Enzymes and Early Signals
Week Of March 21 – March 27, 2026
This week’s newsletter is heavy on early-phase data, which I think tells an interesting story about where the obesity pipeline is headed. There are a lot of new ideas entering clinical trials. Early signals are way more uncertain than late-stage readouts, but they’re worth watching because they show the range of biological targets being explored. Obesity affects over a billion people globally and the condition looks different across populations, so there is room for fundamentally different approaches.
Novo Nordisk just started a Phase 1 for something that isn’t a GLP-1 agonist. LX9851, licensed from Lexicon Pharmaceuticals in a deal worth up to $1 billion, inhibits an enzyme called ACSL5 to block fat absorption and trigger the gut’s own satiety signaling. Preclinical data showed it prevented weight regain after semaglutide was stopped, which is one of the biggest unsolved problems in the space. I go into the biology in both the Trial Spotlight and Mechanism Explained. Elsewhere, Viking completed enrollment for its Phase 3 VANQUISH-2 trial of VK2735, BrightGene’s oral dual agonist posted up to 8% weight loss at just 8 weeks, and Novo’s triple agonist UBT251 beat semaglutide on HbA1c in a Phase 2 study. On the cautionary side, Aardvark paused its entire pipeline after cardiac signals emerged with its bitter taste receptor approach. Novel mechanisms carry novel risks.
Separately, a new meta-analysis in Diabetes, Obesity and Metabolism (20 RCTs, ~15,800 patients) found that incretins don’t cause disproportionate lean mass loss compared to lifestyle interventions achieving similar weight reduction - challenging a persistent narrative. Resistance training was the real differentiator, cutting lean mass loss to 17.5% of total weight lost versus ~26% for both drugs and diet alone. Worth thinking about as muscle-sparing drugs like enobosarm and bimagrumab enter trials alongside GLP-1s: are they additive with exercise, or a substitute for it?
🔥 THIS WEEK’S KEY DEVELOPMENTS
Viking Completes Enrollment for Phase 3 Obesity Trial of VK2735.
Viking Therapeutics has completed patient enrollment for its Phase 3 VANQUISH-2 trial of subcutaneous VK2735, a dual GLP-1/GIP receptor agonist. The 78-week study enrolled approximately 1,000 adults with obesity or overweight and type 2 diabetes. The trial’s primary endpoint is the percent change in body weight from baseline compared to placebo after 78 weeks of treatment.
Press | Trial: NCT07104383 | Mechanism: dual GLP-1/GIP agonist
BrightGene’s oral dual agonist BGM0504 shows up to 8% weight loss at 8 weeks.
China-based BrightGene reported early data from two Phase 1 studies of oral BGM0504, a dual GLP-1/GIP agonist. In the U.S. study (80 patients, doses 20-80 mg), cohorts saw weight loss between 2.7% and 8.2% after five to eight weeks of daily dosing. A China study (75 participants, 10-80 mg) showed 1-5.6% weight loss at four weeks. GI side effects were mostly mild and transient. These are preliminary analyses of ongoing studies, with detailed results reserved for a future conference. BrightGene’s subcutaneous BGM0504 is further ahead, already in Phase 3 trials including a head-to-head against Zepbound.
Press | Mechanism: dual GLP-1/GIP agonist
Novo Nordisk’s triple agonist UBT251 outperforms semaglutide in Phase 2 diabetes trial.
Novo Nordisk’s GLP-1/GIP/glucagon triple agonist UBT251 beat semaglutide in a Phase 2 trial in Chinese patients with type 2 diabetes. After 24 weeks, UBT251 achieved HbA1c reductions of up to 2.16% compared to 1.77% for semaglutide. Novo plans to initiate a global Phase 2 trial this year. Triple agonists like UBT251 target all three metabolic hormone receptors simultaneously, potentially offering greater efficacy than dual agonists like tirzepatide.
Press | Mechanism: triple agonist (GLP-1/GIP/glucagon)
📰 PRESS
Wave’s higher-dose obesity drug WVE-007 disappoints, stock halved.
Press | Mechanism: RNA interference (siRNA)
Oral Wegovy launch gains traction, but access remains a challenge.
