Delving into the Latest Updates on Tolebrutinib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

BTKI'168, BTKI('168), PRN-2246

+ [3]

Target

BTK

Action

inhibitors

Mechanism

BTK inhibitors(Tyrosine-protein kinase BTK inhibitors)

Therapeutic Areas

Immune System DiseasesNervous System DiseasesOther Diseases+ [1]

Active Indication

Multiple Sclerosis, Secondary ProgressiveMultiple SclerosisMultiple sclerosis relapse+ [2]

Inactive Indication

Multiple Sclerosis, Chronic Progressive

Originator Organization-

Active Organization

Sanofi Winthrop Industrie SA

Sanofi (China) Investment Co. Ltd.

Sanofi

+ [3]

Inactive Organization-

License Organization

Principia Biopharma, Inc.

Sanofi

Drug Highest PhaseApproved

First Approval Date

United Arab Emirates (27 Aug 2025),

Multiple Sclerosis, Secondary Progressive

RegulationPriority Review (United States), Breakthrough Therapy (United States), Priority Review (Australia)

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Structure/Sequence

Molecular FormulaC26H25N5O3

InChIKeyKOEUOFPEZFUWRF-LJQANCHMSA-N

CAS Registry1971920-73-6

This Phase II hybrid decentralized multicenter study examines the outcomes of stopping Bruton tyrosine kinase inhibitor (BTKi) therapy in patients with chronic lymphocytic leukemia (CLL) who have remained in remission for at least two years. The primary objective is to determine how long patients remain free from disease progression or death after discontinuing treatment, measured as event free survival.
The study also evaluates whether stopping BTKi therapy leads to improvements in quality of life and reductions in treatment related side effects. Researchers will follow patients over time to assess if the cancer returns, whether resistance to therapy develops, and how patients feel during the treatment free period.
In addition, the trial will investigate how discontinuing BTKi therapy affects immune function, including whether immune recovery occurs and infection risk decreases.
Preliminary data indicate that patients may experience a treatment free interval exceeding two years after stopping therapy, with associated improvements in quality of life. By prospectively evaluating a time limited treatment strategy, this trial aims to determine whether durable disease control can be maintained off therapy while also assessing the resolution of BTKi related adverse events and changes in patient reported outcomes.
Overall, the study seeks to determine whether patients can safely discontinue BTKi therapy and potentially restart treatment later if needed, thereby maintaining disease control while reducing the burden of continuous therapy.

Start Date01 May 2026

Sponsor / Collaborator

Lineberger Comprehensive Cancer Center

NCT07120633

/ RecruitingNot ApplicableIIT

The Efficacy of AntiCD19 CAR-T Combined With BTKi in the Treatment of Newly Diagnosed High-risk CLL Patients, and to Explore Its Efficacy and Safety of Limited-term Treatment in These Patients

At present, there is a lack of relevant research on the first-line treatment of high-risk CLL patients with BTKi combined with CAR-T. Therefore, our center plans to conduct a study on the treatment of newly diagnosed high-risk CLL patients with AntiCD19 CAR-T combined with BTKi, in order to increase the uMRD rate of newly diagnosed high-risk patients, thereby improving the long-term prognosis of high-risk CLL patients and reducing the long-term medication rate of CLL patients, providing more treatment options and hope for newly diagnosed high-risk CLL patients.

Start Date01 Sep 2025

Sponsor / Collaborator

Affiliated Hospital of Xuzhou Medical University

NCT06372145

/ Active, not recruitingPhase 3

An Interventional, Phase 3 Extension Study to Investigate Long-term Safety and Tolerability of Tolebrutinib in Participants With Relapsing Multiple Sclerosis, Primary Progressive Multiple Sclerosis, or Nonrelapsing Secondary Progressive Multiple Sclerosis

This is a Phase 3 extension, global, multicenter study to assess the long-term safety and tolerability of tolebrutinib in adult participants (aged ≥18 years) with RMS, PPMS, or NRSPMS who were previously enrolled in the Phase 2b LTS (LTS16004) or 1 of the 4 Phase 3 tolebrutinib pivotal trials (GEMINI 1 [EFC16033], GEMINI 2 [EFC16034], HERCULES [EFC16645], or PERSEUS [EFC16035]).
SUBSTUDY: ToleDYNAMIC substudy

