The pipeline stops arguing about efficacy
A triple agonist heads for the regulators, the oral race becomes a question of factories and capital, and the list of tolerability problems keeps growing.
One read on the month, with every source graded and numbered.
Efficacy is settled. The fight moved to the factory.
Lilly said it will submit a Biologics License Application for retatrutide to the FDA in the first quarter of 2027, once its manufacturing data package is complete. The company rests that filing on “five positive Phase 3 studies”; the two reported this month are TRIUMPH-2, in adults with type 2 diabetes and obesity or overweight, and TRIUMPH-3, in severe obesity with established cardiovascular disease [1][2]. Both readouts are company-reported topline, nothing is filed yet, and the label will decide how much of the trial effect survives into practice. In the same month the European Commission approved the Wegovy pill [3], six months and three weeks after the FDA cleared it on 22 December 2025 [23]. That gives Novo a head start over Lilly’s oral.
Lilly and its manufacturing partner Resilience jointly committed $750M to expand Cincinnati-area production of Lilly’s KwikPen injectable device [7]. You only spend that much on device manufacturing if you expect the demand, and the pen is a part of the supply chain this category rarely discusses in public. When every leading asset clears the efficacy bar, what separates them is form, supply, and geography, and a better efficacy number does nothing for any of the three.
The same two trials were reported as a success and as a failure
Kailera said its oral obesity pill succeeded in a late-stage trial in China, on company-reported results [4]. A second outlet covered the same two Phase 3 trials, in obesity and in diabetes, and made high side-effect rates its headline [5]. Both were written from a single company release, published that morning [24], which carried the numbers for either case.
In HARBOR-1, the 556-patient obesity trial, nausea reached about 70% and vomiting 67 to 69%, against 16% and 5% on placebo. Discontinuation because of treatment-emergent adverse events was 4.1% at 120 mg and 3.1% at 180 mg, against 2.7% on placebo. The side-effect rates are alarming. Almost nobody stopped taking the drug because of them. Quartz reported the shares down 10% that Tuesday [25]; they closed at $22.24, down 4.6% on the day [26].
Which of those numbers a reader takes away depends on which outlet they opened. A China-origin oral clearing late-stage trials at home is a signal about who the next wave of competitors will be.
The next fight is over mechanism
Kalohexis, an Endevica spinout, filed confidentially for an IPO on a melanocortin pipeline that runs the same receptor pair in both directions: 710GO, an oral MC3R/MC4R agonist in Phase 1 for general obesity, and mifomelatide, an injectable MC3R/MC4R antagonist in Phase 2 for cancer cachexia. The obesity asset is the one being pitched against the incretins [6]. The filing tests whether public investors will fund an obesity mechanism that is not a GLP-1 derivative. That filing is still a confidential draft, so there is no answer yet.
Agonist and antagonist programmes have competed on GIPR for years with no account of why pushing the receptor in opposite directions produces weight loss either way. In mice, the two act through different brain regions: the area postrema for agonism, the hypothalamus for antagonism’s synergy with GLP-1 and amylin agonists [8]. This is mouse work, and the antagonist effect is synergistic rather than standalone. It still tells the competing agonist and antagonist programmes where in the brain to look.
Lilly registered an experimental compound, LY3841136, with tirzepatide, alone and in combination [15]. Combining two drugs is a different way to add efficacy than building a third receptor into a single molecule. Two reviews set the frame for all of it: one on the nutrient and non-nutrient regulators of insulin secretion [9], and one proposing that insulin resistance be read as an adaptive response to chronic nutrient excess [10]. The second is the more consequential, because that framing changes what counts as a treatment target. Outside the incretins, ATTEMPT randomised 98 youth aged 12 to 21 with type 1 diabetes and hyperfiltration to dapagliflozin or placebo over a 16-week treatment period. The molecular kidney reading published this month does not rest on those 98: it comes from a biopsy substudy at a single one of the trial’s three sites, in participants aged 18 or older, with 16 biopsies at baseline and 11 at follow-up. Its authors call the findings hypothesis-generating [11].
The indication is widening while the randomised evidence stays mixed
Two separate registrations put tirzepatide into addiction medicine. One tests it for smoking cessation [12]; the other, first posted in October 2024 and NIDA-funded, places it alongside buprenorphine for opioid use disorder [13]. Both records were updated in July. Neither has reported.
