Great question! 🙏(You're reading it right and may be one of the few people to read the entire article😊)
On the drug curve alone the model agrees with you- at wk 30 the VANQUISH-1 schedule sits about 1.8pp BEHIND the Maintenance schedule (-21.9% vs -23.7% on my chart's footing), because it reaches 17.5mg 14 weeks later. The two catch up by ~wk 48 and are the same line by wk 72.
➡️ What put the VANQUISH-1 line ahead of the Maintenance Trial's actual at wk 30 in my chart is the placebo term, not the titration. That chart carries SURMOUNT-1's placebo response (2.4pp) because VANQUISH-1, like SURMOUNT-1, counsels every arm on diet and exercise. The Maintenance Trial's placebo arm did nothing (-0.1 at wk 21, +0.3 at wk 33), so the two aren't on the same footing at wk 30. Strip the 2.4 out and VANQUISH-1 reads -19.6% at wk 30, under the Maintenance arm.
➡️ This is really the cross-trial issue from the article showing up inside my own chart- the drug curve is the same, the assumed placebo response of the trial around it is not.
I ran both titration schedules at 17.5mg (Maintenance and VANQUISH-1) through my model to illustrate the impact of the titration scheme on WL vs time- chart below, on the same footing as the article's projection.
$VKTX - @bioinvestor24 makes excellent points in the quoted post. 🙏 I agree with all of them, and want to add detail on one:
➡️ The +5 mg step at Week 10 in #VK2735 VENTURE (10 → 15 mg) did not produce an outsized AE signal. The Week 1 spike in that arm came from a 5 mg opening dose in drug-naive patients. This is the only arm that started there. The other arms opened at 2.5 mg.
➡️ 15 mg arm, Week 1: 27 GI events, nausea in 17 of 35 (48.6%). Week 10: 4 GI events total - nausea 3 (8.6%), vomiting 1, no diarrhea, no constipation. A real uptick, but not a Week 1 repeat and gone by Week 11.
➡️ This isn't unique to a step-up week. The 5 mg arm logged 12 GI events in Week 4; 5 mg Week 2 and 10 mg Week 4 logged 6 each.
➡️Small scattered clusters show up throughout the study.
Caveats: n=35 per arm, so one patient moves a rate ~3 points, and by Week 10 that arm is already tolerized.
Here are some slides including a modified one from my original article (green = the nuance). Take a look for yourself:
One observation in $VKTX phase 2 from 2024 is the broad wt loss across population. At 15 mg dose 100% lost > 5% and 89% lost > 10% in 13 wks.
There were 35 pts in this arm and 7 DC drug for whatever reason ( 28 finished the study on drug ) . But 31 pts lost > 10% .. and 35 lost > 5%
it shows that pts didn’t stop early .. there was 10 to 15 mg step up that made a few pts uncomfortable which VK is avoiding in all subsequent studies.
When I look at $PFE Vesper 3 with 24% vomit ( double $LLY TZP) and 20% DC from any reason , I wonder how they will be able to combine with their amylin ( 37% vomit in MAD) ? No wonder they new phase 2 B is like 900 pts as ptiabaky still can’t figure the right combination doses despite doing 200 pt trial in 2025-26
Same issue will face $ABBV if they end up relying on amylin combination with any future asset. And $RHHBY ..
and $NVO is doing now 7.2 mg sema / CagriSema trial 😂
Knowing that a number of pts are de escalation due to excessive wt loss on VK2735 and $LLy retatrutide trials .. not sure if combinations will have serious role in future… or be competitive with excellent single agent approaches
$PTGX is on a roll‼️ Just got approval for another partnered peptide drug. MIMRYLO (aka rusfertide) was approved Aug 28. They got a best-case "broad and clean label" according to JPMorgan.
➡️As a result, Protagonist got another big milestone payment ($275M) and will receive double-digit pure profit royalties on this second drug with blockbuster potential (ICYMI - ICOTYDE was the first).
$VKTX - The GI profile in the induction phase matters even though it is not the same as the titration in Vanquish. If it is good (as in consistent with the class and equal/better than say Tirzepatide's) then VK2735 will have another way to dose -> 2-week titration blocks rather than 4. Yes, this would be "off-label" but there is a lot of that happening now with both approved and compounded GLP1s varieties.
Consider also:
➡️There is a segment of the market that will want to lose weight fast and would possibly risk the AE profile to do it. Getting to the top dose of 17.5mg in 12 weeks (the time it takes in induction) rather than 26 weeks would also save them money as an incentive.
➡️This would be a material competitive advantage over Tirzepatide should this 12-week titration prove viable. (Tirzepatide takes 20 weeks to get to its top dose of 15mg)
➡️ Being able to titrate up quickly says something about VK2735 tolerability that reads through to the Ph3 Vanquish study in a positive predictive way.
VK2735's TMax at 70-90h is later/longer than key other GLP1's (E.g. Tirz, Reta, Sema, etc.) . It is a big reason VK2735 is likely to succeed in the Maintenance Trial with 2 week titration blocks IMO.
@Doctor_Salomon @semodough @pharmdca @GilaMonstrum
$VKTX
Would not pay attention to GI profile from induction phase of the ph2 maintenance study. It’s almost a waste of time since the GI AEs from phase 3 (what matters) likely to be lot lower given the slow titration.