Start Date16 Apr 2024

Sponsor / Collaborator

Sanofi

100 Clinical Results associated with Tolebrutinib

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100 Translational Medicine associated with Tolebrutinib

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100 Patents (Medical) associated with Tolebrutinib

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490

Literatures (Medical) associated with Tolebrutinib

31 Dec 2026·ANNALS OF MEDICINE

A single-center retrospective study suggests a potential benefit of BTK inhibitor-based therapy in patients with histologic transformation of Waldenström macroglobulinemia

Article

Author: Shen, Haorui ; Li, Jianyong ; Qu, Xiaoyan ; Wang, Sanmei ; Miao, Yi ; Fan, Lei ; Tian, Tian ; Zhao, Yuxiao ; Xia, Yi ; Liu, Hailing ; Xu, Ji

BACKGROUND:

Histologic transformation from Waldenström macroglobulinemia (WM) to diffuse large B-cell lymphoma (DLBCL) is a rare but clinically challenging event.

METHODS:

In this retrospective study, we analyzed 15 cases of histologic transformation among WM patients treated at the Department of Hematology, Jiangsu Province Hospital, between October 2015 and February 2025.

RESULTS:

The median age at transformation was 67 years, with a median time from initial WM diagnosis to transformation of 8 months (range: 0-177 months). Six patients (40%) received no WM-directed therapy before transformation. At transformation, 13 patients (86.7%) had stage IV disease. Extranodal involvement was frequent: 6 patients (40%) had ≥2 extranodal sites involved, with the most common sites being bone/bone marrow (each 33.3%), central nervous system (CNS, 20.0%), and nasopharynx/testis/gastrointestinal tract/peritoneum/skin (each 13.3%). Involvement of immune-privileged sites (CNS, testis) was observed in 5 patients (33.3%). Immunophenotyping revealed 13 cases (86.7%) as non-germinal center B-cell (non-GCB) DLBCL. Prognostic analysis showed a median overall survival (OS) of 26.0 months from transformation. Patients receiving Bruton's tyrosine kinase inhibitor (BTKi)-based regimens after transformation showed significantly prolonged OS (p = 0.007). Additionally, patients receiving BTKi-based therapy at any point showed a trend toward improved survival (p = 0.092).

CONCLUSIONS:

Although rare, histologic transformation from WM to DLBCL exhibits aggressive clinical behavior, frequent extranodal involvement, and poor prognosis. BTKi-based regimens may provide significant survival benefits in this patient population.

01 May 2026·DRUG RESISTANCE UPDATES

Advances and resistance adaptation in BTK-targeted therapy for B-cell malignancies

Review

Author: Hwang, Inah ; Hwang, Soo-Yeon ; Yang, Sieun ; Paik, Jihye ; Oh, Jihye

Bruton's tyrosine kinase (BTK) is a key signaling component downstream of the B-cell receptor (BCR) and plays an essential role in the survival and proliferation of multiple B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström macroglobulinemia (WM). BTK inhibitors (BTKi) have demonstrated substantial clinical benefit and are now widely incorporated into frontline treatment strategies. However, the long-term effectiveness of BTKi is frequently limited by the emergence of both intrinsic and acquired resistance. BTKi resistance reflects a dynamic process of cellular adaptation rather than a single dominant mechanism. Malignant B cells maintain viability under BTK inhibition through multiple, interconnected alterations, including changes in BTK structure or function, reprogramming of proximal BCR signaling, activation of alternative survival pathways, tumor microenvironment-mediated immune modulation, and metabolic and epigenetic remodeling. In this review, we summarize recent advances in BTK-targeted therapeutics and present a mechanistic framework for understanding BTKi resistance as an adaptive and context-dependent process. We discuss emerging resistance mechanisms that extend beyond canonical signaling pathways and review therapeutic strategies aimed at addressing these adaptive responses, including non-covalent BTK inhibitors, BTK degraders, and rational combination regimens. This perspective highlights translational strategies to improve the depth and durability of responses to BTK-targeted therapies.

