Beyond GLP-1: ALK7–Activin E as a More Targeted Approach to Obesity Therapy

Obesity is an increasingly significant global health issue characterized by excessive fat accumulation. Although glucagon-like peptide-1 receptor (GLP-1R) agonists have become effective weight-loss medications for obesity, these drugs are expensive, unevenly supplied, and require continuous use. Side effects and insufficient efficacy also limit the use of these drugs in certain populations. In recent years, there has been growing attention to the roles of TGFβ family ligands and receptors in adipocyte proliferation, differentiation, and function. Among them, ALK7 and its ligand Activin E have stood out due to their clearly defined mechanisms in regulating fat metabolism and strong supporting evidence from pharmacological animal studies.

ALK7–Activin E Pathway Regulates Lipid Metabolism

ALK7 (Activin receptor-like kinase 7), also known as Activin RIC, is a type I receptor of the transforming growth factor-β (TGF-β) superfamily. It is primarily expressed in adipose tissue, where it binds to ligands such as Activin E and GDF3 to suppress lipolysis, leading to decreased levels of non-esterified fatty acids (NEFA). Among these ligands, Activin E is the most functionally relevant for ALK7 in adult metabolic tissues. It is composed of two INHBE (Inhibin βE) chains and is mainly secreted by the liver. After Activin E binds to ALK7 receptors in adipose tissue, it activates Smad2/3 signaling, suppresses the expression and activity of ATGL (adipose triglyceride lipase) and HSL (hormone-sensitive lipase), reduces β-adrenergic signaling sensitivity, inhibits lipolysis, and decreases the efflux of free fatty acids.

The signaling cascades of Activin E and other TGF β family proteins in adipocytes[1]

This mechanism reflects a protective metabolic feedback loop: when energy is abundant or fatty acid levels are high, the liver leverages Activin E to signal adipose tissue to stop releasing more fatty acids, preventing the liver or muscles from being overwhelmed by lipid overload. However, in obesity or fatty liver, ALK7 expression in adipose tissue and INHBE expression in the liver have been reported to be upregulated, resulting in sustained inhibition of lipolysis and blunted β-adrenergic responsiveness. Studies have confirmed that compared with normal mice, ALK7 knockout mice accumulate significantly less fat [2], and anti-ALK7 therapies can remarkably reduce obesity and improve obesity-related metabolic disorders in mice [3]. Therefore, inhibiting ALK7 and Activin E (or INHBE) helps make adipocytes more sensitive to β-adrenergic stimulation, enhancing lipolysis and reducing fat mass [4].

In addition, ALK7 has been found to play an important role in pancreatic islet plasticity, where ALK7 can interfere with cell functions via Activin B-mediated Ca2+ flux reduction. Mice lacking ALK7 show normal pancreatic morphology but develop an age-dependent syndrome, including progressive hyperinsulinemia (appearing first), reduced insulin sensitivity, hepatic steatosis, impaired glucose tolerance, and islet hypertrophy[5]. Through its dual actions (suppressing adipocyte lipolysis and negatively regulating glucose-stimulated insulin secretion), ALK7 takes on the role of an accomplice in obesity and has emerged as a new target in obesity drug development.

Challenges and Progress in Therapeutic Development Targeting ALK7 and INHBE (or Activin E)

Targeting ALK7

ALK7 shares high homology with ALK4 and ALK5, making it difficult to screen and isolate inhibitors with high selectivity. Furthermore, ALK7 often forms complexes with different type II receptors and multiple ligands (Activins, GDFs, etc.). Blocking ALK7 or a single binding interface alone may not sufficiently inhibit compensatory signaling pathways, resulting in limited therapeutic efficacy. These challenges affect both antibody and small-molecule inhibitor drug development.

Current ALK7-targeting drugs are mainly siRNA-based and designed for adipose tissue targeting. siRNA can silence mRNA, bypassing the selectivity issue, and sequences can be rapidly optimized. Arrowhead’s ARO-ALK7 is the world’s first adipocyte-targeted RNA interference therapy to enter clinical trials. Preclinical data shows that ARO-ALK7 significantly reduced body-weight gain in DIO mice (up to 39% inhibition), reduced fat mass by 50%, and did not induce hepatic steatosis.

In addition to ARO-ALK7, companies such as Alnylam, Sanegene Bio, and SiranBio are also advancing therapies targeting ALK7. Inhibiting ALK7 essentially cuts off “stop lipolysis” signals and may therefore result in strong fat-reduction effects, but may also carry other potential systemic safety risks.

