Filgotinib effectiveness and safety as second or third-line therapy in patients with ulcerative colitis: data from a real-world study
Article information
, Giammarco Mocci3,*, Francesco Costa4, Linda Ceccarelli4, Edoardo Savarino5, Caterina De Barba5, Caterina Mucherino6, Elvira D’Antonio6, Laura Montesano6, Manuela Marzo7, Franco Scaldaferri8,9, Daniele Napolitano8, Daniela Pugliese8,9, Antonietta Gerarda Gravina10, Raffaele Pellegrino10, Rocco Spagnuolo11, Francesco Luzza11, Antonio Cuomo12, Laura Donnarumma12, Giovanni Maconi13, Giovanni Cataletti13, Lorenzo Bertani14, Giorgia Bodini15, Andrea Pasta15, Simona Piergallini16, Mariaelena Serio17, Antonella Scarcelli17, Pietro Capone18, Fabio Cortellini19, Stefano Rodino20, Ladislava Sebkova20, Giuliana Vespere21, Silvia Sedda21, Vittorio D’Onofrio21, Leonardo De Luca21, Federica Gaiani22, Stefano Kayali22, Cristiano Pagnini23, Maria Giovanna Graziani23, Maria Carla Di Paolo23, Leonardo Allegretta24, Alessia Immacolata Cazzato24, Stefano Scorza24, Antonio Ferronato25, Davide Giuseppe Ribaldone26, Giovanni Aragona27, Patrizia Perazzo27, Giacomo Forti28, Michela Di Fonzo29, Federico Iacopini29, Roberta Pica30, Claudio Cassieri30, Francesca Maria Onidi3, Paolo Usai Satta3, Walter Elisei31, Marcello Picchio32, Alfredo Papa8,9
Abstract
Background/Aims
Real-world data on the use of filgotinib (FILGO) in patients with ulcerative colitis (UC) are limited. This study aims to provide consistent results on the effectiveness and safety of FILGO in treating UC.
Methods
A retrospective assessment of clinical and endoscopic activity was conducted in a cohort of patients with UC according to the full Mayo score. The primary co-endpoints of the study were the evaluation of the effectiveness and safety of FILGO.
Results
We enrolled 102 patients with a median follow-up of 24 weeks (interquartile range, 8–24 weeks). At 8 weeks and the end of follow-up, clinical remission was achieved by 38 (37.2%) and 47 (46.1%) patients, respectively. Clinical remission was achieved in 13 of 18 patients (72.2%) receiving first-line therapy, 7 of 19 patients (36.8%) receiving second-line therapy, and 27 of 65 patients (41.5%) receiving third-line therapy (P= 0.002). Clinical remission at 8 weeks predicted clinical remission at the end of follow-up (P= 0.021). Age > 40 years (P= 0.046) and being on second- or third-line of treatment (P= 0.005) were negative predictors for clinical remission. Seventy-one patients (69.6%) achieved a clinical response. At endoscopic evaluation, mucosal healing was observed in 18 out of 30 patients (60.0%). Steroid-free remission was present in 38 out of 46 patients (82.6%). Five patients (4.9%) needed colectomy. Adverse events were recorded in 6 patients (5.8%): 2 cases (2%) were severe, requiring discontinuation of FILGO.
Conclusions
Our real-world data confirms that FILGO is safe and effective for patients with UC. Its efficacy is significantly improved when used as a first-line treatment.
INTRODUCTION
Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease (IBD), resulting from a complex interaction between genetic and environmental factors without an apparent specific trigger [1,2].
Our evolving treatment paradigms recognize the need to treat symptoms and achieve biochemical and endoscopic remission whenever possible, improving quality of life and reducing the risk of long-term disease- and drug-related complications [3]. Anti-tumor necrosis factor-α (anti-TNF-α) antibodies were the first drugs developed to achieve these endpoints [4,5]. However, up to 30% of patients experience primary non-response and up to 50% show secondary loss of response due to intolerance, immunogenicity or mechanistic failure with anti-TNF therapies. Therefore, new treatments have been developed in the last two decades [6,7].
