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Robert Terkeltaub, MD, explains the results from a phase 2, dose-finding study to determine the safety and efficacy of tigulixostat in patients with gout.
Rheumatology Network interviewed Robert Terkeltaub, MD, to discuss his ACR presentation, “Phase 2 Study Results from a Randomized, Double-blind, Placebo-controlled, Dose-finding Study to Evaluate Efficacy and Safety of Tigulixostat, a Novel Non-purine Selective Xanthine Oxidase Inhibitor, in Gout Patients with Hyperuricemia.” Terkeltaub is Professor of Medicine at the University of California, San Diego and Chief of Rheumatology at the VA Medical Center in San Diego.
Rheumatology Network: What initially sparked your interest in addressing the efficacy and safety of tigulixostat in gout patients?
Robert Terkeltaub, MD: Well, this is a pharma-done study. I'm an advisor, as is Dr Kenneth Saag, to the program. In terms of my interest in advising, I think it's pretty clear when we treat gout patients that we could benefit from having more urate-lowering options in our toolkit. Allopurinol has a fair number of safety issues and dosing limitation issues, especially related to genetics, ethnic, and racial factors in terms of hypersensitivity, as well as issues in terms of some allopurinol resistance described in certain patient populations including Mexican Americans, and South and East Asians, who have a particularly high frequency of a gene variant that is involved in handling allopurinol oxipurinol. We also have issues in dosing allopurinol in patients with more advanced forms of chronic kidney disease. The dosing in the United States is limited compared to the worldwide dosing and so we're often stuck, as clinicians, in terms of having options for primary uric acid lowering that work in specific subsets of patients. We would benefit from other uric acid lowering options. Xanthine oxidase inhibition is the primary targeted route for lowering serum urate. I'm really enthusiastic about new xanthine oxidase inhibitor strategies where we have potent, effective, and safe agents.
RN: Can you tell me a bit about the study design your team developed?
RT: This was a randomized, multicenter, double-blinded, placebo-controlled phase 2 study. It took place in the United States because United States gout patients are different than gout patients outside of the country. There was also a very small active comparator group. But the primary purpose here was to explore the doses that are safe and effective and then to pursue more advanced drug development strategies.
RN: And what were the results of this study?
RT: There were 3 doses of tigulixostat: 50, 100, and 200 milligrams received once daily and comparisons were relative to placebo. There really wasn't much difference between the 50 and 100 milligram dose, but the 200 milligram dose was substantially more potent. But basically, you're looking at the proportion of subjects who achieved serum urate target. The proportion of subjects who achieved a serum urate of less than 5 milligrams per deciliter was the primary endpoint. This is a more potent and effective target for limiting uric crystal deposits and promoting the resolution of uric crystal deposits. So, the fact that we were looking at a target level of less than 5 milligrams per deciliter was a significant feature of the study.
A secondary endpoint was the more conventional study endpoint of a serum urate target of less than 6 milligrams per deciliter. Typically, with allopurinol use in clinical trial settings, in terms of getting people below 6 milligrams per deciliter, you're talking about 30% to 40%. Here at Week 12 we had between 44% and 47% of people on the lower doses reaching that endpoint of less than 5 milligrams per deciliter. At 200 milligrams a day, 62.2% achieved this goal. And then when you looked at the secondary endpoint, the more conventional endpoint, and one where allopurinol will typically get somewhere between 30% and 40% of people to serum urate target, 50 and 100 milligrams per day got about 60% of people to that particular conventional serum urate target and a whopping 78.4% with 200 milligrams per day. Placebo was negligible at about 3%.
This is very potent, urate-lowering agent. The advantage of a serum urate target of less than 5 is that that's the bare minimum target that we use for people with palpable tophi, which is about 15% to 20% of patients.
RN: Were you surprised by the results of this study?
RT: I was pleased by the results of the study. But I mean, there was background experience that argued for this particular study design and that we would see results that look like this. Importantly, this is the first study in the United so, you really don't know until you try it in that particular population. And gout patient populations are different in Japan and Korea and China from the way they are in the United States, for example. I'm pleased to see that this drug was so effective and then that there were no particular safety signals.
RN: Is there anything else you would like our audience to know about the study or gout before we wrap up?
RT: This is one of a multitude of agents that are now being developed. And I think that the approaches to treating gout are going to benefit from not only monotherapies like this, but also potentially combining approaches to tackle how uric acid is handled in the kidneys and how uric acid is handled in the gut. We're improving the ways that we have of cleaning out urate in the vasculature for the most severely ill patients with gout by tuning immune suppression to recombinant urate therapy. So, it's a pretty exciting era to be working on advancing the effectiveness of care in this disease. This is an example of some of the drug development that's going on that looks very promising.