Real-World Efficacy and Safety of Adalimumab Biosimilar (HS016) in Biologic-Naïve Patients with Perianal Fistulizing Crohn’s Disease: A Prospective, Single-Arm, Observational Study

Abstract

Background and Aims

Anti-tumor necrosis factor (TNF-α) agents are first-line therapies for perianal fistulizing Crohn’s disease (PFCD), but evidence for adalimumab (ADA) biosimilar HS016 in biologic-naïve PFCD patients remains limited. This study explored the efficacy and safety of HS016 in this patient population.

Methods

This prospective, single-arm, real-world observational study recruited biologic-naïve PFCD patients at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. Induction therapy included subcutaneous HS016 (160 mg at week 0, 80 mg at week 2, 40 mg Q2W from week 4–12), and maintenance therapy (week 14–52) used 40/80 mg Q2W. Primary efficacy and safety endpoints were the fistula clinical remission (FCrem) at week 54 and adverse events (AEs) incidence. Secondary endpoints included FCrem at week 14 and 26, fistula clinical response (FCres), radiological fistula part response (RFRS), radiological fistula healing (RFH), intestinal endoscopic response(IEres), intestinal endoscopic remission(IErem), intestinal clinical response(ICres), intestinal clinical remission(ICrem) at week 14, 26 and 54. Exploratory endpoints included changes in the scores of CDAI, PDAI, VAS and IBDQ, as well as the levels of Hb, ALb, CRP, ESR and FC.

Results

A total of 60 patients were enrolled, with 42 completing the study. The proportions of FCres, FCrem, RFRS, RFH, IEres, IEresm, ICres, and ICrem at week 26 were 56.67%, 40.00%, 30.00%, and 31.67%, 55.00%, 45.00%, 68.89%, and 55.56%, respectively. The rates of PFCD patients achieving FCres, FCrem, RFRS, RFH, IEres, IEresm, ICres, and ICrem at week 54 were 48.33%, 38.33%, 31.67%, 26.67%, 71.11%, 60.00%, 60.00%, and 53.33%, respectively. Following HS016 dose escalation, some patients exhibited improved fistula activity and endoscopic findings. During treatment, 3 patients (5%) developed transient rashes, with no treatment discontinuation required.

Conclusion

HS016 exhibits significant efficacy and an acceptable safety profile in biologic-naïve PFCD patients, though the incremental maintenance strategy shows limited efficacy.

Introduction

Crohn’s disease (CD) is a chronic intestinal inflammatory disorder arising from the complex interplay of genetic, environmental, and gut microbiome factors.1 Fistulas and perianal lesions represent frequent complications in CD, with perianal fistula serving as the cardinal manifestation of fistulizing CD (FCD), comprising approximately 55% of FCD cases.2 Notably, 20% of CD patients develop perianal lesions, including perianal skin tags, anal stenosis, anal fistulas, and perianal abscesses.3 Perianal FCD (PFCD) is characterized by complex, multi-branched fistular networks, which elicit distressing clinical symptoms such as perianal pain, purulent discharge, and fecal incontinence.4 Compared with CD patients without perianal fistulas, PFCD patients exhibit significantly higher rates of hospitalization, surgical interventions, and disability, accompanied by marked impairment in quality of life.5,6 Importantly, PFCD is associated with an increased risk of anorectal and fistula-related malignancies.7 These clinical burdens underscore the urgency of advancing therapeutic strategies for PFCD as a key focus of clinical research.

The advent of biologics has revolutionized the therapeutic landscape for CD, particularly in achieving endoscopic mucosal healing. However, while a subset of CD patients achieve clinical remission as measured by the Crohn’s Disease Activity Index (CDAI), perianal fistulas often persist. Therefore, PFCD therapy remains a significant challenge that demands a targeted approach in clinical practice, particularly for complex perianal fistulas.8,9 Anti-tumor necrosis factor (TNF-α) agents form the therapeutic cornerstone in PFCD.10,11 American Gastroenterological Association (AGA) guidelines recommend infliximab (IFX) as first-line therapy with high-level evidence, whereas the efficacy of adalimumab (ADA) is supported by lower-tier evidence.12–14 The small-molecule drug upadacitinib (UPA) has also demonstrated promising efficacy in PFCD.15 While IFX and UPA may be more effective than ADA in ameliorating intestinal symptoms, they are associated with less favorable safety profiles-a trade-off that complicates clinical decision-making.16 Thus, there is a critical need for prospective studies to strengthen the evidence base for ADA, thereby optimizing patient outcomes in this challenging subset of CD.