Filgotinib (FILGO) is a potent and selective inhibitor of the Janus kinase family, a family of tyrosine kinases that mediate cytokine signaling through interactions with type I and II cytokine receptors [8]. Janus kinase inhibitors (JAKi) have several advantages over biologics, including rapid onset of action, lack of immunogenicity, greater patient convenience, and no infusion requirement since they are administered orally [8]. Tofacitinib has been the first JAKi to be licensed for the treatment of UC, demonstrating significant efficacy and safety in both controlled [9], and real-world (RW) studies [10].
FILGO, a JAK1 inhibitor, was found to be effective in treating UC in a recent randomized, placebo-controlled phase 2b/3 study (SELECTION trial) [11]. Currently, the RW effectiveness of FILGO in treating UC patients is mainly based on data from a few studies, characterised by relatively small cohort sizes [12,13], and mainly from Japan [13-16].
Therefore, we aimed to evaluate the clinical and endoscopic efficacy and safety of FILGO in a RW experience of 30 Italian centers.
METHODS
This is a retrospective, observational, multicenter study including consecutive UC patients treated with FILGO in 30 Italian IBD centers (namely centers identified by the Italian National and Regional Health Systems as able to manage IBD patients). We assessed patients enrolled from 1 September, 2023 to 31 July, 2024 who completed at least the induction treatment.
Eligible patients were men and women over 18 years with an established UC diagnosis based on standard endoscopic, radiological, and histological criteria [1,17]. Moreover, according to drug indication, all the patients presented with mild-to-moderate active disease [18]. Demographic and clinical data were collected using a common shared database. Data collected at baseline were gender, age at diagnosis, smoking status, disease extension, disease duration, previous immunosuppressive and previous biologic therapies use (anti-TNF-α, anti-interleukin [IL]-12/23 or anti-integrin, JAKi), concomitant medications at baseline, C-reactive protein and fecal calprotectin levels, Mayo score, and Mayo subscore for endoscopic assessment.
The study was conducted following clinical practice guidelines. All patients gave written informed consent before undergoing endoscopy and FILGO treatment. The present study follows the principles of the Declaration of Helsinki. Ethics committee approval was obtained by “Brotzu” Hospital (Cagliari, Italy, PROT. PG/2022/18006).
1. Study Treatment
Filgotinib (Jyseleca, Bologna, Italy) was approved in Italy for UC patients treatment after first-line anti-TNF-α failed except for patients with contraindications to other biologic drugs [18]. It was administered as induction therapy at 200 mg per day for 8 weeks via the oral route to obtain remission, and the same dosage was also used to maintain remission in case of clinical response.
2. Clinical Assessment
According to the Montreal classification, disease extension was assessed at baseline and during follow-up [19]. Severity was evaluated according to the full Mayo score [20]. All included patients had active disease despite concomitant treatment, defined as a Mayo score ≥ 3 points [20]. Patients were clinically assessed at entry, after 2, 4, and 6 months, and after that, every 6 months. Biochemical assessment was performed at every control visit or whenever the clinician considered it necessary. In addition, in a subgroup of 82 patients, the number of days required (during the first 8 weeks of treatment) to obtain the disappearance of rectal bleeding, abdominal pain and urgency was assessed using daily patients’ reported outcomes.
3. Endoscopy
All patients had to have an ileocolonoscopy before beginning FILGO treatment, as this is standard protocol in the participating centers. During the follow-up, at least 6 months after enrollment in the study, patients underwent ileocolonoscopy according to the clinician’s judgment. Endoscopic severity was assessed in these patients according to the Mayo subscore for endoscopy [20].
