Eficacia y seguridad de guselkumab y secukinumab en pacientes adultos con psoriasis vulgar severa, no respondedores a terapia tópica y sistémica convencional y no tributario a terapia biológica antagonista al factor de necrosis tumoral por antecedente de neoplasia maligna / Efficacy and safety of guselkumab and secukinumab in adult patients with severe psoriasis vulgaris, non-responsive to conventional topical and systemic therapy and not amenable to biological therapy antagonistic to tumor necrosis factor due to a history of malignancy

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021 y ampliada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 97-IETSI-ESSALUD2022, se ha elaborado el presente dictamen, el cual expone la evaluación de la eficacia y seguridad de guselkumab y secukinumab en pacientes adultos con psoriasis vulgar severa, no respondedores a terapia tópica y sistémica convencional y no tributario a terapia biológica antagonista al factor de necrosis tumoral disponible en EsSalud por antecedente de neoplasia maligna, en comparación de la mejor terapia de soporte. Así, la médica Evelyn Giuliana Castro Vargas, especialista en dermatología, a través del Comité Farmacoterapéutico del Hospital Nacional Alberto Sabogal Sologuren y siguiendo la Directiva N° 003-IETSI-ESSALUD-2016, envía al Instituto de Evaluación de Tecnologías en Salud e Investigación - IETSI la solicitud de autorización de uso del producto farmacéutico guselkumab no incluido en el Petitorio Farmacológico de EsSalud. ASPECTOS GENERALES La psoriasis es una enfermedad dermatológica inflamatoria crónica no transmisible que afecta aproximadamente del 1 % al 3 % de la población mundial (Augustin et al., 2010) con una prevalencia de alrededor del 2.5 % en el Perú (Rodríguez-Zúñiga, 2016). Esta enfermedad es considerada como un problema de salud pública y de elevada carga para la sociedad (Parisi et al., 2013), lo que se explica por su alto riesgo de morbilidad y porque deteriora la calidad de vida y la salud mental de las personas que lo padecen (Boehnoke & Schón, 2015). El fenotipo de psoriasis más común es la psoriasis vulgar, que se caracteriza por la presencia de placas eritematosas, gruesas y escamosas que se presentan mayormente en cuero cabelludo, glúteos, tronco y extremidades (codos y rodillas). La psoriasis suele clasificarse en leve, moderada y severa, según la clinimetría de las mediciones del Psoriasis Area and Severity Index (PASI), la Body surface area (BSA) y la calidad de vida medida a partir del Dermatology Life Quality Index (DLQI) (Finlay, 2015; Robinson et al., 2012). Es decir, la enfermedad severa se define por tener más de 10 puntos en el PASI, más del 10 % de la superficie corporal (BSA) afectada por la enfermedad, o más de 10 puntos en el DLQI (Strober et al., 2019). Los tratamientos para los pacientes con psoriasis vulgar severa tienen como objetivo lograr una reducción de por lo menos el 75 % o 90 % de la severidad de enfermedad inicial medida por la escala PASI (i.e. PASI75 o PASI90, respectivamente) luego de al menos tres meses de tratamiento efectivo (Belinchón Romero et al., 2021). Asimismo, se considera que, si después de 16 a 24 semanas de la aplicación de un esquema terapéutico efectivo no se ha logrado por lo menos alcanzar el PASI75 con DLQI < 5 o un PASI90, se considera que el paciente no ha respondido al tratamiento (i.e. falla terapéutica) (Aschoff et al., 2021). Así, entre los tratamientos disponibles para la psoriasis tenemos la terapia tópica que se utiliza en los casos de psoriasis leve a moderada', y la terapia sistémica, en casos de psoriasis de moderada a severa2. Dentro de la terapia sistémica, tenemos a los agentes sistémicos convencionales (metotrexato, ciclosporina o acitretina) y la terapia biológica. Ésta última se utiliza generalmente en los casos de falla al tratamiento con agentes sistémicos convencionales (Gisondi et al., 2017). Las terapias biológicas se clasifican según el mecanismo de acción, es decir, según la inhibición dirigida a citoquinas específicas del sistema inmune, tales como el factor de necrosis tumoral alfa (TNF), la interleucina (IL) 17 (IL17) y la IL23 (Fellner, 2016). METODOLOGIA: Se realizó una búsqueda bibliográfica exhaustiva con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad de guselkumab y secukinumab en pacientes adultos con psoriasis vulgar severa no respondedores a terapia tópica y sistémica convencional y no tributario a terapia biológica anti TNF disponibles en EsSalud por antecedente de neoplasia maligna. La búsqueda se realizó en las bases de datos bibliográficas de PubMed, The Cochrane Library, Web of Science y LILACS (Literatura Latinoamericana y del Caribe en Ciencias 'de la Salud). Asimismo, se realizó una búsqueda dentro de la información generada en las páginas web de grupos o instituciones que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), tales como: el National Institute for Health and Care Excellence (NICE), la Agency for Healthcare Research and Quality's (AHRQ), la Scottish Intercollegiate Guidelines Network (SIGN), la New Zealand Guidelines Group (NZGG), la National Health and Medical Research Council (NHMRC), el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI), el Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), la Canadian Agency for Drugs and Technologies in Health (CADTH), el Scottish Medicines Consortium (SMC), la Haute Authorité de Santé (HAS), el Institute for Quality and Efficiency in Health Care (IQWiG), la Comissáo Nacional de lncorporagáo de Tecnologías no Sistema Único de Saúde (CONITEC), el Institute for Clinical and Economic Review (ICER) y en la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA). Además, se realizó una búsqueda de las guías en las principales instituciones o sociedades especializadas en dermatología y en psoriasis, tales como la American Academy of Dermatology (AAD), la British Association of Dermatologists (BAD), la European Academy of Dermatology and Venereology (EADV), y la International Psoriasis Council (IPC). Adicionalmente, se llevó a cabo una búsqueda manual en el motor de búsqueda Google utilizando los términos: "Psoriasis guidelines"; revisando documentos de interés en las diez primeras páginas. Finalmente, se realizó una búsqueda adicional en la página web de registro de ensayos clínicos (EC) www.clinicaltrials.gov, para identificar EC en curso o aún no publicados. RESULTADOS: Luego de la búsqueda bibliográfica hasta diciembre de 2022, se identificaron: una GPC de la BAD publicada en el 2020 (Smith et al., 2020); y una RS con MA en red (Sbidian et al., 2022) publicada en el 2022 que fue seleccionada como evidencia indirecta para responder a la pregunta PICO del presente dictamen. CONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación aprueba el uso de guselkumab en pacientes adultos con psoriasis vulgar severa, no respondedores a terapia tópica y sistémica convencional y no tributario a terapia biológica anti TNF antecedente de neoplasia maligna, como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud, según lo establecido en el Anexo N° 1. La vigencia del presente informe preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de mayor evidencia que pueda surgir en el tempo.

