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

ChiCTR2200055554

/ RecruitingPhase 2IIT

An Open, Single-Center Clinical Observation Study to Assess the Efficacy and Safety of The Thiotepa for Primary Central Nervous System Lymphoma (PCNSL) Patients

Start Date01 Apr 2022

Sponsor / Collaborator

Lanzhou University Second Hospital

100 Clinical Results associated with Tolebrutinib

100 Translational Medicine associated with Tolebrutinib

100 Patents (Medical) associated with Tolebrutinib

431

Literatures (Medical) associated with Tolebrutinib

01 Apr 2026·DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE

Aspergillus fumigatus brain abscess in an immunocompromised patient receiving a second-generation Bruton Tyrosine Kinase inhibitor (BTKi)

Article

Author: Alexiou, George A ; Voulgaris, Spyridon ; Kafritsas, Georgios ; Romeo, Eleni ; Kittas, Christos ; Lampros, Marios

Chronic lymphocytic leukemia (CLL) is a frequent type of adult leukemia. Bruton Tyrosine Kinase inhibitors (BTKi) are first-line treatments for CLL. Despite being efficient, BTKi have also been associated with significant side effects, including arrhythmias, hemorrhagic complications, and opportunistic infections. Zanubrutinib is a second-generation BTKi that recently received FDA approval for CLL and is associated with improved outcomes and a better safety profile compared to first-generation BTKi. In the present study, we report a case of a patient with CLL, with an in-range absolute neutrophil count and an isolated Aspergillus fumigatus brain abscess mimicking a brain tumor. The lesion was excised "en bloc", and lesion cultures revealed Aspergillus fumigatus sensitive to amphotericin and voriconazole. The patient received postoperative treatment with voriconazole. While invasive fungal infections with brain involvement have been previously reported, to our knowledge, this is the first documented case of an isolated Aspergillus fumigatus brain abscess in a patient receiving zanubrutinib.

07 Feb 2026·Future Oncology

Real-world characteristics, treatment patterns, and outcomes of patients with mantle cell lymphoma by line of therapy

Article

Author: Ogbu, Uzor ; Bai, Claire ; Wang, Ching-Kun ; de Nigris, Enrico ; Zettler, Christina M. ; Fernandes, Laura L. ; Prescott, Jennifer ; Sineshaw, Helmneh M.

BACKGROUND:

Approvals of Bruton's tyrosine kinase inhibitors (BTKis) and other novel agents have changed the Mantle Cell Lymphoma (MCL) treatment paradigm, necessitating assessment of contemporaneous, real-world (rw) treatment and outcomes by line of therapy (LOT).

METHODS:

Patients diagnosed with MCL on or after 1 January 2012 who initiated first-line (1 L) treatment in the COTA database were eligible, excluding those with concurrent primaries, history of hematologic malignancies, clinical trial participation, or missing/imprecise key dates. Rw time to next treatment (rwTTNT) and overall survival (rwOS) were evaluated using the Kaplan-Meier method from LOT start (index).

RESULTS:

Of 499 patients, most were ≥ 50 years (94.8%), male (71.5%), treated in the community (58.7%), and diagnosed with stage III/IV disease (91.2%). The most common 1 L regimen was bendamustine+rituximab (BR)±R maintenance (12.6%/23.0%, respectively). Fifty (10.0%) patients received 1 L autologous stem cell transplant. One hundred and seventy-three patients (34.7%) received 2 L, of which 72 (41.6% of 2 L) received 3 L, of which 29 (40.3% of 3 L) received 4 L +. BTKi monotherapy was the most frequently administered therapy in 2 L (26.0%).Median rwTTNT and rwOS from 1 L to 4 L were 36.8-3.2 and 86.2-8.7 months, respectively.

CONCLUSIONS:

Outcomes of patients who received 2 L+ for MCL remain poor, highlighting unmet need in the contemporary treatment paradigm.

