Experimental and Investigational Pharmacotherapy for Psoriatic Arthritis: Drugs of the Future

Figures & data

Table 1 EULAR 2019, GRAPPA 2015 and ACR/NPF 2018 Recommendations for the Management of PsA: Similarities and Differences

Feature	EULAR 2019 ^44	GRAPPA 2015 ^43	ACR/NPF 2018 ^45
Composition of the recommendations committee	Physicians and patients involved in the development process Rheumatologists and dermatologists involved in the development process
	Additional representation of allied health professionals	Greater representation of dermatologists	Relatively few dermatologists involved; patients in the expert and voting panels and separate patient panel; allied health professionals involved in the expert and voting panels
Structure of recommendations	Flow diagram with caveats	Flow diagrams for each feature with caveats	Pairwise comparisons
Drugs
Methotrexate	Considered alongside other csDMARDS with no specific preference, with methotrexate preferred in those with relevant skin involvement	Considered alongside other csDMARDS with no specific preference	Generally considered alongside other oral small molecules
TNF inhibitors	Recommended for use after failure of csDMARDS for predominant peripheral disease or earlier in predominant axial or entheseal disease No clear preference given to TNF inhibitors as the first-line bDMARDs		Conditionally recommended first in treatment naïve PsA over oral small molecules Conditional preference for TNF inhibitors over other biologics
		Potential to use as a first-line therapy, before csDMARDs, in patients with severe active disease
IL-17 (secukinumab, ixekizumab)	Recommended alongside TNF inhibitors		Conditionally recommended after TNFi but may be used earlier in setting of contraindications to TNFi or patients with severe psoriasis or nail disease.
	Preferred when there is relevant skin involvement	Ixekizumab data not available
IL 12/23 (ustekinumab)	Recommended alongside TNF inhibitors		Conditionally recommended after IL17i except in IBD and in patients who desire less frequent injections
Apremilast	May be considered in patients with mild disease and an inadequate response to at least one csDMARD, in whom neither a bDMARD nor a JAK inhibitor is appropriate	Recommended for use after failure of csDMARDs or if csDMARDs are contraindicated Conditionally recommended before csDMARDs in certain cases	Considered alongside other oral small molecules
Tofacitinib	May be considered in patients with peripheral arthritis and an inadequate response to at least one csDMARD and at least one bDMARD, or when a bDMARD is not appropriate	Not available	Recommended after TNFi

Table 2 Main Data Derived from Phase III Randomized Controlled Trials of New Anti-Interleukin (IL)-17 Agents Under Investigation in Psoriatic Arthritis

RCT; Clinicaltrials.Gov Number [Reference]	Patients Randomized (n)	Study Design	Primary Outcome Results
AMVISION 1; NCT02029495^Citation74,Citation75	478 with active PsA (≥ 3 SJC and ≥ 3 TJC) despite prior cs- and bDMARDs.	Randomization to BRO 140 or 210 mg or placebo; PBO patients were switched to BRO 210 mg at Wk 24 with early escape possible from Week 16	At week 24, an higher rate of patients treated with BRO achieved ACR20 compared to placebo (210 mg: 55% [95% CI: 48–61%]; 140 mg: 51% [95% CI: 45–57%]) vs PBO (24% [95% CI: 19–30%]; both P: 0.0001).
AMVISION 2; NCT02024646^Citation73,Citation75	484 PsA patients with active PsA (≥ 3 SJC and ≥ 3 TJC) despite prior cs- and bDMARDs.	Randomization to BRO 140 or 210 mg or placebo; PBO patients were switched to BRO 210 mg at Week 24 with early escape possible from Wk 16.	At week 24, an higher rate of patients treated with BRO achieved ACR20 compared to placebo (210 mg: 55% [95% CI: 48–61%]; 140 mg: 51% [95% CI: 45–57%]) vs PBO (24% [95% CI: 19–30%]; both P: 0.0001).
BE ACTIVE; NCT02969525^Citation76	206 PsA patients with active PsA despite exposure to one TNFi.	Randomly assigned (1:1:1:1:1) to placebo, 16 mg BMK, 160 mg BMK, 160 mg BMK with a one-off 320 mg loading dose, or 320 mg bimekizumab every 4 weeks. After 12 weeks, patients assigned to the placebo and 16 mg BMK groups were randomly reassigned to either 160 mg or 320 mg BMK.	At week 12, BMK at the doses of 16 mg and 160 mg (with or without a 320 mg loading dose) was associated with significant improvements in ACR50 compared with placebo, with an acceptable safety profile.
BE COMPLETE; NCT03896581^Citation77	390 active PsA with a history of inadequate response to or intolerance to at least one bDMARD.	Randomization to BMK or placebo; 16 weeks.	No results posted; Primary outcome: ACR 50 response at Week 16.
BE OPTIMAL; NCT03895203^Citation78	840 patients with active PsA.	Randomization to BMK or ADA or placebo; 16 weeks.	No results posted; Primary outcome: ACR 50 response at Week 16.

