AKL Therapeutics combines synthesized plant metabolites to create promising oral OA treatment.

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Following promising clinical study data, UK-based biopharma AKL Therapeutics is gearing up to take its lead compound, APPA, into a Phase 2b clinical trial for osteoarthritis. APPA, an Nrf2 and NFkB modulator, is a patented, combination oral therapy of two synthetically produced isomers, both of which are secondary metabolites of plant origin.

APPA targets multiple signaling pathways to address the complex disorder of OA and has been shown to reduce bone turnover, cartilage degradation and pain, in addition to disease modification in two animal models.

Longevity.Technology: Osteoarthritis affects one in seven adults in the US, with more than half of patients of working age. There are currently no effective and well tolerated oral therapies that provide long term relief for the symptoms of OA or reduce its progression. With APPA, AKL believes it has the only drug with a mechanism of action that targets the multiple signaling pathways in bone, cartilage and inflammation that are involved in OA. To learn more, we caught up with the company’s CSO, Alan Reynolds.

“Our founder, Dr Nicholas Larkins is a veterinarian with a particular research interest in treating dogs and other animals with osteoarthritis,” says Reynolds. “He was studying secondary plant metabolites for their potential in this area, and he narrowed in on two of the most promising.”

Anti-inflammatory properties

The plants from which APPA is derived have, says Reynolds, been used in Asian medicine for many years for their anti-inflammatory properties.

“There was some background information that suggested that these particular molecules might be effective in diseases where there’s inflammation involved, so that was the starting point,” he says. “But neither had enough of an effect on their own. He then started to combine them in different ratios and found a particular ratio that showed great potential, which led to the formation of AKL and the development of APPA.”

The early work conducted at AKL focused on synthesizing the metabolites in the lab to ensure the purity of the compounds could be guaranteed.

“You can extract from plants, and you can get around 90 percent purity, but you’ve always got some other bits and pieces in there, and it varies batch to batch,” says Reynolds. “The quality of the product is likely to be more variable as a plant extract, and manufacturing scalability is also a factor. It just made a lot of sense to produce APPA by synthesis rather than by extraction.”

Hitting multiple OA pathways

Osteoarthritis involves a complex interplay between catabolic and anabolic effects of chondrocytes (cells responsible for cartilage formation and repair), and other cells involving the entire joint, driven by inflammatory processes. To be effective, says Reynolds, an OA treatment needs to target multiple pathways.

“Most OA drugs in development only affect a particular target, a single pathway,” he explains. “And although we don’t yet know what the exact target of APPA is, we do know that it affects multiple pathways that are involved in the chronic damage that occurs in osteoarthritis.

“With APPA, we’ve shown a reduction in cell senescence, a reduction in gene expression of a number of inflammatory cytokines, reductions in key MMP-3 and MMP-13 proteins that break down cartilage, and improved medial cartilage proteoglycan content. In addition to upregulation of Nrf2, one of the most important effects is that APPA also reduces NFkB activation, which is one of the key drivers of inflammation. A lot of these are probably downstream effects from the reduction of NFkB.”

Clinical trial progress

In both rat and canine trials, APPA was shown to deliver significant pain relief benefits and disease modification results. This led the company to conduct both Phase 1 and 2 clinical studies in humans, which showed APPA was well tolerated and no significant safety signals were noted.

The APPA Phase 2a trial was designed to assess the efficacy of APPA in subjects with varying degrees of osteoarthritis, and, in predefined subgroups, to identify those who would benefit the most. The trial found that subjects with more severe disease benefited most with a statistically significant improvement in pain vs placebo.

As a result, AKL is now raising funding for a Phase 2b trial of APPA as a potential treatment for patient populations with more severe OA. This is also the largest patient group and with the highest unmet need.

“We’re raising funding for the Phase 2b study and making sure we get the trial design right – that’s going to be very important,” says Reynolds. “We have a fast-track approval from the MHRA in the UK, which should help expedite approval for the study and things like that.”

“It’s important to realize that, for a disease modifying drug in OA, the FDA requires not only that you can show you slow down the progression of the disease, but you’ve also got to show hard clinical data in terms of efficacy on pain, or function, or lack of joint replacement. So, the fact that we’ve shown benefits on pain, and have the potential for modifying the disease, puts us in a unique position in this space.”

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