Dose Escalation Assessment Among Targeted Immunomodulators in the Management of Inflammatory Bowel Disease.

BACKGROUND: The need for individualized treatment regimens is becoming more important in the management of patients with inflammatory bowel disease (IBD). Gastroenterologists may dose adjust either by increasing the dose or shortening the dosing interval from the initial recommended maintenance dose to achieve an appropriate clinical response. Understanding the role of dose escalation in the treatment of IBD in clinical practice provides payers in the United States insight into the real-world cost-effectiveness of targeted immunomodulators (TIMs) in the management of IBD. OBJECTIVE: To assess the prevalence and magnitude of dose escalation for approved IBD therapies. METHODS: Using the Source Healthcare Analytics database, patients with IBD who initiated treatment with a drug of interest from July 2015 to June 2017 were identified. Patient utilization of the TIMs was tracked for 12 months following initiation. All included patients had at least 2 diagnoses for ulcerative colitis or Crohn disease before TIM initiation and at least 5 claims for a drug of interest within the 12 months following initiation. Dose escalation was defined as an increase of at least 30% in the average daily dose (ADD) relative to the patient's expected maintenance dose on 2 consecutive prescriptions. The proportion of patients with dose escalation in the first 12 months after treatment initiation was determined. The magnitude of dose escalation was determined by calculating the patient's ADD across all noninduction dose claims and comparing it with the expected daily dose. Dose escalation prevalence and magnitude were used to quantify the equivalent patient treatment rate representing the number of patients per 100 that could have been treated with standard dosing, given the prevalence of dose escalation in the treated population. RESULTS: 7,028 patients (2,406 infliximab, 1,966 adalimumab, 1,745 vedolizumab, 472 ustekinumab, 285 certolizumab pegol, and 154 golimumab) met eligibility criteria and were included in the study. Among IBD therapies, dose escalation occurred most frequently with infliximab (39%), followed by adalimumab (28%), vedolizumab (23%), ustekinumab (22%), certolizumab pegol (20%), and golimumab (14%). The magnitude of dose escalation was greatest for ustekinumab (131%), followed by infliximab (70%), vedolizumab (62%), adalimumab (59%), certolizumab pegol (50%), and golimumab (45%). The calculated patient equivalence was highest for infliximab (128) and ustekinumab (128) compared with adalimumab (116), vedolizumab (114), certolizumab pegol (110), and golimumab (106). CONCLUSIONS: Among patients with IBD, dose escalation occurred with all TIMs examined with varying degrees of prevalence and magnitude. Real-world utilization patterns of TIMs indicate that dose escalation is an important part of the clinical management of IBD and needs to be considered when evaluating the cost-effectiveness of IBD treatments. DISCLOSURES: Financial support for this study was provided by AbbVie, which participated in study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. All authors contributed to the development of the publication and maintained control over the final content. Ehrenberg and McDonald are employees of IQVIA, which received funding from AbbVie to participate in this research. Griffith and Theigs are employed by AbbVie and may own stock or stock options in AbbVie.

