Hey Greens! Life has been keeping me busy. Thought I would discuss the SA article real quick. I'm actually at a computer so I can actually type some stuff out- it's a novel. They said that in earlier stuff MDGL's drug increased ALT level up to 40, "suggesting injury to the liver." I believe that's what your question is directed towards.
So I was a little surprised to see that the writer was long on VKTX. And I do think he tried to present it unbiased. Hey, in my book, any press is good press, as we are still mostly unknown. But I think that he made the whole issue much more complicated than it really is. He was too proud to figure out what could be summed up as "we don't know X... Y... Z... etc... and so he made some guesses, and a few weird ones at that. He tried to use a bunch of science to say things that can be easily said. And sad to say, but aside from the stuff that he probably cut and paste directly from biochem books and trial discussions, he added absolutely nothing. Which is fine, but I think he didn't do a good job of organizing the delivery of data, and keeping separate what the old drugs did vs. what our new class of beta receptors Have done thus far. I'm assuming it was somewhat difficult for most folks to keep straight- which I suspect was the real goal. Nothing scares people more than a bunch of science with scary potential bad things that have not happened yet in phase 1 or phase 2... but maybe in a longer phase 3 lol.
Was very hard for him to keep separate---
1. The known side effects of thyroid receptor activators that were developed a long time ago that failed (with the reason being that most of them activate other sites or have too much thyroid alpha receptor activation)
vs...
2. Explaining that we are trying to avoid all of those things with this new class of molecule, and that trials to date haven't shown the rate limiting stuff we saw in the failed drugs, but we don't know for sure if they might show up to some extent.
Because really what we have here... is a drug that has yet to show any major or rate limiting side effect. So what does he do... he gives the entire history of why all the other thyroid drugs have failed... yet he never brings it full circle and explains that so far, everything has looked good. And he makes it seem like we found this drug on accident and not that they have been developing it for years and the earlier pipeline stuff that is coming.
So MDGL's drug supposedly raised ALT to "40" range in the trial. And MDGL supposedly went to lengths to avoid enrolling patients who might have liver issues due to other reasons.
Not a big deal in my book, for a lot of reasons. So, there are a a few liver markers that we check in medicine, but the biggest two we look at are the ALT and AST. Every lab is a little different with normal ranges, but usually 40 is just a tiny bit up... I see drinkers occasionally with 200-300 liver tests... people with acute hepatitis have liver tests sometimes in the thousands. To give you an idea, when I see people that are decent drinkers, have hepatitis c, take too much Tylenol on a regular basis, etc etc etc... their ALT is generally much higher than 40. In fact, I don't usually bat an eye at an ALT of 40 when I see it. I would tell the patient 'hey your one liver test is a tiny bit up, get it rechecked... and view it as a red herring... ie... having nothing to do with why they were there, the vast majority of the time. Now keep in mind, I'm not a family doc... if I was, I would recheck that ALT a couple more times over time, and if it stays up just a little bit (which 40 is just a little bit in my book), then you need to figure out what is doing it... ie... cut out the Tylenol, avoid certain herbal supplements, etc etc etc. The list of drugs that are hard on the liver... much harder than an isolated ALT of 40 when used in moderation... oh my... I wouldn't have enough space in this novel haha.
So here's my argument with the entire SA piece. Misses the forest through the trees, every time with them. Do they have any freakin' clue what we are doing here with this drug!? They are literally trying to prevent LIVER TRANSPLANTS and to reduce long term scarring and inflammation associated with NASH. For perspective... say our drug is kinda harmful to the liver... it would have to be pretty darn harmful to stop it from being considered for use. Because say it's harmful. If I had a drug that MINIMALLY ELEVATED Liver Function Testing that I would be using for a little while to treat and reduce the fat burden and chronic inflammation of NASH that leads to a transplant, I would prescribe the heck out of it. We do it all the time, the same exact thing. Look at all those Hepatitis C drugs. You deal with a lot of short term side effects, to get a lot of progress on a bad disease. It wouldn't be rate limiting. And it is going to take forever to prove MDGL's drug would even be causing the ALT elevation. These are NASH patients... NASH is a heterogenous disease... it's like a fever... lots of things can cause your temperature to be elevated. Not all of these people have the same cause of NASH... a lot of them are diet, but some of them have some weird genetic stuff going on- that can raise liver tests under different circumstances. Hence the need for phase 3 to make get a little better idea that it doesn't happen to everyone... and that it returns to normal awhile after you finish the drug, etc etc, common stuff.
So again, this stuff, to me... if that's the worst they got to throw at our class of molecule, we're doing something right.
I also objected greatly to the writer basically stating that these drugs MIGHT give you symptoms of LOW thyroid, might give you symptoms of HIGH thyroid. And then like selectively listing some of them off... like saying that people with high thyroid are at increased risk for blood clots- RANDOM. As a doc... let me tell you how many times I've found high thyroid... and thought... gee... maybe they have a blood clot caused by high thyroid. ZERO. Now the real deal, is that people who get high thyroid are a lot more likely to have underlying cancer... which will give you a blood clot. So give me a break dude. I'm overly narrowing the scope, for illustrative purposes, and could go on and on about this. The list of possible symptoms from low or high thyroid is a mile and a half long. This is where his lack of science background got real obvious... that he was just the messenger of a few textbooks. A better way to put this... rather than throwing out a few random symptoms from a mega-list... would be to say this...
