Lutikizumab HiSCR75 Win Faces Modest Delta and Payer Parity Hurdle

AbbVie's Lutikizumab Achieves Primary Endpoint in Phase 3 HS Trial

AbbVie announced positive topline results from the Phase 3 INTREPID study, evaluating lutikizumab, an investigational dual IL-1α/1β antagonist, in adults and adolescents with moderate to severe hidradenitis suppurativa (HS). The study successfully met its primary endpoint, with 31.4% of lutikizumab-treated patients achieving HiSCR75 at Week 16 compared to 23.4% for placebo (p≤0.001). Lutikizumab also achieved 8 ranked secondary endpoints, demonstrating significant improvements in HS-related skin pain and reductions in HS flares. The drug was generally well tolerated, with a safety profile consistent with previous studies and no new safety concerns identified, supporting its continued investigation for HS.

• The INTREPID study's primary endpoint, HiSCR75 at Week 16, was significantly met by lutikizumab, with 31.4% of patients achieving this response compared to 23.4% on placebo (p≤0.001). This marks the first Phase 3 study to demonstrate statistically significant HiSCR75 response rates at Week 16 as the primary endpoint for adults and adolescents with HS, setting a rigorous bar for defining clinical response.
• Beyond the primary endpoint, lutikizumab showed statistically significant improvements across key ranked secondary endpoints. Patients experienced rapid and significant reductions in HS-related skin pain, with 26.2% achieving NRS3 and 36.0% achieving NRS30 at Week 8, compared to 15.0% and 22.8% for placebo, respectively (both p<0.0001). Additionally, the occurrence of HS flares was significantly reduced (18.4% vs 28.1% for placebo, p<0.0001), addressing critical patient burdens.
• Lutikizumab maintained a safety profile consistent with prior studies, showing general tolerability with no new safety concerns. Treatment-emergent adverse event rates were similar between lutikizumab and placebo groups. These positive Phase 3 results reinforce AbbVie's commitment to HS innovation, with regulatory submissions planned for the second half of 2027 and future studies exploring lutikizumab in combination with other investigational agents like ABBV-295 and ABBV-701.

The Persistent Challenges in Hidradenitis Suppurativa Treatment

Management of hidradenitis suppurativa (HS) remains challenging despite combined medical and surgical options. Prolonged diagnostic delay, limited durability of systemic therapies, and substantial pain and quality-of-life burden continue to limit outcomes.

• Prolonged diagnostic delay and misdiagnosis: Mean diagnostic delay was 12.4 years, with mean time from disease onset to biologic initiation of 14.8 years. In a cohort of 26 Finnish patients, mean diagnostic delay was 13.7 years, and in a cohort of 37 patients a significant delay (>2 years) was reported in 29/37 (78.4%) cases. Abscesses were described as the most frequent alternative diagnosis in HS patients (53.2%), and patients with HS suffer from a 43.3% reduction in working ability.

• Loss of efficacy, resistance and relapse with biologic therapy: Loss of efficacy of adalimumab with progression of disease within ongoing biologic therapy led to repeated hospitalizations and need for additional intravenous antibiotics, zinc, colchicine and pain relievers with only partial, non-durable improvement. Case reports concerning 42 patients who received adalimumab reported a cumulative response rate of 58% (≥50% in 23 patients) with a relapse rate of 71% (10 out of 14 patients). In therapeutic resistance, other advanced alternatives such as golimumab, anakinra, etanercept are available, with frequent switch to third-line agents such as Ustekinumab, Tildarkizumab, Certolizumab or Ixekizumab, while disadvantages include loss of efficacy/development of resistance over time, multiple side effects and frequent recurrence after discontinuation of treatment.

• Limited efficacy and low quality of evidence for conventional systemic and topical therapies: Topical antibiotics often yield limited efficacy and pose risks of antibiotic resistance. The therapeutic effect of isotretinoin is questionable, and overall the quality of evidence was low and differed between agents, making direct comparisons difficult. Treatment failure is common, including failing multiple medical therapies over six years and worsening under adalimumab s.c. 40 mg/week combined with clindamycin (300 mg bd), and a 45-year-old patient on adalimumab 40 mg weekly for 9 months with lack of improvement and progression.

• Dependence on specialized, combined surgical management: Several attempts at surgical treatment/incision in non-specialized units remained generally unsuccessful or with nondurable, unsatisfactory clinical outcome, while in extensive cases a combination of surgical and conservative therapy is necessary. Deroofing recurrence rate was 10% (12/115) at 3 months and 11% (13/108) at 12 months, and wide local excision outcomes including recurrence rate are dependent on the region affected and the type of surgery.

• High symptom burden, psychosocial impact and metabolic comorbidity: Pain was rated the most bothersome symptom, with mean DLQI score of 8.31 and mean BDI-21 score of 10.69, and women consistently had higher scores than men for every item of the DLQI. Prior bariatric surgery was not associated with statistically significant differences in quality of life, depressive symptoms, anxiety symptoms, or pain after adjustment (all p>0.05), with lower mean DLQI (8.13 vs 8.62), PHQ-9 (5.73 vs 7.50), GAD-7 (5.87 vs 6.31), and VAS pain (2.80 vs 3.69). HS is associated with metabolic comorbidities such as obesity and diabetes, including a case with elevated HbA1c of 12.8% confirming diabetes, and a case with heart failure (NYHA II-III, EF 35-40%) and hypochromic microcytic anaemia (Hb 7.8 g/dL) with severe pain (8-9/10, NRS).

