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New And Emerging Therapies In Gout
Dr. Uma KumarProfessor & Head
Department of RheumatologyAll India Institute of Medical Sciences
New Delhi, India
Hyperuricemia
MSU crystal deposition
GOUTY ARTHRITIS
Urate SupersaturationCrystallization
InflammationJoint destruction
Dietary purine load
Endogenous purine synthesis
Renal excretion
Gut excretion
Urate lowering therapy (ULT)
Anti-inflammatory
Gout
URATE RESORPTION: Anion exchange transporters
• Apical surfaceURAT1OAT4OAT10
• Basolateral surfaceGLUT9a
URATE SECRETION:
• Basolateral surfaceOAT1OAT3
• Apical surfaceMRP4ABCG2NPT1NPT4
Lesinurad
Uric acid/urate (~100%)
Excretion (~10%)
ProbenecidBenzbromaroneProbenecid
Benzbromarone
MSU
TLR2/4
NLRP3 (Cryopyrin)Activation
Caspase-1
Pro-IL-Iβ IL-1β
TNF/ IL-6
Macrophage: IL-1β (Central to the pathogenesis of gouty inflammation)
RilonaceptCanakinumab
NSAIDsSteroidsColchcine
None of the available drugs including NSAIDs, steroids or colchicine are universally effective or completely safe
Limitations of Existing Gout Drugs
• NSAIDs/Colchicine/GC/ACTH
• XOI/Uricases/Uricosurics
Benefit
Risk
• Elderly• Comorbidities (CKD,
PUD, Hepatic dysf. Etc.)• Intolerance• Unresponsiveness
Need for Safer
Agents
Pain
General disability
Walking disability
N=120 (60 steroids 35/day x 5 days) (60 neproxen 500 bid x 5 days)
Oral prednisolone and naproxen are equally effective in the initial treatment of gouty arthritis over 4 days.
Lancet 2008; 371: 1854–60
Another notable recent advance Demonstration of efficacy and safety of low-dose
colchicineThe AGREE (Acute Gout Flare Receiving Colchicine Evaluation) study compared low- and high-dose colchicine using a randomized, placebo-controlled design.
Arth
ritis R
heum
201
0; 6
2:10
60–8
Allopurinol/FebuxostatAllopurinol Febuxostat
MOA XOI XOI(more selective)
Cost/month
200-300 Rs. 900-1000 Rs.
Starting Dosage
100mg OD 40 mg OD
Dosage 200 to 900 mg daily
40-80 mg OD
Renal adjustment
Yes No(caution in CrCl <30 ml/min)
Magnitude of urate lowring more with FEBUXOSTAT A systematic review and meta-analysis.Eur Rev Med Pharmacol Sci. 2016 Mar;20(5):983
APEX
FACT
The urate-lowering efficacy and safety of febuxostat in the treatment of the
hyperuricemia of gout : the CONFIRMS trialCONFIRM
Michael A Becker, H Ralph Schumacher, Luis RE spinoza , Alvin F Wells, Patricia Mac
Donald, Eric Lloyd, Christopher Lademacher
Anti-inflammatory ULT Dual
Rilonacept/ Canakinumab
Lesinurad Arhalofenate
Bucillamine
Drugs in clinical/pre-clinical trial
Immunereszumab RDEA3170: Tranilast
Pentra KUX-1151 RLBN1001
Ulodesine Levotofisopam
Emerging therapies
ANTI-INFLAMMATORY DRUGS
IL-1 INHIBITORS
RILONACEPT:
• Soluble, dimeric, decoy receptor fusion protein
• Non selective IL-1 antagonist
• Binds and inhibits IL-1α and IL-1β
• Proposed indication: Prevention of Gout flare during initiation of ULT
USFDA/EMA rejected its approval in May 2012
No added benefit upon conventional treatmentRisk of malignancySmall study period (16 weeks) inadequate for efficacy and safety
CANAKINUMAB:
• A fully human mAb targeted against IL-1β
• Proposed indication:
• Treatment of gouty arthritis in patients who cannot obtain adequate response with NSAIDS or colchicine.
