APPA reduces senescence & reactive oxygen species production

New data presented at the European League against Rheumatism (EULAR) demonstrates that APPA reduces the number of senescent chondrocytes, and inhibits ROS production in human articular chondrocytes.

Today AKL unveils new data at the Virtual European Congress of Rheumatology (EULAR) 2021 (June 2-5). Findings from the study indicate our investigational oral osteoarthritis (OA) drug APPA can reduce reactive oxygen species (ROS) production and senescence of human articular chondrocytes, both indicators associated with OA pathogenesis. 

Results from the study, conducted by Instituto de Investigación Biomedica da Coruña, Spain, found that APPA, an NRf2 and NFkB regulator, has a clear anti-inflammatory effect on human articular chondrocytes, and could reduce extracellular matrix degradation of cartilage. This could be a result of APPA’s capacity to modulate ROS production and reduce senescence.

Increasing evidence suggests that many age-related chronic diseases such as OA are associated with hallmarks of ageing, including cellular senescence, epigenetic alterations, mitochondrial dysfunction, altered autophagy and intercellular communication . In chondrocytes, senescence-associated secretory phenotype factors, such as pro-inflammatory cytokines and extracellular matrix degrading enzymes, can contribute to the development and progression of OA.   

Consultant Rheumatologist Professor Robert Moots, who led APPA’s Phase I trial at the University of Liverpool, said: “Osteoarthritis is a multi-factoral disease of the whole joint that causes significant pain and disability. Today’s treatments provide only modest relief at best and carry the risk of significant side-effects –  my patients continue to wait for novel approaches to address this worldwide issue more effectively. These findings suggest APPA is able to reduce inflammation and the destruction of cartilage and may have an exciting role to play in the treatment of this miserable chronic disease.”

Alan Reynolds, Chief Scientific Officer at AKL, said: “We are pleased to see the results from this study which found that APPA reduced the number of senescent chondrocytes, and inhibited ROS production in human articular chondrocytes. This research builds on previous work from INBIC and other laboratories that showed APPA modifies a number of pathways involved in the development of OA. Based on these latest findings, we hope APPA will play a role in slowing the progression of this chronic and disabling condition.”

These results build on data recently published in Osteoarthritis and Cartilage which indicate APPA can modulate cellular function, reduce inflammation and inhibit bone resorption associated with joint degradation caused by the disease. In addition, data published in the journal Inflammopharmacology in 2020 showed that APPA provides an anti-inflammatory effect in activated neutrophils by regulating the cross-talk between these two signalling molecules in the inflammatory process. Similarly, APPA was shown to significantly decrease joint damage scores, improve weight-bearing and reduce incapacity in a series of rat meniscal tear models of OA. 

APPA, which is currently in a Phase II clinical trial with results expected in July 2021, is a leading oral new chemical entity (NCE) in the biopharma pipeline that targets multiple signalling pathways to deliver both pain relief and disease modification in OA. Other drugs currently in development mostly inhibit single pathways. 

OA affects 7% of the global population, more than 500 million people worldwide, and is the third most rapidly rising condition worldwide, just behind diabetes and dementia.

[1] Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-217.

[2] Diekman BO, Sessions GA, Collins JA, Knecht AK, Strum SL, Mitin NK, et al. Expression of p16(INK)(4a) is a biomarker of chondrocyte aging but does not cause osteoarthritis. Aging cell. 2018:e12771.

[3] Benderdour M, Martel-Pelletier J, Pelletier JP, Kapoor M, Zunzunegui MV, Fahmi H. Cellular Aging, Senescence and Autophagy Processes in Osteoarthritis. Current aging science. 2015;8(2):147-57.

[4] New studies suggests APPA protects against joint damage

[5] Inflammopharmacology volume 28, pages1223–1235(2020)

[6]  Osteoarthritis and Cartilage 20 (2012) S54–S296