Session Information
Session Type: Late-Breaking Abstracts
Background/Purpose: Inadequate response to allopurinol monotherapy is common. Lesinurad (RDEA594) is a selective uric acid reabsorption inhibitor (SURI) under investigation for treatment of gout in combination with xanthine oxidase inhibitors. Two randomized, double-blind, placebo-controlled, phase III clinical trials of lesinurad in combination with allopurinol (ALLO) are reported.
Methods: Two replicate studies (CLEAR 1, CLEAR 2) evaluated lesinurad (200 mg or 400 mg oral, once daily) in combination with ALLO vs ALLO + placebo in subjects with gout aged 18-85 years (NCT01510158/NCT01493531). Subjects were required to be on stable ALLO doses ≥300 mg (≥200 mg for moderate renal impairment), have serum uric acid (sUA) ≥6.5 mg/dL at screening, and history of ≥2 gout flares in the prior 12 months. Primary endpoint was the proportion of subjects meeting sUA target of <6.0 mg/dL by Month 6. Secondary endpoints included mean gout flare rate requiring treatment from Months 6 through 12 and proportion of subjects with complete resolution of ≥1 target tophus by Month 12. Safety assessments included assessment of treatment-emergent adverse events and laboratory data.
Results: Subjects in CLEAR 1 (N=603) and CLEAR 2 (N=610), respectively, were primarily white (76% and 79%) and male (94% and 96%); mean ages (51.9 ± 11.28 and 51.2 ± 10.90 years) and mean years since gout diagnosis (11.84 ± 9.37 and 11.53 ± 9.26 years) were similar in both trials. The majority of subjects (91% and 84%) were receiving ALLO 300 mg (range: 200-900 mg) daily; 14% and 23% respectively had tophi at screening, and baseline sUA was 6.94 ± 1.27 and 6.90 ± 1.19 mg/dL. Primary outcomes are reported in the figure.
No significant differences between treatment groups were observed for mean gout flare rates (end of Month 6 to 12) or subjects with complete tophus resolution. Safety data are reported in the table. Serum creatinine increases were observed, which resolved in most cases without interrupting study medication.
Table: CLEAR 1 and CLEAR 2: TEAEs and laboratory data
|
|
PBO + ALLO |
LESU200 + ALLO |
LESU400 + ALLO |
|||
|
CLEAR 1 N=201 |
CLEAR 2 N=206 |
CLEAR 1 N=201 |
CLEAR 2 N=204 |
CLEAR 1 N=201 |
CLEAR 2 N=200 |
|
|
% subjects experiencing ≥1 AE |
68.7% |
70.9% |
73.1% |
74.5% |
77.6% |
80.5% |
|
% subjects with serious AEs |
5.5% |
3.9% |
4.5% |
4.4% |
8.0% |
9.5% |
|
% subjects with renal-related AEs |
3.5% |
4.9% |
4.0% |
5.9% |
10.0% |
15.0% |
|
% subjects with serious renal-related AEs |
0% |
0.5% |
0% |
0% |
0.5% |
1.0% |
|
% subjects with kidney stone TEAEs |
2.0% |
0.5% |
1.0% |
0% |
2.5% |
3.0% |
|
% subjects with ≥1.5x increase in sCr |
1.0% |
3.4% |
6.0% |
5.9% |
15.9% |
15.0% |
|
Number (%) of sCr elevations resolved |
2/2 |
4/7 |
12/14 |
12/12 |
35/44 |
32/39 |
|
AE: adverse event; ALLO: allopurinol; LESU200: lesinurad 200 mg; LESU400: lesinurad 400 mg; PBO: placebo; sCr: serum creatinine; TEAE: treatment-emergent adverse events. |
||||||
Conclusion: In two replicate multinational studies of inadequate responders to ALLO, lesinurad (200 or 400 mg) in combination with ALLO significantly increased the proportion achieving sUA target at 6 months by ~2-2.5-fold compared to ALLO alone. Lesinurad was generally well tolerated, particularly at the 200 mg dose where the AE profile was comparable to ALLO alone, with the exception of a higher incidence in predominately reversible sCr elevations. Combination therapy with lesinurad + ALLO may represent a future treatment option for gout patients on ALLO who warrant additional therapy.
Disclosure:
K. G. Saag,
Ardea Biosciences, a wholly owned subsidiary of AstraZeneca,
2,
Crealta,
2,
Takeda,
2,
Ardea Biosciences, a wholly owned subsidiary of AstraZeneca,
5,
Takeda,
5;
S. Adler,
AstraZeneca,
1,
AstraZeneca,
3;
N. Bhakta,
Ardea Biosciences, a wholly owned subsidiary of AstraZeneca,
1,
Ardea Biosciences, a wholly owned subsidiary of AstraZeneca,
3;
M. Fung,
Ardea Biosciences, a wholly owned subsidiary of AstraZeneca,
3;
J. Kopicko,
Ardea Biosciences, a wholly owned subsidiary of AstraZeneca,
1,
Ardea Biosciences, a wholly owned subsidiary of AstraZeneca,
3;
C. Storgard,
Ardea Biosciences, a wholly owned subsidiary of AstraZeneca,
1,
Ardea Biosciences, a wholly owned subsidiary of AstraZeneca,
3;
T. Bardin,
Ipsen,
2,
Menarini,
2,
AstraZeneca,
5,
Ipsen,
5,
Menarini,
5,
Novartis Pharmaceutical Corporation,
5,
Savient,
5,
Sobi,
5,
AstraZeneca,
8,
Ipsen,
8,
Menarini,
8,
Novartis Pharmaceutical Corporation,
8,
Savient,
8,
Takeda,
8.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lesinurad-a-novel-selective-uric-acid-reabsorption-inhibitor-in-two-phase-iii-clinical-trials-combination-study-of-lesinurad-in-allopurinol-standard-of-care-inadequate-responders-clear-1-and-2/