Abbreviations: ACR, American College of Rheumatology; ADA, adalimumab; APR, apremilast; bDMARDs, biologic disease modifying anti rheumatic drugs; BRO, brodalumab; BMK, bimekizumab; CRP, C-reactive protein; csDMARDs, conventional synthetic disease modifying anti rheumatic drugs; NSAIDs, nonsteroidal anti-inflammatory drugs; PBO, placebo; PsA, psoriatic arthritis; RCT, randomized controlled trials; TNFi, TNF inhibitor.

Table 3 Main Data Derived from Phase III Randomized Controlled Trials of Anti-Interleukin (IL)-23 Agents Under Investigation in Psoriatic Arthritis

RCT; Clinicaltrials.Gov Number [Reference]	Patients Randomized (n)	Study Design	Primary Outcome Results
DISCOVER 1; NCT03162796^Citation82	381 active PsA patients despite previous csDMARDs, APR, and/or NSAIDs. Participants may have been previously treated with up to 2 anti-TNF.	Randomization to GSK 100 mg every 4 weeks, or 100mg every 8 weeks, or placebo; patients on placebo shifted to GSK every 8 weeks at 24 weeks.	ACR20 response rates at week 24 were significantly higher among patients treated with GSK every 4 weeks or every 8 weeks than among those given placebo, at 59% and 52% versus 22%, respectively, with percentage differences versus placebo of 37% (95% CI 26–48) for the every 4 weeks group and 30% (19–41) for the every 8 weeks group (both p<0.0001).
DISCOVER 2; NCT03158285^Citation83	741 active PsA patients despite previous csDMARD, APR, and/or NSAIDs.	Randomization to GSK 100mg every 4 weeks (n=246), or 100mg every 8 weeks (n=248), or placebo (n=247).	Significantly greater proportions of patients in the GSK every 4 weeks group (156 [64%] of 245 [95% CI 57–70]) and every 8 weeks group (159 [64%] of 248 [58–70]) than in the placebo group (81 [33%] of 246 [27–39]) achieved an ACR20 response at week 24 (percentage differences vs placebo 31% [95% CI 22–39] for the every 4 weeks group and 31% [23–40] for the every 8 weeks group; both p<0.0001).
COSMOS; NCT03796858^Citation84	285 active PsA patients with an Inadequate response to TNFis.	Randomization to GSK 100mg every 8 weeks, or placebo.	No results posted. Primary endpoint: ACR20 at 24 weeks.
INSPIRE 1; NCT04314544^Citation87	472 active PsA patients with a prior exposure to TNFis.	Randomization to TIL or placebo.	No results posted. Primary endpoint: ACR20 at 24 weeks.
INSPIRE 2; NCT04314531^Citation86	292 anti-TNF naïve subjects with active PsA.	Randomization to TIL or placebo.	No results posted. Primary endpoint: ACR20 at 24 weeks.
KEEPsAKE 1; NCT03675308^Citation88	964 active PsA who have a history of inadequate response to or intolerance to at least one csDMARD.	Randomization to RZB or placebo.	No results posted. Primary endpoint: ACR20 at 24 weeks.
KEEPsAKE 2; NCT03671148.^Citation89	429 active PsA who have a history of inadequate response to or intolerance to at least one bDMARD.	Randomization to RZB or placebo.	No results posted. Primary endpoint: ACR20 at 24 weeks.

