@DrNadolsky @bioinvestor24 I'd love to see somebody weird like Abbvie or AstraZeneca buy them just to break the duopoly
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FlexNP
3.4K posts
FlexNP
@rn_flex
Primary care NP, lover of balanced glucagon agonism, incretin nerd, photographer, mountain lover, coonhound rescuer
Primary care land เข้าร่วม Ekim 2021
223 กำลังติดตาม684 ผู้ติดตาม
@rn_flex @bioinvestor24 Can we just make sure it’s not part of the duopoly
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Presuming sky doesn’t fall on obesity in a year or so and $LLy MC doesn’t collapse by > 50% .. $VKTX could still close the mother of all deals based on what we are hearing from drug performance in vanquish phase 3 ( as most institutions still believe the drug is toxic based on the awkward oral data ) vs tirzepatide performance
( and presuming CEO agrees to sell prior to 2027 data ?)
Option Millionaires@OMillionaires
$TERN buyout while $VKTX just sits there....
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@JCanNuSH Presume metformin adds 20% to that Ph3 Reta data and you're at approximately 20.1%, 18.6% and 13.3% weight loss at 40 weeks which is 🤯🤯
Triumph-2 allows metformin and SGLT2i so yeah. Expect to see some unbelievable and previously unheard of weight loss numbers for diabetics.
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🕵️ How does metformin affect weight loss in Type 2 Diabetes trials for GLP-1s?
➡️ No surprise, metformin usually increased weight loss, often by 20% or more.
Two sets of studies didn’t meet this bar
➡️ 36mg orforglipron - probably because the non-metformin study included far more women (72% compared to 52%) than the metformin one, inflating the results of the non-metformin study.
➡️ 14mg oral semaglutide (Rybelsus). I dunno what happened here. 🤷♀️ Both trials had roughly the same WL performance at 26 weeks.
▪️For each med, I looked at trials of similar duration - one without metformin and one with metformin.
▪️These were T2D trials - not T2D weight loss trials.
▪️No comparison for semaglutide 2mg, dulaglutide 4.5mg, or oral semaglutide 25 or 50mg because they did not have a study without metformin.
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@PAH78573620 @bioinvestor24 I mean then fire your companies CSO. It's the same AA sequence as tirzepatide but with a different fatty acid linker. That's it. Even if they want $30B for it, you'll make that back extremely rapidly once approved.
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@rn_flex @bioinvestor24 Significantly derisked…but not derisked enough for a CEO to roll the dice for what $VKTX would be willing to accept now.
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@MichaelAlbertMD @MWeintraubMD Achieve-4 the first short 2 year CVOT of orforglipron will have full data readout at ADA 2026. If that shows CV benefits then I think it's safe to say it's a class effect.
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@MWeintraubMD At the end of the day, I believe it will be mostly class-translatable.
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Are obesity and metabolic therapies becoming commoditized?
We’re likely heading toward a landscape where 10–20 agents can reliably deliver ~20–30% long-term weight loss.
If that holds true, the differentiation won’t be the molecule—it will be the model:
>How therapies are selected
>How they’re sequenced or combined
>How side effects are anticipated and managed
>Add'l services
In other words, the competitive edge shifts from the drug to the system that deploys it.
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🤔Thoughts on the VK2735 maintenance study that should release results later this year: the most important part of this study is NOT the maintenance data — it’s the 19 week data we’ll get on the performance of the subcutaneous doses.
That’s a 50% increase in treatment time compared to the previous 13 week datasets we’ve seen. Plus we’ll get data on the higher doses as well (17.5mg is the current P3 max dose, but wasn’t tested in the earlier Phase 2 study.) $VKTX
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@rn_flex I *know*. I assume it’s being run in another like Australia or something.
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@bioinvestor24 Gotta hype something up I guess? I mean by the time these trials end....the landscape will be significantly more crowded so how are they gonna differentiate their molecule? Monthly dosing? Day late and two dollars short.
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I guess $PFE management has short term memory and has forgotten number of trials that $NVO ran on their inferior pipeline that is not making a difference. 😂
U only need to run one trial on a great molecule and you can run dozens on bad ones that take u no where.
Albert Bourla@AlbertBourla
Today, we dosed the first participant in VESPER-5, our second Phase 3 obesity study in just a few months. At least ten pivotal studies are planned for our lead investigational treatment this year, with more than 20 across our ambitious pipeline. We said we'd move fast after acquiring Metsera. We meant it.