4. Primary Endpoints
The co-primary endpoints were: (1) to assess the effectiveness of FILGO in obtaining clinical remission, defined as a partial Mayo score ≤1 or as a full Mayo score ≤2 (with no single score’s item >1) [21], at follow-up, in UC patients refractory to previous treatment (including anti-TNF-α and anti-IL-12/23 and anti-integrin) at 8 weeks and at the median follow-up available after starting treatment. We defined FILGO use as first, second-line, or third-line when used as naive to biologic (first-line therapy, in patients with contraindication to be treated with anti-TNF-α) and resistant or dependent to steroids [1], or when used in patients who failed one or more anti-TNF-α treatment (second-line therapy), or when used in patients who failed anti-TNF-α and anti-integrin or anti-IL-12/23 treatment (third-line therapy); (2) to assess the safety of FILGO, recording the adverse events (AEs). The AEs were classified as early (occurring during the first 8 weeks of treatment) and late (occurring after this date), and graded as mild (not requiring the therapy to stop treatment) and severe (requiring to stop treatment). The occurrence of opportunistic infections was also regarded as an AE. This was defined as an infection caused by microorganisms with limited pathogenic capacity under normal circumstances. It can cause disease because of the predisposing effect of another disease or its treatment [22].
5. Secondary Endpoint
As secondary points, we assessed the following: (1) clinical response, defined as a decrease of at least 2 points in the Mayo score [21], at 8 weeks and at the median follow-up available after starting treatment; (2) mucosal healing, defined as a Mayo subscore for endoscopy of ≤1 [21]; (3) steroid-free remission during the study [21]; (4) rate of colectomy; (5) the number of days required to obtain the disappearance of diarrhea, abdominal pain and urgency; or (6) the impact of the treatment on cholesterol (total and low-density lipoprotein, assessed as mg/dL), triglycerides (assessed as mg/dL), and creatine phosphokinase (assessed as UI/L) levels.
6. Statistical Analysis
MedCalc Release 14.8.1 was used to analyze the data. The study group’s characteristics were examined as the median (interquartile range [IQR]) for continuous non-parametric variables and as a number (percentage) for categorical variables. The chi-square test was used to compare categorical variables, and the Mann-Whitney test was used for continuous variables. Clinical remission was considered the primary endpoint. Because of the varying length of follow-up, the predictive value of clinical parameters was assessed using time-to-event methods for censored observations. The duration of follow-up was calculated from the date of starting therapy to the date of the event or censorship. Time-to-event analysis was carried out using Kaplan-Meier estimates to draw the cumulative incidence curves, compared by log-rank tests, and by univariate and multivariate Cox’s proportional hazards models of prognostic variables. P-values of <0.05 were statistically significant.
RESULTS
The study group comprised 102 patients (50.9% male, with a median age of 47 years [IQR, 35–58 years]). The median follow-up length was 24 weeks (IQR, 8–24 weeks). The characteristics of the study group are reported in Table 1. Most patients suffered from pancolitis (59.8%) and were treated with FILGO after failure of anti-TNF-α plus anti-integrin or anti-IL-12/23 (63.7%). The patients naive to biologic therapies, namely patients taking FILGO as first-line after failure of steroids, suffered from pancolitis in 13 out of 18 (72.2%) of cases and from left-sided colitis in 5 (27.8%) of cases. No patients were used as a fourth-line therapy (namely failure to anti-TNF, anti-integrin, anti-IL-12/23, and JAKi).
Characteristics of the Study Group
1. Primary Outcomes
At 8-week follow-up, clinical remission was achieved in 38 patients (37.2%); at the end of median follow-up, clinical remission was achieved in 47 patients (46.1%). Clinical remission was obtained by 13 out of 18 (72.2%) of patients in first-line therapy, by 7 out of 19 (36.8%) of patients in second-line therapy, and by 27 out of 65 (41.5%) of patients in third-line therapy (P=0.002, log-rank test) (Fig. 1). At univariate analysis clinical remission at 8-week follow-up (odds ratio [OR], 6.70; 95% confidence interval [CI], 2.59–17.30; P<0.001) significantly predicts final clinical remission (Fig. 2A), while age >40 years (OR, 0.47; 95% CI, 0.23–0.96; P=0.006) and being on second- and third-line treatment (OR, 0.22; 95% CI, 0.06–0.74; P=0.014), were negative factors for clinical remission (Fig. 2B and C). At multivariate analysis, clinical remission at 8-week follow-up (OR, 2.21; 95% CI, 1.13–4.34; P=0.021) was the only factor predicting clinical remission, while both age >40 years (OR, 0.46; 95% CI, 0.22–0.99; P=0.046) and being on second/third line treatment (OR, 0.31; 95% CI, 0.14–0.69; P=0.005) were negative predictive factors for clinical remission (Table 2).
