Response to: Letter to Editor Regarding “Spesolimab Efficacy and Safety in Patients with Moderate-to-Severe Palmoplantar Pustulosis: A Multicentre, Double-Blind, Randomised, Placebo-Controlled, Phase IIb, Dose-Finding Study”

First, Hu et al. ask whether the sometimes self-limiting nature of PPP could help to explain the lack of significant difference in the primary endpoint of our study. We consider this a possibility and have acknowledged the fact that variations in PPP disease severity over time could have masked a treatment effect of spesolimab during the trial [1]. As Hu et al. mention, demonstrating a significant difference between a trial drug and placebo in PPP trials is indeed challenging because of the disease course. In our trial, methods to minimise natural disease improvement concealing a potential treatment effect of spesolimab were implemented, such as excluding patients with a PPP Area and Severity Index (PPP ASI) total reduction ≥ 5 between screening and baseline [1]. While it is possible that the primary endpoint at Week 16 may have coincided with natural disease improvement in some subjects, improvements in severity scores in the placebo arm were only modest.

Second, Hu et al. rightly point out the potential influence of infections on the symptoms of PPP. Our trial was designed to exclude patients who may have had an infection at randomisation. Patients were excluded if they were experiencing an active systemic infection (with the exception of the common cold) during the 2 weeks prior to randomisation as well as chronic or relevant acute infections including human immunodeficiency virus, viral hepatitis and/or active or latent tuberculosis. Furthermore, patients who had received surgical treatment for a focal infection (such as tonsillectomy or dental therapy) within 6 months of randomisation were also excluded. If a patient experienced a severe, serious, opportunistic or tuberculosis infection during the trial, trial medication was paused until the active infection had resolved and could be restarted when the patient had recovered, according to the investigator’s assessment. The incidence of infections and infestations was largely balanced between spesolimab (24.8%) and placebo (32.6%). Given the frequency and nature of these infections, we do not consider them likely to have had a significant differential effect between the placebo and spesolimab arms.

Third, the smoking status of patients included in the trial was questioned. As documented in the publication (Table 1), the smoking status of patients was generally balanced between spesolimab and placebo: 54.1% of spesolimab (combined) patients were current smokers, 25.7% were former smokers, and 20.2% had never smoked. Among placebo-treated patients, 46.5% currently smoked, 34.9% were former smokers, and 16.3% had never smoked [1]. Subgroup analysis by smoking history was performed on the primary endpoint (PPP ASI [percent change from baseline]) as well as the secondary endpoints (50% improvement in PPP ASI, 75% improvement in PPP ASI and Palmoplantar Pustulosis Physician Global Assessment of 0 [clear] or 1 [almost clear]). However, no difference in treatment effect based on smoking status was found, and the small subgroup numbers mean that no formal comparison can be made based on smoking status.

Finally, Hu et al. emphasise the importance of genetic testing of patients with PPP when evaluating the efficacy of spesolimab. Specific mutations of interest include IL36RN, CARD14 and AP1S3 mutations, all of which have been reported in patients with PPP [3]. In our trial, all patients were genotyped at screening to investigate the potential influence of IL36RN, CARD14 and AP1S3 mutations on spesolimab treatment. In total, 16.4% of patients carried a potentially pathogenic mutation, including CARD14 (12.5%), AP1S3 (4.6%) and IL36RN (0.7%). DNA sequencing for genotyping was not completed for 10.5% of patients. To explore the impact of these mutations on the efficacy of spesolimab treatment, subgroup analysis by gene mutation status was performed on the primary and secondary endpoints; however, due to the low numbers of patients with a genetic mutation, these efficacy analyses were inconclusive. This low frequency of mutations in known disease susceptibility genes, in particular IL36RN, is comparable to that seen in larger cohorts of patients with PPP [4].