10 Mar 2026·Blood Advances

Real-world safety and effectiveness of zanubrutinib vs ibrutinib in CLL: the CLL-ZANU2024 Italian cohort

Article

Author: Murru, Roberta ; Laurenti, Luca ; Trentin, Livio ; Pietrantuono, Giuseppe ; Malandruccolo, Luigi ; Ibatici, Adalberto ; Riva, Marcello ; Mele, Anna ; Gentile, Massimo ; Fama, Angelo ; Morabito, Fortunato ; Romeo, Azzurra ; Amodio, Nicola ; Schiattone, Luana ; Innocenti, Idanna ; Stelitano, Caterina ; Tedeschi, Alessandra ; Scardino, Stefania ; Vigna, Ernesto ; Zammit, Valentina ; Scortechini, Ilaria ; Anticoli Borza, Paola ; Bulian, Pietro ; Miccolis, Rosanna ; Liso, Arcangelo ; Pocali, Barbara ; Postorino, Massimiliano ; Farina, Giuliana ; Sportoletti, Paolo ; Coscia, Marta ; Moratti, Massimo ; Giordano, Claudia ; Pitino, Annalisa ; Varettoni, Marzia ; Angeletti, Ilaria ; Martino, Enrica Antonia ; Di Martina, Valentina ; Vozella, Federico ; Motta, Marina ; Catania, Gioacchino ; Visentin, Andrea ; Galieni, Piero ; Galimberti, Sara ; Califano, Catello ; Fraticelli, Vincenzo ; Ferrario, Andrea ; Caserta, Santino ; Tripepi, Giovanni ; Merli, Michele ; Figuera, Amalia ; Derenzini, Enrico ; Mauro, Francesca Romana ; Pasquale, Raffaella ; Frustaci, Anna Maria ; Gattei, Valter ; Maggi, Alessandro ; Morello, Lucia ; Innao, Vanessa ; Pepe, Sara ; Cantelli, Martina ; Ballotta, Laura ; Chiarenza, Annalisa ; Angotzi, Francesco ; Malaspina, Francesco ; Bruzzese, Antonella ; Ferrarini, Isacco ; Pennese, Elsa ; Giordano, Giulio ; Moia, Riccardo ; Del Principe, Maria Ilaria ; Musto, Pellegrino ; Mancuso, Salvatrice ; Giordano, Annamaria ; Rossi, Marco ; Caracciolo, Daniele ; Sanna, Alessandro ; Nocilli, Laura ; Conte, Esmeralda ; Vitale, Candida ; Loseto, Giacomo ; Di Renzo, Nicola ; Marasca, Roberto ; Di Raimondo, Francesco ; Gaidano, Gianluca

Abstract:

Bruton tyrosine kinase inhibitors (BTKis) have dramatically changed the therapeutic landscape of chronic lymphocytic leukemia (CLL), with ibrutinib, first-in-class, demonstrating durable efficacy even in high-risk patients. However, off-target adverse events (AEs) have raised concerns, prompting the development of more selective second-generation BTKis, such as zanubrutinib, designed to improve tolerability while maintaining efficacy. Despite encouraging results from clinical trials, real-world data comparing zanubrutinib with ibrutinib remain limited. In this multicenter, retrospective study, we analyzed 934 patients with CLL treated outside clinical trials, including 393 receiving zanubrutinib and 541 receiving ibrutinib. We evaluated time to treatment discontinuation (TTD) and time to next treatment or death (TTNTD) in both the overall cohort and a propensity score–matched population. Patients who were treated with zanubrutinib experienced lower 12-month discontinuation rates (overall: 12.6% vs 21.4%; matched: 12.4% vs 20.2%) and higher 12-month TTNTD rates (overall: 91.9% vs 83.0%; matched: 93.2% vs 83.4%). Multivariable analyses confirmed zanubrutinib as an independent predictor of longer TTD and TTNTD, whereas high-risk features, including age, relapsed/refractory disease, Binet stage C, TP53 disruption, Eastern Cooperative Oncology Group 2 to 3, and congestive heart failure, were consistently associated with poorer outcomes. AEs leading to discontinuation, particularly atrial fibrillation, bleeding, and infections, were less frequent with zanubrutinib, reflecting its favorable safety profile. These findings provide real-world evidence that zanubrutinib offers more durable disease control and improved persistence compared with ibrutinib, reinforcing its clinical value as a preferred second-generation BTKi. Nevertheless, the relatively short follow-up for zanubrutinib warrants cautious interpretation of long-term outcomes, and underscores the need for ongoing observation to fully characterize its durability and safety.

