Withdrawal and Re-treatment with Filgotinib in Ulcerative Colitis: Post Hoc Analyses of the Phase 2b/3 SELECTION and SELECTIONLTE Studies

BACKGROUND AND AIMS Maintenance treatment for ulcerative colitis may be discontinued for multiple reasons. This post hoc analysis assessed the efficacy and safety of re-treatment with filgotinib, an oral, once-daily, Janus kinase 1 preferential inhibitor, in the phase 2b/3 SELECTION trial and its long-term extension [LTE] study in ulcerative colitis. METHODS Partial Mayo Clinic Score [pMCS] response and remission were evaluated in patients who received induction with filgotinib 200 mg [FIL200] or 100 mg [FIL100], were randomized to treatment withdrawal [placebo] during maintenance, and following disease worsening, were re-treated with open-label FIL200 in the LTE study. Factors were evaluated for association with pMCS remission at LTE week 12, and safety outcomes were reported. RESULTS Analyses included 86 patients [FIL200: n = 51; FIL100: n = 35]. Median time to disease worsening following treatment withdrawal was 15.1 weeks (95% confidence interval [CI]: 9.1-18.7) for FIL200-induced patients and 9.6 weeks [95% CI: 6.3-12.0] for FIL100-induced patients. Three-quarters [75%] of patients achieved a pMCS response within 4-5 weeks of re-treatment in both groups. At LTE week 48, pMCS remission was achieved by 45.1% and 51.4% of FIL200- and FIL100-induced patients, respectively. Factors independently associated with restoring efficacy included no concomitant use of corticosteroids at induction baseline, and high albumin levels, pMCS remission and endoscopic score at maintenance baseline. No new safety signals were reported among re-treated patients. CONCLUSIONS In induction responders, re-treatment with FIL200 following temporary withdrawal from therapy restores response and/or remission in the majority of patients within 12 weeks. Re-treatment is well-tolerated

Impact of Concomitant Thiopurine on the Efficacy and Safety of Filgotinib in Patients with Ulcerative Colitis: Post hoc Analysis of the Phase 2b/3 SELECTION Study

BACKGROUND AND AIMS: SELECTION is the first study to assess the impact of concomitant thiopurine and other immunomodulator [IM] use on the efficacy and safety of a Janus kinase inhibitor, filgotinib, in patients with ulcerative colitis. METHODS: Data from the phase 2b/3 SELECTION study were used for this post hoc analysis. Patients were randomized [2:2:1] to two induction studies [biologic-naive, biologic-experienced] to filgotinib 200 mg, 100 mg, or placebo. At week 10, patients receiving filgotinib were re-randomized [2:1] to continue filgotinib or switch to placebo until week 58 [maintenance]. Outcomes were compared between subgroups with and without concomitant IM use. RESULTS: At week 10, a similar proportion of patients in +IM and -IM groups treated with filgotinib 200 mg achieved Mayo Clinic Score [MCS] response [biologic-naive: 65.8% vs 66.9%; biologic-experienced: 61.3% vs 50.5%] and clinical remission [biologic-naive: 26.0% vs 26.2%; biologic-experienced: 11.3% vs 11.5%]. At week 58, a similar proportion of patients in +IM and -IM groups treated with filgotinib 200 mg achieved MCS response [biologic-naive: 74.2% vs 75.0%; biologic-experienced: 45.5% vs 61.4%] and clinical remission [biologic-naive: 51.6% vs 47.4%; biologic-experienced: 22.7% vs 24.3%]. The probability of protocol-specified disease worsening during the maintenance study in patients treated with filgotinib 200 mg did not differ between +IM and -IM groups [p = 0.6700]. No differences were observed in the incidences of adverse events between +IM and -IM groups in induction/maintenance studies. CONCLUSIONS: The efficacy and safety profiles of filgotinib treatment in SELECTION did not differ with or without concomitant IM use

Integrated safety analysis of filgotinib for ulcerative colitis: Results from SELECTION and SELECTIONLTE