The GI AEs from the maintenance DO matter since they have read thru to EOW or monthly dosing. Monthly dosing is a bit ambitious IMO but if GI AEs are low, it becomes really attractive.
Don't think any MS note had any comments like that and I don't believe BL made any statements like that either. Again-the Maintenance study titration has not been publicly disclosed AFAIK.
➡️If you have a link on MS or can reference someplace that BL stated a limit on titration steps for the ph1 maintenance study please share. I would note that there are no 5mg steps in the ph3 study so possibly that is where you got "no 5mg jumps" but that doesn't apply to the maintenance study induction phase. Here is the Phase 3 VANQUISH titration scheme:
Where did you get the information that Viking will not escalate (titrate)by more than 2.5 mg in the induction phase of the ph1 maintenance study? (I don't believe this has been disclosed.)
➡️After the first 3 wks. of being on the drug, up titrating by 5mg wasn't all that much different than going by 2.5 in the Venture ph2. Brian's comments lead me to believe there will be at least one 5mg jump after say 5-6 wks. Here is the time course of AE's from venture ⏬⏬⏬⏬⏬
I would hope they clear this up very soon and set expectations - too many unknowns right now. I’ll also make a follow‑on guess about the one arm where they titrate to 17.5 mg at some point (around week 17?) and stay there until week 31. This arm has N=15, which is really small, so we could see very wide variance. (In the Venture Ph2 SubQ study, N was 35 for the 10 mg and 15 mg doses.)
If I interpolate the data for TRZ at 33 weeks (SURMOUNT‑1), I think that landed around 17–18% WL. Interpolating the Reta Ph2 data at 33 weeks, I think Reta hit ~20% at that point.
➡️ So again, using TRZ and RETA as yardsticks -assuming a normal obesity‑population baseline, a titration schedule starting at 2.5 mg and increasing in 2.5 mg increments (mildly aggressive since they’re not 4‑week blocks), and the realities of the calendar with respect to WL - I would guess absolute WL of 15–17% for VK2735 over around 20 weeks. Out to 33 weeks, I would guess VK2735 is in the 19–22% range. (@GilaMonstrum modeled ~20.6% for this arm I believe and Noumena's analysis/models have been spot on in the past IMO) Even getting close to Reta without the tingling, arrythmia etc would be very positive IMO.
ALT From June Corp presentation slide 32 with highlights
ALT @GilaMonstrum Model https://x.com/GilaMonstrum/status/2064769526403592592/photo/1
Interesting points. I think @sarathmandava99 is correct that it is 21 weeks now not 19 as Brian said in the cc. Per the current company presentation its 21. (key slide included).
I'm noting that BL also said the highest dose was there for a 3 week period. Really wish they would disclose the titration schedule clearly for all arms.
If I had to make a new guess for the 17.5 mg arm(s) titration it would be New guess for titration on the key 17.5mg arms is now: 2.5mg x 3wks, 5.0 x 3wks, 7.5 x 4wks, 12.5 x 4wks and 17.5 x 7 wks. (21 total for induction +12 week maint = 33 total)
I like the idea that it is now 21 weeks for induction vs 19. Viking needed to provide some longer data like others have provided in ph2. (I actually would like to have seen the induction phase go out to 26 weeks but 21 is better than 19 and I will take it)
$VKTX - @GilaMonstrum - I'm very interested in your simulations. (They're outstanding 🙏🙏🙏!!)
As you lose weight, your basal metabolic rate (BMR) goes down and some motivation is lost the closer you get to your goal so I agree that the closer you get to max WL effect, the less weight you lose per wk. However, given #VK2735 has a 8-10 day 1/2 life, the blood plasma concentration was still changing/rising at the end of the Venture ph2 so isn't there some effect that should maintain the WL trajectory slope till you settle out for around 4-6 half lives (i.e. around 6-7 weeks for VK2735)?
Secondly- the fact that Viking raised the terminal dose to 17.5 mg tells me they think they could get better/more receptor engagement by increasing the max dose. Agree?
Finally for the Ph1 maintenance trial the induction phase will have approx. 165 subjects all on the same titration schedule. The induction phase can be looked at as a large single arm and I expect the WL results there will drive the $VKTX PPS even more so than the 31 wk maintenance results (12 weeks of maintenance). My best guess at the induction titration schedule needed for this study is 2.5mg x 3wks, 5.0 x 3wks, 7.5 x 3wks, 12.5 x 3 wks and 17.5 x 7 wks. So this starts small, and jumps by 2.5 until week 9 and then makes two 5.0 mg jumps to end at 17.5 for 7 wks to "settle out" in prep for evaluation of Maintenance doses.
My guess is based upon BL comments and my "spit ball" analysis of the ph2 venture subq AE's. If you look at all the arms except the 15mg in that trial they started at 2.5 and didn't have a lot of AE's. The 15mg arm had one 5mg jump that didn't seem to be too bad on AE's and it suggested that once you had drug in circulation after a reasonable exposure you could raise by 5mg. So my guess is an aggressive schedule but reasonable. (I've attached the titration schedule from the ph 2 venture along with the time sequenced AE's on the 10 & 15 mg arms in the second pic to this post for reference)
Could you use this titration schedule to estimate a WL range out to 19 weeks? Or if you have other thoughts, please share. TIA.
