Until recently, psoriasis treatment was focused primarily on managing acute dermatological symptoms. However, psoriasis is now regarded as a chronic systemic inflammatory condition and long-term systemic maintenance therapy is recognised as the preferred method of clinical management. Greater understanding of immunological pathways involved in psoriasis has led to the development of targeted psoriasis treatments (Nograles et al., 2010; Nast et al., 2012; Boehncke & Boencke, 2014).
Find out more about targeted treatments and the differences between onset of action and maintenance of response from Professor Andrew Blauvelt.
Psoriasis treatment adherence
A systematic literature review confirms that adherence rates in psoriasis patients are suboptimal regardless of type of treatment or disease severity and highlights the need to improve patient compliance and satisfaction with treatment (Belinchon et al., 2016).
Professor Andrew Blauvelt describes the importance of patient compliance in selecting treatment.
Traditional systemic antipsoriatic agents and interferon were most frequently discontinued due to adverse events (AEs), whilst all other biologics were most frequently discontinued due to lack of efficacy with respect to cutaneous lesions (Arnold et al., 2016).
Patients' preferences should be taken into account in the treatment decision-making process in order to improve patients' adherence and ultimately improve clinical outcomes (Belinchon et al., 2016).
Due to the range of clinical manifestations and comorbidities associated with psoriasis, a multidisciplinary and comprehensive management approach is required and has been recommended by the European League Against Rheumatism (EULAR) since 2012 (Cohen et al., 2012; Boehncke et al., 2010; Gossec et al., 2012; Mease et al., 2014).
Patient-oriented care requires that therapy is aligned with the patients’ needs/treatment goals. The German Psoriasis registry (PsoBest) has demonstrated that the majority of patients with moderate-to-severe psoriasis aspire to a normal everyday life with a low treatment burden (Blome et al., 2016).
Current unmet needs
Despite significant advances in treatment for psoriasis, unmet needs still remain:
Find out more about the unmet needs for patients from Professors Andrew Blauvelt and Ulrich Mrowietz.
Topical treatments are used as first-line therapy in mild psoriasis (<3% of body surface area [BSA] affected), and in some cases may be used in moderate disease (3–10% BSA affected) (Nast et al., 2012; Boehncke & Boehncke, 2014), or as an adjunct to systemic therapy for recalcitrant lesions.
Professor Andrew Blauvelt describes the use of topical treatments and how the boundaries between mild and moderate disease are increasingly considering patient quality of life.
The use of simple emollients (applied to skin and used as soap substitutes) can be helpful in treating psoriasis and may be the only treatment necessary in very mild psoriasis (Cohen et al., 2012).
Vitamin D analogues
The most common active topical treatment for psoriasis is a vitamin D analogue (such as calcitriol, calcipotriol or tacalcitol), which can be used alone or in combination with a potent once-daily topical steroid, or on a cyclical basis with a steroid for 4 weeks, and then alone for 4 weeks (to allow breaks from continuous steroid treatment) (Cohen et al., 2012). Combination treatments of calcipotriol and betamethasone dipropionate are available in foam and suspension formulations and have been recently approved for use in younger patients (BioSpace, 2019).
Corticosteroids can be used in mild to moderate psoriasis, particularly in sensitive sites such as the face, flexures and genitalia. However, as with topical corticosteroids used for any indication, long-term use can lead to tachyphylaxis, skin thinning and atrophy and, with extensive use, the possibility of adrenal suppression.
The inclusion of salicylic acid in topical steroids can be effective in hyperkeratotic disease to remove scales (Cohen et al., 2012).
Coal tar preparations have been used for the management of psoriasis for many decades, but are messy, have a strong odour and can stain clothing. Newer lotion formulations may overcome some of these drawbacks but may also be less effective (Cohen et al., 2012).
For scalp psoriasis, coal tar shampoos can be used, but must be left in place for 5–10 minutes before being washed out (Cohen et al., 2012).
Note: coal tar is no longer available in most European countries or in the USA.
As with coal tar, dithranol has been used to treat widespread plaque psoriasis for many decades. It is a strong irritant to unaffected skin, and therefore must be applied with extreme care, or a barrier preparation must be applied to the skin around the psoriatic plaques. In order to minimise irritation, it should be commenced at a low strength (for example 0.1%) and gradually increased every few days as tolerance permits (Cohen et al., 2012; BNF, 2015).
Dithranol can also be used as a short contact treatment, in which it is applied, left in place for about an hour and then removed (Cohen et al., 2012; BNF, 2015).
Topical retinoid formulations are no longer available in many countries.
Tazarotene is a topical retinoid with similar efficacy to vitamin D analogues, but it is a severe irritant and should be applied only to the psoriatic plaques, avoiding the surrounding skin (Cohen et al., 2012; BNF, 2015).
Tazarotene in combination with halobetasol propionate
Halobetasol propionate is the propionate salt form of halobetasol, a synthetic corticosteroid with anti-inflammatory, antipruritic, and vasoconstrictor activities (PubChem, 2019).
In a study of 212 patients with moderate-to-severe psoriasis where patients applied treatment once daily for 8 weeks and were followed for 4 weeks post-treatment, a fixed-combination of halobetasol propionate 0.01% and tazarotene 0.045% was found to be more effective than its individual active ingredients. The halobetasol propionate/tararotene combination lotion was associated with significant and rapid improvements of psoriasis (63.5% reduction in mean baseline Investigator Global Assessment x Body Surface Area composite scores).
Importantly, the addition of tazarotene to the fixed combination was shown to help sustain post-treatment benefit (Stein et al., 2018).
A tazarotene/halobetasol propionate lotion received approval from the FDA in April 2019.
Phototherapy is a mainstay of psoriasis treatment. Various phototherapy modalities, each with a specific pattern of therapeutic and adverse effects, have been developed for psoriasis including ultraviolet B (UVB), psoralen ultraviolet A (PUVA), pulsed dye laser, photodynamic therapy, intense pulsed light and light-emitting diodes (Zhang et al., 2018). Photochemotherapy combines UVA radiation with oral or topical psoralen, a skin-sensitising agent which enhances the effects of the irradiation. Broadband ultraviolet B (UV-B; 290–320 nm) and narrowband UV-B (311–313 nm) are well established treatments for several skin diseases including psoriasis, atopic dermatitis and vitiligo (Morita, 2018). The pulsed dye laser often improves nail psoriasis (Zhang et al., 2018). Although further studies are needed, low-level light/laser therapy, the near infrared and visible red light with low energy show promise for treating psoriasis. These modalities show strong penetration and biological effects (Zhang et al., 2018).
Mechanism of action
Although phototherapy is a long-established and widely used treatment option in psoriasis, the biological mechanisms of action have only relatively recently been described (Wong et al., 2013). Essentially, UV phototherapy seems to improve psoriasis by inducing apoptosis and immunosuppression. For instance, phototherapy seems to restore normal regulatory T cell (Treg) function and reduces circulating levels of T-helper (Th)17 cells. Excimer light (308-nm) therapy also increases levels of regulatory T cells (Morita , 2018). So, phototherapy seems to act through a combination of pathways, including:
Administration and dosing
Phototherapy can be administered:
- in hospital
- in the outpatient clinic
- in the patient's home
Although typical regimens for NB-UVB involve dosing three times per week for at least 3 months, treatment must be independently developed to suit each patient's needs. Note: UVB phototherapy should not be used in inflammatory psoriasis, where it may lead to increased inflammation (Cohen et al., 2012; BNF, 2015; Lapolla et al., 2011).
Efficacy and safety
Clinical trials demonstrate that narrowband-UVB is more effective than broadband-UVB and safer than PUVA (Lapolla et al., 2011). A meta-analysis of 41 randomised clinical trials encompassing 2,416 patients reported that a mean of 73% of patients showed PASI 75 following treatment with PUVA or broadband UVB. PASI 75 rates were lower with narrowband UVB (62%) and bath PUVA (47%; soaking skin in psoralen liquid). Mean clearance rates were highest with PUVA (79%) followed by narrowband UVB (68%), broadband UVB (59%) and bath PUVA (58%) (Almutawa et al., 2013). Narrowband-UVB can induce remissions of psoriasis lasting 4–6 months (Morita, 2018).
Phototherapy is generally well tolerated. In the meta-analysis, broadband UVB was associated with the highest rates of asymptomatic or symptomatic (blistering) erythema: 64% and 8% respectively. Asymptomatic or symptomatic erythema also occurred in 57% and 2% respectively of those treated with narrowband UVB. PUVA (45% and 17% respectively) and bath PUVA (34% and 21%) were also associated with asymptomatic and symptomatic erythema. Moreover, 33% of patients receiving PUVA reported nausea or vomiting andthe rates of withdrawal due to adverse events (AE) were highest for broadband UVB and PUVA (both approximately 5%) and lower for narrowband UVB (2%) and bath PUVA (<1%), suggesting that the short-term adverse events were mild (Almutawa et al., 2013). Longer-term AEs include:
Visit our Guidelines section to learn more about current recommendations for using phototherapy for the treatment of psoriasis.
Systemic treatments for psoriasis are usually reserved for moderate to severe disease (3 to >10% body surface area [BSA] affected) (Nast et al, 2012; Boehncke & Boehncke, 2014; Nast et al., 2015). Systemic treatments include oral drugs, subcutaneous injections and intravenous infusions (Nast et al., 2012; Nast et al., 2015).
Is there still a place for non-biologic treatments? Find out from Professor Ulrich Mrowietz.
Ciclosporin was approved in Europe for the treatment of psoriasis in the early 1990s, and is indicated in the treatment of plaque psoriasis which has not responded to other treatments (Pathirana et al., 2009; Colombo et al., 2012; Nast et al., 2015).
Mechanism of action
Ciclosporin binds to cyclophilin and inhibits phosphatase activity which leads to reduced cytokine production (Pathirana et al., 2009).
Table 5. Ciclosporin dosing (Neoral SPC, 2016).
Clinical improvements are typically observed after 4 weeks with a maximal response at 8 to 16 weeks (Pathirana et al., 2009).
A review of 15 clinical studies of ciclosporin in psoriasis found that after 12–16 weeks of treatment, approximately 50% of patients achieved a PASI 75 response (Pathirana et al., 2009).
Ciclosporin is recommended only as a short-term induction therapy, since long-term use is associated with (Pathirana et al., 2009; Nast et al., 2015):
- Impaired renal function
- Increased risk of malignancies (such as melanoma and lymphoma)
- Hepato-gastric symptoms
- Increased risk of infections
- Gingival hyperplasia
Methotrexate is classed as a disease modifying antirheumatic drug (DMARD). It was approved in Europe for the treatment of psoriasis in 1958 and is indicated in the treatment of moderate-to-severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy (Pathirana et al., 2009).