01 Feb 2026·Journal of Managed Care & Specialty Pharmacy

Real-world overall survival comparison between first-line Bruton tyrosine kinase inhibitors in treating chronic lymphocytic leukemia/small lymphocytic lymphoma: An analysis of Veterans Health Administration data

Article

Author: Lax, Angela ; Khan, Wasiulla ; Chen, Jingyi ; Bokun, Alex ; Shi, Lizheng ; Mu, Fan ; Ghosh, Sabyasachi ; Cook, Erin E. ; Wu, Eric ; Graf, Solomon A. ; Qureshi, Zaina P. ; Fitzgerald, Lindsey ; Chen, Grace ; Lin, Yilu

BACKGROUND:

Three covalent Bruton's tyrosine kinase inhibitors (BTKis) are approved first-line (1L) treatments for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). However, limited real-world data, especially in veterans, evaluate long-term outcomes associated with the different BTKis.

OBJECTIVE:

To describe and compare real-world overall survival (rwOS) among patients with CLL/SLL treated with BTKis in the Veterans Health Administration electronic medical record database.

METHODS:

This was a retrospective cohort study of patients with CLL/SLL who initiated 1L monotherapy of ibrutinib, acalabrutinib, or zanubrutinib between November 2019 and September 2023. Patients were grouped into 3 cohorts based on the BTKi initiated: (1) ibrutinib, (2) acalabrutinib, or (3) acalabrutinib or zanubrutinib (given small sample initiating zanubrutinib). Key inclusion criteria were 1L monotherapy treatment with a BTKi, at least 2 diagnoses of CLL/SLL, and continuous enrollment at least 12 months prior to and at least 28 days after the initiation of the BTKi. rwOS comparing the BTKi cohorts was analyzed using Kaplan-Meier methodology and adjusted Cox proportional hazards models. Sensitivity analyses adjusting for different sets of covariates were conducted.

RESULTS:

The study included samples of 1,059, 504, and 612 patients treated with ibrutinib, acalabrutinib, and acalabrutinib or zanubrutinib (108 received zanubrutinib), respectively. Median rwOS was not reached in any cohort. In the main analysis comparing the ibrutinib and acalabrutinib cohorts, after adjustment for baseline characteristics, treatment with acalabrutinib was associated with an increased risk of death compared with ibrutinib (hazard ratio [HR], 1.33; 95% CI, 1.01-1.76; P = 0.042). In the main analysis comparing the ibrutinib and acalabrutinib or zanubrutinib cohorts, the adjusted risk of death was numerically higher for acalabrutinib- or zanubrutinib-treated patients compared with ibrutinib (HR, 1.32; 95% CI, 1.00-1.74; P = 0.050). For both comparisons, sensitivity analyses indicated similar trends in rwOS.

CONCLUSIONS:

As new therapies emerge, this study highlights the comparative effectiveness of BTKis in the real world, potentially informing current clinical practice.

295

News (Medical) associated with Tolebrutinib

27 Feb 2026

·www.biospace.com

Novartis receives positive CHMP opinion for remibrutinib in chronic spontaneous urticaria (CSU)

