US Label Research Articles

PERSISTENCE WHILE ON LABELED MAINTENANCE DOSE AMONG ADVANCED THERAPY-EXPERIENCED PATIENTS WITH ULCERATIVE COLITIS INITIATED ON USTEKINUMAB OR ADALIMUMAB

Abstract BACKGROUND Persistence on biologics in ulcerative colitis (UC) is a useful real-world treatment performance measure particularly important in advanced therapy (ADT)-experienced patients. Dose escalation on biologics is an indicator of suboptimal treatment response associated with higher biologic costs. This study compared persistence while on labeled maintenance dose among ADT-experienced patients with UC initiated on ustekinumab or adalimumab. METHODS Adults with UC initiated on ustekinumab or adalimumab (index date: 10/21/2019-03/02/2022) were selected from the IQVIA PharMetrics® Plus database. Patients were ADT-experienced (i.e., ≥1 claim for a non-index UC-indicated ADT agent) and without other auto-immune diseases in the 12-month baseline period. Cohorts were balanced on baseline characteristics using inverse probability of treatment weights. Persistence while on the labeled maintenance dose was defined as (1) no gaps between days of therapy supply (ustekinumab, >120 days; adalimumab, >60 days); (2) absence of any dose change relative to the maintenance dose per US label. Composite endpoints of being persistent while corticosteroid-free (<14 consecutive days of corticosteroid supply after day 90 post-index) and persistent while on monotherapy (no immunomodulators or non-index ADT) were also assessed. Endpoints were assessed from the maintenance phase start until the earliest of discontinuation (event), corticosteroid use (event), immunomodulator, non-index advanced therapy use (event), dose change (censored), 12 months follow-up or data end (censored) using weighted Kaplan-Meier analyses and Cox proportional hazards models. RESULTS Weighted cohorts included 693 ustekinumab and 294 adalimumab patients (Fig. 1). At 12 months after the maintenance phase start, 88.7% and 65.8% of the ustekinumab versus adalimumab cohort were persistent while on the labeled maintenance dose with persistence 4.77 times higher in the ustekinumab cohort (p-value:<0.001; Fig. 2a). Further, 55.7% and 44.6% of the ustekinumab versus adalimumab cohort were persistent and corticosteroid-free while on the labeled maintenance dose; persistence was 1.48 times higher in the ustekinumab cohort (p-value:0.002; Fig. 2b). Finally, 77.2% and 47.3% of the ustekinumab versus adalimumab cohort were persistent and on monotherapy while on the labeled maintenance dose; persistence was 3.29 times higher in the ustekinumab cohort (p-value:<0.001; Fig. 2c). CONCLUSIONS ADT-experienced patients with UC treated with ustekinumab were significantly more persistent while on the labeled maintenance dose, including persistent while corticosteroid-free and while on monotherapy versus patients treated with adalimumab. Findings may help inform treatment strategies for ADT-experienced patients with UC. Figure 1 Selected baseline characteristics in weighted ustekinumab and adalimumab cohorts Figure 2 Persistence while on US labelled dose among weighted ustekinumab and adalimumab cohorts: a) persistent on index biologic, b) persistent and corticosteroid-free, c) persistent and on monotherapy

PERSISTENCE WHILE ON LABELED MAINTENANCE DOSE AMONG ADVANCED THERAPY-NAÏVE PATIENTS WITH ULCERATIVE COLITIS INITIATED ON USTEKINUMAB OR ADALIMUMAB

Abstract BACKGROUND In the real-world setting, biologic therapy in patients with ulcerative colitis (UC) may require dose escalation if initial response is limited or due to loss of response. Dose escalation leads to higher treatment costs and may cause difficulties obtaining prior authorization and approvals from health plans. This study compared treatment persistence while on labeled maintenance dose among advanced therapy (ADT)-naïve patients with UC on ustekinumab or adalimumab. METHODS Adults with UC initiated on ustekinumab or adalimumab (index date: 10/21/2019 - 03/02/2022) were selected from the IQVIA PharMetrics® Plus database. Patients were ADT-naïve (i.e., no claim for UC-indicated ADT) and had no other autoimmune diseases in the 12-month baseline period before the index date. Cohorts were balanced on baseline characteristics using inverse probability of treatment weights. Persistence while on the labeled maintenance dose was defined as (1) no gaps between days of therapy supply (ustekinumab, >120 days; adalimumab, >60 days), and (2) absence of any dose change from the maintenance dose per US label. Composite endpoints of being persistent while corticosteroid-free (<14 consecutive days of corticosteroid supply after day 90 post-index) and persistent while on monotherapy (no immunomodulators or ADT) were also evaluated. Endpoints were assessed from the maintenance phase start until the earliest of discontinuation (event), corticosteroid use (event), immunomodulator or ADT use (event), dose change (censored), 12 months follow-up, or data end (censored) using weighted Kaplan-Meier and Cox proportional hazards model analyses. RESULTS There were 371 and 1,726 patients in the weighted ustekinumab versus adalimumab cohort, respectively (Fig. 1). At 12 months after the maintenance phase start, 88.6% and 61.7% of the ustekinumab versus adalimumab cohort were persistent while on the labeled maintenance dose; persistence was 4.21 times higher in the ustekinumab cohort (p-value: <0.001; Fig 2a). Further, 70.0% and 43.9% of the ustekinumab versus adalimumab cohorts were persistent and corticosteroid-free while on the labeled maintenance dose; persistence was 2.31 times higher in the ustekinumab cohort (p-value: <0.001; Fig 2b). Finally, 84.4% and 55.1% of the ustekinumab versus adalimumab cohorts were persistent while on monotherapy and on the labeled maintenance dose; persistence was 3.38 times higher in the ustekinumab cohort (p-value: <0.001; Fig 2c). CONCLUSIONS ADT-naïve patients with UC initiated on ustekinumab were significantly more persistent while on the labeled maintenance dose, including persistent while corticosteroid-free and while on monotherapy, compared to patients initiated on adalimumab. Results may help with selecting a biologic for ADT-naive patients with UC. Figure 1 Selected baseline characteristics in weighted ustekinumab and adalimumab cohorts Figure 2 Persistence while on US labelled dose among weighted ustekinumab and adalimumab cohorts: a) persistent on index biologic, b) persistent and corticosteroid-free, c) persistent and on monotherapy

