tolebrutinib · program

Tolebrutinib for Multiple sclerosis

ApprovedApprovedSanofi (SNY)
  • FDA Breakthrough Therapy (Non-Relapsing Secondary Progressive MS; Granted 2024-12-13)
  • FDA Priority Review (NrSPMS NDA; Accepted 2025-03-25)

Tolebrutinib (SAR442168, ex-Principia PRN2246), an oral brain-penetrant covalent BTK inhibitor, for multiple sclerosis - the first medicine approved anywhere for secondary progressive MS without relapses. The Phase 3 program spanned the disease spectrum: HERCULES (nrSPMS, n=1131) met its primary endpoint, delaying 6-month confirmed disability progression by 31% vs placebo (HR 0.69; 95% CI 0.55-0.88; p=0.0026); GEMINI 1 and 2 (relapsing MS, n=974/899) missed their annualized-relapse-rate primary endpoints vs teriflunomide but delayed pooled 6-month confirmed disability worsening by 29% (nominal p=0.023); PERSEUS (primary progressive MS, n=767) missed its composite confirmed-disability-progression primary endpoint (2025-12-15) and Sanofi will not pursue PPMS registration. Regulatory arc: FDA Breakthrough Therapy 2024-12-13; US NDA for nrSPMS accepted with Priority Review 2025-03-25 (PDUFA 2025-09-28, extended to 2025-12-28); complete response letter 2025-12-24, with press reporting citing FDA concern over severe drug-induced liver injury (a class signature that also drove a 2022 partial clinical hold) - further FDA guidance was expected by end of Q1 2026 and no resubmission has been announced as of 2026-08-14. In the EU, CHMP recommended approval 2026-04-24 and the European Commission approved Cenrifki 2026-06-23 for SPMS without relapses in the last two years, with strict liver-monitoring requirements; tolebrutinib is also provisionally approved in the UAE (2025-07) and approved in Australia (no event codes exist for those regulators).

Data current as of

Development timeline

ApprovedJun 2026
  1. European Commission approved Cenrifki (tolebrutinib) for secondary progressive MS without relapses in the last two years - the compound's first major-market marketing authorization and the first disability-targeting medicine approved for this population. NOT FDA-approved: the US nrSPMS NDA received a CRL 2025-12-24 and no resubmission has been announced as of 2026-08-14.↗
  2. EC approvalEuropean Commission approves Cenrifki (tolebrutinib) - first disability-targeting medicine for non-relapsing SPMS↗
Filed (NDA)Mar 2025 – Apr 2026
  1. CHMP opinionCHMP recommends EU approval of Cenrifki (tolebrutinib) for secondary progressive MS without relapses↗
  2. Complete Response LetterFDA issues complete response letter for tolebrutinib in non-relapsing secondary progressive MS↗
  3. missedPERSEUS Phase 3 missed its primary endpoint in primary progressive MS: tolebrutinib did not delay time to 6-month composite confirmed disability progression vs placebo (n=767, 2:1); Sanofi will not pursue regulatory registration in PPMS.↗
  4. PDUFA date setFDA extends tolebrutinib review by three months; new target action date 2025-12-28↗
  5. US NDA for non-relapsing secondary progressive MS accepted for Priority Review with target action date 2025-09-28 (later extended to 2025-12-28 after a major amendment, then resolved as a complete response letter on 2025-12-24). EU submission was also under review, yielding a CHMP positive opinion 2026-04-24. Dated to the FDA acceptance announcement; the underlying submission was earlier but its exact date was not separately announced.↗
  6. NDA/BLA filedFDA accepts tolebrutinib NDA for non-relapsing secondary progressive MS with Priority Review↗
  7. PDUFA date setPDUFA target action date set: 2025-09-28 (Priority Review)↗
Phase 3Jun 2020 – Dec 2024
  1. Breakthrough TherapyFDA grants Breakthrough Therapy designation to tolebrutinib for non-relapsing secondary progressive MS↗
  2. metHERCULES full results at ECTRIMS 2024: 31% delay in time to onset of 6-month confirmed disability progression vs placebo (HR 0.69; 95% CI 0.55-0.88; p=0.0026); confirmed disability improvement nearly doubled (10% vs 5%; HR 1.88; nominal p=0.021).↗
  3. mixedGEMINI 2 Phase 3 missed its primary endpoint: tolebrutinib did not reduce annualized relapse rate vs teriflunomide in relapsing MS; disability benefit appeared only in the pooled GEMINI 1+2 key secondary (29% delay in 6-month CDW, nominal p=0.023).↗
  4. mixedGEMINI 1 Phase 3 missed its primary endpoint: tolebrutinib did not reduce annualized relapse rate vs teriflunomide in relapsing MS; pooled GEMINI 1+2 key secondary showed a 29% delay in 6-month confirmed disability worsening (HR 0.71; 95% CI 0.53-0.95; nominal p=0.023).↗
  5. metHERCULES Phase 3 met its primary endpoint: tolebrutinib delayed time to onset of 6-month confirmed disability progression vs placebo in non-relapsing secondary progressive MS - the first Phase 3 win in this population.↗
  6. Clinical holdFDA places partial clinical hold on US tolebrutinib trials over drug-induced liver injury cases↗
  7. AcquisitionSanofi completes ~$3.68 billion acquisition of Principia Biopharma, taking full control of tolebrutinib↗
  8. GEMINI 2 (NCT04410991) started 2020-06-11, the first of four Phase 3 studies; GEMINI 1 followed 2020-06-30, PERSEUS 2020-08-13, and HERCULES 2020-09-24. Date is the earliest actual Phase 3 start on ClinicalTrials.gov.
Phase 2Mar 2019
  1. Phase 2b dose-finding study NCT03889639 (DRI15928) started in relapsing MS: 130 participants, tolebrutinib 5/15/30/60 mg once daily. Sanofi ran the study under its 2017 license/collaboration with originator Principia Biopharma (acquired outright in September 2020).