Randomised trials of semaglutide in addiction have already begun to report. A 108-participant trial in adults with moderate-to-severe alcohol use disorder and comorbid obesity met its primary endpoint in May: heavy drinking days fell 13.7 percentage points further on semaglutide than on placebo [20]. Two smaller phase 2 trials read weaker. One was null on both co-primary outcomes in adults with daily cigarette use [21]; the other was positive on laboratory self-administration and on drinks per drinking day, but not on how many days participants drank [22]. So the tirzepatide bets are being placed while the semaglutide evidence is still mixed.
The observational signal points the same way: a multi-target emulation built from four separate target trials, covering 40,703 adults with alcohol use disorder and either type 2 diabetes or obesity who met the criteria for at least one of them, reported an association between GLP-1 use and a lower observed risk of alcohol-related hospitalisation [19]. It is not a trial and it does not demonstrate an effect. In two of the four trials the authors flag residual confounding, because non-alcohol-related hospitalisation fell as well, though by less than the alcohol-related outcome.
The indication is widening in other directions too. Novo registered cagrilintide and CagriSema in children and adolescents with excess body weight [14], where the age at which treatment starts is the variable with the least long-term evidence behind it. And a trial of semaglutide for NAFLD fibrosis is registered under a title calling it real-world [16]; the design is randomised, placebo-controlled and triple-masked. “Real-world” names its setting, not its design.
What the drugs cost the person taking them
A retrospective cohort study in TriNetX electronic health records matched 438,474 patients with type 2 diabetes taking a GLP-1 against an equal number prescribed other type 2 diabetes medicines, and found more smell and taste disturbance in the treated group (hazard ratio 1.48, 95% CI 1.37 to 1.61) [17]. It is an association and does not demonstrate cause. Chemosensory effects are easy to dismiss and hard to live with, and they plausibly interact with the eating behaviour these drugs are prescribed to change.
About 11% of US adults say they currently take a GLP-1 for weight loss (15% have ever taken one), against a self-reported obesity rate of 36.4% so far in 2026 [18]. Both are self-reported; Gallup notes its obesity estimates run below clinically measured ones, and its own series peaked at 39.9% in 2022. Nothing approved this month narrows the gap between prevalence and uptake.
If you are building an obesity asset
$750M went into US injector-pen manufacturing this month, an oral won approval in Europe, and a China-origin oral cleared late-stage trials at home. Now that efficacy is settled, you compete on whether you can make it at volume, what form it comes in, and where you are allowed to sell it.
Changes if a new result separates the leading drugs on weight loss again, or pen capacity runs short sooner than the $750M assumes.
If your mechanism is not a GLP-1
Kalohexis, a clinical-stage biotech, filed to go public on a melanocortin target (MC3R/MC4R), testing whether the market will fund an obesity drug that is not a GLP-1. Separately, researchers located where in the brain the two rival GIPR approaches act, which gives programmes betting on GIPR direction somewhere specific to look. Neither is settled: the filing is confidential, and the brain work is in mice.
Changes if the IPO goes through, or a study in people finds the same split between brain regions.
If you read this category from headlines
One company’s results were written up as a win by one outlet and as a safety problem by another, from the same release. That release held both numbers: about 70% of patients had nausea, and 3 to 4% stopped because of side effects. Coverage made the first its headline, and the stock fell.
Changes if the full results are published, or a trial compares it directly against an approved oral drug.
The trials this issue draws on, with what each has and has not shown. Registrations record where sponsors are placing bets; none of them has reported.
