Current unmet needs and emerging novel pharmacotherapies in psoriatic arthritis

KEYWORDS:

• Psoriatic arthritis
• deucravacitinib
• filgotinib
• upadacitinib

1. Introduction

Psoriatic arthritis (PsA) is a chronic, inflammatory disease characterized by peripheral arthritis, axial disease, dactylitis, enthesitis, skin and nail involvement. The pathogenesis of PsA is incompletely understood, but innate and adaptive cells and proinflammatory cytokines are involved, particularly the interleukin (IL)-23/IL-17 axis [1]. Despite advances in understanding, this heterogenous disease remains difficult to diagnose. Observational studies demonstrate early diagnosis is key as it allows treatment to be initiated and subsequent joint damage to be minimized. Currently, there are no validated biomarkers to aid clinicians in making a diagnosis. One study showed that there can be a mean delay of up to 5 years between a patient presenting with joint pains and formal diagnosis of PsA [2].

Management of PSA can often be equally as difficult. Little data is available on precision medicine in PsA. Immunophenotyping, based upon T-helper cell subsets and thus utilizing therapy based upon mechanism of action of targeted therapy has shown a significantly improved treatment response with relation to ACR20 response in comparison to traditional therapy selection in a proof of concept study [3]. While an exciting potential avenue, this work remains in its infancy currently.

Treating PsA is in general regarded challenging by clinicians, because of its heterogeneity and varying clinical phenotypes. Effective treatment of PsA often requires a multi-disciplinary approach. Beyond joint disease, active disease negatively impacts metabolic profile, bone health, mood, and cardiovascular risk, leading to significant burden on quality of life (QoL), longevity and work productivity. As with other diseases categorized as ‘spondylarthropathy,’ frequently uveitis and inflammatory bowel disease can co-exist and develop in parallel, increasing complexity and treatment dilemmas. Moreover, the clinical course of each manifestation can vary in gender propensity, age of onset and severity creating a clinical enigma.

An ideal therapy would be one efficacious across all phenotypes. Given the spectrum of the disease, the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) have developed guidelines providing conditional indications for therapy type, with a domain-based strategy allowing clinicians to choose therapy based upon presentation. Peripheral arthritis, axial disease, enthesitis, dactylitis, skin disease and nail disease are addressed individually with over-arching principles addressing the need for multi-disciplinary input across specialties, particularly with dermatology. The latest guidelines [4] seek to incorporate 8 domains, providing context and evidence for treating co-existent inflammatory pathology such as inflammatory bowel disease and uveitis. By offering a preferential drug treatment approach, they recognize that a ‘one size fits all’ approach to treatment is unlikely to be successful. This is exemplified by the phosphodiesterase four inhibitor apremilast, which has significant real-world data for its use in skin disease, but due a moderate effect size in polyarticular PsA has been superseded by both biologic disease modifying antirheumatic therapy (bDMARD) and JAK (Janus kinase) as an option in the latest update of EULAR recommendations [5].

Although there has been progression understanding the pathobiology of the disease that have resulted in targeted therapies (see Table 1), there remains a requisite for further studies as some patients fail or are intolerant of the currently available therapies. Clinical trials of biologic disease modifying antirheumatic drug (bDMARD) inform us that up to 40% of patients are primary non-responders to different classes of treatment, with this number increasing to over 50% in obesity, which is more prevalent in the PsA population [6]. Multinational real-world data in these patients show that they experience poorer QoL, physical functioning and work impairment, citing delays in switching therapy as being a factor [7]. However, the phenomenon of secondary non-response is also well-recognized in patients with PsA, and up to 30% of patients will discontinue TNF inhibitors (TNFi) at 1 year [8]. In addition to this, concerns over long-term safety profiles of current available biologics may limit their use and patients can find treatments difficult due to regular blood monitoring, concerns of side effects, method of administration as well as impact on metabolic risk, which in turn can lead to poor compliance and dissatisfaction [9]. Finally, despite multiple mechanisms of therapy currently being available, swapping to an alternative mechanism of action (MoA) has not demonstrated superiority to treating patients with the same MoA after failure of the previous therapy,in a recent real-life single-center cohort [10].

