On December 8, 2025 Recursion (Nasdaq: RXRX), a clinical-stage TechBio company decoding biology to radically improve lives, reported positive Phase 1b/2 data from the ongoing TUPELO trial of REC-4881, an investigational allosteric MEK1/2 inhibitor for familial adenomatous polyposis (FAP).

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Through an unbiased phenotypic screen of thousands of compounds, the earliest version of the Recursion OS identified selective MEK1/2 inhibition as a highly specific mechanism capable of reversing APC loss-of-function signatures. Using high-content cellular phenomics driven by AI, REC-4881 emerged as one of the strongest phenotypic rescue hits, reverting APC-deficient cells toward a healthy state and suppressing ERK/MAPK hyperactivation downstream of APC loss. Guided by this AI-driven insight, Recursion in-licensed REC-4881 from Takeda and redirected REC-4881—originally evaluated clinically in solid tumors—as a mechanistically aligned therapeutic candidate for FAP. REC-4881 is now the first MEK1/2 inhibitor ever studied clinically for this disease.

"The durable polyp-burden reduction demonstrated by REC-4881—especially the sustained effect seen at Week 25, 12 weeks after completing therapy—is highly encouraging for the FAP community," said Jessica Stout, D.O., Assistant Clinical Professor, University of Utah School of Medicine, and Principal Investigator of the TUPELO study. "Given the near-100% lifetime risk of colorectal cancer and the absence of any approved medical therapies, patients today often face a lifetime of intensive surveillance and life-altering surgeries. These Phase 2 results provide a meaningful basis for hope and support the potential for REC-4881 to offer a much-needed non-surgical option for this debilitating, life-long disease."

"These Phase 2 results mark a meaningful validation of the Recursion OS," said Chris Gibson, Ph.D., Co-Founder and CEO of Recursion. "An unbiased phenotypic insight from our platform and driven by AI—linking MEK1/2 inhibition to APC loss-of-function biology—has now translated into rapid, substantial, and durable reductions in polyp burden in patients. This is a powerful example of how even the earliest versions of the Recursion OS can uncover therapeutic opportunities in diseases with no approved pharmacotherapy options. And since this discovery, we’ve only added to the breadth, depth, and power of the Recursion OS; we believe this is the first of many potential medicines that will advance as our flywheel of discovery accelerates".
In the Phase 2 portion of the study, REC-4881 demonstrated rapid and durable reductions in polyp burden, with 43% median reduction in evaluable patients after 12 weeks of treatment. 75% of evaluable patients had a reduction in polyp burden in this same period. Importantly, the effect persisted well beyond the dosing period: 82% of evaluable patients (9 of 11) maintained reductions at Week 25—12 weeks after stopping therapy—with a 53% median decrease from baseline. These results are especially meaningful when considered alongside real-world natural history analyses showing that untreated FAP patients are expected to experience increases when left untreated .
"This program reflects a full validation cycle of the Recursion OS: an unbiased phenotypic signal identifying MEK1/2 inhibition as a rescue mechanism for APC loss-of-function, followed by mechanistic confirmation, clinical translation, and now encouraging human data in a disease with no approved medical therapies," said Najat Khan, Ph.D., Chief R&D and Commercial Officer and incoming President and CEO. "REC-4881, an allosteric MEK1/2 inhibitor, represents a first precision-medicine approach for the causal biology of FAP. In TUPELO, we are seeing rapid, substantial, and durable reductions in polyp burden — including sustained benefit after patients stop therapy. Equally important, our ClinTech and real-world data capabilities have been instrumental in guiding this program — from refining eligibility to contextualizing a single-arm dataset with a first-of-its-kind natural history study".