Abbreviations: ACR, American College of Rheumatology; ADA, adalimumab; APR, apremilast; bDMARDs, biologic disease modifying anti rheumatic drugs; CRP, C-reactive protein; csbDMARDs, conventional synthetic disease modifying anti rheumatic drugs; GSK, Guselkumab; NSAIDs, nonsteroidal anti-inflammatory drugs; PBO, placebo; PsA, psoriatic arthritis; RCT, randomized controlled trials; RZB, Risankizumab; TIL, Tildrakizumab; TNFi, TNF inhibitor.

Table 4 Main Data Derived from Phase III Randomized Controlled Trials of JAK Inhibitors Under Investigation in Psoriatic Arthritis

RCT; Clinicaltrials.Gov Number [Reference]	Patients Randomized(n)	Study Design	Primary Outcome Results
Phase III RCT; NCT01519089^Citation105	94 patients with moderate-to-severe PsA (n=12) and/or plaque psoriasis patients (n=87).	Randomization to tofacitinib 5 or 10 mg BID or PBO.	Tofacitinib was reported effective in achieving ACR20 at week 16.
OPAL Broaden; NCT01877668^Citation106	422 PsA patients who had an inadequate response to csDMARDs and TNFis naïve.	Randomization to tofacitinib 5 mg BID (n = 107), tofacitinib 10 mg BID (n = 104), ADA 40 mg once every 2 weeks (n = 106), and placebo. At month 3, tofacitinib either 5 mg or 10 mg BID was given to all patients on PBO.	The rates of ACR20 response were significantly higher at month 3 in patients treated with tofacitinib as compared with PBO.
OPAL Beyond; NCT01882439^Citation107	394 PsA patients who had an inadequate response to at least one TNFi.	Randomization to tofacitinib 5 mg BID (132 patients), tofacitinib 10 mg BID (132 patients), and placebo (131 patients). Patients on placebo shifted to tofacitinib either 5 mg (66 patients) or 10 mg BID (65 patients) at month 3.	The rates of ACR20 response were significantly higher at month 3 in patients treated with tofacitinib as compared with PBO.
PENGUIN 1; NCT04115748^Citation114	1001 patients with active PsA naïve to bDMARDs.	Randomization to filgotinib 100 or 200 mg daily, or ADA 40 mg once every 2 weeks, or PBO.	No results available. Primary outcome ACR20 at 12 weeks.
PENGUIN 2; NCT04115839^Citation115	390 PsA patients who had an inadequate response or are intolerant to bDMARDs.	Randomization to filgotinib 100 mg or 200mg daily, or placebo.	No results available. Primary outcome ACR20 at 12 weeks.
SELECT-PsA 1; NCT03104400^Citation117	1705 patients with active PsA naïve to bDMARDs, who have an inadequate response to csDMARDs.	Randomization to UPA 15 or 30 mg daily, or ADA 40 mg once every 2 weeks, or PBO.	UPA achieved noninferiority compared with ADA and statistically significant ACR responses at week 12 vs placebo (ACR20 rates were 70.6% with UPA15 and 78.5% with UPA30 vs 36.2% with PBO (p < 0.001 for UPA15/30 vs PBO) and 65.0% with ADA (non-inferiority, p < 0.001 for UPA15/30 vs ADA; superiority, p < 0.001 for UPA30 vs ADA).
SELECT-PsA 2; NCT03104374.^Citation119	641 with moderately to severely active PsA who have an inadequate response to bDMARDs.	Randomization to UPA 15 mg or 30 mg daily, or PBO; ACR20 at 12 weeks	UPA 15 or 30mg had statistically significant ACR responses at week 12 vs PBO (56.9% and 63.8% vs 24.1%; p < 0.0001 for both comparisons).

Abbreviations: ACR, American College of Rheumatology; ADA, adalimumab; bDMARDs, biologic disease modifying anti rheumatic drugs; BID, twice daily; CRP, C-reactive protein; csDMARDs, conventional synthetic disease modifying anti rheumatic drugs; NSAIDs, nonsteroidal anti-inflammatory drugs; PBO, placebo; PsA, psoriatic arthritis; RCT, randomized controlled trials; TNFi, TNF inhibitor; UPA, upadacitinib.

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