Biosimilars demonstrate high similarity to reference biologics in pharmacokinetics, efficacy, safety, and immunogenicity profiles, while offering enhanced medical accessibility due to their cost advantage.17 Given the escalating global disease burden of inflammatory bowel disease (IBD), biosimilars have emerged as a pivotal strategy to balance therapeutic efficacy with economic sustainability.18 HS016, a biosimilar of ADA, was approved by China’s National Medical Products Administration in 2019 for the treatment of CD and ulcerative colitis.19 A study by Wang et al demonstrated that HS016 exhibited favorable efficacy and safety in Chinese IBD patients, achieving clinical response and remission rates of 50.8% (31/61) and 45.9% (28/61) at week 52, respectively.20

This study represents the first prospective analysis of HS016 in biologic-naïve patients with PFCD, evaluating efficacy and safety from clinical, endoscopic, and radiological perspectives. Our findings aim to provide evidence-based support for optimizing step-up treatment algorithms in this therapeutically challenging population.

Methods

Study Design

This study was a 54-week single-center, prospective, uncontrolled, observational, real-world study, and it was conducted at Union Hospital, Huazhong University of Science and Technology from July 2021 to July 2023. Patient eligibility underwent assessment over a 6-week screening period. During this timeframe, data concerning patient demographics, medical history, as well as prior and concurrent medications were gathered. Moreover, the following evaluations were carried out: blood routine examination, liver and kidney function tests, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and opportunistic infection screening[including hepatitis B/C virus, Human Immunodeficiency Virus (HIV), syphilis, Epstein-Barr Virus (EBV), cytomegalovirus (CMV), enterovirus, and tuberculosis T-Cell Spot Test], fecal calprotectin (FC), CDAI,21 perianal Crohn’s disease activity index (PDAI),22 colonoscopy[evaluated Simple Endoscopic Score for Crohn’s Disease (SES-CD)], colonic biopsy, perianal magnetic resonance imaging (MRI)[evaluated Van Assche scores (VAS)23], and Inflammatory Bowel Disease Questionnaire (IBDQ). In addition, According to the classification criteria of the AGA,24 PFCD was categorized into simple and complex subtypes, with the definitions of the AGA classification for perianal fistulas detailed in Supplementary Table 1.

This study was performed in compliance with the Declaration of Helsinki, the Good Clinical Practice Guidelines developed by the International Conference on Harmonization, and the pertinent laws and regulations regarding drug administration and data protection in the countries where the trial took place. The study protocols, amendments, and informed consent materials were examined and authorized by the ethics committee of Union Hospital prior to the trial’s initiation. All patients provided written informed consent both before enrolling in the trial and before any study-related procedures were started.

Sample Size Justification

The sample size of this study was determined via a priori power analysis for a single-arm proportion test, with parameters derived from published real-world data on fistula clinical remission (FCrem) rates of ADA in patients with PFCD. Key calculation parameters and rationale are as follows

(1) Assumed effect size: Based on literature reporting that ADA achieves a 33% FCrem rate at week 56 in PFCD patients,25 the expected FCrem rate for HS016 (the investigational agent) was conservatively set at 33%.

(2) Type I error rate (α): A two-sided α=0.05 was adopted, consistent with standard statistical conventions for clinical research.

(3) Statistical power (1−β): Set at 80%, a widely accepted threshold to ensure sufficient ability to detect the hypothesized clinically meaningful effect while balancing study feasibility.

(4) Null hypothesis threshold (H₀): A clinically irrelevant minimal remission rate of 20% was defined as the non-effective threshold, representing the lowest rate deemed without clinical value.

