Delivered-To: tjphuhs@gmail.com Received: by 2002:adf:f3cb:0:b0:441:282b:bd with SMTP id g11csp1557724wrp; Fri, 24 Apr 2026 08:51:35 -0700 (PDT) X-Received: by 2002:a05:6214:5190:b0:8ac:b677:c408 with SMTP id 6a1803df08f44-8b02815238bmr485829926d6.44.1777045895233; Fri, 24 Apr 2026 08:51:35 -0700 (PDT) ARC-Seal: i=1; a=rsa-sha256; t=1777045895; cv=none; d=google.com; s=arc-20240605; b=aRrxp9T+kOZh7UxqfjLlV6LfYI2R6kMVxSniForiZm2aP6oh2ilDu+RX/t23T3UyxQ RHQ31O7HZjCosguBCMC/KP1Go1kjSu/QhGV6XzyxLeIqvQj/Jdt6mGypvGYzyicDY5fr +f5NSzmzv+Gc9Sl4V8ULcvYfTRWwEkRNRILqAL/78KS92jTmtID4gFCSnYfFGiwzg3m7 7hraBJUgwyF9wv9k3WFghuKy1fAHtxdDGgxBl04Bqrm2TEGhCXByridak5kKg4A7KitT mEuOAs+VZYITUGq9118IF1Ec73GKqPj9ayj/+zRX+uPpxl5Mjr9dhnkjd06S48fdAI2d JNmA== ARC-Message-Signature: i=1; a=rsa-sha256; c=relaxed/relaxed; d=google.com; s=arc-20240605; h=list-unsubscribe-post:list-unsubscribe:list-post:list-id :list-archive:list-url:list-owner:reply-to:in-reply-to:references :sender:feedback-id:date:message-id:to:from:subject:mime-version :dkim-signature:dkim-signature; bh=oAghnd6p6rCoE2lZYmP7GCZe5W7L6ODnfN+F6nGFHyQ=; fh=9zP21OW67FFZD2VV42mGudo540Qp4aalMWxJB5kMYug=; b=TpppSwv5Jiw75OT+a6cKbd3SoA4b1WTt/+dd5UfkJPnPREgQvSIUskbKeTtDkZ3z8m YNLJWB5pJfgu36xllvMZ6M8o9gTZSBsjB5P/fpt3z18mPiPWAsLa5fqUsjt2in+NnLLw Az/hagi6W7FVYe7zZuIEL6nh4qBOQDWC5MGdAe0UpdgdvsWuYDT9GtnjzBayJEVLTnOm KmSbTFXCKyfMf1QUZyhJhb34ZD2/AMq7LhiKFJ2mvVCHMgg8WesabJ2Bm6LDondd/nxt DdY7EP+OkXLj5HT3XaUHk5DA40NMmHRkz8V1fNqwBdImXatVpWnyHbJKkcOqYn5DL8CM QDZw==; dara=google.com ARC-Authentication-Results: i=1; mx.google.com; dkim=pass header.i=@mg2.substack.com header.s=mailo header.b=ojj1l9kE; dkim=pass header.i=@mailgun.org header.s=mg header.b=m6R9bLX5; spf=pass (google.com: domain of bounce+a6cce7.4d1858-tjphuhs=gmail.com@mg2.substack.com designates 159.112.244.19 as permitted sender) smtp.mailfrom="bounce+a6cce7.4d1858-tjphuhs=gmail.com@mg2.substack.com"; dmarc=pass (p=REJECT sp=REJECT dis=NONE) header.from=substack.com Return-Path: Received: from v519.v5375b7fa.use4.send.mailgun.net (v519.v5375b7fa.use4.send.mailgun.net. [159.112.244.19]) by mx.google.com with UTF8SMTPS id 6a1803df08f44-8b02ac84d96si273153086d6.148.2026.04.24.08.51.34 for (version=TLS1_2 cipher=ECDHE-ECDSA-AES128-GCM-SHA256 bits=128/128); Fri, 24 Apr 2026 08:51:35 -0700 (PDT) Received-SPF: pass (google.com: domain of bounce+a6cce7.4d1858-tjphuhs=gmail.com@mg2.substack.com designates 159.112.244.19 as permitted sender) client-ip=159.112.244.19; Authentication-Results: mx.google.com; dkim=pass header.i=@mg2.substack.com header.s=mailo header.b=ojj1l9kE; dkim=pass header.i=@mailgun.org header.s=mg header.b=m6R9bLX5; spf=pass (google.com: domain of bounce+a6cce7.4d1858-tjphuhs=gmail.com@mg2.substack.com designates 159.112.244.19 as permitted sender) smtp.mailfrom="bounce+a6cce7.4d1858-tjphuhs=gmail.com@mg2.substack.com"; dmarc=pass (p=REJECT sp=REJECT dis=NONE) header.from=substack.com DKIM-Signature: a=rsa-sha256; v=1; c=relaxed/relaxed; d=mg2.substack.com; q=dns/txt; s=mailo; t=1777045894; x=1777053094; h=List-Unsubscribe-Post: List-Unsubscribe: List-Post: List-Id: List-Archive: List-Owner: Reply-To: In-Reply-To: References: Sender: Sender: Date: Message-Id: To: To: From: From: Subject: Subject: Content-Type: Mime-Version: X-Feedback-Id; bh=oAghnd6p6rCoE2lZYmP7GCZe5W7L6ODnfN+F6nGFHyQ=; b=ojj1l9kEGovxCF6PxZIilK1ZrwgmandcEET3j8/eul6EOUzW6VkqWPMYejgqh9zFbdae1ooAvRl84slKD7uAPaOTJRTczApsklqcBNvG+UQI2tvSWmQVln7LRpoTi46tVwIJKgBZkOPuaMO5tZ38HtQWZmM7pbqD4weavfS2vl4= DKIM-Signature: a=rsa-sha256; v=1; c=relaxed/relaxed; d=mailgun.org; q=dns/txt; s=mg; t=1777045894; x=1777053094; h=List-Unsubscribe-Post: List-Unsubscribe: List-Post: List-Id: List-Archive: List-Owner: Reply-To: In-Reply-To: References: Sender: Sender: Date: Message-Id: To: To: From: From: Subject: Subject: Content-Type: Mime-Version: X-Feedback-Id; bh=oAghnd6p6rCoE2lZYmP7GCZe5W7L6ODnfN+F6nGFHyQ=; b=m6R9bLX5hdTnfHzF66RPoW5PjNTjj3sAR2t+PVEX42pbeXj1s8OREo6thbR8x+M6KCnkF/uhjwv0gfK6mGGoalpmj4xzyNZDXWjenzNOfZyMUC45UQChaH/rlNPkyXo/f63LgruZBDhqZUjEJmSL/dW6/zMtaatXHDZ3HP+Nzf8= X-Mailgun-Sid: WyIxODZiYSIsInRqcGh1aHNAZ21haWwuY29tIiwiNGQxODU4Il0= X-Feedback-Id: postmaster@mg2.substack.com:post:5a78b6d5cd16820001f2a9d4:mailgun Received: by 132e6712e2dc2e6a9504908dbbefc71781bb98f7de2079f30d8612f96345a324 with HTTP id 69eb9186759e38c337b2e6d7; Fri, 24 Apr 2026 15:51:34 GMT X-Mailgun-Sending-Ip: 159.112.244.19 Mime-Version: 1.0 Content-Type: multipart/alternative; boundary="84fb8a3013e56cc2fbf4528043920abe7893cce751484422f91bb561692e" Subject: Quintuple Agonist for Obesity: One Drug, 5 Receptors From: Dave Knapp from On The Pen To: tjphuhs@gmail.com X-Mailgun-Tag: post X-Mailgun-Track-Clicks: false Message-Id: <20260424155108.3.f42d9a98f24a22c0@mg2.substack.com> Date: Fri, 24 Apr 2026 15:51:08 +0000 Feedback-Id: post-195360886:cat-post:pub-4808993:substack Sender: Dave Knapp from On The Pen References: In-Reply-To: Reply-To: Dave Knapp from On The Pen List-Owner: List-Url: List-Archive: List-Id: List-Post: List-Unsubscribe: List-Unsubscribe-Post: List-Unsubscribe=One-Click X-Mailgun-Variables: {"category": "post", "email_generated_at": "1777045894845", "is_freemail": "true", "post_audience": "everyone", "post_id": "195360886", "post_type": "newsletter", "pub_community_enabled": "true", "publication_id": "4808993", "subdomain": "onthepen", "user_id": "273622398"} --84fb8a3013e56cc2fbf4528043920abe7893cce751484422f91bb561692e Content-Type: text/plain; charset="utf-8" Content-Transfer-Encoding: quoted-printable View this post on the web at https://onthepen.substack.com/p/quintuple-agon= ist-for-obesity-one Yesterday I dropped something that moved faster than I expected, and the re= actions ended up being just as telling as the data itself. An Eli Lilly fun= ded scientist is set to present rodent data at the American Diabetes Associ= ation meeting on a quintuple agonist, a five pathway compound that has alre= ady edged out retatrutide in rat weight loss. Retatrutide has been treated = as the ceiling by a lot of people in this space, so even early animal data = suggesting something may surpass it forces a reset in how people think abou= t what comes next. JOIN US FOR TODAY=E2=80=99S TGIF LIVE @ Noon Eastern! What stood out to me right away was how many of you didn=E2=80=99t react wi= th shock, but rather recognition. I saw comments like =E2=80=9CGLP 5 droppe= d before GTA6,=E2=80=9D which honestly captures how fast this category is m= oving, and others joking that at this rate there will be no receptors left = to agonize. One of my favorites compared this progression to the evolution = of a five blade razor, which is funny on the surface but actually pretty ac= curate in terms of how the industry keeps stacking functionality into a sin= gle product. Even the darker humor showed up, with an OTP O.G. community me= mber, Cloakster, joking that =E2=80=9Cthe rodent test subjects for the quin= tuple agonist all literally disappeared before trial end,=E2=80=9D which en= capsulates the internet=E2=80=99s general processing of just how aggressive= this all sounds. A lot of you also went straight to the peptide community and said this look= s like what people have been doing for years by combining cagrilintide with= incretin based therapies oftentimes layering in retatrutide. I understand = that instinct because both approaches are trying to hit multiple receptors = at once and push beyond what a single pathway drug can do. That said, this = is not exactly