Disease trajectory of SLE clinical endpoints and covariates affecting disease severity and probability of response: Analysis of pooled patient‐level placebo (Standard‐of‐Care) data to enable model‐informed drug development
Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple organ systems. Many investigational agents have failed or shown only modest effects when added to standard of care (SoC) therapy in placebo‐controlled trials, and only two therapies have been approved for SLE in...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-02-01
|
| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.12888 |
| _version_ | 1797905439660179456 |
|---|---|
| author | Kosalaram Goteti Jonathan French Ramon Garcia Ying Li Florence Casset‐Semanaz Aida Aydemir Robert Townsend Cristina Vazquez Mateo Matthew Studham Oliver Guenther Amy Kao Marc Gastonguay Pascal Girard Lisa Benincosa Karthik Venkatakrishnan |
| author_facet | Kosalaram Goteti Jonathan French Ramon Garcia Ying Li Florence Casset‐Semanaz Aida Aydemir Robert Townsend Cristina Vazquez Mateo Matthew Studham Oliver Guenther Amy Kao Marc Gastonguay Pascal Girard Lisa Benincosa Karthik Venkatakrishnan |
| author_sort | Kosalaram Goteti |
| collection | DOAJ |
| description | Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple organ systems. Many investigational agents have failed or shown only modest effects when added to standard of care (SoC) therapy in placebo‐controlled trials, and only two therapies have been approved for SLE in the last 60 years. Clinical trial outcomes have shown discordance in drug effects between clinical endpoints. Herein, we characterized longitudinal disease activity in the SLE population and the sources of variability by developing a latent disease trajectory model for SLE component endpoints (Systemic Lupus Erythematosus Disease Activity Index [SLEDAI], Physician's Global Assessment [PGA], British Isles Lupus Assessment Group Index [BILAG]) and composite endpoints (Systemic Lupus Erythematosus Responder Index [SRI], BILAG‐based Composite Lupus Assessment [BICLA], and Lupus Low Disease Activity State [LLDAS]) using patient‐level historical SoC data from nine phase II and III studies. Across all endpoints, in predictions up to 52 weeks from the final disease trajectory model, the following baseline covariates were associated with a greater decrease in SLE disease activity and higher response to placebo + SoC: Hispanic ethnicity from Central/South America, absence of hypocomplementemia, recent SLE diagnosis, and high baseline disease activity score using SLEDAI and BILAG separately. No discernible differences were observed in the trajectory of response to placebo + SoC across different SoC medications (antimalarial and immunosuppressant such as mycophenolate, methotrexate, and azathioprine). Across all endpoints, disease trajectory showed no difference in Asian versus non‐Asian patients, supporting Asia‐inclusive global SLE drug development. These results describe the first population approach to support a model‐informed drug development framework in SLE. |
| first_indexed | 2024-04-10T10:05:18Z |
| format | Article |
| id | doaj.art-1557da4204d843a4921890da95fb3dbf |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-04-10T10:05:18Z |
| publishDate | 2023-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-1557da4204d843a4921890da95fb3dbf2023-02-15T21:42:18ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062023-02-0112218019510.1002/psp4.12888Disease trajectory of SLE clinical endpoints and covariates affecting disease severity and probability of response: Analysis of pooled patient‐level placebo (Standard‐of‐Care) data to enable model‐informed drug developmentKosalaram Goteti0Jonathan French1Ramon Garcia2Ying Li3Florence Casset‐Semanaz4Aida Aydemir5Robert Townsend6Cristina Vazquez Mateo7Matthew Studham8Oliver Guenther9Amy Kao10Marc Gastonguay11Pascal Girard12Lisa Benincosa13Karthik Venkatakrishnan14EMD Serono Research and Development Institute, Inc (an affiliate of Merck KGaA, Darmstadt Germany) Billerica Massachusetts USAMetrum Research Group Tariffville Connecticut USAMetrum Research Group