(5) single-arm proportion power calculation formula:

Where P₀= 20%, P₁= 33%, Z_α/2= 1.96, and Z_β=0.84, the required evaluable sample size was calculated as approximately 43.

(6) Expected dropout rate: Given the 52-week long treatment cycle and the substantial disease burden of PFCD, an expected dropout rate of 20% was incorporated—consistent with attrition data from real-world PFCD studies.

Thus, the final sample size was determined as 43/(1−20%)≈54. As this was a single-arm observational study, the sample size was rounded down to 60 for practical clinical feasibility, including streamlined recruitment management, standardized follow-up scheduling and alignment with real-world single-center study operational norms for this patient population.

Participants

Male and female participants aged ≥18 years were eligible if they met the following key inclusion criteria: diagnosis of CD confirmed through clinical, histological, endoscopic, and pathological examinations; diagnosis with perianal fistulas for at least 3 months with ≥1 fistula drainage tubes; biologic-naïve patients, defined by no prior biologics treatment. Participants meeting any key exclusion criteria were ineligible: other biologics within three months before enrollment; Pregnant women, lactating women or women of childbearing age who are unwilling to use contraception; active infection.

Procedures

The study adopted a two-stage design: an induction period (weeks 0 to 12) and a maintenance period (weeks 14 to 54). PFCD participants were enrolled in the induction stage, receiving subcutaneous HS016 at 160 mg (week 0), 80 mg (week 2), and then 40 mg every 2 weeks through week 12. For the maintenance period, PFCD participants were administered subcutaneous HS016 at 40 mg or 80 mg every 2 weeks until week 54, with dosage titrated based on response.

Multi-dimensional assessments were conducted by two IBD-specialized gastroenterologists at weeks 14, 26, and 54. Treatment adjustment criteria were as follows: ①Patients with primary non-response or drug-related adverse events would undergo treatment regimen modification;②Those with non-response to any of clinical, endoscopic, and radiological assessments would switch to 80 mg every 2 weeks; ③Patients with favorable response would maintain the standard dosage of 40 mg every 2 weeks. Detailed procedures are illustrated in Figure 1.

Figure 1.

Procedures of HS016 in patients with PFCD.

Efficacy Assessments

Participants were subjected to comprehensive assessments after 12, 24, and 52 scheduled infusions of HS016. Comprehensive assessment items included perianal enhanced MRI, endoscopic assessment, CDAI, SES-CD, PDAI, IBDQ, VAS, FC, ESR, CRP, albumin (Alb) and hemoglobin (Hb). All endoscopic and MRI assessments were read centrally by gastroenterologists or radiologists who were unaware of patients’ clinical status and treatment visit.

The primary efficacy endpoint was the FCrem26 at weeks 26 and 54. FCrem was defined as the absence of any draining fistula on two successive visits (at least 4 weeks apart). Secondary efficacy endpoints at weeks 14, 26, and 54 were fistula clinical response (FCres) (defined as a decrease of >50% in the number of draining fistulas according to the fistula drainage assessment index),26 radiological fistula healing (RFH) (defined as the absence of a high-signal track on fat saturated T₂ sequences),27 radiological fistula part response (RFRS) (defined as a reduction in the number and volume of fistulas, and a >10% decrease in the MRI signal),27 intestinal endoscopic response (IEres) (defined as SES-CD≤2), intestinal endoscopic remission (IErem) (defined as a reduction in SES-CD of >50%), intestinal clinical remission(ICrem) (defined as a CDAI <150 points), intestinal clinical response (ICres) (defined as a reduction of >70 points in CDAI and/or CDAI<150 points).

Additional secondary efficacy endpoints were the change from baseline in CDAI, PDAI, VAS, IBDQ, Hb, Alb, CRP, ESR, and FC at week 14, 26, and 54.

Safety Assessments

Treatment-emergent adverse events (TEAEs), including opportunistic infections, infusion reactions, allergic reactions, abnormal liver and renal function, leukopenia, new-onset malignancies, and even death, were reported according to the Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary version 21.0.

