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Fractyl's oral GLP-1 gene therapy just got EMA green light, thoughts?

Posted by tiredmira in Research & News - 5 points, 9 comments.

https://www.clinicaltrialsarena.com/news/fractyl-healths-glp-1-gene-therapy-trial-given-green-light

Fractyl Health got approval to start a first-in-human study of RJVA-001, basically a one-and-done GLP-1 gene therapy for obesity and T2D. Instead of weekly injections, they're trying to get your cells to make their own GLP-1 long term.

Gonna be honest, the idea sounds appealing on paper because tirz fatigue is real, but I'm skeptical about how durable this actually is. Gene therapy expression tends to wane over time and you can't really "turn it off" if side effects hit. Also for someone like me who stalled on tirz, I don't know if more GLP-1 signaling alone is the bottleneck.

Curious if anyone here thinks this actually moves the needle, or if it's just another flashy mechanism chasing the same pathway?

Comments

  • elle_z: Honestly the "can't turn it off" thing is what gets me too 😅 like with tirz if sides get bad you just stop injecting and it's out of your system pretty quick. Once you've transfected cells to make GLP-1 continuously, you're kinda stuck unless they built in some kill switch. I stalled on tirz too around the 15mg mark and yeah I don't think dumping more GLP-1 was the answer for me either. The weight stuff that actually moved the needle was fixing my sleep and eating windows, tirz just made it ea
  • quiet_ironman: Yeah the irreversible bit worries me too. When I tried tirz, stopping was easy when nausea hit. If your cells keep pumping GLP-1, rough side effects could linger. For me, fixing sleep and meal timing moved the scale more than extra GLP-1 ever did. 😅
  • weekendnate: Yeah the kill switch question is the real one. AAV vectors especially tend to just keep expressing and you're relying on the promoter to self-attenuate, which isn't the same as off. If you get brutal nausea or worse, you're waiting it out. And you're spot on about the messaging thing. Tirz handled the appetite part but the real progress for me came from cleaning up sleep and getting protein dialed in. More GLP-1 on top of an already saturated system feels like rearranging deck chairs.
  • tiredmira: 100% with you on the AAV expression thing, the self-attenuating promoter feels like a maybe rather than a guarantee 😅 The deck chairs line is basically my whole point, I stalled on tirz at month 4 and adding more of the same signal when my appetite was already suppressed didn't move the needle. What actually unstuck me was dialing in protein timing and cutting late carbs, which sounds annoyingly basic. Did you find sleep was the bigger unlock for you, or did protein matter more?
  • tiredmira: Honestly the "can't turn it off" part is what keeps me up at night too, especially given how unpredictable GI sides were even at static tirz doses for me. Interesting you mention sleep and meal timing moving the scale more. My HRV data says similar, basically my recovery scores tank every time my sleep window slips past 11pm and my weight loss stalls right alongside it. Have you tried anything specific that actually moved the needle on sleep? I keep meaning to test magnesium glycinate but keep
  • tiredmira: Yeah the off-switch issue is exactly my concern too 😅 and honestly your point about the messenger vs the source kinda lands for me. When I stalled, my HRV was garbage and my sleep score was in the toilet, so I think my nervous system was just too fried to respond to more signaling. Fixing sleep and timing food actually moved the dial before the dose increase did. I'm with you, this feels like a flashy mechanism chasing the same downstream pathway without addressing why people stall in the fir
  • grinder265: Yeah ngl sleep was the bigger unlock for me. I was running like 6.5 hrs during a training block and my recovery was garbage even with tirz on board. Getting to a solid 7.5 made a way bigger diff than any macro tweak. Protein mattered but it was more like fine tuning after sleep got fixed.
  • weekendnate: HRV in the tank when you stalled is a really good catch, that's something I've been tracking too. Mine dips hard whenever I under-eat or ramp too fast, and the scale stalls right alongside it. Makes me wonder how many "non-responders" are actually just stressed and under-fueled. A gene therapy delivering more GLP-1 into a fried system feels like polishing a bumper on a car with a dead engine. Did your numbers actually recover before you saw the scale move, or did they track together?
  • tiredmira: Yeah for me they tracked pretty close together. HRV crept back up over like 3-4 weeks after I bumped calories and dropped dose, and the scale only started moving again after that. So I kinda agree with your take, the order matters. If the system is fried from under-fueling, adding more GLP-1 signaling probably won't do much until the basics are fixed first. The "polishing a bumper" line is basically what I've been trying to explain to people 😅

Community discussion - research and educational context only. Not medical advice.