1 Recommendations

Generalised pustular psoriasis (GPP), also known as von Zumbusch psoriasis, is a rare form of psoriasis. It is characterised by flares, during which pustules appear all over the body, but especially in skin folds, the genital regions and the fingertips. Large areas of the skin also become inflamed. Other symptoms of GPP flares include fever, swelling, joint pain and fatigue. GPP flares can be life threatening if left untreated, because they can lead to organ failure. The disease course may be unpredictable. People living with GPP experience a substantial negative impact on their daily activities, social interactions and mental wellbeing, which extends to their loved ones. The patient expert explained that it can be difficult to get a diagnosis and that the fear and anxiety of a flare can be all consuming. Patient experts reported that GPP flares make it difficult to wear clothing because it is painful when anything touches the skin during a flare. The physical appearance of the condition can be very stressful and cause anxiety. The committee recognised the substantial impact GPP flares have on physical and mental health. It acknowledged the unmet need for effective treatments for GPP flares. The committee concluded that people with GPP would value a treatment option with faster flare resolution and control, with tolerable side effects.

There are no licensed treatments and no specific guidelines in the UK for GPP flares, so best available care (BAC) draws on treatments licensed for other forms of psoriasis (see section 3.3). BAC treatments can be slow to elicit response, often do not fully resolve symptoms and have notable side effects. The company proposed that spesolimab would be expected to replace current first-line and subsequent treatments for GPP flares. The EAG was unable to obtain further clinical expert opinion for verifying the appropriate positioning of spesolimab in the treatment pathway. Clinical experts at the committee meeting confirmed that spesolimab would be offered alongside first-line treatment of GPP flares. The committee concluded that spesolimab could be used in first-line treatment of GPP flares.

The company did a structured expert elicitation (SEE) exercise to collect information on BAC, in terms of the efficacy and safety profiles of the treatments used in the NHS for GPP flares. The exercise comprised 2 rounds of elicitation (individual and group round), concluding in an expert consensus response to questions. The company used data from the SEE exercise to inform the model for BAC treatments from the end of week 1 through to the end of the time horizon. These active treatments included:

• topical steroids, ciclosporin, methotrexate, acitretin or infliximab at first-line treatment (week 1)

• biologicals including infliximab, guselkumab, ustekinumab or secukinumab at second-line treatment (weeks 2 to 4)

• biologicals including guselkumab, ustekinumab or secukinumab at third-line treatment (week 5 and later).
  
  Clinical experts stated that the treatments that reasonably reflect the BAC for GPP flares in the NHS are:

• ciclosporin or acitretin (used in some parts of the UK) at first line (week 1)

• infliximab and methotrexate at second-line treatment (weeks 2 to 4)

• other biologicals at third-line treatment (week 5 and later).
  
  The current BAC also includes rest, hydration, pain medicine and topical emollients. The committee concluded that current BAC for GPP flares in the NHS is mainly ciclosporin at first line (week 1), and in some parts of the UK acitretin is also used at first line. At second line (weeks 2 to 4) infliximab with methotrexate is used and third-line treatments (week 5 and later) are biologicals (guselkumab, ustekinumab or secukinumab). The committee concluded that the relevant BAC comparators for spesolimab as a first-line treatment for GPP flares are ciclosporin and acitretin.

The key clinical evidence came from the Effisayil 1 trial (n=53) a multicentre, randomised, double-blind phase 2 study comparing spesolimab with placebo for treating moderate-to-severe GPP flares in adults. Before randomisation, participants had to stop biological therapies, systemic non-biological therapies and other treatments such as phototherapy and topical treatments. Participants were randomised on day 1 to have 900 mg intravenous spesolimab or placebo. Escape treatment during days 2 to 7 was allowed for worsening disease, with these people deemed non-responders in day 8 analyses. Placebo response data from the Effisayil 1 trial was unavailable because over 80% of people who had placebo switched to spesolimab on day 8. From day 9 to week 12, safety was assessed, and people who had recurrent flares could have a 900‑mg rescue dose of spesolimab. Beyond week 12, people with no flare symptoms could enter the Effisayil ON extension study.

The primary outcome of the Effisayil 1 trial was Generalised Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 at week 1. The secondary outcome was GPPGA total score of 0 or 1 at week 1. The clinical experts agreed that using a GPPGA pustulation subscore of 0 or 1 appropriately reflects the resolution of a flare, with 0 being completely resolved. But, the GPPGA pustulation score is not used in the NHS and the extent of visible pustules is assessed instead. The proportion of people who achieved a GPPGA pustulation subscore of 0 or 1 (clear or almost clear skin) was higher in the spesolimab arm compared with the placebo arm, with a risk difference of 46.0%. The committee concluded that spesolimab was more effective than placebo in resolving GPP flares, but there is uncertainty in the size of the treatment effect. This is because in the trial people in the placebo arm did not have systemic biological or systemic non-biological treatments and only had supportive care such as hydration, pain medicines and emollients.