REAL-WORLD LONG-TERM TREATMENT PERSISTENCE AMONG BIO-NAÏVE PATIENTS WITH CROHN’S DISEASE AND HISTORY OF FISTULA INITIATED ON USTEKINUMAB

Abstract BACKGROUND Fistula is a common complication of Crohn’s disease (CD). Treatment with certain biologics have been associated with fistula healing and closure, reduction of symptoms and need for surgical treatments. In clinical practice, biologic persistence and effectiveness are correlated. This study described long-term persistence among bio-naïve patients with CD and history of fistula who were initiated on ustekinumab (anti-interleukin 12/23 antibody). METHODS Adults with CD and history of intestinal fistula initiated on ustekinumab (index date) between 9/23/2016 and 3/2/2022 were selected from the IQVIA PharMetrics® Plus database and followed for the maximum of 24 months. Patients were bio-naïve (i.e., no claim for CD-indicated biological agents) in the 12-month baseline period before the index date. Patients with other auto-immune diseases during the baseline period were excluded. Persistence on ustekinumab was defined as the absence of gaps between days of therapy supply of >120 days (i.e., over twice the duration of the US label maintenance cycle of 8 weeks or 60 days). Composite endpoints of being persistent while on monotherapy (no immunomodulators or biologics other than ustekinumab) and persistent while corticosteroid-free (<14 consecutive days of corticosteroid supply after day 90 post-index) were also assessed. Persistence endpoints were assessed from the index date until the earliest of discontinuation (event), immunomodulator or non-index biologic use (event), corticosteroid use (event), 24 months follow-up or data end (censoring) using Kaplan-Meier analyses. RESULTS The sample included 445 patients (mean age: 42.8 years; 56.6% female; Fig. 1). Among these, 63.1% had CD involving the small intestine, and 59.6% had CD involving the large intestine. The most common type of fistula was anal fistula (36.0%). At 24 months after ustekinumab initiation, 64.2% of patients remained persistent (95% confidence interval [CI]: 55.8-71.4; Fig. 2a). Furthermore, 53.3% of patients were persistent while on monotherapy (95%CI: 45.1-60.7; Fig. 2b). Finally, 45.6% of patients were persistent while being corticosteroid-free (95%CI: 36.9-53.8; Fig. 2c). CONCLUSIONS This study quantified long-term persistence on ustekinumab among bio-naïve patients with CD and history of fistula. Over half of patients initiated on ustekinumab were persistent and persistent while on monotherapy 24 months after the treatment initiation. These findings support ustekinumab as a treatment option for long-term management of CD with history of fistula. Figure 1 Selected baseline characteristics Figure 2 (a) Persistent on ustekinumab, (b) persistent and on monotherapy, c) persistent and corticosteroid-free

P509 Upadacitinib improves symptomatic responses in patients with moderately to severely active Crohn’s disease

Abstract Background Upadacitinib (UPA), an oral Janus kinase inhibitor approved for the treatment of moderately to severely active Crohn’s disease (CD), has demonstrated the ability to provide rapid symptom relief within the first week of induction treatment in patients with CD.1 As symptomatic remission is critical for patients, this phase 3 post hoc analysis evaluated the impact of UPA on patient-reported outcomes (PROs) of abdominal pain score (APS) and stool frequency (SF) over the full induction and maintenance time periods. Methods Data were pooled from the U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836) induction studies evaluating patients with moderately to severely active CD with an average daily APS ≥ 2 and/or SF ≥ 4 and received UPA 45 mg (UPA45) once daily (QD) or PBO for 12 weeks. Patients who achieved clinical response to 12 weeks of UPA45 induction were re-randomised in a maintenance study (U-ENDURE, NCT03345823) to receive UPA 15 mg (UPA15) QD, UPA 30 mg (UPA30) QD, or PBO for 52 weeks. APS and SF were recorded in a daily diary and evaluated over time. Results The average daily APS (mean: PBO 1.9, UPA45 1.9) and SF (mean: PBO 5.6, UPA45 5.4), were similar between the treatment groups at induction baseline (BL). Of patients reporting BL APS ≥ 1 (PBO 91.6%, UPA45 92.4%) or BL SF ≥ 2.8 (PBO 85.6%, UPA45 85.2%), higher proportions of patients receiving UPA vs PBO achieved APS = 0 or SF ≤ 1, or complete resolution of symptoms (APS = 0 and SF ≤ 1) at week 12 of induction, as well as at week 52 of maintenance (all P ≤ .001; Figure 1A). During induction, the mean change from BL in APS and SF was improved with UPA45 vs PBO starting at week 2 through to week 12 (all P < .001; Figure 1B-C). Throughout the 52-week maintenance period, a higher proportion of patients receiving UPA15 or UPA30 achieved APS ≤ 1 or SF ≤2.8 vs PBO (Figure 1B-C). Patients treated with UPA30 demonstrated a numerically higher rate of symptomatic response vs UPA15. In patients who met the Crohn's Disease Activity Index (CDAI) criteria per US labeling (CDAI ≥ 220 at induction BL; clinical response [CR-100] at week 12 with UPA45),2 comparable symptom improvements were observed over time compared to the overall study population. Conclusion Patients with moderately to severely active CD demonstrated improvements in APS and SF as early as 2 weeks after UPA induction treatment. A greater proportion of patients achieved PRO-defined remission within 12 weeks of UPA induction treatment compared with PBO, which were sustained through week 52 of UPA maintenance treatment.

