ADHERENCE AND PERSISTENCE TO TREATMENT WITH INFLIXIMAB: ANALYSIS OF A PATIENT SUPPORT PROGRAM COHORT IN BRAZIL.

BACKGROUND: Monoclonal antibodies have proven efficacy in the management of several conditions and infliximab (IFX) is one of the most important drugs of the class. Some recent data have shown low rates of both persistence and adherence to several available biologics. OBJECTIVE: The objective of this study was to describe adherence and persistence rate to IFX treatment and also persistence in the patient support program (PSP), among patients diagnosed with inflammatory bowel diseases (IBD) or rheumatic diseases (RD) enrolled in the program of a large pharmaceutical company in Brazil. METHODS: Retrospective observational analysis using the PSP database. IBD or RD patients using IFX enrolled on the PSP database between September 2015 and August 2019 were retrospectively evaluated to identify the persistence rate and adherence and followed up until March 1, 2020. Patients were excluded if treatment start date was prior to program entry; first infusion prior to September 1st, 2015 or after August 31st, 2019; the patients did not started treatment; and patients with "OTHERS" in "Indication" field. Persistence was assessed considering both persistence in the program ("PSP persistence") and persistence on IFX in the PSP ("IFX persistence in the PSP"). PSP persistence was defined as the proportion of patients remaining in the program at 6, 12, 24, 36 and 48 months after initiating IFX. To determine IFX persistence in the PSP, censoring was defined at the time the patient left the program, died, or was lost to follow-up. Adherence to treatment was measured by medication possession ratio ((MPR) - All days supply / elapsed days from first prescription to last day of medication possession)). Descriptive statistics were initially used. Kaplan-Meier curve, the median time estimated by the survival function, Cox regression model, and restricted mean survival time (RMST) were used to evaluate the treatment persistence time at 24 months and the logistic regression model was performed aiming to identify variables associated with adherence (MPR ≥80%). RESULTS: A total of 10,233 patients were analyzed, 5,826 (56.9%) with the diagnosis of RD and 4,407 (43.1%) of IBD. At the end of the follow-up (median 9.1 months from PSP entry to the last infusion), persistence in the PSP was 65.6%, 48.2%, 31.0%, 20.7% and 13.1% at 6, 12, 24, 36 and 48 months, respectively. Considering persistence on IFX in the PSP, estimates were 93.7%, 87.8%, 77.0%, 62.4% and 53.0% at 6, 12, 24, 36 and 48 months, respectively. Variables associated with the risk of non-persistence were gender, country region and diagnosis of rheumatoid arthritis and ankylosing spondylitis. Median MPR was 94.2%, while the percentage of patients with MPR ≥80% was 91.0%. Variables associated with MPR≥80% were country region and diagnosis of Crohn's disease. CONCLUSION: Many patients leave the program without discontinuing IFX, since the 12-month persistence were very different between program and medication estimates, while high adherence rates were observed among patients enrolled in the PSP. Data highlights the benefits of a PSP.

Adesão e persistência ao tratamento com infliximabe: análise de uma coorte de um programa de suporte ao paciente no Brasil / Adherence and persistence to treatment with infliximab: analysis of a patient support program cohort in brazil