Mechanism of action
Methotrexate acts by competitively inhibiting dihydrofolate reductase, resulting in reduced nucleic acid synthesis in T cells and keratinocytes, and leading to antiproliferative and immunomodulatory effects (Pathirana et al., 2009).
Most clinicians initiate methotrexate as first-line systemic therapy for psoriasis patients; however, long-term use is complicated by multiple toxicities (Belge et al., 2014; Gyulai et al., 2015).
Methotrexate can be administered once weekly by injection or orally, but has a slow onset of action and may take several weeks to achieve a clinical response (Pathirana et al., 2009; Nast et al., 2015). Experienced dermatologists do not always use a test dose and the majority use a starting and maintenance dose of 10 mg weekly (Gyulai et al., 2015).
Table 6. Methotrexate dosing (Methotrexate 10 mg tablets SPC, 2015; Methofill® SPC, 2018).
Hear from Professor Andrew Blauvelt how the onset of action is important for different patient groups.
The EMA recently released HCP recommendations on dosing as “Mistakes in prescribing or dispensing methotrexate as well as misunderstandings of the dosing schedule have led to patients taking the medicine daily instead of weekly for inflammatory disease, with serious consequences, including fatalities” (EMA, 2019).
Although the limited number of studies investigating the efficacy of methotrexate were performed during the 1960s and 1970s and may not have complied with today’s methodological standards, there is a large amount of clinical experience relating to the use of methotrexate in psoriasis (Pathirana et al., 2009). In the control arm of a study assessing adalimumab, 32% of patients taking methotrexate achieved PASI 75 and 41% achieved clear or minimal PGA at week 16 (Papp et al., 2017). In the control arm of another study assessing adalimumab, 35.5% of patients taking methotrexate achieved PASI 75 and 1.9% PASI 100 at Week 16 (Saurat et al., 2008).
Patients with concomitant psoriatic arthritis
Methotrexate was found to be more effective in patients with psoriasis without concomitant psoriatic arthritis; PASI 90 score was significantly lower in patients without psoriatic arthritis than those with psoriatic arthritis at Week 8 (3.1% vs. 11.2%, respectively; p=0.02) and Week 12 (14.8% vs. 25.2%, respectively; p=0.049).
The most important serious adverse events associated with methotrexate are myelosuppression and hepatotoxicity, both of which require dose reduction or discontinuation of treatment.
Patients receiving methotrexate also appear to be at a greater risk of infection compared to the biologic systemic treatments apremilast (hazard ratio [HR] 0.50; 95% CI, 0.26–0.94), etanercept (HR, 0.75; 95% CI, 0.61–0.93) and ustekinumab (HR, 0.65; 95% CI, 0.47–0.89) (Dommasch et al., 2019).
Overview of side effects (Pathirana et al., 2009):
- very frequent - nausea, malaise, hair loss
- frequent - elevated transaminases, bone marrow suppression, gastrointestinal ulcers
- occasional - fever, chills, depression, infections
- rare - nephrotoxicity, liver fibrosis, cirrhosis
- very rare - interstitial pneumonia, alveolitis
Patients with concomitant psoriatic arthritis
The incidence of side effects was found to be higher in patients treated with methotrexate with psoriatic arthritis than patients with psoriasis alone (52.3% vs. 35.5% of patients experienced one or more adverse event; p=0.01) (Yan et al., 2019).
Frequent testing of blood counts and liver function should form part of the regular monitoring of patients on methotrexate to allow early detection of these AEs (Pathirana et al., 2009; Nast et al., 2015).
Acitretin is a systemic retinoid approved for the treatment of psoriasis in the late 1980s. It is indicated for the treatment of severe psoriasis in adults. However, because of significant adverse effects associated with its use, it should only be prescribed by those knowledgeable in the systemic use of retinoids (Pathirana et al., 2009).
Mechanism of action
Although the exact mode of action is unknown, retinoids reduce the proliferation of epidermal keratinocytes and reduce the intra-epidermal migration of neutrophils (Pathirana et al., 2009).
There is no general agreement on the optimal dose regimen and a dose regimen customised to the clinical response and patient's needs has been proposed (Chiricozzi et al., 2017).
Table 7. Acitretin dosing (Pathirana., 2009; Nast., 2015).
Acitretin, an active metabolite of etretinate, is highly efficacious as monotherapy in some specific clinical subtypes of psoriasis and demonstrates dose-sparing effects when used as combination therapy with conventional systemic drugs or biologics (Dogra et al., 2014).
Acitretin is a derivative of vitamin A and hence vitamin A toxicity (presenting as cheilitis and xerosis) is a frequently reported, but reversible, side-effect that responds to dose reduction.
Fumaric acid esters
Fumaric acid ester (FAE) is a well-established treatment that was licensed in Germany in 1994. FAEs can be used for induction and long-term maintenance and are associated with limited toxicity (Nast et al., 2015).
FAEs improve psoriasis symptoms by inhibiting the production of pro-inflammatory cytokines such as IL-12 and IL-23 (Belge et al., 2014; Litjens et al., 2004; Ghoreschi et al., 2011a).
Oral FAE therapy for psoriasis was first reported in 1959 and has become widely used in Northern Europe, particularly in German-speaking countries and the Netherlands (Naldi & Griffiths, 2005).
Dimethyl fumarate (DMF) is considered to be the most active compound among the FAEs and is clinically effective in psoriasis and multiple sclerosis (MS) (Pathirana et al., 2009; Bovenschen et al., 2010; Ghoreschi et al., 2011a).
Mechanism of action
DMF and its monoester inhibit the maturation of dendritic cells, which play an important role in the development and maintenance of immunologic reactions that lead to an inflammatory response.
Monomethyl fumarate can induce a shift in the secretion of Th1-cytokines to a Th2-type pattern and DMF can induce apoptosis, particularly in activated T cells (Pathirana et al., 2009).
In a recent European expert consensus meeting on the clinical use of DMF in moderate-to-severe plaque-type psoriasis, a panel of 10 dermatologists concluded that DMF should be considered in systemic-naïve patients with moderate-to-severe psoriasis (Pathirana et al., 2009).
Contraindications for DMF include severe renal or hepatic impairment or severe gastrointestinal disorders.
It was advised by the panel that flexible and individualised dosing of DMF should be used, taking into consideration individual patient needs, starting on a low dose and slowly titrating up until the patient reaches the maintenance phase. A slow increase in dose is meant to improve tolerance, especially with regard to the gastrointestinal tract (Pathirana et al., 2009).
A clinically meaningful improvement is seen after 6–8 weeks of therapy in psoriasis patients; this improvement continues during prolonged treatment.
The BRIDGE study
The EMAs decision to approve Skilarence® across Europe was based on the results from a Phase III, double-blind, placebo-controlled, non-inferiority trial (BRIDGE) assessing the efficacy and safety of a new formulation of DMF (LAS41008/Skilarence) compared with placebo and Fumaderm®, which demonstrated that LAS41008 is effective in the treatment of adults with moderate-to-severe chronic plaque psoriasis (Mrowietz et al., 2017).
At week 16 (Mrowietz et al., 2017):
Although Skilarence® can be seen as advantageous compared to alternative therapies as there is no evidence of drug–drug interactions and the medication is suitable for co-medicating, patients should be closely monitored, especially for leucocyte and lymphocyte counts, and given realistic expectations of the typical side effects.
Side effects have been reported to often occur exclusively during initiation and up-titration, and lessen as patients become established on the treatment.
Gastrointestinal side effects
Gastrointestinal complaints and flush symptoms are the most frequent adverse events during treatment with fumarates (Pathirana et al., 2009). Gastrointestinal side effects include diarrhoea, abdominal distension, abdominal pain, nausea, vomiting, dyspepsia, constipation and flatulence, and occur in up to 60% of patients on FAE treatment (Mrowietz et al., 2017). The general consensus of the expert panel is that these effects often cause issues between Weeks 3–6 but stabilise or improve by Weeks 8–9 (Mrowietz et al., 2018).
Progressive multifocal leukoencephalopathy
In 2014 the US Food and Drug Administration (FDA) reported that a multiple sclerosis patient treated with DMF developed progressive multifocal leukoencephalopathy (PML) and later died. As a result, information describing PML was added to the drug label (FDA, 2014).
Novel systemic treatment apremilast
Apremilast, an oral, small molecule inhibitor of phosphodiesterase 4 (PDE4), was approved in Europe in 2014 for the treatment of moderate-to-severe chronic plaque psoriasis, based on the results of pivotal Phase III ESTEEM clinical trials (EMA, 2014; Otezla® SPC, 2015).
Mechanism of action
Apremilast inhibits specific intracellular metabolic processes and key signalling pathways relevant to psoriasis, leading to the down-regulation of the inflammatory response by modulating expression of TNFα, IL-23, IL-17 and other inflammatory cytokines (EMA, 2014; Otezla SPC, 2015).
Apremilast is orally administered twice-daily and is contraindicated during pregnancy. During pivotal trials the greatest improvement was observed within the first 24 weeks of treatment and discontinuation should be considered if no evidence of therapeutic benefit is seen after 24 weeks (Otezla SPC, 2015).
A recent, retrospective study indicated that apremilast can be safely and effectively combined with photo-, systemic and/or biological agents in psoriasis patients with an inadequate response to these agents alone with gastrointestinal side effects manageable in the majority of patients (AbuHilal et al., 2016).
ESTEEM 1: Apremilast 30mg twice daily versus placebo
PASI 75 non-responders: 24.1% of patients were PASI non-responders at Weeks 32 and 52
PASI 50: ~50% of patients who were PASI non-responders achieved PASI 50 at Weeks 32 and 52
Pruritis: ~30% reduction in pruritis visual analogue scale scores
ESTEEM 2: Apremilast 30 mg twice daily versus placebo (re-randomisation of patients achieving PASI 50)
PASI 50 at Week 52: 80.0% of patients re-randomised to APR versus 11.7% re-randomised to placebo achieved PASI 50 at Week 52
ESTEEM post-hoc analyses
Post-hoc analyses of the ESTEEM trials have demonstrated that at Week 16:
- Significantly more apremilast patients achieved a Palmoplantar Psoriasis Physician Global Assessment (PPPGA) score 0 (clear) or 1 (almost clear) vs. placebo
- 48% vs. 27%; p=0.021 (Bissonnette et al., 2016)
- A significantly greater reduction in Nail Psoriasis Severity Index (NPSI) score was observed with apremilast vs. placebo
- -22.5% vs. +6.5%; p<0.0001 (Rich et al., 2016)
- Apremilast improves all health-related quality of life (HRQoL) patient reported outcomes (PROs) in moderate-to-severe psoriasis vs. placebo (Thaçi et al., 2017)
Despite the encouraging results from the ESTEEM trials, a comparison of the relative efficacy of apremilast and methotrexate in moderate-to-severe psoriasis revealed there is no statistically significant difference in PASI 75 between apremilast and methotrexate, with apremilast treatment associated with substantially increased costs (Armstrong et al., 2016a).