Tariffville Connecticut USAEMD Serono Research and Development Institute, Inc (an affiliate of Merck KGaA, Darmstadt Germany) Billerica Massachusetts USAEMD Serono Research and Development Institute, Inc (an affiliate of Merck KGaA, Darmstadt Germany) Billerica Massachusetts USAEMD Serono Research and Development Institute, Inc (an affiliate of Merck KGaA, Darmstadt Germany) Billerica Massachusetts USAEMD Serono Research and Development Institute, Inc (an affiliate of Merck KGaA, Darmstadt Germany) Billerica Massachusetts USAEMD Serono Research and Development Institute, Inc (an affiliate of Merck KGaA, Darmstadt Germany) Billerica Massachusetts USAEMD Serono Research and Development Institute, Inc (an affiliate of Merck KGaA, Darmstadt Germany) Billerica Massachusetts USAMerck KGaA Darmstadt GermanyEMD Serono Research and Development Institute, Inc (an affiliate of Merck KGaA, Darmstadt Germany) Billerica Massachusetts USAMetrum Research Group Tariffville Connecticut USAMerck Institute of Pharmacometrics Lausanne SwitzerlandEMD Serono Research and Development Institute, Inc (an affiliate of Merck KGaA, Darmstadt Germany) Billerica Massachusetts USAEMD Serono Research and Development Institute, Inc (an affiliate of Merck KGaA, Darmstadt Germany) Billerica Massachusetts USAAbstract Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple organ systems. Many investigational agents have failed or shown only modest effects when added to standard of care (SoC) therapy in placebo‐controlled trials, and only two therapies have been approved for SLE in the last 60 years. Clinical trial outcomes have shown discordance in drug effects between clinical endpoints. Herein, we characterized longitudinal disease activity in the SLE population and the sources of variability by developing a latent disease trajectory model for SLE component endpoints (Systemic Lupus Erythematosus Disease Activity Index [SLEDAI], Physician's Global Assessment [PGA], British Isles Lupus Assessment Group Index [BILAG]) and composite endpoints (Systemic Lupus Erythematosus Responder Index [SRI], BILAG‐based Composite Lupus Assessment [BICLA], and Lupus Low Disease Activity State [LLDAS]) using patient‐level historical SoC data from nine phase II and III studies. Across all endpoints, in predictions up to 52 weeks from the final disease trajectory model, the following baseline covariates were associated with a greater decrease in SLE disease activity and higher response to placebo + SoC: Hispanic ethnicity from Central/South America, absence of hypocomplementemia, recent SLE diagnosis, and high baseline disease activity score using SLEDAI and BILAG separately. No discernible differences were observed in the trajectory of response to placebo + SoC across different SoC medications (antimalarial and immunosuppressant such as mycophenolate, methotrexate, and azathioprine). Across all endpoints, disease trajectory showed no difference in Asian versus non‐Asian patients, supporting Asia‐inclusive global SLE drug development. These results describe the first population approach to support a model‐informed drug development framework in SLE.https://doi.org/10.1002/psp4.12888 |
| spellingShingle | Kosalaram Goteti Jonathan French Ramon Garcia Ying Li Florence Casset‐Semanaz Aida Aydemir Robert Townsend Cristina Vazquez Mateo Matthew Studham Oliver Guenther Amy Kao Marc Gastonguay Pascal Girard Lisa Benincosa Karthik Venkatakrishnan Disease trajectory of SLE clinical endpoints and covariates affecting disease severity and probability of response: Analysis of pooled patient‐level placebo (Standard‐of‐Care) data to enable model‐informed drug development CPT: Pharmacometrics & Systems Pharmacology |
| title | Disease trajectory of SLE clinical endpoints and covariates affecting disease severity and probability of response: Analysis of pooled patient‐level placebo (Standard‐of‐Care) data to enable model‐informed drug development |
| title_full | Disease trajectory of SLE clinical endpoints and covariates affecting disease severity and probability of response: Analysis of pooled patient‐level placebo (Standard‐of‐Care) data to enable model‐informed drug development |
