Ponesimod as add-on treatment in patients with active relapsing multiple sclerosis under dimethyl fumarate (POINT): A phase 3, randomized, placebo-controlled clinical trial

Ludwig Kappos; Michel Burcklen; Daniele D'Ambrosio; Robert J. Fox; Mark S. Freedman; Eva Kubala Havrdova; Brian Hennessy; Reinhard Hohlfeld; Anna Larbalestier; Alexandre Lemle; Ewa Lindenstrøm; Fred Lublin; Xavier Montalban; Tatiana Sidorenko; Till Sprenger; Andrea Vaclavkova; Jens Wuerfel; Carlo Pozzilli

doi:10.1016/j.msard.2025.106616

Ponesimod as add-on treatment in patients with active relapsing multiple sclerosis under dimethyl fumarate (POINT): A phase 3, randomized, placebo-controlled clinical trial

Ludwig Kappos
, Michel Burcklen
, Daniele D'Ambrosio
, Robert J. Fox
, Mark S. Freedman
, Eva Kubala Havrdova
, Brian Hennessy
, Reinhard Hohlfeld
, Anna Larbalestier
, Alexandre Lemle
, Ewa Lindenstrøm
, Fred Lublin
, Xavier Montalban
, Tatiana Sidorenko
, Till Sprenger
, Andrea Vaclavkova
, Jens Wuerfel
, Carlo Pozzilli

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Combining two oral therapies with different mechanisms could be an attractive treatment strategy for multiple sclerosis (MS) to increase efficacy; however, evidence of such efficacy and safety is lacking. Objectives: The phase 3 randomized, double-blind, placebo-controlled POINT study evaluated efficacy and safety of ponesimod 20 mg versus placebo as an add-on therapy to ongoing dimethyl fumarate (DMF) treatment in patients with active relapsing MS despite DMF monotherapy. Methods: Patients (18–55 years) were randomized (1:1) to ponesimod+DMF or placebo+DMF orally once-daily for ≤156 weeks. Primary endpoint was annualized relapse rate (ARR) at end-of-study (EOS). Secondary endpoints were 12-week confirmed disability accumulation (CDA), time-to-first confirmed relapse, and number of combined unique active lesions (CUALs) on brain Magnetic resonance imaging (MRI) at EOS. Results: The study was prematurely terminated due to slow recruitment; of 600 planned patients, 136 (23 %; [ponesimod: n = 68, placebo: n = 68]) were randomized. Primary endpoint (ARR) was not met (rate ratio, ponesimod+DMF versus placebo+DMF: 1.2; p = 0.5252). Ponesimod+DMF group showed a lower mean number of CUALs/year (rate ratio: 0.37; p = 0.0072). Other efficacy outcomes did not differ between the treatment groups. Adverse events (AEs) were comparable between groups (ponesimod+DMF: 48 [71.6 %]; placebo+DMF: 53 [77.9 %]); dizziness was the most commonly reported AE in the ponesimod+DMF group (10.4 %). Conclusions: This terminated study did not demonstrate the superiority of ponesimod+DMF on clinical efficacy endpoints. In the exploratory analysis ponesimod+DMF versus DMF alone appeared associated with a lower disease activity as assessed by MRI. No new safety signals were reported for ponesimod+DMF. ClinicalTrials.gov identifier: NCT02907177 URL: https://clinicaltrials.gov/study/NCT02907177

Original language	English
Article number	106616
Journal	Multiple Sclerosis and Related Disorders
Volume	102
DOIs	https://doi.org/10.1016/j.msard.2025.106616
State	Published - Oct 2025

Keywords

Annualized relapse rate
Combination therapy
Dimethyl fumarate
MRI lesions
Multiple sclerosis
Ponesimod

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10.1016/j.msard.2025.106616

Cite this

Kappos, L., Burcklen, M., D'Ambrosio, D., Fox, R. J., Freedman, M. S., Havrdova, E. K., Hennessy, B., Hohlfeld, R., Larbalestier, A., Lemle, A., Lindenstrøm, E., Lublin, F., Montalban, X., Sidorenko, T., Sprenger, T., Vaclavkova, A., Wuerfel, J., & Pozzilli, C. (2025). Ponesimod as add-on treatment in patients with active relapsing multiple sclerosis under dimethyl fumarate (POINT): A phase 3, randomized, placebo-controlled clinical trial. Multiple Sclerosis and Related Disorders, 102, Article 106616. https://doi.org/10.1016/j.msard.2025.106616