| Trial | Year | Population | What it showed |
|---|---|---|---|
| TRIUMPH-2retatrutide in type 2 diabetes with obesity | 2026 | Type 2 diabetes with obesity or overweight (n=1,152) | Up to −20.8% body weight at 80 weeks vs −4.0% on placebo. Company-reported topline. [2] |
| TRIUMPH-3retatrutide in severe obesity with cardiovascular disease | 2026 | Severe obesity with established cardiovascular disease (n=1,949) | Up to −22.6% vs −3.2% on placebo. Company-reported topline. [2] |
| HARBOR-1oral HRS-7535 in obesity | 2026 | Obesity, China (n=556) | Met its primary endpoint. Nausea about 70%; discontinuation from adverse events 4.1% and 3.1% vs 2.7% on placebo. Company-reported. [24] |
| ATTEMPTdapagliflozin in youth with type 1 diabetes | 2026 | Youth aged 12–21 with type 1 diabetes and hyperfiltration (n=98) | Molecular kidney readout drawn from a 27-biopsy substudy in participants aged 18+. Authors call it hypothesis-generating. [11] |
| —semaglutide in alcohol use disorder with obesity | 2026 | Moderate-to-severe AUD with comorbid obesity (n=108) | Met its primary endpoint: heavy drinking days fell 13.7 percentage points further than placebo. [20] |
| —semaglutide in adults who smoke daily | 2026 | Adults smoking daily (n=24, phase 2a) | Null on both co-primary outcomes. [21] |
| Semaglutide in alcohol use disorder | 2025 | Non-treatment-seeking adults with AUD (n=48) | Positive on laboratory self-administration and drinks per drinking day; null on number of drinking days. [22] |
| —tirzepatide for smoking cessation | registered 2026 | — | No results yet. [12] |
| NIDA CTN-0152tirzepatide with buprenorphine for opioid use disorder | registered 2024 | Opioid use disorder | No results yet. [13] |
| —cagrilintide and CagriSema in children and adolescents | registered 2025 | Ages 8–18 with excess body weight | No results yet. [14] |
| —LY3841136 with tirzepatide in obesity | registered 2024 | Obesity | No results yet. [15] |
| —semaglutide for NAFLD fibrosis | registered 2023 | NAFLD with obesity or type 2 diabetes | No results yet. [16] |
Every source behind the read above, numbered to its [n] marker and graded by where its evidence comes from.
Source gradeRegulatoryGuidelineTrialPeer-reviewedPreprintTrade press
Industry & deals
- Trade press Lilly, with new data, to seek FDA approval of obesity drug retatrutide
- Trade press Lilly's triple agonist heads to regulators after two more Phase 3 obesity wins
- Trade press Novo gains head start on Lilly with European Commission approval of Wegovy pill
- Trade press Kailera says its obesity pill succeeds in a late-stage trial in China
- Trade press Hengrui and Kailera's GLP-1 pill posts encouraging efficacy but high side-effect rates
- Trade press Kailera Therapeutics Announces Positive Topline Data from Two Hengrui Pharma Phase 3 Clinical Trials of Oral Small Molecule GLP-1 Receptor Agonist HRS-7535/KAI-7535
- Trade press Kailera’s weight loss pill met its trial goal. But nausea hit 70% of patients
- Trade press Kailera Therapeutics (Nasdaq: KLRA) daily price history
- Trade press Endevica spinout Kalohexis submits confidential IPO filing to develop obesity challenger to GLP-1s
- Trade press Lilly, Resilience commit $750M to boost US diabetes, obesity med production
- Trade press Wegovy® pill approved in the US as first oral GLP-1 for weight management
Literature
- Peer-reviewed Distinct brain regions mediate regulation of food intake in response to GIPR agonism or antagonism
- Peer-reviewed Nutrient and non-nutrient regulators of insulin secretion
- Peer-reviewed Insulin resistance and type 2 diabetes as allostatic responses to chronic nutrient excess
- Peer-reviewed SGLT2 inhibition modulates metabolic, vascular, and inflammatory molecular markers in the kidney in youth with type 1 diabetes
- Peer-reviewed Once-weekly semaglutide versus placebo in patients with alcohol use disorder and comorbid obesity: a randomised, double-blind, placebo-controlled trial
- Peer-reviewed Once-Weekly Semaglutide in Adults With Daily Cigarette Use: A Randomized Clinical Trial
- Peer-reviewed Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial
Trials & clinical
- Trial Multi-site trial of tirzepatide for smoking cessation
- Trial Tirzepatide as an adjunct to buprenorphine for opioid use disorder
- Trial Cagrilintide and CagriSema in children and adolescents with excess body weight
- Trial LY3841136 and tirzepatide, alone or in combination, for weight management in adults with obesity or overweight and type 2 diabetes
- Trial Semaglutide treatment in the real-world for fibrosis due to NAFLD in obesity and type 2 diabetes
Tolerability & access
- Peer-reviewed Smell and Taste Disturbances Among Glucagon-Like Peptide-1 Receptor Agonist Users
- Trade press In U.S., GLP-1 Usage Reaches New High
- Peer-reviewed Association between GLP-1 receptor agonists and alcohol-related hospitalisations among adults with alcohol use disorder: multi-target trial emulation study
Radar scans the literature, registered trials, industry and deals, and tolerability and access each month, then surfaces the items that matter and grades each by where its evidence comes from. Registered trials are reported as direction of travel, never as results, and company-reported topline is labelled as such. This is issue No. 2; the source list grows as the scanner's coverage widens.
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