New data suggest investigational osteoarthritis drug may have promising senotherapeutic effect

AKL Therapeutics’ investigational oral osteoarthritis drug APPA may have a dual effect on senescence with potential in other diseases of aging.

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New data presented at the 2023 Osteoarthritis Research Society International (OARSI) World Congress in Denver, Colorado suggest that AKL Therapeutics’ investigational oral osteoarthritis (OA) drug APPA may have a dual effect on senescence – the process in which cells stop dividing as a natural consequence of aging. Senescence plays a major role in the development of many age-related diseases, including osteoarthritis (OA) [1].

The study, using a human chondrocyte (cartilage-forming) cell line, was carried out at the Institute of Biomedical Research of A Coruña (INIBIC) in Spain. It found that APPA appears to not only reduce the number of harmful senescent cells which build up in the cartilage causing inflammation – a senolytic effect – but could also potentially reverse the senescence process so cells can function normally again – a senomorphic effect.

READ MORE: Making sense of senolytics and tackling senescence

The study found that APPA significantly reduced the number of senescent cells (p=0.020) and increased the number of cells – indicated by the number of nuclei (p=0.062) – in the chondrocyte cell line in which senescence had been induced.

Alan Reynolds, Chief Scientific Officer at AKL Therapeutics, says: “These latest findings raise the tantalising possibility that APPA could modify the progression of debilitating OA for patients by eliminating or delaying the adverse effects of cellular senescence and the process of ageing.”

Plant-derived osteoarthritis drug ready for further Phase 2 trials
Alan Reynolds, Chief Scientific Officer at AKL Therapeutics

“Frailty and mobility issues have a significant impact as we age, often leading to people living many years in pain and ill health. If we can reduce senescence, which contributes to joint damage in OA and is involved in many other age-related diseases, we can hopefully help improve people’s healthspan, so they age in better physical and mental health.”

Longevity.Technology: As we age, dysfunctional senescent cells – often dubbed “zombie” cells – build up in the body while secreting harmful chemicals which cause inflammation and damage surrounding tissue – a process known as senescence. As senescence is now known to play a major role in the development of many age-related diseases, including OA, Chronic Obstructive Pulmonary Disease (COPD), Alzheimer’s, Parkinson’s, osteoporosis and diabetes, senescent cells have become one of the most promising targets for healthy aging research [2].

Developing a new class of drugs called senotherapeutics to eliminate or delay the damaging effects of this cellular senescence is a new frontier in medicine. Senotherapeutics have the potential to increase healthspan by delaying the worse effects of aging, which would reduce the burden of age-related diseases and could save healthcare systems billions every year [3].

David Miles, Chief Executive Officer at AKL Therapeutics, says: “With a unique mechanism of action, APPA is the only oral drug that targets the multiple signalling pathways in bone, cartilage and inflammation involved in OA, delivering pain relief to multiple joints [4]. With this latest data now showing that APPA has a potential senomorphic effect, we’ve recently filed a patent application and will look to carry out further studies on other senescence-related diseases to investigate its potential as a senotherapeutic.”

APPA is an oral, patented, fixed-dose combination of two synthetically produced, synergistic, secondary metabolites of plant origin. Previous human clinical trials have shown that APPA has a good safety profile, is well-tolerated and reduces pain in OA [5]. Importantly, it has been shown to reduce levels of cartilage-damaging enzymes and levels of bone destruction [6]. The Phase 2a trial found that those with more severe disease benefited most from APPA with a statistically significant improvement in pain vs placebo [5].

READ MORE: Plant-derived osteoarthritis drug ready for further Phase 2 trials

AKL is now raising funding for a Phase 2b trial of APPA as a potential treatment for patients with more severe OA – the largest patient group which also has the highest unmet need [7]. AKL was granted an Innovation Passport for APPA in 2021 by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) which sets out an accelerated roadmap of future development and regulatory milestones.

There are currently no effective and well tolerated oral therapies that provide long-term pain relief or reduce the progression of OA, a common, debilitating, degenerative disease of the joints involving the cartilage, bone, and its surrounding tissues. OA is the most common joint disease worldwide, affecting an estimated 10% of men and 18% of women over 60 years of age [8]. Globally, the prevalent cases of OA increased by 113.25%, from 247.51 million in 1990 to 527.81 million in 2019, with OA of the knee contributing most to the overall burden [9].

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