Statistical Analysis

Efficacy analyses are based on the modified intention-to-treat population, defined as all patients who received at least one dose of study drug. For the efficacy analyses, baseline was defined as the last observed measurement before day 1 of HS016. Comparisons of continuous variables between two groups were performed using the t-test or Wilcoxon rank-sum test. For within-subject comparisons across weeks 0, 14, 26, and 54 (repeated measurements of the same patient at different time points), we used repeated-measures analysis of variance (ANOVA) (for normally distributed data) or Friedman test (for non-normally distributed data). The post-hoc pairwise comparisons were conducted using Bonferroni correction for all 6 pairwise comparisons among the four time points, with statistical significance defined as P < 0.0083 (adjusted for 6 pairwise comparisons: 0.05/6 = 0.0083). Comparisons of categorical variables between groups were carried out using the chi-square test.For missing repeated-measure data in the modified intention-to-treat population, a complete-case analysis was applied, where only patients with fully available longitudinal data at the assessed time points (weeks 0, 14, 26, and 54) were included in the corresponding within-subject comparative analyses.

Results

Patients Characteristics

Between July 2021 and July 2023, 60 patients were recruited. All participants were administered the study intervention; 57 patients finished the induction phase, and 42 patients remained in the extension phase at data cutoff (Figure 2). Additionally, Table 1 presents the baseline characteristics of all 60 patients.

Figure 2.

Study flowchart of HS016 in patients with PFCD.

Table 1.

Baseline Characteristics

Variables	N (%)
Sex
Men	47 (78.3%)
Women	13 (21.7%)
BMI (kg/m2)	20.98±4.13
Age of onset
≤16 years (A1)	2 (3.3%)
17–40 years (A2)	54 (90%)
>40 years (A3)	4 (6.67%)
Disease behavior
Nonstricturing, nonpenetrating (B1)	40 (66.7%)
Stricturing (B2)	20 (33.3%)
Penetrating (B3)	0 (0.00%)
Location of disease
Ileal (L1)	11 (18.3%)
Colonic (L2)	8 (13.3%)
Ileocolonic (L3)	41 (68.3%)
Upper Gastrointestinal (L4)	35 (58.3%)
Types of fistula
Simple	25 (41.7%)
Complex	35 (58.3%)
Fistula anatomical location
Intersphincteric	34 (56.7%)
Transsphincteric	19 (31.7%)
Suprasphincteric	5 (8.3%)
Extrasphincteric	2 (3.3%)
Previous surgery
Fistulotomy	13 (21.7%)
Incision and Drainage of Perianal Abscess	12 (20.0%)
Partial Resection of the Small Intestine	3 (5.0%)
Intestinal Perforation Repair Surgery	1 (1.7%)
Hemorrhoidectomy	2 (3.3%)
Previous medications
5-Aminosalicylic acid	60 (100.0%)
Corticosteroids	1 (1.7%)
Immunosuppressant	3 (5.0%)
Disease activity assessment markers
Hb (g/L)	120.28±18.38
Alb (g/L)	36.07±5.11
CRP (mg/L)	14.25 (7.22,34.53)
ESR (mm/h)	16.50 (10.00,36.00)
FC (μg/g)	322.28 (134.66,422.34)
IBDQ (points)	161.62±24.17
CDAI (points)	251.50 (184.00,272.55)
SES-CD (points)	14.50 (8.25,20.00)
PDAI (points)	8.0 (6.0,9.0)
VAS (points)	10.0 (8.0,13.0)

Note: L4 may coexist with L1, L2 and L3 simultaneously.

Abbreviations: CDAI, Crohn’s Disease Activity Index; PDAI, Perianal Disease Activity Index; VAS, Van Assche scores; IBDQ, Inflammatory Bowel Disease Questionnaire; Hb, Hemoglobin; Alb, Albumin; CRP, C-reactive Protein; ESR, Erythrocyte Sedimentation Rate; FC, Fecal Calprotectin.

