benefit human health? I have no idea, but unless we discover that the drug is hurting patients, I think its fine for Loyal to carry on.
Large breed dogs often die of heart disease which is often due to dilated cardiomyopathy (heart becomes enlarged and can’t pump blood effectively). This enlargement can come from hypertrophic cardiomyopathy (overgrowth of the heart muscle).
Dilated cardiomyopathy and hypertrophic cardiomyopathy are two different conditions that I’ve not seen co-occur. They are basically sign-flipped versions of each other.
Dilated cardiomyopathy is when heart tissue becomes weaker and thinner. It stretches out like an overfilled balloon, and can’t beat with the same strength. Symptoms include tiredness, shortness of breath, in severe cases progressing into inability to circulate blood (heart failure).
Hypertrophic cardiomyopathy is when the heart tissue becomes stronger and thicker. The inner heart space becomes too narrow and can cause a heart valve to get stuck in the “closed” position, stopping the outflow of blood. This type of cardiomyopathy often stays asymptomatic and undiagnosed by routine checkups, until one day a young athletic person presents with a symptom of “sudden cardiac death”.
The only feature they both share in common that comes to mind is that the heart becomes larger on X-ray (Cardiomegaly).
The term “efficacy nod” is a little confusing, the FDA term is “reasonable expectation of effectiveness”, which makes more sense to me, it sounds like the drug has enough promise that the FDA thinks its worth continuing testing. They may not have actual effectiveness data yet, just evidence that it’s safe and a reasonable explanation for why it might work.
That’s what I thought too, but the FDA’s website indicates that a company that gets conditional approval can sell a drug where they have adequately demonstrated safety but have not demonstrated efficacy. The company can then sell this provisionally approved drug for 4.5 years after receiving conditional approval without having to demonstrate efficacy.
That said, conditionally approved drugs have to have a disclaimer on the packaging that says “Conditionally approved by FDA pending a full demonstration of effectiveness under application number XXX-XXX.”.
I personally don’t expect very high efficacy, and I do expect that Loyal will sell the drug for the next 4.5 years. However, as long as Loyal is clear about the nature of the approval of the drug, I think this is basically fine. People should be allowed to, at their own expense, give their pets experimental treatments that won’t hurt them and might help them. They should also be able to do the same for themselves, but that’s a fight for another day.
I personally don’t expect very high efficacy, and I do expect that Loyal will sell the drug for the next 4.5 years. However, as long as Loyal is clear about the nature of the approval of the drug, I think this is basically fine. People should be allowed to, at their own expense, give their pets experimental treatments that won’t hurt them and might help them. They should also be able to do the same for themselves, but that’s a fight for another day.
Agreed! Beyond potentially developing a drug, think Loyal’s strategy has the potential to change regulations around longevity drugs, raise profits for new trials, and bring attention/capital to the longevity space. I don’t see many downside risks here unless the drug turns out to be unsafe.
It can change regulations around longevity drugs in both directions. If the product gets brought by people and found ineffective, people will complain that the FDA was not stringent enough and the FDA has the motivation to be more stringent.
Are there examples of ineffective drugs leading to increased FDA stringency? I’m not as familiar with the history. For example, people agree that Aducanumab is ineffective, has that cause people to call for greater scrutiny? (genuinely asking, I haven’t followed this story much).
There are definitely examples of a drug being harmful that caused increased scrutiny. But unless we get new information that this drug is unsafe, that doesn’t seem to be the case here.
The report included three recommendations that it believed FDA should immediately implement, including:
Keeping proper documentation of the agency’s interactions with drug companies
Creating clear protocols for when the agency can create joint presentations with companies
Updating its guidance for the development of new Alzheimer’s drugs
So the FDA was tasked to do more bureaucracy.
When it comes to this drug, the drug is approved as an animal drug which at the moment does not require clinical trials to be approved. If there’s a case of a lot of animal owners being dissatisfied with the FDA for allowing ineffective animal drugs, that does support a call to regulate animal drugs more like human drugs that require clinical trials to be marketed.
