New data by AKL Therapeutics suggests investigational oral osteoarthritis drug APPA may have a promising senotherapeutic effect with potential in other diseases of ageing

STEVENAGE, England, March 20, 2023 /PRNewswire/ -- New data* presented at the 2023 Osteoarthritis Research Society International (OARSI) World Congress in Denver, Colorado (March 17^th-20^th) suggest that AKL Therapeutics' investigational oral osteoarthritis (OA) drug APPA** may have a dual effect on senescence¹ ? a process in which cells stop dividing as a natural consequence of ageing.² Senescence plays a major role in the development of many age-related diseases, including osteoarthritis (OA).³

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.¹ 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).^1,4

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.¹

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.³

"Frailty and mobility issues have a significant impact as we age, often leading to people living many years in pain and ill health.^5,6 If we can reduce senescence, which contributes to joint damage in OA⁷ and is involved in many other age-related diseases, we can hopefully help improve peoples' healthspan, so they age in better physical and mental health."⁸

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.² They have become one of the most promising targets for healthy ageing research 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 Disease, Parkinson's Disease, osteoporosis, and diabetes.⁹

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.¹⁰ Senotherapeutics have the potential to increase healthspan by delaying the worse effects of ageing, which would reduce the burden of age-related diseases and could save healthcare systems billions every year.¹¹

David Miles, Chief Executive Officer at AKL Therapeutics, says: "With a unique mechanism of action,^12-15 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. 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.^16,17 Previous human clinical trials have shown that APPA has a good safety profile, is well-tolerated and reduces pain in OA.^18,19 Importantly, it has been shown to reduce levels of cartilage-damaging enzymes and levels of bone destruction.^13-15 The Phase 2a trial found that those with more severe disease benefited most from APPA with a statistically significant improvement in pain vs placebo.¹⁸

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.²⁰ 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.²¹

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.²² OA is the most common joint disease worldwide, affecting an estimated 10% of men and 18% of women over 60 years of age.²³ 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.²⁴

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About AKL Therapeutics

• AKL Therapeutics is looking to radically improve healthspan with a novel multifactorial approach to OA.
• With a primary focus on OA, AKL is also conducting research exploring its lead molecule APPA's effect on senescence, a major contributor to many chronic diseases of ageing including cardiovascular disease and neurodegenerative diseases.
• AKL Therapeutics, a trading name of AKL Research and Development, is based at the Stevenage Bioscience Catalyst, Stevenage, Herts UK. For more information, visit us at: http://akltherapeutics.com.

REFERENCES:

1. Fernandez-Moreno M, Hermida Gómez T, Larkins N, Reynolds A, Blanco-Garcia F. Effect of APPA (combination of apocynin and paeonol) compound on cellular senescence using human articular chondrocytes. Osteoarthritis and Cartilage. 2023; 31 (Supplement 1):S401-402 Abstract 447.

2. Lagoumtzi SM, Chondrogianni N. Senolytics and senomorphics: Natural and synthetic therapeutics in the treatment of aging and chronic diseases. Free Radic Biol Med. 2021 Aug 1; 171:169-190.

3. Coryell PR, Diekman BO, Loeser RF. Mechanisms and therapeutic implications of cellular senescence in osteoarthritis. Nature reviews Rheumatology. 2021 Jan; 17(1):47-57.

4. Zhang L, Pitcher LE, Prahalad V, Niedernhofer LJ, Robbins PD. Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. FEBS J. 2023 Mar; 290(5):1362-1383.

5. Howlett SE, Rutenberg AD, Rockwood K. The degree of frailty as a translational measure of health in aging. Nature Aging. 2021 2021/08/01; 1(8):651-665.

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9. Cellular Senescence in Disease: Academic Press, 2021.

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12. Cross AL, Hawkes J, Wright HL, Moots RJ, Edwards SW. APPA (apocynin and paeonol) modulates pathological aspects of human neutrophil function, without supressing antimicrobial ability, and inhibits TNF? expression and signalling. Inflammopharmacology. 2020 Oct; 28(5):1223-1235.

13. Fernandez-Moreno M, Larkins N, Reynolds A, Hermida Gómez T, Blanco FJ. APPA (apocynin and paeonol) reduces ROS production and senescence in human articular chondrocytes. Annals of the rheumatic diseases. 2021; 80(Suppl 1):1051 Abstract AB0036.

14. Fernandez-Moreno M, Larkins N, Reynolds A, Hermida-Gomez T, Blanco FJ. Biological effect of APPA (Apocynin and Paeonol) in human articular chondrocytes. Osteoarthritis and Cartilage. 2021; 29 (supplement1):S358 Abstract 432.

15. Thudium CS, Bay-Jensen AC, Gantzel T, Dziegiel M, Larkins N, Reynolds A. Characterizing the effect of APPA on tissue turnover in cartilage and bonetissue cultures. Osteoarthritis and Cartilage. 2021; 29 (Supplement1):SS152 Abstract 183.

16. Savla SR, Laddha AP, Kulkarni YA. Pharmacology of apocynin: a natural acetophenone. Drug Metab Rev. 2021 Mar 10:1-21.

17. Wu M, Gu Z. Screening of bioactive compounds from moutan cortex and their anti-inflammatory activities in rat synoviocytes. Evid Based Complement Alternat Med. 2009 Mar; 6(1):57-63.

18. Bihlet AR, Byrjalsen I, Andersen JR, Metnik A, Reynolds A, Larkins N, et al. The efficacy and safety of a fixed-dose combination of apocynin and paeonol in symptomatic knee oa: A double-blind, randomized, placebo-controlled clinical trial. Annals of the rheumatic diseases. 2022; 81(Suppl 1):321 Abstract POS0180.

19. Larkins N. Efficacy and safety of the combination of apocynin and paeonol (APPA): an uncontrolled named patient case series. Data on file. 2019.

20. Conaghan PG, Peloso PM, Everett SV, Rajagopalan S, Black CM, Mavros P, et al. Inadequate pain relief and large functional loss among patients with knee osteoarthritis: evidence from a prospective multinational longitudinal study of osteoarthritis real-world therapies. Rheumatology (Oxford, England). 2015 Feb; 54(2):270-277.

21. MHRA awards Innovation Passport for APPA in Osteoarthritis. AKL Therapeutics. https://akltherapeutics.com/appa-granted-innovation-passport-by-mhra/ [Accessed 16 March 2023]

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24. Long H, Liu Q, Yin H, Wang K, Diao N, Zhang Y, et al. Prevalence Trends of Site-Specific Osteoarthritis From 1990 to 2019: Findings From the Global Burden of Disease Study 2019. Arthritis & rheumatology (Hoboken, NJ). 2022 Jul; 74(7):1172-1183.

<sup>Date of preparation: March 2023
* Available on request.
**Please note: APPA is an investigational medicine and not yet approved for use.</sup>