A more recent study indicated that patients treated only with apremilast are less likely to get infections compared to those treated with methotrexate (Dommasch et al., 2019).
Find out why treatment for palmoplantar pustulosis is an unmet need for psoriasis treatment from Professor Ulrich Mrowietz.
The LIBERATE trial
The Phase IIIb trial LIBERATE evaluated the efficacy and safety of apremilast vs. placebo in biologic-naïve patients with moderate-to-severe plaque psoriasis, and the safety of switching from etanercept to apremilast.
It demonstrated that the efficacy of apremilast was sustained over 52 weeks both in patients who continued on apremilast and also in patients who switched from etanercept to apremilast (Reich et al., 2016a).
The UNVEIL trial
Meanwhile, the Phase IV UNVEIL trial assessed the efficacy and safety of apremilast in systemic- and biologic-naïve patients with moderate plaque psoriasis over 52 weeks. In the initial 16-week randomised, double-blind, placebo-controlled phase of the study, patients receiving apremilast achieved a significantly greater change from baseline in the product of sPGA and BSA scores (PGAxBSA) than placebo (-48.1% vs. -10.2%, p<0.0001) (Strober et al., 2017a).
Patients receiving apremilast also experienced a significantly greater improvement in DLQI score than patients given placebo (Strober et al., 2017a).
-4.8 vs. -2.4; p=0.0008
UNVEIL extension phase
In the UNVEIL extension phase all patients received apremilast and were followed for up to 52 weeks. Among those patients that completed the study, all efficacy improvements observed at Week 16 were maintained at Week 52 (Stein Gold et al., 2018).
Find out the importance of maintenance of response in some patient groups from Professor Andrew Blauvelt.
The efficacy and relative safety of biologic agents greatly improved the treatment of psoriasis and allowed long-term maintenance therapy, with the ultimate goal of achieving clearance of skin symptoms in moderate-to-severe psoriasis patients (Boehncke & Boehncke, 2014; Boehncke & Schön, 2015; Dommasch et al., 2019).
Find out how patients’ attitudes to biologic treatment have changed from Professor Ulrich Mrowietz.
Currently, approved biologic treatments for moderate-to-severe psoriasis in Europe and in the USA include the TNFα antagonists (and in some cases their biosimilar versions as well), ustekinumab (which inhibits IL-17 and IL-23) IL-17 antagonists and IL-23 antagonists.
It is now well established that low rates of adherence to psoriasis treatment have a negative impact on outcome and increase total health care costs. The FDA approval in January 2019 of a patient-controlled injector for guselkumab builds on other self-injection options, such as adalimumab, to help empower patients and increase treatment adherence (Humira® SPC, 2003; Aldredge & Young, 2016; Tremfya® SPC, 2017; Tremfya® PI, 2017).
Professor Andrew Blauvelt describes the importance of treatment adherence and how it affects treatment selection.
Biologic drug survival
A growing number of studies confirm the high persistence rates with biological treatment in a variety of populations with psoriasis. ORBIT (Outcome and Retention Rate of Biologic Treatments for Psoriasis), a retrospective observational study on biologic drug survival in daily practice, described an overall median drug survival of 31.0 months. The results from ORBIT also indicate that drug survival was lower in obese patients than in patients with body mass index (BMI) <30 and was significantly higher for ustekinumab than for any other biologic agent (p<0.001) (Vilarrasa et al., 2016).
Since then, numerous real world evidence studies confirmed the high persistence rates. For instance, a study from Greece reported 74.5% persistence with secukinumab at 104 weeks in people with moderate–to–severe psoriasis, including those with scalp and palmoplantar psoriasis (Rompoti et al., 2019). An Italian group found retention rates with ustekinumab after 2 and 8 years of 81% and 59% respectively in people with moderate–to–severe plaque psoriasis. The mean retention time was 5.4 years (Galluzzo et al., 2019). An analysis of a German claims database of previously biologic naïve patients, reported an overall 1-year persistence rate with biologics for psoriasis of 56%. However, the analysis suggested that 1-year persistence was highest with ustekinumab (80%) (Mahlichb et al., 2019).
Persistence may, however, differ between biologics. A meta-analysis of 37 studies encompassing 32,631 patients with psoriasis found that persistence decreased between Year 1 and Year 4 of treatment. Etanercept was most commonly discontinued because loss of efficacy. Infliximab was most frequently discontinued because of adverse effects (Lin et al., 2018).
TNFα represents a key therapeutic target within the psoriasis inflammatory cascade. This cytokine has multiple effects on the development and maintenance of psoriasis, including increased keratinocyte proliferation and increased recruitment of T cells to the skin (Menter et al., 2008). You can read more about the role of this cytokine in psoriasis development here.
Four agents selectively block the role of TNFα and have demonstrated efficacy in psoriasis clinical trials:
- certolizumab pegol
Profesor Andrew Blauvelt describes TNFα inhibiting approaches when considering the challenge of psoriasis treatment.
Although the heterogeneity of the therapeutic response to TNFα antagonists is primarily due to genetic factors, a retrospective study demonstrated a significant association between better response and (De Simone et al., 2016):
View the cytokines in psoriasis section of Disease Awareness for further details on the important role of TNFα, IL-23, IL-17 and IFNγ in psoriasis pathophysiology.
A chimeric, human-murine monoclonal antibody (mAb) that binds with high affinity to TNFα. Infliximab was approved in 2006 for the treatment of moderate-to-severe plaque psoriasis in adult patients who failed to respond to/have a contraindication to/are intolerant of other systemic therapies including cyclosporin, methotrexate or PUVA (Remicade SPC, 2015).
To view infliximab biosimilars click here.
Approval of infliximab for psoriasis was based on the two Phase III EXPRESS clinical studies.
EXPRESS: IFX 5 mg/kg vs. placebo
PASI scores at Week 50: 50%, 61% and 45% of patients receiving IFX achieved PASI 75 and PASI 90.
EXPRESS II: IFX 3 mg and 5 mg/kg vs. placebo
PASI scores at Week 24: 82% of patients receiving IFX maintained PASI 75 vs. 4% receiving placebo (p<0.001); 37% receiving IFX vs. 1% receiving placebo maintained PASI 90 (p<0.001).
PASI scores at Week 50: Better PASI responses were obtained with 5 mg/kg and with continuous maintenance vs. intermittent treatment.
Find out from Professor Andrew Blauvelt about considering maintenance of response vs. fast onset of action.
The REALITY health-related quality of life study
Results from REALITY, a prospective, observational, real-world, open-label study of infliximab in moderate-to-severe psoriasis demonstrated substantial improvements in health-related quality of life (HRQoL) (Shear et al., 2016).
At Week 50, the Mean Dermatologic Life Quality Index (DLQI) improved (decreased) from 12.7 at baseline to 4.7
At Week 98 mean DLQI was 2.8
47.5% of patients achieved a DLQI of 0
The independent PIECE (Psoriasis Infliximab versus Etanercept Comparison Evaluation) study
Until recently, there was a lack of independent (non-pharmaceutical sponsored) data comparing the efficacy of infliximab and etanercept in psoriasis. The PIECE (Psoriasis Infliximab versus Etanercept Comparison Evaluation) study was a prospective randomised controlled trial comparing infliximab and etanercept in moderate-to-severe psoriasis that addressed this gap.
The PIECE study demonstrated that although infliximab is associated with a rapid and significantly higher level of short-term efficacy compared to etanercept (at Week 24, PASI 75 was achieved in 72% infliximab vs. 34.8% etanercept, p=0.01) there was no significant difference with longer term maintenance treatment (de Vries et al., 2017):
At Week 48, PASI 75 was achieved in 66.7% infliximab patients vs. 50% etanercept patients (p=0.65).
Data have now demonstrated that infliximab maintenance at a dose of 5 mg/kg every eight weeks produces an effective, safe and sustainable response for up to two years (Matoula et al., 2015).
A chimeric, fusion protein consisting of the soluble portion of the p75-TNF receptor (TNFR) and the Fc fragment of human IgG1. Etanercept was approved in 2004 for the treatment of moderate-to-severe plaque psoriasis in adult patients who failed to respond to/have a contraindication to/are intolerant of other systemic therapy including cyclosporin, methotrexate, psoralen or PUVA (Enbrel SPC, 2015).
To date, the most commonly used dosing regimen is 50 mg once weekly (Enbrel SPC, 2015).
As for infliximab, recent years has seen the arrival of etanercept biosimilars. To view more information on etanercept biosimilars click here.
Although etanercept is licensed for both intermittent and continuous psoriasis treatment (Enbrel SPC, 2015), historically there has been a lack of long-term, real-life data describing the effects of a drug-free interval between treatment cycles.
A non-interventional, open-label, multicentre, observational study to evaluate the long-term, real-world outcomes of etanercept treatment demonstrated that the mean duration of drug-free intervals was relatively short (12.9 weeks [±12.8]) and most patients experienced improvements in disease activity and HRQoL within 12 weeks of either continuous or intermittent etanercept treatment (Luger et al., 2016).
Approval of etanercept for psoriasis was based on the results of two Phase III studies described below.
ETN low (25 mg weekly), medium (25 mg twice weekly) or high dose (50 mg twice weekly) vs. placebo
PASI responses were paralleled by improvements in PGA/QoL.
ETN 25 mg or 50 mg twice weekly vs. placebo (Papp et al., 2005)
Etanercept was well tolerated in the two Phase III studies (Leonardi et al., 2003; Papp et al., 2005).
A recombinant human IgG1 monoclonal antibody specific for human TNFα. Adalimumab was approved in 2008 for the treatment of moderate-to-severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy (Humira® SPC, 2003).
Several adalimumab biosimilars are under development with approvals already gained for some. Click here to read more.
Approval of adalimumab in psoriasis was based on the results of two Phase III clinical trials (REVEAL and CHAMPION).
REVEAL: adalimumab 40 mg once every two weeks vs. placebo
Between weeks 33 to 52 (following re-randomisation to ADA or placebo) 5% of adalimumab vs. 28% placebo patients lost response (p<0.001).
CHAMPION: ADA vs. MTX
Adalimumab showed a rapid response with a 57% improvement in mean PASI scores at Week 4.
Post hoc analyses: Adalimumab in patients with prior exposure to systemic therapy
A post-hoc analysis of REVEAL and CHAMPION demonstrated that adalimumab was effective regardless of prior exposure to systemic therapies; PASI 75 response rates were similar overall vs. patients who did not respond to methotrexate, cyclosporin or PUVA (Papp et al., 2016a).
ESPRIT: long-term observational registry
Initial (5-year) results have recently been published from ESPRIT, an ongoing, 10-year, observational registry evaluating long-term safety and efficacy of adalimumab in moderate-to-severe psoriasis in routine clinical practice (Menter et al., 2015). These results demonstrate that efficacy remains stable over five years with no new safety signals (Menter et al., 2015). The study is due to be completed in September 2022.