In-Use Stability of SB12 (Eculizumab, Soliris Biosimilar) Diluted in Saline and Dextrose Infusion Solution after an Extended Storage Period.

SB12 is a biosimilar to eculizumab reference product [SolirisTM (Soliris is a trademark of Alexion Pharmaceuticals, Inc.)] that acts as a C5 complement protein inhibitor. The infusion stability of in-use (diluted) SB12 outside the conditions stated in the reference product's label is unknown. The objective of this study was to assess the stability of SB12 after extended storage in conditions not claimed in the originator label. Infusion stability was assessed in SB12 samples (diluted in 0.9% NaCl, 0.45% NaCl, and 5% dextrose, final concentration of 5mg/mL per clinical trial protocol and the reference product's label) kept at 5±3°C for up to 3months, then 30±2°C/65±5% relative humidity (RH) for 72h. The product was stored in different containers [polyolefin (PO) bags, glass bottles and syringes], and the protocol followed International Conference on Harmonisation (ICH) and European Medicines Agency (EMA) requirements for stability evaluation of biological products. Stability was evaluated using complementary assays, including pH, protein concentration (A280), purity (size exclusion-high-performance liquid chromatography, capillary electrophoresis-sodium dodecyl sulfate, and imaged capillary isoelectric focusing), biological activity (C5 binding and inhibition), and safety (subvisible particles). Except for charge variants in SB12 diluted in 5% dextrose, all results met the stability acceptance criteria. There were no major changes in terms of physicochemical stability, biological activity, and subvisible particles. The infusion stability of SB12 after extended storage (5±3°C for up to 3months, then 30±2°C/65±5% RH for72 h) was demonstrated for longer periods and at higher temperatures than what is stated in the EU and US labels of the reference product. The physicochemical properties, biological activity, and subvisible particles of in-use SB12 diluted in 0.9%NaCl and 0.45%NaCl were maintained under the described conditions and for all tested containers. However, instability was observed for the diluted SB12 in 5%dextrose. These results may reduce the workload of clinical staff and minimize drug waste from treatment delays without any loss in product quality and biological activity.

A systematic review of pregnancy-related clinical intervention of drug regimens due to pharmacokinetic reasons

Background and objectivePublished works have discussed the pharmacokinetic interactions of drugs with pregnancy, but none comprehensively identify all the approved United States Food and Drug Administration (FDA) and European Medicines Administration (EMA) drugs that have a pregnancy-related intervention. The objective of this systematic review is to comprehensively identify medications that have clinically meaningful interventions due to pharmacokinetic reasons.MethodsAn in-depth search of clinical data using the PDR3D: Reed Tech Navigator™ for Drug Labels was conducted from 1 June to 12 August 2022. The PDR3D was analyzed using the search terms “pregnant” and “pregnancy” within the proper label section. Regarding the US labels, the terms were searched under the “dosage and administration” section, whereas with the EU labels, the terms were searched within the “posology and method of administration” section. If a finding was discovered within the search, the rest of the label was analyzed for further information. Clinical relevance was based on whether an intervention was needed.ResultsUsing the search strategy, 139 US and 20 EU medications were found to have clinically meaningful interventions in pregnancy. The most common explanations for clinical relevance included hepatic metabolism, protein binding, renal elimination, and P-gp influence. Of the US labels: 40 were found to undergo hepatic metabolism, 11 were found to be influenced by renal elimination, 12 were found to be influenced by protein binding, 7 were found to be influenced by P-gp, and the remaining drugs required further research. Of the EU labels: 11 were found to undergo hepatic metabolism, 3 were found to be influenced by renal elimination, 3 were found to be influenced by protein binding, 1 was found to be influenced by P-gp, and the remaining drugs required further research.ConclusionThis comprehensive review of clinically relevant interventions in pregnancy will potentially aid in the treatment of pregnant females when they are undergoing therapy, provide intervention and dosing guidance for physicians, and save time for prescribers and pharmacists. Advances in non-clinical predictions for pregnancy dosing may guide the need for a future clinical evaluation.

