Taipei, Taiwan, November 8th, 2023 – Foresee Pharmaceuticals (TPEx: 6576), (“Foresee”) announced today preclinical data in the European Heart Journal, demonstrating that activation of Aldehyde Dehydrogenase 2 (ALDH2) with Foresee's oral ALDH2 activator AD-9308, significantly ameliorates heart failure via the modulation of the Dicer-miRNA pathway in the heart.
The article is cited “Kiyuna L, Candido D, Bechara L, Jesus I, Ramalho L, Krum B, et al. 4-hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification. European Heart Journal 2023; doi:10.1093/eurheartj/ehad662” is the result of a collaboration with leading academic clinical translation experts in the area of cardiometabolic diseases. The article is available at: https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehad662.
Key highlights of the study include:
- 4-HNE, a reactive aldehyde byproduct of mitochondrial dysfunction in heart failure, and primary substrate of ALDH2, covalently inhibits Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis, leading to impaired miRNA processing
- End-stage human failing hearts from three different heart failure etiologies display defective 4-HNE clearance, decreased Dicer activity, and miRNA biogenesis impairment
- Increasing 4-HNE clearance through pharmacological reactivation of ALDH2 with Foresee’s oral allosteric ALDH2 activator, AD-9308 restored Dicer activity
- AD-9308 treatment improves cardiac function and reduced remodeling in rodent heart failure models, and it is proposed that the underlying mechanism of action, via the activation of ALDH2, leads to a reduction in ALDH2 substrate, 4-HNE, reduction of 4-HNE-Dicer adducts, restoration of Dicer activity and improvement of mi-RNA maturation.
"We have established a long-standing and very stimulating collaboration with Foresee, and over the past few years have generated a very compelling body of translational data related to ALDH2 biology and the therapeutic applications of Foresee's ALDH2 activators in cardiovascular and muscle diseases. This new publication elucidates a novel mechanism of disease pathology in heart failure and allows us to better understand the pathways by which their ALDH2 activators significantly improve cardiac function and reduced remodeling in the rodent heart failure models. " said Dr. Julio C.B. Ferreira, professor, Institute of Biomedical Sciences, School of Medicine, University of Sao Paulo.
“The data further builds our understanding of the biological role of ALDH2 in cardiometabolic diseases and further strengthens our view on the promise of our ALDH2 activators across a diverse group of diseases where mitochondrial dysfunction plays a pivotal role,” said Dr. Wenjin Yang, Chief Scientific Officer at Foresee.
Foresee is planning to initiate a Phase 2 study in patients with pulmonary hypertension-interstitial lung disease (PH-ILD) with its lead first-in-class oral ALDH2 activator, FP-045, in 2024, and working diligently to build a broad franchise leveraging our multiple ALDH2 activators, including AD-9308 and another 2nd generation compound, across several therapeutic areas, including cardiometabolic diseases.
About ALDH2
ALDH2 (Aldehyde Dehydrogenase 2) is a mitochondrial matrix enzyme and key regulator of mitochondrial quality control systems/health and regulator of reactive aldehydes/carbonyls, oxidative stress, inflammation, and fibrosis. Activation of ALDH2 is a compelling therapeutic strategy for improving mitochondrial quality and regulatory mechanisms for treating the treatment of rare/orphan diseases and severe diseases of aging, including cardiometabolic diseases. The key role of ALDH2 in disease is supported by strong genetic/GWAS evidence related to a dominant-negative ALDH2*2 polymorphism.
About Foresee Pharmaceuticals Co., Ltd.
Foresee is a Taiwan and US-based biopharmaceutical company listed on the Taipei Exchange (TPEx: 6576). Foresee's R&D efforts are focused in two key areas, namely its unique Stabilized Injectable Formulation (SIF) long-acting injectable technology with derived drug products targeting specialty markets and secondly, its transformative preclinical and clinical first-in-class NCE programs targeting rare and severe disease areas with high unmet needs. Foresee's product portfolio includes late and early-stage programs. CAMCEVI® 42 mg, for the treatment of advanced prostate cancer, is now approved in the U.S., Canada, EU and Taiwan and launched in the U.S. in April 2022. Additionally, U.S. and EU regulatory submissions are under preparation for CAMCEVI® 21 mg. For the second indication of CAMCEVI® 42 mg, central precocious puberty (CPP), the Phase 3 clinical study, has been initiated. FP-025, a highly selective oral MMP-12 inhibitor targeting inflammatory and fibrotic diseases, has been investigated in a Phase 2 proof-of-concept study in allergic asthmatic patients. The study has been completed with positive outcomes, with future development in rare immune-fibrotic diseases. FP-045 is a highly selective oral small molecule allosteric activator of ALDH2, a mitochondrial enzyme, for which a Phase 1b/2 Fanconi Anemia study is currently being initiated, and a Phase 2 study in pulmonary hypertension-interstitial lung disease (PH-ILD) patients is in planning. www.foreseepharma.com