Assessing Efficacy and Safety of treatments in progressive Multiple Sclerosis
SYNOPSIS AND RESULTS
Except for Ocrelizumab, previous phase-III randomized controlled trials largely failed in finding benefit of disease modifying drugs (DMDs) among patients affected by primary progressive multiple sclerosis (PPMS). Consistently with these findings, most of the Real word studies drove to the same conclusion, finding no substantial differences between treated and untreated patients in the real clinical setting. However, some recent results highlighted that a sustained exposure to DMDs, especially when the drug is administered at a young age and in patients with inflammatory activities, may exert a protective role, reducing the risk of hard disability milestones. RCTs suffer from low generalizability and explore the effect of therapy for a time-window that rarely cover more than two years. Moreover, variables like the duration of DMT exposure or the delay in treatment initiation are not evaluated in the setting of clinical trials, but they may be crucial in the real-world setting. In the absence of previous licensed therapeutic options, DMTs have been used off-label in PPMS patients, and registry-based cohort study represents a major source of real-world data to elucidate the above issues. We hypothesized that, among PPMS patients, those who had active disease at baseline or experienced superimposed relapses during follow-up might benefit from DMT. Moreover, to better understand the effects of DMTs, we evaluated the type of DMT, the delay in treatment initiation and the duration of DMT exposure.
Data start
Data end
2019-02-27
2020-11-01
PARTICIPATING CENTERS
- Lorenzo Razzolini, medico specialista in Neurologia. Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy. lorenzo.razzolini@alice.it;
- Luisa Pastò medico specialista in Neurologia. Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy. luisapasto@gmail.com;
- Mattia Fonderico, medico specializzando. Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy. mattia.fonderico@unifi.it
OUTCOME
Introduction and aims Except for Ocrelizumab, previous phase-III randomized controlled trials largely failed in finding benefit of disease modifying drugs (DMDs) among patients affected by primary progressive multiple sclerosis (PPMS). Consistently with these findings, most of the Real word studies drove to the same conclusion, finding no substantial differences between treated and untreated patients in the real clinical setting. However, some recent results highlighted that a sustained exposure to DMDs, especially when the drug is administered at a young age and in patients with inflammatory activities, may exert a protective role, reducing the risk of hard disability milestones. RCTs suffer from low generalizability and explore the effect of therapy for a time-window that rarely cover more than two years. Moreover, variables like the duration of DMT exposure or the delay in treatment initiation are not evaluated in the setting of clinical trials, but they may be crucial in the real-world setting. In the absence of previous licensed therapeutic options, DMTs have been used off-label in PPMS patients, and registry-based cohort study represents a major source of real-world data to elucidate the above issues. We hypothesized that, among PPMS patients, those who had active disease at baseline or experienced superimposed relapses during follow-up might benefit from DMT. Moreover, to better understand the effects of DMTs, we evaluated the type of DMT, the delay in treatment initiation and the duration of DMT exposure.
Results Using the Italian MS Registry, we selected PPMS patients with at least three EDSS evaluations and three years of follow-up. Study baseline was defined as the first EDSS evaluation for untreated patients and the date of the first DMT initiation for treated patients. Of the 1139 patients we included (629 females, mean ± Standard Deviation [SD] baseline age 48.3 ± 11.1 years, mean EDSS score 4.1 ± 1.8), 746 (65%) received a DMT during the follow-up. In the whole sample, after a mean (SD) follow-up of 11.8 (± 6.3) years, 438 (38%) reached the EDSS 7.0. In the multivariable Cox regression models, the use of DMT, analysed as dichotomous variable, did not influence the risk of reaching EDSS 7 (aHR = 1.09, 95% CI 0.88-1.36, p = 0.417). However, in patients with superimposed relapses, DMT exposure significantly reduced the risk of reaching EDSS 7 (aHR = 0.61, 95% CI 0.42-0.87, p =0.007). Moreover, we found that, among good responders to DMT, those who persisted on treatment had the most beneficial effect (aHR = 0.45, 95% CI 0.29-0.71, p = 0,001). These results have been confirmed after propensity-score matching.