A Real-World Evidence Review of Post-Marketing Safety and Compliance with Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) in the US

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic condition characterized by complement-mediated, life-threatening hemolysis and thrombosis which are associated with significant impacts on health-related quality of life (HRQoL). Pegcetacoplan is the first targeted complement component 3 (C3) therapy approved for adults with PNH (US) and adults with PNH plus anemia despite receiving a complement component 5 inhibitor (C5i) for ≥3 months (EU). In clinical trials including patients with PNH who were C5i-experienced or -naive, pegcetacoplan significantly improved levels of hemoglobin (Hb) and lactate dehydrogenase (LDH) and reduced transfusion burden. Pegcetacoplan had a favorable safety profile in parent studies and an ongoing long-term, rollover, open-label extension study (NCT03531255). Compliance with pegcetacoplan treatment was high across all clinical studies. In the US real-world OPERA and Adelphi PNH Disease Specific Programme™ (DSP) patient-reported outcomes (PRO) studies, improvements in levels of Hb and LDH, along with self-reported fatigue and cognitive outcomes, were observed. Pegcetacoplan treatment also led to reductions in the frequency and severity of PNH symptoms (including shortness of breath and fatigue) and improvements in social, physical, and emotional HRQoL domains in the US real-world Voice of the Patient PRO study. Further, both patient and physician satisfaction with pegcetacoplan treatment was high in the Adelphi PNH DSP study. However, to date, compliance and safety with pegcetacoplan treatment in the real-world setting have not been described. The objective of this real-world evidence review study was to evaluate compliance and safety with pegcetacoplan treatment in patients with PNH in the US post-marketing setting. Methods: Post-marketing data from the US, including the number of patients who received pegcetacoplan and reported safety events, were collected and analyzed from the pegcetacoplan Risk Evaluation and Mitigation Strategies (REMS) program which controls the distribution of pegcetacoplan and the pharmacovigilance safety database through May 13, 2023. Treatment compliance was calculated as the proportion of days a patient had the drug in possession, divided by the total number of days of follow-up, using central pharmacy prescription refill data. Thrombosis (a leading cause of death in patients with PNH prior to the availability of complement inhibitors) and meningococcal infections (a potential risk with complement inhibitors) were safety events of interest. To reduce the risk of serious meningococcal infections, clinical trial protocols and pegcetacoplan labeling required vaccination against Streptococcus pneumoniae; N meningitidis types A, C, W, Y, and B; and Haemophilus influenzae type B before starting treatment with pegcetacoplan. If pegcetacoplan treatment must be initiated before vaccination, the US label mandates prophylactic antibiotic use. In this study, the rates of thrombosis and meningococcal infection per 100 patient-years were estimated based on the total number of thrombosis and meningococcal infection events reported in the REMS program. Results: As of May 13, 2023, the cumulative pegcetacoplan exposure was 273.10 patient-years in the US post-marketing setting. Based on prescription refill data, compliance with pegcetacoplan treatment was ~98%. There were 2 confirmed thrombotic events reported and the incidence of thrombotic events was 0.73 events/100 patient-years in 273.10 patient-years. Similar to clinical trials, no meningococcal infections were reported in the US post-marketing setting. Conclusions: The high compliance rate and favorable safety profile of pegcetacoplan in the US post-marketing setting were consistent with clinical trial observations. These data, coupled with the effectiveness on hematologic parameters and improvements in symptoms and HRQoL reported in pegcetacoplan real-world PRO studies, support a positive benefit:risk profile for pegcetacoplan in the real-world setting.

A Novel Method for Deriving Adverse Event Prevalence in Randomized Controlled Trials: Potential for Improved Understanding of Benefit-Risk Ratio and Application to Drug Labels.

Adverse event (AE) data in randomized controlled trials (RCTs) allow quantification of a drug's safety risk relative to placebo and comparison across medications. The standard US label for Food and Drug Administration-approved drugs typically lists AEsby MedDRA Preferred Term that occur at ≥ 2% in drug and with greater incidence than in placebo. We suggest that the drug label can be more informative for both patients and physicians if it includes, in addition to AE incidence (percent of subjects who reported the AE out of the total subjects in treatment), the absolute prevalence (percent of subject-days spent with an AE out of the total subject-days spent in treatment) and expected duration (days required for AE incidence to be reduced by half). We also propose a new method to analyze AEs in RCTs using drug-placebo difference in AE prevalence to improve safety signal detection. AE data from six RCTs in schizophrenia were analyzed (five RCTs of the dopamine D2 receptor-based antipsychotic lurasidone and one RCT of the novel trace amine-associated receptor 1 [TAAR1] agonist ulotaront). We determined incidence, absolute prevalence, and expected duration of AEs for lurasidone and ulotaront vs respective placebo. We also calculated areas under the curve of drug-placebo difference in AE prevalence and mean percent contribution of each AE to this difference. A number of AEs with the same incidence had different absolute prevalence and expected duration. When accounting for these two parameters, AEs that did not appear in the 2% incidence tables of the drug label turned out to contribute substantially to drug tolerability.The percent contribution of a drug-related AE to the overall side effect burden increased the drug-placebo difference in AE prevalence, whereas the percent contribution of a placebo-related AE decreased such difference, revealing a continuum of risk between drug and placebo. AE prevalence curves for drug were generally greater than those for placebo. Ulotaront exhibited a small drug-placebo difference in AE prevalence curves due to a relatively low incidence and short duration of AEs in the ulotaront treatment arm as well as the emergence of disease-related AEs in the placebo arm. Reporting AE absolute prevalence and expected duration for each RCT and incorporating them in the drug label is possible, is clinically relevant, and allows standardized comparison of medications. Our new metric, the drug-placebo difference in AE prevalence, facilitates signal detection in RCTs. We piloted this metric in RCTs of several neuropsychiatric indications and drugs, offering a new way to compare AE burden and tolerability among treatments using existing clinical trial information.

Availability of calorie information on online menus from chain restaurants in the USA: current prevalence and legal landscape.