In REVEAL, less than 2% of patients discontinued the study. In CHAMPION, adverse events were similar across treatment groups; discontinuation was greatest with methotrexate.
A recombinant humanised antibody Fab' fragment with specificity for TNFα conjugated to an approximately 40kDa polyethylene glycol. Certolizumab pegol was approved for the treatment of moderate-to-severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy in 2018. (Cimzia SPC, 2018).
Originally approved for the treatment of other immune-mediated inflammatory diseases such as rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis and psoriatic arthritis.
Phase III development of certolizumab pegol involved three studies that enrolled approximately 1,000 patients, including patients with and without prior treatment experience with biologic products (ClinicalTrials.gov, certolizumab, 2015).
CIMPASI-1 CZP 400 mg loading dose at weeks 0, 2 and 4, then CZP 200 mg or 400 mg every two weeks versus placebo.
Dose modification at Week 16:
PGA 0/1 responder rate:
CIMPASI-2 was a replicate study run in parallel to CIMPASI-1.
PGA 0/1 responder rate:
PGA 0/1 responder rate:
Etanercept responders switched to certolizumab pegol at Week 16 also showed higher PASI 75, PASI 90 and PGA 0/1 responder rates at weeks 32 and 48.
PASI 75 responder rates at weeks 32 and 48:
- 90% ETN-CZP vs. 25% ETN-PBO and 82% ETN-CZP vs. 8.3% ETN-PBO
PASI 90% responder rates at weeks 32 and 48:
- 68% ETN-CZP vs. 16.7% ETN-PBO and 78% ETN-CZP vs. 4.2% ETN-PBO
PGA 0/1 responder rates at weeks 32 and 48:
- 80% ETN-CZP vs. 12.5% ETN-PBO and 72% ETN-CZP vs. 4.2% ETN-PBO
There was also a large proportion of ETN non-responders, who when switched to certolizumab pegol at Week 12, achieved PASI 75, PASI 90 and PGA 0/1 at weeks 32 and 48 (Lebwohl et al., 2018a).
At Week 32
- 60% PASI 75, 25.7% PASI 90% and 42.9% PGA 0/1
At Week 48
- 62.9% PASI 75, 51.4% PASI 90 and 57.1% PGA 0/1
A pooled analysis of data from CIMPASI-1, CIMPASI-2 and CIMPACT assessed the durability of response to certolizumab pegol (CZP) over a 48-week period.
Of 180 patients treated with CZP 400 mg Q2W that achieved PASI 75 at Week 16, 98.0% had maintained that response at Week 48 (Augustin et al., 2018).
IL-23 has been shown to play an important role in the pathophysiology of psoriasis (Boehncke & Schön, 2015). The first interleukin antagonist to be approved was ustekinumab, which inhbits IL-12 and IL-23 inhibitor whose clinical efficacy is associated with indirect inhibition of Th17 cell expansion and function due to antagonism of its regulator cytokine, IL-23 (Chandrakumar et al., 2014).
Learn more about cytokines in psoriasis for further details on the important role of TNFα, IL-12/23, IL-17 and IFNγ in psoriasis pathophysiology.
A human IgG1κ mAb that binds to the p40 protein subunit shared by both the IL-12 and IL-23 cytokines. Ustekinumab was approved in 2009 for the treatment of moderate-to-severe plaque psoriasis in patients who are inadequately controlled by/are intolerant to other systemic therapies or phototherapies (Stelara SPC, 2015).
Approval of ustekinumab in psoriasis was based on the efficacy and safety data from two Phase III clinical trials, PHOENIX 1 and PHOENIX 2.
Comparable efficacy of ustekinumab (standard dose) has been demonstrated in both adults and psoriasis patients aged 12–17 with no unexpected adverse events (Landells et al., 2015).
Further studies into ustekinumab have analysed real-world data, assessed its impact on patient-related outcomes and looked into the efficacy of ustekinumab vs. other psoriasis treatments.
In this study ustekinumab was administered at a dose of either 45 mg or 90 mg at Weeks 0 and 4, then every 12 weeks versus placebo.
Week 40: Long-term responses seen in 58.8% (UST 45 mg) and 67.2% (UST 90 mg)
1 year: PASI 75 response was greater for UST maintenance versus withdrawal (p<0.0001)
In this study ustekinumab was administered at a dose of either 45 mg or 90 mg at Weeks 0 and 4, then every 12 weeks versus placebo.
Among partial responders at Week 28 (90 mg UST): 68% randomised to eight weekly dosing achieved PASI 75 at Week 52 versus 33% remaining on twelve weekly dosing.
In ‘real world’ clinical settings, after an average of 15.4 months, ustekinumab treatment resulted in a 59% decrease from baseline in affected BSA (Ehst et al., 2015). However, due to the high cost per injection, ustekinumab may not be cost-effective in terms of loading doses required (Rouse et al., 2015).
In addition to its clinical efficacy, ustekinumab has demonstrated improvements in psychological well-being, QoL and various PROs (Nguyen et al., 2015; Augustin et al., 2017).
A prospective, interventional study further revealed that ustekinumab treatment reduces psoriasis-related work productivity impairment and activity impairment in moderate-to-severe psoriasis patients (Beroukhim et al. 2016).
Ustekinumab vs. other psoriasis treatments
Efficacy and safety of ustekinumab and other psoriasis treatments in a real-world setting was assessed using the PSOLAR registry data (Papp et al., 2015b; Strober et al., 2016b).
Recent analyses concluded that ustekinumab in patients with psoriasis:
- Is more effective than infliximab, etanercept and adalimumab, with no increased risk of malignancy, major adverse cardiovascular events (MACE), serious infection, or mortality (Papp et al., 2015b; Strober et al., 2016b).
- Presents a lower risk of infections compared to methotrexate treatment (hazard ratio, 0.65; 95% CI, 0.47-0.89) (Dommasch et al., 2019).
- Offers superior drug survival compared with infliximab, adalimumab and etanercept (PSOLAR; Menter et al., 2016a).
The PSOLAR efficacy findings were confirmed by data from the prospective, BioCAPTURE registry comparing one- and five-year efficacy of adalimumab, etanercept and ustekinumab in psoriasis patients in daily clinical practice. BioCAPTURE suggested that after one year, PASI 75 is more often achieved with adalimumab and ustekinumab than etanercept and that after five years, ustekinumab has the highest efficacy (p=0.019) (Zweegers et al., 2017).
Learn more about the safety of biologic therapies section and access more information on PSOLAR here.
Ustekinumab for paediatric psoriasis
Childhood onset of psoriasis occurs in around one third of cases, yet most of the research concerning the safety and efficacy of biologics for the treatment of this disease has been carried out on exclusively adult patient populations (Lansang et al., 2020).
As a result of the lack of data regarding the use of biologic treatments in children, only a limited number of these agents are currently available to paediatric patients. In fact, until recently the TNF-α inhibitors, adalimumab and etanercept, were the only biologic agents approved for the use in patients under 12 years with moderate to severe psoriasis in Europe, while ustekinumab was approved for the treatment of adolescents aged 12–17 years (Lansang et al., 2020).
However, as of January 2020, the approval for ustekinumab has been expanded to cover patients aged 6–11 years by the European Commission (Janssen, 2020; Stelara® Summary of Product Characteristics, 2020). This update was made in response to the results of the phase III CADMUS Jr study, which investigated the safety, efficacy and pharmacokinetics of subcutaneously administered ustekinumab in patients aged 6–11 years with moderate to severe chronic plaque psoriasis, and found that it was associated with improvement in disease severity and had a favourable safety profile in this population (; Philip, 2019).
In the future, it is likely that the number of biologic treatments available for the management of paediatric psoriasis will continue to grow as further clinical data regarding their use in this patient population is published.
Of note, the results of a phase III trial investigating the safety, tolerability and efficacy of ixekizumab in patients aged 6–<18 years with moderate to severe plaque psoriasis were recently presented at the European Academy of Dermatology and Venereology Congress (EADV) which took place in Madrid, Spain in October 2019 (Papp, 2019). This study represents the first clinical data pertaining to the use of an IL-17A inhibitor in this group of patients and provided evidence in support of the use of ixekizumab for the treatment of paediatric psoriasis (Lilly, 2019b).
Similarly, the PROTOSTAR study, which is currently recruiting participants, is set to investigate the safety, efficacy and pharmacokinetics of subcutaneously administered guselkumab for the treatment of chronic plaque psoriasis in patients aged 6–18 years (NCT03451851).
The IL-23/IL-17 axis has been identified as the primary signalling pathway that leads to the characteristic changes observed in psoriatic skin (Hawkes et al., 2017; Kim & Krueger, 2017).
Ustekinumab targets IL-12 and IL-23 through the common p40 subunitSeveral new therapies selectively block the p19 subunit of IL-23 (Fotiadou et al., 2018), with guselkumab being the first IL-23 antagonist to be approved receiving EMA and FDA approval in 2017 (European Medicines Agency, 2017; Chan et al., 2018).
To view novel therapeutics currently in development, click here.
In March 2018 the FDA approved the second IL-23 antagonist, tildrakizumab for the management of adult patients with moderate-to-severe plaque psoriasis (Ilumya PI, 2018). This was closely followed by European approval in September 2018 (Sun Pharma press release, 2018). In April 2019, risankizumab received European and FDA approval for moderate-to-severe plaque psoriasis (Abbvie press release, 2019a; Abbvie press release, 2019b).
IL-23 plays an important upstream role in the proliferation of IL-17. Because of this, IL-23 cytokine inhibitors have attracted much interest in the long-term treatment of psoriatic arthritis (Sakkas et al., 2019). In 2020, data for the first-ever Phase III studies evaluating the efficacy and safety of a selective IL-23 p19 inhibitor in the treatment of active adult psoriatic arthritis (PsA) were published. The data shows an improvement in psoriatic arthritis signs and symptoms when treated with guselkumab compared to placebo (Deodhar et al., 2020; Mease et al., 2020).
A fully human IgG1 λ monoclonal antibody that binds the p19 subunit of IL-23. Guselkumab was approved in 2017 for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy (Tremfya SPC, 2017; Chan et al., 2018).
Guselkumab binds the p19 subunit of IL-23, blocking its interaction with the IL-23 receptor and hence preventing IL-23-mediated signalling (Tremfya SPC, 2017; Chan et al., 2018).
Learn more about cytokines in psoriasis for further details on the important role of TNFα, IL-12/23, IL-17 and IFNγ in psoriasis pathophysiology.
Approval was based on the results from three randomised, double-blind, active-controlled Phase III studies in adults with moderate-to-severe psoriasis (VOYAGE-1, VOYAGE-2 and ECLIPSE) who were candidates for phototherapy or systemic therapy (Tremfya® SPC, 2017).