Conclusions This study suggests that inflammatory activity may be a modifiable component of long-term disability outcomes in PPMS patients. Moreover, in PPMS patients who have inflammatory activity during follow-up, longer exposure to DMT may increase the beneficial effect of treatment. To optimize treatment decision-making in PPMS further profiling of the best candidates to treatment is needed.
Pubblicazioni e Comunicazioni a Congressi/ Publications and Congress Presentations Oral presentations Fonderico M. “Disease modifying treatment may delay time to wheelchair in primary progressive multiple sclerosis: a real-life cohort”. 8th Joint ACTRIMS-ECTRIMS MEETING, 11th September 2020. Fonderico M. “Disease modifying treatment may delay time to wheelchair in primary progressive multiple sclerosis: a real-life cohort”. 51° National Congress of Italian Society of Neurology, Milan, 28-30th November 2020
PUBLICATIONS
Fonderico M. “Disease modifying treatment may delay time to wheelchair in primary progressive multiple sclerosis: a real-life cohort”. 8th Joint ACTRIMS-ECTRIMS MEETING, 11th September 2020.
Fonderico M. “Disease modifying treatment may delay time to wheelchair in primary progressive multiple sclerosis: a real-life cohort”. 51° National Congress of Italian Society of Neurology, Milan, 28-30th November 2020
Portaccio E, Fonderico M, Iaffaldano P, Pastò L, Razzolini L, Bellinvia A, De Luca G, Ragonese P, Patti F, Brescia Morra V, Cocco E, Sola P, Inglese M, Lus G, Pozzilli C, Maimone D, Lugaresi A, Gazzola P, Comi G, Pesci I, Spitaleri D, Rezzonico M, Vianello M, Avolio C, Logullo FO, Granella F, Salvetti M, Zaffaroni M, Lucisano G, Filippi M, Trojano M, Amato MP; Italian Multiple Sclerosis Register Centers Group. Disease-Modifying Treatments and Time to Loss of Ambulatory Function in Patients With Primary Progressive Multiple Sclerosis. JAMA Neurol. 2022 Sep 1;79(9):869-878. doi: 10.1001/jamaneurol.2022.1929. PMID: 35877104 Clinical Trial.
Fondazione Italiana Sclerosi Multipla – FISM – Ente del Terzo Settore/ETS e, in forma abbreviata, FISM ETS. Iscrizione al RUNTS Rep. N° 89695 - Fondazione con Riconoscimento di Personalità Giuridica - C.F. 95051730109
Assessing Efficacy and Safety of treatments in progressive Multiple Sclerosis
Except for Ocrelizumab, previous phase-III randomized controlled trials largely failed in finding benefit of disease modifying drugs (DMDs) among patients affected by primary progressive multiple sclerosis (PPMS). Consistently with these findings, most of the Real word studies drove to the same conclusion, finding no substantial differences between treated and untreated patients in the real clinical setting. However, some recent results highlighted that a sustained exposure to DMDs, especially when the drug is administered at a young age and in patients with inflammatory activities, may exert a protective role, reducing the risk of hard disability milestones.
RCTs suffer from low generalizability and explore the effect of therapy for a time-window that rarely cover more than two years. Moreover, variables like the duration of DMT exposure or the delay in treatment initiation are not evaluated in the setting of clinical trials, but they may be crucial in the real-world setting.
In the absence of previous licensed therapeutic options, DMTs have been used off-label in PPMS patients, and registry-based cohort study represents a major source of real-world data to elucidate the above issues.
We hypothesized that, among PPMS patients, those who had active disease at baseline or experienced superimposed relapses during follow-up might benefit from DMT. Moreover, to better understand the effects of DMTs, we evaluated the type of DMT, the delay in treatment initiation and the duration of DMT exposure.
- Lorenzo Razzolini, medico specialista in Neurologia. Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy. lorenzo.razzolini@alice.it;
- Luisa Pastò medico specialista in Neurologia. Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy. luisapasto@gmail.com;
- Mattia Fonderico, medico specializzando. Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy. mattia.fonderico@unifi.it
Introduction and aims
Except for Ocrelizumab, previous phase-III randomized controlled trials largely failed in finding benefit of disease modifying drugs (DMDs) among patients affected by primary progressive multiple sclerosis (PPMS). Consistently with these findings, most of the Real word studies drove to the same conclusion, finding no substantial differences between treated and untreated patients in the real clinical setting. However, some recent results highlighted that a sustained exposure to DMDs, especially when the drug is administered at a young age and in patients with inflammatory activities, may exert a protective role, reducing the risk of hard disability milestones.
