MABp1 IN HIDRADENITIS SUPPURATIVA REFRACTORY TO ADALIMUMAB

Hidradenitis Suppurativa Clinical Trial

Official title: A Double-blind, Randomised, Placebo-controlled Clinical Trial of the Efficacy of MABp1, a- First-in-class True Human Antibody Targeting Interleukin-1alpha, in Patients With Hidradenitis Suppurativa Not Eligible for antiTNF Therapy

Status Completed

Clinical Trial Summary

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder. Although adalimumab is recently licensed for moderate to severe HS, many cases fail to respond or relapse during treatment. Favorable outcomes from a recently conducted double-blind randomized clinical study on the efficacy of anakinra, one interleukin(IL)-1alpha blocker, in hidradenitis suppurativa (HS), led to validate the efficacy of MABp1, a true human antiIL-1α antibody in these cases.

Clinical Trial Description

Hidradenitis suppurativa (HS) is a chronic devastating skin disorder affecting areas rich in apocrine glands. Nodules appear in the affected areas; they progressively become swollen and rupture with the release of pus. This process occurs repeatedly leading to sinus tract formation and scars. This disease course creates a frustrating situation not only for the patients but also for physicians. Traditional treatments comprise short-courses of antibiotics and surgical excision. However, relapse is the rule so that HS leads to severe impairment of the quality of life. The Dermatology Quality Life Index (DQLI) for HS is 8.9, being higher than any other skin disorder.

This devastating disorder has often been neglected and considered a rare situation. However, HS seems to indiscriminately affect the global population. A large epidemiological survey in France reports 0.97% disease prevalence.

The exact pathophysiology of HS is unknown. Both familial and non-familial cases of HS exist. Familial HS is less than 5% of cases and it is usually inherited through the dominant autosomal mode. Mutations in genes encoding for the gene complex of nicastrin-γ-secretase are predominant in hereditary HS. However, little is known on the genetic predisposition of non-familial HS that comprises the great majority of cases. Two studies by the investigators have been conducted to explore the predisposition of HS among patients who carry single nucleotide polymorphisms (SNPs) of gene encoding for pro-inflammatory cytokines namely TNF and IL-12RB1. Results have shown that carriage of haplotypes comprising minor frequency SNP alleles at the promoter region of TNF increases the likelihood for HS; furthermore these patients are less likely to respond to treatment with anti-TNF agents. In parallel, haplotyping for gene SNPs of exon 7 and exon 10 of IL-12RB1 comprising seven constitutive SNPs has shown that carriage of the h2 haplotype composed by four minor frequency SNP alleles is associated with more severe disease phenotypes. These results indicate a strong component of the implication of the innate immune responses in the pathogenesis of HS. In conjunction with this and following a successful phase II trial, the two phase III PIONEER studies ended up with significant improvement of patients after 12 weeks of treatment with adalimumab. A novel score, HS clinical response (HiSCR) score, was introduced in these trials and it is now suggested for the evaluation of the efficacy of any new formulation in HS. Using this score, it was found that the success rate of adalimumab to achieve a positive HiSCR after 12 weeks of treatment ranged between 40 and 60%. This means that several patients do not respond to adalimumab treatment whereas others may relapse after some initial response.

The investigators have recently concluded a phase 2, double-blind, randomized study of the efficacy of anakinra treatment administered 100mg subcutaneously daily for 12 consecutive weeks compared to placebo in 19 patients; 10 were allocated to the placebo arm and nine to the anakinra arm (EudraCT2011-005145-12, www.clinicaltrials.gov NCT01558375). Results were favorable for the clinical efficacy of anakinra. The primary endpoint defined to be disease activity was marginally achieved in the modified intent-to-treat population. Regarding the secondary endpoints, treatment with anakinra was very effective in: a) prolonging the time to new exacerbation compared to the placebo arm; and b) modulating cytokine stimulation from peripheral blood mononuclear cells. More precisely, the production of interferon-γ was significantly decreased and the production of IL-22 was increased compared to the placebo arm. HiSCR score was not initially included as a study endpoint because this score has not been developed when the trial was submitted to the authorities. Retrospective validation of the HiSCR score showed significant reduction at week 12 in 7 patients (77.8%) treated with anakinra compared to three patients (30%) treated with placebo (p: 0.039).

The considerable efficacy of anakinra that blocks interleukin (IL)-1alpha (IL-1α) leads to consider a significant role of IL-1α in the pathogenesis of HS. MABp1 is a first-in-class true human monoclonal antibody cloned directly from a human B lymphocyte and specifically targets IL-1α. Results from a first-in-man trial were recently published, in which fifty-two patients with metastatic cancer were enrolled in an open-label phase 1 study. The drug was well-tolerated, tumor responses were observed, and interestingly, treatment was accompanied by an increase of lean body weight.

The purpose of this clinical study is to evaluate the safety and the efficacy of MABp1 compared to placebo in patients with moderate to severe HS who either failed previous treatment with antiTNF regimens or who relapsed under antiTNF regimens or who are treatment naïve and they are unwilling to receive subcutaneous adalimumab treatment. The rationale behind the promising success of MABp1 relies on recent findings showing heterogeneity of cytokines in skin lesions with several patients expressing huge concentrations of TNFα the lesions and other who express low concentrations of TNFα but huge concentrations of IL-1α. ;

Related Conditions & MeSH terms

• Hidradenitis
• Hidradenitis Suppurativa

• NCT number: NCT02643654
• Study type: Interventional
• Source: University of Athens
• Status: Completed
• Phase: Phase 2
• Start date: December 2015
• Completion date: February 2017