RE:RE:RE:RE:liver fibrosis progression via VEGF-A I think you're right that the specifics of thtx's patients matter somewhat. Yes they are full nafld spectrum rather than just late stage NASH but I think it goes much further. My memory is the mean BMI for THTX study was 30, that's roughly means maybe half were obese and half only fall in the overweight category. For mdgl's trial the average bmi was 35, so likely all obese. The other issue is that hiv patients hepatotoxicity, inflammation and fibrosis is not just being driven by fat accumulation it's also driven by hiv related factors so theoretically you could remove all the toxic fat from a patients liver and they'd still have processes driving the inflammation and fibrosis.
I don't think it clear exactly how these gene effects fit into the whole picture. It seems to me two possibilities.
1) The drug (or more likely GH or IGF-1) are directly impacting these genes
or
2) The drug is lowering liver fat and then the lowered liver fat is causing the change in gene activity because of the reduced hepatotoxicity.
Both are great as MOA for the drug but If it's 2), which seems the most likely, then the impact from the hiv factors are going to be of most importance in obscuring what the drug is really capable of. Nobody really expects that Egrifta can counteract the hepatotoxicity of ART drug or HIV virus, I think the hope was they'd see the fat-busting effect through the fog of hiv-related effects. If you think of the results from that perspective then any improvements in fibrosis and/or NASH stats are impressive. Right now we are looking at data where the drug is being severely handicapped by the patients it's being tested on. We desperately need to see this drug in action against non-hiv patients to really understand what it's capable of.
I so want to see some sort of interim data readout. Getting that data in non-hiv patients has the potential to massively shift the profile of this drug in the eyes of the market, it's too painful to think we wait 2.5 years for that. Akero style 2a or Mdgl style Ph3 open arm incorporated into the next trial would be such a valuable add on.
Wino115 wrote: As I think about this, one part stands out to me --the fact that there is a relationship between the overexpression of these genes and the level of fibrosis. It explains a lot behind the numbers in the Phase 2 NAFLD trial. I think it's important in showing how a drug can work that the cellular change your drug is acting on is done on a genetic trait that is abundant in the damaged cells and not sparse.
We all know that one reason the HIV NAFLD Phase 2 trial was not ideal was that they didn't really have enough of the full NASH patient cohort with high fibrosis levels. So while they all saw liver fat fall a lot, the other indicators didn't fall as much because they weren't all that bad to begin with, on average. So there wasn't as much "material" to work with to get those results, in essence. It stands to reason if you get a much larger sample, all of whom have F2 or F3 and a much higher NAS score, then you will have more of the expression of these genes in the inflammed tissue and your drug will have a lot more to work with within the liver environment. This finding has to have excited them some bit given that. It's a bit like when you try to lose weight, the first 5 or 10 is a lot easier then the next 10 because you have so much more to work with when you start.
I posted the granular patient data from the MGH patent document and it generally shows this at work. But there's just not enough data to say anything statistically significant and when you look at individual numbers you can see some cases where you don't see this effect. But there were two patients that saw fibrosis stage lowered by 2 levels - one lost 70% of their hepatic fat fraction and the other 37%. The 70% patient didn't have a ton of fat in there to begin with (only 5.4%) whild the 37% patient had a very high level of fat (33% lowered to 21%). So patient one took a relatively healthy liver and made it super healthy while patient two just mildly improved the super high fat level but saw a huge improvement in NAS score and fibrosis score. The latter (patient 55) is sort of the poster child for Egrifta in NASH. You'd have to think if they went another 6 months on Egrifta they would have seen that fat level fall further and the scores fall further. But there are also anecdotal one-offs that are the opposite -- like patient 3. They lost a ton of liver fat but saw inflammation go up and fibrosis go up. In any trial you will have responders and non-responders so that's not odd and wouldn't negate the thesis. So what you hope is that they've learned something about Patient 3 versus Patient 55 and can see, down to the genetic level, what went on in both. It could be loads of factors, but maybe it's something like the above where the overexpression of that gene sequence was just not there, but it was in Patient 55. That's the kind of stuff that would be fascinating and that they can really use to build a patient cohort that is "built right" for Egrifta working in that fluid way -- high fat being lowered, lower fat lowering all 3 NAS score components and lowering fibrosis by at least 1 stage. There's enough tantalizing information in that small trial to get excited about seeing it in a much larger trial with much more conductive patients for your trial to show the efficacy across a larger and more statistically powerful trial.
