LONG-TERM EFFECTIVENESS, SAFETY, AND TOLERABILITY OF TWICE-DAILY DOSING WITH DEFERASIROX IN CHILDREN WITH TRANSFUSION-DEPENDENT THALASSEMIAS UNRESPONSIVE TO STANDARD ONCE-DAILY DOSING

Background: Patients with transfusion-dependent thalassemia (TDT) risk iron overload and require iron chelation therapy. Salvage therapy is warranted for patients demonstrating poor chelation responses. Patients and methods: We retrospectively studied the serum-ferritin (SF) and liver-iron-concentration (LIC) outcomes of patients with TDT treated with twice-daily dosing of deferasirox (TDD-DFX) for > 24 months, after failing to respond to once-daily deferasirox (OD-DFX). Results: We enrolled 22 patients (14 males and 8 females; median age, 9.2 [3–15.5] years). The median erythron transfusion was 216 (206–277) ml/kg/year. The median TDD-DFX treatment period was 30 (24–35) months. Before initiating TDD-DFX, the median SF level was 2,486 (1,562–8,183) ng/ml, while the median LIC was 6.5 (3.2–19) mg/g dry wt. There were 18 responders (81.8%) and 4 nonresponders. The median SF-level change was -724 (-4 916 to 1,490) ng/mL. The median LIC change was -2.14 (-13.7 to 6.8) mg/g dry wt. The 1-year and end-of-study SF levels and LICs were statistically significant (SF, P = 0.006/0.005; and LIC, 0.006/0.005, respectively). There were no treatment interruptions secondary to adverse events. In the follow-up of the TDD-DFX-responder group, 11 of the 18 had a reduced dose, whereas the remaining 7 continued with the same dose. Conclusions: TDD-DFX appears to be an alternative treatment approach for patients refractory to OD-DFX, with a favorable long-term safety profile. Further studies with larger groups and pharmacogenetic analyses of inadequate responders are warranted to better determine the efficacy and safety profile of TDD-DFX.

Tildrakizumab Inadequate Responders Switching to an Alternative IL-23 Inhibitor: A Case Series

Background: Biologic switching is not uncommon in the treatment of psoriasis and is most often due to inadequate response of adverse events. Staying within or switching out of the class is still based on expert opinion but there are published data on intra-class switching with TNF-alpha and IL-17 inhibitors. Less is known about the IL-23 inhibitors because of their limited time in the market. We would like to present our experience with inadequate responders to tildrakizumab, a selective IL23 inhibitor, who were switched to an alternative IL-23 inhibitor. Case Description: This is a case series of 6 patients at a single institution considered inadequate responders to tildrakizumab, which included primary failures, secondary failures, and intermediate responders, who were subsequently switched to another IL-23 inhibitor. Conclusion: All 6 patients who were inadequate responders to tildrakizumab showed significant improvement after switching to another IL-23 inhibitor, with 5/6 reaching IGA 0/1 after 16 weeks of treatment.

IDENTIFYING INADEQUATE RESPONSE AMONG CROHN’S DISEASE PATIENTS ON A BIOLOGIC IN A REAL-WORLD ADMINISTRATIVE CLAIMS DATABASE