the same thing, even if the receptor targets overlap. Stacking separate compounds means each drug has its own absorption curve, i= ts own half life, and its own receptor activity profile. You are essentiall= y running multiple independent signals at the same time and hoping they lin= e up in a way that produces a net benefit. A multi agonist is one engineere= d molecule with a single pharmacokinetic profile that is designed to engage= multiple receptors in a coordinated and predictable way. The ratios are fi= xed, the timing is unified, and the interaction across receptors is intenti= onal rather than incidental. That is the difference between experimentation= and something that can be reproduced, studied, and ultimately approved. I also want to clear up something that took off in the replies almost immed= iately, because I am already seeing people refer to this compound as =E2=80= =9C2839 LB.=E2=80=9D That is not the name of the drug. It is simply the pre= sentation identifier from the ADA program that I included in the screenshot= =2E We do not have a public name for th= is molecule yet. What we do know is th= at the work is being presented by the Indiana Biosciences Research Institut= e and that most of the authors listed are sponsored by Lilly, which tells y= ou where this is coming from even if the branding has not been attached yet= =2E The part that matters more than the jokes or the naming confusion is what t= his signals when you place it next to everything we have been covering here= on our substack and podcast around classification and control. Lilly has a= lready learned that building a powerful molecule does not mean you control = how it is used or where it ends up. Compounding expanded when access broke = down, and the gray market filled in the gaps when patients could not get wh= at they needed through traditional channels. Retatrutide, in particular, de= veloped demand in places Lilly does not control, and once that happens Lill= y no longer has to solve for efficacy alone, they are solving for control. That is where the biologic conversation starts to matter. We have been writ= ing about this for a while, especially in the context of retatrutide and ho= w Lilly may try to position future therapies in a way that changes how they= are regulated and protected. Small molecule drugs are inherently more vuln= erable to replication and modification within existing frameworks. Biologic= s introduce a different level of complexity, a different regulatory pathway= , and a different set of barriers. A quintuple agonist fits into that shift in a way that is hard to ignore. I= ncreasing the number of pathways is not just about amplifying weight loss, = it also increases the complexity of the molecule itself. Complexity makes m= eaningful replication more difficult, and that aligns with a broader strate= gy of maintaining control in a world where patients have already shown they= will find alternatives when access is limited. That is why the reaction to this post felt different. It was not just peopl= e reacting to a new potential drug. It was people connecting dots between w= hat has been happening in the peptide community, what Lilly has experienced= with compounding and gray market demand, and what this next generation of = molecules might represent. If this compound holds up beyond rodent data and eventually shows similar s= ignals in humans, it will represent another leap forward in what is biologi= cally possible for people living with obesity. The question that follows is= the same one that has followed every breakthrough in this category so far.