A paper in Nature Cancer  details exciting research about a new drug that could be the first to prevent and treat fibrosis. The drug, called PXS-5505, inhibits crosslinking and stabilisation of scar tissue (the collagen matrix) produced by myofibroblasts, reducing tissue stiffness. We wrote about this drug in our earlier blog 'New drug holds promise for arthrofibrosis'.
In this Expert Primer interview Gary Phillips, the CEO of Pharmaxis, talks about their new anti-fibrotic drug PXS-5505. Gary Phillips and Dr Kayley Usher discuss how the drug might help people with arthrofibrosis. Please note that this drug is not available yet, and needs to undergo clinical trials for treating arthrofibrosis.
We've listed some highlights and important take-aways from the interview below.
Lysyl OXidase enzyme (LOX)
"If any of us ended up hurting ourselves with a cut on the skin, for example, then the body often responds after the wound healing process by flooding the area with collagen fibres as a part of the process by which the wound gets closed."
"The wound is like a kind of the fiberglass mesh that you can buy from a DIY store, and it's floppy and loose, and it looks like strands of wool or cotton. But those strands and that mat of floppy mesh actually becomes stiff when you add a hardener to it, and that in a sense is what the lysyl oxidase enzyme is. You can think of it in broad terms as a hardener."
"You can imagine all these fibres now getting a little links between them and as those links form, facilitated by the enzyme, then they form a stiff tissue and the more crosslinks there are, the stiffer the tissue gets, and your body has a kind of a feedback loop. So as the tissue becomes stiffer, it tends to cause an increase in the activation of more myofibroblasts, which then causes more collagen and more LOX to be secreted and therefore more scar tissue."
"Your scar, although it looks the same, actually quite a high percentage of it is changing every year because some of the scar is eaten up and new scar tissue is laid down in exactly the same format. So you've got this balance. In a situation like arthrofibrosis that can get out of kilter. So the rate at which the body is chewing through existing scar tissue is slower than the amount of new scar tissue which is being formed. So over time, the amount of scar tissue builds up and we end up with an excess of scar tissue, which then causes problems with function and obviously goes on to cause all the other symptoms of pain. And this process is the same whether we were talking about fibrotic process in the skin, in a joint, in the kidney, your heart, your liver, exactly the same thing is happening. It's all about the collagen, myofibroblasts, lysyl oxidase. You'll find that everywhere."
"What our drug is aiming to do is by inhibiting the lysyl oxidase enzymes, you can slow down the rate of formation of new fibrosis and therefore the body's natural tendency to chew through existing fibrosis starts to get the upper hand again and in the end it comes back into balance. And therefore, when you use our drug in models of fibrosis, you actually can measure a decrease in the amount of fibrosis that you find. We can count the cross links and the collagen and we can show that we reduce the number of cross links in the collagen and all of that puts the system back into balance and therefore you end up with hopefully a healthy level of scar tissue and not an unhealthy one."
"PXS-5505 is a small molecule drug and it's got penetration. The drug goes everywhere in the body, so it's, we believe, it's a very effective drug inhibiting lysyl oxidase enzyme and it's also in those studies so far has proven to be really safe as well."
"From what we've seen so far it is a remarkably well tolerated drug. We're not seeing any serious adverse effects of the drug at all over six months."
"In five out of the nine (myelofibrosis patients) we could show a reduction of at least one grade in fibrosis in their bone marrow and start to see improvements in red cells and platelets as well."
"It (PXS 5505) does reduce fibrosis and now it's a question of identifying other areas and other diseases where that antifibrotic effect can be used for the benefit of patients."
"And then we looked at the amount of collagen in the biopsies taken from those (burns) patients after three months and we could show a 30% reduction in collagen in the patients who are on the active drug versus the patients that were on the placebo."
"In the skin (study) we're showing differences in collagen and therefore probably the fibrosis at three months."
"It would appear that different parts of the body, depending on your age and how old the injury is, the collagen and the scar tissue turns over at a different rate.
So you would expect somebody that's older with a far older injury, maybe the turnover would be slower and therefore it would take longer to rebalance this fibrotic process."
"We need to trial it (PXS-5505) in patients to find out what actually happens there and obviously how much of a reduction do you need in order to produce a clinical benefit."
"I think fibrosis is about the myofibroblast activation more than the number."
"It's really a question of what state they're in and as they become activated by environmental factors and injuries and surgeries and things, then they become activated and that's what causes the problem."
"So by reducing the enzyme activity, we can make the tissue softer, then that's a positive feedback loop and you'll see less myofibroblasts becoming activated."
"If you have an injury, the first reaction of the body is inflammation and then if the inflammation is chronic then it becomes fibrosis."
"The fibrosis follows inflammation, so probably using an anti-inflammatory together with something which is reducing the ongoing fibrosis will be quite a useful combination to get the most rapid resolution of symptoms that these patients are suffering from."
"Removing the fibrosis is not an overnight thing. It isn't like taking a paracetamol or an ibuprofen for a headache, you've gotta be, we think, on treatment for a matter of months rather than weeks in order to turn around a resolution for it."
"You might well use this drug in a preventative fashion rather than people using it once they have some fibrosis there which is causing them problems.
You might be able to treat it maybe for two or three months after surgery, which would then set you up for a much better long term outcome."
"It's like patients that scar badly. Doctors, plastic surgeons know, that this patient is going to scar every time I operate them… and they can do what they want, but they are very likely to scar again. So there's also a population here which are probably at high risk and it’s worth thinking about how we treat them."
"It would appear that once we reach adulthood, the collagen that we've laid down in the connective tissue and the rest of our bodies, which is essential, has an extremely slow turnover rate, we can measure it in decades. So treating the lysyl oxidase (to inhibit the enzyme) stops the formation of new collagen but doesn't speed up the digestion of the old tissue, really doesn't have any impact at all on these tissues."
"So you're looking at making a significant change to the way people can live their daily lives."
"Fibrosis is a natural process and there are patients whose metabolism for whatever reason is chewing through the fibrosis that bit quicker. So they’re gonna be quick, but I think everybody probably ends up at the same spot."
"I'm pretty confident that we would have a very high responder rate if reducing the fibrosis leads to an improvement in benefits for the patients anyway."
Chitty, J. L. et al. A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer. Nat Cancer, doi:10.1038/s43018-023-00614-y (2023).