Remibrutinib, a highly selective oral BTKi, has potential to be first targeted therapy approved for CSU in Europe Improvements with remibrutinib observed as early as Week 1 in REMIX 1 & 2, with favorable safety pro no liver safety concerns through Week 52 1 CSU affects nearly 4 million people in Europe, with over 50% of patients remaining symptomatic despite H1-antihistamines 2-4 Basel, February 27, 2026 – Novartis announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending marketing authorization for remibrutinib. The opinion supports its use as an oral treatment for chronic spontaneous urticaria (CSU) in adult patients with inadequate response to H1‑antihistamine treatment. “The introduction of remibrutinib represents a major advancement, providing clinicians with an oral Bruton’s tyrosine kinase inhibitor (BTKi) treatment, with improvements in symptoms observed as early as Week 1,” said Prof. Dr. med. Martin Metz, Deputy Director, Institute of Allergology, Charité Universitätsmedizin Berlin. “CSU continues to impose a substantial unmet medical need, as many patients struggle to achieve adequate disease control with currently available therapies.” The positive CHMP opinion is supported by results from the pivotal REMIX-1 and REMIX-2 Phase III trials. Remibrutinib showed improvements in itch and hives as early as Week 1, with benefits sustained through Week 52 1 . Improvements in quality of life and sleep were also observed early in treatment 1 . Remibrutinib was well tolerated and demonstrated a favorable safety profile, including no liver safety concerns across both studies through Week 52 1 . “People living with CSU often endure years of frustration, and difficulty being taken seriously. For many, the unpredictable itch flare‑ups can make it hard to sleep, focus on daily responsibilities, or even perform their jobs at times,” said Tonya Winders, President and CEO, Global Allergy & Airways Patient Platform (GAAPP). “The arrival of a new oral treatment option brings us one step closer to ensuring that every person has the opportunity to live fully again.” “Today’s positive CHMP opinion is an important step towards addressing the significant unmet needs of adults living with CSU in Europe,” said Patrick Horber, M.D., President, International, Novartis. “We will continue to collaborate with regulatory authorities globally to make this important medicine, discovered and developed by Novartis, available to patients who need it most.” Following the CHMP recommendation for approval, the European Commission (EC) is expected to issue a final decision within approximately two months. About remibrutinib Remibrutinib is a highly selective, oral BTK inhibitor that blocks the BTK pathway involved in the release of histamine, a key driver of itchy hives (wheals) and swelling 5-7 . By reducing histamine release, remibrutinib helps relieve the symptoms of chronic spontaneous urticaria (CSU) 8,9 . In the US and China, remibrutinib is approved for the treatment of adult patients with CSU who have an inadequate response to H1-antihistamines, under the brand name Rhapsido ® . Remibrutinib has shown positive topline results in chronic inducible urticaria (CIndU) across the three most prevalent subtypes in the pivotal Phase III RemIND trial. It is also being investigated in other immune-mediated conditions, such as hidradenitis suppurativa (HS) and food allergy, in addition to other indications in the company’s Neuroscience portfolio 10 - 14 . About REMIX-1 and REMIX-2 REMIX-1 ( NCT05030311 ) and REMIX-2 ( NCT05032157 ) are two identically designed, global, multicenter, randomized, double-blind, parallel-group, placebo-controlled Phase III trials, consisting of 925 patients who remained symptomatic on second-generation H1-antihistamines. Remibrutinib demonstrated superiority in change from baseline versus placebo in itch (ISS7), hives (HSS7), and weekly urticaria activity (UAS7) at Week 12. Remibrutinib has a demonstrated safety pro requires no lab monitoring. The most common adverse events (incidence ≥3%) were nasal congestion, sore throat, and runny nose (nasopharyngitis), bleeding, headache, nausea, and abdominal pain 1 4 ,1 5 . About chronic spontaneous urticaria (CSU) CSU is the medical term for chronic hives that last for 6 weeks or longer, where the underlying cause is internal rather than exposure to any allergen or external trigger 4,7,1 6 . CSU affects approximately 40 million people worldwide 4,1 7 . It is characterized by the sudden appearance of itchy hives (wheals) and/or deep tissue swelling (angioedema), which can occur on the face, throat, hands, and feet 7,1 8 . CSU affects all ages but occurs most frequently between the ages of 20-40 years, with women affected nearly twice as often as men 7 . CSU causes significant emotional distress, with the majority of patients suffering from sleep deprivation, and high rates of mental disorders, such as anxiety or depression, as well as decreased work productivity 7 . About Novartis Immunology At Novartis, we’re advancing bold science with the goal of bringing relief and a renewed sense of hope to people living with autoimmune diseases. Building on our legacy of first-in-class innovation across rheumatology, dermatology and allergy, and a diverse industry-leading pipeline, we’re committed to shaping what’s next in Immunology. Disclaimer This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise. About Novartis Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people’s lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 300 million people worldwide. Reimagine medicine with us: Visit us at and connect with us on LinkedIn , Facebook , X/Twitter and Instagram . References Metz M, Giménez-Arnau A, Hide M, et al. Long-term efficacy and safety of remibrutinib in patients with chronic spontaneous urticaria in the Phase 3 REMIX-1 and REMIX-2 studies. Presented as a late oral abstract session on clinical trials at EAACI 2024; May 31-June 3, 2024; Valencia, Spain Fricke J, Ávila G, Keller T, Weller K, Lau S, Maurer M, Zuberbier T, Keil T. Prevalence of chronic urticaria in children and adults across the globe: Systematic review with meta-analysis. Allergy. 2020;75(2):423–432. doi:10.1111/all.14037 Worldometer. Europe Population (2025). Available at: [Last accessed February 2026] Maurer M, Weller K, Bindslev-Jensen C, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report. Allergy 2011; 66: 317-330. Maurer M, Berger W, Giménez-Arnau A, et al. Remibrutinib, a novel BTK inhibitor, demonstrates promising efficacy and safety in chronic spontaneous urticaria. J Allergy Clin Immunol 2022; 150: 1498-1506. Angst D, Gessier F, Janser P, et al. Discovery of LOU064 (remibrutinib), a potent and highly selective covalent inhibitor of Bruton's Tyrosine Kinase. J Med Chem 2020; 63: 5102-5118. Powell RJ, Leech SC, Till S, et al. BSACI guideline for the management of chronic urticaria and angioedema. Clin Exp Allergy 2015; 45: 547-565. Jain V, Giménez-Arnau A, Hayama K, et al. Remibrutinib demonstrates favorable safety pro sustained efficacy in chronic spontaneous urticaria over 52 weeks. J Allergy Clin Immunol 2024; 153: 479-486. Patient. Antihistamines. Last updated 12 October 2022. Available from: [Last accessed: February 2026]. ClinicalTrials.gov. NCT03827798. Study of efficacy and safety of investigational treatments in patients with moderate to severe hidradenitis suppurativa. Available from: . [Last accessed: February 2026] ClinicalTrials.gov. NCT05432388. Study of efficacy, safety and tolerability of remibrutinib in adult participants with an allergy to peanuts. Available from: [Last accessed: February 2026]. ClinicalTrials.gov. NCT05147220. Efficacy and safety of remibrutinib compared to teriflunomide in participants with relapsing multiple sclerosis (RMS) (REMODEL-1). Available from: [Last accessed: February 2026]. ClinicalTrials.gov. NCT05156281. Efficacy and safety of remibrutinib compared to teriflunomide in participants with relapsing multiple sclerosis (RMS) (REMODEL-2). Available from: [Last accessed: February 2026]. ClinicalTrials.gov. NCT05030311. A Phase 3 study of efficacy and safety of remibrutinib in the treatment of CSU in adults inadequately controlled by H1 antihistamines (REMIX-1). Available from: [Last accessed February, 2026]. ClinicalTrials.gov. NCT05032157. A Phase 3 study of efficacy and safety of remibrutinib in the treatment of CSU in adults inadequately controlled by H1- antihistamines (REMIX-2). Available from: [Last accessed February, 2026]. Zuberbier T, Abdul Latiff AH, Abuzakouk M, et al. The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. Allergy 2022; 77: 734-766. The World Bank. Population, total. Available from: [Last accessed: February 2026]. AAAAI (American Academy of Allergy, Asthma & Immunology). Hives (urticaria) and angioedema overview. Available from: (urticaria)-and-angioedema-overview [Last accessed: February 2026]. # # # Novartis Media Relations E-mail: media.relations@novartis.com Novartis Investor Relations Central investor relations line: +41 61 324 7944 E-mail: investor.relations@novartis.com