RCTs suffer from low generalizability and explore the effect of therapy for a time-window that rarely cover more than two years. Moreover, variables like the duration of DMT exposure or the delay in treatment initiation are not evaluated in the setting of clinical trials, but they may be crucial in the real-world setting.
In the absence of previous licensed therapeutic options, DMTs have been used off-label in PPMS patients, and registry-based cohort study represents a major source of real-world data to elucidate the above issues.
We hypothesized that, among PPMS patients, those who had active disease at baseline or experienced superimposed relapses during follow-up might benefit from DMT. Moreover, to better understand the effects of DMTs, we evaluated the type of DMT, the delay in treatment initiation and the duration of DMT exposure.
Results
Using the Italian MS Registry, we selected PPMS patients with at least three EDSS evaluations and three years of follow-up. Study baseline was defined as the first EDSS evaluation for untreated patients and the date of the first DMT initiation for treated patients.
Of the 1139 patients we included (629 females, mean ± Standard Deviation [SD] baseline age 48.3 ± 11.1 years, mean EDSS score 4.1 ± 1.8), 746 (65%) received a DMT during the follow-up. In the whole sample, after a mean (SD) follow-up of 11.8 (± 6.3) years, 438 (38%) reached the EDSS 7.0. In the multivariable Cox regression models, the use of DMT, analysed as dichotomous variable, did not influence the risk of reaching EDSS 7 (aHR = 1.09, 95% CI 0.88-1.36, p = 0.417). However, in patients with superimposed relapses, DMT exposure significantly reduced the risk of reaching EDSS 7 (aHR = 0.61, 95% CI 0.42-0.87, p =0.007). Moreover, we found that, among good responders to DMT, those who persisted on treatment had the most beneficial effect (aHR = 0.45, 95% CI 0.29-0.71, p = 0,001). These results have been confirmed after propensity-score matching.
Conclusions
This study suggests that inflammatory activity may be a modifiable component of long-term disability outcomes in PPMS patients. Moreover, in PPMS patients who have inflammatory activity during follow-up, longer exposure to DMT may increase the beneficial effect of treatment.
To optimize treatment decision-making in PPMS further profiling of the best candidates to treatment is needed.
Pubblicazioni e Comunicazioni a Congressi/ Publications and Congress Presentations
Oral presentations
Fonderico M. “Disease modifying treatment may delay time to wheelchair in primary progressive multiple sclerosis: a real-life cohort”. 8th Joint ACTRIMS-ECTRIMS MEETING, 11th September 2020.
Fonderico M. “Disease modifying treatment may delay time to wheelchair in primary progressive multiple sclerosis: a real-life cohort”. 51° National Congress of Italian Society of Neurology, Milan, 28-30th November 2020
Fonderico M. “Disease modifying treatment may delay time to wheelchair in primary progressive multiple sclerosis: a real-life cohort”. 8th Joint ACTRIMS-ECTRIMS MEETING, 11th September 2020.
Fonderico M. “Disease modifying treatment may delay time to wheelchair in primary progressive multiple sclerosis: a real-life cohort”. 51° National Congress of Italian Society of Neurology, Milan, 28-30th November 2020
Portaccio E, Fonderico M, Iaffaldano P, Pastò L, Razzolini L, Bellinvia A, De Luca G, Ragonese P, Patti F, Brescia Morra V, Cocco E, Sola P, Inglese M, Lus G, Pozzilli C, Maimone D, Lugaresi A, Gazzola P, Comi G, Pesci I, Spitaleri D, Rezzonico M, Vianello M, Avolio C, Logullo FO, Granella F, Salvetti M, Zaffaroni M, Lucisano G, Filippi M, Trojano M, Amato MP; Italian Multiple Sclerosis Register Centers Group. Disease-Modifying Treatments and Time to Loss of Ambulatory Function in Patients With Primary Progressive Multiple Sclerosis. JAMA Neurol. 2022 Sep 1;79(9):869-878. doi: 10.1001/jamaneurol.2022.1929. PMID: 35877104 Clinical Trial.