Because the Effisayil 1 trial enrolled adults with GPP presenting with moderate-to-severe flares, it was uncertain whether the trial was generalisable to people with mild flares. Clinical experts explained that the majority of flares they treat range from moderate-to-severe, and mild flares are likely to progress to moderate or severe flares relatively quickly. The clinical experts anticipated that all people with GPP flares would be offered spesolimab, regardless of flare intensity, and using spesolimab for mild flares could reduce exacerbation of the flare. The EAG had concerns about the generalisability of the Effisayil 1 trial results to the UK. A high proportion (55%) of the people in the Effisayil 1 trial were Asian because 51% of the trial sites were in Asia, compared with only 30% from Europe. None of the trial sites were in the UK. People in the trial were slightly older than people with GPP flares in the NHS, with more women enrolled than men. Clinical experts stated that gender is not a treatment effect modifier. Clinical expert opinion was that the trial was representative of the ethnicity of people with GPP flares in the NHS. But they added that about half the people treated for GPP flares in the NHS would be on maintenance biological therapies for concomitant plaque psoriasis. The committee concluded that all people with GPP flares of all intensities are expected to be offered spesolimab in clinical practice. It also concluded that the ethnicity of the people in the trial is generalisable to the NHS. It noted that there were trial participants from Japan. Clinical expert opinion was that more data on spesolimab use in Japan could aid decision making. The committee also concluded that evidence in the first week of the trial is not generalisable to the NHS. This is because it provides no evidence on the efficacy of spesolimab in people who are having other biological treatments as maintenance therapy for concomitant plaque psoriasis.

For week 1 in the company's model, the source of BAC treatment composition and costs was the placebo arm of Effisayil 1, in which people had no standard care treatments. This approach ensured consistency with the trial design but raised concerns about alignment with clinical practice. After week 1 the company used the SEE exercise to inform the modelling of comparator treatments and costs. This was because of cross over to open-label spesolimab from day 8 for people in the placebo arm. The EAG preferred to use the SEE exercise to model BAC treatments and costs in week 1 and after instead, because it could better capture treatments used in the NHS. Clinical experts stated that it is unlikely that people with a GPP flare would not be offered any pharmacological treatment for a week. The committee acknowledged that the SEE exercise is a lower-quality source of evidence than a clinical trial. But it concluded that it was still an appropriate source to inform the costs and treatments of the BAC arm for week 1 and after week 1. This is because the estimates could be more aligned with NHS clinical practice.

The company assumed that there is an increased mortality risk associated with a GPP flare for people in intensive care. The company applied a daily rate of death of 0.096% for people in intensive care. This was derived from a French National Health System database study, in which 2.6% (15 of 569) people died within 4 weeks after their last flare. The company used all-cause and disease-related mortality for resolved GPP flares in both the intervention and comparator arms. Following clinical expert opinion, the committee concluded that it did not accept the assumption that people treated with spesolimab have a 0% probability of being admitted to intensive care (see section 3.13).

The company model assumes faster flare resolution with spesolimab, with reduced hospitalisation rates and reduced intensive care admission rates. The company assumed that 77.6% of people having BAC were hospitalised for treatment of GPP flares (Wolf et al. 2024). The company assumed that only 38.8% of people having spesolimab would be hospitalised. This was calculated by applying a 48.4% relative reduction in active flare rates (defined as a GPPGA pustulation subscore greater than 1) from Effisayil 1 to the proportion hospitalised having BAC. The company model assumes that GPP flares treated with spesolimab never require intensive care admission, whereas some people having BAC do need intensive care admission. The exact proportion is confidential and cannot be reported here. The EAG questioned whether the reduction in hospitalisation rates assumed for spesolimab is too optimistic, given that there is no empirical evidence available from the trial. It also raised the issue of double counting the treatment benefits of faster flare resolution, reduced probability and duration of hospitalisation, reduced intensive care admissions, and reduced mortality. Clinical experts stated that it is realistic to expect that using spesolimab will lead to fewer hospital admissions and faster flare resolutions, leading to shorter hospital stays. They also stated that it is unlikely that GPP flares treated with spesolimab would not require intensive care admission. This is because people with GPP may have comorbidities that mean intensive care admission is needed to treat the flare. The committee agreed that if UK data for inpatient and intensive care admission rates are not available, then it would prefer data from Wolf et al. It noted that using the 77.6% value from Wolf et al., with a reduction of about 50% to bring the assumed inpatient rate to 38.8%, is a generous upper bound estimate. Clinical experts stated that in the NHS, GPP flares are treated with BAC rather than placebo, so the difference in efficacy between spesolimab and placebo may be overestimated in the trial. For estimating the proportion requiring intensive care admission, it preferred to use the 11.5% proportion for the BAC arm and reduce this proportionally for the spesolimab arm. The committee concluded that it would prefer more UK clinical data on inpatient and intensive care admission rates and duration of stay for GPP flares treated with BAC and spesolimab, if available.

The company did not make a case for the severity modifier to be applied.

The company did not make a proposal for managed access after carrying out a feasibility assessment. It concluded that current UK data sources do not allow use of routinely collected data to reduce uncertainties and there are no appropriate processes in place to establish new data collection. Clinical expert opinion was that data collection is possible.