Daily rapamycin treatment in older dogs showed improvements in heart function without requiring a washout period.

“so we were pretty confident or I was pretty confident after talking to them that if we took their dosing strategy that we're unlikely to see any significant side effects over a 10-week period so I said the cardiac function was the functional endpoint that we were using really the goal of that 10-week study though was to confirm just a phase one base we could do this that we could get people to participate they would actually give their dog the medication and that we didn't see any significant side effects”

“so the studies have varied is between six and ten weeks all of them saw improvements it's not clear whether you get bigger improvements by longer treatments so it's kind of in that range and these animals also require a washout to see the benefit no washout so these are measures of heart function taken while inks are still on the rapamycin and these animals were dosed daily so yes all three of those studies used the encapsulated rapamycin in the diet so they were getting the drug daily and it was not and this is where it gets a little bit complicated because I'd say”

“so yes all three of those studies used the encapsulated rapamycin in the diet so they were getting the drug daily and it was not and this is where it gets a little bit complicated because I'd say 85% of the studies on Aging or age-related functional measures in mice with rapamycin have been done with an encapsulated form of rapamycin in the diet we call it Arafa and so that's different from a pill right because mice are gonna eat throughout the night so they're probably not experiencing exactly the same pharmacokinetics that you would experience from a pill or the other kinds of experiments that people have done in mice have been injections where you get you know this rapid peak in the drug and then a pretty steep drop-off as the drug starts to get earlier nobody's ever done that like the 24-hour measures of rapamycin blood level on the mice getting very different yeah so I don't know how different it is but it's probably different in the sense that it's probably a more stable level of rapamycin in the blood for a longer period of time rings I mean I would expect that the e-rep animals are gonna have lower Peaks and higher troughs I mean that would be that would be the expectation yes but I don't know that anybody's ever really looked at that so having said that I think all three of the studies that looked at heart function in mice used the ear app and it was a pretty low dose of the the common eight milligrams per kilogram it's 14 parts per million in the food I don't remember off the top of my head what that works out to in milligrams per kilogram I feel like it's in the about the two range Wow but much well yeah but again you have to you have to keep in mind that you can't translate the dosing across species very well”

“the blood chemistry showed no significant changes with rapamycin which was actually a little bit surprised”

“this the owner of this dog didn't tell us this before she came into the study had actually been aware of this and was giving her dog echocardiogram before coming into the study that dog had low cardiac function but it was not yet to the point where it was clinically but as dilated cardiomyopathy so our cardiologist in the study also not knowing the dog's history of having prior echoes did not flag the dog is needing to be excluded so the dog was randomized it just happened to be randomized into the higher rapamycin dose and its function was that was one of the dogs where we saw the largest improvement in function”

“so we did so we've done one study where it was a 10-week study of rapamycin in middle-aged healthy companion dogs and we chose heart function as our short-term measure and that again was based on Mouse data where two different actually three different labs now have shown that if you take 20 to 24 month old Mouse that's maybe then that's like a 40 year old now it's more like a 60 to 65 year old person that if you just look at the heart of a 24 month old Mouse compared to let's say a six month old Mouse you can see declines in heart function just like you can in people and and the parameters that have been studied with the respect to rapamycin specifically are mostly measures of left ventricular function so ejection fraction fractional shortening things like that and this is done by echo cardio rafi so it's relatively non-invasive so you can see a decline in function with age and what what has been seen now in three independent studies is that six to ten weeks of treatment with rapamycin is enough to cause those measures of heart function in the old mouse to go back about half way to what you would see in a young mouse so it doesn't bring you all the way back to a teenager but it gets you back to you know maybe a 35 year old heart if you're doing this sort of mouse to human equivalents”

“yeah enormous yeah well ince back into the normal range yeah and has that patient or that patient has that woman shared with you what the resulting decline in EF has been the trial about I've got the data out to about six months and and we're just now trying to reconnect with her to see if if she has additional data that she'll share with us by about six months out the ejection fraction and fractional shortening we're back right at the point when the dog came into the study”

“the dogs on rapamycin that got the biggest benefits were the ones that started with the lowest function which is not surprising but that also is encouraging because that's that's kind of what you'd expect right the Dodge would have undergone a greater age-related decline are likely to be the ones that are gonna get the biggest benefit from a treatment that's actually affecting that”

“and what what has been seen now in three independent studies is that six to ten weeks of treatment with rapamycin is enough to cause those measures of heart function in the old mouse to go back about half way to what you would see in a young mouse so it doesn't bring you all the way back to a teenager but it gets you back to you know maybe a 35 year old heart if you're doing this sort of mouse to human equivalents”

“when you look at the cardiomyopathy model meaning it's a type of heart failure that dogs experience and you look at how rapamycin can improve ejection fraction you can get these answers in a really quick period of time”

“we saw improvements in heart function now I will say it's a small cohort they were on sort of the borderline of statistical significance so two of the three measures that we had as our primary endpoints the three measures were ejection fraction fractional shortening and eja ratio”

“in our first clinical trial which was it was designed to really only be a safety trial there were 24 dogs uh 16 got rapamycin 8 got the placebo but we had the dogs also get echocardiograms before and after the treatment period and in that study there were statistically significant improvements in two measures two of the three measures of left ventricular function by echocardiography in the dogs that got rapamycin compared to the placebo”

“what was i think to me most interesting in that that data was that the improvements that we saw were exclusively found in the dogs that came in with lower function now one thing to note is none of these dogs had functions so low that it would be clinically diagnosed as heart failure right so it was it was normal age-related declines in function and it was exclusively the dogs with the lowest function that showed the improvements from rapamycin”

“there's there's really good data three at least three maybe four now studies from from different labs in mice showing that if you look at age-related declines in heart function particularly left ventricular function so the several measures of left ventricular function decline with age that rat that eight to ten weeks of rapamycin is enough to reverse those changes and make the the young heart by echocardiography look functionally like a make the old heart look like a young heart”