New data from AKL Research and Development advances understanding of its investigational osteoarthritis drug APPA to protect against joint damage

AKL Research and Development (AKLRD), a pharmaceutical company which develops novel solutions for inflammatory diseases with a high unmet need, unveils new data at the Osteoarthritis Research Society International (OARSI) Virtual World Congress (April 29 – May 1) indicating its investigational oral osteoarthritis (OA) drug APPA can modulate cellular function, reduce inflammation and inhibit bone resorption associated with joint degradation caused by the disease.

Results from one study, conducted by Nordic Biosciences using ex vivo tissue explants, found that
APPA, an NRf2 and NFkB regulator, reduces inflammation-derived tissue turnover in human cartilage
explants and inhibits RANKL-mediated osteoclastogenesis and bone resorption by human
osteoclasts. These findings indicate that APPA modulates the cellular function of both chondrocytes
and osteoclasts, respectively responsible for the maintenance and repair of cartilage and bone,
suggesting it may inhibit the mechanism associated with joint degradation in arthritic disease.

Results from a second study, conducted by Instituto de Investigación Biomedica da Coruña, using
human articular chondrocytes, showed that APPA significantly reduces the gene expression induced
by inflammatory cytokines IL-1β of IL-8, TNF-α and cartilaginous degrading enzymes MMP-13 and
MMP-3. In addition, experiments using human cartilage explants stimulated with IL-1β, found that
APPA significantly increases levels of proteoglycans in the intermedial layer.

Consultant Rheumatologist Professor Robert Moots, who led APPA’s Phase I trial at Liverpool
University’s Institute of Ageing and Chronic Disease, said: “Osteoarthritis is a cause of much misery
and pain worldwide. Despite advances in understanding the pathological processes that underlie
this, our best treatments today remain embarrassingly crude – cut out the sore joint or prescribe
painkillers. These new data add important new pieces to the jigsaw puzzle that suggests a potentially
exciting and effective role for APPA in treating this chronic and debilitating disease.”

These latest results build on previously published data in the journal Inflammopharmacology in 2020
showing that in activated neutrophils APPA as an NFkB and Nrf2 gene transcription modulator,
provides an anti-inflammatory effect 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

Alan Reynolds, Chief Scientific Officer at AKLRD, said: “We are encouraged to see the results from
these two studies which provide an important step in understanding the effects of APPA on the
tissues involved in the joint. This builds on earlier research looking at neutrophils which showed that
APPA may have significant anti-inflammatory potential. Taken together, this growing body of
evidence suggests that APPA appears to work across multiple pathways to reduce pain and slow the
progression of damage in patients with osteoarthritis, a disease which is a significant burden on
those it affects.”

Regulatory guidance from the FDA states that any new OA drug targeting disease modification must
also demonstrate symptomatic pain relief.1 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.

Because OA is a disease of the whole joint, any new drug is likely to need to show it has an effect on
the multiple signalling pathways involved in bone, cartilage and synovium with the aim of treating
pain, improving function and halting disease progression. The disease affects 7% of the global
population, more than 500 million people worldwide, and it is the third most rapidly rising condition
worldwide, just behind diabetes and dementia.

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