FormalPara Key Summary Points

Why carry out this study?

Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening autoinflammatory skin disease; standard treatment guidance for this condition often follows that of plaque psoriasis, despite limited evidence on the efficacy of anti-psoriatic drugs, including biologics, in GPP.

Spesolimab is effective in treating GPP flares, but the relapsing nature of GPP means that there is an unmet need for treatments to prevent the occurrence of GPP flares, which the Effisayil™ 2 study (NCT04399837) will assess.

What was learned from the study?

Effisayil™ 2 is the first placebo-controlled study in patients with GPP that focuses on flare prevention, through maintenance treatment with subcutaneous spesolimab.

The efficacy and safety data from Effisayil™ 2 will provide valuable information on the use of maintenance spesolimab treatment in preventing GPP flares and delivering sustained symptom management.

Introduction

Generalized pustular psoriasis (GPP) is a rare, severe, autoinflammatory skin disease characterized by recurrent flares of widespread erythema and edema with sterile pustules that may coalesce to form lakes of pus [1,2,3,4]. During a GPP flare, patients may experience fever, leukocytosis, fatigue, and painful skin [1, 2, 5, 6]. GPP may also lead to potentially life-threatening complications including kidney, liver, respiratory and heart failure, and sepsis [1, 5, 7]. Standard treatment guidance for GPP often follows that of plaque psoriasis, despite limited evidence on the efficacy of anti-psoriatic drugs, including biologics, in GPP [8]. In Japan, Taiwan, and Thailand, a number of biologic agents targeting pro-inflammatory pathways associated with GPP have been approved for patient use, but the rarity of the disease means that their approval is based on a limited number of open-label clinical trials with small numbers of participants [2, 9,10,11,12].

In an open-label, proof-of-concept study (NCT02978690), patients experiencing a GPP flare became clear or almost clear of GPP by Week 4 post treatment with a single dose of spesolimab (a humanized anti-interleukin-36 receptor monoclonal antibody) [14]. After this, the Effisayil™ 1 study (NCT03782792) was the first randomized clinical trial to investigate a targeted treatment for GPP, and reported that adult patients with a GPP flare treated with spesolimab achieved rapid pustular and skin clearance [15]. The results from this study were integral to the recent approval of spesolimab by the US FDA as a first treatment option for GPP flares [16]. The relapsing nature of GPP (recurrent flares or persistent disease with intermittent flares) highlights the need to develop treatments to prevent flares [3], with a recent survey revealing that among dermatologists whose patients experience frequent flares, 67% felt that currently available treatments fail to adequately prevent new flares [13].

The aims of the Effisayil™ 2 study were to assess whether maintenance treatment with subcutaneous (SC) dosing regimens of spesolimab prevent the occurrence of GPP flares, and to determine the optimal dosing regimen of spesolimab SC maintenance treatment.

Methods

Study Design

Effisayil™ 2 (NCT04399837) is a phase 2, multicenter, randomized, parallel-group, double-blind, placebo-controlled, dose-finding study to evaluate the efficacy and safety of spesolimab in preventing GPP flares in patients with a history of GPP. Patients will be randomized 1:1:1:1 to three groups receiving a SC 600-mg loading dose of spesolimab followed by a 300-mg maintenance dose administered every 4 weeks (q4w) or every 12 weeks (q12w), or a 300-mg loading dose of spesolimab followed by a 150-mg maintenance dose administered q12w, and one group receiving placebo, for 48 weeks (Fig. 1). To maintain treatment blinding, patients in all treatment arms will receive one loading dose, administered as four injections of 150-mg spesolimab or placebo at Week 1/Day 1, followed by a maintenance dose administered as two injections of 150-mg spesolimab or placebo at subsequent dosing visits in the 4-week schedule. Patients who complete the treatment period in this study will be offered the option of entering into an ongoing open-label extension (OLE) study to assess the long-term safety and efficacy of spesolimab treatment in patients with GPP (NCT03886246), providing they agree to participate in the OLE study and meet the OLE study eligibility criteria.

Fig. 1
figure 1

Overall study design, with loading and maintenance phase treatment arms, and handling of GPP flares during the randomized maintenance treatment period. *GPP flare defined as an increase in GPPGA total score of ≥ 2 from baseline and the pustular component of GPPGA of ≥ 2. †Administered 1 week after initial treatment with OL spesolimab in response to a GPP flare if patients meet qualifying criteria: for patients with GPPGA total score of ≥ 3 and a pustular component of GPPGA of ≥ 2 at baseline, if the GPPGA total score is ≥ 2 and the pustular component of GPPGA is ≥ 2; and for patients with GPPGA total score of 2 and a pustular component of GPPGA of ≥ 2 at baseline, if the pustular component of GPPGA is ≥ 2. ‡12 weeks after initial treatment with OL spesolimab in response to a GPP flare. §Other medication for GPP may be prescribed, but intensified spesolimab maintenance should be attempted first. Patients may be treated with other medication for GPP at the investigator’s discretion, but the patient will be discontinued from any further study drug. GPP generalized pustular psoriasis, GPPGA Generalized Pustular Psoriasis Physician Global Assessment, IV intravenous, LD loading dose, OL open-label, OLE open-label extension, q4w every 4 weeks, q12w every 12 weeks, R randomization, SC subcutaneous