Table 1. Current biological and small-molecule therapies available in the UK

Generic name ()	Class	Target	Molecular Structure	Dose Regime
Adalimumab	TNF inhibitor	TNF	Fully human monoclonal Antibody	40 mg s.c fortnightly
Etanercept	TNF inhibitor	TNF	Receptor fusion protein	50 mg s.c weekly
Infliximab	TNF inhibitor	TNF	Chimeric monoclonal Antibody	5 mg/kg i.v every 8 weeks post induction
Golilumab	TNF inhibitor	TNF	Fully human monoclonal Antibody	50 mg s.c monthly
Certolizumab pegol	TNF inhibitor	TNF	Humanized monoclonal Antibody	200 mg s.c fortnightly post induction
Ixekizumab	IL-17 Inhibitor	IL-17a	Fully human monoclonal Antibody	80 mg s.c monthly post induction
Secukinumab	IL-17 Inhibitor	IL-17a	Recombinant human monoclonal Antibody	150 mg s.c monthly post induction
Ustekinumab	Il12-23/12 Inhibitor	P40 subunit	Fully human monoclonal Antibody	45 mg* s.c three monthly post induction *90 mg used in BW >100 kg
Apremilast	PDE4 Inhibitor	PDE4	Small molecule	30 mg oral twice daily after induction
Tofacitinib	JAK Inhibitor	JAK 1&3	Small molecule	5 mg oral twice daily

Consequently, novel therapies, targeting new mechanisms of action continue to be developed to bridge the gap of this unmet need in pharmacological therapy of disease diversity, as well as primary and secondary inefficacy. In the next section of this article, we review the agents currently being studied in PsA. This includes the JAK1 inhibitors upadacitinib and filgotinib, Tyrosine Kinase 2 (TYK2) inhibitor deucravacitinib, IL-17A/F inhibitor bimekizumab and IL-23inhibitors guselkumab, tildrakizumab and risankizumab.

2. JAK 1 inhibitors

Blockade of the JAK receptor downregulates the production of cytokines important in the pathogenesis of PsA, including TNF-α, IL-17, IL-6, IL-23 [11]. Tofacitinib, an orally administered inhibitor of predominantly JAK1 and JAK3 is approved in combination with MTX for the treatment of PsA

Upadacitinib (UPA) a selective and reversible JAK1 inhibitor has demonstrated its efficacy across multiple measures of disease activity in PsA following two pivotal phase 3 trials.

The SELECT-PsA 1 [12] was a 24-week study enrolling 1704 patients evaluating UPA (15 mg and 30 mg) compared to placebo (PBO) and adalimumab (ADA) (40 mg) in bDMARD naïve PsA patients. Both 15 mg and 30 mg doses of UPA met the primary endpoint of ACR20 response at week 12 (70.6% and 78.5% respectively) versus PBO (36.2%), and 65.0% with ADA. The 30 mg dose achieved superiority to ADA in ACR20 response at week 12, whereas both doses achieved non-inferiority versus ADA. Both doses also significantly inhibited radiographic progression at week 24 compared to PBO and achieved PASI 75 at week 16 compared to PBO.

The SELECT-PsA 2 [13] was a 24-week study enrolling 641 patients with active PsA evaluating UPA (15 mg and 30 mg) compared to PBO in bDMARD-inadequate responders. Both doses of UPA achieved the primary endpoint of ACR20 response at week 12 versus PBO (56.9% and 63.8% vs 24.1%). MDA was achieved in 28.9% of patients receiving 30 mg of UPA compared to 2.8% in PBO. An extension of this study showed maintained efficacy at 56 weeks. The safety profile of UPA was consistent with previously reported results across indications, with no new safety signals.

Filgotinib, another selective oral JAK 1 inhibitor was evaluated in the phase 2 study EQUATOR [14] which included 131 patient who were already treated with a csDMARD and were allocated to filgotinib 200 mg or PBO. At 16 weeks 80% achieved the primary end point of an ACR20 response in the filgotinib group vs 33% in the PBO group and 80% also achieved a PsARC response in comparison to PBO. The response was observed as early as week 1. While treatment-emergent adverse events were similar between both groups, there have been concerns regarding testicular toxicity. Results from the MANTA-Ray testicular safety study are pending.

3. TYK 2 inhibitors

TKY2 is an intracellular kinase that mediates IL-23, IL-12 and interferon α/β. Deucravacitinib selectively inhibits this kinase through an allosteric mechanism by binding to the regulatory domain of TYK2, differing from the JAK inhibitors, which bind to the active site of the kinase domain.

Preliminary phase II data [15] showed deucravacitinib was effective for the treatment of active PsA which included 15% of patients who had previous TNFi therapy. Both the 6 mg and 12 mg doses of deucravacitinib demonstrated significant ACR 20 response at week 16 in comparison to PBO (52.9%, 62.7% and 31.8% respectively). Both doses were superior to PBO in achieving several secondary endpoints including ACR50/70 and enthesitis resolution. No safety signals regarding venous thromboembolism or changes in hematological parameters were identified.