Phase 3Drug ApprovalClinical Result

20 Feb 2026

·firstwordpharma.com

Biopharma bites: Blockbuster hopes for Brinsupri, Biogen stops MS study, plus mRNA patent fight heats up

Insmed guides for $1B in Brinsupri salesBiogen bins mid-stage MS studyModerna's mNEXSPIKE faces patent suitInsmed guides for $1B in Brinsupri salesHaving been approved in the US last August, and subsequently authorised in the EU, as the first treatment for non-cystic fibrosis bronchiectasis (NCFB), Insmed now expects Brinsupri (brensocatib) to generate revenue of at least $1 billion in 2026. "Our US commercial launch…continues to exceed our expectations," said CEO Will Lewis.The oral, once-daily DPP1 inhibitor — designed to block the activation of neutrophil serine proteases in neutrophils that are responsible for the underlying inflammation in NCFB — generated sales of $144.6 million in the fourth quarter of 2025 and $172.7 million for the full year.Insmed expects regulatory decisions for Brinsupri for the treatment of NCFB in the UK and Japan in 2026. However, the company cautioned that it "continues to evaluate the potential effect of evolving US policies," which could impact the timing of potential international commercial launches.-Matthew DennisBiogen bins mid-stage MS study Biogen this week terminated the Phase II FUSION study evaluating BIIB091 in patients with relapsing multiple sclerosis (MS), according to an update on ClinicalTrials.gov. The candidate, a reversible, non-covalent BTK inhibitor, was being studied alone or in combination with diroximel fumarate; the trial had enrolled 127 patients. The study discontinuation comes as at least one BTK inhibitor seems to have found its footing in MS. While the drug class has shown tantalising promise in treating the disease, none have yet reached the finish line — though Roche's fenebrutinib may be nearing approval (see – Physician Views Results: Neurologists share cautious optimism for Roche's fenebrutinib in PPMS).However, Sanofi was recently hit with a controversial FDA rejection for its BTK inhibitor, tolebrutinib, to treat non-relapsing secondary progressive MS. For more on how BTK inhibitors may shake up the MS treatment landscape, see KOL Views Q&A: What Sanofi’s PERSEUS, Roche’s FENtrepid divergence says about BTK inhibitors in MS.-Elizabeth EatonModerna's mNEXSPIKE faces patent suit BioNTech has filed a patent infringement lawsuit alleging that Moderna's next-generation COVID-19 vaccine unlawfully infringes on a patent related to the German company's own mRNA shot, Comirnaty. The complaint, filed Thursday in US District Court for the District of Delaware, claims Moderna's mNEXSPIKE infringes US Patent No. 12,133,899, which covers a streamlined mRNA vaccine design that allows for lower dosing. The case intensifies a long-running legal battle between the companies behind two of the world's most successful COVID-19 vaccines. BioNTech developed Comirnaty with Pfizer, while Moderna brought its own shot, Spikevax, to market in late 2020. In 2022, Moderna sued BioNTech and Pfizer, claiming they "unlawfully copied" its mRNA inventions to make Comirnaty; that case remains ongoing. Moderna recently highlighted mNEXSPIKE, which was approved by the FDA in 2025, as a significant growth driver with expected approvals this year in Europe and Japan. According to BioNTech's complaint, mNEXSPIKE accounted for 55% of COVID-19 vaccines sold by Moderna in the 2025-2026 respiratory virus season. A spokesperson for Moderna said Thursday it would defend itself against the new allegations.-Anna Bratulic