Improvement in DLQI:
- At Week 16 change in DLQI was
- -11.2 for GUS (p<0.001 vs. placebo; not stated vs. ADA)
- -9.3 for ADA
- -0.6 for placebo
- At Week 24 change in DLQI was
- -11.6 for GUS (p<0.001 vs. ADA)
- -9.5 for ADA
- At Week 48 change in DLQI was
- -11.8 for GUS (p<0.001 vs. ADA)
- -9.2 for ADA
Drug survival at Week 48:
- Discontinuation for any reason was 8.5% GUS vs. 15.6% ADA (p=0.0053)
- HR: 1.88 (95% CI, 1.19–2.98) p=0.007
- Discontinuation due to lack of efficacy/worsening psoriasis was 0.9% GUS vs. 5.1% ADA (p=0.0017)
- HR: 5.71 (95% CI, 1.68–19.5) p=0.0054
- Discontinuation due to adverse events was 3.0% GUS vs. 2.8% ADA (p=0.297)
VOYAGE-1 extension study
VOYAGE-1 continues with an open-label extension study, running from Week 48 to Week 100. At Week 52, all patients began receiving GUS 100 mg every 8 weeks. Patients initially randomised to adalimumab at Week 0 entered a washout period after their final dose of adalimumab at Week 47 and initiated GUS 100 mg at Week 52 and every 8 weeks thereafter.
The study is due to be completed in 2022 (Janssen, 2019a).
Overall, PASI 75, PASI 90 and IGA response rates at Weeks 52, 100 and 156 remained consistent.
VOYAGE-2 (guselkumab response following withdrawal/a switch to adalimumab)
The VOYAGE-2 study addressed whether benefits observed in patients who responded to guselkumab would be maintained following withdrawal (Reich et al., 2017b).
Clinical outcomes were significantly better in patients who were maintained with treatment compared with those who received placebo.
- Among patients re-randomised to placebo, the median time to loss of PASI 90 response was 15.2 weeks (23 weeks after the last guselkumab dose).
- At Week 48, the PASI 90 response had been sustained in 88.6% of patients in the maintenance group versus 36.8% in the withdrawal (placebo) group.
- Significant differences were observed between the groups in both clinical responses (IGA, PASI) and patient-reported outcomes (DLQI, PSD) at Week 48 (p<0.001) (Reich et al., 2017b).
Switching from adalimumab to guselkumab following non-response was also assessed in the VOYAGE-2 study.
Patients who did not respond to adalimumab (n = 112/228) saw an improvement in responses relative to baseline following switching treatments.
At Week 48, 66.1% of patients switched to guselkumab achieved PASI 90 while 28.6% achieved PASI 100 (Reich et al., 2017b).
VOYAGE-2 extension study
The VOYAGE-2 extension study investigated patients who had been enrolled in VOYAGE-2 but did not achieve PASI 90 at Week 28 (Guenther et al., 2018).
Patients with an inadequate response to adalimumab at Week 28 showed marked improvements in patient reported outcomes (DLQI and PSSD) from Week 28 through Week 100 after switching to guselkumab (Guenther et al., 2018).
Table 8. Guselkumab efficacy results in the VOYAGE-2 extension study (Guenther et al., 2018).
VOYAGE pooled analysis
An analysis of pooled data taken from the VOYAGE 1 and 2 studies assessed the number of patients achieving PASI 100 and compared this to the patient reported achievement of no symptoms or signs though the PSSD.
In the pooled analysis of 1,829 patients:
- 22.9% achieved PASI 100
- 18.9% reported a PSSD symptom score of 0
- 13.3% reported a PSSD sign score of 0
These results highlight the need to consider patient-reported outcomes for symptoms and signs of psoriasis when assessing therapeutic response (Gordon et al., 2018a).
ECLIPSE (guselkumab versus secukinumab)
Results from a further Phase III study, ECLIPSE, were published in December 2018. ECLIPSE is the first head-to-head study to compare efficacy between guselkumab and secukinumab, finding guselkumab to be superior in achieving the primary endpoint, the proportion of patients achieving a PASI 90 response at Week 48 compared to secukinumab (84.5% vs. 70%; p<0.001) (Janssen, 2018).
Professor Andrew Blauvelt discussed the ECLIPSE study and reiterates the importance of head-to-head studies.
POLARIS (guselkumab versus fumaric acid esters)
A recently completed Phase IIIb national, multicentre, randomised, open-label, assessor-blinded, active comparator trial (POLARIS; NCT02951533) compared the efficacy of guselkumab to fumaric acid esters (FAE) in patients with moderate-to-severe psoriasis who are candidates for, and naïve to, systemic treatment in Germany (Eyerich et al., 2018; Thaci et al., 2018a).
In this study, 81.7% of patients receiving guselkumab achieved PASI 90 versus 13.6% receiving FAE at Week 24 (p<0.0001) (Thaci et al., 2018a).
While 27.6% of patients receiving FAE discontinued due to adverse events, no patients receiving guselkumab had to discontinue for this reason. This is consistent with the more favourable safety profile observed for guselkumab than FAE (Eyerich et al., 2018; Thaci et al., 2018a).
DISCOVER-1 and DISCOVER-2 (Guselkumab versus placebo in adult psoriatic arthritis)
The safety and efficacy of guselkumab in adult PsA was assessed in the DISCOVER-1 and DISCOVER-2, phase 3, double-blind, placebo-controlled trials (Deodhar et al., 2020; Mease et al., 2020).
DISCOVER-1 comprised 383 patients with active PsA who had inadequate response to standard therapies (for example NSAIDs, DMARDs or apremilast) and were biologically naïve or had prior TNF inhibitor (TNFi) treatment. DISCOVER-2 comprised 741 biologic-naïve patients with active PsA who also had inadequate response to standard therapies.
In both DISCOVER-1 and DISCOVER-2, patients were randomly assigned 1:1:1 to guselkumab 100mg every four weeks (n=128 and n=245, respectively), guselkumab 100 mg every eight weeks (n=127 and n=248, respectively) or placebo (n=126 and n=246, respectively). The primary endpoint was an ACR 20 at Week 24, which is defined as a 20% improvement in the number of tender and swollen joints as well as a 20% improvement in three of the five other assessment tools: patient global assessment, physician global assessment, functional ability measure, visual analogue pain scale and C-reactive protein (CRP).
In both the DISCOVER-1 and DISCOVER-2 studies, the primary endpoints were achieved. DISCOVER-1 results showed that 59% (n=76) of patients receiving guselkumab every four weeks and 52% (n=66) of patients receiving guselkumab every eight weeks achieved an American College of Rheumatology 20 (ACR 20) response by Week 24 compared to 22% (n=28) of the placebo group (p< 0.001) (Deodhar et al., 2020). Consistent response rates were observed in the subgroups with or without prior TNFi use.
DISCOVER-2 results showed that 64% (n=156) of patients receiving guselkumab every four weeks and 64% (n=159) of patients receiving guselkumab every eight weeks achieved an American College of Rheumatology 20 (ACR 20) response by Week 24 compared to 33% (n=81) of the placebo group (p< 0.001) (Mease et al., 2020).
Several secondary endpoints were also met at Week 24 including: ARC50/70, disease activity (DAS-28 CRP), physical function (HAQ-DI), skin clearance (IGA), improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), quality of life (SF-36 PCS and MCS), resolution of soft tissue inflammation (enthesitis and dactylitis) as well as plaque psoriasis severity (PASI 75/90/100) and structural damage (vdH-S) (Deodhar et al., 2020; Mease et al., 2020).
Safety data for DISCOVER-1 showed serious adverse events in 0.0% (n=0) every four weeks, 3% (n=4) every eight weeks and one death in the placebo group (Deodhar et al., 2020). Safety data for DISCOVER-2 showed serious adverse events occurred in 3% (n=8) every four weeks, 1% (n=3) every eight weeks and 3% (n=7) in the placebo group. No patients died through Week 24 (Mease et al., 2020).
The DISCOVER-1 and DISCOVER-2 studies provide data for the efficacy of guselkumab, every four and eight weeks, in treating in adult patients with active PsA who were biologic-naïve or had previously been treated with TNFi. The studies showed that patients treated with guselkumab showed improvements for joint and skin symptoms, physical function, quality of life and resolved enthesitis/dactylitis relative to placebo. These data support the use of selective inhibition of IL-23 to treat psoriatic arthritis.
In November 2017, Guselkumab was approved in the EU for the treatment of adult patients with moderate to severe plaque psoriasis (European Medicines Agency, 2017). It has also been approved in the United States (TREMFYA SmPC, 2019). Guselkumab is however not currently licensed in the paediatric population.
Guselkumab is self-administered subcutaneously. A Phase III study, ORION has resulted in the FDA approving the first single-dose, patient-controlled, guselkumab injector for the treatment of moderate-to-severe plaque psoriasis in adults in 2019.
ORION required patients to assess their experience of the device at Week 0, 4 and 12, based on six topics:
- feelings about injections
- skin reactions
Patients’ scores were reported on a 0–10 scale, where the higher number indicates an increased positive experience; mean patient satisfaction score was 9.18, and mean score for ease of use was 9.24. In addition, efficacy and safety of the treatment were recorded with 75.8% ofguselkumab patients achieving PASI 75, 50% of guselkumab patients achieving PASI 100 and 80.6% of guselkumab patients achieving IGA 0/1 at Week 16 (compared to 0% of patients receiving placebo). Injection-site reactions were considered mostly mild and transient in nature (Janssen, 2019b; Ferris et al., 2019).
An IgG1 κ humanised monoclonal antibody targeting the p19 subunit of IL-23. Tildrakizumab was approved in by the FDA in March 2018 (for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy systemic therapy) and by the EMA in September 2018 (for the treatment of moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy) (Ilumya® PI; 2018; Sun Pharma press release, 2018).
In these Phase III studies outlined below tildrakizumab was associated with significantly higher proportions of patients with moderate-to-severe psoriasis achieving PASI 75 and clear or minimal PGAs than placebo.
ReSURFACE 1 (tildrakizumab versus placebo)
ReSURFACE 2 (tildrakizumab versus etanercept)
ReSURFACE 2 also showed that tildrakizumab 200 mg was associated with significantly higher proportions of patients achieving PASI 75 and PGA responses at Week 12 than etanercept, an effective anti-TNFα treatment for psoriasis (Reich et al., 2017a).
In patients who were non-responders or partial responders to etanercept in the reSURFACE 2 study, who joined a 2-year extension phase, tildrakizumab 200 mg resulted in PASI 75 responses in almost 9 out of 10 patients after 3 doses and these responses were maintained at Week 148 (Thaci et al., 2018b).
ReSURFACE extension (long-term response of tildrakizumab)
In the long-term extension to reSURFACE 1 and reSURFACE 2, tildrakizumab 100 mg and 200 mg demonstrated maintenance efficacy in the treatment of moderate-to-severe psoriasis for at least two years of treatment (Papp et al., 2018a).