Mechanisms of ARO-ALK7 and its fat-reducing effect in DIO mice [6]

 

Targeting INHBE (or Activin E)

Therapies targeting the ligand INHBE (or Activin E) include siRNA and antibodies, mostly designed for liver targeting. Compared with inhibiting ALK7, inhibiting INHBE reduces the strength of the outgoing signal and is theoretically milder. Representative drugs include Arrowhead’s ARO-INHBE and Wave’s WVE-007.

On October 29, 2025, Wave announced interim Phase 1 data for WVE-007. One month after a single injection, dose-dependent reductions in Activin E levels were observed in the 240 mg and 400 mg groups, reaching up to 85%, exceeding the threshold associated with weight loss in preclinical models. In the 75 mg group, reductions in Activin E remained stable during a 6-month follow-up, suggesting that WVE-007 may enable dosing only 1–2 times per year. WVE-007 also demonstrated a favorable safety and tolerability profile. These encouraging clinical results have boosted confidence in future INHBE-targeting RNA interference therapies.

Interim data of the INLIGHT trial of WVE-007 released by Wave Life Sciences[7]

In fact, inhibiting Activin E cannot completely shut down the liver’s intrinsic metabolic regulation. Even with reduced Activin E signaling, the liver still retains mitochondrial metabolism and glucose oxidation pathways. Meanwhile, increased fatty acid supply from enhanced lipolysis and improved insulin sensitivity can increase overall metabolic flexibility. Therefore, animal and early-phase clinical studies have observed fat reduction, decreased liver fat, and improved insulin sensitivity without a global decline in energy metabolism. 

Investigational Drugs targeting Activin E & ALK7

The ALK7–Activin E axis offers a new direction for obesity treatment: targeting adipose tissue to lift excessive negative feedback signaling that promotes fat storage, reducing fat mass without reducing muscle. This approach may be particularly suitable for patients who cannot use GLP-1R agonists and related molecules. Moreover, ALK7 and Activin E inhibitors complement GLP-1R agonists, which primarily reduce energy intake. Their combination could help complete the therapeutic landscape for obesity.

KACTUS continues to keep up with the drug developments in obesity and other metabolic diseases and has developed several high-quality target protein products including ALK7 to support the diverse needs of related drug-development programs:

Immobilized Human ALK7, His Tag at 0.5 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-ALK7 Antibody, hFc Tag with the EC50 of 3.15 ng/ml determined by ELISA (QC Test).

Anti-ALK7 Antibody, hFc Tag captured on CM5 Chip via Protein A can bind Human ALK7, His Tag with an affinity constant of 0.67 nM as determined in SPR assay (QC Test).

Product List:

Reference:

[1] Activin Actions in Adipocytes. J Clin Endocrinol Metab. 2025 Jun 17;110(7):1803-1810. doi: 10.1210/clinem/dgaf233.

[2] Activin E is a transforming growth factor β ligand that signals specifically through activin receptor-like kinase 7. Biochem J. 2024 Apr 10;481(7):547–564. doi: 10.1042/BCJ20230404

[3] Activin E–ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice. Proc Natl Acad Sci U S A. 2023 Jul 31;120(32):e2309967120. doi: 10.1073/pnas.2309967120

[4] Targeting activin receptor–like kinase 7 ameliorates adiposity and associated metabolic disorders. JCI Insight. 2023 Feb 22;8(4):e161229. doi: 10.1172/jci.insight.161229

[5] Activin B receptor ALK7 is a negative regulator of pancreatic beta-cell function. Proc Natl Acad Sci U S A. 2008 May 20;105(20):7246-51. doi: 10.1073/pnas.0801285105.

[6] https://ir.arrowheadpharma.com/static-files/4bd5dfda-7baa-4b13-8d37-ec794e750bff

[7] https://ir.wavelifesciences.com/node/12451/pdf

[8] Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity. Proc Natl Acad Sci U S A. 2008 May 20;105(20):7252-6. doi: 10.1073/pnas.0800272105.

[9] Insulin Regulates Lipolysis and Fat Mass by Upregulating Growth/Differentiation Factor 3 in Adipose Tissue Macrophages. Diabetes. 2018 Sep;67(9):1761-1772. doi: 10.2337/db17-1201.

[10] Roles of activin receptor-like kinase 7 signaling and its target, peroxisome proliferator-activated receptor γ, in lean and obese adipocytes. Adipocyte. 2013 Oct 1;2(4):246-50. doi: 10.4161/adip.24974.