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Randomization

Randomization of patients will be conducted according to the use of systemic GPP medications at randomization, region (Japan versus outside of Japan) and age at screening (adults aged 18–75 years versus adolescents aged 12– < 18 years). The randomization list will be generated using a pseudo-random number generator so that the resulting treatment will be both reproducible and non-predictable. An Interactive Response Technology will be used to screen eligible patients, perform drug assignment, manage initial/re-supply ordering of drug supplies and handle emergency un-blinding. The sponsor will remain blinded to the randomized treatment assignments until the last patient has completed or discontinued early from the 48-week treatment period of the trial and the database is considered ready for unblinding to perform the primary analysis of the trial.

Patient Population

Study participants will be male or female aged ≥ 12–75 years at screening and weigh ≥ 40 kg, with a known and documented history of GPP as per the European Rare and Severe Psoriasis Expert Network (ERASPEN) criteria [3], regardless of IL36RN mutation status, with at least two prior presentations of GPP flares with fresh pustulation. At screening and randomization, patients must present with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 (clear or almost clear). The GPPGA score is a minimally modified version of the Physician Global Assessment (PGA) that is widely used and understood by dermatologists, created with the help of leading global experts in GPP and psoriasis vulgaris [17]. Patients not on concurrent GPP treatment at randomization must have had at least two flares within the past year, at least one of which must have been associated with fever, elevated C-reactive protein or white blood cell count, asthenia, and/or myalgia. Patients on concurrent GPP treatment until shortly before randomization (≤ 12 weeks prior to randomization) must have a history of flaring during concurrent treatment, or after dose reduction or discontinuation of concurrent treatment. Those on concurrent treatment with retinoids, methotrexate and/or ciclosporin must stop this treatment on the day of randomization. At randomization, participants will be tested for mutations in the IL36RN, CARD14, and AP1S3 genes to evaluate the potential influence of these mutations on disease activity and/or spesolimab efficacy, but mutation status will not factor into decisions regarding patient inclusion or randomization. A full list of inclusion and exclusion criteria is provided in Table 1. Participants will be recruited in 34 countries and areas across global regions: Argentina, Australia, Belgium, Bulgaria, Chile, China, Columbia, Croatia, Czech Republic, Egypt, France, Georgia, Germany, Greece, Italy, Israel, Japan, Republic of Korea, Malaysia, Mexico, the Netherlands, Philippines, Poland, Russia, Singapore, South Africa, Spain, Thailand, Tunisia, Turkey, Taiwan, Ukraine, USA, and Vietnam.

Table 1 Patient inclusion and exclusion criteria
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A total of 120 patients are planned to be recruited to achieve a power of over 90% for at least one successful dose of spesolimab in the 300-mg q4w and 300-mg q12w maintenance dose groups versus placebo for the primary and key secondary endpoints.

Treatment Administration in Response to Patients Experiencing a GPP flare

If a patient experiences a first GPP flare, defined as an increase in GPPGA total score by ≥ 2 from baseline and the pustular component of GPPGA ≥ 2, during the randomized maintenance treatment period of this study, an open-label intravenous (IV) dose of 900-mg spesolimab will be administered (Fig. 1). After treatment with open-label IV 900-mg spesolimab in response to a GPP flare, a patient may qualify to receive a second dose of open-label IV 900-mg spesolimab 1 week later if flare symptoms persist, as defined by criteria shown in Fig. 1. Patients who respond to one or two doses of open-label IV 900-mg spesolimab before Week 34 of randomization will be switched back to maintenance treatment (open-label SC spesolimab) at 12 weeks after the first 900-mg IV dose, either in this study or as part of the ongoing OLE study.

Handling of Investigator-Prescribed Other Medication for GPP

During the randomized maintenance treatment period, it is strongly recommended that investigators avoid prescription of medication currently used for the treatment of GPP. During the randomized maintenance treatment period, and during the first 4 weeks following spesolimab treatment in response to a GPP flare, if a patient is given any investigator-prescribed medication other than spesolimab for treatment of GPP symptoms or worsening of GPP clinical status, the patient will be discontinued from any further study drug (Fig. 1). The exception to this is that patients may be prescribed topical treatments/topical corticosteroids, methotrexate, ciclosporin and retinoids, at the discretion of investigators, 4 weeks following a dose of open-label IV 900-mg spesolimab in response to a GPP flare, and also during the open-label maintenance treatment period.