ReSURFACE pooled analysis
Pooled results from the reSURFACE 1 and reSURFACE 2 trials showed that treatment with tildrakizumab resulted in significant and sustained improvements in DLQI (Reich et al., 2018a). Similarly, health-related quality of life outcomes in the reSURFACE 1 study showed that improvements observed at Week 12 were maintained at Week 28 and up to Week 64 (Griffiths et al., 2018). However, not all patients with PASI 100 had DLQI 0/1 (Blauvelt et al., 2019).
A humanised IgG1 monoclonal antibody targeting the p19 subunit of IL-23. Risankizumab was approved by the FDA and EMA in April 2019 for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy (AbbVie, 2019; Skyrizi SPC, 2019).
Risankizumab is under investigation for the treatment of other inflammatory diseases, including Crohn's disease, ulcerative colitis, atopic dermatitis and psoriatic arthritis.
UltIMMa-1 and UltIMMa-2 (risankizumab versus placebo and ustekinumab)
Improvement in DLQI in UltIMMA-1:
- DLQI 0/1 score at Week 16 was 66% for risankizumab- and 43% for ustekinumab-treated patients (p<0.001)
- DLQI 0/1 score at Week 52 was 75% for risankizumab- and 47% for ustekinumab-treated patients (p<0.001)
Results were similar for UltIMMA-2 (Gordon et al., 2018b).
IMMhance, (risankizumab versus placebo, crossover design)
At Week 16 patients randomised to placebo were switched to risankizumab and at Week 28 patients who had achieved sPGA 0/1 were re-randomised to risankizumab (maintenance) or placebo (withdrawal) and followed until Week 104. The primary endpoint of IMMhance from Week 28 to Week 104 was sPGA 0/1 at one year, this was achieved in 87% of the maintenance group and 61% of the withdrawal group (p <0.001) (AbbVie press release, 2017).
Improvement in DLQI in IMMvent (Crowley et al., 2018; Reich et al., 2019c):
- DLQI 0/1 score at Week 16 was 65.8%% for risankizumab- and 48.7% for adalimumab-treated patients (p<0.001)
- DLQI 0/1 score at Week 44 was 66.0% for risankizumab- and 28.6% for adalimumab-treated patients
Risankizumab integrated analyses
An integrated analysis of 1,305 patients included in the three Phase III trials evaluated the efficacy of risankizumab across different subpopulations based on demographics and disease characteristics. The data revealed that the efficacy of risankizumab was comparable to the pooled population for all subpopulations assessed including those with prior biologic failure (Lebwohl et al., 2018b; Strober et al., 2018).
An additional integrated analysis confirmed that risankizumab offered superior efficacy, and a comparable safety profile, to placebo in patients with moderate-to-severe psoriasis. Furthermore, it was also superior to placebo in the treatment of psoriasis with involvement of nails, hands and/or feet, and scalp (Bachelez et al., 2018).
Due to the central role of IL-17A in the psoriatic inflammatory process, development of antibodies to IL-17A has led to new targeted treatments for psoriasis (Yamauchi & Bagel, 2015). Three monoclonal antibodies targetting IL-17A (brodalumab [indirectly, by blocking the IL-17 receptor, IL-17RA], secukinumab and ixekizumab [both by selectively binding IL-17A]) are approved for use in psoriasis.
Click here for further details on the important role of TNFα, IL-12/23, IL-17 and IFNγ in psoriasis pathophysiology.
Table 9. Approvals of IL-17 antagonists for psoriasis (EMA, 2015; FDA, 2015; Yamauchi & Bagel, 2015; EMA, 2016; FDA, 2016; FDA, 2017; EMA, 2017).
A human IgG1 mAb that selectively binds to IL-17A and inhibits its interaction with the IL-17 receptor. Secukinumab was approved in 2015 for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy (Cosentyx SPC, 2015).
Secukinumab has been approved in Europe (EMA, 2015) and in the USA (FDA, 2015) for the treatment of moderate-to-severe plaque psoriasis at a dose of 300 mg (once a week for 4 weeks, then monthly) based on the efficacy and safety results of a series of pivotal Phase III studies. A number of further trials have examined the efficacy of secukinumab in different dosing formats, versus other treatments, and in specific populations and psoriatic conditions such as nail and palmoplantar psoriasis.
Let’s take a look across some of these earlier trials at PASI 75 responses (Figure 33) and the proportion of patients achieving IGA 0/1 (Figure 34).
In a number of these trials secukinumab also showed superior efficacy over placebo and etanercept in PASI 90 and PASI 100 scores (Langley et al., 2014; Lebwohl et al., 2015a; Blauvelt et al., 2015a; Paul et al., 2015b).
CLEAR and CLARITY (secukinumab versus ustekinumab)
SCULPTURE (secukinumab retreatment-as-needed vs. fixed interval dosing and extension study)
The fixed interval regimen showed a clear benefit compared to the retreatment regimen at 52 weeks (Mrowietz et al., 2015). The SCULPTURE study was extended to five years, with PASI 75/90/100 and DLQI 0/1 responses being sustained over five years (Bissonette et all., 2018b).
TRANSFIGURE and GESTURE (secukinumab versus placebo in nail and palmoplantar psoriasis)
The SIGNATURE trial (secukinumab in patients who had previously failed one or more anti-TNF)
Meanwhile, the SIGNATURE open-label, non-comparator study assessed the efficacy and safety of secukinumab over 72 weeks in patients with moderate-to-severe psoriasis who had failed one or more anti-TNF therapies. The data revealed that for patients who had failed one anti-TNF previously, the PASI 75 after 16 weeks was 71%, but for those who had failed multiple therapies this dropped to 48%. For all patients in the study, the PASI 90 at Week 72 was 39% while the most commonly reported adverse event was nasopharyngitis (29.1%) (Warren et al., 2018).
The ARROW trial (secukinumab versus guselkumab in recalcitrant plaques resistant to ustekinumab)
In May 2018, the ARROW trial was announced which will assess the mechanistic superiority of direct IL-17A inhibition with secukinumab versus IL-23 inhibition with guselkumab in treating recalcitrant plaques resistant to ustekinumab (NCT03553823).
Additional analyses and extension trials
FIXTURE and ERASURE additional analyses and extension
These analyses and extension study showed that (Blauvelt et al., 2015c; Gottlieb et al., 2015; Lebwohl et al., 2015a; 2017; Strober et al., 2015; 2016a, 2017b):
- efficacy of secukinumab was sustained for two years
- continuous treatment prevented relapse
- secukinumab resulted in positive patient-reported outcomes (impact, pain and anxiety, HRQoL)
- secukinumab showed significant improvements in psoriasis physical functioning in patients with concomitant PsA
- there was a long-term effect of secukinumab on PASI following discontinuation of treatment
The impact of psoriasis varies with body region affected and the presence of extensive and highly visible lesions affecting exposed areas including the head and neck can be difficult to treat and may result in substantial psychosocial burdens. In a pooled analysis of four Phase III studies, secukinumab provided robust and sustained efficacy for moderate-to-severe psoriasis affecting the trunk, upper limbs and lower limbs (at Week 52, PASI 90/100 responses in 78.4%/71.1%, 67.3%/59.1% and 63.9%/55.3% respectively) (Menter et al., 2016b) and robust and sustained efficacy for head and neck psoriasis (at Week 52, PASI 90/100 responses in 76.0%/68.7%) (Kircik et al., 2016).
Also find out about the ECLIPSE study comparing secukinumab with guselkumab from Professor Andrew Blauvelt.
Quality of life
The social stigma of psoriasis significantly affects quality of life (QoL). Results from a secukinumab Phase II study suggest that in moderate-to-severe psoriasis, patients receiving early treatment with secukinumab demonstrate QoL improvements, with significantly higher Dermatology Life Quality INDEX (DLQI) responses vs. placebo (40.8% vs. 1.6%, p<0.001) (Augustin et al., 2016).
A further pooled analysis of results from four Phase III clinical trials (ERASURE, FIXTURE, FEATURE and JUNCTURE) have also reported positive results, showing improvements in patient QoL with secukinumab. The trials included patients with moderate-to-severe psoriasis who were randomised to receive placebo (n = 282) or secukinumab 300 mg (n = 309) who reported problems at baseline in a questionnaire on mobility, self-care, or usual activities – work, study, housework, family or leisure activities.
Real-world data from the PROSPECT analysis, which included patients prescribed secukinumab, was presented at the 27th European Academy of Dermatology and Venerology (EADV) Congress in Paris, France. The data demonstrated a pronounced improvement in quality of life.
- 59% of real-world patients receiving secukinumab experienced little or no impact of their skin disease on their quality of life at 24 weeks (Thaçi et al., 2018b)
These findings suggest that the goal of helping patients feel better through improved QoL and ability to function is equally important as achieving skin clearance (Feldman et al., 2019).
A pooled analysis of safety data from a large cohort (3,430 patients) across ten Phase III studies demonstrated that secukinumab is well tolerated with a safety profile consistent with previous reports (van de Kerkhof et al., 2016).
- Exposure-adjusted incidence rates for AEs, serious AEs, infections and serious infections were 236.1, 7.4, 91.1 and 1.4 per 100-patient-years for secukinumab 300 mg and 239.9, 6.8, 85.3 and 1.1 per 100-patient-years for secukinumab 150 mg (van de Kerkhof, 2016).
- Only 2.9% of patients discontinued treatment due to AEs (Mease et al., 2015). Nasopharyngitis and upper respiratory tract infections were the most frequently reported AEs and the incidence of inflammatory bowel disease, Crohn’s disease, neutropenia, MACE and malignancy were low (Mease et al., 2015).
Treatment with mAbs may be associated with the production of antidrug antibodies (ADA) that may impact drug pharmacokinetics, diminish response and lead to hypersensitivity reactions. A recent analysis indicated that the immunogenicity of secukinumab across six Phase III clinical trials was low, with only 0.4% of secukinumab treated patients developing treatment-emergent ADAs and these were not associated with loss of efficacy or issues of clinical concern (Reich et al., 2017c).
A humanised IgG4 monoclonal antibody with neutralising activity against IL-17A. Ixekizumab was approved in 2016 for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic or phototherapy (Taltz SPC, 2016).
Phase III development of ixekizumab involved 3,866 patients – making it one of the largest Phase III development programmes in moderate-to-severe plaque psoriasis so far (Gordon et al., 2016).
UNCOVER (ixekizumab versus placebo or etanercept)
In addition, an sPGA score of 0 or 1 was achieved significantly more with ixekizumab every 2 weeks (81.8%, 83.2%, and 80.5%) and ixekizumab every 4 weeks (72.9%, 75.4%, and 76.4%) compared with placebo (3.2%, 2.4%, and 6.7) in all 3 trials and etanercept (36% and 41.2 %) in UNCOVER 2 and UNCOVER 3 (Shelton et al., 2019). Follow-up data from the UNCOVER 3 trial has showed the at PASI 75 was maintained in 94.1% of patients at week 108 (Blauvelt et al., 2017c) and 80.5% of patients at Week 156 (Leonardi et al., 2018).
