CagriSema phase 2 paper sits at the boundary between what this community can usefully discuss and what it cannot, and I think it falls on the discussable side, narrowly.
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Compounds · Cagrilintide & amylin analogues · continued
The CagriSema phase 2 paper and what a fixed combination buys — the long version posts 61–90
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
The phase 3 combination programme is where the clinically interesting numbers will come from. Phase 2 established that the combination does something; the size of it in a larger population is a separate question.
The strength of my opinion here exceeds the strength of my evidence.
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l.chevalier, post #1: The CagriSema phase 2 paper and what a fixed combination buys — the long version Writing it up because I had to work it out twice and would rather nobody else did. A narrow question about CagriSema phase 2 paper, deliberately narrow, because the broad version has been asked here four times and produced four long threads and no answer.… Go to post
This follows post #61 rather than contradicting it.
The honest summary of the evidence base: a coherent mechanism, good phase 2 data in combination, and much less standalone human data than the volume of discussion implies.
If that is already documented somewhere, ignore me and link it.
The strongest argument against my own position on CagriSema phase 2 paper, stated as well as I can state it, since nobody else has yet.
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z.okonkwo, post #8: Appreciated. The plain phrasing does more work here than a longer post would. Go to post
Nausea appears in the amylin-analogue literature as it does in the incretin literature, and the two are not additive in a simple way when the drugs are combined. The combination trials report tolerability separately for that reason.
f.amankwah, post #61: CagriSema phase 2 paper sits at the boundary between what this community can usefully discuss and what it cannot, and I think it falls on the discussable side, narrowly. Go to post
CagriSema phase 2 paper would be much easier to settle if anyone reported the denominator. Almost nobody reports the denominator.
The arithmetic in post #68 is right; the assumption feeding it is the part to check.
Is synergy the right word for the combination data? A phase 2 trial cannot establish whether effects are synergistic or additive. Synergy is a mechanistic claim that requires a designed experiment to support it. The combination works, but the mechanism is unsettled.
It took me longer than it should have to see that.
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compounding_ruth, post #5: On CagriSema phase 2 paper, the part that usually goes wrong is that the question is asked as though it has one answer. It has a range, and the width of the range is the interesting bit. If you can post the two or three numbers you are working from, several people here will check the arithmetic rather than argue about the conclusion. Go to post
I read the earlier replies on CagriSema phase 2 paper twice before writing this, because I had assumed the opposite and wanted to be sure I was disagreeing with what was said rather than what I expected.
Picking up post #72: that is the part I would want checked first.
Combination products complicate the certificate question considerably. Two active components mean two purity determinations and a ratio, and a single figure for a combination tells you almost nothing.
Reading it again, the caveat matters more than the finding.
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b.okonkwo, post #62: Nothing to add on the substance. Thank you for taking the question at face value. Go to post
On post #70 — agreed on the reasoning, with one qualification.
The honest answer on CagriSema phase 2 paper is that it depends, and the useful part is the list of what it depends on. Four items, in rough order of how much they matter.
Most people get the first two right and then argue about the fourth.
Reading the phase 2 paper: it establishes tolerability and efficacy in a selected population on a defined dose escalation. It does not establish the lowest effective dose or the durability over years.
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Where I part company with post #74, and it is a narrow parting.
Published human data on cagrilintide alone is thinner than on the combination, which is the reverse of what most people assume from how it is discussed here.
Scoping that to what I have actually seen rather than what I have read.
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Adding the measurement that post #76 says would settle it.
The most useful reply I ever got about CagriSema phase 2 paper was a request to state my units. It sounds like pedantry and it has saved me twice.
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l.aaltonen, post #73: Picking up post #72: that is the part I would want checked first. Combination products complicate the certificate question considerably. Two active components mean two purity determinations and a ratio, and a single figure for a combination tells you almost nothing. Reading it again, the caveat matters more than the finding. Go to post
Research-use-only cagrilintide is not approved for human use and the published evidence base is a clinical-trial evidence base. Those two facts sit uncomfortably together and both are true.
Posting it because the silence on this was starting to look like agreement.
I read post #78 twice before replying, because I had assumed the opposite.
The monoisotopic mass sits near 3749.9 Da, and the same caveat applies as everywhere else: a mass consistent with the proposed structure is a necessary condition and not a sufficient one.
Adding a source would improve this post and I do not have one to hand.
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p.iyer_pharmd, post #66: The strongest argument against my own position on CagriSema phase 2 paper, stated as well as I can state it, since nobody else has yet. Go to post
On post #80 — agreed on the reasoning, with one qualification.
Gastric emptying: both amylin and GLP-1 slow it, through partly overlapping but distinct mechanisms. Whether the slowing at a higher magnitude produces disproportionate nausea or is tolerable is a question phase 3 exists to answer.
That is all I can say without guessing.
Bookmarking this. I will come back when I have something worth adding.
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Offering a way to settle CagriSema phase 2 paper rather than another opinion about it. Two measurements, taken the same way, a fortnight apart. If the difference is within the noise, the question was not answerable at this precision.
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Post #83 is right about the mechanism and I think understates the practical bit.
If you are new and reading this thread for the answer to CagriSema phase 2 paper: the answer is conditional, the conditions are in the third reply, and the rest of the thread is worth skipping.
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impurity_table, post #60: Post #56 and I disagree about the size of the effect, not about the direction. Combination products complicate the certificate question considerably. Two active components mean two purity determinations and a ratio, and a single figure for a combination tells you almost nothing. Go to post
Worth separating two things that post #83 runs together.
On storage: aggregation-prone peptides are the ones where repeated warming and cooling does the most damage, and where a solution that looks fine may already have changed. Visual inspection is a weaker test here than usual.
This follows post #83 rather than contradicting it.
The arithmetic on CagriSema phase 2 paper is the easy part and it is where the errors are, which is an uncomfortable combination. Show your working and someone will catch it.
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The CagriSema phase 2 paper: a fixed combination of the two components in one weekly injection. The trade-off of a fixed combination is that you cannot titrate the components independently and you cannot attribute effect to one component from a combination trial.
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z.onwuka, post #54: Clear enough that I do not think I have a follow-up, which is unusual. Go to post
This is the answer, and the reason it is the answer is the more useful part.
c.ostergaard, post #34: Reading the phase 2 paper: it establishes tolerability and efficacy in a selected population on a defined dose escalation. It does not establish the lowest effective dose or the durability over years. Go to post
Second-hand on CagriSema phase 2 paper, so weight it accordingly — someone whose method I trust told me this and I have not verified it myself.