About FAP

FAP is one of the most clinically significant hereditary colorectal cancer syndromes and is caused by inactivating mutations in the APC gene, leading to the growth of hundreds to thousands of gastrointestinal polyps and a near 100% risk of developing colorectal cancer before the age of 40 if left untreated. With no approved pharmacotherapies, excisions followed sequentially by debilitating, life altering surgeries remain the only option to remove polyps and polyp burdened organs, typically involving colectomy in the early 20s. While this procedure removes immediate colon cancer risk, it does not address the underlying disease biology and does not prevent future polyp formation. Patients will continue to develop polyps in the rectum or upper GI tract, with approximately 50% of patients requiring subsequent life-altering surgical procedures to manage the persistent disease. Current treatment approaches lead to substantial long-term loss of quality of life, affecting continence, fertility, and long-term gastrointestinal function in relatively young patients. Approximately 90% of FAP patients go on to develop duodenal adenomas, with 6% eventually undergoing a high-morbidity risk duodenectomy to control polyp growth. FAP affects an estimated 50,000 individuals across the US and EU5 (France, Germany, Italy, Spain, and the UK).

Background on REC-4881 and Recursion’s Platform Insights

REC-4881 was discovered using one of the earliest versions of the Recursion OS (v0.1), through an unbiased, high-content AI-driven phenotypic screening approach in APC-deficient human cell models. Because FAP is driven by loss-of-function mutations in the APC gene, the platform was designed to identify molecules capable of rescuing APC-dependent biology—guided entirely by cellular phenotype, without presupposing any specific mechanism. Using AI/ML to extract and compare over a thousand morphological features that distinguish "diseased" from "healthy" states, the Recursion OS screened numerous investigative compounds and identified REC-4881 as one of the most robust phenotype-rescuing hits. In follow-up assays, REC-4881 consistently reverted APC-deficient cells toward a healthy-state phenotype and demonstrated potent, selective, and concentration-dependent MEK1/2 inhibition that was not seen across hundreds of other oncogenes and tumor suppressor models tested.

Importantly, the Recursion OS highlighted MEK1/2 inhibition as a mechanistic strategy to exploit a therapeutic vulnerability arising from APC loss in FAP—a disease area where MEK1/2 inhibition had not previously been investigated as a therapeutic strategy in a clinical setting. Based on this novel insight, Recursion in-licensed REC-4881 from Takeda, where it had been evaluated in solid tumors, and redirected it as the first MEK1/2 inhibitor advanced clinically for FAP. This program represents the power of a phenotype-first AI-driven discovery model: the platform surfaced a mechanistically aligned therapeutic opportunity solely through scaled high-dimensional exploration.

Today, the Company is using the Recursion OS 2.0 platform—including proprietary ClinTech capabilities of large-scale real-world evidence (RWE) analytics—to further advance the REC-4881 program. This includes a comprehensive natural history collaboration with Amsterdam University Medical Center, home to one of the largest and longest-running FAP registries, as well as analysis of more than 1,000 US FAP patients and 250,000 physician notes processed through Recursion’s custom LLM-based pipeline. Together, these data reinforce the relentlessly progressive nature of FAP, highlight the absence of spontaneous polyp regression, and demonstrate the substantial burden of repeated polyp-removal procedures and major surgeries experienced by real-world patients.

ClinTech insights also helped refine the design of the ongoing TUPELO trial, including expanding age eligibility from ≥55 to ≥18. This expansion was based on a thorough risk-benefit analysis, enabling evaluation of REC-4881 in younger patients who represent a substantial portion of FAP patients. REC-4881 has received Fast Track and Orphan Drug designations from the US FDA, as well as Orphan Drug designation from the European Commission.