= Will it actually reach people who need it in a meaningful way, or will it = live inside a system where access is still dictated by pricing, coverage, a= nd regulatory friction. And whether folks believe it or not, yes, there are= indeed people with metabolic disease severe enough to demand exactly this = type of innovation. But innovation without access means very little. What yesterday confirmed for me is that the direction is clear. Multi pathw= ay therapies are not a fringe idea anymore. They are being formalized, engi= neered, and pushed through the system at the highest level. What is less cl= ear is whether the system itself is going to evolve with them, or whether w= e are about to watch the same access story play out again with a much more = advanced molecule at the center of it. So I want to hear where you land on this. Do you see this as validation of = what has been happening outside the system, or do you see it as the system = absorbing those ideas and tightening control at the same time. And if a dru= g like this makes it through the pipeline, do you trust that it will be acc= essible to the people who need it, or do you think patients will once again= be forced to find their own way. Unsubscribe https://substack.com/redirect/2/eyJlIjoiaHR0cHM6Ly9vbnRoZXBlbi5= zdWJzdGFjay5jb20vYWN0aW9uL2Rpc2FibGVfZW1haWw_dG9rZW49ZXlKMWMyVnlYMmxrSWpveU= 56TTJNakl6T1Rnc0luQnZjM1JmYVdRaU9qRTVOVE0yTURnNE5pd2lhV0YwSWpveE56YzNNRFExT= 0RrMExDSmxlSEFpT2pFNE1EZzFPREU0T1RRc0ltbHpjeUk2SW5CMVlpMDBPREE0T1Rreklpd2lj= M1ZpSWpvaVpHbHpZV0pzWlY5bGJXRnBiQ0o5LkU2MTdkeld3RFZlRElBQkhPcmdFV0dndDAyMi0= tT1ZiWWUtQ2NRTjk3eVkiLCJwIjoxOTUzNjA4ODYsInMiOjQ4MDg5OTMsImYiOnRydWUsInUiOj= I3MzYyMjM5OCwiaWF0IjoxNzc3MDQ1ODk0LCJleHAiOjIwOTI2MjE4OTQsImlzcyI6InB1Yi0wI= iwic3ViIjoibGluay1yZWRpcmVjdCJ9.mYgD2WTrocCpAco7tk-8YCH7WrwfW2LzNCNE9aa4mfY= ? --84fb8a3013e56cc2fbf4528043920abe7893cce751484422f91bb561692e Content-Type: text/html; charset="utf-8" Content-Transfer-Encoding: quoted-printable = Quintuple Agonist for Obesity: One Drug, 5 Receptors3D""
Meet the GLP5 as the gym bros have already dubbed it= =2E..
͏     ­͏     ­͏   =   ­͏     ­͏     ­͏= ;     ­͏     ­͏     &#= 173;͏     ­͏     ­͏   &= #8199; ­͏     ­͏     ­͏=     ­͏     ­͏     = 73;͏     ­͏     ­͏   &#= 8199; ­͏     ­͏     ­͏ =     ­͏     ­͏     = 3;͏     ­͏     ­͏   = 199; ­͏     ­͏     ­͏ &= nbsp;   ­͏     ­͏     ­= ;͏     ­͏     ­͏   Q= 99; ­͏     ­͏     ­͏ &n= bsp;   ­͏     ­͏     ­= ͏     ­͏     ­͏   ̳= 9; ­͏     ­͏     ­͏ &nb= sp;   ­͏     ­͏     ­&= #847;     ­͏     ­͏    = ; ­͏     ­͏     ­͏ &nbs= p;   ­͏     ­͏     ­&#= 847;     ­͏     ­͏    = ­͏     ­͏     ­͏  = ;   ­͏     ­͏     ­= 47;     ­͏     ­͏     = ­͏     ­͏     ­͏  =   ­͏     ­͏     ­T= 7;     ­͏     ­͏     &= #173;͏     ­͏     ­͏   =   ­͏     ­͏     ­͏= ;     ­͏     ­͏     &#= 173;͏     ­͏     ­͏   &= #8199; ­͏     ­͏     ­͏=     ­͏     ­͏     = 73;͏     ­͏     ­͏   &#= 8199; ­͏     ­͏     ­͏ =     ­͏     ­͏     = 3;͏     ­͏     ­͏   = 199; ­͏     ­͏     ­͏ &= nbsp;   ­͏     ­͏     ­= ;͏     ­͏     ­͏   Q= 99; ­͏     ­͏     ­͏ &n= bsp;   ­͏     ­͏     ­= ͏     ­͏     ­͏   ̳= 9; ­͏     ­͏     ­͏ &nb= sp;   ­͏     ­͏     ­&= #847;     ­͏     ­͏    = ; ­͏     ­͏     ­͏ &nbs= p;   ­͏     ­͏     ­&#= 847;     ­͏     ­͏    = ­͏     ­͏     ­͏  = ;   ­͏     ­͏     ­= 47;     ­͏     ­͏     = ­͏     ­͏     ­͏  =   ­͏     ­͏     ­T= 7;     ­͏     ­͏     &= #173;͏     ­͏     ­͏   =   ­͏     ­͏     ­͏= ;     ­͏     ­͏     &#= 173;͏     ­͏     ­͏   &= #8199; ­͏     ­͏     ­͏=     ­͏     ­͏     = 73;͏     ­͏     ­͏   &#= 8199; ­͏     ­͏     ­͏ =     ­͏     ­͏     = 3;͏     ­͏     ­͏   = 199; ­͏     ­͏     ­͏ &= nbsp;   ­͏     ­͏     ­= ;͏     ­͏     ­͏   Q= 99; ­͏     ­͏     ­͏ &n= bsp;   ­͏     ­͏     ­= ͏     ­͏     ­͏   ̳= 9; ­͏     ­͏     ­͏ &nb= sp;   ­͏     ­͏     ­&= #847;     ­͏     ­
Forwarded this email? S= ubscribe here for more