ABSTRACT Background: Monoclonal antibodies have proven efficacy in the management of several conditions and infliximab (IFX) is one of the most important drugs of the class. Some recent data have shown low rates of both persistence and adherence to several available biologics. Objective: The objective of this study was to describe adherence and persistence rate to IFX treatment and also persistence in the patient support program (PSP), among patients diagnosed with inflammatory bowel diseases (IBD) or rheumatic diseases (RD) enrolled in the program of a large pharmaceutical company in Brazil. Methods: Retrospective observational analysis using the PSP database. IBD or RD patients using IFX enrolled on the PSP database between September 2015 and August 2019 were retrospectively evaluated to identify the persistence rate and adherence and followed up until March 1, 2020. Patients were excluded if treatment start date was prior to program entry; first infusion prior to September 1st, 2015 or after August 31st, 2019; the patients did not started treatment; and patients with "OTHERS" in "Indication" field. Persistence was assessed considering both persistence in the program ("PSP persistence") and persistence on IFX in the PSP ("IFX persistence in the PSP"). PSP persistence was defined as the proportion of patients remaining in the program at 6, 12, 24, 36 and 48 months after initiating IFX. To determine IFX persistence in the PSP, censoring was defined at the time the patient left the program, died, or was lost to follow-up. Adherence to treatment was measured by medication possession ratio ((MPR) - All days supply / elapsed days from first prescription to last day of medication possession)). Descriptive statistics were initially used. Kaplan-Meier curve, the median time estimated by the survival function, Cox regression model, and restricted mean survival time (RMST) were used to evaluate the treatment persistence time at 24 months and the logistic regression model was performed aiming to identify variables associated with adherence (MPR ≥80%). Results: A total of 10,233 patients were analyzed, 5,826 (56.9%) with the diagnosis of RD and 4,407 (43.1%) of IBD. At the end of the follow-up (median 9.1 months from PSP entry to the last infusion), persistence in the PSP was 65.6%, 48.2%, 31.0%, 20.7% and 13.1% at 6, 12, 24, 36 and 48 months, respectively. Considering persistence on IFX in the PSP, estimates were 93.7%, 87.8%, 77.0%, 62.4% and 53.0% at 6, 12, 24, 36 and 48 months, respectively. Variables associated with the risk of non-persistence were gender, country region and diagnosis of rheumatoid arthritis and ankylosing spondylitis. Median MPR was 94.2%, while the percentage of patients with MPR ≥80% was 91.0%. Variables associated with MPR≥80% were country region and diagnosis of Crohn's disease. Conclusion: Many patients leave the program without discontinuing IFX, since the 12-month persistence were very different between program and medication estimates, while high adherence rates were observed among patients enrolled in the PSP. Data highlights the benefits of a PSP.

RESUMO Contexto: Os anticorpos monoclonais têm eficácia comprovada no manejo de diversas condições e o infliximabe (IFX) é um dos medicamentos mais importantes da classe. Alguns dados recentes demonstram baixas taxas de persistência e adesão a vários dos biológicos disponíveis. Objetivo: O objetivo deste estudo foi descrever a adesão e persistência ao tratamento com IFX e a persistência no programa de suporte ao paciente (PSP), entre pacientes diagnosticados com doenças inflamatórias intestinais (DII) ou doenças reumáticas (DR) inscritos no PSP de uma grande indústria farmacêutica no Brasil. Métodos: Análise observacional retrospectiva utilizando o banco de dados do PSP. Pacientes com DII ou DR usando IFX inscritos no banco de dados do PSP entre setembro de 2015 e agosto de 2019 foram avaliados retrospectivamente para identificar a taxa de persistência e adesão e acompanhados até 1º de março de 2020. Os pacientes foram excluídos se a data de início do tratamento fosse anterior à entrada no programa; primeira infusão antes de 1º de setembro de 2015 ou após 31 de agosto de 2019; o paciente não iniciou o tratamento; e pacientes com "OUTROS" no campo "indicação". A persistência foi avaliada considerando tanto a persistência no programa ("persistência PSP") quanto a persistência em uso de infliximabe no PSP ("persistência IFX no PSP"). A persistência no PSP foi definida como a proporção de pacientes que permaneceram no programa aos 6, 12, 24, 36 e 48 meses após o início do IFX. Para determinar a persistência do IFX no PSP, a censura foi definida quando o paciente deixou o programa, morreu ou perdeu o acompanhamento. A adesão ao tratamento foi medida pela razão de posse do medicamento (MPR)): todos os dias de fornecimento / decorridos da primeira prescrição ao último dia de posse do medicamento). A estatística descritiva foi inicialmente utilizada. A curva de Kaplan-Meier, o tempo mediano estimado pela função de sobrevida, o modelo de regressão de Cox e o tempo de sobrevida médio restrito (RMST) foram utilizados para avaliar o tempo de persistência do tratamento em 24 meses e o modelo de regressão logística foi realizado para identificar variáveis associadas à adesão (MPR ≥80%). Resultados: Foram analisados 10.233 pacientes, 5.826 (56,9%) com diagnóstico de DR e 4.407 (43,1%) de DII. Ao final do seguimento (mediana de 9,1 meses desde a entrada no PSP até a última infusão), a persistência no PSP foi de 65,6%, 48,2%, 31,0%, 20,7% e 13,1% aos 6, 12, 24, 36 e 48 meses, respectivamente. Considerando a persistência no IFX no PSP, as estimativas foram de 93,7%, 87,8%, 77,0%, 62,4% e 53,0% aos 6, 12, 24, 36 e 48 meses, respectivamente. As variáveis associadas ao risco de não persistência foram sexo, região do país e diagnóstico de artrite reumatoide e espondilite anquilosante. A mediana do MPR foi de 94,2%, enquanto o percentual de pacientes com MPR ≥80% foram de 91,0%. As variáveis associadas a MPR ≥80% foram região do país e diagnóstico de doença de Crohn. Conclusão: Muitos pacientes abandonam o programa sem interromper o IFX, pois a persistência em 12 meses foi muito diferente entre as estimativas do programa e da medicação, enquanto altas taxas de adesão foram observadas entre os pacientes inscritos no PSP. Os dados destacam os benefícios de um PSP.