Drug ApprovalPhase 2VaccinemRNAPatent Infringement

18 Feb 2026

·www.biospace.com

Opinion: Ongoing Regulatory Uncertainty Means Innovation Is Now Higher Risk

iStock, Yutthana Gaetgeaw Regulatory uncertainty is no longer background noise. It is a material investment risk that reshapes how capital is deployed and pipelines are prioritized. In the more than 40 years I have been in the life science industry, companies and their investors have operated under the assumption that while regulatory review may be rigorous, the rules of the game are generally known. That assumption is now being tested. Changes in leadership at the FDA, less predictable policy signals and evolving approval standards have introduced a new level of uncertainty, one that directly affects development strategy, valuation models and investor appetite for risk. On a positive note, the potential to approve a drug based on a single Phase 3 trial—a change touted by the FDA last year—is explicitly designed to reduce development time and cost, accelerating the time it takes to go from clinical testing to the market. But other recent developments, such as issuing rejections based on unexpected changes to new drug approval criteria, may have far-reaching negative consequences for companies with new products in their pipelines, including affecting how their investors take risk into account in their valuation models. The FDA is not signaling a retreat from innovation, but companies and investors need to weigh the impact these new policies may have on how therapies are developed, financed and ultimately delivered to patients. FDA Moderna’s Outright Flu Refusal Just the Latest Case of Crossed FDA Signals The FDA’s refusal to review Moderna’s mRNA-based flu vaccine is part of a larger communications crisis unfolding at the agency over the past nine months that has also ensnarled Sarepta, Capricor, uniQure and many more. February 13, 2026 · 6 min read · Heather McKenzie Read more Potential Impact of the One-Trial Standard According to FDA Commissioner Marty Makary, the agency plans to move toward requiring a single pivotal clinical study , rather than the traditional two, for many medical products. The stated goal is to accelerate approvals by reducing time and cost, based on the premise that a well-designed trial, supported by robust confirmatory evidence, can provide sufficient statistical confidence. Industry reaction has been cautiously optimistic. Faster paths to approval and greater flexibility in trial design are welcome developments. However, I heard two concerns from executives at the J.P. Morgan Healthcare Conference and Biotech Showcase this year: A single trial default could reduce the breadth and generalizability of clinical evidence. Narrower datasets may lead to weaker labels, negatively affecting physician prescribing behavior and market access. To explore whether the new single-trial standard could indeed increase adoption risk, Litmys , the commercial strategy consulting firm where I work, partnered with Doximity , the largest digital professional network for U.S. healthcare professionals, and physician Nicole Chase to conduct a survey of 100 primary care and family practice physicians. The results were instructive. Physicians were largely indifferent to whether approval was based on one trial or two, provided the product was adequately studied. What mattered most to them was safety pro duration of patient exposure, followed by meaningful endpoints, robustness of clinical benefit and the overall number of study participants. Interestingly, most of the physicians don’t evaluate trial data thoroughly on their own but rely on data summaries, guideline bodies and the experience of KOLs and peers. Specialists may view the issue differently, but these findings suggest that a one-trial standard may not, by itself, be a commercial impediment in primary care. Surprise CRLs: When the FDA Pulls the Rug Out On New Year’s Eve, I received a call from a venture capitalist friend. “What’s going on with Corcept?” he asked. “They hit their endpoint, still got a CRL, and the stock’s down 50%.” On December 31, Corcept Therapeutics announced it had received a complete response letter (CRL) for relacorilant in hypertension secondary to hypercortisolism. While the FDA acknowledged