314

News (Medical) associated with Tolebrutinib

25 Apr 2026

·endpoints.news

Sanofi’s tolebrutinib gets CHMP backing for certain MS patients despite FDA rejection

Sanofi’s tolebrutinib is on track to get an approval in Europe for a type of multiple sclerosis even after receiving a complete response letter from the FDA in December. On Friday, the European Medicines Agency’s human medicines committee recommended approval of the BTK inhibitor for secondary progressive multiple sclerosis (SPMS) without relapses in the past two years. The decision was based in part on data from the Phase 3 HERCULES trial, which showed tolebrutinib delayed time to onset of six-month confirmed disability progression by 31% versus placebo. The FDA rejected tolebrutinib for non-relapsing SPMS in December 2025. In January, the agency published a CRL, which detailed four reasons for the decision, including a serious risk of severe drug-induced liver injury (DILI) and uncertainties about benefits in specific patient subgroups. At that time, Sanofi described the rejection as “unexpected” and said the FDA had raised concerns too late for the company to make changes. DILI has been a long-running concern with the drug, with the FDA placing a clinical hold on Phase 3 tolebrutinib studies in 2022 that was later lifted. Sanofi said in a press release Friday that strict adherence to liver monitoring requirements is necessary to reduce DILI risk. Certain data from a couple of Phase 3 trials called GEMINI 1 and 2 in relapsing multiple sclerosis also contributed to the recommendation by the EMA’s Committee for Medicinal Products for Human Use (CHMP). While those trials did not meet the primary endpoints, there were efficacy signals in certain secondary metrics. Elsewhere, tolebrutinib flunked a late-stage trial called PERSEUS in primary progressive multiple sclerosis. The lead investigator for that study told Endpoints News that a confluence of factors led to its failure, including slow enrollment, slow disease progression at baseline and changing endpoints. CHMP provides its opinions on drug approvals to the European Commission, which then has the final decision but it typically follows CHMP’s recommendations. Sanofi obtained tolebrutinib in a $3.7 billion acquisition of Principia Biopharma in 2020. The content above comes from the network. if any infringement, please contact us to modify.

AcquisitionDrug ApprovalAccelerated Approval

24 Apr 2026

·endpoints.news

Novartis pulls Pluvicto prostate cancer label expansion filing in the EU

Novartis has withdrawn its EU application for Pluvicto’s expansion into earlier prostate cancer treatment, despite US and UK approval for the same indication. The Swiss drugmaker failed to gain favor with the European regulators for the radioligand therapy’s label expansion, despite winning over the FDA last month, tripling the number of patients who can receive the therapy. The UK’s Medicines and Healthcare products Regulatory Agency approved Pluvicto’s label expansion in that earlier setting in February. Novartis had applied for Pluvicto to be extended as a treatment for adults with prostate-specific membrane antigen (PSMA)-positive, metastatic castration-resistant prostate cancer (mCRPC) who have no or mild symptoms after the disease progressed, despite using a hormone-blocking drug and when chemotherapy is not an option. But the European Medicines Agency human medicines committee (CHMP) said the benefits of Pluvicto didn’t outweigh the risks, according to a Friday release . The committee further noted Pluvicto had no impact on how long patients lived when compared with the hormone-blocking drug. Novartis withdrew its label expansion application on March 23. Pluvicto has been approved in the EU since December 2022 for adults with progressive, PSMA-positive mCRPC. CHMP provides opinions on drug approvals and label expansions to the European Commission, which has the final decision but typically follows CHMP’s recommendations. Also on Friday, CHMP gave its positive opinion for Sanofi’s tolebrutinib to be approved, despite the FDA’s rejection late last year. The committee further recommended the approval of: CHMP also recommended approving nine label expansions. Endpoints is fielding the next Biopharma Sentiment Index (BPSI) — a concise, three-minute survey that distills thousands of industry views into a clear quarterly benchmark. This year is pivotal for biopharma, and we need your perspective on where things are going. Take the survey here.