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: Immune dysregulation contributes to poorer outcomes in COVID-19. Objective: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia. Design, Setting, and Participants: Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021. Interventions: Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day). Main Outcomes and Measures: The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale. Results: Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies. Conclusions and Relevance: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

Infliximab for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: Immune dysregulation contributes to poorer outcomes in severe Covid-19. Immunomodulators targeting various pathways have improved outcomes. We investigated whether infliximab provides benefit over standard of care. Methods: We conducted a master protocol investigating immunomodulators for potential benefit in treatment of participants hospitalized with Covid-19 pneumonia. We report results for infliximab (single dose infusion) versus shared placebo both with standard of care. Primary outcome was time to recovery by day 29 (28 days after randomization). Key secondary endpoints included 14-day clinical status and 28-day mortality. Results: A total of 1033 participants received study drug (517 infliximab, 516 placebo). Mean age was 54.8 years, 60.3% were male, 48.6% Hispanic or Latino, and 14% Black. No statistically significant difference in the primary endpoint was seen with infliximab compared with placebo (recovery rate ratio 1.13, 95% CI 0.99-1.29; p=0.063). Median (IQR) time to recovery was 8 days (7, 9) for infliximab and 9 days (8, 10) for placebo. Participants assigned to infliximab were more likely to have an improved clinical status at day 14 (OR 1.32, 95% CI 1.05-1.66). Twenty-eight-day mortality was 10.1% with infliximab versus 14.5% with placebo, with 41% lower odds of dying in those receiving infliximab (OR 0.59, 95% CI 0.39-0.90). No differences in risk of serious adverse events including secondary infections. Conclusions: Infliximab did not demonstrate statistically significant improvement in time to recovery. It was associated with improved 14-day clinical status and substantial reduction in 28- day mortality compared with standard of care. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

Impact of switching to infliximab biosimilars on treatment patterns among US veterans receiving innovator infliximab.

OBJECTIVE: To compare treatment patterns of United States (US) veterans stable on innovator infliximab (IFX) who switched to an IFX biosimilar (switchers) or remained on innovator IFX (continuers). METHODS: US Veterans Healthcare Administration data (01/2012-12/2019) were used to identify adults with rheumatoid arthritis (RA), psoriatic arthritis (PsA), plaque psoriasis (PsO), ankylosing spondylitis (AS), or Crohn's disease and ulcerative colitis (i.e. inflammatory bowel disease [IBD]), treated with innovator or biosimilar IFX. Index date was the first IFX biosimilar administration for switchers or a random innovator IFX administration for continuers. Patients were required to have ≥5 innovator IFX administrations during the 12 months pre-index (prevalent population). Patients with ≥12 months of observation prior to the first innovator IFX administration were analyzed as the primary population (incident population), and data were assessed from start of innovator IFX. Inverse probability of treatment weighting was used to balance baseline characteristics between cohorts. Treatment patterns were evaluated post-index; continuers were censored before switching to IFX biosimilar. Discontinuation was defined as switching to another biologic (including innovator IFX) or having ≥120 days between 2 consecutive index treatment records. RESULTS: In the incident population, mean [median] duration of follow-up was 737 [796] days among switchers (N = 838) and 479 [337] days among continuers (N = 849). Compared to continuers, switchers were 2.88-times more likely to discontinue index therapy (hazard ratio [HR] = 2.88, p < .001) and 4.99-times more likely to switch to another innovator biologic (HR = 4.99, p < .001). Of 653 switchers switching to another innovator biologic, 594 (91.0%) switched back to innovator IFX. Results were similar among the prevalent population and RA and IBD subgroups. CONCLUSION: Patients switching from innovator to biosimilar IFX were more likely to discontinue treatment and switch to another innovator biologic (notably back to innovator IFX) than those remaining on innovator IFX; however, reasons for discontinuation and switching are unknown.