that the pivotal GRACE trial met its primary endpoint and the GRADIENT study provided confirmatory evidence, the agency concluded it could not reach a favorable benefit-risk determination without additional evidence of effectiveness. Just a week earlier, Sanofi received a surprise CRL for tolebrutinib in non-relapsing secondary progressive multiple sclerosis. Despite prior feedback, the FDA determined that even with Risk Evaluation and Mitigation Strategies (REMS), the risk of severe drug-induced liver injury could not be mitigated for any identifiable patient population. These cases followed similar stories from Replimmune, Capricor and Biohaven, and the trouble has continued into 2026. In January, it was Atara Biotherapeutics and Pierre Fabre who received a surprise CRL, this one for Ebvallo, a T cell therapy for EBV-positive post-transplant lymphoproliferative disease. And then in February, the FDA shocked the industry by refusing to even review Moderna’s investigational mRNA-based flu vaccine, despite having agreed to the trial design that supported the application. FDA FDA Reversals Send UniQure, Biohaven, Capricor, More Into a ‘Tailspin’ Since July, several biotechs have been forced to pivot as previous agreements with the FDA around evidence required for approval were reversed, a phenomenon that, according to experts, could portend a more restrictive regulator. November 24, 2025 · 7 min read · Heather McKenzie Read more In each case, sponsors met predefined clinical objectives, yet approval and even review was denied based on evolving benefit-risk interpretations rather than on any new negative data. Industry reaction has been sharply critical and increasingly anxious that the FDA is applying more conservative, less predictable benefit‑risk standards even when pivotal trials meet their primary endpoints. These recent CRLs following seemingly successful Phase 3 trials suggest a tougher, less forgiving interpretation of benefit-risk and higher expectations for trial robustness, safety margins and execution quality. The rejections could also undermine confidence in the value of earlier advice from the agency. For investors and CEOs, these new clinical requirements and their implications for a new drug’s approval challenge a foundational assumption of investors around valuing biotechs. Repricing Regulatory Risk The FDA is signaling a shift toward a greater emphasis on safety and robust real world evidence updates to its benefit-risk framework (BRF). The BRF now directs reviewers to document residual safety uncertainties, therapeutic context and risk management options, making “durable” and well-characterized safety a more visible driver of decisions. The BRF guidance emphasizes that the benefit must outweigh risk given disease severity and unmet need. Uncertainty around long term or off-target safety can block approval even when primary efficacy endpoints are met. Recent CRLs where sponsors hit their prespecified endpoints but FDA cited inability to conclude a favorable benefit-risk balance demonstrate that this framework is being applied more stringently. Valuation models going forward will need to assume a higher probability of CRLs and account for the impact on decisions to conduct a single Phase 3 trial. Will longer and more expensive clinical trials be needed to justify approval? For CEOs, this environment demands both earlier and deeper FDA engagement and greater transparency with investors about agreed-upon endpoints, inclusion criteria and sources of regulatory risk. Notably, recent CRLs show that demonstrating a drug’s incremental clinical value is no longer primarily a post-approval marketing exercise. Sponsors must now establish early and credibly that a product meaningfully improves upon the existing standard of care for a serious disease. This clarity should make the FDA more willing to accept uncertainty, single pivotal trials and narrower safety margins. Regulatory uncertainty is no longer background noise. It is a material investment risk that reshapes how capital is deployed and pipelines are prioritized, and which companies ultimately succeed. Those that integrate regulatory realism into development strategy and investor communication will be better positioned than those that continue to play by the old rules.

