Pipeline Therapeutics

Introduction

Since early 2000, there has been a dramatic increase in the number of publications and clinical trials devoted to moderate to severe hidradenitis suppurativa (HS). HS is a complex disease process in which a complete mechanism is still unknown. Recent data on pathogenesis are presented in earlier chapters, and a currently proposed model is presented in Fig. 34.1 . Drugs currently in the therapeutic pipeline target a broad range of inflammatory pathways that may be important in the pathogenesis of HS.

This chapter summarizes the drugs, procedures, and complementary and alternative medicine (CAM) modalities currently in clinical trials for HS. Outcome measures for HS clinical trials have been presented in Chapter 13 . Table 34.1 lists drug trials for HS registered at www.clinicaltrials.gov as of January 1, 2020, which are active, recruiting, not yet recruiting, or recently completed but results are unpublished. Potential therapeutic targets currently being studied in drug clinical trials include neutrophils, the complement pathway, inflammatory cytokine signaling pathways such as interleukin (IL)-17, IL-23, and IL-1α/β, as well as the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. Fig. 34.1 illustrates where these agents may act in the pathogenic pathway of HS. Surgical, procedural, CAM treatments, and wound care approaches currently under investigation and registered as of the same date are listed in Table 34.2 .

Neutrophils and Complement

Hair follicle content exposed to the dermis, due to follicular occlusion and subsequent rupture, provokes a robust neutrophilic infiltration via inflammatory cytokines (e.g., IL-8), lipid signaling (e.g., leukotriene B4 [LTB4]), and complement activation (e.g., C3a, C5a). These chemoattractants, as well as others, bind to over 30 chemokine, selectin, and integrin receptors on the neutrophil’s surface. Neutrophils have been implicated in the pathogenesis of HS due to the large number of neutrophils seen in early lesions and several case reports and series suggesting efficacy for anti-neutrophil agents, such as dapsone and colchicine, in HS.

Primed neutrophils produce reactive oxygen species (ROS); secrete granules containing antimicrobial peptides (AMPs), alarmins, and proteases; and release neutrophil extracellular traps (NETs). These result in tissue damage as well as recruitment and activation of macrophages, that produce pro-inflammatory cytokines, such as IL-1α/β, TNF-α, and granulocyte-colony stimulating factor (G-CSF), recruiting more neutrophils. In vitro, stimulated neutrophils from HS patients secrete higher levels of ROS compared to healthy controls and produce NETs, even without stimulation. In HS lesional tissue, NETs have been detected that correlate with disease activity.

Currently, researchers are investigating two novel drugs that target neutrophil recruitment in HS. CSL324 is a fully human G-CSF receptor monoclonal antibody. The G-CSF receptor signals via the JAK1/STAT3 signaling pathway. It regulates mobilization of neutrophils from the bone marrow into the peripheral circulation as well as neutrophil recruitment to tissues via changes to cellular adhesion and chemokine receptors on the neutrophil surface. In animal models, G-CSF receptor inhibition reduces neutrophilic inflammation without causing neutropenia or reducing neutrophil function. CSL324 is currently in its first-in-human study, a phase I, open-label, two-dose regimen trial in patients with HS and palmoplantar pustulosis.

LYS006, an inhibitor of LTA4 hydrolase, is currently being studied for acne, Crohn’s disease, and non-alcoholic fatty liver disease (NAFLD), in addition to HS. LTA4 hydrolase catalyzes the rate-limiting step in converting LTA4 into LTB4, a potent neutrophil chemotactic agent. LTB4 has been shown to be critical for the recruitment and clustering of neutrophils into localized collections (abscess). LTB4 and LTB4-induced pathways in HS have been found to be increased in lesional skin, suggesting that this lipid pathway could be an important target for HS treatment. A three-arm randomized controlled trial studying LYS006 vs. iscalimab (CFZ533, anti-CD40) vs. placebo is presently recruiting.

Activated neutrophils are able to initiate the complement alternative pathway on their cell surfaces. Anaerobic bacteria, such as Porphyromonas spp. can also cleave and activate complement. The resulting complement fragments, including C3a and C5a, are strong chemoattractants for both neutrophils and macrophages. C5a has also been shown to induce NET release in activated neutrophils and prime monocytes to produce TNF-α and IL-6. In HS, the complement pathway may be an important contributor to the heightened neutrophilic inflammatory response. With increased levels of C5a found in both tissue and plasma of HS patients, C5a and its receptor have become therapeutic targets for HS treatment.

IFX-1 is a monoclonal IgG4 kappa antibody against human C5a. Selective C5a inhibition leaves the membrane attack complex (MAC) intact, minimizing immunosuppression, especially for encapsulated organisms. An early open-label study of IFX-1 indicated an 83% treatment response rate after three months in patients with severe HS. A phase IIb clinical trial for IFX-1 in HS patients was recently completed and the results were released in two press releases. Unfortunately, IFX-1 failed to meet its primary end point (a statistically significant dose-dependent improvement in HS Clinical Response [HiSCR] over placebo), although there was a significant improvement in the DLQI. Secondary endpoint and post-hoc analysis demonstrated significant reductions in draining fistulas and IHS4 score in the high-dose IFX-1 group compared to controls. The company has indicated that it plans to continue to develop IFX-1 as a treatment for HS, and an open-label extension study is continuing. Avacopan, an orally available small-molecule C5a receptor antagonist with demonstrated efficacy in ANCA-associated vasculitis, is now undergoing a Phase II clinical trial in moderate to severe HS patients.

Cytokines

There are numerous cytokines that have been implicated in the pathogenesis of HS. To date, the inhibition of TNF-α has been the mainstay of medical treatment. Currently, the only United States Federal Drug Administration (FDA) approved medication for HS is adalimumab, a fully human, IgG1 monoclonal antibody targeting TNF-α. Unfortunately, only 40% to 60% of patients achieve HiSCR, and of those that achieve HiSCR, some lose their response over time. Data from studies on inflammatory bowel disease suggest that secondary loss of response is either due to mechanistic failure or low drug concentrations, with or without the development of anti-drug antibodies. Poor adherence to therapy has been associated with secondary loss of response due to low drug concentrations and increased immunogenicity. A phase IV randomized trial is planning to evaluate the practical administration of adalimumab for HS, specifically whether a novel electronic medication monitoring device compared with usual care can improve clinical outcomes and adherence compared with usual care. In addition to issues related to adherence and loss of response to TNF-α inhibitors, many patients are not able to tolerate or never respond to TNF-α inhibition initially. Thus, researchers have started investigating new cytokine targets, such as interleukin (IL)-17, IL-23, and IL-1α/β. The following section highlights each cytokine, its association with HS, and preliminary results from clinical studies. Clinical trials data of adalimumab are further discussed in Chapter 18 .