The Automatic Substitution of Biosimilars: Definitions of Interchangeability are not Interchangeable.

In the USA, an interchangeability designation provides biosimilar sponsors with a pathway for achieving what is standard for small-molecule generics: pharmacy-level auto-substitution for an innovator. No other major health authority links interchangeability to automatic substitution, as all require the involvement of the prescriber or patient in a medication change. This editorial considers the clinical impact and practicality of auto-substitution. First, interchangeability is linked to non-medical switching (NMS), the practice of switching treatment in patients with stable disease for non-clinical reasons. NMS may generate negative sentiment in those unwilling or reluctant to switch, which can adversely impact treatment outcomes (i.e., nocebo effect). Indeed, in real-world studies of tumor necrosis factor inhibitors, discontinuation rates have been shown to be higher in patients switched to biosimilars for non-medical reasons than in historical cohorts maintained on innovators. Second, interchangeability may impede pharmacovigilance and traceability, as not all jurisdictions require innovators and biosimilars to have distinct biologic names. Third, an interchangeability designation from the US Food and Drug Administration only permits a biosimilar to be automatically substituted for its innovator, not other biosimilars (if available). Pharmacist education would be needed to avoid off-label, automatic substitution among biosimilars of a single innovator. Last, once granted, an interchangeability designation exists in perpetuity under current US federal law. However, the supply chains of innovators and biosimilars are maintained independently, with no requirement for reconfirmation of biosimilarity or interchangeability. We feel that additional guidance is needed for the auto-substitution of biosimilars and innovators to become a reality.

Switching and Discontinuation Patterns Among Patients Stable on Originator Infliximab Who Switched to an Infliximab Biosimilar or Remained on Originator Infliximab.

OBJECTIVE: To compare switching and discontinuation patterns of patients stable on originator infliximab (IFX) who switched to an IFX biosimilar (switchers) or remained on originator IFX (continuers) in the United States. METHODS: Symphony Health Solutions' Patient Transactional Datasets (10/2012-03/2019) were used to identify adults with ≥2 claims for either rheumatoid arthritis (RA), psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, or inflammatory bowel disease (IBD); and ≥1 claim for originator or biosimilar IFX. The index date was the first IFX biosimilar claim for switchers or a random originator IFX claim for continuers. All patients were required to have ≥5 originator IFX claims during the 12 months pre-index (prevalent population). The subset of patients with ≥12 months of observation prior to the first originator IFX claim was also analyzed (incident population). Switchers were matched 1:3 to continuers. Discontinuation was defined as having ≥120 days between 2 consecutive index treatment claims. RESULTS: Prevalent switchers (N=1109) were 3.57-times more likely than continuers (N=3327) to switch to another originator biologic (hazard ratio [HR]=3.57, p<0.001). Of 249 prevalent switchers who switched to another originator biologic, 200 (80.3%) switched back to originator IFX. Incident switchers (N=571) were 2.55-times more likely than continuers (N=1713) to switch to another originator biologic (HR=2.55, p<0.001). Of 118 incident switchers who switched to another originator biologic, 90 (76.3%) switched back to originator IFX. Prevalent switchers were 1.25-times more likely than continuers to discontinue index therapy (HR=1.25, p<0.001). Similar results were observed in RA (prevalent population; switching: HR=3.49, p<0.001; discontinuation: HR=1.23, p=0.009) and IBD (prevalent population; switching: HR=3.82, p<0.001; discontinuation: HR=1.29, p=0.003) subgroups. CONCLUSION: Patients switching from originator to biosimilar IFX were more likely to switch to another originator biologic (notably back to originator IFX) and discontinue index treatment than those remaining on originator IFX; however, reasons for switching are unknown.

Remicade® (infliximab): 20 years of contributions to science and medicine.