Results of the Phase 2 Data for Ongoing REC-4881 Trial

Efficacy and Durability Findings
As of the November 25, 2025 data cutoff in the open-label Phase 2 portion of TUPELO, treatment with REC-4881 (4 mg QD) demonstrated meaningful and durable reductions in polyp burden in patients with FAP.
Week 13 Assessment
●REC-4881 produced a median 43% reduction in total polyp burden among 12 efficacy-evaluable patients.
●The majority of evaluable patients responded, with 75% showing reductions in polyp burden after 12 weeks of therapy.
●40% of patients (4 out of 10) achieved a ≥1-point improvement in Spigelman stage—a clinically meaningful measure of upper GI disease severity to assess surveillance and clinical management.
●Other investigational agents currently under evaluation in separate studies generated approximately 17–29% median reduction in polyp burden after 12 months of treatment; no off-treatment durability was reported (Biodexa press release, June 24 2024)

Week 25 Assessment
●After 12 weeks of treatment, patients went off treatment for an additional 12-weeks. Durability of effect was maintained during the off-treatment observation period with 82% of patients responding (>0% reduction; 9 out of 11) at Week 25.
●73% achieved durable ≥30% reductions in polyp burden with a 53% median reduction in total polyp burden observed.
●40% of patients (4 out of 10) maintained a ≥1-point improvement in Spigelman stage from baseline.

Safety Summary
As of the data cutoff, treatment with 4 mg REC-4881 demonstrated a safety profile generally consistent with prior MEK1/2 inhibitors.
●Across the combined Phase 1b and Phase 2 safety cohorts (n=19), 94.7% of patients reported at least one treatment-related adverse event (TRAE), the majority of which were Grade 1/2 in severity. The most frequent TRAEs (≥10%) included: dermatitis acneiform / rash and blood CPK increase.
●Grade 3 TRAEs occurred in 15.8% of patients; no Grade ≥4 TRAEs have been reported to date.
●Treatment modifications were infrequent, with 2 of 19 patients experiencing dose interruption.

About the TUPELO Trial Design and Expanded Population
The Phase 1b/2 TUPELO trial is evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of REC-4881 monotherapy in patients with familial adenomatous polyposis (FAP).
Study Design and Analysis
Efficacy is assessed via upper and lower endoscopy at baseline, Week 13 (on-treatment), and Week 25 (off-treatment).
●The primary endpoint is percent change from baseline in polyp burden, which is the sum of all polyp diameters in the GI.
●The Efficacy Evaluable Population includes patients with measurable disease at baseline who received ≥75% of study drug and had at least one post-baseline endoscopic assessment.
Disease staging uses the Spigelman system for upper GI polyposis and the InSiGHT classification for the lower GI tract.
Natural History Analyses
To better understand the natural history of FAP and to contextualize the single-arm efficacy of REC-4881, we collaborated with Amsterdam University Medical Center to analyze a registry of ~200 patients with FAP. 55 of these patients met the key inclusion criteria of TUPELO. We also leveraged our clinical development technology (ClinTech) platform to analyze US electronic health records (EHR), including physician notes, of ~1,000 FAP patients to assess disease progression and treatment patterns in the US. Both studies revealed high patient burden and progressive natural history of the disease. Results of the studies suggest that the natural history of FAP is to progress with relentless precancerous polyp progression: 87% of untreated patients in the registry experienced annualized increase in polyp burden. 10% were stable and 3% experienced a modest decrease in polyp burden. Mean increase of 60% and median increase of 28% in annualized polyp burden was observed. At least 75% of patients in the US EHR database had a major invasive surgery along with frequent polypectomies during follow-up.

Next Steps
Recursion plans to expand the population from ≥55 to ≥18 years old and further optimize dosing schedule. In parallel, the Company intends to engage the FDA in 1H26 to define a potential registration pathway.

(Press release, Recursion Pharmaceuticals, DEC 8, 2025, View Source [SID1234661271])

On December 8, 2025 Akeso, Inc. (9926.HK) ("Akeso" or the "Company") reported that at the 2025 ESMO (Free ESMO Whitepaper) Asia Congress, updated results from the pivotal Phase III HARMONi-6 study (AK112-306) were shared in an oral presentation by Professor Shun Lu from Shanghai Chest Hospital. The study evaluates ivonescimab (a first-in-class PD-1/VEGF bispecific antibody) combined with chemotherapy versus tislelizumab combined with chemotherapy in first-line treatment for advanced squamous non-small cell lung cancer (sq-NSCLC).

