Recall(New to the series?)
The drugs in this post don't all fit neatly into the GLP-1/GIP/glucagon receptor framework — some use amylin receptor co-agonism, some use a GIP antagonist rather than agonist, and some are exploring monthly or quarterly dosing intervals. For the foundational receptor context, see The Receptor Game.
The single → dual → triple agonist progression is the main trunk of the GLP-1 drug tree. This family is the branches: drugs that add mechanistically distinct pathways (amylin), invert the expected GIP effect (MariTide's antagonist approach), push dosing intervals far past weekly, or offer an entirely separate mechanism for patients who can't tolerate GLP-1 drugs.
None of these are approved in the US or EU as of mid-2026. They represent where Phase 2 and early Phase 3 data is pointing next.
CagriSema — Novo Nordisk
At a glance
| Brand names | Not yet approved — [verify projected brand name] |
| Targets | GLP-1R + AMYR/CTR (GLP-1 + amylin co-agonism) |
| Developer | Novo Nordisk |
| Modality | SC injection, once-weekly (co-formulated single pen) |
| Approval status | Phase 3 — REDEFINE 1 data reported; filing status [verify] |
| Key efficacy | ~22.7% weight loss at 68 weeks (REDEFINE 1, Phase 3) |
| Indications | Obesity, T2D |
How it works
CagriSema combines two separate molecules in a single injection: semaglutide (GLP-1R agonist) and cagrilintide (an analog of amylin, a pancreatic hormone co-secreted with insulin). They hit different receptors — GLP-1R and AMYR/CTR — with complementary effects.
Amylin (and amylin analogs) slow gastric emptying, suppress glucagon, and signal satiety through pathways in the brainstem that are distinct from GLP-1's hypothalamic effects. The combination theory: GLP-1 and amylin are both endogenous satiety hormones that work through different circuits, so combining them should produce additive appetite suppression without redundancy.
The practical execution is a co-formulated injection with 2.4mg semaglutide + 2.4mg cagrilintide — you get both molecules from one weekly injection.
Trial data
Phase 2 (COMBINE 1): 15.6% weight loss at 32 weeks — comparable to semaglutide alone at this timeframe, somewhat underwhelming as a Phase 2 result for a combination. Phase 3 REDEFINE uses longer duration and higher doses; the thesis is that the combination's advantage appears at longer treatment periods.
REDEFINE 1 (Phase 3, obesity, 68 weeks): ~22.7% weight loss — substantially outperforming semaglutide alone and competitive with tirzepatide's SURMOUNT-1 numbers. The longer duration vs Phase 2 is where the amylin combination advantage became visible.
REDEFINE 2 (T2D), REDEFINE 3 (cardiovascular outcomes) — ongoing; results [verify current status].
Intuition(Why add amylin instead of another receptor)
Amylin and GLP-1 are both released after eating and both signal satiety, but through anatomically distinct pathways — GLP-1 primarily via the hypothalamus, amylin primarily via the area postrema and nucleus tractus solitarius in the brainstem. The hypothesis is that they're additive rather than redundant, because they're talking to different parts of the satiety circuit. The Phase 3 REDEFINE data supports this: ~22.7% is meaningfully more than semaglutide's 14.9% in STEP 1.
Dosing and administration
Once-weekly subcutaneous injection from a co-formulated pen containing both cagrilintide and semaglutide. Titration follows a similar slow-escalation approach to Wegovy — starting at lower doses and stepping up over 16–20 weeks to the full 2.4mg/2.4mg maintenance dose. Specific final titration schedule [verify against approved label once filed].