Cost-Effectiveness of Targeted Pharmacotherapy for Moderate to Severe Plaque Psoriasis.

BACKGROUND: Newer classes of targeted drugs for moderate to severe plaque psoriasis are more effective and more expensive than older classes, posing a difficult and potentially costly decision about whether to use them as initial targeted treatments. OBJECTIVE: To estimate the clinical and economic outcomes of initial targeted treatment for the following drugs: adalimumab, etanercept, and infliximab (TNFα inhibitors); apremilast (PDE4 inhibitor); ustekinumab (IL-12/23 inhibitor); and ixekizumab, secukinumab, and brodalumab (IL-17 inhibitors). METHODS: We developed a Markov model to simulate patient outcomes as measured by quality-adjusted life-years (QALYs) and health care costs over a 10-year period. We assumed that patients who fail initial targeted treatment either proceed to subsequent therapy or discontinue targeted treatment. Effectiveness estimates for initial treatment were defined as improvement in Psoriasis Area and Severity Index (PASI) from baseline and derived from a 2018 network meta-analysis. Wholesale acquisition drug costs were discounted by a class-specific, empirically derived rebate percentage off of 2016 costs. We conducted one-way and probabilistic sensitivity analyses to assess uncertainty in results. RESULTS: The incremental benefits compared with no targeted treatment were, in descending order: ixekizumab 1.68 QALYs (95% credible range [CR] = 1.11-2.02), brodalumab 1.64 QALYs (95% CR = 1.08-1.98), secukinumab 1.51 QALYs (95% CR = 1.00-1.83), ustekinumab 1.43 QALYs (95% CR=0.94-1.74), infliximab 1.27 QALYs (95% CR = 0.89-1.55), adalimumab 1.15 QALYs (95% CR = 0.76-1.44), etanercept 0.97 QALYs (95% CR = 0.61-1.25), and apremilast 0.87 QALYs (95% CR = 0.52-1.17). Costs of care without targeted treatment totaled $66,451, and costs of targeted treatment ranged from $137,080 (apremilast) to $255,422 (ustekinumab). Probabilistic sensitivity analysis results indicated that infliximab and apremilast are likely to be the most cost-effective initial treatments at willingness-to-pay thresholds around $100,000 per QALY, while IL-17 drugs are more likely to be cost-effective at thresholds approaching $150,000 per QALY. Acquisition cost of the initial targeted drug and utility of clinical response were the most influential parameters. CONCLUSIONS: Our findings suggest that initial targeted treatment with IL-17 inhibitors is the most effective treatment strategy for plaque psoriasis patients who have failed methotrexate and phototherapy. Apremilast, brodalumab, infliximab, ixekizumab, and secukinumab are cost-effective at different willingness-to-pay thresholds. Additional research is needed on whether the effectiveness of targeted agents changes when used after previously targeted agents. DISCLOSURES: Funding for this study was contributed by the Institute for Clinical and Economic Review (ICER). Ollendorf, Chapman, Pearson, and Kumar are current employees, and Loos and Liu are former employees, of ICER, an independent organization that evaluates the evidence on the value of health care interventions, which is funded by grants from the Laura and John Arnold Foundation, Blue Shield of California Foundation, and the California HealthCare Foundation. ICER's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Alnylam, AstraZeneca, Blue Shield of California, Cambia Health Solutions and MedSavvy, CVS Caremark, Editas, Express Scripts, Genentech, GlaxoSmithKline, Harvard Pilgrim Health Care, Health Care Service Corporation, OmedaRx, United Healthcare, Johnson & Johnson, Kaiser Permanente, Premera Blue Cross, Merck, National Pharmaceutical Council, Takeda, Pfizer, Novartis, Lilly, Humana, Prime Therapeutics, Sanofi, and Spark Therapeutics. Linder owns stock in Amgen, Biogen, and Eli Lilly; has contingent value rights in Sanofi Genzyme (related to alemtuzumab for multiple sclerosis); has received grant support from Astellas Pharma not related to this study and Clintrex, which was supported by AstraZeneca on an unrelated topic; and has received an honorarium from the Society of Healthcare Epidemiology of America (SHEA) as part of the SHEA Antimicrobial Stewardship Research Workshop Planning Committee, an educational activity supported by Merck. No other authors have potential conflicts of interest.