UNCOVER-A showed that there was similar pharmacokinetics and efficacy of ixekizumab whether administered subcutaneously by prefilled syringe or autoinjector (Callis Duffin et al., 2017).
An integrated analysis of UNCOVER-2 and -3 evaluated absolute PASI outcomes relative to other measures of response (Puig et al., 2019). Response was assessed throughout 12 weeks as the proportion of patients achieving absolute PASI band cut-offs who also reached established response criteria. Most PASI band ≤2 responders also achieved PASI 90 (70.1–100%), sPGA (0/1) (91.3–96.1%), DLQI (0/1) (63.0–67.7%), Patient Global Assessment of Disease Severity (0/1) (80.3–86.7%), and Itch Numeric Rating Scale improvement ≥4 (87.2-87.6%). Agreement sharply decreased for less stringent PASI criteria. These data indicate that PASI ≤2 represents significantly meaningful clinical and health-related quality of life improvements and may be a suitable treatment target for moderate-to-severe plaque psoriasis
Find out the importance of absolute PASI scores from Professor Ulrich Mrowietz.
IXORA-S (ixekizumab versus ustekinumab)
IXORA-R (ixekizumab versus guselkumab)
The IXORA-R head-to-head trial, designed to evaluate superiority between ixekizumab and guselkumab is currently on-going. It is the first head-to-head trial between an anti-IL-17 and anti-IL-23 therapy using the PASI 100 score as a primary endpoint. At 12 weeks, ixekizumab met the primary and secondary endpoints and 24 week data is expected in 2020 (Lilly, 2019a).
Find out more about this head-to head study from Professor Andrew Blauvelt
Quality of life
A small–scale quality of life study for patients from a single US dermatology referral practice indicated that the DLQI 0–/1 score improved to 67% at 12 months from 21% prior to treatment, with a significant decrease in disease severity (Leonardi et al., 2019).
Work productivity versus placebo and etanercept
It has been proposed that therapies reducing the symptoms and severity of psoriasis may improve work productivity and quality of life. Assessment of work productivity in patients from UNCOVER-1, -2 and -3 revealed greater short- and long-term improvements (Week 12 and Week 60, respectively) in work productivity vs. placebo and etanercept (Armstrong et al., 2016b).
The safety profile of long-term ixekizumab treatment with up to 3 years of continuous use remains consistent with previous reports, with no evidence of cumulative toxicity (Armstrong et al., 2018).
A recombinant fully human monoclonal immunoglobulin IgG2 antibody that binds with high affinity to human IL-17RA. Brodalumab was approved in 2017 for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy (Kyntheum SPC, 2017).
Brodalumab is considered to have a rapid onset of efficacy, with an estimated time for 25% of patients to achieve PASI 75 at 2.1 weeks, compared with 4.8 weeks for ustekinumab (Blauvelt et al., 2017a).
At Week 52, the majority of patients maintained sPGA 0/1 (63/61% of 210 mg brodalumab dose group and 43/45% of the 140 mg group) and 94/93% of patients who switched from placebo to brodalumab (210 mg dose) and 91/82% of those who switched from ustekinumab reached PASI 75 in AMAGINE-2/3 (Lebwohl et al., 2015b).
At Week 120, sPGA 0/1 was reached in 76.5% of brodalumab 210 mg patients, with PASI 75, 90 and 100 response rates of 88.4%, 76.8% and 56.2% (Menter et al., 2018).
Professor Andrew Blauvelt discussed when a rapid onset of efficacy is an important consideration in treatment selection.
Quality of life
The AMAGINE trials used the psoriasis symptom inventory (PSI) to assess patient-reported outcomes. A PSI response (reduction of ≤8 points from baseline score) was achieved in 61% and 53% of patients in 210 mg and 140 mg brodalumab patients in AMAGINE-1 at 12 weeks and 4% of placebo patients. In AMAGINE-2 and -3, 68 and 61% of brodalumab 210 mg patients achieved PSI response in comparison to 55 and 52% of patients treated with ustekinumab and 6 and 7% with placebo.
Brodalumab development was halted in 2015 due to the emergence of a suicide signal (four patients completed suicide in the psoriasis clinical trials). In an analysis of five clinical trials involving 4,464 patients with 9,162 patient-years of brodalumab exposure, a lack of evidence was reported linking brodalumab to suicidal ideation (Lebwohl et al., 2018c). As a precaution, brodalumab in the United States is available only through a risk evaluation and mitigation strategy (REMS) and in Europe suicidal ideation and behaviour is listed as a special warning and precaution for use (Kyntheum SPC, 2017).
Risk of infection
A large meta-analysis of TNFα antagonists in psoriasis/psoriatic arthritis demonstrated a significant increase in the risk of infection (odds ratio [OR] 1.18; 95% Cl 1.05–1.33) (Dommasch et al., 2011).
Because the main physiological function of IL-17 is protection from infectious diseases, safety concerns associated with IL-17 inhibitors include an increased risk of infections especially infections due to Candida species (Lønnberg et al., 2014).
A recent systematic review of the published clinical trial data assesses the potential of IL-17 inhibitors to promote Candida infections in patients with psoriasis or psoriatic arthritis (Saunte et al., 2017). The analysis describes that Candida infections were reported in 4.0% of patients treated with brodalumab, 2.1% with secukinumab, and 3.3% with ixekizumab, compared with 0.3%, 2.3% and 0.8% of those assigned to placebo, ustekinumab or etanercept, respectively. Although the incidence of Candida infection was found to be increased by a small degree during treatment with IL-17 inhibitors, all patients undergoing such treatment should be monitored for fungal infection and treated as necessary (Saunte et al., 2017).
A French, nationwide, retrospective study has recently shown that tuberculosis remains an issue in patients treated with TNFα antagonists despite adherence to tuberculosis prevention guidelines (Guinard et al., 2016). The researchers involved in this study suggest that prophylactic measures do not fully prevent tuberculosis and rapid initiation of effective anti-tuberculosis treatment is essential even in patients with negative mycobacteriological examination who present with symptoms suggestive of mycobacterial infection (Guinard et al., 2016).
In contrast, IL-17 inhibitors do not seem to increase the risk of tuberculosis. The risankizumab IMMHANCE study enrolled 31 subjects with latent tuberculosis, none of whom received prophylaxis during the study. None developed active tuberculosis during a mean of 55 weeks risankizumab treatment (Skyrizi SPC, 2019).
Rates of malignancy
A large meta-analysis of TNFα antagonists in psoriasis/psoriatic arthritis demonstrated a non-significant increase in the risk of malignancies (OR 1.48; 95% Cl of 0.71–3.09) (Dommasch et al., 2011).
Development of malignancies has also been associated with IL-17 inhibitors (Lønnberg et al., 2014).
Rates of major adverse cardiovascular events
As patients with psoriasis are at an increased risk of cardiovascular diseases, there has been interest in the rates of major adverse cardiovascular events (MACE) with treatments for psoriasis. A meta-analysis of MACE rates in randomised controlled trials for psoriasis found one case of MACE in 3,858 patients treated with TNFα inhibitors, 10 cases of MACE in 3,179 patients treated with IL-12/23 inhibitors (ustekinumab and briakinumab) and no cases in 1,474 patients receiving placebo (Ryan, 2011). These results did not reach statistical significance but highlight a possible safety issue (Leonardi, 2014).
The PSOLAR disease-based registry
Analyses of Psoriasis Longitudinal Assessment and Registry (PSOLAR), a large, international, long-term, prospective, disease-based registry that assesses AEs and efficacy in 12,095 psoriasis patients treated with systemic therapies, have demonstrated that (Gottlieb et al., 2014; Kalb et al., 2015; Papp et al., 2015b; Strober et al., 2016b):
Another potential safety signal associated with IL-17 inhibitors is the increased risk of other immune-mediated comorbidities such as inflammatory bowel disease (IBD) (Lønnberg et al., 2014).
No increased incidence of inflammatory bowel disease (IBD) has been reported among patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis treated with the IL-17 inhibitor secukinumab in the clinical trial program (Schreiber et al., 2016). During the 12- to 16-week studies of secukinumab that included 2,877 patients, there was one case of Crohn's disease and one case of ulcerative colitis among patients with psoriasis compared with none among 793 patients receiving placebo.
In longer-term studies (52 to 112 weeks), rates of inflammatory bowel disease remained low. Among 3,430 psoriasis patients treated with secukinumab, the exposure-adjusted incidence rate of Crohn's disease was 3 per 100 patient-years (95% CI 0.02-0.32) (Schreiber et al., 2016).
Dose reduction as a safety strategy
One strategy which may potentially avoid the long-term immunosuppressive effects and associated risks of biologic therapy is dose reduction once patients reach maintained symptom control.
Results from a multicentre, pragmatic, randomised controlled trial recently highlighted the possibilities of this strategy as 120 patients with a low level of disease (PASI ≤5 and DLQI ≤5 for the last 6 months) were randomised to either remain on their usual dose of therapy or to receive a stepwise reduction in biologic doses by prolonging treatment intervals. Patients were monitored every 3 months and returned to the previously effective dose in the case of flare-ups (PASI >5 and/or DLQI >5) (Atalay et al., 2018).
The study observed a slightly higher PASI score at Month 12 for those receiving a reduced dose (3.4 ± 1.8) in comparison to the usual dose group (2.2 ± 1.7), giving a mean difference, after correcting for baseline PASI, of 1.1 (95% CI 0.574–1.722). The study was designed to include a 0.5 margin for noninferiority, meaning the dose reduction was inferior in comparison to the usual care. However, during a presentation of the results at the European Academy of Dermatology and Venereology (EADV) Congress in 2018, Dr van den Reek suggested this may have been too restrictive in hindsight and that the accepted minimal clinically important difference is 3.2 points.
- Despite the results suggesting dose reduction was inferior, the strategy did appear to be successful; at Month 12, 50% of patients in the dose-reduction arm were well maintained at 50% of their original dose
- 17% were receiving 67% of their original dose
Importantly, at Month 12:
- no severe adverse events had been reported
- there was no significant difference in DLQI scores between the two groups (p=0.1)
- there was no significant difference in persistent flares (p=0.5)
Future analysis of the cost-effectiveness and investigations surrounding possible biomarkers of response success are needed to fully understand the possibilities of this strategy.
The CONDOR-X extension trial
The CONDOR-X extension trial is currently ongoing and will provide insights into the effects of dose reduction after the 12-month period (Atalay et al., 2018; Dermatology News, 2019).
A biosimilar (otherwise known as a generic biologic) is defined as ‘a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product)’ (EMA, 2014).