Efficacy Assessments in All Population

Perianal Fistulas Efficacy in All Population

The FCres rates at weeks 14, 26, and 54 were 68.33% (41/60), 56.67% (34/60), and 48.33% (29/60) (primary efficacy point), while the FCrem rates were 45.00% (27/60), 40.00% (24/60), and 38.33% (23/60), respectively. Additionally, the RFRS rates at weeks 14, 26, and 54 were 41.67% (25/60), 30.00% (18/60), and 31.67% (19/60) in sequence, whereas the RFH rates were 36.67% (22/60), 31.67% (19/60), and 26.67% (16/60). The above efficacy data are illustrated in Figure 3.

Figure 3.

Perianal fistulas efficacy in all population.

Notably, 25.00% (15/60) of patients achieved FCrem at both weeks 14 and 54, while 16.67% (10/60) simultaneously met the RFH endpoint, as illustrated in Figure 4.

Figure 4.

Proportion of patients who had FCrem, RFH, ICrem, and IErem at both weeks 14 and 54.

Intestinal Clinical and Endoscopic Efficacy in All Population

Since the baseline CDAI scores of 15 patients were less than 150 points, they were excluded from the intestinal clinical efficacy assessments. The ICres rates at weeks 14, 26, and 54 were 62.22% (28/45), 68.89% (31/45), and 71.11% (32/45), while the ICrem rates were 46.67% (21/45), 55.56% (25/45), and 60.00% (27/45), respectively. Additionally, the IEres rates at weeks 14, 26, and 54 were 56.67% (34/60), 55.00% (33/60), and 60.00% (36/60), while the IErem rates were 38.33% (23/60), 45.00% (27/60), and 53.33% (32/60), respectively. The above efficacy data are illustrated in Figure 5.

Figure 5.

Intestinal endoscopic and clinical efficacy in all population.

Notably, 44.44% (20/45) and 36.67% (22/60) of patients achieved ICrem and IErem at both weeks 14 and 54, respectively, as illustrated in Figure 4.

Exploration Outcomes

After administration of HS016, the patients exhibited reduced inflammatory burden, as manifested by a significant decrease in CDAI, PDAI, VAS, CRP, FC, and ESR, improved nutrition as manifested by an increase in Alb and Hb, and improved quality of life assessment as manifested by an improvement in IBDQ (Supplementary Table 2).

Efficacy Assessments in Subgroup

Step-Up Therapy in Patients with PFCD

Throughout the study period, a total of 14 patients received 80mg HS016. Among them, 5 were in clinical remission at baseline (CDAI < 150) and excluded from clinical response analysis. At week 14, 8 patients with poor response received 80 mg HS016 every 2 weeks. By week 26, their FCres, FCrem, IEres, and IErem rates were 25.00% (2/8), 12.50% (1/8), 37.50% (3/8), and 12.50% (1/8), respectively. Of these 8 patients, 2 continued the same 80 mg biweekly HS016 maintenance regimen at week 26, while the remaining 6 withdrew from the study. At week 26, 6 new patients with poor response were added to the 2 continuing the 80mg biweekly HS016 regimen. In total, 8 patients opted for dose escalation and continued treatment until week 54. By week 54, the FCres, FCrem, IEres, and IErem rates were 21.43% (3/14), 14.29% (2/14), 42.86% (6/14), and 28.57% (4/14), respectively.