Estimated cumulative clinical remission probability during follow-up by indications for therapy (P=0.002, log-rank test).
Estimated cumulative clinical remission probability during follow-up. (A) By clinical remission at 8-week follow-up (P<0.001, logrank test). (B) By age (P=0.006, log-rank test). (C) By line of treatment (P=0.014, log-rank test).
Association of Clinical Characteristics with Remission
2. Secondary Outcomes
Clinical response was achieved in 71 patients (69.6%). Endoscopic assessment was performed in 30 patients after an average of 24 weeks: Mucosal healing was observed in 18 out of 30 patients (60.0%). Steroid-free remission was present in 35 out of 42 patients (83.3%). Surgery was necessary in 5 patients (4.9%). After the initiation of FILGO, the disappearance of UC-related symptoms was achieved as follows: diarrhea after a median of 9 days (IQR, 5–15 days), abdominal pain after 7 days (IQR, 5–14 days), and urgency after 7 days (IQR, 5–15 days). At baseline and during follow-up, serum creatine phosphokinase and triglyceride levels were similar (Fig. 3A and B). At the same time, total cholesterol was significantly higher without any relevant difference in low-density lipoprotein levels (Fig. 3C and D).
Serum levels at baseline and during follow-up. (A) Creatine phosphokinase levels at baseline and during follow-up. All follow-up values, given as median (error bar, interquartile range), were similar during follow-up (P=0.943, Mann-Whitney test). (B) Triglycerides levels at baseline and during follow-up. All follow-up values, given as median (error bar, interquartile range), had not significantly varied during follow-up (P=0.995, Friedman test). (C) Cholesterol levels at baseline and during follow-up. All follow-up values, given as median (error bar, interquartile range), increased significantly during follow-up (P =0.003, Mann-Whitney test). (D) Low-density lipoprotein at baseline and during follow-up. All follow-up values, given as median (error bar, interquartile range), had not significantly varied during follow-up (P=0.214, Mann-Whitney test).
3. Adverse Events
The AE rate was low, they were recorded in only 6 patients (5.8% of the population): in 4 cases (3.92% of the population) they were mild and did not require the suspension of FILGO treatment; in 2 cases (1.96%) they were severe and required stopping FILGO administration (Table 3). Significantly, no instances of major adverse cardiovascular events and venous thromboembolic events were recorded. About the severe case of generalized infection, the patient was admitted to the Emergency Room with fever >39°C and therefore admitted to the Division of Infectious Diseases with a diagnosis of “generalized infection.” The FILGO treatment was stopped, but no further information was drawn because the patient was lost to follow-up after discharge.
Adverse Events in the Study Group (102 Patients)
DISCUSSION
Currently, the management of UC remains challenging due to low response rates, frequent primary and secondary failures, and intolerance. Data on the effectiveness of FILGO are scarce. We aimed to describe the efficacy of FILGO in RW clinical practice in a large cohort of UC patients from different IBD centers in Italy.