"We have no idea what the downstream effects are when we selectively activate the thyroid beta receptor. It could potentially cause symptoms of low or high thyroid in various regards. The trials have all been too short to know if this would happen with longer term use."
Once he started talking like high thyroid can give you blood clots, I was close to smashing the computer lol.
Which again was another point of his... the trials have been short, so maybe we aren't seeing bad stuff because of how short they are, and we will see stuff in phase 3. So what? Who on earth suggested that this has to be a long term med?!? It could be used for short course, as it already dramatically reduces fat burden (if data continues to show that)... who says you keep giving it.
Moral of the story... the liver is incredibly resilient. Fun fact (med school was a long time ago).... but when they give someone a liver transplant... they cut a small piece of liver from a healthy person, and insert it into the recipient. That small piece essentially grows into a new liver. It is ongoing damage and scarring that really gets people's livers to the point where that regenerative potential is lost, like a tipping point of no return. So yes, we tolerate a little stress on the liver all the time with meds, knowing that the overall result is net positive in other realms. For example, over the counter Tylenol... responsible for more liver transplants than almost everything out there.
We are way too early to know how long you would use this for, and how much it helps NASH. Until you figure out how much benefit we get, it's kind of dumb to say that you need to have ZERO side effects. But hey, I'm happy still having zero. And very smart to see us using lower doses in this trial... to keep us on pace with MDGL's side effect profile. We are doing things right... it is smart to learn from there mistakes, even if that minimal ALT spike from MDGL earlier in trials was a red herring... VKTX was listening. Bravo guys. Then again... our lipid reducing effect is so huge... I personally think they reduced the dose because the higher dose from previous was just overkill.
Ok... final point... and this is the stuff I have been hinting at all along. Example... if you take a bunch of testosterone, like a bodybuilder does, your body stops making it own for awhile, it alters your estrogen level, etc... then your body adapts back to varying degrees over time. This is the stuff the guy was hinting at saying that selectively activating the thyroid-beta receptor might somehow suppress production of other thyroid hormones, or too much activation of the beta receptor might selectively give you symptoms of high thyroid that correspond to that receptor. This has always been an issue in the back of my mind, and one that I have dismissed as being a concrete barrier to approval... because our drug has thus far done HUGE things in SHORT periods of time. This isn't based on medicine fact, just my own theory, so buyer beware. If we can dramatically reduce the liver fat burden and buy someone a bunch of time to get their diet and exercise regimen and life back on track etc... with just like 12 weeks of dosing... why should I really care if it is doing some subtle thyroid stuff that we probably would barely notice in a larger study, with the pathway suppression/activation stuff. Wouldn't the means justify the ends? I've seen tons and tons of patients with low thyroid, and a fair amount with high thyroid. High thyroid can be more worrisome, because it is much more likely to be cancer etc (and cancer causes blood clots lol... hence a little of the blood clot risks lol, that we might not see with a drug lol). You know how many people I've thrown in the hospital for low or high thyroid... lol... could count them on one hand... after years in an ER. The body generally tolerates it, in the vast majority of cases, without too much trouble (if it goes on forever and ever you get some weirdness, admitted... but I don't think anyone has ever suggested that a short course of beta thyroid activation could forever alter the thyroid axis lol)... unless someone is insanely high or low thyroid, the body goes on in a state of subtle adapting. It's tolerated. Nobody has yet to find the OBVIOUS effects of VERY high or VERY low thyroid in these samples of patients studied (heart rate or temperature alterations, confusion, fluid retention, blah blah blah ;) ). Say it makes the thyroid a little off... I see zero reason why that would limit its use as a short to medium use therapy or intermittent therapy when trying to prevent Liver Transplant in NASH patients.
Kind of one of those 'would you rather' scenarios... Would you rather have a super fatty liver and need a liver transplant, or be a little high or low thyroid for awhile, like millions of other people out there... and then you stop the drug, liver is doing better, and fix your life, and your thyroid resumes it's normal state over a little bit of time? Sounds better than kissing your cousin lol. The reason why liver transplant is a death sentence for some folks, is because of the high doses of immunosuppressants needed to prevent rejection of that new liver... which wreak havoc on the immune system and the body.
And again, these are ALL still THEORETICAL STUFF that might happen in phase 3's.... we still are showing no major side effects. The nice part about being a new molecule... and technically they designed us to avoid all the stuff that the earlier drugs failed because of... how well we do it... time will tell.
Please feel free to ask any specific questions. Can you see why I only hinted at this before and didn't throw it all out there... it's beyond the scope... and honestly... none of this really scares me while waiting on a phase TWO trials... nor would they stop me from better on a phase 3, in this specific circumstance, whatsoever. I'm optimistic that results will be just like MDGL's. Heck... probably better.
Hope all is well Greens. You and Bull and Alex have made this a decent journey for me. Take care buddy. And again... ask away if I said stuff in a weird or confusing way. I could talk for hours on this stuff and theories and give examples of similar situations... but you don't see me picking one or two examples and making an SA article out of it ;)
Stay warm all, and happy trading
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