Quintuple Agonist for Obesity: One Drug, 5 Re= ceptors

Meet the GLP5 as the gym bros have already dubbed it...

<= table class=3D"post-meta" role=3D"presentation" width=3D"100%" border=3D"0"= cellspacing=3D"0" cellpadding=3D"0" style=3D"margin: 1em 0;height: 20px;al= ign-items: center;"><= /tr>
On The Pen GLP-1 News
 
=3D""
= 3D""
3D""
READ IN APP3D=
 

Yesterday I dropped something that moved faster than I expected, and the r= eactions ended up being just as telling as the data itself. An Eli Lilly fu= nded scientist is set to present rodent data at the American Diabetes Assoc= iation meeting on a quintuple agonist, a five pathway compound that has alr= eady edged out retatrutide in rat weight loss. Retatrutide has been treated= as the ceiling by a lot of people in this space, so even early animal data= suggesting something may surpass it forces a reset in how people think abo= ut what comes next.

JOIN US FOR TODAY’S TGIF = LIVE @ Noon Eastern!

What stood = out to me right away was how many of you didn’t react with shock, but= rather recognition. I saw comments like “GLP 5 dropped before GTA6,&= #8221; which honestly captures how fast this category is moving, and others= joking that at this rate there will be no receptors left to agonize. One o= f my favorites compared this progression to the evolution of a five blade r= azor, which is funny on the surface but actually pretty accurate in terms o= f how the industry keeps stacking functionality into a single product. Even= the darker humor showed up, with an OTP O.G. community member, Cloakster, = joking that “the rodent test subjects for the quintuple agonist all l= iterally disappeared before trial end,” which encapsulates the intern= et’s general processing of just how aggressive this all sounds.

3D"X
On The Pen™
@ManOnThePen
🚨 BREAKING @EliLillyandCo NEWS: $LLY will release a= nimal study data for at QUINTUPLE AGONIST at #ADA2026 For reference: Tirzep= atide =3D GLP1/GIP Retatrutide =3D GLP1/GIP/Glucagon New Mol =3D GLP1/GIP/G= lucagon/Amylin/Calcitonin Early rat studies outperformed retatrutide!
=
7:25 PM · Apr 23, 2026 · 525K Views
67 Replies &#= 183; 61 Reposts= · 836 Likes

<= /p>

A lot of you also went straight to the peptide community an= d said this looks like what people have been doing for years by combining c= agrilintide with incretin based therapies oftentimes layering in retatrutid= e. I understand that instinct because both approaches are trying to hit mul= tiple receptors at once and push beyond what a single pathway drug can do. = That said, this is not exactly the same thing, even if the receptor targets= overlap.