On August 24, 1998, Remicade® (infliximab), the first tumor necrosis factor-α (TNF) inhibitor, received its initial marketing approval from the US Food and Drug Administration for the treatment of Crohn's disease. Subsequently, Remicade was approved in another five adult and two pediatric indications both in the USA and across the globe. In the 20 years since this first approval, Remicade has made several important contributions to the advancement of science and medicine: 1) clinical trials with Remicade established the proof of concept that targeted therapy can be effective in immune-mediated inflammatory diseases; 2) as the first monoclonal antibody approved for use in a chronic condition, Remicade helped in identifying methods of administering large, foreign proteins repeatedly while limiting the body's immune response to them; 3) the need to establish Remicade's safety profile required developing new methods and setting new standards for postmarketing safety studies, specifically in the real-world setting, in terms of approach, size, and duration of follow-up; 4) the study of Remicade has improved our understanding of TNF's role in the immune system, as well as our understanding of the pathophysiology of a range of diseases characterized by chronic inflammation; and 5) Remicade and other TNF inhibitors have transformed treatment practices in these chronic inflammatory diseases: remission has become a realistic goal of therapy and long-term disability resulting from structural damage can be prevented. This paper reviews how, over the course of its development and 20 years of use in clinical practice, Remicade was able to make these contributions.

Early Dose Optimisation of Golimumab in Nonresponders to Induction Treatment for Ulcerative Colitis Is Effective and Supported by Pharmacokinetic Data.

BACKGROUND AND AIMS: In nonresponders to golimumab induction for ulcerative colitis, we assessed clinical response rates and golimumab serum concentrations when the 100-mg dose was used early in the course of maintenance. METHODS: This post-hoc analysis of golimumab maintenance dosing [in the PURSUIT-M study] examined clinical outcomes and golimumab concentrations in early [Week 6] responders and nonresponders to induction, including subgroups based on body weight. RESULTS: In nonresponders to golimumab induction [assessed at Week 6], the 100-mg maintenance dose [starting at Week 6] resulted in a meaningful proportion [28.1%] of patients achieving a partial Mayo response at Week 14. After 1 year of maintenance, clinical outcome [response, remission, mucosal healing, corticosteroid-free state] rates in these "late" [Week 14] responders were similar to those in early [Week 6] responders. Golimumab concentrations in early nonresponders were approximately half those of early responders, suggesting that early nonresponders had more rapid golimumab clearance. Examined by body weight, the early nonresponders weighing <80 kg and receiving 100 mg had golimumab concentrations similar to the early responders [weighing <80 kg or ≥80 kg and receiving 50 mg or 100 mg, respectively]. CONCLUSIONS: Early use of the 100-mg maintenance dose leads to positive clinical outcomes in a meaningful proportion of patients who did not respond to golimumab at Week 6. Early nonresponders <80 kg who received the 100-mg maintenance dose achieved adequate golimumab concentrations and a clinically meaningful proportion of these patients had a late clinical response.PURSUIT-M protocol number C0524T18; ClinicalTrials.gov, NCT00488631; EudraCT, 2006-003399-37.

Ensuring Product Quality, Consistency and Patient Supply over Time for a Large-Volume Biologic: Experience with Remicade®.

Biologics are produced from living organisms in complex, multi-stage manufacturing processes and contain inherent variability, which must be understood and controlled during manufacturing to avoid unexpected changes in key quality attributes that may contribute to clinically meaningful differences. The process must also meet large commercial demand, while simultaneously being able to accommodate change without sacrificing product consistency. The four key components of successful biologics manufacturing are (1) a stable, well-defined proprietary cell line; (2) a good manufacturing practice (GMP)-compliant supply chain with a process control strategy defining acceptable levels of variability for target product/process attributes and capable of managing complex material flows; (3) a tightly controlled procedure for implementation of proposed process changes that ensures product consistency; and (4) built-in redundancy and flexibility providing the ability to adapt rapidly to unexpected developments. This report describes the requirements for the manufacturing and distribution of biologics, using Remicade® (infliximab, Janssen Biotech, Horsham, PA, USA) as an example of best practices. Since Remicade's first marketing approval in 1998, Janssen has manufactured > 150 million vials used to treat > 2.6 million patients around the world for a variety of inflammatory diseases. Remicade displays a highly consistent quality attribute profile and meets all product/process specifications across multiple manufacturing sites and process scales. Janssen's experience with Remicade demonstrates that deep product knowledge, extensive manufacturing experience, diligent product/process monitoring and a sustained commitment to compliance and research are required to ensure quality, consistency and uninterrupted patient supply for large-volume biologics over the long term.