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Little improvement seen in OA therapeutics
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TORONTO — Philip Conaghan, MD, professor of musculoskeletal medicine at the University of Leeds, England, said that while paradigms have changed and new therapies are emerging in rheumatoid arthritis, there has been little improvement in osteoarthritis.
“Actually, things have gotten worse in OA,” he said. “We have lost therapies in the last 20 years.”
He noted that acetaminophen has been shown to offer patients no improvement in pain, and, of course, opioid use is all but verboten except in carefully regulated doses in specific patient populations.
“With this talk, I am going to focus on pharmacological approaches,” Conaghan said. “It is not because I think they are the best thing since sliced bread. It is because there is a real adherence problem with exercise. It works, but people don’t do it.”
Conaghan narrowed the discussion to therapies that are at least in phase 2 trials. The talk was broken down by target: cartilage, inflammation, cytokines, bones and nerves, and agents that could potentially act on multiple targets.
Targeting cartilage and inflammation
The fibroblast growth factor 18 (FGF-18) drug sprifermin is a promising drug in phase 2 trials that has been shown to have some effect on cartilage, according to Conaghan. “It stimulates chondrocyte proliferation,” he said.
Conaghan suggested that many of the trials of this drug have had a short duration of follow-up, but that longer follow-up is necessary to understand a disease like OA, which can take time to progress.
Thinking about inflammation as a target, Conaghan said that steroids continue to be a mainstay of OA therapy. “Steroids are one of the pharmacological agents we have confidence in for reducing inflammation,” he said.
Microsphere nanotechnology represents a potential area for elevating the efficacy of anti-inflammatory agents, according to Conaghan. He discussed phase 3, single-dose trials of triamcinolone acetonide extended-release (TA–ER). “Most drugs clear the joint very quickly,” he said. “With nanotechnology, we can keep the therapy in the joint. Somehow, you have got to find a way to keep it in there to make it work.”
As for other anti-inflammatory agents, Conaghan briefly addressed the use of colchicine in knee OA. “Leung and colleagues didn’t show any benefit to symptoms in OA,” he said. However, he suggested that further investigation of this agent may be warranted.
Targeting cytokines, bone
Conaghan lamented that while TNF-alpha inhibitors have been “stupendously effective” in RA, the results have been much less dramatic in OA.
Looking at other monoclonal antibodies, lutikizumab (Abbvie) is an IL-1 inhibitor that underwent investigation for pain and MRI endpoints in the ILLUSTRATE-K trial. “The 100-mg dose just made statistical significance, but really there was not a positive pain signal out of this study,” Conaghan said.
Similarly, trials of adalimumab (Humira, Abbvie) showed no benefit as assessed by AUSCAN or HOAMRIS features, according to Conaghan. In the HERO trial, researchers added hydroxychloroquine to the normal pain management regimen of patients. Conaghan pointed out that there was no benefit at 6 months’ follow up.
Using the bone as a target, Conaghan and colleagues looked at cathepsin K inhibition as a possible strategy in a 2017 trial. The phase 2 trial followed patients for 6 months. “It was not obvious to me that there were symptom benefits,” he said. “But on MRI measures, what we see for the first time is structural progression of OA. This is a clue we are starting to get some structural benefit.”
“At the moment, we have two agents worth looking at,” Conaghan said. “Sprifermin for cartilage, and cathepsin K for bone.”
Multi- target agents, nerves
Lorecivivint (Samumed) may be the most promising agent in the WNT signaling class, according to Conaghan. “A lot of people are looking at this,” he said. “It may improve chondrocyte function, it has a mild pro-anabolic effect, some anti-inflammatory effect. There is potential effect on a number of tissues.”
In discussing nerves as a target, Conaghan highlighted findings from Lane and colleagues investigating tanezumab (Pfizer) in 2010. “This was an important study, but it is almost 10 years old, and that drug is still not out there,” he said. “We need to get going with tanezumab again.”
Phase 2 data of CNTX-4975 (Centrexion) showed dose ascending benefits in OA as a peripheral nerve modulator. While general trends in OA have focused on the role of centralized pain, Conaghan believes that modulating peripheral pain may be an effective strategy.
To that point, Conaghan suggested that before any of these trials can be truly successful, a more complete understanding of pain may be necessary. “People with widespread pain can’t discriminate their pain so well,” he said. “When designing trials, we should choose people who can identify their pain to one joint, rather than those who have pain in multiple joints.”
Conaghan suggested that taking these parameters into account and designing trials in a more targeted is essential to moving the ball forward in therapeutics in OA. “We need to look at previous studies and let the drugs guide the way,” he said.
In a final thought, Conaghan urged investigators to focus on all forms of OA. “So much of what we do is in the knee,” he said. “The hip has been forgotten, largely because there is now a wonderful operation. And the hand has been forgotten, which is really sad.” – by Rob Volansky
Reference:
Conaghan P, et al. Concurrent Session 11. Presented at: OARSI 2019 World Congress on Osteoarthritis; May 2-5; Toronto.
Disclosure: Conaghan reports consulting relationships or speaker’s bureau affiliation with AbbVie, Flexion, Medivir, Novartis, Samumed and TissueGene.