Objectives The purpose of this analysis was to assess the frequency of inadequate response (IR) over 1 year from biologic initiation among Crohn’s disease (CD) patients in the United States using a claims-based algorithm. Baseline factors associated with IR to a biologic were also analyzed. Methods This was a retrospective cohort study using claims data from the HealthCore Integrated Research Database. Adult patients with CD who initiated a biologic (TNFi: adalimumab, certolizumab, infliximab; non-TNFi: natalizumab, ustekinumab, and vedolizumab) from 7/1/2016 to 8/31/2018 and had continuous enrollment ≥6 months before and ≥12 months after index date (date of first biologic claim) were included. The index biologic was defined as the first biologic prescribed during the study time period. The claims-based algorithm used in this study to identify IR was originally developed and validated in rheumatoid arthritis and was modified for CD patients. Patients were identified as having IR to their index biologic if during the 12 months after index date they had one or more of the following: low adherence (defined as proportion of days covered (PDC)<80%), switched/added new biologic, added a new conventional therapy, increased dose/frequency of biologic, addition or dose increase of oral glucocorticoids, used a new pain medication, or had surgery for CD. Baseline patient characteristics were compared between responders and IRs using Chi-square tests for categorical variables and t-tests for continuous variables. A multivariable logistic regression model was constructed to identify baseline characteristics associated with IR to the index biologic. Results A total of 2,437 CD patients were included in this analysis. Mean age was 41 years, 53% were female, 81% initiated a TNFi, and 19% initiated a non-TNFi as their index biologic (Table 1). Over the 1-year follow-up period, 62% of CD patients had an IR to their biologic: 41% of patients had low adherence, 14% switched/added a new biologic, 13% added a new conventional therapy, 12% had a dose/frequency increase of their index biologic, 12% had an addition/dose increase of oral glucocorticoids, 8% used a new pain medication, and 5% had surgery. Inadequate responders were more likely to be female (odds ratio (OR)=1.36; p<0.001), have historical use of TNFi (OR=1.94; p<0.001), and be on a consumer-driven health plan (OR=1.28; p<0.001); while patients with baseline use of conventional therapy were more likely to be responders (OR=0.72; p<0.001) (Table 2). Conclusion Over 62% of CD patients had an inadequate response to their index biologic within 1 year after initiation, mostly driven by low adherence. This modified claims-based algorithm for CD appears useful to classify inadequate responders in health plan claims data. Additional research is needed to further validate this algorithm in a clinical setting.

IL-23 skin and joint profiling in psoriatic arthritis: novel perspectives in understanding clinical responses to IL-23 inhibitors

ObjectivesTo determine the relationship between synovial versus skin transcriptional/histological profiles in patients with active psoriatic arthritis (PsA) and explore mechanistic links between diseased tissue pathology and clinical outcomes.MethodsTwenty-seven active PsA patients were enrolled in an observational/open-label study and underwent biopsies of synovium and paired lesional/non-lesional skin before starting anti-tumour necrosis factor (TNF) (if biologic-naïve) or ustekinumab (if anti-TNF inadequate responders). Molecular analysis of 80-inflammation-related genes and protein levels for interleukin (IL)-23p40/IL-23p19/IL-23R were assessed by real-time-PCR and immunohistochemistry, respectively.ResultsAt baseline, all patients had persistent active disease as per inclusion criteria. At primary end-point (16-weeks post-treatment), skin responses favoured ustekinumab, while joint responses favoured anti-TNF therapies. Principal component analysis revealed distinct clustering of synovial tissue gene expression away from the matched skin. While IL12B, IL23A and IL23R were homogeneously expressed in lesional skin, their expression was extremely heterogeneous in paired synovial tissues. Here, IL-23 transcriptomic/protein expression was strongly linked to patients with high-grade synovitis who, however, were not distinguishable by conventional clinimetric measures.ConclusionsPsA synovial tissue shows a heterogeneous IL-23 axis profile when compared with matched skin. Synovial molecular pathology may help to identify among clinically indistinguishable patients those with a greater probability of responding to IL-23 inhibitors.