| | Hep Fat Fraction | NASH Score | Steatosis | Inflammatn | Balooning | Fibrosis | Resolution & no Chg Fibro | Fibro -1 no chg Steohep |
| Patient # | Base | Yr 1 | Absolute Chg | Relative Chg% | Base | Yr 1 | Point Change | Base | Yr 1 | Base | Yr 1 | Base | Yr 1 | Base | Yr 1 | Fibro Chg | | |
| 2 | 8.1 | 2.9 | -5.2 | -64% | 2 | 1 | -1 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | NO | No |
| 3 | 11.9 | 3.9 | -8.0 | -68% | 3 | 4 | 1 | 1 | 1 | 1 | 2 | 1 | 1 | 3 | 4 | 1 | NO | No |
| 4 | 10.6 | 7.9 | -2.7 | -26% | 2 | 2 | 0 | 1 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | NO | No |
| 7 | 17.0 | 2.9 | -14.1 | -83% | | | | | | | | | | | | | | |
| 12 | 5.4 | 1.8 | -3.6 | -67% | 2 | 1 | -1 | 1 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | Yes | No |
| 13 | 24.0 | 23.1 | -0.9 | -4% | 3 | 1 | -2 | 2 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | NO | No |
| 18 | 5.4 | 1.6 | -3.8 | -70% | 1 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 1b | 0 | -2 | Yes | Yes |
| 20 | 9.1 | 10.2 | 1.1 | 12% | 3 | 2 | -1 | 1 | 1 | 1 | 1 | 1 | 0 | 1a | 1a | 0 | NO | No |
| 24 | 33.2 | 17.4 | -15.8 | -48% | 3 | 3 | 0 | 2 | 2 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | NO | No |
| 26 | 15.0 | 2.1 | -12.9 | -86% | | | | | | | | | | | | | | |
| 28 | 14.3 | 10.2 | -4.0 | -28% | 2 | 1 | -1 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | NO | No |
| 29 | 19.9 | 19.9 | 0.0 | 0% | 2 | 4 | 2 | 1 | 2 | 1 | 1 | 0 | 1 | 10 | 10 | 0 | NO | No |
| 31 | 11.7 | 6.0 | -5.7 | -49% | 2 | 2 | 0 | 1 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | NO | No |
| 34 | 7.5 | 5.4 | -2.1 | -28% | 1 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 2 | 2 | 0 | Yes | No |
| 36 | 9.1 | 23.9 | 14.8 | 163% | 1 | 4 | 3 | 1 | 3 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | NO | No |
| 37 | 13.0 | 8.9 | -4.2 | -32% | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | NO | No |
| 50 | 24.0 | 20.0 | -4.0 | -17% | 7 | 7 | 0 | 2 | 3 | 3 | 2 | 2 | 2 | 3 | 3 | 0 | NO | No |
| 51 | 5.0 | 1.4 | -3.6 | -72% | 2 | 1 | -1 | 1 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | Yes | No |
| 53 | 17.0 | 9.0 | -8.0 | -47% | 3 | 3 | 0 | 1 | 1 | 1 | 1 | 1 | 1 | 2 | 3 | 1 | NO | No |
| 55 | 33.3 | 21.0 | -12.3 | -37% | 7 | 4 | -3 | 2 | 2 | 3 | 1 | 2 | 1 | 2 | 1a | -2 | No | Yes |
| ALL Avg | 14.7 | 10.0 | -4.7 | -32% | 3 | 2 | -1 | | | | | | | 1 | 1 | 0 | | |
| Avg ex #36 | 15.0 | 9.2 | -5.8 | -43% | | | | | | | | | | | | | | |
| | | | | | | | | | | | | | | | | | | |
| Average HFF ≥ 14% | 22.0 | 14.0 | -8.0 | -39% | 4 | 3 | -1 | | | | | | | 3 | 2 | -1 | | |
| Average NAS ≥ 3 | 21.8 | 14.9 | -6.8 | -30% | 4 | 3 | -1 | | | | | | | 2 | 2 | 0 | | |
| Average HFF ≥ 14% & NAS Score ≥ 3 | 26.3 | 18.1 | -8.2 | -30% | 5 | 4 | -1 | | | | | | | 2 | 1 | -1 | | |
Wino115 wrote: The close relationship between the three genes is interesting. I didn't see any poster from that AASLD presentation or a paper so this fills in some of the blanks on how those three work together. Here's another interesting statement from your find:
"...it was significantly associated with fibrosis stage...." and that "..blocking it attenuated liver fibrosis progression..."
This is important because we saw that result even in the less-than-optimal HIV NAFLD study and because one of the endpoints to meet is lowering NAS score and no fibrosis progression. This genetic link would possibly support Grinspoons view that it will stop that progression and that if you do it for longer, it will reverse it. It's good to see this kind of confirming science from people outside of the THTX realm. It backs up some of what they're finding and what they think the MOA could be to make it a very solid NASH approach.
jeffm34 wrote: TGF-β1 (transforming growth factor β1) was found to be mainly responsible for the up-regulation of CD147. Bioinformatic and experimental data suggest a functional link between CD147 expression and VEGF-A (vascular endothelial growth factor A)/VEGR-2 (VEGF receptor 2) signalling-mediated angiogenesis in fibrotic liver tissues.
Tesamorelin decreases TGF-B1 which appears to down regulate CD147 which decreases VEGF-A