@article{40bd3603aea9423c8e2c5eb6047dc60e,

title = "Ponesimod as add-on treatment in patients with active relapsing multiple sclerosis under dimethyl fumarate (POINT): A phase 3, randomized, placebo-controlled clinical trial",

abstract = "Background: Combining two oral therapies with different mechanisms could be an attractive treatment strategy for multiple sclerosis (MS) to increase efficacy; however, evidence of such efficacy and safety is lacking. Objectives: The phase 3 randomized, double-blind, placebo-controlled POINT study evaluated efficacy and safety of ponesimod 20 mg versus placebo as an add-on therapy to ongoing dimethyl fumarate (DMF) treatment in patients with active relapsing MS despite DMF monotherapy. Methods: Patients (18–55 years) were randomized (1:1) to ponesimod+DMF or placebo+DMF orally once-daily for ≤156 weeks. Primary endpoint was annualized relapse rate (ARR) at end-of-study (EOS). Secondary endpoints were 12-week confirmed disability accumulation (CDA), time-to-first confirmed relapse, and number of combined unique active lesions (CUALs) on brain Magnetic resonance imaging (MRI) at EOS. Results: The study was prematurely terminated due to slow recruitment; of 600 planned patients, 136 (23 \%; [ponesimod: n = 68, placebo: n = 68]) were randomized. Primary endpoint (ARR) was not met (rate ratio, ponesimod+DMF versus placebo+DMF: 1.2; p = 0.5252). Ponesimod+DMF group showed a lower mean number of CUALs/year (rate ratio: 0.37; p = 0.0072). Other efficacy outcomes did not differ between the treatment groups. Adverse events (AEs) were comparable between groups (ponesimod+DMF: 48 [71.6 \%]; placebo+DMF: 53 [77.9 \%]); dizziness was the most commonly reported AE in the ponesimod+DMF group (10.4 \%). Conclusions: This terminated study did not demonstrate the superiority of ponesimod+DMF on clinical efficacy endpoints. In the exploratory analysis ponesimod+DMF versus DMF alone appeared associated with a lower disease activity as assessed by MRI. No new safety signals were reported for ponesimod+DMF. ClinicalTrials.gov identifier: NCT02907177 URL: https://clinicaltrials.gov/study/NCT02907177",

keywords = "Annualized relapse rate, Combination therapy, Dimethyl fumarate, MRI lesions, Multiple sclerosis, Ponesimod",

author = "Ludwig Kappos and Michel Burcklen and Daniele D'Ambrosio and Fox, \{Robert J.\} and Freedman, \{Mark S.\} and Havrdova, \{Eva Kubala\} and Brian Hennessy and Reinhard Hohlfeld and Anna Larbalestier and Alexandre Lemle and Ewa Lindenstr{\o}m and Fred Lublin and Xavier Montalban and Tatiana Sidorenko and Till Sprenger and Andrea Vaclavkova and Jens Wuerfel and Carlo Pozzilli",

note = "Publisher Copyright: {\textcopyright} 2025",

year = "2025",

month = oct,

doi = "10.1016/j.msard.2025.106616",

language = "English",

volume = "102",

journal = "Multiple Sclerosis and Related Disorders",

issn = "2211-0348",

publisher = "Elsevier B.V.",

}

Kappos, L, Burcklen, M, D'Ambrosio, D, Fox, RJ, Freedman, MS, Havrdova, EK, Hennessy, B, Hohlfeld, R, Larbalestier, A, Lemle, A, Lindenstrøm, E, Lublin, F, Montalban, X, Sidorenko, T, Sprenger, T, Vaclavkova, A, Wuerfel, J & Pozzilli, C 2025, 'Ponesimod as add-on treatment in patients with active relapsing multiple sclerosis under dimethyl fumarate (POINT): A phase 3, randomized, placebo-controlled clinical trial', Multiple Sclerosis and Related Disorders, vol. 102, 106616. https://doi.org/10.1016/j.msard.2025.106616

Ponesimod as add-on treatment in patients with active relapsing multiple sclerosis under dimethyl fumarate (POINT): A phase 3, randomized, placebo-controlled clinical trial. / Kappos, Ludwig; Burcklen, Michel; D'Ambrosio, Daniele et al.
In: Multiple Sclerosis and Related Disorders, Vol. 102, 106616, 10.2025.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Ponesimod as add-on treatment in patients with active relapsing multiple sclerosis under dimethyl fumarate (POINT)

T2 - A phase 3, randomized, placebo-controlled clinical trial

AU - Kappos, Ludwig

AU - Burcklen, Michel

AU - D'Ambrosio, Daniele

AU - Fox, Robert J.

AU - Freedman, Mark S.