Complex and Simple PFCD

As shown in Supplementary Table 3, the baseline data of patients with simple PFCD and complex PFCD showed no statistically significant differences (P_sex=0.711, P_BMI=0.669, P_{Age of onset}=0.273, P_{Disease behavior}=0.853, P_{Location of disease}=0.819, P_{Fistula anatomical location}=0.073, P_{Previous surgery}=0.447, P_{Corticosteroids}=0.493, P_{Immunosuppressant}=0.741, P_Hb=0.404, P_Alb=0.673, P_CRP=0.600, P_ESR=0.626, P_FC=0.664, P_IBDQ=0.995, P_CDAI=0.535, P_SES-CD=0.594, P_PDAI=0.068, and P_{Van Assche}=0.066). Figures 6 and 7 showed that whether in the induction remission phase or maintenance remission phase, there were no statistically significant differences in perianal fistula efficacy[complex PFCD vs. simple PFCD at weeks 14, 26, and 54: FCres-65.71% vs. 72.00% (P=0.606), 48.57% vs. 68.00% (P=0.134), and 45.71% vs. 52.00% (P=0.631); FCrem-40.00% vs. 52.00% (P=0.357), 34.29% vs. 48.00% (P=0.285), and 31.43% vs. 48.00% (P=0.193); RFRS-42.86% vs. 40.00% (P=0.825), 28.57% vs. 32.00% (P=0.775), and 28.57% vs. 36.00% (P=0.542); RFH-31.43% vs. 44.00% (P=0.319), 25.71% vs. 40.00% (P=0.241), and 22.86% vs. 32.00% (P=0.430)], intestinal clinical efficacy[complex PFCD vs. simple PFCD at weeks 14, 26, and 54: ICres-57.69% vs. 68.42% (P=0.463), 69.23% vs. 68.42% (P=0.745) and 69.23% vs. 73.68% (P=0.745); ICrem-50.00%vs. 42.11% (P=0.600), 50.00% vs. 63.16% (P=0.745) and 53.85% vs. 68.42% (P=0.324)], and intestinal endoscopic efficacy[complex PFCD vs. simple PFCD at weeks 14, 26, and 54: IEres-54.29% vs. 60.00% (P=0.660), 51.43% vs. 60.00% (P=0.458), and 57.14% vs.64.00% (P=0.593); IErem-34.29% vs. 44.00% (P=0.445), 40.00% vs. 52.00% (P=0.326), and 51.43% vs.56.00% (P=0.726)] between patients with complex and simple PFCD.

Figure 6.

Perianal fistulas efficacy between patients with complex and simple PFCD.

Figure 7.

Intestinal endoscopic and clinical efficacy between patients with complex and simple PFCD.

Additionally, the proportion of FCrem at both weeks 14 and 56 in patients with simple PFCD showed a trend of a higher rate than that in patients with complex PFCD (36.00%, 9/25 vs. 17.14%, 6/35) (P=0.096).

Safety

During the follow-up period, only 3 patients developed mild rashes after the first injection of HS016. These rashes resolved spontaneously, and no rashes occurred in subsequent doses. Additionally, no active infections, new-onset tumors, or deaths were observed in the patients.

Discussion

With the deepening understanding of PFCD, therapeutic strategies for this condition have advanced rapidly. Traditional medications such as glucocorticoids and the immunosuppressant azathioprine show limited efficacy in managing PFCD. Moreover, these agents carry notable safety risks, including increased susceptibility to infections, hepatotoxicity, and nephrotoxicity.11,14 In contrast, combining biological agents with gradual glucocorticoid tapering has been proven to significantly reduce the risk of anal fistula progression in patients with CD.28

Anti-TNF-α agents, especially IFX, remain the first-line treatment for PFCD.29 A long-term follow-up study reported that the cumulative probabilities of initial fistula closure with IFX at 1, 3, 5, and 10 years were 33%, 59%, 73%, and 88%, respectively. The cumulative probabilities of sustained complete fistula closure (without recurrence) at 1, 3, and 5 years were 22%, 43%, and 57%, respectively.30 Another open-label Phase III multicenter randomized controlled trial showed that approximately 33% of PFCD patients achieved FCrem after 1 year of ADA treatment, and 60% after 2 years.25 A meta-analysis indicated that IFX (either monotherapy or combined with azathioprine) is the preferred initial treatment for biologic-naive moderate-to-severe CD, followed by ADA.29 Additionally, a separate meta-analysis suggested that IFX has a superior response-inducing effect compared to ADA in fistulizing CD, though no significant difference was observed in remission induction.31 It should be noted that direct head-to-head randomized controlled trials between these two agents are still lacking. When contextualizing these anti-TNF-α data with our findings, we found that the FCrem rate of HS016 at week 54 (38.33%) was comparable to the mid-term efficacy of ADA reported in previous studies (33% after 1 year). This consistency validates HS016 as a potential alternative to the originator ADA for PFCD treatment.