Readouts

  • 2025-12-15ReportedTopline datamissedNCT04458051

    PERSEUS Phase 3 missed its primary endpoint in primary progressive MS: tolebrutinib did not delay time to 6-month composite confirmed disability progression vs placebo (n=767, 2:1); Sanofi will not pursue regulatory registration in PPMS. ↗

  • 2024-09-20ReportedFull resultsmetNCT04411641

    HERCULES full results at ECTRIMS 2024: 31% delay in time to onset of 6-month confirmed disability progression vs placebo (HR 0.69; 95% CI 0.55-0.88; p=0.0026); confirmed disability improvement nearly doubled (10% vs 5%; HR 1.88; nominal p=0.021). ↗

  • 2024-09-02ReportedTopline datamixedNCT04410991

    GEMINI 2 Phase 3 missed its primary endpoint: tolebrutinib did not reduce annualized relapse rate vs teriflunomide in relapsing MS; disability benefit appeared only in the pooled GEMINI 1+2 key secondary (29% delay in 6-month CDW, nominal p=0.023). ↗

  • 2024-09-02ReportedTopline datamixedNCT04410978

    GEMINI 1 Phase 3 missed its primary endpoint: tolebrutinib did not reduce annualized relapse rate vs teriflunomide in relapsing MS; pooled GEMINI 1+2 key secondary showed a 29% delay in 6-month confirmed disability worsening (HR 0.71; 95% CI 0.53-0.95; nominal p=0.023). ↗

  • 2024-09-02ReportedTopline datametNCT04411641

    HERCULES Phase 3 met its primary endpoint: tolebrutinib delayed time to onset of 6-month confirmed disability progression vs placebo in non-relapsing secondary progressive MS - the first Phase 3 win in this population. ↗

Clinical trials in Multiple sclerosis

NCT04411641EFC16645Phase 3Completedn=1131

HERCULES - A Phase 3, Randomized, Double-blind, Efficacy and Safety Study Comparing SAR442168 to Placebo in Participants With Nonrelapsing Secondary Progressive Multiple Sclerosis

Started Sept 2020· Primary completion Aug 2024· 📍 306 sites across 31 countries (United States, Russia, Spain, China)

NCT04458051EFC16035Phase 3Completedn=767

PERSEUS - A Phase 3, Randomized, Double-blind, Efficacy and Safety Study Comparing SAR442168 to Placebo in Participants With Primary Progressive Multiple Sclerosis

Started Aug 2020· Primary completion Nov 2025· 📍 277 sites across 42 countries (United States, Japan, Russia, Spain)

NCT04410978EFC16033Phase 3Completedn=974

GEMINI 1 - A Phase 3, Randomized, Double-blind Efficacy and Safety Study Comparing SAR442168 to Teriflunomide (Aubagio) in Participants With Relapsing Forms of Multiple Sclerosis

Started Jun 2020· Primary completion Jul 2024· 📍 179 sites across 24 countries (China, United States, Japan, Italy)

NCT04410991EFC16034Phase 3Completedn=899

GEMINI 2 - A Phase 3, Randomized, Double-blind Efficacy and Safety Study Comparing SAR442168 to Teriflunomide (Aubagio) in Participants With Relapsing Forms of Multiple Sclerosis

Started Jun 2020· Primary completion Jul 2024· 📍 186 sites across 28 countries (United States, Spain, France, Russia)

NCT03889639DRI15928Phase 2Completedn=130

A Phase 2b Dose-finding Study for SAR442168, a Bruton's Tyrosine Kinase Inhibitor, in Participants With Relapsing Multiple Sclerosis

Started Mar 2019· Primary completion Jan 2020· 📍 48 sites across 10 countries (United States, Czechia, Russia, Ukraine)

Formulations

FormulationRouteRegimenPharmacokinetics
Tolebrutinib oral 60 mg once daily
60 mg PO once daily, taken with a meal per the EU (Cenrifki) approval, across all four Phase 3 studies (HERCULES, GEMINI 1, GEMINI 2, PERSEUS). The Phase 2b dose-finding study (NCT03889639) tested 5, 15, 30 and 60 mg once daily; 60 mg was carried into Phase 3.
OralOnce daily—