| title_fullStr | Disease trajectory of SLE clinical endpoints and covariates affecting disease severity and probability of response: Analysis of pooled patient‐level placebo (Standard‐of‐Care) data to enable model‐informed drug development |
| title_full_unstemmed | Disease trajectory of SLE clinical endpoints and covariates affecting disease severity and probability of response: Analysis of pooled patient‐level placebo (Standard‐of‐Care) data to enable model‐informed drug development |
| title_short | Disease trajectory of SLE clinical endpoints and covariates affecting disease severity and probability of response: Analysis of pooled patient‐level placebo (Standard‐of‐Care) data to enable model‐informed drug development |
| title_sort | disease trajectory of sle clinical endpoints and covariates affecting disease severity and probability of response analysis of pooled patient level placebo standard of care data to enable model informed drug development |
| url | https://doi.org/10.1002/psp4.12888 |
| work_keys_str_mv | AT kosalaramgoteti diseasetrajectoryofsleclinicalendpointsandcovariatesaffectingdiseaseseverityandprobabilityofresponseanalysisofpooledpatientlevelplacebostandardofcaredatatoenablemodelinformeddrugdevelopment AT jonathanfrench diseasetrajectoryofsleclinicalendpointsandcovariatesaffectingdiseaseseverityandprobabilityofresponseanalysisofpooledpatientlevelplacebostandardofcaredatatoenablemodelinformeddrugdevelopment AT ramongarcia diseasetrajectoryofsleclinicalendpointsandcovariatesaffectingdiseaseseverityandprobabilityofresponseanalysisofpooledpatientlevelplacebostandardofcaredatatoenablemodelinformeddrugdevelopment AT yingli diseasetrajectoryofsleclinicalendpointsandcovariatesaffectingdiseaseseverityandprobabilityofresponseanalysisofpooledpatientlevelplacebostandardofcaredatatoenablemodelinformeddrugdevelopment AT florencecassetsemanaz diseasetrajectoryofsleclinicalendpointsandcovariatesaffectingdiseaseseverityandprobabilityofresponseanalysisofpooledpatientlevelplacebostandardofcaredatatoenablemodelinformeddrugdevelopment AT aidaaydemir diseasetrajectoryofsleclinicalendpointsandcovariatesaffectingdiseaseseverityandprobabilityofresponseanalysisofpooledpatientlevelplacebostandardofcaredatatoenablemodelinformeddrugdevelopment AT roberttownsend diseasetrajectoryofsleclinicalendpointsandcovariatesaffectingdiseaseseverityandprobabilityofresponseanalysisofpooledpatientlevelplacebostandardofcaredatatoenablemodelinformeddrugdevelopment AT cristinavazquezmateo diseasetrajectoryofsleclinicalendpointsandcovariatesaffectingdiseaseseverityandprobabilityofresponseanalysisofpooledpatientlevelplacebostandardofcaredatatoenablemodelinformeddrugdevelopment AT matthewstudham diseasetrajectoryofsleclinicalendpointsandcovariatesaffectingdiseaseseverityandprobabilityofresponseanalysisofpooledpatientlevelplacebostandardofcaredatatoenablemodelinformeddrugdevelopment AT oliverguenther diseasetrajectoryofsleclinicalendpointsandcovariatesaffectingdiseaseseverityandprobabilityofresponseanalysisofpooledpatientlevelplacebostandardofcaredatatoenablemodelinformeddrugdevelopment AT amykao diseasetrajectoryofsleclinicalendpointsandcovariatesaffectingdiseaseseverityandprobabilityofresponseanalysisofpooledpatientlevelplacebostandardofcaredatatoenablemodelinformeddrugdevelopment AT marcgastonguay diseasetrajectoryofsleclinicalendpointsandcovariatesaffectingdiseaseseverityandprobabilityofresponseanalysisofpooledpatientlevelplacebostandardofcaredatatoenablemodelinformeddrugdevelopment AT pascalgirard diseasetrajectoryofsleclinicalendpointsandcovariatesaffectingdiseaseseverityandprobabilityofresponseanalysisofpooledpatientlevelplacebostandardofcaredatatoenablemodelinformeddrugdevelopment AT lisabenincosa diseasetrajectoryofsleclinicalendpointsandcovariatesaffectingdiseaseseverityandprobabilityofresponseanalysisofpooledpatientlevelplacebostandardofcaredatatoenablemodelinformeddrugdevelopment AT karthikvenkatakrishnan diseasetrajectoryofsleclinicalendpointsandcovariatesaffectingdiseaseseverityandprobabilityofresponseanalysisofpooledpatientlevelplacebostandardofcaredatatoenablemodelinformeddrugdevelopment |