Safety and Tolerability of Concomitant Administration of Multiple-Dose AM833 With Semaglutide 2.4 MG for Weight Management
Notice bibliographique
Résumé
Abstract Background: Combining weight management medications with different modes of action may provide more effective treatment options for people with obesity. Subcutaneous (sc) AM833, a long-acting amylin analog, and sc semaglutide 2.4 mg, a glucagon-like peptide-1 receptor agonist, are both under clinical development for weight management. Methods: This was a randomized, double-blind, placebo-controlled, phase 1 trial to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of concomitant administration of six ascending doses of weekly AM833 (0.16, 0.3, 0.6, 1.2, 2.4, or 4.5 mg) + semaglutide vs placebo + semaglutide in subjects with overweight or obesity. The 20-week trial included a 16-week escalation period followed by a 4-week treatment period at target dose and a 5-week follow-up. Eligible subjects were male or female of non-childbearing potential, aged 18–55 years, with BMI 27−39.9 kg/m2. The primary endpoint was number of adverse events (AE) from baseline to follow-up. Secondary endpoints included PK parameters (area under the curve [AUC] 0–168 h [AUC0-168], maximum concentration [Cmax], half-life [t1/2] and time to Cmax [tmax]). Changes in body weight (exploratory endpoint) were analyzed separately for AM833 0.16−2.4 mg + semaglutide (vs pooled placebo) and AM833 4.5 mg + semaglutide (vs matched placebo) due to a different semaglutide dose escalation regimen used in this treatment arm. Results: Of 96 subjects randomized, 95 were exposed to treatment (59% male; mean age 40.6 years, body weight 95.7 kg, BMI 32.1 kg/m2) and 80 (83%) completed the trial. The number of AEs ranged from 37–89 with AM833 (0.16–4.5 mg) + semaglutide and 132 with pooled placebo + semaglutide. Most AEs were mild or moderate and the proportion of subjects with ≥1 AE was similar across treatment arms. About one-third of all AEs were gastrointestinal (GI) disorders (n=207 of 566), primarily nausea, dyspepsia, and vomiting. A greater proportion of subjects reported GI AEs with AM833 1.2–4.5 mg + semaglutide vs placebo + semaglutide. The second most common AEs were injection site reactions (n=72), all mild and not dependent on AM833 dose. Exposure to AM833 was proportional to dose for both AUC0-168 and Cmax, and did not affect semaglutide exposure and elimination. AM833 0.16−4.5 mg t1/2 ranged from 159–195 h and median tmax ranged from 24–72 h. At week 20, body weight changes from baseline with AM833 1.2 and 2.4 mg + semaglutide were greater vs pooled placebo + semaglutide (−15.7% and −17.1% vs −9.8%, respectively; p<0.001) and with AM833 4.5 mg + semaglutide vs matched placebo + semaglutide (−15.4% vs −8.0%; p<0.01). Conclusion: Treatment with AM833 at all tested doses + semaglutide was generally well tolerated with an acceptable safety profile. PK data support once-weekly dosing. The combination of AM833 1.2, 2.4, or 4.5 mg + semaglutide led to greater weight loss compared with placebo + semaglutide.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».