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Beyond the previously reported efficacy data presented at the ESMO (Free ESMO Whitepaper) 2025 Presidential Symposium and simultaneously published in The Lancet, this presentation further disclosed patient-reported quality of life outcomes based on the EORTC QLQ-C30 questionnaire.

Both prolonging survival and improving quality of life are core indicators for evaluating cancer treatments. The results published at 2025 ESMO (Free ESMO Whitepaper) Asia demonstrate that, compared to the tislelizumab-based regimen, treatment with ivonescimab plus chemotherapy not only significantly prolongs progression-free survival (PFS) but also offers better tolerability, enables higher treatment adherence, and provides patients to maintain better overall health status and quality of life over a longer period. These findings highlight the comprehensive clinical value of the ivonescimab regimen in delivering both survival and quality-of-life benefits for patients.

Quality of life (QoL) assessments from the HARMONi-6 study show that, compared with PD-1 inhibitor plus chemotherapy, ivonescimab plus chemotherapy not only significantly prolongs progression-free survival (PFS) but also helps patients maintain better overall health status. Time to deterioration in "Global Health Status/Quality of Life" was meaningfully delayed in the ivonescimab arm (HR = 0.94), indicating a trend toward reduced risk of QoL worsening versus the control group.
The ivonescimab-based regimen met the primary PFS endpoint versus the tislelizumab-based regimen, delivering a decisive, strongly positive outcome with both statistical significance and clear clinical benefit. PFS was substantially prolonged with ivonescimab plus chemotherapy compared with tislelizumab plus chemotherapy.
The hazard ratio for PFS between the ivonescimab and tislelizumab arms was 0.60 (P < 0.0001), corresponding to an absolute PFS improvement (ΔPFS) of 4.24 months (11.14 months vs. 6.90 months). This benefit was consistent across all PD-L1 expression subgroups.
The HARMONi-6 study enrolled 532 patients with well-balanced baseline characteristics. Among these patients, 92.3% had stage IV disease at enrollment. The squamous histology profile of the patients reflected real-world patterns, with approximately 63% of patients exhibiting the central squamous subtype (66.9% in the ivonescimab arm vs. 59.4% in the control arm). PD-L1 expression levels were also aligned with clinical expectations.

The results from the HARMONi-6 study further validate the breakthrough clinical value of the ivonescimab-plus-chemotherapy regimen compared to PD-1-plus chemotherapy regimen. The ivonescimab-plus chemotherapy regimen addresses a critical clinical gap when anti-angiogenic agents such as bevacizumab demonstrated severe safety considerations in the treatment of sq-NSCLC. Since ivonescimab’s initial approval in 2024, it has been evaluated in multiple clinical studies and used in real-world settings involving over 40,000 patients, where its transformative clinical benefits have been consistently demonstrated.

Across the immuno-oncology landscape, ivonescimab has shown clinical superiority to both PD-1 based treatments, which are currently the optimal standard of care for many cancers, and to also VEGF-targeted therapies in anti-angiogenesis based treatments.

In July 2025, based on the HARMONi-6 study results, the supplemental New Drug Application (sNDA) for ivonescimab in combination with chemotherapy as first-line treatment for sq-NSCLC was accepted for review by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA). Akeso’s partner, Summit Therapeutics, is currently carrying out a global multicenter Phase III HARMONi-3 study, evaluating ivonescimab plus chemotherapy versus pembrolizumab plus chemotherapy as first-line therapy for advanced NSCLC (both squamous and non-squamous subtypes).