The first interesting result is that the remission rate of our cohort increased during treatment with FILGO, from 37.2% at 8 weeks to 46.1% at the end of the follow-up. Although these results cannot be entirely comparable with that of a placebo-controlled trial, as expected these results are better than those reported in the SELECTION study [11], and are close to the same remission rate reported in the current literature. In RW studies, the remission rate at 24 weeks ranged from 45.8% to 76.4% [12-16]; a recent large RW clinical study reports that the remission rate increased from 36% at week 10 to 51% at week 26 [23], even if not all studies report this increasing remission rate [24]. This probably means that it is essential to continue the treatment with FILGO until week 24 even in patients having response but not remission at week 8, as the remission rate may progressively increase. Therefore, FILGO appears to have the same behavior as vedolizumab, which may take up to 6 months to achieve remission [25]. Moreover, in our experience, the remission rate with FILGO seems to be similar to that of tofacitinib, with the latter having a clinical remission rate at 8 and 24 weeks of 36.7% and 45.2%, respectively [10]. This could mean that JAKi work similarly and that there are no differences in the use of tofacitinib or FILGO in these patients. On the other hand, this could be just a trend, and as observed with other drugs, we need to evaluate late responders by making long-term comparisons between tofacitinib and upadacitinib.
The same effectiveness of FILGO and tofacitinib seems to be confirmed by Akiyama et al. [16], who found no difference between FILGO and tofacitinib in treating mild-to-moderate UC. The situation may be different if we compare FILGO with upadacitinib, because Nogami et al. [15] and Akiyama et al. [16] found superiority of upadacitinib over FILGO in achieving clinical remission (65.7% vs. 46.9% and 72.8% vs. 50.6%, respectively). However, both these studies are from Japan, and no data are currently available from other countries. Furthermore, in the Akiyama study the baseline severity of patients treated with FILGO was lower than that of those treated with tofacitinib, finding that may be a bias when comparing these 2 drugs [16]. Further studies comparing the 3 currently available JAKi are needed before drawing any conclusions.
Another important point from this study is that the remission rate with FILGO was significantly higher in patients naive to biologic therapies than in patients already treated with anti-TNF-α and/or anti-integrin. We observed a remission rate of 72.2% in patients treated as first-line therapy, 36.8% as second-line therapy, and 41.5% as third-line therapy. Again, in the Italian population, this behavior seems to be the same as tofacitinib, which worked better in patients with bio-naive UC than in bio-experienced patients [24]. This result differs from that reported in the SELECTION trial [11], and some RW studies [14,23]. All these studies found no differences in achieving remission with FILGO when treating bio-naive or bio-experienced UC patients. Since disease characteristics (severity, extent, use of drugs, etc.) are similar in these studies, other causes must be searched. One hypothesis could be related to patients’ characteristics. We enrolled only Italian patients living in Italy: intrinsic population characteristics (e.g., diet or genetics) could explain a more significant response in naive patients. Another hypothesis is that a high expectation towards the therapy could justify a greater efficacy in naive patients (placebo effect). Conversely, patients who have already failed biotechnological treatment could have a more negative approach to a new therapy (nocebo effect). Whatever the explanation, in our population, FILGO is more effective in patients naive to biotechnological therapies.
Among the factors influencing the positive response to FILGO, we found that clinical remission at 8-week follow-up was a positive predictive factor, while age >40 years and being on second/third line treatment were negative predictos for clinical remission at maxiamal follow-up both at univariate and multivariate analysis. Regarding the lower effectiveness in patients older than 40, we can hypothesize that middle-aged patients may benefit less from FILGO treatment. We also know that elderly IBD patients may have a similar effectiveness rate to younger IBD patients, although with higher AEs [26]. Furthermore, these interesting results need further investigation. Another potential factor that may influence the FILGO remission rate is that it cannot be optimized because the dose for induction and maintenance is the same.
Regarding the other secondary endpoints, the most critical issue of interest is the time to symptom resolution. The original SELECTION trial [11], and the available RW studies did not investigate this aspect. This is surprising, since controlled [9,27], and RW studies [10,28] have shown that tofacitinib rapidly improves symptoms. A post-hoc analysis of the SELECTION trial found the drug effective in inducing a rapid resolution of symptoms [29]. The results of this study are consistent with these data: FILGO seems to induce the resolution of rectal bleeding, abdominal pain, and urgency in less than 10 days. The colectomy rate was 4.9%, in line with what was reported in the other studies [12-16,23].