• In pooled data from the 12-week b-RELIEVED and b-RELIEVED II studies, infections were reported in 20%, serious infections in 1.8% and injection-site reactions in 4.9% of the 225 patients receiving canakinumab.
Results from two randomised, multicentre, active-controlled, double blind trials and their initial extensions. Ann Rheum Dis 2012; 71:1839–1848.
FDA Briefing Document Supplemental BLA 125319: Ilaris (canakinumab)
• USFDA rejected its approval in June 2011
• EMA approved for gouty arthritis in 2013
NSAIDs/ colchicine Contraindication Intolerance Inefficacy
Repeated treatment with corticosteroids is not appropriate
FDA Arthritis Advisory Committee. Hyattsville, Maryland, June 21, 2011.http://www.ema.europa.eu/ema/
Khanna D. 2012 ACR guidelines for management of gout: Arthritis Care Res. 012;64(10):1447–61.
Despite the lack of an FDA indication for this drug, the 2012 American College of Rheumatology (ACR) recommendations for the management of gout propose the use of canakinumab 150 mg SC as an option for severe gout refractory to standard treatment
• FREQUENT GOUTY ATTACKS ≥ 3/ YEAR WITH:
• ADVERSE EVENTS:
Neutropenia & serious infections Hypersensitivity reaction Hyperuricemia Hypertriglyceridemia Cost
BUCILLAMINE:
• DMARD (used as 1st line DMARD for RA in Japan and Korea)
• Antioxidant
• Endogenous glutaredoxin (Gtx) and thioredoxin (TRx) systems in a reduced state by transfer of thiol groups
• Inhibition of inflammosome activation
NankeY. Mod Rheumatol Jpn Rheum Assoc. 2009;19(6):681–6..
• Pre-clinical trials:
Inhibition of Il-1β & IL-6 from mouse macrophages in response to MSU
• Clinical trial:
A randomized, multicenter phase IIa open-label, active comparator trial is underway to assess the efficacy and safety of two regimens of bucillamine compared to colchicine for the treatment of acute gout in patients with moderate to severe gout.
• Tsuji F. Clin Exp Immunol. 1999;115(1): 26–31• Bucillamine for the Treatment of Acute Gout Flare.
www.clinicaltrials.gov/ct2/show/NCT02330796?term=gout&recr=Open&rank=9
Urate Lowering Therapy (URT)
Selective inhibits uric acid reabsorption
• URAT1• OAT4• USFDA approval: Dec 2015 , EMA approval: Feb 2016
Indication:
In combination with XOI in gout patients who have not achieved target serum urate levels with a XOI alone• Dose: 200mg oral qd
• Not approved for monotherapy
LESINURAD:
• CLEAR1• CLEAR2
Replicate 12-month, multicenter, randomized, double-blind, placebo-controlled clinical trials in gout patients with inadequate response to Allopurinol
LESINURAD
ABSTRACT NUMBER: L10Lesinurad, 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)
CRYSTAL Study12 month, multinational, randomized, double-blind, placebo-controlled, phase III clinical trial of LESU in combination with Febuxostat in patients with tophaceous gout
LIGHT STUDYLesinurad 400 mg as monotherapy as an option for patients intolerant or with
contraindications to XOIs, showed a significant reduction in SU compared to placebo
However, only 29.9% achieved SU below 6 mg/dl, and effectiveness was not as
encouraging as those observed in the combination trials. In this trial, there was a
higher frequency of SCr elevations in individuals receiving lesinurad (8.4%) and
almost half of them did not present resolution of SCr elevation by the end of the trial
Tausche, A., Ann Rheum Diseases 2015:74;769.