Drug ApprovalAccelerated Approval

24 Apr 2026

·firstwordpharma.com

Sanofi gets some good news for BTK inhibitor tolebrutinib, as EU body backs approval

Sanofi's oral brain-penetrant BTK inhibitor tolebrutinib is faring better at the hands of regulators in the EU than in those across the Atlantic, with the drug set to be approved by the European Commission in the coming months for the treatment of secondary progressive multiple sclerosis (SPMS) without relapses.The expected authorisation — following a positive opinion from the EMA's Committee for Medicinal Products for Human Use (CHMP) announced on Friday — is in stark contrast to the FDA's rejection of tolebrutinib in December. In previously disclosing the US agency's knockback, Sanofi gave little away, other than reiterating that disability progression remains a large unmet medical need in MS.Submissions for tolebrutinib in the EU and US are based on the Phase III HERCULES study, in which the drug significantly delayed the time to onset of six-month confirmed disability progression by 31% compared to placebo. In announcing its positive opinion, the EMA also highlighted that tolebrutinib was associated with a 38% reduction in the adjusted mean number of new and/or enlarging T2-hyperintense lesions per year compared with patients given placebo.However, the EMA also noted that tolebrutinib — which will be marketed as Cenrifki — can lead to increased levels of liver enzymes. Sanofi said that strict adherence to liver monitoring requirements, and prompt management of liver enzyme elevations, are important to mitigate the risk of drug-induced liver injury.Tolebrutinib gained provisional approval in the United Arab Emirates last year for non-relapsing SPMS, while marketing applications in other countries are under review.However, Sanofi was forced at the end of 2025 to abandon planned regulatory filings in primary progressive multiple sclerosis (PPMS) after the Phase III PERSEUS study fell short on the main efficacy goal of delaying disability progression. That setback, along with the FDA's stance, led to the company recently recording an associated impairment charge of nearly €1.7 billion ($2 billion).

Phase 3Drug ApprovalClinical ResultAccelerated Approval

100 Deals associated with Tolebrutinib

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R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Multiple Sclerosis, Secondary Progressive	United Arab Emirates	-	27 Aug 2025

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Sclerosis	NDA/BLA	European Union	Sanofi Winthrop Industrie SA	23 Apr 2026
Multiple sclerosis relapse	NDA/BLA	Canada	Sanofi-Aventis Recherche & Développement SA	01 Aug 2025
Myasthenia Gravis	NDA/BLA	Canada	Sanofi	01 Aug 2025
Multiple Sclerosis, Chronic Progressive	Phase 3	United States	Sanofi	13 Aug 2020
Multiple Sclerosis, Primary Progressive	Phase 3	United States	Sanofi	13 Aug 2020
Multiple Sclerosis, Primary Progressive	Phase 3	China	Sanofi	13 Aug 2020
Multiple Sclerosis, Primary Progressive	Phase 3	Japan	Sanofi	13 Aug 2020
Multiple Sclerosis, Primary Progressive	Phase 3	Argentina	Sanofi	13 Aug 2020
Multiple Sclerosis, Primary Progressive	Phase 3	Australia	Sanofi	13 Aug 2020
Multiple Sclerosis, Primary Progressive	Phase 3	Austria	Sanofi	13 Aug 2020