BACKGROUND: Filgotinib 200 mg (FIL200) is an approved treatment for adults with moderately to severely active ulcerative colitis (UC). AIM: To report integrated safety data from the phase 2b/3 SELECTION study (NCT02914522) and its ongoing long-term extension study SELECTIONLTE (NCT02914535). METHODS: Safety outcomes were analysed in adults with moderately to severely active UC who received FIL200, filgotinib 100 mg (FIL100) or placebo once daily throughout the 11-week SELECTION induction study, the 47-week SELECTION maintenance study (if applicable) and SELECTIONLTE (if applicable). Exposure-adjusted incidence rates (EAIRs) per 100 censored patient-years of exposure with 95% confidence intervals were reported for treatment-emergent adverse events (AEs). Certain AE data were presented in subgroups, including age and prior biologic exposure status. RESULTS: This interim analysis included 1348 patients representing 3326.2 patient-years of exposure. Baseline characteristics of patients entering SELECTION were similar across treatment groups. EAIRs for serious infection, thromboembolic events and major adverse cardiovascular events (MACE) were consistently low across treatment groups. Most patients with MACE had cardiovascular risk factors. The EAIR for herpes zoster was numerically higher for FIL200 than for placebo. Infection incidences were numerically higher in biologic-experienced than biologic-naive patients. Higher incidences of certain AEs in patients 65 years of age or older were as expected. Four deaths occurred, including three cardiovascular deaths, none of which was considered related to filgotinib. CONCLUSION: FIL200 and FIL100 were well tolerated with no unexpected safety signals in patients with moderately to severely active UC, regardless of previous biologic exposure or age

Rapid and Sustained Symptom Relief in Patients With Ulcerative Colitis Treated With Filgotinib: Data From the Phase 2b/3 SELECTION Trial

INTRODUCTION Patients with ulcerative colitis (UC) regard rapid onset of action among the most important aspects of their treatment. We used the partial Mayo Clinic Score (pMCS) and component patient-reported subscores to assess the rapidity and sustainability of response to filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, in adults with moderately to severely active UC in the phase 2b/3 SELECTION trial. The association between early symptomatic improvements and health-related quality of life (HRQoL) outcomes was also assessed. METHODS In these post hoc analyses of the double-blinded, randomized, placebo-controlled 58-week SELECTION trial (NCT02914522), rectal bleeding and stool frequency diary data on days 1-15 and pMCS remission and response at multiple time points including weeks 10 and 58 were evaluated. HRQoL was assessed using the Inflammatory Bowel Disease Questionnaire at weeks 10 and 58. RESULTS Filgotinib 200 mg relative to placebo improved rectal bleeding and stool frequency within 7 days ( P < 0.05). By week 2, greater proportions of filgotinib 200 mg-treated patients than placebo-treated patients achieved pMCS remission (biologic-naive, 15.1% vs 8.0%, P = 0.0410; biologic-experienced, 10.3% vs 4.2%, P = 0.0274). A similar treatment effect was observed at week 58 ( P < 0.0001). Day 7 rectal bleeding and stool frequency subscores were associated with the Mayo Clinic Score response at weeks 10 and 58. Patients in pMCS remission at weeks 10 and 58 had greater improvements in the Inflammatory Bowel Disease Questionnaire score than those not in pMCS remission. DISCUSSION Filgotinib 200 mg daily resulted in rapid and sustained improvements in both UC symptoms and HRQoL

Barriers for Access to New Medicines: Searching for the Balance Between Rising Costs and Limited Budgets

Introduction: There is continued unmet medical need for new medicines across countries especially for cancer, immunological diseases and orphan diseases. However, there are growing challenges with funding new medicines at ever increasing prices along with funding increased medicine volumes with the growing prevalence of both infectious diseases and non-communicable diseases across countries. This has resulted in the development of new models to better manage the entry of new medicines, new financial models being postulated as well as strategies to improve prescribing efficiency. However, more needs to be done. Consequently, the primary aim of this paper is to consider potential ways to optimise the use of new medicines balancing rising costs with increasing budgetary pressures to stimulate debate especially from a payer perspective. Methods: A narrative review of pharmaceutical policies and implications, as well as possible developments, based on key publications and initiatives known to the co-authors principally from a health authority perspective. Results: A number of initiatives and approaches have been identified including new models to better manage the entry of new medicines based on three pillars (pre-, peri-, and post-launch activities). Within this, we see the growing role of horizon scanning activities starting up to 36 months before launch, managed entry agreements and post launch follow-up. It is also likely there will be greater scrutiny over the effectiveness and value of new cancer medicines given ever increasing prices. This could include establishing minimum effectiveness targets for premium pricing along with re-evaluating prices as more medicines for cancer lose their patent. There will also be a greater involvement of patients especially with orphan diseases. New initiatives could include a greater role of multicriteria decision analysis, as well as looking at the potential for de-linking research and development from commercial activities to enhance affordability. Conclusion: There are a number of ongoing activities across countries to try and fund new valued medicines whilst attaining or maintaining universal healthcare. Such activities will grow with increasing resource pressures and continued unmet need