The patents for many of the biologics currently used to treat psoriasis will expire over the next few years, opening the door for biosimilars, and as a result this topic has become the subject of significant discussion and debate amongst dermatologists (Puig et al., 2015). The possibility of reducing costs and extending biologic coverage to a greater number of patients is one of the most attractive aspects of the arrival of biosimilars (Puig et al., 2015).
Biologics are large and highly complex protein molecules, so development and production are highly influenced by multiple factors including glycosylation and the presence of impurities (Blauvelt, 2016a). Rigorous pre-clinical analytical assessments to determine similarity to the originator biologic are critical and are considered to be the foundation for regulatory approval of biosimilars (Blauvelt, 2016a).
For a biosimilar to be approved, it must demonstrate that it has a highly similar structure, biological activity, efficacy, safety, and immunogenicity profile as that of the originator molecule (EMA, 2014).
Clinical practice considerations
Although the approval of biosimilars is now a reality for dermatologists, in order to successfully and confidently integrate biosimilars into clinical practice, physicians must continue to practice strict pharmacovigilance and understand factors such as (Feldman, 2015b):
- variation in innovator/reference products
- extrapolation of data, naming and labelling
- interchangeability and automatic substitution
In some countries a proportion of prescriptions have to be for biosimilar rather than originator treatments. Find out more about this from Professor Ulrich Mrowietz.
While infliximab has been approved for the treatment of moderate-to-severe plaque psoriasis for over a decade, recent years have seen the approval of biosimilar versions of the infliximab molecule (GaBI online, 2018). The first biosimilar version of a biologic to be approved and enter the markets for psoriasis was Remsima® (a biosimilar of infliximab) (EMA, 2013; Puig et al., 2015).
Table 10. Infliximab biosimilars approved or in clinical development for chronic plaque psoriasis (Adapted from Gisondi et al., 2019)
The introduction of infliximab biosimilars could lead to considerable drug cost-related savings across the licensed disease areas (Jha, 2015).
Two etanercept biosimilars are currently approved in Europe with several more under development or currently seeking approval (Benepali® SPC, 2018; Erelzi® SPC, 2018).
Table 11. Etnacercept biosimilars approved or in clinical development for chronic plaque psoriasis (adapted from Gisondi et al., 2019)
For a number of years, adalimumab has been the highest grossing drug in the world and so is a prime candidate for biosimilar development. Several biosimilars are under development with approvals gained for some in both Europe and the USA.
Six adalimumab biosimilars have already been approved in Europe.
Table 12. Adalimumab biosimilars approved or in clinical development for chronic plaque psoriasis (adapted from Gisondi et al., 2019).
Ustsekinumab is indicated for the treatment of psoriasis, psoriatic arthritis and Crohn’s disease. In recent years, ustekinumab has brought growing revenues and in 2016 achieved global sales of around US$ 3.2 billion, with further sales growth also anticipated (Formycon, 2019). A number of companies are developing ustekinumab biosimilars with Phase I studies planned in late 2019.
Biologic treatments in clinical development
Developments in understanding the immunological pathways involved in psoriasis pathogenesis have provided insights into potential new targets and have led to the development of novel biological treatments.
Find out from Professor Andrew Blauvelt about the treatments currently in development that dermatologists are excited about.
While the first IL-23 antagonist, guselkumab, was approved for use in moderate-to-severe plaque psoriasis in 2017, additional IL-23 antagonists remain under development (Tremfya® SPC, 2017).
The IL-23 antagonist mirikizumab is currently in Phase III trials assessing its efficacy in psoriasis and Crohn’s disease (Gisondi et al., 2019).
A Phase II trial has been completed demonstrating that mirikizumab improves patient-reported signs and symptoms of psoriasis by Week 16. (Reich et al., 2018b). Phase III trials for ulcerative colitis and psoriasis are ongoing (ClinicalTrials.gov, mirikizumab).
Table 13. Efficacy and safety of mirikizumab in a Phase II trial.
Bimekizumab is a potent and selective biologic in Phase III of clinical development. Bimekizumab neutralises both the IL-17A and IL-17F pro-inflammatory cytokines. In preclinical experiments the simultaneous neutralization of both IL-17A and IL-17F resulted in a higher suppression of cytokine responses and neutrophils chemotaxis than the neutralization of either cytokines (Gisondi et al., 2019).
In the BE ABLE 1 Phase IIb trial, PASI 90 and PASI 100 were achieved with bimekizumab at Week 12 by 75% and 60% of those treated with 160 mg with loading dose and by 79.1% and 55.8% of those treated with 320 mg (Papp et al., 2018b).
Humanised monoclonal antibody against IL-17A, netakimab has completed a multicentre, randomised, double-blind, placebo-controlled Phase II trial (Gisondi et al., 2019). In this trial 92.68% of patients with plaque psoriasis who received the 120 mg dose achieved PASI 75 by Week 12 (Samtsov et al., 2017). The drug is now in phase III of development (NCT03390101).
Novel molecule M1095 is a nanobody targeting IL-17A and IL-17F. Nanobodies are small antibody fragments derived through recombinant gene technology. Nanobodies are more stable than conventional antibodies. They also have an excellent tissue penetration and exhibit a low immunogenicity (Steeland et al., 2016). M1095 completed a phase I trial and a phase II trial is ongoing (NCT03384745).
Other biologics have also been developed, with novel mechanisms of action.
Humanized monoclonal antibody neihulizumab (AbGn- 168H) targets CD162, which is expressed on activated T-cells, which then causes apoptosis of activated T lymphocytes. No results for Neihulizumab were published, despite the fact it has has undergone phase II trials for psoriasis and psoriatic arthritis, Two trials on ulcerative colitis and graft versus host disease (GVHD) are currently active (Gisondi et al., 2019).
Namilumab is an inhibitor of granulocyte-macrophage colony stimulating factor (GM-CSF). In a recent phase II multicentre, randomised, double-blind, placebo-controlled clinical trial in plaque psoriasis, there was no significant difference between percentage of patients reaching PASI 75 at 12 weeks with placebo versus namilumab (Papp et al., 2019).
Transduction of many of the receptors involved in cytokine signalling pathways in psoriasis requires association with kinases from the Janus kinase (JAK) family, which consists of four members: JAK1, JAK2, JAK3 and TYK2. JAK inhibitors can, therefore, interfere with cytokine signalling and suppress cellular activation and the inflammatory pathways involved in psoriasis (Thomas et al., 2010; Ghoreschi et al., 2011b; Sohn et al., 2013; Belge et al., 2014).
Find out from Professor Andrew Blauvelt about the treatments currently in development that dermatologists are excited about.
Tofacitinib is a JAK inhibitor approved for the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis in the USA and is one of the most advanced and well-studied JAK inhibitors in clinical development for psoriasis (Belge et al., 2014; Xeljanz® PI, 2018).
OPT Pivotal-1, -2 and open-label extension
Long-term data from OPT Pivotal-1 and -2 demonstrated sustained efficacy over two years. Psoriasis patients who received tofacitinib (5 mg or 10 mg, both bd), achieved PASI 75 at Week 16 in higher percentages: 5 mg 39.9%; 10 mg 59.2% (OPT Pivotal-1) and 5 mg 46.0%; 10 mg 59.6% (-2), compared with those who received placebo; 6.2% (OPT Pivotal-1) and 11.4% (-2) (Papp et al., 2015c). Results from OPT Pivotal-1 and -2 further suggested that efficacy is reduced in patients with higher BMI and those with prior biologic experience, and, achieving a PASI 50 response after 8 weeks of treatment is a reliable predictor of achieving a PASI 75 response at Week 16 (Menter et al., 2016c; Tan et al., 2017).
The results showed that tofacitinib 10 mg bd (but not 5 mg bd), was superior to placebo and not inferior to etanercept at Week 12, as assessed by PASI 75 response rates (39.5% for 5 mg, 63.6% for 10 mg, 58.8% for etanercept and 5.6% for placebo) and Physician Global Assessment scores (Bachelez et al., 2015).
In addition, a recent meta-analysis, which included seven randomised controlled trials involving 3,743 patients, showed that tofacitinib 10 mg twice daily was effective in treating chronic plaque psoriasis as measured by PGA responses, PASI 75, and PASI 90 (Tian et al., 2019).
Tofacitinib treatment results in significant improvements across multiple patient-related outcomes and these improvements were maintained over 52 weeks (Valenzuela et al., 2016; Feldman et al., 2016).
Improvements with tofacitinib were significantly greater than placebo and comparable to etanercept (by Week 12, 47.3% tofacitinib and 43.6% etanercept had a DLQI score of 0/1 vs. 7.8% for placebo [p<0.0001 both comparisons]). Improvements in itch were greater and more rapid with tofacitinib than placebo and etanercept (p<0.0001 and p<0.005) with effects observed after just one day of treatment (Valenzuela et al., 2016).
Baricitinib is an oral JAK1/JAK2 inhibitor that has been approved for the treatment of rheumatoid arthritis and is currently in development for other immune-mediated disorders including psoriasis (Papp et al., 2016d; Olumiant® PI, 2018; Olumiant® SPC, 2018).
Efficacy and safety
Efficacy and safety of baricitinib were investigated in a Phase II trial (Papp et al., 2016d).
Ruxolitinib is a topical JAK1/JAK2 inhibitor that has been approved for the treatment of myeloproliferative disease and is currently being tested in Phase II trials for psoriasis (Fragoulis et al., 2019).
PF-04965842, itacitinib and solcitinib
These are selective JAK-1 inhibitors which have also been found to be more effective than placebo in Phase II psoriasis trials (Fragoulis et al., 2019).
Mechanism of action
Tyrosine kinase 2 (TYK2) associates with the receptors for several cytokines including IL-12, IL-23, IL-6, IL-10 and type 1 interferon (Sohn et al., 2013). Blocking TYK2 is believed to inhibit the signal transducer and activator of transcription (STAT) dependent pathway resulting in decreased production of IL-12 and IL-23.
Results from a Phase II, double-blind trial of the TYK2 inhibitor BMS-986165 revealed treatment with the TYK2 inhibitor was more effective than placebo at reducing PASI score in patients with moderate to severe psoriasis. The study randomised 267 patients to receive one of five doses of BMS-986165 (3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, 12 mg daily), or a matching oral placebo.
The percentage of patients achieving the primary endpoint, a PASI score reduction of 75% or greater from baseline, increased as the dose of BMS-986165 increased:
- Percentage of patients achieving a ≥75% reduction in PASI score at Week 12:
Adverse events were reported in 51% of the placebo group and 55–80% of patients in the active treatment groups, with 5 serious adverse events reported across all 3 mg active treatment groups and the placebo group.
The results of the Phase II study have shown promise for the future of TYK2 inhibitors, but larger studies are required to determine the durability of the effects and safety of BMS-986165 (Papp et al., 2018c).
Find out from Professor Andrew Blauvelt about TYK2 inhibitors and other treatments currently in development that dermatologists are excited about.
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