(Press release, Akeso Biopharma, DEC 8, 2025, View Source [SID1234661288])

On December 8, 2025 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to bringing a first-in-class pipeline of induced pluripotent stem cell (iPSC)-derived off-the-shelf cellular immunotherapies to patients for broad accessibility, reported updated clinical data from its ongoing Phase 1 trial evaluating its FT819 off-the-shelf iPSC-derived CAR T-cell program in systemic lupus erythematosus (SLE) and unveiled new preclinical data from next-generation off-the-shelf iPSC-derived CAR T-cell programs for hematologic malignancies and autoimmune diseases at the 2025 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in Orlando, Florida.

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"We are very pleased with the accelerating patient enrollment, the expansion of U.S. clinical sites, and the addition of international clinical sites, which together are enabling broader access to FT819 for patients suffering with lupus," said Bob Valamehr, Ph.D., M.B.A., President and Chief Executive Officer of Fate Therapeutics. "The updated FT819 clinical data continue to demonstrate meaningful and durable responses with the use of less-intensive conditioning chemotherapy and a differentiated safety profile, reinforcing our goal to commence a registrational study for FT819 in 2026 and highlighting the potential of FT819 as an ideal CAR T-cell therapy for various autoimmune diseases. At the same time, our next-generation programs, FT836 and FT839, are showing substantial progress, with enhanced potency, functional persistence, and multifunctional engineering that are designed to extend the benefits of our platform across hematologic malignancies and solid tumors. These advances highlight the continued momentum of our iPSC-derived off-the-shelf CAR T-cell pipeline and our commitment to delivering scalable, on-demand and broadly accessible CAR T-cell therapies worldwide."

The clinical update includes data from the Company’s ongoing Phase 1 basket trial of FT819, its lead product candidate, across 13 enrolled patients; 12 with SLE (10 of whom have at least one month of post-treatment follow-up) and one with systemic sclerosis. The updated results demonstrate sustained clinical responses, durable B-cell depletion in a potential dose-response manner, and a differentiated safety profile without the need for intensive-conditioning chemotherapy that typically consists of multiple days of combined doses of cyclophosphamide and fludarabine. With the strength of this clinical data, the Company continues to advance preparations for a pivotal study and is engaged in discussions with the United States Food and Drug Administration (FDA) under its Regenerative Medicine Advanced Therapy (RMAT) designation regarding plans to initiate registrational trial of FT819 in 2026.

At ASH (Free ASH Whitepaper), the Company also presented new preclinical data for two next-generation iPSC-derived CAR T-cell programs designed for use in both oncology and autoimmunity. These programs demonstrate substantial improvements in functional activity and persistence, drug product consistency and uniformity, and breadth of antigen-targeting mechanisms compared with existing autologous and in vivo CAR T-cell platforms.

FT819-102 Clinical Trial Update

FT819 is an off-the-shelf CD19-targeting chimeric antigen receptor (CAR) T-cell product engineered to improve safety and efficacy. Analogous to master cell lines used to mass produce biopharmaceutical drug products such as monoclonal antibodies, a precisely engineered clonal master iPSC line serves as the starting cell source to manufacture FT819, overcoming numerous limitations associated with patient- and donor-sourced CAR T-cell therapies. FT819 is well-defined and uniform in composition, produced at a low cost of goods, and can be stored in inventory for off-the-shelf, on-demand availability to potentially reach a broad patient population.

As of a November 25, 2025 data cut off date, 12 SLE patients were treated by 5 enrolling clinical sites, with 14 clinical sites in total (11 in United States and 3 in United Kingdom) now activated. Baseline characteristics were consistent with a high disease burden patient population:

median SLE duration was 8.7 years, median 7 prior therapies;
median 14 Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) (baseline range 8-20);
mean 2.3±0.4 Physician Global Assessment (PGA); and
mean 23±13 Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-Fatigue) score.
As of an October 22, 2025 data cut off date, 10 SLE patients had ≥ 1 month follow up, with 6 of the 10 patients having active lupus nephritis. Preliminary data in Regimen A (with patients receiving a single FT819 dose after pretreatment with either a single dose of cyclophosphamide or two doses of bendamustine) show mean SLEDAI-2K score across both dose levels (DL1, 360 million cells; DL2, 900 million cells) decreased progressively from baseline:

DL1 SLEDAI-2K score decreased from a mean of 15.2 (n=5) at baseline to a mean of 10 at month 3 (n=2), and to a mean of 6 at month 6 (n=2), representing mean percent drops of 50% and 70%, respectively; and
DL2 SLEDAI-2K score decreased from a mean of 14.3 (n=3) at baseline to a mean of 6 at month 3 (n=2) and to 4 at month 6 (n=1), representing mean percent drops of 65% and 78%, respectively.
Clinical SLEDAI-2K (excluding anti-dsDNA and complement) of 0 was achieved in 5 out of 10 patients, two of whom had resumed an immunosuppressive agent that had previously failed to achieve a clinical SLEDAI-2K of 0 prior to FT819. Two lupus nephritis patients had greater than 3-month follow up, with both achieving complete renal response (CRR) at 2 months and 6 months, respectively. FACIT-fatigue scores improved meaningfully for all patients who had more than one assessment. B-cell depletion was observed, with reconstitution towards predominately naïve cells within the first 3 months. There were no observed dose limiting toxicities; no Grade >2 CRS, ICANS, or GVHD were reported. All patients were treated with FT819 that was available on-demand.

Below are links to the Company Presentations at the 2025 ASH (Free ASH Whitepaper) Annual Meeting & Exposition:

Saturday December 6, 2025

Targeting of tumor antigen CD38 and stress antigens MICA/B by CAR T cells provides a unique approach for the comprehensive treatment of multiple myeloma
Poster Presentation Number: 2350

Session Title: CAR-T Cell Therapies: Basic and Translational: Poster I

Session Time: 5:30 PM – 7:30 PM ET

Sunday December 7, 2025

Development of next generation multi-antigen targeting off-the-shelf CAR T cells for conditioning-free treatment of B-cell lymphoma
Poster Presentation Number: 4121

Session Title: CAR-T Cell Therapies: Basic and Translational: Poster II

Session Time: 6:00 PM – 8:00 PM ET

Monday December 8, 2025

The development of an off-the-shelf CAR T-cell therapy targeting CD19 and CD38 for broad application in autoimmune disease
Poster Presentation Number: 5895

Session Title: CAR-T Cell Therapies: Basic and Translational: Poster III

Session Time: 6:00 PM – 8:00 PM ET

(Press release, Fate Therapeutics, DEC 8, 2025, View Source [SID1234661256])

On December 8, 2025 Syndax Pharmaceuticals (Nasdaq: SNDX), a commercial-stage biopharmaceutical company advancing innovative cancer therapies, reported key Revuforj (revumenib) presentations spanning the acute leukemia treatment continuum that have been presented at the 67th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held in Orlando, Florida, December 6-9, 2025. In total, Syndax and its collaborators will present 12 Revuforj abstracts at the 2025 ASH (Free ASH Whitepaper) Annual Meeting. Revuforj is the Company’s oral, first-in-class, FDA-approved menin inhibitor.

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"We are thrilled to share new data, including the first real-world evidence for the class, showing that revumenib is highly efficacious with a favorable safety profile in multiple acute leukemia subtypes and settings, including in combination with standard of care therapies. Notably, the datasets show deep responses in R/R and frontline NPM1m and KMT2Ar acute leukemia, as well as encouraging safety and early efficacy in post-HSCT maintenance," said Nick Botwood, MBBS, Head of Research & Development and Chief Medical Officer at Syndax. "With the initiation earlier this year of the pivotal frontline trial in patients unfit for intensive chemotherapy, and the recent initiation of our pivotal frontline trial in fit patients, Syndax is well positioned to further expand the clinical data supporting revumenib and lead in the frontline setting with this exciting new class of therapy."