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASH2025	Not Applicable	Chronic Lymphocytic Leukemia First line	2,037	continuous BTKi therapy	pxujqazdqj(zburkrspws): Δ = 0.5 (95.0% CI, -4.8 to 5.8), P-Value = 0.85 View more	Positive	06 Dec 2025
				TL venetoclax-BTKi regimens
ASH2025	Not Applicable	Chronic Lymphocytic Leukemia First line	3,178	BTKi (ibrutinib, zanubrutinib, or acalabrutinib)	stvthmhgvj(peyaaxtyts) = nfbsknjxkr aiavafwdaa (kvojiuhwur ) View more	Negative	06 Dec 2025
				VenObin (venetoclax & obinutuzumab)	stvthmhgvj(peyaaxtyts) = pqtturppkz aiavafwdaa (kvojiuhwur ) View more
ASH2025	Not Applicable	Lymphoplasmacytic Lymphoma \| Waldenstrom Macroglobulinemia First line	101	BTKi (Bruton Tyrosine kinase inhibitor, Ibrutinib 140mg QD, or Zanubrutinib 160mg BID)	epmpqlpxjg(osqaappwmk) = fohjxfxptb tdoasdmhqa (wasyybkeuh ) View more	Positive	06 Dec 2025
				VD (Bortezomib 1.3mg/m2,d1,8,15, Dexamethasone, 20mg, d1,2,8,9,15,16,22,23)	xspsxeeelx(pajgrhercq) = xbggcervmf qixnnysqzq (gkvfbhqhyl ) View more
ASH2025	Not Applicable	Chronic Lymphocytic Leukemia First line	787	BTKi +/- CD20mAb	nsvbfvioji(ktbgkvmlkd) = not reached lkirwtwehm (xvrkfvzrdp ) View more	Positive	06 Dec 2025
				BCL2i + CD20mAb
NCT04410978 (GEMINI 1, CTgov)	Phase 3	Multiple sclerosis relapse	974	Teriflunomide (Teriflunomide 14 mg)	fbmxizqfll = aealhhsnwn uswdllwojo (mcvllgaavl, eyxrzqzssi - dfnsygtteh) View more	-	18 Jun 2025
				Tolebrutinib (Tolebrutinib 60 mg)	fbmxizqfll = aaojxdwpre uswdllwojo (mcvllgaavl, xpekwdzyxr - indgvzpnae) View more
NCT04411641 (HERCULES, CTgov)	Phase 3	Multiple Sclerosis, Secondary Progressive	1,131	placebo+tolebrutinib (DB: Placebo)	zlkvzlbwui(mpqbdcvgmj) = xbnbjmrdyy lxohsilxvt (cicdlvvkzd, trvxxlzwtb - cwgaxdgbuh) View more	-	18 Jun 2025
				Tolebrutinib (DB: Tolebrutinib 60 mg)	zlkvzlbwui(mpqbdcvgmj) = kzhmokrmte lxohsilxvt (cicdlvvkzd, ansgvvqlul - sfwoxboyqm) View more
NCT04410991 (GEMINI 2, CTgov)	Phase 3	Multiple sclerosis relapse	899	Teriflunomide (Teriflunomide 14 mg)	cgbklhhgxo = ejluobgout tppnezvnok (pnkutiubde, nsgijirtxd - wglwmylwre) View more	-	18 Jun 2025
				Tolebrutinib (Tolebrutinib 60 mg)	cgbklhhgxo = txzrahfvyl tppnezvnok (pnkutiubde, wbcluotaht - xovltpmaaw) View more
NCT04411641 (HERCULES, Pubmed \| N Engl J Med)	Phase 3	Multiple Sclerosis, Secondary Progressive	1,131	Tolebrutinib 60 mg once daily	eajbgtayoh(rvibtjtivu) = tvdfejxpqn mkflbokpmu (gjmwloswey )	Positive	15 May 2025
				Placebo	eajbgtayoh(rvibtjtivu) = xpxzrduely mkflbokpmu (gjmwloswey )
NCT04410978 \| NCT04410991 (GEMINI 1, Pubmed \| N Engl J Med) Manual	Phase 3	Multiple sclerosis relapse	-	Tolebrutinib 60 mg once dailyTolebrutinib 60 mg once daily	mbgvjgotjn(gmqfvpapqn) = vviukrzcut pejvpojcdp (ygmqadkifi ) View more	Negative	08 Apr 2025
				Teriflunomide 14 mg once daily	mbgvjgotjn(gmqfvpapqn) = bhctgsmqez pejvpojcdp (ygmqadkifi ) View more
ASH2024	Not Applicable	Chronic Lymphocytic Leukemia \| Small Lymphocytic Lymphoma	-	BTKi	bvpujehmkq(cokztqeseu) = pqyxpcmems caiyfjuxmr (dwlmdubrfc )	-	09 Dec 2024
				Anticoagulant/Antiplatelet	bvpujehmkq(cokztqeseu) = mmmjnmdgbj caiyfjuxmr (dwlmdubrfc )