Development status
| Milestone | Status |
|---|---|
| Phase 2 COMBINE 1 | Complete — 15.6% at 32 weeks |
| REDEFINE 1 (obesity Phase 3) | Complete — 22.7% at 68 weeks |
| REDEFINE 2 (T2D Phase 3) | [verify current status] |
| REDEFINE 3 (CVD Phase 3) | [verify current status] |
| FDA filing | [verify — expected 2025–2026] |
Safety profile
GI side effects additive from both components — nausea and vomiting rates in REDEFINE 1 were higher than semaglutide alone, consistent with two complementary gastric-slowing mechanisms acting simultaneously. Discontinuation rates due to GI adverse events [verify vs semaglutide comparator in Phase 3]. Same thyroid C-cell black box warning applies via the semaglutide component. No novel safety signals attributable to cagrilintide identified in Phase 3 data reported to date.
MariTide (AMG 133) — Amgen
At a glance
| Targets | GLP-1R agonist + GIPR antagonist (antibody-peptide conjugate) |
| Developer | Amgen |
| Modality | Subcutaneous injection, monthly |
| Approval status | Phase 3 |
| Indications | Obesity |
How it works
MariTide is structurally unlike any other drug in this series. It's a bispecific antibody-peptide conjugate: a monoclonal antibody targeting GIPR (blocking it) with GLP-1R agonist peptides attached. It simultaneously activates GLP-1R and antagonizes GIPR — the opposite of tirzepatide's approach, which agonizes both.
This is pharmacologically provocative: tirzepatide's GIP co-agonism is currently the evidence-based case for GIPR activation in obesity. MariTide is betting on the old theory — that blocking GIPR is beneficial — or at least that GIPR antagonism in fat tissue alongside GLP-1R agonism produces a different and useful effect profile. The antibody format also allows monthly dosing (long antibody half-life) rather than weekly.
Trial data
Phase 2: ~17.3% weight loss over 52 weeks with monthly injections. Notably, weight loss appeared to continue accumulating through the full 52-week period without plateau, unlike the typical semaglutide curve that flattens around 40–52 weeks. If that non-plateauing effect holds in Phase 3, it could imply a different long-term weight loss trajectory.
The monthly dosing interval is the clearest differentiator — if efficacy is competitive with weekly injectables, a once-monthly schedule meaningfully improves the maintenance burden.
Dosing and administration
Once-monthly subcutaneous injection. The antibody-based format means no cold-chain requirements beyond standard biologic storage. Monthly cadence reduces the patient touchpoint burden vs weekly injectables significantly over a multi-year treatment course.
Development status
| Milestone | Status |
|---|---|
| Phase 2 | Complete — 17.3% at 52 weeks |
| Phase 3 | Enrolling |
| FDA filing | ~2027 estimated |
Safety profile
Phase 2 GI profile consistent with GLP-1 class. The GIPR antagonism approach is mechanistically distinct from tirzepatide's agonism — no unexpected safety signals attributable to the antibody format identified in Phase 2. Heart rate elevation similar to class. Full Phase 3 safety database pending.
ASC30 — Ascletis
At a glance
| Targets | GLP-1R (single agonist, ultra-long-acting) |
| Developer | Ascletis |
| Modality | SC injection, monthly → quarterly |
| Approval status | Phase 2 complete |
| Key efficacy | Positive Phase 2 weight loss data (specific numbers not yet public) |
| Indications | Obesity, T2D |
How it works
ASC30 is a GLP-1R agonist engineered for an extremely long half-life — designed to achieve therapeutic drug levels with monthly injections initially, moving toward quarterly dosing as maintenance. The mechanism is standard GLP-1 agonism; the innovation is purely pharmacokinetic.
The motivation: weekly injection burden is significant for a disease requiring years of maintenance therapy. A quarterly injection would substantially improve real-world adherence, particularly for patients in healthcare systems with less frequent clinical contact.
Trial data
Phase 2 data showed positive weight loss and glycemic results; specific efficacy numbers not yet fully public pending publication. Phase 3 design pending.
Dosing and administration
Monthly subcutaneous injection during induction phase, targeting quarterly dosing as maintenance. Specific titration schedule not yet public.
Development status
| Milestone | Status |
|---|---|
| Phase 2 | Complete — positive results |
| Phase 3 design | Pending |
| FDA filing | Timeline not yet public |
Safety profile
Phase 2 safety consistent with GLP-1 class. No novel signals identified. Full profile pending Phase 3.