4. IL-23 inhibitors

IL-23 is thought to be a key regulatory cytokine in PsA pathogenesis. Guselkumab, tildrakizumab and risankizumab are three IL-23 inhibitors showing promise.

Guselkumab is a fully human monoclonal antibody that binds to the p19 protein subunit of interleukin IL-23. By binding to this subunit, it blocks the binding of extracellular IL-23 to the cell surface IL-23 receptor, inhibiting IL-23-mediated intracellular signaling, activation, and cytokine production.

The phase 3 DISCOVER-1 trial [16], enrolled 381 patients who were either bDMARD naïve or had previously been treated with up to two TNFis. ACR20 response rates at week 24 were significantly higher among patients treated with guselkumab every 4 weeks or 8 weeks than among those on PBO, at 59.4% and 52.0% versus 22.2%, respectively.

In the larger phase 3 DISCOVER-2 trial [17] only biologic naïve patients were selected. Nonetheless, a significantly greater proportion of patients treated with guselkumab every 4 weeks or every 8 weeks versus PBO achieved an ACR20 response at week 24, at rates of 63.7% and 64.1% versus 32.9%, respectively. Radiographic progression, was significantly smaller for participants treated with guselkumab every 4 weeks versus PBO. Rates of enthesitis and dactylitis were assessed using pooled data from both trials. 63.5% and 59.4% of patients given guselkumab every 4 weeks and every 8 weeks, respectively, achieved complete resolution of dactylitis, compared with 42.2% in the PBO group. A corresponding 44.9%, 49.6%, and 29.4% experienced resolution of enthesitis. A similar favorable safety profile was observed as per previous studies in psoriasis patients.

Tildrakizumab, a high-affinity anti–interleukin-23p19 monoclonal antibody, approved to treat moderate-to-severe plaque psoriasis is under investigation for treatment of PsA. In a phase 2b study [18] at week 24, 71.4%–79.5% of tildrakizumab-treated versus 50.6% of PBO patients achieved ACR20.

In the phase 3, KEEPsAKE-1 [19] trial of biologic naïve patients and KEEPsAKE-2 [20] of bDMARD inadequate responders, risankizumab (150 mg) another anti–interleukin-23p19 monoclonal antibody was evaluated in patients with active PsA. 57% and 51% percent, respectively, of patients receiving risankizumab achieved the primary endpoint of ACR20 response at week 24 versus 34% and 27% receiving PBO. The safety results were consistent with the known profile of risankizumab in psoriasis patients.

5. IL17 A-F inhibitors

IL-17 consists of six different members (A to F) with A being the target of the currently licensed secukinumab and ixekizumab. Itself, it appears to have a moderate inflammatory capability, but serves as a recruiting and amplifying factor for other pathways such as IL-6, IL-8 and anti TNF, with elevated levels of TH17+ CD4 and CD8 cells in psoriasis and PSA patients. IL-17A and IL17-F appear to be synergists in pathological bone formation, suggesting neutralization of both cytokines impedes this process greater than only IL-17A [19].

Bimekizumab is a humanized monoclonal antibody that neutralizes both A and F [21]. Currently it is undergoing phase 3 trials in PsA and psoriasis. Evidence from the phase 2b dose ranging trial BE ACTIVE [22] in which 206 patients were enrolled showed good efficacy and safety profile in biologic naïve patients for bimekizumab doses of 16 mg and 160 mg (with or without a 320 mg loading dose). The onset of action was rapid and sustained ACR 50 response at 48 weeks, with results now extending to 108 weeks of follow-up.

6. Expert opinion

Despite advances in treatment options, a large proportion of patients remain uncontrolled with minimal disease activity only achieved in 17% taking csDMARDS and 57% in bDMARDs which is associated with a significant negative effect [23]. This may partly be attributable to disease heterogeneity with current therapies not addressing all disease manifestations. A high proportion of patients express a dissatisfaction with current therapies suggesting a need to develop more effective and less burdensome therapies for PsA.

There therefore remains a significant unmet need in patients with PsA.

In our opinion until specific biomarkers (immunophenotyping) are identified which will predict treatment responses that will enable clinicians to tailor specific biological treatment to the appropriate PsA patients there will always remain a significant proportion of patients who do not achieve their agreed treatment goals of either low disease activity or remission. Research in this field currently continues to focus on new treatment options with new biological targets. In this editorial we have highlighted several new studies examining potential targets that have shown promise. It is hoped that subsequently they will provide additional therapies and broaden the armamentarium of drugs for PsA. However, it is noteworthy that these new therapies are still not equally effective in treating all domains of the disease as is the case with the current available therapies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.