Pegloticase Plus Methotrexate Shows Hypertension Benefit in Gout Patients, with Richard Johnson, MD

Richard Johnson, MD
Credit: University of Colorado

An analysis of the pivotal MIRROR trial examining use of pegloticase plus methotrexate (Krystexxa) suggests use of the urate-lowering agent was associated with greater decreases in systolic blood pressure than pegloticase alone in patients with gout and uncontrolled hypertension.

Presented at the American Society of Nephrology Kidney Week 2023by Richard Johnson, MD, professor in the Division of Renal Diseases and Hypertension at the University of Colorado, results indicate patients receiving pegloticase plus methotrexate experienced a mean reduction in systolic blood pressure approximately 5 mmHg greater than their counterparts receiving pegloticase alone, with results also providing insight into the effects of baseline kidney function on blood pressure reduction.¹

"As we seek to address the overall burden of uncontrolled gout, especially in those with coexisting chronic kidney disease, it is critical to further understand the benefits of treatment," said Brad Marder, MD, medical director, nephrology at Amgen.² "Recognizing the high prevalence of hypertension among these patients, we're excited to present data that offers new insight into the potential role of urate reduction with KRYSTEXXA with methotrexate in regulating blood pressure."

Using data from the phase 4 MIRROR trial, which served as the basis for the US Food and Drug Administration’s approval of the supplemental Biologics License Application for pegloticase injection for coadministration with methotrexate in July 2022,³ investigators designed an analysis to compare blood pressure changes observed in the trial according to the intervention group. Of note, in the MIRROR trial, investigators measured blood pressure before exposure to the intervention and every 2 weeks thereafter.¹

Results of the investigators’ analyses indicated use of pegloticase plus methotrexate was associated with a greater reduction in mean systolic blood pressure than with pegloticase plus placebo (-6±16 vs. -1±18 mmHg). When assessing blood pressure through the end of the 52-week treatment period. Further analysis suggested there was no significant difference in blood pressure reduction achieved with pegloticase plus methotrexate with a baseline eGFR of 60 mL/min/1.73m2 or greater (Systolic: 133±13 mmHg; Diastolic: 83±9 mmHg; N=98) and less than 60 (Systolic: 130±15 mmHg; Diastolic: 80±7 mmHg) experienced similar blood pressure changes from baseline early in treatment. However, by week 24 this change was more pronounced in those with an eGFR of 60 mL/min/1.73m2 or greater group, with investigators pointing out this trend was sustained through week 52.¹

For more on this study and how it helps inform the role of pegloticase plus methotrexate in uncontrolled gout, check out our Q&A with Johnson from Kidney Week 2023.

HCPLive Nephrology: Can you discuss the impact of uncontrolled hypertension in patient populations with gout?

Johnson: In any situation, uncontrolled hypertension is not good. People with uncontrolled hypertension are at really increased risk for cardiovascular disease for stroke, and heart failure. So, it's something clinicians really try to manage. Interestingly, there's been a long-known link between gout and hypertension. In fact, sometimes when people first present with gout, they'll present with hypertension at the same time. It's a common association.

HCPLive Nephrology: When launching this study, were you expecting to see this type of blood pressure reduction with urate-lowering therapy?

Johnson: Well, there's long been a well-known association of high blood pressure with gout and with uric acid. There has been animal data that has suggested uric acid may actually have a role in hypertension. This has been supported more recently by Mendelian randomization studies that look at genetic polymorphisms that control uric acid seem to be associated with increased risk for hypertension. So, there is a well-known association of uric acid with hypertension and there is some evidence that lowering uric acid can lower blood pressure, especially in younger people.

What was particularly striking in this study was that pegloticase, when given with methotrexate, was really able to knock down blood pressure quite significantly. This is really a striking finding. A few years ago, back in 2019, we reported in another study, that pegloticase when it was given every 2 weeks was associated with a very significant reduction in blood pressure. So, this is really the second study to show that lowering uric acid with pegloticase can lower blood pressure.

HCPLive Nephrology: How does this underline the role of pegloticase plus methotrexate in the management of patients with gout?

Johnson: Pegloticase plus methotrexate is a really fantastic therapy for treating tophaceous gout because it helps to remove tophi and reduces the crystals in people with uncontrolled gout. It's a really fantastic treatment tool. A lot of people who cannot respond to other medicines will respond to pegloticase and they can drop their serum uric acid to very low levels, which allows the crystals to be dissolved. So pegloticase is a very valuable treatment for uncontrolled gout.

What is really exciting about this study is that the pegloticase is also lowering blood pressure. Hypertension is a major risk factor for cardiovascular disease, for kidney disease, for stroke, and for heart failure. So, to see that this therapy could really significantly reduce blood pressure is really a very striking finding.

References:

1. Marder BA, Johnson RJ, Choi H, Obermeyer KL, LaMoreaux B, Lipsky PE. Blood Pressure Changes with Intensive Urate Lowering in Uncontrolled Gout Patients with and Without CKD. Paper Presented at: American Society of Nephrology Kidney Week 2023. November 1-5, 2023.
2. Amgen presents new data that show blood pressure decreases for adults treated with KRYSTEXXA® (pegloticase). Amgen. November 2, 2023. Accessed November 2, 2023. https://www.amgen.com/newsroom/press-releases/2023/11/amgen-presents-new-data-that-show-blood-pressure-decreases-for-adults-treated-with-krystexxa-pegloticase.
3. FDA approves KRYSTEXXA® (pegloticase) injection co-administered with methotrexate, expanding the labeling to help more people with uncontrolled gout achieve a complete response to therapy. Business Wire. July 8, 2022. Accessed November 6, 2023. https://www.businesswire.com/news/home/20220708005097/en/FDA-Approves-KRYSTEXXA%C2%AE-pegloticase-Injection-Co-Administered-With-Methotrexate-Expanding-the-Labeling-to-Help-More-People-with-Uncontrolled-Gout-Achieve-a-Complete-Response-to-Therapy.