Federal law requires calorie information on chain restaurant menus. We sought to assess the prevalence of calorie disclosures on online menus and determine if the menus are controlled by restaurants subject to US labelling requirements. Cross-sectional. Restaurant websites and mobile apps for restaurant located in New York City, Los Angeles, Chicago, and Houston. US chain restaurants (top seventy-five by number of outlets) and third-party platforms (TPP): Grubhub, Uber Eats, DoorDash. There was at least one calorie disclosure (for at least one food or beverage, in at least one location) on sixty-eight of seventy-two (94 %) menus on restaurant websites or apps, thirty-two of fifty-five (58 %) menus on DoorDash, six of forty-nine (12 %) menus on Grubhub and thirty of fifty-nine (51 %) menus on Uber Eats. There was consistent calorie labelling (all foods and beverages, all locations) on forty-three of seventy-two (60 %) menus on restaurant websites or apps, fifteen of fifty-five (27 %) menus on DoorDash, three of forty-nine (6 %) menus on Grubhub and eleven of fifty-nine (19 %) menus on Uber Eats. Only four restaurant chains consistently labelled calories for all items, in all locations, on all platforms where their menus were found. All three TPP provided restaurants the ability to enter and modify menu items, making the menus subject to US labelling requirements. Only Uber Eats provided guidance to restaurants on entering calorie information. As consumers increasingly rely on TPP for restaurant ordering, menus on these platforms should include calories in order to promote transparency and nutrition.

43054 The Psoriasis Study of Health Outcomes (PSoHO) in biologic-naïve and -experienced patients: A post-hoc analysis of patients receiving treatment according to US labels

43054 The Psoriasis Study of Health Outcomes (PSoHO) in biologic-naïve and -experienced patients: A post-hoc analysis of patients receiving treatment according to US labels

Population pharmacokinetic modeling and dosing simulation of avalglucosidase alfa for selecting alternative dosing regimen in pediatric patients with late-onset pompe disease

Avalglucosidase alfa (AVAL) was approved in the United States (2021) for patients with late-onset Pompe disease (LOPD), aged ≥ 1 year. In the present study, pharmacokinetic (PK) simulations were conducted to propose alternative dosing regimens for pediatric LOPD patients based on a bodyweight cut-off. Population PK (PopPK) analysis was performed using nonlinear mixed effect modeling approach on pooled data from three clinical trials with LOPD patients, and a phase 2 study (NCT03019406) with infantile-onset Pompe disease (IOPD: 1–12 years) patients. A total of 2257 concentration-time points from 91 patients (LOPD, n = 75; IOPD, n = 16) were included in the analysis. The model was bodyweight dependent allometric scaling with time varying bodyweight included on clearance and distribution volume. Simulations were performed for two dosing regimens (20 mg/kg or 40 mg/kg) with different bodyweight cut-off (25, 30, 35 and 40 kg) by generating virtual pediatric (1–17 years) and adult patients. Corresponding simulated individual exposures (maximal concentration, Cmax and area under the curve in the 2-week dosing interval, AUC2W), and distributions were calculated. It was found that dosing of 40 mg/kg and 20 mg/kg in pediatric patients < 30 kg and ≥ 30 kg, respectively, achieved similar AVAL exposure (based on AUC2W) to adult patients receiving 20 mg/kg. PK simulations conducted on the basis of this model provided supporting data for the currently approved US labelling for dosing adapted bodyweight in LOPD patients ≥ 1 year by USFDA.

Safety and tolerability of agalsidase beta infusions shorter than 90 min in patients with Fabry disease: post-hoc analysis of a Japanese post-marketing study

BackgroundAgalsidase beta, an enzyme replacement therapy for Fabry disease, is dosed biweekly at 1 mg/kg body weight, with increasing infusion rates based on tolerability. The US label specifies ≥ 90-min infusions for all patients; the US and EU labels require ≤ 15 mg/hr infusions in patients < 30 kg. The Japanese label allows infusions up to 30 mg/hr, allowing < 90-min dosing for some patients weighing < 45 kg. Japanese post-marketing data were analyzed for rate of infusion-associated reactions (IARs), adverse events (AEs), and serious AEs (SAEs) based on infusion rate and patient attributes (weight, antibody status).ResultsData were available for 436 reduced-duration infusions (< 90 min) and 2242 standard infusions (≥ 90 min). SAEs were rare (0.6%), and the frequency of all safety events decreased over the treatment course. Little impact of infusion duration on safety outcomes was observed: IARs and AEs were numerically more common when infusion duration was ≥ 90 min compared to < 90 min (IARs: 2.0% vs 0.9%; AEs: 2.9% vs 1.4%), while the rate of SAEs was similar (0.4% vs 0.5%). IAR, AE, and SAE frequencies decreased significantly with increasing infusion rates, and this trend was consistent in patients < 30 kg. Safety events tended to be less frequent in patients < 30 kg vs those ≥ 30 kg (IARs: 1.8% vs 2.1%; AEs: 2.3% vs 3.6%; SAEs: 0.0% vs 0.6%), although the differences were not statistically significant. IARs occurred in < 1% of all infusions in the < 30 kg group, 84% of which were < 90 min. More anti-agalsidase beta antibody-positive patients experienced IARs (41.9% vs 30.7%; P = 0.0445) and AEs (61.1% vs 49.3%; P = 0.0497) vs antibody-negative patients; however, there was no significant difference in the frequency of SAEs. In patients with available data, no changes in antibody status were observed after infusion durations were reduced to < 90 min.ConclusionsThe results of this post-hoc analysis demonstrated no significant impact of infusion duration on safety outcomes, and no significant difference in outcomes between patients of different weights. These findings suggest that infusion times in patients who are tolerating treatment can, with careful monitoring, be gradually decreased.

