azelaprag (BGE-105) / Amgen, BioAge Labs - LARVOL DELTA

The Apelin Receptor Agonist Azelaprag Shows Cardioprotective Effects as Monotherapy and Enhanced Benefits with Semaglutide in a Diet-Induced Obesity Model of Heart Failure with Preserved Ejection Fraction (ADA 2025) - "Available on Friday, June 13, 2025 at 08:00am CDT."

Monotherapy • Metabolic Disorders • Obesity

The Oral Apelin Receptor Agonist Azelaprag Enhances Glycemic Control in Preclinical Models of Diabetic Obesity Both as Monotherapy and in Combination with Tirzepatide (ADA 2025) - "Available on Friday, June 13, 2025 at 08:00am CDT."

Combination therapy • Monotherapy • Preclinical • Metabolic Disorders • Obesity

STRIDES: Efficacy and Safety of Oral Azelaprag Plus Once Weekly Tirzepatide Compared with Tirzepatide Alone in Participants with Obesity Aged 55 Years and Over (clinicaltrials.gov) - P2 | N=204 | Terminated | Sponsor: BioAge Labs, Inc. | Suspended ➔ Terminated; Dosing of both study drugs has been discontinued due to observation of liver transaminitis without clinically significant symptoms in some subjects receiving azelaprag. All participant visits have been completed.

Trial termination • Genetic Disorders • Obesity

Advancement of next-generation APJ agonists with discontinuation of azelaprag (GlobeNewswire) - "BioAge has terminated development of azelaprag, an orally available small molecule agonist of APJ, for obesity and other chronic diseases. The decision follows observations of liver transaminitis without clinically significant symptoms, and without clear dose dependence, in some patients in the azelaprag arms of the STRIDES Phase 2 clinical trial for obesity....BioAge is developing structurally distinct APJ agonists in its pipeline, with the goal of nominating a development candidate by the end of 2025."

Discontinued • Pipeline update • Obesity

STRIDES: Efficacy and Safety of Oral Azelaprag Plus Once Weekly Tirzepatide Compared with Tirzepatide Alone in Participants with Obesity Aged 55 Years and Over (clinicaltrials.gov) - P2 | N=204 | Suspended | Sponsor: BioAge Labs, Inc. | Trial completion date: Dec 2025 ➔ Feb 2025 | Recruiting ➔ Suspended | Trial primary completion date: Sep 2025 ➔ Jan 2025

Trial completion date • Trial primary completion date • Trial suspension • Genetic Disorders • Obesity

BioAge Labs Announces Discontinuation of STRIDES Phase 2 Clinical Trial Evaluating Azelaprag in Combination with Tirzepatide for the Treatment of Obesity (GlobeNewswire) - "BioAge Labs...announced that the Company has made the decision to discontinue the ongoing STRIDES Phase 2 study of its investigational drug candidate azelaprag as monotherapy and in combination with tirzepatide after liver transaminitis without clinically significant symptoms was observed in some subjects receiving azelaprag....STRIDES is a randomized, double-blind, placebo-controlled Phase 2 clinical trial of azelaprag as monotherapy and in combination with tirzepatide that planned to enroll approximately 220 individuals with obesity aged 55 years and older....Of 204 subjects enrolled in STRIDES as of today, 11 subjects in the azelaprag treatment groups were observed to have transaminase elevations with no clinically significant symptoms. Dosing of all subjects will be discontinued, and no additional subjects will be enrolled. Clinical follow-up of enrolled subjects will continue off drug....The Company intends to share updated plans for azelaprag in Q1 2025."

P2 data • Trial termination • Obesity

The APJ Agonist Azelaprag Improves Weight Loss and Body Composition in DIO Mice on a CB1 Antagonist (OBESITY WEEK 2024) - "Addition of azelaprag to rimonabant significantly increased weight loss and improved body composition relative to monotherapy with the CB1 antagonist. Our data suggest that the combination of CB1 inhibition and apelin pathway activation results in a synergistic change in metabolic processes. These findings highlight the potential of azelaprag as a therapeutic candidate in combination approaches to treating obesity and related metabolic conditions."

Preclinical • Genetic Disorders • Obesity

The Apelin Receptor Agonist Azelaprag Reduces Weight Gain & Improves Body Composition in DIO Mice (OBESITY WEEK 2024) - "Azelaprag monotherapy effectively delayed weight gain, improved body composition, and increased body temperature in DIO mice without affecting food intake. Our data suggest that apelin pathway activation delays weight gain by regulating homeostatic energy balance and stimulating energy expenditure. These findings provide evidence that azelaprag is a promising therapeutic candidate for obesity and related metabolic conditions."