Petrelintide — Zealand Pharma / Roche
At a glance
| Brand names | Not yet approved |
| Targets | AMYR (amylin receptor agonist — no GLP-1R involvement) |
| Developer | Zealand Pharma / Roche |
| Modality | SC injection, once-weekly |
| Approval status | Phase 2 — [verify Phase 3 initiation status] |
| Key efficacy | ~10.7% weight loss (Phase 2) |
| Indications | Obesity (standalone and combination) |
How it works
Petrelintide is not a GLP-1 drug. It's an amylin receptor agonist — it activates the amylin pathway without touching GLP-1R. This makes it mechanistically orthogonal to the rest of this series.
The reason it matters: GLP-1 agonists cause nausea and vomiting as a direct consequence of GLP-1R activation. A subset of patients discontinues due to intolerable GI side effects. Petrelintide offers an alternative satiety mechanism — amylin-pathway appetite suppression — without GLP-1R engagement, potentially serving a population that benefits from pharmacological weight management but can't tolerate GLP-1 drugs.
It also positions as a combination partner: adding petrelintide to an existing GLP-1 agonist could be additive in the same way CagriSema stacks semaglutide and cagrilintide, but as separate prescribable drugs rather than a fixed-dose combination. This gives prescribers flexibility that a co-formulated product doesn't.
Trial data
Phase 2: ~10.7% weight loss at [verify trial duration and name] — lower than GLP-1 agonists and dual agonists, but the relevant comparison isn't semaglutide. For patients who can't tolerate GLP-1R agonism at all, 10.7% with a clean tolerability profile is a meaningful number where the alternative is nothing.
Combination data with a GLP-1 agonist background therapy [verify — Zealand has indicated combination trials are planned].
Dosing and administration
Once-weekly subcutaneous injection. Specific dose range and titration schedule [verify — Phase 2 protocol details not fully public].
Development status
| Milestone | Status |
|---|---|
| Phase 2 (standalone obesity) | Complete — ~10.7% weight loss |
| Phase 2 (combination with GLP-1) | [verify status] |
| Phase 3 initiation | [verify — expected 2025–2026] |
| Roche partnership scope | [verify — development and commercialization rights] |
| FDA filing | Timeline not yet public |
Safety profile
Amylin receptor agonism causes GI side effects — nausea, vomiting — but through a distinct mechanism from GLP-1R activation. The GI profile in Phase 2 appeared generally milder than GLP-1 class comparators [verify discontinuation rates], which is the core tolerability proposition for patients switching from or unable to start a GLP-1 drug. No GLP-1-related cardiovascular or thyroid signals applicable. Novel safety signals specific to petrelintide [verify Phase 2 safety summary].
The shape of this family
These drugs represent three different bets on what the next structural innovation in obesity pharmacology looks like:
- Combination pathways (CagriSema, petrelintide) — adding mechanistically distinct satiety hormones rather than more incretin receptor targets
- Dosing interval (MariTide, ASC30) — same or similar mechanisms, dramatically longer half-lives, tackling the maintenance adherence problem
- Receptor inversion (MariTide's GIP antagonism) — challenging the current consensus on how GIPR engagement helps weight loss
None of these are yet proven in Phase 3. CagriSema is the furthest along and has the strongest data. MariTide's monthly dosing is the most commercially differentiated if it lands. Petrelintide serves a distinct patient population if it works. ASC30 is speculative but elegant if quarterly dosing is achievable at therapeutic levels.
Summary(Family summary)
Emerging modalities are the experiments the field is running after establishing that incretin receptor agonism works. CagriSema (Phase 3, ~22.7% weight loss) adds amylin to semaglutide and is the nearest to approval. MariTide inverts the GIP approach to monthly dosing with a bispecific antibody format. Petrelintide offers a GLP-1-free alternative pathway for intolerant patients. ASC30 explores whether quarterly dosing is achievable. All are Phase 2–3; Phase 3 data will determine which of these bets were right.