Treatment persistence among bio-naïve patients with Crohn’s disease initiated on ustekinumab or adalimumab

Objectives To compare persistence and describe dose titration among bio-naïve patients with Crohn’s disease (CD) initiated on ustekinumab or adalimumab. Methods Bio-naïve adults with CD who initiated ustekinumab or adalimumab (index date) from 23 September 2016 (ustekinumab US approval for CD) to 1 August 2019 were selected from IQVIA PharMetrics Plus. Cohorts were balanced on baseline characteristics measured over 12 months pre-index using inverse probability of treatment weights. Persistence was defined as no gaps (ustekinumab: >120 days; adalimumab: >60 days) between days of supply. Dose escalation was defined as ≥2 consecutive sub-cutaneous claims 100% above the US label daily dose in the maintenance phase; de-escalation was a return to the daily dose for ≥2 consecutive claims. Outcomes were described using weighted Kaplan-Meier models; persistence outcomes were compared using Cox’s proportional hazards models. Results At 12 months post-index, patients in the ustekinumab (n = 948) versus adalimumab (n = 4143) cohort had a significantly higher rate of persistence on index biologic (hazard ratio [HR] 1.50; 95% confidence interval [CI]: 1.29–1.74). A total of 830 (87.6%) patients in the ustekinumab cohort and 3713 (89.6%) in the adalimumab cohort began the maintenance phase; within 12 months, 11.2% and 16.9%, underwent a dose escalation, and 26.6% and 6.3%, respectively, subsequently de-escalated to the per US label daily exposure. Conclusions Bio-naïve patients with CD initiated on ustekinumab were more persistent than patients initiated on adalimumab; moreover, these patients had numerically lower dose escalation and higher de-escalation rates than patients initiated on adalimumab. Findings support the use of ustekinumab as a first-line treatment for bio-naïve patients with CD.

SUPERIOR PERSISTENCE WHILE ON LABELED MAINTENANCE DOSE AMONG BIO-NAÏVE PATIENTS WITH CROHN'S DISEASE INITIATED ON USTEKINUMAB COMPARED TO ADALIMUMAB

Abstract BACKGROUND Treatment of Crohn’s disease (CD) may require biologics. Dose escalation may be necessary to maintain efficacy, while adverse events or non-response may lead to treatment discontinuation. This analysis aimed to generate real-world evidence of persistence to ustekinumab versus adalimumab while on labeled maintenance dose (United States [US] prescribing information) among bio-naïve patients with CD in the US. METHODS Adults with CD initiated on ustekinumab or adalimumab from 09/23/2016 (approval of ustekinumab for CD in the US) to 08/01/2019 were selected from a de-identified health insurance claims database (IQVIA PharMetrics® Plus). Patients who used other biologics indicated for CD or had diagnoses for other autoimmune disorders in the 12 months before the initiation of the index agent (baseline) were excluded. Cohorts were balanced on baseline characteristics using inverse probability of treatment weights. Persistence to the index agent while on labeled maintenance dose was defined as (1) absence of gaps between days of therapy supply &amp;gt;120 days for ustekinumab (twice the 8-week on-label maintenance dosing interval) or &amp;gt;60 days for adalimumab (twice the mode of days of supply in claims) and (2) absence of any dose change during the maintenance phase relative to the dose per US label. It was assessed from the index date until the earliest of discontinuation (event), dose change during the maintenance phase (censoring), or the last day of index agent supply before the end of follow-up (censoring). Weighted Kaplan-Meier and Cox proportional hazards models were used to assess the outcome at 12 months post-index. RESULTS 948 bio-naïve patients with CD were included in the ustekinumab cohort (mean age 42.5 years old; 58.1% female) and 4,143 in the adalimumab cohort (mean age 42.3 years old; 56.7% female). During the baseline period, 8.4% and 9.2% previously had CD-related surgery, 66.6% and 67.7% used corticosteroids, and 25.9% and 26.3% used immunomodulators in the ustekinumab and adalimumab cohorts, respectively. At 12 months post-index, a higher proportion of patients in the ustekinumab cohort versus adalimumab cohort were persistent to the index biologic while on labeled maintenance dose (74.1% vs 65.4%; Fig. 1). Patients in the ustekinumab versus adalimumab cohort had a 47% higher rate of persistence while on labeled maintenance dose (hazard ratio [HR] 1.47; 95% confidence interval [CI]: 1.25-1.73; P-value: &amp;lt;0.001*). CONCLUSIONS Bio-naïve patients with CD initiated on ustekinumab were significantly more persistent while on labeled maintenance dose compared to patients initiated on adalimumab. These results are consistent with previous work, which demonstrated significantly higher persistence to the index agent and a trend of lower dose escalation rates among bio-naïve patients with CD initiating ustekinumab versus adalimumab.

Examining Real-World Adherence to Nusinersen for the Treatment of Spinal Muscular Atrophy Using Two Large US Data Sources.