Preclinical • Genetic Disorders • Obesity

Activation of Apelin Receptor Inhibits Cystogenesis in a Mouse Model of Polycystic Kidney Disease (KIDNEY WEEK 2024) - "Tolvaptan is approved for ADPKD treatment, but its use is limited by various adverse effects, leaving an unmet clinical need for safe and effective therapy. Targeting apelin receptor signaling may be a novel therapeutic strategy for treating ADPKD. Future experiments will explore the molecular mechanisms mediating the effects of apelin on cystogenesis."

Preclinical • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Hypotension • Nephrology • Polycystic Kidney Disease • Renal Disease

Macrocyclic peptides and small molecules targeting the apelin receptor as promising analgesics (Neuroscience 2024) - "We also used a scaffold-hoping strategy to create new druggable small-molecule ligands starting from the first identified Gαi-biased small-molecule ligand at APJ, CMF-019, and studied their functional activity in comparison with other small-molecule agonists (BMS986224, AMG986)...The small molecule LT02-20 was also effective in reversing the formalin-induced pain behaviors, while the parent compound CMF-019 had no analgesic effect. Overall, these results highlight the therapeutic potential of biased macrocyclic APJ analogs and small molecules for managing pain."

Addiction (Opioid and Alcohol) • CNS Disorders • Pain • ARRB1

STRIDES: Efficacy and Safety of Oral Azelaprag Plus Once Weekly Tirzepatide Compared With Tirzepatide Alone in Participants With Obesity Aged 55 Years and Over (clinicaltrials.gov) - P2 | N=220 | Recruiting | Sponsor: BioAge Labs, Inc.

New P2 trial • Genetic Disorders • Obesity

The Apelin Receptor Agonist Azelaprag Increases Weight Loss in Diet-Induced Obese Mice on Incretin Agonists and Restores Body Composition and Muscle Function to That of Lean Controls (ADA 2024) - " DIO mice on tirzepatide (10 nmol/kg) lost 16% of body weight, while mice on tirzepatide+azelaprag (1.1 g/L) lost 39%, bringing body weight in range of lean controls. Addition of azelaprag to incretin regimens increased weight loss while restoring body composition and muscle function relative to monotherapy. In the clinic, combination therapy has the potential to amplify healthy weight loss, enabling next-generation oral incretin drugs to achieve efficacy comparable to current injectables with improved tolerability."

Preclinical • Metabolic Disorders • Obesity

BioAge Labs Presents Preclinical Data for Apelin Receptor Agonist Azelaprag for Obesity Demonstrating Significant Improvements in Weight Loss and Body Composition When Combined with Incretin Drugs (Businesswire) - "BioAge Labs, Inc...today announced preclinical data for its lead product candidate azelaprag....The data were presented in a talk by BioAge’s Chief Medical Officer and EVP-Research Paul Rubin, MD, at the American Diabetes Association's 84th Scientific Sessions. The conference, being held June 21–24 in Orlando....In a mouse model of obesity, the addition of azelaprag to the GLP-1/GIP receptor agonist tirzepatide increased total weight loss to 39%, approximately double that of tirzepatide monotherapy, restoring body weight to the range observed in lean control mice. Furthermore, the combination restored body composition and muscle function to that of lean controls. Similar results were observed when azelaprag was combined with semaglutide....BioAge plans to initiate a Phase 2 trial in mid-2024 evaluating azelaprag in combination with tirzepatide (Zepbound) in older adults with obesity."

New P2 trial • Preclinical • Metabolic Disorders • Obesity

Pharmacokinetics Study of Azelaprag (BGE-105) in Older Adult Healthy Volunteers (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: BioAge Labs, Inc. | Not yet recruiting ➔ Completed

Trial completion

BioAge Announces $170 Million Oversubscribed Series D Financing to Accelerate Development of Obesity and Metabolic Disease Therapeutics (Businesswire) - "BioAge Labs...announced today the completion of an oversubscribed Series D financing round of $170 million led by Sofinnova Investments....he funding will be used to support Phase 2 clinical development of BioAge’s lead compound azelaprag, an oral apelin receptor agonist, in combination with Lilly’s Zepbound (tirzepatide) and other incretins for treatment of obesity."

Financing • Metabolic Disorders • Obesity

Pharmacokinetics Study of Azelaprag (BGE-105) in Older Adult Healthy Volunteers (clinicaltrials.gov) - P1 | N=16 | Not yet recruiting | Sponsor: BioAge Labs, Inc.