MANTA and MANTA-RAy: Rationale and Design of Trials Evaluating Effects of Filgotinib on Semen Parameters in Patients with Inflammatory Diseases

Introduction: The phase 2 MANTA and MANTA-RAy studies were developed in consultation with global regulatory authorities to investigate potential impacts of filgotinib, a Janus kinase 1 preferential inhibitor, on semen parameters in men with active inflammatory diseases. Here we describe the methods and rationale for these studies. Methods and Rationale: The MANTA and MANTA-RAy studies included men (aged 21–65 years) with active inflammatory bowel disease (IBD) and rheumatic diseases, respectively. Participants had no history of reproductive health issues, and the following semen parameter values (≥ 5th percentile of World Health Organization reference values) at baseline: semen volume ≥ 1.5 mL, total sperm/ejaculate ≥ 39 million, sperm concentration ≥ 15 million/mL, sperm total motility ≥ 40% and normal sperm morphology ≥ 30%. Each trial included a 13-week, randomized, double-blind, placebo-controlled period (filgotinib 200 mg vs placebo, up to N = 125 per arm), for pooled analysis of the week-13 primary endpoint (proportion of participants with ≥ 50% decrease from baseline in sperm concentration). All semen assessments were based on two samples (≤ 14 days apart) to minimize effects of physiological variation; stringent standardization processes were applied across assessment sites. From week 13, MANTA and MANTA-RAy study designs deviated owing to disease-specific considerations. All subjects with a ≥ 50% decrease in sperm parameters continued the study in the monitoring phase until reversibility, or up to a maximum of 52 weeks, with standard of care as treatment. Overall conclusions from MANTA and MANTA-RAy will be based on the totality of the data, including secondary/exploratory measures (e.g. sperm motility/morphology, sex hormones, reversibility of any effects on semen parameters). Conclusions: Despite the complexities, the MANTA and MANTA-RAy studies form a robust trial programme that is the first large-scale, placebo-controlled evaluation of potential impacts of an advanced IBD and rheumatic disease therapy on semen parameters. Trial Registration: EudraCT numbers 2017-000402-38 and 2018-003933-14; ClinicalTrials.gov identifiers NCT03201445 and NCT03926195

Validation of endoscopic activity scores in patients with Crohn's disease based on a post hoc analysis of data from SONIC

Mucosal healing might alter midterm and long-term outcomes of patients with Crohn's disease (CD) and has become an important end point in clinical trials. However, the minimal degree of mucosal improvement (endoscopic response) required to alter midterm outcomes is not known. We aimed to determine the best definition of endoscopic response by evaluating data on the Simple Endoscopic Score for Crohn's Disease (SES-CD) and the Crohn's Disease Endoscopic Index of Severity (CDEIS) from the Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease (SONIC trial). We analyzed data from 172 patients who participated in the SONIC trial, were found to have endoscopic lesions at baseline, and underwent a second endoscopic examination at week 26 of treatment with infliximab, azathioprine, or both. Mucosal healing was defined as absence of ulcers. A central reader calculated SES-CD and CDEIS results. Different cutoff values were set for endoscopic response based on the SES-CD or CDEIS. The diagnostic ability of these different cutoff values was evaluated using receiver operating characteristic (ROC) curves, positive likelihood ratios (PLR), and negative likelihood ratios (NLR). Corticosteroid-free clinical remission (CFREM) at week 50 was used as a binary classifier. Based on analyses of ROC curves, PLR, and NLR, endoscopic response was defined as a decrease from baseline in SES-CD of at least 50%. At week 26, mucosal healing and endoscopic response were achieved in 48% and 65% of patients, respectively. Mucosal healing at week 26 was associated with CFREM at week 50, with 56% sensitivity, 65% specificity, a PLR of 1.60, and an NLR of 0.67. Endoscopic response at week 26 was associated with CFREM at week 50, with 74% sensitivity, 48% specificity, a PLR of 1.42, and an NLR of 0.54. Endoscopic response, defined as a decrease from baseline in CDEIS of at least 50%, yielded similar results. In patients with CD, mucosal healing and endoscopic response (defined as a decrease from baseline in SES-CD or CDEIS of at least 50%) at week 26 of treatment identified those most likely to be in CFREM at week 50. The ability of the proposed endoscopic response cutoff value to predict midterm CFREM should be validated in an independent, prospective cohort. Its correlation with changes in long-term disease progression still needs to be demonstration. ClinicalTrials.gov, Number: NCT0009445