Lesinurad more effective in combination
ARHALOFENATE
• Peroxisome Proliferator-Activated Receptor-ligand (PPAR)-γ modulator (partial inhibitor)
• Serendipitously discovered to have urate lowering properties during clinical trials for diabetes
• Dual anti-inflammatory/ uricosuric drug
Inhibits Il-1β upregulation URAT1OAT4/ OAT10 blocker
EdwardsNL, So A. RheumDis ClinN Am. 2014;40(2):375–87
• Dose-dependent reductions in serum urate and other metabolic parameters in several studies conducted to date in healthy volunteers and patients with type 2 diabetes.
Saha, Meta-Analysis of Urate Lowering in Four Phase 2 Studies in Type 2 Diabetes. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2584
• Phase 2 proof-of-concept studies in monotherapy, and as add-on to XO-inhibitors, have been initiated in the target population of gout patients with hyperuricemia.
• phase IIb trial at 54 centers ,239 gout patients to assess arhalofenate safety and efficacy in both controlling inflammation and lowering sU .
• Randomization 1:2:2:2:2 to placebo, arhalofenate 600mg or 800 mg, allopurinol 300 mg,or allopurinol 300 mg combined with colchicine 0.6 mg doseonce daily for 12 weeks
URICOSURIC
Verinurad (RDEA3170): URAT1 inhibitor, three times more potent that benzbromarone and 100 times more potent that probenecid
Phase II, randomized, open-label studies are evaluating the pharmacodynamic effects and safety of RDEA3170 administered in combination with febuxostat, and in combination with allopurinol versus febuxostat and allopurinol monotherapy, respectively.
Miner J TP: Ann Rheum Dis. 2012; 71(Suppl 3): 446. Ann Rheum Dis. 2013; 71(Suppl 3):446
TRANILAST
• TGFβ, PGE2, and Il-1 inhibitor• Also inhibits URAT1, GLUT9• Approved for Asthma in Japan & Korea
RLBN1001
• Combined URAT1 & XO inibitor
• LEVOTOFISOPAM
• S-enantiomer of tofisopam (BZD)
https://clinicaltrials.gov/ct2/show/NCT00995618?term=tranilast&rank=4].Warrell RPKA. Arthritis Rheum. 2014;66(11 (Suppl)):S366.
Noveck RJ W. Arthritis Rheum. 2012; 64:(Suppl 10).
• KUX-1151: Combined URAT1 & XOIPhase II Exploratory Clinical Study of KUX-1151 [https:// clinicaltrials.gov/ct2/show/study/NCT02190786].
• UR-1102: URAT1, OAT1 and OAT3 inhibitor, that has shown a higher potency than benzbromarone in in vitro studies
• ULODESINE (BCX4208): Purine nucleoside phosphorylase (PNP) inhibitor
Study to Evaluate sUA Lowering Activity, Safety and Efficacy of Oral Ulodesine Added to Allopurinol [https://clinicaltrials.gov/ct2/ show/NCT01265264?term=ulodesine&rank=2
ANTI-INFLAMMATORY
• PENTRA
Small, short-acting antibody-like fragments of size 25 kDa.∼
PENTRA® bodies have excellent tissue penetration and are highly effective in neutralizing their targets.
The high potency and small size may allow IL-1β-directed PENTRA®
bodies to have a fast onset and short action in combating acute gouty inflammation
• IMMUNERESZUMAB: IL-1 β vaccine
Conclusion
Newer therapeutic agents are on the horizon, but gout can still be well treated with our current agents, especially in light of recent insights into treatment strategies
Question - 1• Which one of the following statements is
INCORRECT?1. Febuxostat is safe in CKD2. Lesinurad is uricosuric agent3. HLA B5801 haplotype is responsible for Allopurinol
hypersensitivity syndrome4. Anakinra is indicated in refractory gout patients 5. Prophylaxis against gout flare is warranted while
starting urate lowering therapy.
Thank you