INTREPID: Lutikizumab's Efficacy and Rigorous HiSCR75 Endpoint

Key hidradenitis suppurativa trials have evaluated adalimumab, bimekizumab and guselkumab using Hidradenitis Suppurativa Clinical Response (HiSCR) and lesion-count endpoints. Designs range from phase 2 placebo-controlled randomized trials to a phase 4 peri-surgical trial and an open-label mode-of-action study, with patient-reported outcomes including Dermatology Life Quality Index and pain scales.

Lutikizumab's Safety and Next Steps in Hidradenitis Suppurativa

In adults with moderate to severe hidradenitis suppurativa who experienced anti-tumor necrosis factor therapy failure, lutikizumab 300 mg every week, 300 mg every other week, and 100 mg every other week through week 16 showed no deaths or treatment-emergent adverse events of neutropenia, serious hypersensitivity reactions, major adverse cardiovascular events, or opportunistic infections reported.

In knee osteoarthritis, lutikizumab (ABT-981) was generally well tolerated in a randomized, double-blind, placebo-controlled, single-center study of multiple subcutaneous injections, with adverse event rates comparable between ABT-981 and placebo (54% vs 63%) and injection site erythema as the most common adverse event reported with ABT-981 vs placebo (14% vs 0%). ABT-981 significantly reduced absolute neutrophil count and serum concentrations of IL-1α/IL-1β, high-sensitivity C-reactive protein, and matrix metalloproteinase-derived type 1 collagen, with decreasing trends in serum concentrations of MMP-derived type 3 collagen and MMP-degraded C-reactive protein. In healthy subjects the most common adverse events associated with ABT-981 were diarrhea and headache, with decreased absolute neutrophil counts observed in response to ABT-981 administration, while in a 50-week study in patients with Kellgren/Lawrence grade 2-3 knee osteoarthritis and synovitis, injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo.

In erosive hand osteoarthritis, injection site reactions and neutropaenia were more common in the lutikizumab 200 mg subcutaneously every 2 weeks group, and discontinuations because of adverse events occurred more frequently with lutikizumab (4/64) versus placebo (1/67), alongside significantly decreased serum high-sensitivity C reactive protein levels, IL-1α and IL-1β levels, and blood neutrophils. Antidrug antibodies were found in 37% of patients with knee osteoarthritis but were not associated with the incidence or severity of adverse events, and immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations in the 50-week knee osteoarthritis study.

Lutikizumab's IL-1 Success: A New Chapter for HS Treatment

The recent announcement of positive topline results from AbbVie's Phase 3 INTREPID study for lutikizumab marks a pivotal moment for patients suffering from moderate to severe hidradenitis suppurativa (HS). This chronic, debilitating inflammatory skin disease continues to present a significant unmet medical need, despite the availability of adalimumab, the only FDA-approved biologic. The variable efficacy of existing treatments underscores the urgent demand for novel therapeutic options.

Lutikizumab, a dual antagonist targeting both IL-1α and IL-1β, offers a differentiated mechanism of action by directly addressing the hyperactive IL-1 pathway, which research has shown to be central to HS pathogenesis. Studies indicate that IL-1β is a highly prominent cytokine in HS lesions, contributing to skin destruction and immune cell infiltration, and can even influence IL-17F expression. By blocking both forms of IL-1, lutikizumab aims to more comprehensively dampen this inflammatory cascade. The successful achievement of the primary endpoint, HiSCR75, along with significant improvements in HS-related skin pain and reductions in flares, provides compelling evidence of its clinical benefit.

For AbbVie, these results represent a strategic opportunity to expand its immunology portfolio beyond TNF-α inhibition and solidify its presence in the HS market. Lutikizumab could emerge as a crucial second-line therapy, particularly for the substantial population of patients who have failed anti-TNF treatments, as suggested by earlier Phase 2 data. This would intensify competition within the HS biologic space, currently seeing the emergence of IL-17 and IL-36 inhibitors.

However, several considerations remain. While the HiSCR75 rate is statistically significant, its clinical relevance will be scrutinized against the efficacy benchmarks set by adalimumab and other promising pipeline assets. The complex and compartmentalized nature of HS inflammation, with varying cytokine profiles, means that not all patients may respond equally to IL-1 blockade, as evidenced by prior reports of non-response to IL-1β antagonists. This highlights a potential need for better patient selection strategies or biomarkers. Furthermore, while the safety profile in the Phase 3 study was generally well tolerated, long-term safety data will be essential for a chronic condition requiring sustained treatment. The successful integration of lutikizumab into clinical practice will depend on its ability to offer a clear, sustained benefit and a favorable risk-benefit profile, ultimately providing a much-needed alternative for patients struggling with this challenging disease.