Mechanism of action (compound-wide)

Covalent, irreversible inhibitor of Bruton's tyrosine kinase (BTK), a TEC-family cytoplasmic kinase expressed in B lymphocytes and myeloid cells including CNS-resident microglia. The acrylamide warhead forms a covalent bond with Cys481 in the BTK ATP-binding pocket, giving durable target inactivation that outlasts the drug's plasma exposure. Tolebrutinib was selected for CNS penetration: in the open-access comparative CNS pharmacology characterization it reacted with BTK ~65-fold faster than evobrutinib (kinact/KI 4.37e-3 vs 6.82e-5 nM^-1 s^-1), inhibited BTK and six related kinases (BLK, TEC, BMX, TXK, ERBB4, EGFR) with IC50 <= 4 nM, showed cellular IC50 of 0.7 nM in microglia and ~10 nM in B cells, and achieved non-human-primate CSF concentrations (CSF:plasma ratio ~0.041) exceeding its microglial IC90 - which evobrutinib and fenebrutinib did not reach. The therapeutic hypothesis is that inhibiting BTK signaling in microglia and CNS-infiltrating B cells modulates smoldering neuroinflammation and thereby slows relapse-independent disability accumulation - consistent with the Phase 3 pattern of disability benefit (HERCULES, and 6-month CDW across GEMINI) without superiority on relapse rate.

TargetActionAffinity
BTKprimaryBTKInhibitor—ⓘ

← Full tolebrutinib compound page (identity, identifiers, all indications)

Sources

  1. Media Update: Patient enrollment of phase III tolebrutinib trials paused in the U.S. - FDA partial clinical hold (2022-06-30) — Sanofi
  2. NCT03889639 (DRI15928) - A Phase 2b Dose-finding Study for SAR442168 in Participants With Relapsing Multiple Sclerosis — ClinicalTrials.gov (U.S. National Library of Medicine)
  3. NCT04410978 (EFC16033, GEMINI 1) - SAR442168 vs Teriflunomide in Relapsing Forms of Multiple Sclerosis — ClinicalTrials.gov (U.S. National Library of Medicine)
  4. NCT04410991 (EFC16034, GEMINI 2) - SAR442168 vs Teriflunomide in Relapsing Forms of Multiple Sclerosis — ClinicalTrials.gov (U.S. National Library of Medicine)
  5. NCT04411641 (EFC16645, HERCULES) - SAR442168 vs Placebo in Nonrelapsing Secondary Progressive Multiple Sclerosis — ClinicalTrials.gov (U.S. National Library of Medicine)
  6. NCT04458051 (EFC16035, PERSEUS) - SAR442168 vs Placebo in Primary Progressive Multiple Sclerosis — ClinicalTrials.gov (U.S. National Library of Medicine)
  7. Sanofi completes Principia Biopharma Inc. acquisition (~$3.68B, $100/share tender; 2020-09-28) — Sanofi (wire copy via PharmiWeb)
  8. Sanofi provides update on tolebrutinib in primary progressive multiple sclerosis - PERSEUS misses primary endpoint (2025-12-15) — Sanofi
  9. Sanofi provides update on tolebrutinib regulatory submission in non-relapsing secondary progressive multiple sclerosis - FDA complete response letter (2025-12-24) — Sanofi
  10. Sanofi's Cenrifki (tolebrutinib) approved in the EU as the first disability-targeting medicine for secondary progressive multiple sclerosis without relapses (2026-06-23) — Sanofi
  11. Sanofi's Cenrifki (tolebrutinib) recommended for EU approval by the CHMP to treat secondary progressive multiple sclerosis without relapses (2026-04-24) — Sanofi
  12. Tolebrutinib demonstrated a 31% delay in time to onset of confirmed disability progression in non-relapsing secondary progressive multiple sclerosis phase 3 study - ECTRIMS 2024 late-breaker, with GEMINI 1/2 detail (2024-09-20) — Sanofi
  13. Tolebrutinib designated Breakthrough Therapy by the FDA for non-relapsing secondary progressive multiple sclerosis (2024-12-13) — Sanofi
  14. Tolebrutinib meets primary endpoint in HERCULES phase 3 study; GEMINI 1 and 2 did not meet ARR primary endpoints (2024-09-02) — Sanofi
  15. Tolebrutinib regulatory submission accepted for priority review in the US for patients with multiple sclerosis (2025-03-25) — Sanofi
  16. Turner TJ, et al. Comparative CNS Pharmacology of the Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating Multiple Sclerosis. Drugs R D. 2024 (open access) — Drugs in R&D (Springer) / PubMed
  17. Update on the US regulatory review of tolebrutinib in non-relapsing, secondary progressive multiple sclerosis - target action date extended to 2025-12-28 (2025-09-22) — Sanofi