On the slight chance that it does end up improving life expectancy of big dogs prone to DCM because it reduces chances of death due to cardiomegaly, would this then be a cardiovascular drug and not a longevity drug? And are the endpoints anything related to cardiac health outcomes (EF/ heart size/others)?
An extension of the logic would be that all cardiac interventions are longevity interventions because heart diseases are the most common cause of death. That seems odd. Were COVID vaccines longevity interventions cz over time the restored the dip in average life span brought about by the pandemic? (This might just be me not understanding the distinctions around what makes a longevity drug in general; is the goal increasing life, increasing quality of life in later decades, or to reduce overall ageing process/wear and tear starting at a young point ie 40s in humans)
Broadly, I’m not too concerned with what we classify a drug as as long as its safe, effective, well-understood, and gets approved by regulatory authorities.
Note: I’m not affiliated with Loyal or any other longevity organization, I’m going off the same outside information as the author.
I think there’s a substantial chance that this criticism is misguided. A couple points:
The term “efficacy nod” is a little confusing, the FDA term is “reasonable expectation of effectiveness”, which makes more sense to me, it sounds like the drug has enough promise that the FDA thinks its worth continuing testing. They may not have actual effectiveness data yet, just evidence that it’s safe and a reasonable explanation for why it might work.
I don’t know what the standard practices are for releasing trial data, especially for an initial trial like this. Are we sure this isn’t standard practice? Even if it isn’t, I don’t think this is sufficient to assume that Loyal is being disingenuous.
Take the outside view here, both Loyal and the FDA have veterinarians who seem to think that the drug is promising.
I also think there’s a reasonable argument to be made for an IGF-1 inhibitor in large-breed dogs. Large breed dogs often die of heart disease which is often due to dilated cardiomyopathy (heart becomes enlarged and can’t pump blood effectively). This enlargement can come from hypertrophic cardiomyopathy (overgrowth of the heart muscle). I don’t know if it’s known why large breed dogs have hypertrophic cardiomyopathy, but maybe IGF-1 makes the heart muscle grow over a dog’s lifetime which would suggest that an IGF-1 inhibitor is worth trying. It’s also suggestive that diabetes is a risk-factor for cardiomegaly (enlarged heart).
With this in mind, we can answer the next point:
So my theory says that high IGF-1 over a lifetime progressively increases the size of the heart muscle until you get dilated cardiomyopathy. Stopping IGF-1 even in middle age might help. We can falsify this theory by checking if large breed dogs show heart enlargement over their lifetime (instead of growth stopping after puberty like it should). Why would heart muscle keep growing while nothing else does? I’m not sure.
Now we can turn to the question: do large breed dogs actually have elevated IGF-1?
Looking at your first figure, the answer seems to be yes! There’s a straightforward correlation between bodyweight and IGF-1 concentration, the slope would likely be higher without the 3 outliers on the right. Notice also that the sample doesn’t have many large breed dogs (great danes weigh 110-180 lbs). I would guess that those 3 dogs are large breed dogs, and they do in fact have IGF-1 levels higher than most of the dogs in the sample.
Now lets turn to the second plot, we see that IGF-1 concentration decreases with age. Remember that there is survivorship bias at higher ages, large breed dogs with higher IGF-1 will die at around 72 months while chihuahuas will live over 150 months. Declining IGF-1 with age is exactly what we should see if we expected IGF-1 to correlate with longevity! The plot supports the theory that IGF-1 is important for aging, you can’t cherry-pick outliers and ignore the overall relationship in the plot.
I’m no expert, but I think there’s interest in IGF-1 inhibitors for longevity. To quote Sarah Constantin:
I would guess this is one of the reasons Loyal had an interest in IGF-1 inhibitors from the outset.
The dose makes the poison! Every drug has negative effects at a high enough dose, the trials will determine if these actually arise at the dose they are using.
I’m no expert, but this evidence doesn’t seem sufficient to stop research on this drug. Will it prove safe or effective? Will it also benefit human health? I have no idea, but unless we discover that the drug is hurting patients, I think its fine for Loyal to carry on.