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@MichaelMindrum SGLT2i + Retatrutide is gonna be the one I'm really looking at in diabetic patients. Caloric drain with SGLT2i then forced ketosis + appetite suppression and weight loss from Reta. Could and probably will match bariatric surgery outcomes in DM2 patients
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It’s a foundational paper for understanding why weight loss plateaus occur with any intervention, and it speaks directly to why combination strategies (e.g., SGLT2i + GLP-1 RA) make mechanistic sense — one creates a caloric drain, the other suppresses the compensatory appetite response. 5/5
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So if you lose 60 g of glucose a day, that is about 250 kcal per day, & 3500 kcal every 2 weeks. That means about a pound of weight every 2 weeks, or 25 lbs a year. So you should be 50 lbs down in 2 yrs and 75 lbs down in 3. But it doesn’t work that way. Why? 1/5
Healthspan@healthspanmed
Caloric restriction works—but almost no one can sustain it. SGLT-2 inhibitors offer a workaround: force 60–80 grams of glucose into the urine daily, and the body responds as if it's fasting—activating AMPK, suppressing mTOR, upregulating SIRT1, and dampening insulin/IGF-1 signaling. Pharmacological fasting without behavioral change. This week's Research Review examines whether the mechanism is sufficient to extend healthspan. gethealthspan.com/research/artic…
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Reta’s results at 40 weeks from TRANSCEND-T2D-1 WITHOUT metformin or other glucose lowering meds.
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Given retatrutide’s phenomenal results in TRANSCEND-T2D-2 (a study in Type 2 diabetes without the dietary focus of a weight loss specific trial), this study is going to be a blood bath.
The only real issue is that they might have to massively reduce Reta doses as time goes on. Minimum starting BMI of 25.
TRANSCEND-T2D-2 - comparing Reta vs Semaglutide for 80 weeks for patients on metformin (which will likely increase overall performance) with or without an SLGT2 inhibitor, and possibly longer (it doesn’t mention an extension but it suggests 26 months for the study).
Two different final doses of Reta are being used, presumably against 2mg Ozempic. One hopes they are using the lower doses.
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I realize I’ve been posting on wanting active comparator trials instead of placebo, and now I’m saying “oh poor active comparator”. 🤷♀️ But it will still be preferable over placebo.
In SUSTAIN-FORTE, 2mg Semaglutide with metformin, we saw 6.4% WL and 2.1% A1C reduction with a baseline body weight of 99.3kg at 40 weeks.
This should be interesting. Again, I think the main issue for Reta here will be an appropriate dose reduction policy so patients don’t have to discontinue due to excessive weight loss.
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@rn_flex Right? Phenomenal results from reta.
I do imagine some folks might not handle the glucagon for Reta well? Or the stronger side effects (which likely can be addressed with slower up titration)? But the different price points may matter here too.
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🧐🕵️ I’ve been staring at $LLY ‘s Phase 2 trial on investigational doses of tirzepatide in patients with T2D and obesity (BMI of 35 and above required for this study). Rumor is they are looking at doses of 20 and 25mg.
💥Primary end point was 44 weeks with an EXTENSION until 80 weeks.
It’s odd to do an extension out so long on a Phase 2. An extension out to 80 weeks (assuming 5mg steps for last two doses) gives them 52 weeks on the final dose - which is what you need for the weight loss indications.
With the FDA signaling that they are willing to reduce trial burden and accept one pivotal trial, would they accept a mere Phase 2 (350 participants) for a label adjustment to add high doses limited to T2D + obesity on Zepbound or Mounjaro?
Primary completion was due in January, but it looks like the extension is dragging it out until October.
The Researcher view indicates that the Primary Completion date is for “data collection date for primary outcome measure” - so that’s the 44 week outcome, rather than the 80 week.
Also, this study theoretically “started” in Sept 2023. WHY is it taking sooo long? I assume they delayed enrollment for some reason (and it does look like they dropped some countries from their original plan).
clinicaltrials.gov/study/NCT06037…
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I’m personally doubtful that higher doses would do much more without adding more anhedonia pressure, but their pursuit of this extension has me questioning that.