P87 CCG biologics pathways: re-introduction of the postcode lottery by stealth

Background NICE guidance approves pathways for inflammatory arthritis biologic therapies. Locally, CCG's commission pathways based on their interpretation of NICE guidance. For patients to have equal access to biologics, CCG pathways in different areas must be uniform. We examined whether CCG biologics pathways complied with this standard. Methods Using Freedom of Information requests, direct requests and internet searches, we found 21 approved biologics pathways in England for rheumatoid arthritis, 12 for psoriatic arthritis and 11 for ankylosing spondylitis. This covered 22.8 million people in England for RA (2017 population estimates). CCG Pathways were compared to NICE guidance with respect to restrictions and number of therapies allowed before an Individual Funding Request (IFR) was needed. Results We studied NICE guidance and determined an 'ideal' pathway for patients requiring > 1 biologic. All CCG pathways followed NICE guidance for 1st line biologics but there was significant variation for biologic failures. 18/21 CCG RA pathways indicated the maximum number of drugs that the CCG would commission without the clinician needing IFR. 7/18 allowed 1-3 biologics serially, 10/18 allowed 4-6 and 1/18 was unrestricted. Rituximab is NICE approved in RA in inadequate responders/intolerance to DMARDs/anti-TNF-α. 17/21 RA pathways allowed rituximab 1stline for haematological or treated solid malignancies, 4/21 did not. 6/21 CCG’s allowed rituximab 5 years after solid organ malignancy, 5/21 after 10 years, 10/21 did not specify or allow this usage. NICE guidelines for RA approve 11 biologics. 14/21 RA pathways allowed all 11 biologics, 7/21 pathways excluded sarilumab, tofacitinib or baricitinib or all three. NICE guidelines for PsA recommend the least expensive drug used first of the injected biologics or JAK inhibitors. IFR was required after 3 drugs in 9/12 pathways with 1/12 allowing 4 lines of therapy. For AS, 5/11 allowed 2 lines of therapy, the remainder 3 or 4 lines. Again, many pathways pre-specified which biologics could be used and excluded other NICE approved drugs at specific stages. Conclusion NICE specify the least expensive drug should be used for injected biologics with variation for administration mode/dosage. CCG’ s commission variably restrictive pathways potentially against NICE guidance, both with number and type of therapies before IFR submission is required. Some pathways allowed little scope to use therapies from earlier pathway points without breaching CCG limits. The IFR process for NICE approved therapies can exhibit wide variation in our experience with different outcomes for similar cases, and is time consuming with CCG decision making being opaque, despite NICE approval being legally enforceable. CCG biologic pathways introduce wide regional variation and potential unfairness in their interpretation of NICE guidance. This may disadvantage the worst affected patients who fail several therapies and prevent access to life changing therapy depending on geographical location. Disclosures J. Mistry None. D. Hill None. A. Kaul None.

Ixekizumab treatment of biologic-naïve patients with active psoriatic arthritis: 3-year results from a phase III clinical trial (SPIRIT-P1)

Objective The aim was to assess the safety and efficacy of up to 156 weeks of ixekizumab (an IL-17A antagonist) treatment in PsA patients. Methods In a phase III study, patients naïve to biologic treatment were randomized to placebo, adalimumab 40 mg every 2 weeks (ADA; active reference) or ixekizumab 80 mg every 2 weeks (IXEQ2W) or every 4 weeks (IXEQ4W) after an initial dose of 160 mg. At week 24 (week 16 for inadequate responders), ADA (after 8-week washout) and placebo patients were re-randomized to IXEQ2W or IXEQ4W. Outcomes were evaluated using a modified non-responder imputation [linear extrapolation for radiographic progression (modified total Sharp score = 0)] during extended treatment until week 156. Results Of 417 patients, 381 entered the extension, and 243 of 381 (63.8%) completed the 156-week study. Incidence rates of treatment-emergent and serious adverse events, respectively, were 38.0 and 5.2 with IXEQ2W (n = 189) and 38.1 and 8.0 with IXEQ4W (n = 197). One death occurred (IXEQ4W). With IXEQ2W and IXEQ4W, respectively, the response rates persisted to week 156 as measured by the ACR response ≥20% (62.5 and 69.8%), ≥50% (56.1 and 51.8%) and ≥70% (43.8 and 33.4%), psoriasis area and severity index (PASI) 75 (69.1 and 63.5%), PASI 90 (64.5 and 51.2%) and PASI 100 (60.5 and 43.6%). Inhibition of radiographic progression also persisted to week 156 in 61% of IXEQ2W and 71% of IXEQ4W patients. Conclusion In this 156-week study of ixekizumab, the safety profile remained consistent with previous reports, and improvements in signs and symptoms of PsA were observed, including persistent low rates of radiographic progression. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01695239, EudraCT 2011-002326-49.