UPA, a novel targeted small-molecule drug, has expanded the therapeutic armamentarium for CD. Compared with biologics, UPA offers the advantages of oral administration, rapid absorption, and favorable bioavailability.32 Regardless of prior biologic exposure, UPA has demonstrated higher rates of clinical and endoscopic improvement than placebo in CD patients.33 A recent article based on a post-hoc analysis of three Phase 3 clinical trials evaluated the efficacy and safety of UPA in patients with PFCD. The results indicated that at week 52, the clinical remission rates for the UPA 15mg and 30mg groups were 36.8% (14/38) and 53.6% (15/28), respectively, endoscopic response rates were 31.6% (12/38) and 53.6% (15/28), respectively, and external fistula orifice closure rates were 18.8% (6/32) and 16.0% (4/25), respectively. Despite these findings, the study still had limitations such as a small sample size and lack of imaging assessment of the fistulas. Notably, during the UPA induction period, the incidence of adverse events such as nasopharyngitis (12.5% vs 4.3%) and upper respiratory tract infections (10.4% vs 4.3%) was higher compared to placebo.15 Another single-center study included 60 patients with complex PFCD and found that ustekinumab (UST) dual intravenous induction therapy improved clinical outcomes, with clinical, endoscopic, and radiological response rates of 63.3%, 73.7%, and 45%, respectively, and remission rates of 43.3%, 45%, and 38.3% at weeks 22–26.34 Nevertheless, this study did not include simple fistula patients for comparison and had a short follow-up period, which limited the evaluation of long-term efficacy.

The present study evaluated the short-term induction and long-term maintenance outcomes in biologic-naive PFCD patients through multi-dimensional assessments (clinical, endoscopic, and radiological). Our results showed that the FCrem, RFH, IErem, and ICrem rates at week 54 were 38.33%, 26.67%, 53.33%, and 60.00%, respectively. Subgroup analysis revealed that complex PFCD patients had numerically lower rates of FCrem (31.43% vs 48.00%, P=0.193) and RFH (22.86% vs 32.00%, P=0.430) than simple PFCD patients, though these differences were not statistically significant. During the follow-up period, only 3 patients developed transient rashes, indicating a favorable safety profile of HS016. These findings suggest that HS016 exhibits efficacy comparable to the originator ADA, further supporting its role as an alternative treatment option for PFCD. The consistency between our results and those of previous studies on IFX, UST, and UPA may be attributed to differences in study design, patient population characteristics, intervention strategies, and follow-up duration.

Loss of response to anti-TNF-α therapy is a common clinical challenge: approximately 33% of initial responders lose efficacy during follow-up, and 34% require dose escalation to maintain therapeutic effects.35 Among anti-TNF-α agents, IFX is associated with a slightly higher risk of response loss (33% vs 30%) and dose escalation (38% vs 36%) than ADA.35 For patients with complex anal fistulas, the failure and recurrence rates of IFX treatment are as high as 13–58% and 41%, respectively.36 A key contributing factor is IFX’s immunogenicity as a human-murine chimeric monoclonal antibody, which can induce anti-drug antibody formation in patients.37 Dose escalation is often required to address loss of response, persistent endoscopic inflammation, and elevated inflammatory markers.38 Therefore, therapeutic drug monitoring (TDM) is crucial for optimizing treatment outcomes. The latest evidence indicates that a higher trough concentration of ADA (optimal level: 12.1 mg/mL) is beneficial for complete fistula healing in PFCD patients,39 making TDM a valuable tool for guiding dose adjustment and treatment regimens. For patients with secondary loss of response who have low serum trough concentrations and low anti-drug antibody levels, empirical dose escalation can help some patients regain response.40 A retrospective study compared high-dose ADA maintenance therapy (40 mg weekly or 80 mg every 2 weeks) with standard-dose therapy (40 mg every 2 weeks) and found that the median time to treatment failure was 6.6 years in the high-dose group versus 3 years in the standard-dose group. The high-dose group had a significantly reduced risk of treatment failure (hazard ratio = 0.27, P=0.002), with no significant safety differences between groups.41 However, an RCT showed that high-dose ADA induction therapy was not superior to standard-dose therapy in moderate-to-severe CD patients,42 and this conclusion has not been validated in PFCD populations.

