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