Regarding safety, our study confirms the high safety profile of FILGO. Approximately 5% of AEs were recorded, and the drug was discontinued in only 2 cases (1.96%), although the short follow-up period (24 weeks) may have influenced this result. However, it aligns with current RW literature, which reports AEs rates ranging from 4.2% to 53.8% [12-16,23]. Significantly, these studies reported only 1 case of major adverse cardiovascular events or venous thromboembolic events [23], confirming the safety of FILGO also in this specific setting. The analysis of cholesterol levels also confirms the safety profile of FILGO. Although a significant increase in total cholesterol was recorded, low-density lipoprotein cholesterol remained substantially stable during the follow-up, which could partially explain the absence of vascular complications.
This study has strengths and limitations. Regarding the strengths, it is one of the first European studies to evaluate the role of FILGO in patients with UC. Another strength is the large population enrolled, which reinforces the results. Finally, the multicenter data collection allowed us to broadly represent the use of this drug in several Italian regions. On the other hand, the study’s retrospective nature and the short-term follow-up (24 weeks) may represent a limitation since some parameters (e.g., underestimating the AEs rate) may not have been recorded.
In conclusion, FILGO was effective and well-tolerated in this multicenter Italian cohort of patients with UC. The ideal positioning of FILGO in treatment algorithms is yet to be defined. However, our results support its role as early treatment for patients with UC who were not previously exposed to biotechnological therapies.
Notes
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
Tursi A served as speaker and/or consultant for AbbVie, Bayer, Fenix Pharma, Galápagos, Janssen, Nalkein, Omega Pharma, and SILA; Mocci G served as speaker and/or advisory board fees for AbbVie, Amgen, Aurora Biopharma, Biogen, Celltrion, Chiesi, Fenix Pharma, Ferring, Galápagos, Janssen, MSD, Omega Pharma, Sandoz, Takeda, and Vifor Pharma; Scaldaferri F has served as a lecturer for AbbVie, Celltrion, Ferring, Janssen, Lilly, Pfizer, Sanofi, and Takeda; Pugliese D received speaker fees from AbbVie, MSD, Takeda, Janssen, and Pfizer; Savarino E has served as a speaker for AbbVie, AGPharma, Alfasigma, Dr Falk, EG Stada Group, Fresenius Kabi, Grifols, Janssen, Innovamedica, Malesci, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Unifarco; has served as consultant for Alfasigma, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Diadema Farmaceutici, Dr Falk, Fresenius Kabi, Janssen, Merck & Co, Reckitt Benckiser, Regeneron, Sanofi, Shire, SILA, Sofar, Synformulas GmbH, Takeda, and Unifarco; he received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, and Unifarco; Maconi G has served as speaker and/or advisory board fees for Alfasigma, Arena, Janssen, Gilead, and Roche; Gravina AG has conducted training activities (e.g., ECM, preceptorship) for AbbVie, Fenix Pharma, Galápagos Biopharma, and Pfizer; Ferronato A has received advisory board fees from AbbVie, Celltrion, and Galápagos; Papa A received speaker fees from Janssen and Alfasigma; the remaining authors declare no competing interests.
Data Availability Statement
All data and related metadata underlying the findings reported in the manuscript are deposited in an appropriate public repository, unless already provided as part of the article.
Author Contributions
Conceptualization: Tursi A. Data curation: Tursi A, Mocci G, Savarino E, Elisei W, Picchio M, Papa A. Formal analysis: Elisei W, Picchio M. Investigation: Tursi A, Mocci G. Methodology: Picchio M, Papa A. Project administration: Tursi A. Resources: all authors. Software: Elisei W, Picchio M. Supervision: Tursi A. Writing - original draft: Tursi A. Writing - review & editing: all authors. Approval of final manuscript: all authors.