Characterization of disease burden, comorbidities, and treatment use in a large, US-based cohort: Results from the Corrona Psoriasis Registry.

BACKGROUND: Psoriasis is an immunodysregulatory inflammatory disease associated with comorbidities affecting quality of life. With the advent of new treatments, there is growing need to assess the long-term safety and efficacy of treatments in a real-world setting. OBJECTIVE: The objective of the Corrona Psoriasis Registry is to study the comparative safety and efficacy of Food and Drug Administration-approved biologic treatments. METHODS: A cross-sectional study of patients enrolled in the registry, who initiated or switched to a systemic therapy at enrollment or previous 12 months. Descriptive characteristics (demographics, clinical and patient-reported outcomes, comorbidities, and treatment history) were examined at registry enrollment. RESULTS: As of October 1, 2016, there were 1942 patients enrolled in the registry: 23% on apremilast, 4% on other nonbiologic systemic medications, 25% on interleukin (IL) 17A inhibitors, 22% on an IL-12/23 inhibitor, and 26% on tumor necrosis factor inhibitors. Overall, mean disease duration was 15.6 years, and 40% had a concurrent psoriatic arthritis diagnosis. About 66% had >3% body surface area involvement and 49% had a moderate or severe Investigator Global Assessment. LIMITATIONS: Selection and channeling bias can result in potential confounding that needs to be addressed in modeled analyses. CONCLUSION: This disease-based registry cohort represents a population exposed to multiple therapies, long disease duration, and multiple comorbidities and can be used to examine comparative safety and efficacy of various therapies.

A safety assessment of biological therapies targeting the IL-23/IL-17 axis in inflammatory bowel diseases.

INTRODUCTION: Many different compounds targeting the interleukin 23/17 axis have been developed and successfully studied in several autoimmune diseases, including inflammatory bowel diseases. Nevertheless, interfering with key immunological pathways raises potential safety concerns. This review focuses on the safety profile of these novel biological therapies. Areas covered: A literature search until March 2017 was performed to collect safety data on different compounds targeting this pathway, with emphasis on ustekinumab and secukinumab. Firstly, the authors discuss briefly how genetics can inform about potential safety issues. Secondly, they extensively describe safety issues (common adverse events, infections, malignancies…), immunogenicity, exposure to ustekinumab in specific populations and provide advice for vaccination. Finally, they address safety profiles of secukinumab and other biological targeting the IL-23/17 axis in IBD. Expert opinion: Current evidence suggests that ustekinumab therapy overweigh the potential drug-related risks. Additional safety data beyond randomized-controlled trials, derived from statistically powered, large prospective studies with long-term follow-up are urgently needed to assess the real-life ustekinumab-related risks and to establish the correct position of these novel class of biologicals in IBD treatment. Combining immunomodulators with ustekinumab seems to be safe, though prospective data specifically addressing this topic are currently missing. Similarly, the combination of different biological therapies still has to be studied.

Burden of disease: psoriasis and psoriatic arthritis.

Psoriatic arthritis (PsA) increases the disease burden associated with psoriasis by further diminishing quality of life, increasing health care costs and cardiovascular risk, and potentially causing progressive joint damage. The presence of PsA influences psoriasis treatment by increasing overall disease complexity and, within the framework of current guidelines and recommendations, requiring the use of conventional disease-modifying anti-rheumatic drugs or tumor necrosis factor-α inhibitors in order to prevent progressive joint damage. Despite its important impact, PsA is still under-diagnosed in dermatology practice. Dermatologists are well positioned to recognize and treat PsA, given that it characteristically presents, on average, 10 years subsequent to the appearance of skin symptoms. Regular screening of psoriasis patients for early evident joint symptoms should be incorporated into daily dermatologic practice. Although drugs effective in PsA are available, not all patients may respond to treatment, and others may lose their initial response over time. New investigational therapies, such as inhibitors of interleukin-17A, interleukin-12/23, Janus kinase 3, or phosphodiesterase-4, may address unmet needs in psoriatic disease, with further research needed to determine the role of these agents in reducing joint damage and other comorbidities.