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@bioinvestor24 I also wonder if some of the tolerability issues are also half life related. It actually has a really short half life, about 4 days, and we know those big peaks and troughs can cause more AE/SE
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$NVO amycretin phase 1-2 data
x.com/bioinvestor24/…
Bioinvestor24@bioinvestor24
Trying to figure $NVO decision to run several phase 3 on amycretin. That is like $2 B investment ? Probably they feel they should look at everything. In the lancet paper , the escalation was slow. Vomit ( and dysesthesia at higher doses ) were still big problems Look at DC rate among higher doses and even the vomit rate was calculated for all ITT pts ( like 4/16 pts in the 5 mg dose). But they claim a lot of DC not due to side effects ? So the vomit rate is significantly higher than 25% even in the smaller 5 mg. If you look at 20 or 60 mg .. the vomit rate is enormous ( although placebo also had high vomit on this sc trial . but Very small placebo sample ..). Look at slow escalation rate so u can’t improve by further slowing . I do not see it as competitive at all with $LLY tirzepatide Cagrisema combo looks better tolerated and seems best novo bet short term , better that the oral sema excitement that I believe will fade once people try and compare different drugs .. Cagrisema showed high vomit rate in phase 1 but was faster escalation and improved in phase 3 ( was still worse than Sema) So these statements by novo management on amylin improving tolerability are at least misleading. Same going on with $PFE now ).
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$NVO doing smaller phase 3 trials on amycretin in obesity… I guess to look at it in other settings like obesity and OA and plan to submit 4500 pt safety package of all trials together to FDA in 3 years. Obesity trial looking at 84 Wks ( 32+ 52) and 136 Wks ?
It is C/W phase 1/2 as escalation was slow and still a problematic molecule with a lot of nausea / vomit at 5 mg and above.
Not sure what can be done in phase 3 despite 32 wks of escalation ( vs 20 wk with $LLy tirzepatide) to mitigate GI issues .
I understand novo attitude of trying everything. We don’t know the tolerability from phase 2 trial in obese diabetics ( Nov 2025 ) ? May be something encouraging was seen but novo didn’t share
Amycretin , CagriSema , and even retatrutide 9 and 12 mg don’t seem to strike the best efficacy / tolerability balance that is seen with tirzepatide to grab consumers from that well designed molecule.
ResearchPulse@ResearchPulse1
Amycretin P3 in knee Osteoarthritis Online at CT. Also called AMAZE-5 trial. We have earlier seen some details about this upcoming P3. But there’s more here. Small trial with just 400 patients and 80w. That’s 4weeks shorter than the other P3 trials already up. Could point towards a bit smaller top dose in this trial. 20mg vs 40mg? 3 active dose groups. I wonder if $NVO has started hiding more informations at CT listings. No mentioning about BMI threshold and that participants must want to lose above 25% to apply. Those inclusion criteria were leaked earlier as seen in below post. From NVO investor presentation AMAZE 5 have earlier been listed as H2H with Tirzepatide. But does not look like it from CT listings. I know they will not repeat their mistake from Redefine 4 where it ended as an open label trial since CagriSema and Zepbound use two very different devices. $LLY $NVO $VKTX clinicaltrials.gov/study/NCT07481…
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@semodough @JCanNuSH They counted bradycardia, PVCs and right bundle branch block arrhythmia for example. All of those are relatively common findings in any large enough sample size and likely completely unrelated to the drug.
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@semodough @JCanNuSH Please for the love of God look at the actual data in the appendix for the phase 3 trial. It's not 19%. It's 5% and it's not a cardiac safety signal there's 15 phase 3 trials of this drug including 2 CVOT/MACE trials. Any true safety signal would have been uncovered long ago.
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$LLY In the phase 2 Retatrutide trial 19% cardiac arrhythmias- need to see that safety in this phase 3 trial ???
Bio Stocks™@BioStocks
$LLY triple agonist Retatrutide demonstrated significant reductions in A1C and weight in Phase 3 trial for the treatment of type 2 diabetes. $NVO For the primary endpoint retatrutide lowered A1C by an avg of 1.7% to 2% across doses at 40 wks Participants taking retatrutide 12 mg lost an average of 36.6 lbs (16.8%) prnewswire.com/news-releases/…
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@semodough @JCanNuSH Do they count PVCs as an arrhythmia?
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This definitely looks like a cardiac safety signal at the higher doses. The GLP-1's all slightly increase pulse rate as a starting point.
dough@semodough
$LLY In the phase 2 Retatrutide trial 19% cardiac arrhythmias- need to see that safety in this phase 3 trial ???
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So funny… I was just thinking this morning, before the $LLY TRANSCEND-T2D-1 results were announced, “I wonder if Lilly is going to hold the Reta data until after Wegovy 7.2mg is approved so that $NVO doesn’t steal their thunder”. Both out, same day. 🤣
Jen Can NuSH@JCanNuSH
🚨Big news day: $NVO Wegovy HD (7.2mg injection) has now been approved by the FDA. Novo Nordisk expects to launch Wegovy® HD in a single-dose pen in the US in April 2026. 18.8% weight loss over 72 weeks compared to 15.5% for 2.4mg. (Efficacy estimand was 20.7% for 7.2mg) ml-eu.globenewswire.com/Resource/Downl…
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