EADV 2023

Treatment and monitoring: Novel approaches in HS

By Eleanor McDermid

The MIRA trial: Sonelokimab

The late-breaking sessions at the European Academy of Dermatology and Venereology (EADV) Congress 2023 featured some promising early clinical data for several novel treatment approaches for hidradenitis suppurativa (HS).

One such trial – the MIRA trial – was of a molecule called sonelokimab, designed to target interleukin (IL)-17A and IL-17F, which are overexpressed in abscesses and nodules of HS relative to uninvolved skin and are associated with tunnels.

Sonelokimab is a humanised nanobody, which presenter Brian Kirby (University College Dublin, Ireland) explained is roughly a third of the size of a conventional monoclonal antibody, potentially allowing greater penetration into inflamed tissue.

Both sonelokimab doses tested achieved the primary endpoint. By week 12, 43.3% of the 67 people randomly assigned to take the 120 mg dose had achieved an improvement of at least 75% in HS Clinical Response (HiSCR75), compared with 34.8% of the 66 people given the 240 mg dose and 14.7% of the 68 people who took placebo.

The response to both doses of sonelokimab was rapid, with significant differences appearing within the first 8 weeks. An additional 33 trial participants were given adalimumab, as a reference for validation, and 36.4% of these people achieved HiSCR75, which Kirby said was consistent with the results of the PIONEER II trial.

Targeting the IL-17 pathway with sonelokimab met the primary endpoint of patients achieving HiSCR75 in the phase 2 MIRA trial

In line with the HiSCR findings, participants taking sonelokimab had significant improvements on the International HS Severity Score System (IHS4), which Kirby noted includes fistulas and tunnels. Moreover, 41.1% of participants with draining tunnels at baseline achieved complete resolution by week 12 after treatment with 120 mg sonelokimab, compared with 23.8% of those in the placebo group.

There were no new safety signals, and sonelokimab was generally well tolerated in this trial. There were no cases of inflammatory bowel disease or serious infections among people taking active treatment, although 6% and 12% of those taking the 120 mg and 240 mg doses, respectively, developed oral candidiasis.

“This is a phase 2 study, but we look forward to phase 3 studies being done for this patient population with this high unmet need”, said Kirby.

The OSIRIS trial: Orismilast

Another phase 2 trial – the OSIRIS trial – investigated orismilast, a next-generation phosphodiesterase-4 B and D inhibitor that has shown promising early results in psoriasis. The OSIRIS findings reveal some issues with tolerability, with 11 of the 20 trial participants discontinuing, primarily because of treatment-related gastrointestinal events.

Orismilast was started at 10 mg and titrated up to 40 mg based on experience in psoriasis, but Gregor Borut Jemec (Zealand University Hospital, Roskilde, Denmark), who presented the findings, said that the titration was too fast, leading to discontinuations.

However, the nine people who did complete the 16-week trial achieved an average 29% reduction in the number of abscesses and lesions and a 39% reduction in total lesions, compared with 6% and 12%, respectively, among those who did not complete.

Likewise, the HiSCR50 and HiSCR75 responses were 67% and 44%, respectively, for those who completed 16 weeks of treatment, versus 27% and 18% for those who discontinued treatment. Other endpoints followed the same pattern.

Jemec stressed that most side effects were mild or moderate and were manageable by individualising the titration, which resulted in people remaining in the trial and gaining benefit from orismilast treatment.

Targeting heat shock proteins

The final HS medication trial in the late-breaking sessions was a pilot randomised, double-blind trial demonstrating the feasibility of targeting heat shock proteins (HSPs) to improve HS symptoms.

Presenting the findings, Hakim Ben Abdallah (Aarhus University Hospital, Denmark) stressed that the trial was proof-of-concept and not powered to detect significant differences between treatments.

Preliminary trial findings may validate heat shock protein 90 (HSP90) as a therapeutic target in HS

Nevertheless, 60% of the 10 trial participants randomly assigned to the experimental HSP90 inhibitor RGRN-305 (250 mg/day) for 16 weeks achieved an HiSCR50 response, compared with 20% of the five participants given placebo. All trial participants stopped any existing HS medications at least 28 days before starting the trial treatments, and 12 weeks prior for biological medications.

Secondary endpoints including HiSCR75, HiSCR90 and IHS4, as well as patient-reported outcomes, gave results that were consistent with the primary endpoint. Adverse events during this short trial were mild and of similar type and frequency between the two treatment groups.

Abdallah therefore concluded that HSP90 inhibition with RGRN-305 is a promising therapeutic approach for HS and worth exploring further.

Non-invasive monitoring

In addition to these intervention trials, the late-breaking sessions also featured a non-invasive means to predict and monitor treatment response in people with HS.

Kristina Navrazhina (Icahn School of Medicine at Mount Sinai, New York, USA) presented her team’s study of RNA sequencing of tape strips as a non-invasive alternative to biopsies, which she noted are uncomfortable, carry a risk of scarring and present particular difficulties in children.

Their study revealed a huge number of genes that were differentially expressed in both lesional and non-lesional skin of 22 people with HS versus the skin of 21 healthy controls.

“Look at how much dysregulation we’re picking up by tape strips, with a non-invasive approach”, said Navrazhina.

These included pathways with established relevance to HS treatment, such as the tumour necrosis factor-α and IL-17 pathways. Here, the presenter highlighted the huge variation in expression of these pathways between individuals with HS, in both lesional and non-lesional skin.

“We know there’s no one-size-fits-all treatment for HS”, said Navrazhina, adding that “we do not have a way to predict which patient will respond – nor do we have a way to monitor the treatment response in a non-invasive way”.

She also highlighted the large amount of dysregulation found even in non-lesional skin and suggested that tape strips could therefore assist with earlier diagnosis.

“Can we shrink the 7-year diagnostic delay that our patients are suffering from?” she asked, and suggested that, overall, use of tape strips could “really improve the quality of life for HS patients”.

Meet the expert: Professor Falk Bechara

Falk G Bechara is Professor of Dermatology, Allergology and Venereology at the Ruhr University Bochum, Germany. He is the Past-President of the German Society of Dermatologic Surgery (DGDC). Professor Bechara coordinates the Skin Cancer Center at the Ruhr University Bochum, with focus on reconstructive dermatologic surgery, and leads the Clinical Study Center for inflammatory skin diseases.

He has published extensively in scientific journals and dermatology textbooks and is a frequent speaker both at national and international conferences.

In 2008, Professor Bechara founded the Hidradenitis Suppurativa / Acne Inversa Center in Bochum, which has become one of the largest in Europe, with a focus on serious cases with demanding surgical challenges.

Disclosures

Professor Bechara has received honoraria for participation in advisory boards, in clinical trials, and/or as a speaker from AbbVie Deutschland GmbH & Co. KG, AbbVie Inc., Boehringer Ingelheim Pharma GmbH & Co. KG, Celltrion, Dr Wolff, Incyte Corporation, Janssen-Cilag GmbH, Mölnlycke, MoonLake, Novartis Pharma GmbH, and UCB Pharma.