Phase 3VaccineCell TherapyAccelerated ApprovalClinical Result

100 Deals associated with Tolebrutinib

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.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
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
Multiple Sclerosis, Primary Progressive	Phase 3	Belarus	Sanofi	13 Aug 2020

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	3,178	BTKi (ibrutinib, zanubrutinib, or acalabrutinib)	uijzxdbuid(svfwwvcvfg) = lctdapqotw bhozvmdcnl (rtpmoehizt ) View more	Negative	06 Dec 2025
				VenObin (venetoclax & obinutuzumab)	uijzxdbuid(svfwwvcvfg) = bjurshszuu bhozvmdcnl (rtpmoehizt ) View more
ASH2025	Not Applicable	Chronic Lymphocytic Leukemia First line	787	BTKi +/- CD20mAb	yeloasyiox(opxwmadrit) = not reached uokvucwuin (stygiwcrve ) View more	Positive	06 Dec 2025
				BCL2i + CD20mAb
ASH2025	Not Applicable	Lymphoplasmacytic Lymphoma \| Waldenstrom Macroglobulinemia First line	101	BTKi (Bruton Tyrosine kinase inhibitor, Ibrutinib 140mg QD, or Zanubrutinib 160mg BID)	bcihbfdgyi(emwtlpxzzx) = zykgnayqiq tdlqkvffsw (kwllxzekil ) View more	Positive	06 Dec 2025
				VD (Bortezomib 1.3mg/m2,d1,8,15, Dexamethasone, 20mg, d1,2,8,9,15,16,22,23)	lwstpjrqkw(bufeijujlv) = mhiuevixjo xhdyhnexkj (waijkapnkj ) View more
ASH2025	Not Applicable	Chronic Lymphocytic Leukemia First line	2,037	continuous BTKi therapy	mrnvjwlyni(crxorqhljq): 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
NCT04410991 (GEMINI 2, CTgov)	Phase 3	Multiple sclerosis relapse	899	Teriflunomide (Teriflunomide 14 mg)	auxemxrndq = xjghpxdmxl mtcmdsourx (kpqfdjiaum, ryvvmyweoj - agaiftrvwz) View more	-	18 Jun 2025
				Tolebrutinib (Tolebrutinib 60 mg)	auxemxrndq = jajrgzfoss mtcmdsourx (kpqfdjiaum, evpdsphqgd - qwlrueayur) View more
NCT04411641 (HERCULES, CTgov)	Phase 3	Multiple Sclerosis, Secondary Progressive	1,131	placebo+tolebrutinib (DB: Placebo)	ivhblymjog(inniddkgnp) = xzpvqeqgug uioizitbpa (lnubvedfkh, ipzphawpgn - ucqeygmpje) View more	-	18 Jun 2025
				Tolebrutinib (DB: Tolebrutinib 60 mg)	ivhblymjog(inniddkgnp) = jusktfpape uioizitbpa (lnubvedfkh, dgfvfqrzwg - tgxhkjmvzc) View more
NCT04410978 (GEMINI 1, CTgov)	Phase 3	Multiple sclerosis relapse	974	Teriflunomide (Teriflunomide 14 mg)	vljvppxeyg = usjzuuuaay ntzuuwcjbu (vomjzquhpz, xvgeosuyqs - tcmkrqnckh) View more	-	18 Jun 2025
				Tolebrutinib (Tolebrutinib 60 mg)	vljvppxeyg = kohzyplhxe ntzuuwcjbu (vomjzquhpz, asiuvgsxol - idhrfhizal) View more
NCT04411641 (HERCULES, Pubmed \| N Engl J Med)	Phase 3	Multiple Sclerosis, Secondary Progressive	1,131	Tolebrutinib 60 mg once daily	cqlrojxfmu(efvcaczpoc) = uoosotsyzw hokyiakeue (egcussjrfu )	Positive	15 May 2025
				Placebo	cqlrojxfmu(efvcaczpoc) = gfbrbnndoh hokyiakeue (egcussjrfu )
NCT04410978 \| NCT04410991 (GEMINI 1, Pubmed \| N Engl J Med) Manual	Phase 3	Multiple sclerosis relapse	-	Tolebrutinib 60 mg once dailyTolebrutinib 60 mg once daily	whxdivftgo(kaziaxtbly) = fytppadpll pmlsjwyyfj (gtjhycwfol ) View more	Negative	08 Apr 2025
				Teriflunomide 14 mg once daily	whxdivftgo(kaziaxtbly) = csiydctdug pmlsjwyyfj (gtjhycwfol ) View more
ASH2024	Not Applicable	Small Lymphocytic Lymphoma	-	BTKi (Ibrutinib)	ayqkbmvkjc(jksglnacci) = A quarter of all pts experienced a non-fatal bleed, resulting in <15% of the pts discontinuing and >50% pts interrupting their BTKi tx ljwrdpgukx (fmndyrgnnz )	-	09 Dec 2024
				Prescription Anticoagulants or Antiplatelets

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