Dilated cardiomyopathy and hypertrophic cardiomyopathy are two different conditions that I’ve not seen co-occur. They are basically sign-flipped versions of each other.
Dilated cardiomyopathy is when heart tissue becomes weaker and thinner. It stretches out like an overfilled balloon, and can’t beat with the same strength. Symptoms include tiredness, shortness of breath, in severe cases progressing into inability to circulate blood (heart failure).
Hypertrophic cardiomyopathy is when the heart tissue becomes stronger and thicker. The inner heart space becomes too narrow and can cause a heart valve to get stuck in the “closed” position, stopping the outflow of blood. This type of cardiomyopathy often stays asymptomatic and undiagnosed by routine checkups, until one day a young athletic person presents with a symptom of “sudden cardiac death”.
The only feature they both share in common that comes to mind is that the heart becomes larger on X-ray (Cardiomegaly).
Thanks for the clarification! Do you know if either condition is associated with abnormal levels of IGF-1 or other growth hormones?
That’s what I thought too, but the FDA’s website indicates that a company that gets conditional approval can sell a drug where they have adequately demonstrated safety but have not demonstrated efficacy. The company can then sell this provisionally approved drug for 4.5 years after receiving conditional approval without having to demonstrate efficacy.
That said, conditionally approved drugs have to have a disclaimer on the packaging that says “Conditionally approved by FDA pending a full demonstration of effectiveness under application number XXX-XXX.”.
I personally don’t expect very high efficacy, and I do expect that Loyal will sell the drug for the next 4.5 years. However, as long as Loyal is clear about the nature of the approval of the drug, I think this is basically fine. People should be allowed to, at their own expense, give their pets experimental treatments that won’t hurt them and might help them. They should also be able to do the same for themselves, but that’s a fight for another day.
Agreed! Beyond potentially developing a drug, think Loyal’s strategy has the potential to change regulations around longevity drugs, raise profits for new trials, and bring attention/capital to the longevity space. I don’t see many downside risks here unless the drug turns out to be unsafe.
It can change regulations around longevity drugs in both directions. If the product gets brought by people and found ineffective, people will complain that the FDA was not stringent enough and the FDA has the motivation to be more stringent.
Are there examples of ineffective drugs leading to increased FDA stringency? I’m not as familiar with the history. For example, people agree that Aducanumab is ineffective, has that cause people to call for greater scrutiny? (genuinely asking, I haven’t followed this story much).
There are definitely examples of a drug being harmful that caused increased scrutiny. But unless we get new information that this drug is unsafe, that doesn’t seem to be the case here.
There was a congressional inquiry that then tasked the FDA to:
So the FDA was tasked to do more bureaucracy.
When it comes to this drug, the drug is approved as an animal drug which at the moment does not require clinical trials to be approved. If there’s a case of a lot of animal owners being dissatisfied with the FDA for allowing ineffective animal drugs, that does support a call to regulate animal drugs more like human drugs that require clinical trials to be marketed.
On the slight chance that it does end up improving life expectancy of big dogs prone to DCM because it reduces chances of death due to cardiomegaly, would this then be a cardiovascular drug and not a longevity drug? And are the endpoints anything related to cardiac health outcomes (EF/ heart size/others)?
An extension of the logic would be that all cardiac interventions are longevity interventions because heart diseases are the most common cause of death. That seems odd. Were COVID vaccines longevity interventions cz over time the restored the dip in average life span brought about by the pandemic? (This might just be me not understanding the distinctions around what makes a longevity drug in general; is the goal increasing life, increasing quality of life in later decades, or to reduce overall ageing process/wear and tear starting at a young point ie 40s in humans)
I agree that the difference between disease-treating interventions (that happen to extend life) versus longevity interventions is murky.
For example, would young people taking statins to prevent heart disease be a longevity intervention?
https://johnmandrola.substack.com/p/why-i-changed-my-mind-about-preventing
See this post arguing that rapamycin is not a longevity drug:
https://nintil.com/rapamycin-not-aging
Broadly, I’m not too concerned with what we classify a drug as as long as its safe, effective, well-understood, and gets approved by regulatory authorities.