AU - Havrdova, Eva Kubala

AU - Hennessy, Brian

AU - Hohlfeld, Reinhard

AU - Larbalestier, Anna

AU - Lemle, Alexandre

AU - Lindenstrøm, Ewa

AU - Lublin, Fred

AU - Montalban, Xavier

AU - Sidorenko, Tatiana

AU - Sprenger, Till

AU - Vaclavkova, Andrea

AU - Wuerfel, Jens

AU - Pozzilli, Carlo

PY - 2025/10

Y1 - 2025/10

N2 - Background: Combining two oral therapies with different mechanisms could be an attractive treatment strategy for multiple sclerosis (MS) to increase efficacy; however, evidence of such efficacy and safety is lacking. Objectives: The phase 3 randomized, double-blind, placebo-controlled POINT study evaluated efficacy and safety of ponesimod 20 mg versus placebo as an add-on therapy to ongoing dimethyl fumarate (DMF) treatment in patients with active relapsing MS despite DMF monotherapy. Methods: Patients (18–55 years) were randomized (1:1) to ponesimod+DMF or placebo+DMF orally once-daily for ≤156 weeks. Primary endpoint was annualized relapse rate (ARR) at end-of-study (EOS). Secondary endpoints were 12-week confirmed disability accumulation (CDA), time-to-first confirmed relapse, and number of combined unique active lesions (CUALs) on brain Magnetic resonance imaging (MRI) at EOS. Results: The study was prematurely terminated due to slow recruitment; of 600 planned patients, 136 (23 %; [ponesimod: n = 68, placebo: n = 68]) were randomized. Primary endpoint (ARR) was not met (rate ratio, ponesimod+DMF versus placebo+DMF: 1.2; p = 0.5252). Ponesimod+DMF group showed a lower mean number of CUALs/year (rate ratio: 0.37; p = 0.0072). Other efficacy outcomes did not differ between the treatment groups. Adverse events (AEs) were comparable between groups (ponesimod+DMF: 48 [71.6 %]; placebo+DMF: 53 [77.9 %]); dizziness was the most commonly reported AE in the ponesimod+DMF group (10.4 %). Conclusions: This terminated study did not demonstrate the superiority of ponesimod+DMF on clinical efficacy endpoints. In the exploratory analysis ponesimod+DMF versus DMF alone appeared associated with a lower disease activity as assessed by MRI. No new safety signals were reported for ponesimod+DMF. ClinicalTrials.gov identifier: NCT02907177 URL: https://clinicaltrials.gov/study/NCT02907177

AB - Background: Combining two oral therapies with different mechanisms could be an attractive treatment strategy for multiple sclerosis (MS) to increase efficacy; however, evidence of such efficacy and safety is lacking. Objectives: The phase 3 randomized, double-blind, placebo-controlled POINT study evaluated efficacy and safety of ponesimod 20 mg versus placebo as an add-on therapy to ongoing dimethyl fumarate (DMF) treatment in patients with active relapsing MS despite DMF monotherapy. Methods: Patients (18–55 years) were randomized (1:1) to ponesimod+DMF or placebo+DMF orally once-daily for ≤156 weeks. Primary endpoint was annualized relapse rate (ARR) at end-of-study (EOS). Secondary endpoints were 12-week confirmed disability accumulation (CDA), time-to-first confirmed relapse, and number of combined unique active lesions (CUALs) on brain Magnetic resonance imaging (MRI) at EOS. Results: The study was prematurely terminated due to slow recruitment; of 600 planned patients, 136 (23 %; [ponesimod: n = 68, placebo: n = 68]) were randomized. Primary endpoint (ARR) was not met (rate ratio, ponesimod+DMF versus placebo+DMF: 1.2; p = 0.5252). Ponesimod+DMF group showed a lower mean number of CUALs/year (rate ratio: 0.37; p = 0.0072). Other efficacy outcomes did not differ between the treatment groups. Adverse events (AEs) were comparable between groups (ponesimod+DMF: 48 [71.6 %]; placebo+DMF: 53 [77.9 %]); dizziness was the most commonly reported AE in the ponesimod+DMF group (10.4 %). Conclusions: This terminated study did not demonstrate the superiority of ponesimod+DMF on clinical efficacy endpoints. In the exploratory analysis ponesimod+DMF versus DMF alone appeared associated with a lower disease activity as assessed by MRI. No new safety signals were reported for ponesimod+DMF. ClinicalTrials.gov identifier: NCT02907177 URL: https://clinicaltrials.gov/study/NCT02907177

KW - Annualized relapse rate

KW - Combination therapy

KW - Dimethyl fumarate

KW - MRI lesions

KW - Multiple sclerosis

KW - Ponesimod

UR - https://www.scopus.com/pages/publications/105011161878

U2 - 10.1016/j.msard.2025.106616

DO - 10.1016/j.msard.2025.106616

M3 - Article

AN - SCOPUS:105011161878

SN - 2211-0348

VL - 102

JO - Multiple Sclerosis and Related Disorders

JF - Multiple Sclerosis and Related Disorders

M1 - 106616

ER -

Ponesimod as add-on treatment in patients with active relapsing multiple sclerosis under dimethyl fumarate (POINT): A phase 3, randomized, placebo-controlled clinical trial

Abstract

Keywords

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