Study Objectives

The aims of the Effisayil™ 2 study are to investigate whether administration of a maintenance dosing regimen of spesolimab prevents the occurrence of GPP flares, and to evaluate which of the three investigated maintenance dosing regimens optimally achieves this aim. Effisayil™ 2 includes both a dose-finding and a confirmatory component; the primary objective is to evaluate the dose–response relationship for three SC dosing regimens of spesolimab versus placebo on the primary endpoint, and demonstrate a non-flat dose–response curve, which would indicate a benefit of spesolimab over placebo. If the primary objective is met, the secondary objective is to demonstrate superiority versus placebo for each of spesolimab 300-mg q4w and spesolimab 300-mg q12w regimens for the primary and key secondary endpoints. Further objectives are to evaluate the safety and tolerability of multiple SC doses of spesolimab in patients with a history of GPP, and to evaluate the safety and efficacy of an IV dose of spesolimab (with the option of a second dose) for treating patients with onset of a GPP flare.

Study Endpoints

The primary efficacy endpoint of the study is time to first GPP flare (increase of ≥ 2 in GPPGA total score from baseline and GPPGA pustulation subscore ≥ 2) up to Week 48. The key secondary efficacy endpoint is the occurrence of at least one GPP flare up to Week 48. Other secondary endpoints are listed in Table 2, and outcomes measures for assessment of efficacy are listed in Table 3.

Table 2 Study endpoints
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Table 3 Outcome measures for assessment of efficacy
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Safety and Adverse Event Assessment

Safety will be assessed descriptively based on treatment-emergent adverse events, adverse events (AEs) of special interest, serious AEs and clinical laboratory values. Intensity of AEs will be assessed using the Rheumatology Common Toxicity Criteria version 2.0, physical examination, vital signs (blood pressure, pulse rate, body temperature), electrocardiogram and immunogenicity (anti-drug antibodies).

Statistical Analysis

The primary analysis for the primary objective will consist of a multiple comparison and modelling (MCPMod)-based testing with respect to a non-flat dose–response curve, to evaluate several possible dose–response models and to identify the best-fitting model or subset of models. The generalized MCPMod procedure for time-to-event endpoints is based on the log hazard ratio of the active doses versus placebo, obtained via a stratified Cox regression model on the time to first GPP flare up to Week 48, stratified by the systemic concomitant use of GPP medications at randomization. The primary analysis for the secondary objective on the time to first GPP flare up to Week 48 for each dose of spesolimab versus placebo will be tested using the stratified log-rank test, stratified by the systemic concomitant use of GPP medications at randomization. In addition to the GPP flare definition per protocol, any use of investigator-prescribed spesolimab or other non-spesolimab medication for GPP will be considered to indicate the onset of a flare. In the event of missing data, only observed GPP flare events will be included in the analysis for the primary endpoint.

Ethics

The study will be conducted in compliance with the ethical principles laid down in the Declaration of Helsinki, in accordance with the International Conference on Harmonisation (ICH) Harmonised Guideline for Good Clinical Practice (GCP), relevant Boehringer Ingelheim Standard Operating Procedures, the EU directive 2001/20/EC, the Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 1997), and other relevant regulations.

Discussion

Rationale for Conducting the Trial

GPP is a disease with a considerable clinical burden for patients, substantially impacting their quality of life [18]. While spesolimab has recently been approved for the treatment of GPP flares [16], current therapies do not completely resolve symptoms, prevent reoccurrence of flares, or provide sustained efficacy. Furthermore, the majority of therapies for treatment or prevention of GPP flares are based on anecdotal retrospective case reports. Preventing GPP flares with a well-tolerated and effective treatment that primarily targets the key inflammatory pathway operating in GPP, will meet a high unmet need to have a proven treatment available for patients with recurrence of this disruptive condition, which is associated with high morbidity and associated mortality. Results of the Effisayil™ 1 study showed that spesolimab is efficacious in the treatment of GPP flares [15]. In this placebo-controlled trial design, Effisayil™ 2 will provide data on the efficacy, sustainability of efficacy, safety, and tolerability of spesolimab in preventing the occurrence of GPP flares in patients with a history of recurrent GPP flares. These data will also build on the results of Effisayil™ 1 by gathering further data on the treatment of flares with open-label IV spesolimab.