Press | Mechanism: GLP-1
Aardvark pauses entire pipeline over cardiac safety concerns.
Press | Mechanism: bitter taste receptor (TAS2R) agonist
Lexicon and Novo Nordisk begin Phase 1 trial for obesity drug LX9851.
Press | Mechanism: ACSL5 inhibitor (non-incretin)
💡 TRIAL SPOTLIGHT
Educational spotlight selected by editors
LX9851 - Novo Nordisk Bets on a Non-Incretin Obesity Mechanism
Novo Nordisk has initiated a Phase 1 trial for LX9851, a first-in-class oral obesity candidate licensed from Lexicon Pharmaceuticals for up to $1 billion. The study is evaluating the safety, tolerability, and pharmacology of single and multiple ascending doses in 96 individuals with overweight or obesity, with completion expected in the first quarter of 2027. LX9851 is a potent inhibitor of Acyl-CoA Synthetase 5 (ACSL5), a novel non-incretin target involved in fat accumulation, and may also promote satiety by activating the “ileal brake” mechanism. This trial initiation, which triggered a $10 million milestone payment to Lexicon, is strategically significant as it signals the obesity market leader’s investment in next-generation, oral combination therapies. Preclinical data showed that LX9851 not only enhanced weight loss when combined with semaglutide but also mitigated weight regain after the GLP-1 agonist was stopped. However, the pursuit of novel non-incretin mechanisms carries inherent risks, underscored by this week’s pause of Aardvark Therapeutics’ entire bitter taste receptor agonist pipeline (ARD-101/ARD-201) due to cardiac signals in a healthy volunteer study, a finding potentially linked to on-target effects in cardiac tissue.
GlobeNewsWire: Lexicon and Novo Nordisk Announce Phase 1 Initiation
🔬 MECHANISM EXPLAINED
Understanding the science behind the therapeutics
ACSL5 Inhibition and the Ileal Brake - A New Path Beyond Incretin Agonism (LX9851)
Novo Nordisk and Lexicon Pharmaceuticals have initiated a Phase 1 trial for LX9851, a first-in-class oral obesity candidate that introduces a novel, non-incretin mechanism to the metabolic disease landscape. LX9851 inhibits Acyl-CoA Synthetase 5 (ACSL5), an intestinal enzyme crucial for activating long-chain fatty acids for absorption and subsequent metabolic processing. By blocking ACSL5, the drug is thought to work through a dual mechanism: it directly reduces the body’s uptake of dietary fats and indirectly triggers the “ileal brake,” a natural feedback loop. This brake is engaged when unabsorbed fats reach the distal ileum, stimulating gut L-cells to release endogenous satiety hormones like GLP-1 and PYY, which in turn slow gastric emptying and suppress appetite. This approach fundamentally differs from current incretin mimetics by amplifying the body’s own physiological signaling rather than supplying exogenous agonists. Because its mechanism does not overlap with GLP-1 receptor agonists, ACSL5 inhibition is highly attractive for combination therapy, with preclinical data showing that LX9851 combined with semaglutide produced greater weight loss and, notably, mitigated weight regain after semaglutide was discontinued.
🆕 NEWLY REGISTERED TRIALS (3 in last week)
Oral KAI-7535 Phase 2 trial evaluating efficacy and safety in adults with obesity or overweight with at least one comorbidity (Kailera, n=320)
[Weight Loss/Efficacy | Oral Formulations | Safety/Tolerability]
Trials: NCT07497880 | Mechanism: GLP-1 receptor agonist
Targeting Agonists of Glucagon-like Peptide-1 Receptor for Multiple Sclerosis Phase 2 investigating the potential of this drug class, typically used for diabetes, in treating MS (Johns Hopkins University, n=120)
[New Indications]
Trials: NCT07497399 (TAG-MS) | Mechanism: GLP-1 receptor agonist
QLG1090 Phase III trial comparing its efficacy and safety against Rybelsus as an add-on to metformin for adults with Type 2 Diabetes (Qilu Pharmaceutical, n=478).
[Safety/Tolerability]
Trials: NCT07487103 | Mechanism: GLP-1 receptor agonist
This newsletter compiles publicly available information from company press releases and ClinicalTrials.gov. Not investment advice.
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