New P1 trial

BioAge Labs Announces Plans for Phase 2 Trial of First-in-Class Apelin Receptor Agonist BGE-105/Azelaprag Co-Administered With Tirzepatide for Treatment of Obesity, in Collaboration With Lilly’s Chorus Organization (Businesswire) - "BioAge Labs, Inc...today announced plans to initiate a Phase 2 trial of its oral apelin receptor agonist BGE-105 (azelaprag) co-administered with the GLP-1/GIP receptor agonist tirzepatide for treatment of obesity. BioAge plans to initiate the trial in mid-2024. Chorus...within Eli Lilly and Company ('Lilly') dedicated to working with biotechs to develop their assets from candidate through clinical proof of concept, will advise and assist BioAge on all aspects of the Phase 2 trial design and execution, under the terms of an agreement signed by both companies. As part of the collaboration, Lilly will also provide BioAge with tirzepatide....The primary endpoint of the Phase 2 trial will be total weight loss, with related secondary endpoints to characterize additional potential benefits of the mechanism. BioAge will also collect aging-related biomarkers from the participants."

New P2 trial • Metabolic Disorders • Obesity

Activation of the apelin receptor, implicated in a key aging pathway by analysis of longitudinal human data, ameliorates multiple mechanisms that drive neuroinflammation and neurodegeneration (Neuroscience 2023) - "Daily oral administration of BGE-105 for 7 days suppressed circulating levels of age-related proinflammatory cytokines, increased levels of BDNF in the hippocampus, and reversed age-induced BBB dysfunction, suggesting that BGE-105 restores the BBB through its anti-inflammatory effects in the periphery. Taken together, our results suggest that apelin receptor agonism with an orally available small molecule represents a novel approach for treating chronic age-related neuroinflammation and neurodegeneration, and for mitigating the effects of inflammation on the BBB."

CNS Disorders • TNFA

A First-in-Human Study of AMG 986, a Novel Apelin Receptor Agonist, in Healthy Subjects and Heart Failure Patients. (PubMed, Cardiovasc Drugs Ther) - P1 | "In healthy subjects and HF patients, short-term AMG 986 treatment was well tolerated. Consistent with this observation, clinically meaningful pharmacodynamic effects in HF patients were not observed. Changes in ejection fraction and stroke volume in HF patients suggest additional studies may be needed to better define the clinical utility and optimal dosing for this molecule."

Journal • P1 data • Cardiovascular • Congestive Heart Failure • Heart Failure

Evaluation of the Pharmacokinetics and Safety of AMG 986 Tablet and Capsule Formulations in Healthy Adult Subjects: A Phase I, Open-Label, Randomized Study. (PubMed, Drugs R D) - "There was a modest 12% decrease in AUC and a 28% decrease in C with the AMG 986 capsule versus the tablet. These differences are not considered to be clinically relevant, suggesting the capsule formulation can be used in subsequent clinical studies of AMG 986."

Journal • PK/PD data • Cardiovascular • Congestive Heart Failure • Heart Failure

A Phase I, Open-label, Single-Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of AMG 986 in Healthy Japanese Subjects. (PubMed, Drugs R D) - "AMG 986 exposure increased with increasing dose, and the increase was less than dose proportional in healthy Japanese subjects. The results of this study could facilitate the subsequent clinical development of AMG 986 for the treatment of Japanese patients with HF."

Journal • PK/PD data • Cardiovascular • Congestive Heart Failure • Heart Failure

A Phase 1, Open-Label Study to Evaluate the Effect of Food and Concomitant Itraconazole Administration on the Pharmacokinetics of AMG 986 in Healthy Subjects. (PubMed, Clin Pharmacol Drug Dev) - "In conclusion, food had no apparent effect on the exposure of AMG 986 200 mg; therefore, food restrictions are not required. Potent cytochrome P450 3A4 and/or P-glycoprotein inhibitors may warrant AMG 986 dose reduction and should be coadministered with caution in patients with heart failure treated with AMG 986."

Journal • P1 data • PK/PD data • Cardiovascular • Congestive Heart Failure • Heart Failure

Effect of Severe Renal Impairment on the Safety, Tolerability, and Pharmacokinetics of AMG 986. (PubMed, Drugs R D) - P1 | "The results of this study support the enrollment of HF patients with RI to clinical trials of AMG 986 without the need for dose adjustments."

Journal • PK/PD data • Cardiovascular • Congestive Heart Failure • Heart Failure • Renal Disease

[VIRTUAL] Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Amg 986, A Novel Small Molecule Apelin Receptor Agonist, In Healthy Subjects And Heart Failure Patients (HFSA 2020) - "In healthy subjects and in HF patients, short-term treatment with AMG 986 was well tolerated."

Clinical • PK/PD data • Cardiovascular • Congestive Heart Failure • Heart Failure • Pain

Study to Evaluate the Safety and Tolerability of AMG 986 in Healthy Subjects and Heart Failure Patients (clinicaltrials.gov) - P1; N=182; Terminated; Sponsor: Amgen; Trial completion date: Jul 2019 ➔ Apr 2019; Recruiting ➔ Terminated; Trial primary completion date: Jul 2019 ➔ Apr 2019; The data do not support the continuation of the development of the program. No safety concerns were found and the study was not terminated due to safety finding

Clinical • Trial completion date • Trial primary completion date • Trial termination