Rationale for Patient Selection

The Effisayil™ 2 study will be conducted in patients who are known to experience frequent GPP flares. Patients may be included who are not receiving ongoing treatment for control of GPP, who are receiving ongoing treatment to control their GPP, but the disease would not be controlled if their medication was reduced or discontinued. These criteria place the study population as the optimal population of patients in which to study GPP flare prevention. Confirmation of GPP diagnosis and flare history will be based on ERASPEN consensus diagnostic criteria [3]. At screening and randomization, patient GPP status will be defined according to the GPPGA, which is a GPP-specific measure adapted from the widely used PGA endpoint [17]. The GPPGA is a robust assessment of disease severity in GPP, and was successfully used as an endpoint in the Effisayil™ 1 study [15]. Blocking for region (Japan versus outside of Japan) and age (adults versus adolescents) will be done to ensure that there are a sufficient number of patients to demonstrate efficacy and safety in each group, and to ensure that there will be a sufficient number of adolescent patients randomized in each treatment group for pediatric investigation. These blocking factors will be treated as operational factors and will not be included in the analyses of efficacy endpoints.

Rationale for Study Endpoints and Outcomes

The study endpoints were selected with the aim of establishing the efficacy and safety of spesolimab for the prevention of GPP flares, with maximal statistical power. Systemic aspects of the GPP flares were assessed using measures including components of the Japanese Dermatological Association GPP severity score, which was developed for the Japanese Ministry of Health as a diagnostic tool for measuring the severity of GPP at presentation [2]. A range of patient-reported outcomes (PROs) will be measured as these provide unique insights into the impact of GPP and the trial intervention from the patients’ perspective, and PROs are considered an important factor by dermatologists when making treatment decisions in patients with psoriasis [19, 20]. Some of these PROs (Psoriasis Symptom Scale, Pain Visual Analogue Scale, Dermatology Life Quality Index) were used successfully in the Effisayil™ 1 study [15], and will evaluate participants’ health-related quality of life, ability to participate in daily activities, and experience of pain.

Rationale for Dose Selection for Flare Prevention, and Using IV Spesolimab in Response to a Flare

The three dosing regimens in the Effisayil™ 2 study were selected to test a wide range in exposure, allowing a thorough evaluation of the exposure–response relationship of spesolimab in patients with GPP. Loading doses of 600 or 300 mg were included to evaluate whether either exposure is efficacious in preventing GPP flares if other regimens are discontinued. The 300-mg q4w and 300-mg q12w maintenance doses are assumed to be closely effective, while the 150-mg q12w dose is assumed to be sub-therapeutic. The dosing intervals of q12w versus q4w were selected to evaluate whether flare prevention could be achieved with a dose administered every 3 months, or whether monthly dosing would be required. Since the incidence of flares in an untreated population is unknown and a high incidence of disease is essential to demonstrate patient benefit from preventative treatment, a placebo regimen is crucial for this study. No active control group is included in the study because there is currently no drug approved for the prevention of GPP flares. In the Effisayil™ 2 study, treatment will be administered subcutaneously because patients will have clear or almost clear skin at randomization, meaning that different spesolimab exposure is expected to be required than is needed for treatment of a flare. In addition, because SC dosing is often preferred by patients, it has the potential to improve participant adherence [21]. In the Effisayil™ 1 study, an IV dose of 900 mg of spesolimab was shown to be effective in the treatment of GPP flares, with an acceptable safety profile [15], and so was selected as the dose for administration if a patient experiences a GPP flare during the Effisayil™ 2 study. In addition, by treating patients with open-label IV 900-mg spesolimab, further data can be collected on the treatment of flares that will add to the evidence provided by the Effisayil™ 1 study.

Study Strengths and Limitations

Effisayil™ 2 is the first study to investigate the use of an antibody against the interleukin-36 receptor as treatment for the prevention of GPP flares, a key step for the efficacy assessment of spesolimab in an intermittently, repeatedly flaring disease. This will be the first and largest randomized, placebo-controlled study conducted in this population to date and will provide robust evidence on the efficacy of spesolimab in preventing the occurrence of GPP flares. Rollover of the study into an OLE will allow further examination of long-term use of spesolimab for the treatment of GPP. Recruitment for Effisayil™ 2 was completed at the time of writing, and common to studies into rare diseases, a challenge for this study was the recruitment of a sufficient number of participants. This challenge was minimized by the inclusion of multiple centers across a range of global regions, and the 3:1 active treatment to placebo allocation ratio providing a more favorable chance of receiving active treatment.

Conclusions

GPP is a disease in which there is a high unmet need for treatments that rapidly control and resolve disease flares, and prevent the occurrence and/or reoccurrence of flares. Effisayil™ 2 is the first placebo-controlled study in patients with GPP that focuses on flare prevention, through maintenance treatment with SC spesolimab. Efficacy and safety data from this study will provide valuable information on the use of maintenance spesolimab treatment in preventing GPP flares and delivering sustained symptom management.