IPG8294 in Obesity Summary

1. Solves a Critical Unmet Medical Needs by GLP-1s: Current GLP-1 therapies often lead to significant loss of lean body mass (muscle). IPG8294 can improve mitochondrial health, allowing for substantial weight loss while preserving lean mass. Preclinical studies demonstrated that combining IPG8294 with GLP-1s achieved a "1+1>2" synergistic effect—enabling "Quality Weight Loss".

2. Oral Convenience and De-risked Data Package: As an oral small molecule, it offers a significant compliance advantage over injections. Phase 1 (dose escalation up to 100 mg MAD) clinical results confirmed a safe, QD oral profile.

3. Stark PK/PD relationship observed in Healthy Subjects and NHPs: IPG8294 exhibited a consistent PK Concentration/NAD Levels relationship in both Healthy Subjects and NHPs.

4. For indications beyond Obesity: the mechanism has shown promise in Neurodegenerative Diseases (AD), Metabolic Dysfunctions (MASH&Diabetes), and Rare Diseases (Primary Mitochondrial Myopathy).

Mechanism of Action

CD38 is the primary NADase in mammals, and its levels increase significantly with aging and obesity population, leading to NAD+ depletion and mitochondrial dysfunction. IPG8294 is a highly potent and selective small molecule inhibitor of CD38 NADase. By blocking CD38 enzymatic activity, it restores intracellular NAD+ levels, which in turn activates Sirtuins (SIRT1/SIRT3). This cascade boosts mitochondrial quality control and enhance fatty acid oxidation, effectively increasing energy expenditure, and robustly reduce inflammation caused by aberrantly released mitochondrial DNA. Unlike direct NAD+ precursors, IPG8294 addresses the "root cause" of NAD+ decline by inhibiting its degradation.

Development stage

1. Phase 1 Completed: The Phase 1 SAD/MAD cohorts in healthy subjects has finished the enrolment successfully. The study demonstrated excellent safety (no Grade >2 AEs) and linear pharmacokinetics supporting once-daily (QD) oral dosing.

2. A Phase 2a PoC trial for obesity is scheduled to initiate in H1 2026.

Phase 1 Clinical Results

> Safety &Tolerability: No Adverse Events greater than Grade 2 were observed across all cohorts.

> Five Cohorts: SAD: 10, 25, 50, 100 mg, MAD: 100 mg for 14 days (100mg T1/2=36h).

> Results showed linear PK characteristics with a half-life and exposure supporting a convenient Once-Daily (QD) oral dosing

> Major early-stage development risks (toxicity,PK unsuitability) have been successfully cleared.

> IPG8294 exhibited a consistent PK /NAD Levels relationship in both Healthy Subjects and NHPs

Preclinical Results Summary

> IPG8294 showed 3.5% additional Body Weight Loss compared to Vehicle

> IPG8294+SMG showed 2.9% additional Body Weight Loss compared to SMG alone

> IPG8294 showed significant blood NAD+ change in DIO mouse model

IPG8294 in Neurological Diseases Summary

■Aging-related diseases, especially neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), are commonly characterized by chronic inflammation, CD38 NADase elevation, and the subsequent irreversible decline of NAD+. Down-regulation of NAD+ causes the dysfunction of the NAD+ consuming enzymes, such as PAPR and SIRT family members, leading to destruction of mitochondrial biogenesis, fusion/fission, and mitophage. The damaged mitochondria not only fail to supply energy to the cells, especially neurons, but also exacerbate inflammation by releasing mitochondrial DNA, which stimulates cGAS-STING-inflammasome pathway. IPG8294 is a potent and specific CD38 NADase inhibitor, which robustly reverse the NAD+ decline and the subsequent mitochondrial damage, thereby rescuing the affected cells.

■Preclinical studies have demonstrated that in Alzheimer’s disease mouse models, IPG8294 significant elevates brain NAD+, reverses the decreased genes associated with mitochondrial biogenesis, fusion/fission, and mitophage, significantly improves the quality of neuronal mitochondria, and robustly rescues synaptic loss, leading to marked improvement of cognitive functions. In mitochondrial myopathy mouse models, IPG8294 treatment also up-regulates NAD+ in the muscle tissues, associated with improvement of mitochondrial quality and muscle functions.

■With the IND approval and Orphan Drug Designation granted by US FDA, Phase I trial is under the way. 

Mechanism of Action

■ Overexpression of CD38 in astrocytes and other neuronal cells is a hallmark of neurodegenerative diseases and mitochondrial myopathy. Elevated CD38 NADase activity causes downregulation of NAD+, leading to the defect of mitochondrial biogenesis and mitophagy, a root cause of neurodegenerative and mitochondrial diseases.

■ IPG8294, a selective CD38 NADase inhibitor, significantly rescues NAD+ depletion and corrects mitochondrial dysfunction.

Key differentiation

■IPG8294 represents a groundbreaking small-molecule inhibitor of CD38 NADase with significant potential in addressing mitochondrial dysfunction. 

■IPG8294 is a disease-modifying agent for the treatment of mitochondrial myopathy, neurodegenerative disorders, and various other aging-related diseases.

In vivo properties

Efficacy of IPG8294 in AD mouse models

■IPG8294 significantly rescue learning and memory deficit in APP/PS1 transgenic mice 

■ IPG8294 reverses synaptic loss in a dose-dependent manner in the brain of APP/PS1 mice.

Publication

Li, Yue, Yuanyuan Liu, Yong Zhang, Yong Wu, Zili Xing, JianFei Wang, and Guo-Huang Fan. 2023. 'Discovery of a First-in-Class CD38 Inhibitor for the Treatment of Mitochondrial Myopathy', Journal of Medicinal Chemistry, 66: 12762-75.