3D"onthepen.official"= onthepen.official
=
850 likes
Dave Knapp on Instagram: "#Tirzepatide =3D 2
#Retatrutide =3D 3
New…
View on Instagram

Stacking separate compo= unds means each drug has its own absorption curve, its own half life, and i= ts own receptor activity profile. You are essentially running multiple inde= pendent signals at the same time and hoping they line up in a way that prod= uces a net benefit. A multi agonist is one engineered molecule with a singl= e pharmacokinetic profile that is designed to engage multiple receptors in = a coordinated and predictable way. The ratios are fixed, the timing is unif= ied, and the interaction across receptors is intentional rather than incide= ntal. That is the difference between experimentation and something that can= be reproduced, studied, and ultimately approved.

I also wa= nt to clear up something that took off in the replies almost immediately, b= ecause I am already seeing people refer to this compound as “2839 LB.= ” That is not the name of the drug. It is simply the presentation ide= ntifier from the ADA program that I included in the screenshot. We do not h= ave a public name for this molecule yet. What we do know is that the work i= s being presented by the Indiana Biosciences Research Institute and that mo= st of the authors listed are sponsored by Lilly, which tells you where this= is coming from even if the branding has not been attached yet.

The part that matters more than the jokes or the naming confusion is w= hat this signals when you place it next to everything we have been covering= here on our substack and podcast around classification and control. Lilly = has already learned that building a powerful molecule does not mean you con= trol how it is used or where it ends up. Compounding expanded when access b= roke down, and the gray market filled in the gaps when patients could not g= et what they needed through traditional channels. Retatrutide, in particula= r, developed demand in places Lilly does not control, and once that happens= Lilly no longer has to solve for efficacy alone, they are solving for cont= rol.

That is where the biologic conversation starts to matt= er. We have been writing about this for a while, especially in the context = of retatrutide and how Lilly may try to position future therapies in a way = that changes how they are regulated and protected. Small molecule drugs are= inherently more vulnerable to replication and modification within existing= frameworks. Biologics introduce a different level of complexity, a differe= nt regulatory pathway, and a different set of barriers.

A q= uintuple agonist fits into that shift in a way that is hard to ignore. Incr= easing the number of pathways is not just about amplifying weight loss, it = also increases the complexity of the molecule itself. Complexity makes mean= ingful replication more difficult, and that aligns with a broader strategy = of maintaining control in a world where patients have already shown they wi= ll find alternatives when access is limited.

=3D""

That is why the reactio= n to this post felt different. It was not just people reacting to a new pot= ential drug. It was people connecting dots between what has been happening = in the peptide community, what Lilly has experienced with compounding and g= ray market demand, and what this next generation of molecules might represe= nt.

If this compound holds up beyond rodent data and eventu= ally shows similar signals in humans, it will represent another leap forwar= d in what is biologically possible for people living with obesity. The ques= tion that follows is the same one that has followed every breakthrough in t= his category so far. Will it actually reach people who need it in a meaning= ful way, or will it live inside a system where access is still dictated by = pricing, coverage, and regulatory friction. And whether folks believe it or= not, yes, there are indeed people with metabolic disease severe enough to = demand exactly this type of innovation. But innovation without access means= very little.

What yesterday confirmed for me is that the d= irection is clear. Multi pathway therapies are not a fringe idea anymore. T= hey are being formalized, engineered, and pushed through the system at the = highest level. What is less clear is whether the system itself is going to = evolve with them, or whether we are about to watch the same access story pl= ay out again with a much more advanced molecule at the center of it.

So I want to hear where you land on this. Do you see this as vali= dation of what has been happening outside the system, or do you see it as t= he system absorbing those ideas and tightening control at the same time. An= d if a drug like this makes it through the pipeline, do you trust that it w= ill be accessible to the people who need it, or do you think patients will = once again be forced to find their own way.

Leave a com= ment

<= /div>

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