Spinal muscular atrophy (SMA) is a rare neuromuscular disease characterized by progressive muscular atrophy and weakness. Nusinersen was the first treatment approved for SMA. Per the US label, the nusinersen administration schedule consists of three loading doses at 14-day intervals, a fourth loading dose 30days later, and maintenance doses every 4months thereafter. Using two large US databases, we evaluated real-world adherence to nusinersen with its unique dosing schedule among generalizable populations of patients with SMA. Patients with SMA treated with nusinersen, likely to have complete information on date of treatment initiation, were identified in the Optum® de-identified electronic health records (EHR) database (7/2017-9/2019), and in the Merative™ MarketScan® Research Databases from commercial (1/2017-6/2020) and Medicaid claims (1/2017-12/2019). Baseline demographics, number of nusinersen administrations on time, and distribution of inter-dose intervals were summarized. Totals of 67 and 291 patients were identified in the EHR and claims databases, respectively. Most nusinersen doses were received on time (93.9% EHR, 80.5% claims). Adherence was higher during the maintenance phase (90.6%) than the loading phase (71.1%) in the claims analysis, in contrast with the EHR analysis (95.5% and 92.6%, respectively), suggesting that not all loading doses of nusinersen may be accurately captured in claims. Inter-dose intervals captured in both databases aligned with the expected dosing schedule. Most nusinersen doses were received on time, consistent with the recommended schedule. Our findings also highlight the importance of careful methodological approaches when using real-world administrative databases for evaluation of nusinersen treatment patterns.

OnabotulinumtoxinA Treatment of Upper Limb Spasticity: Analysis of US Practice Patterns From the ASPIRE Study

<h3>Research Objectives</h3> To examine onabotulinumtoxinA (onabotA) utilization patterns within 8 additional muscle groups consistent with updated US label in patients with upper limb (UL) spasticity from the Adult Spasticity International Registry (ASPIRE) study over a 2-year period1-6. <h3>Design</h3> Multicenter, prospective, observational study (NCT01930786). <h3>Setting</h3> US clinical sites. <h3>Participants</h3> Adult patients who received onabotA to UL muscles for spasticity. <h3>Interventions</h3> Total onabotA dose ≤400 U per treatment session consistent with US label. <h3>Main Outcome Measures</h3> OnabotA treatment utilization. <h3>Results</h3> Of 443 US patients, 336 had UL spasticity, 45 of whom received ≤400 U onabotA injections in selected muscles consistent with the newly approved label. Mean age (SD) was 51.3 (16.0) years, 26 (58%) were male, and 23 (51%) were onabotA-naive. Postures treated included clenched fist (71.1%), flexed wrist (55.6%), flexed elbow (73.3%), thumb in palm (20.0%), intrinsic plus hand (20.0%), and pronated forearm (31.1%). Treated postures presenting in patients who received onabotA injections only in muscles consistent with label before July 2021 included clenched fist (93.8%), flexed wrist (100%), flexed elbow (12.1%), and thumb in palm (33.3%). Treated postures in patients who received onabotA injections in muscles consistent with the expanded label in July 2021 included clenched fist (100%), flexed wrist (100%), flexed elbow (100%), thumb in palm (100%), intrinsic plus hand (100%), and pronated forearm (100%). The majority of patients (80.0%) had >1 abnormal posture. Of 38 adverse events (AEs), 1 treatment-related AE (muscular weakness) and no treatment-related serious AEs were reported. <h3>Conclusions</h3> This ASPIRE post hoc analysis provides real-world evidence of the opportunity to educate on the expanded label for onabotA, highlighting elbow, forearm, and finger postures and the ability to treat, on-label, multiple UL postures more holistically. <h3>Author(s) Disclosures</h3> GEF: Consultant for, research grants from Allergan (an AbbVie company), Ipsen, Merz. WF: Research grants: NIH. MCM: Research support: AbbVie, Merz; Advisory board: Ipsen, Pacira. KN: Nothing to report. M Schwartz: Biostatistical consultant: Allergan (an AbbVie company). M Sadeghi, AZ: Employee: AbbVie. AE: Consultant: Allergan (an AbbVie company), Ipsen, Merz; Research grants: Allergan (an AbbVie company), Ipsen.

Use of Cytopoint in the Allergic Dog

Allergic dermatitis is the most common type of skin disease in dogs. Of all dogs, 20 to 30% present with some type of allergic dermatitis. Pruritus is one of the most important signs of allergic dermatitis and is often the most challenging to control. Interleukin-31 (IL-31) has been found to be one of the main initiators of pruritus in dogs with allergic dermatitis. Cytopoint®, a caninized monoclonal anti-IL-31 antibody, has been shown to be effective for the treatment of dogs against allergic dermatitis and atopic dermatitis. US label indication. A recent retrospective study reported that Cytopoint achieved treatment success in 87.8% of the cases with allergic dermatitis. No prospective cohort studies have been performed investigating the effects of Cytopoint in dogs with allergic dermatitis using the dosing protocol prescribed on the product label in the United States. In this study, our objectives were to assess the efficacy of Cytopoint for treatment of canine allergic dermatitis of variable etiologies and management of the associated pruritus, and add to the body of evidence available to the veterinarian as they make treatment recommendations. Dogs included in this study had moderate to severe pruritus according to the Pruritus Visual Analog Scale (PVAS; ≥ 50 mm) and a history of likely continuation of pruritus at the time of presentation. On day 0, investigators recorded the initial body weight and every patient received one dose of Cytopoint (minimum 2 mg/kg SQ) and an isoxazoline product for parasite control. Treatment success for this study was defined as a ≥20 mm reduction in PVAS from Day 0. On Day 7, 94% of the dogs had achieved treatment success. On Day 28, 98% had achieved treatment success and cumulatively by day 56, 100% of the dogs achieved treatment success. This prospective study provides evidence that Cytopoint effectively treats dogs with allergic dermatitis of different types and the associated pruritus.

Model-informed bridging of rivaroxaban doses for thromboprophylaxis in pediatric patients aged 9 years and older with congenital heart disease.