In our study, dose adjustment of HS016 was personalized based on disease severity and drug tolerability assessed by IBD-specialized gastroenterologists. Patients who responded well to HS016 received standard-dose maintenance therapy (40 mg every 2 weeks) from week 14 or 26. For patients with poor responses, a flexible dose-escalation strategy (80 mg every 2 weeks) was implemented. Ultimately, 16 patients underwent dose escalation at different stages: 8 patients were escalated from week 14 to 26 (2 of whom maintained the escalated dose after achieving FCrem), and 8 patients were escalated from week 26 to 54 (4 of whom achieved FCrem). These results suggest that dose escalation of HS016 is effective for some PFCD patients. Unfortunately, TDM was not available for all patients in our study, so treatment decisions were based solely on clinical assessment rather than drug concentration monitoring. However, a previous study indicated that dose adjustment guided by TDM yields comparable efficacy to that guided by clinical assessment in maintenance therapy.42 It is also important to note that TNF-α antagonists are associated with a 1.5-2-fold increased risk of serious infections.14 Caution should be exercised when implementing dose escalation in PFCD patients, especially those with baseline complications such as perianal abscesses.

This is the first prospective observational real-world study focusing on biologic-naive PFCD patients. Unlike previous studies that only assessed single-dimensional outcomes, our research adopted a comprehensive evaluation approach covering clinical symptoms, endoscopic findings, radiological fistula status, nutritional indicators, and inflammatory markers. The long follow-up duration (54 weeks) provided valuable insights into the long-term efficacy and safety of HS016 in clinical practice. Additionally, subgroup analysis of simple and complex PFCD patients offered specific data support for personalized treatment strategies in different PFCD subtypes.

While this study has several notable strengths, including being the first prospective observational real-world study focusing on biologic-naive PFCD patients, adopting a comprehensive multi-dimensional assessment approach covering clinical symptoms, endoscopic findings, radiological fistula status, nutritional indicators, and inflammatory markers, and conducting a relatively long follow-up of 54 weeks to provide insights into the short-term induction and long-term maintenance efficacy of HS016 as well as performing subgroup analysis between simple and complex PFCD patients to offer specific data support for personalized treatment strategies, it also has certain limitations that should be acknowledged. Firstly, this was a single-center, small-sample, non-randomized controlled trial, which limits the generalizability of the results and reduces statistical power. Secondly, the study population mainly included patients with moderate clinical and endoscopic activity, lacking data on patients with mild or severe PFCD . Thirdly, patients were not randomly assigned to maintenance therapy regimens, and subsequent treatment (either standard-dose or dose-escalated) was selected based on their comprehensive clinical, endoscopic, and fistula responses rather than a standardized protocol. Additionally, TDM was not performed for all patients, which may have affected the accuracy of dose adjustment strategies. Finnally, although the follow-up period exceeded 1 year, it was still insufficient to evaluate the long-term risks of HS016, such as the risk of secondary tumors, meaning longer follow-up observations exceeding 5 years are needed to draw more convincing conclusions on the long-term benefits and risks of maintenance remission treatment.

In conclusion, the present study is the first prospective observational real-world study conducted in biologic-naive PFCD patients. The results indicate that HS016 improves clinical symptoms, endoscopic findings, fistula status, nutritional indicators, and inflammatory burden in PFCD patients, with a favorable safety profile. However, its efficacy is relatively limited, particularly for complex fistulas. In addition, this study provides important data support for evaluating the efficacy and safety of HS016 in clinical practice, and is expected to offer evidence-based medical support for future treatment decisions in this special PFCD patient population.

Funding Statement

This work was supported by National Key Research and Development Program of China (2023YFC2507300) and National Natural Science Foundation of China (No. 82470562).

Trial Registration Number

https://www.chictr.org.cn/showproj.html?proj=130582; ChiCTR2100049326

Data Sharing Statement

The datasets used in this study can be obtained from the corresponding author (Liangru Zhu) upon request.

Ethics Approval

Written informed consent was obtained from the patients for the publication. The studies involving human participants were reviewed and approved by the ethics committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (20210097).

Author Contributions

All authors made a significant contribution to the work reported, whether that was in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors have declared no conflicts of interest in this work.