2018 starts with some disappointing news for CRPS sufferers: the clinical trial of a promising new drug has been halted early.
As I reported back in May, Axsome Therapeutics has been running the CREATE-1 trial which aimed to see if Zoledronic acid (referred to as AXS-02 in the trial) helped to control the pain of CRPS sufferers. Zoledronic acid (also known as Zoledronate) is a bisphosphonate drug, from the same family as Neridronate, which is offered to CRPS patients by a team in Italy who claim that this could cure CRPS.
What was the trial?
The CREATE-1 trial was running in multiple locations across the globe and last year, researchers were actively trying to find UK CRPS sufferers to participate. The trial involved patients taking either the real medicine or a placebo for a six-week period and recording what effect, if any, it had on their CRPS symptoms. Trial participants didn’t know whether they were receiving Zoledronate or not, and they were asked to keep track of the impact not only on their pain, but also on wider symptoms related to pain, like mobility and what everyday activities they were able to perform.
It looked promising and many thought we might finally be on the verge of a breakthrough in actually treating CRPS as opposed to simply managing its symptoms.
CRPS trial stopped due to ‘futility’
Unfortunately, we were wrong. On January 9th, Axsome Therapeutics announced that after analysis conducted by an independent data monitoring committee, the CREATE-1 trial was going to be stopped due to ‘futility’. That means, simply, that the clinical trial is not going to achieve its objectives. In other words, the drug is not doing what the researchers hoped it would; there’s no compelling evidence to show that it definitely helps CRPS sufferers with their pain.
Drug may help with osteoarthritis
Interestingly, whilst the CRPS trial has not succeeded, Axsome were concurrently running a trial of the same drug in patients suffering with knee osteoarthritis. After reviewing the evidence, the same independent committee has recommended that trial proceed to the next level; Zoledronic acid therefore clearly has the potential to be useful in some illnesses, just sadly not for CRPS.
What are the implications of these results?
It’s an interesting question. The CREATE-1 trial is not the only opportunity for CRPS patients to try bisphosphonates; as I mentioned above, the treatment is available for those who can afford it in Italy and as Richard Lowes wrote previously, German drug manufacturer Grünenthal is looking into bringing both Neridronate and Zoledronate to market for CRPS sufferers.
Indeed, it seemed that a race was beginning amongst the pharmaceutical companies to be the first to make these medicines widely available for the treatment of CRPS. And not just for altruistic reasons, either; CRPS is a vastly expensive illness because it’s just so hard to treat and it can have such a devastating effect on otherwise fit and healthy people. There’s a lot of money to be made by the first organisation that finds a genuinely effective way of treating the disease rather than simply attempting to manage the pain and associated problems it causes.
Does it mean that other bisphosphonate treatments don’t work either?
So, does the apparent failure of one bisphosphonate have implications for the others? I’m not a scientist so I can’t answer this conclusively; what I can say is that as a patient, the news definitely makes me wonder about how effective other similar treatments might be. I think it’s entirely possible that it could put sufferers off spending thousands of pounds on a trip to Italy.
After all, although there are some differences between the various types of bisphosphonate, they all operate in pretty much the same way: they bind to the surface of bones and stop bone breakdown. I don’t understand why one treatment of this type would fail when others seem to be so successful. For example, there’s clinical research published by the Italian team in which they treated 82 CRPS-I patients with infusions of Neridronic acid. These results were impressive, showing consistent and ongoing benefits for their patients. I don’t know how their results can be so far from Axsome’s conclusions. The fact that there’s no universally positive narrative emerging about bisphosphonates for CRPS is concerning.
Ineffective for recently diagnosed CRPS patients
Another point worth bearing in mind is that the Axsome trial was only recruiting those who’d suffered from CRPS for less than six months. It’s generally agreed that CRPS is easiest to treat in those who’ve had it the shortest time, and the Italian team state on their website that whilst they believe they can help any CRPS sufferer, those who’ve had it for less than six months are significantly more likely to be cured. By the time you’ve suffered with the condition for several years it becomes far harder to treat. The fact that Axsome’s trial wasn’t able to significantly and consistently benefit even these easiest-to-treat patients sounds a warning bell for me. If this therapy didn’t work for the patients with the best chance of getting better then I worry that the chances of it helping someone like me might be close to non-existent.
What does it mean for CRPS sufferers?
At the moment, the news that the trial will be stopped is all we have. Axsome Therapeutics haven’t yet published any of the data that led the independent committee to the decision that it wasn’t worth continuing so it’s impossible to analyse right now. Until that information comes out, we could speculate over a million and one different reasons for the chasms in the clinical research (and this article would be a lot longer) so I think we just have to wait until more is released to draw conclusions.
I find myself really disappointed by the news, though. I’d personally built up some hope that this trial could be both effective in treating the devastating pain of CRPS and also able to shed some light on the mechanism of why and how this terrible condition develops. I’d planned on definitely trying it if the opportunity arose.
For now the door isn’t shut on bisphosphonates as a ‘cure’ for CRPS, but its golden reputation as the potential new treatment of choice has certainly taken a significant knock. I’m choosing to hope that whatever information eventually comes out of this failed clinical trial leads us to a better understanding of CRPS and how to treat it, rather than just another medical avenue shut down. Come on scientists, please don’t let me down.