Rivaroxaban is approved in various regions for the treatment of acute venous thromboembolism (VTE) in children aged between 0 and 18 years and was recently investigated for thromboprophylaxis in children aged between 2 and 8 years (with body weights <30 kg) with congenital heart disease who had undergone the Fontan procedure. In the absence of clinical data, rivaroxaban doses for thromboprophylaxis in post‐Fontan children aged 9 years and older or ≥30 kg were derived by a bridging approach that used physiologically‐based pharmacokinetic (PBPK) and population pharmacokinetic (popPK) models based on pharmacokinetic (PK) data from 588 pediatric patients and from adult patients who received 10 mg once daily for thromboprophylaxis after major orthopedic surgeries as a reference. Both models showed a tendency toward underestimating rivaroxaban exposure in post‐Fontan patients aged between 2 and 5 years but accurately described rivaroxaban PK in post‐Fontan patients aged between 5 and 8 years. Under the assumption that hepatic function is not impaired in post‐Fontan patients, PBPK and popPK simulations indicated that half of the rivaroxaban doses for the same body weight given to pediatric patients treated for acute VTE would yield in pediatric post‐Fontan patients exposures similar to the exposure observed in adult patients receiving 10 mg rivaroxaban once daily for thromboprophylaxis. Simulation‐derived doses (7.5 mg rivaroxaban once daily for body weights 30–<50 kg and 10 mg once daily for body weights ≥50 kg) were therefore included in the recent US label of rivaroxaban for thromboprophylaxis in children aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

Time without symptoms or toxicity (TWiST) in patients with newly diagnosed advanced ovarian cancer receiving maintenance olaparib or placebo plus bevacizumab: Analysis of PAOLA-1/ENGOT-ov25 phase III trial.

5562 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial (NCT02477644), maintenance olaparib plus bevacizumab (bev) provided a significant progression-free survival (PFS) benefit, compared with placebo plus bev, in patients (pts) with newly diagnosed advanced ovarian cancer in response after platinum-based chemotherapy (Ray-Coquard et al. NEJM 2019). A subgroup analysis revealed a substantial PFS benefit in HRD-positive (including BRCA1/BRCA2 mutation) pts (median PFS 37.2 vs 17.7 months) leading to US and EU labels for this combination. We analyzed TWiST in PAOLA-1, using several definitions of toxicity (TOX) and by molecular subgroups. Methods: Pts were randomized 2:1 to maintenance olaparib (300 mg bid) plus bev (15 mg/kg, Day 1, q3w) or placebo plus bev, stratified by first-line treatment outcome and tumor BRCAm status. TWiST is defined as PFS minus time with TOX after randomization and before disease progression or censoring for progression, and was a prespecified exploratory endpoint. Definitions of significant symptoms or TOX were explored using the following approaches: 1) all grade ≥2 adverse events (AEs); and 2) all grade ≥2 AEs selected to be correlated to olaparib (fatigue, nausea, vomiting, and anemia). Area under PFS curve was split into TOX:TWIST ratio and compared between the two arms. Results: Between May 7, 2015 and August 31, 2017, 806 eligible pts were randomly assigned to olaparib plus bev (n = 537) or placebo plus bev (n = 269), with a median duration of treatment with olaparib of 17.3 months (range 0.03–33.0) for olaparib plus bev arm and 15.6 months (range 0.07–26.2) for placebo plus bev at data cutoff for primary endpoint analysis. In the Intent-to-treat population, median duration of TWiST for all grade ≥2 AEs for olaparib plus bev vs placebo plus bev arms was 14.1 months (95% confidence interval [CI] 12.5–16.1) vs 7.7 months (95% CI 5.9–9.1), respectively; and 21.9 months (95% CI 20.2–22.5) vs 16.6 months (95% CI 14.6–18.0) considering only grade ≥2 AEs linked to olaparib. The difference was particularly significant within the HRD-positive subgroup where median duration of TWiST was 24.4 months (95% CI 19.3–not evaluable [NE]) vs 7.4 months (5.8–11.2) for TOX linked to all grade ≥2 AEs, and 36.6 months (95% CI 31.9–NE) vs 17.4 months (15.1–19.4) linked to olaparib AEs only for the olaparib plus bev and placebo plus bev arms, respectively. Conclusions: The substantial PFS benefit provided by maintenance olaparib plus bev vs placebo plus bev in pts with newly diagnosed advanced ovarian cancer was supported by significant TWiST benefit. TWiST analyses, including all grade ≥2 symptoms or toxicity related to treatment, confirmed the clinically meaningful benefit from the combination, notably in the HRD-positive subgroup. Clinical trial information: NCT02477644.

Practical Advice for Primary Care Clinicians on the Safe and Effective Use of Vortioxetine for Patients with Major Depressive Disorder (MDD).

Primary care clinicians have a vital role to play in the diagnosis and management of patients with major depressive disorder (MDD). This includes screening for MDD as well as identifying other possible psychiatric disorders including bipolar disorder and/or other comorbidities. Once MDD is confirmed, partnering with patients in the shared decision-making process while considering different treatment options and best management of MDD over the course of their illness is recommended. Vortioxetine has been approved for the treatment of adults with MDD since 2013, and subsequent US label updates indicate that vortioxetine may be particularly beneficial for specific populations of patients with MDD, including those with treatment-emergent sexual dysfunction and patients experiencing certain cognitive symptoms. Given these recent label updates, this prescribing guide for vortioxetine aims to provide clear and practical guidance for primary care clinicians on the safe and effective use of vortioxetine for the treatment of MDD, including how to identify appropriate patients for treatment.