Overview of Key Revumenib Data Presented at the 67th ASH (Free ASH Whitepaper) Annual Meeting

Early real-world experience with revumenib outside of a clinical trial setting: A single center retrospective review of efficacy and tolerability (Abstract #3448)

This presentation reported efficacy and tolerability data from a single-center retrospective review of 17 patients treated with Revuforj outside of a clinical trial. The median age was 54 years (range: 23-79). 47% (8/17) of patients had KMT2Ar, 29% (5/17) had NPM1m, and 18% (3/17) had NUP98r acute leukemia. Patients had a median of four prior lines of therapy (range: 0-6), including 71% (12/17) with prior venetoclax and 35% (6/17) with prior hematopoietic stem cell transplant (HSCT).

Revuforj was used as part of combination therapy in 82% (14/17) of patients, with venetoclax and a hypomethylating agent being the most common partner. Of the 17 patients treated with Revuforj, 13 patients were included in the efficacy analysis (four patients were excluded: one with false positive KMT2Ar test result, one who received Revuforj only as post-HSCT maintenance, and two who received Revuforj as a treatment for measurable residual disease (MRD) positive disease). The overall response rate (ORR) was 77% (10/13), the composite complete remission (CRc) rate was 62% (8/13), and the CR/CRh rate was 31% (4/13). 75% (9/12) of patients were MRD negative at best response. Four patients proceeded to receive a HSCT after revumenib therapy. Among patients who received a HSCT, 75% (3/4) received revumenib as post-HSCT maintenance.

The early real-world evidence supports the safety and tolerability of Revuforj in clinical practice. The rate of Grade 3 or 4 non-hematological adverse events was 24% (4/17). There was no differentiation syndrome (DS) or QTc prolongation above Grade 3. DS and QTc did not lead to treatment discontinuation in any patient. The rate of revumenib dose reductions and discontinuations was low at 6% (1/17) and 6% (1/17), respectively.

"Among a real-world group of heavily pre-treated NPM1m, KMT2Ar, and NUP98r patients who received Revuforj as a monotherapy or in combination, it is very encouraging to observe the vast majority of patients achieve MRD negative responses and to see a meaningful number of patients proceed to a stem cell transplant with durable ongoing remissions. Along with excellent clinical activity, we observed that Revuforj was well-tolerated, including in combination with other therapies," said David Sallman, M.D., Associate Member in the Department of Malignant Hematology at Moffitt Cancer Center. "Our results underscore the potential for Revuforj to transform the standard of care for patients with menin-dependent acute leukemias."

Retrospective review of revumenib as post-HSCT maintenance in children with HOX-driven AML (Abstract #3461)

This study retrospectively analyzed ten pediatric patients with HOX-driven AML who received revumenib maintenance after HSCT at a single-center. The median age was 10 years (range: 1-18). 80% (8/10) had KMT2Ar and 20% (2/10) had NUP98r AML. 50% (5/10) of patients had ≥2 prior HSCTs.

Patients completed a median of 2 cycles (range: 1-4) of revumenib pre-HSCT. Patients began revumenib following HSCT, with planned continuation for up to 12 months. Patients resumed revumenib a median of 111 days (range: 58-175) post-HSCT. Patients completed a median of 11 revumenib cycles (range: 3-25) post-HSCT. At a median follow-up of 19 months (range: 4-41), all ten patients were alive, with one relapse, yielding a 90% relapse-free survival.

Revumenib was well tolerated in the post-HSCT maintenance setting, with most adverse events being low grade and manageable. No patients discontinued therapy due to drug-related toxicity.

Results from Phase 2 SAVE trial of revumenib with venetoclax and decitabine/cedazuridine in patients with newly diagnosed AML (Abstract #47)

The Phase 2 SAVE trial is an investigator-sponsored trial evaluating the all-oral combination of revumenib with venetoclax and decitabine/cedazuridine in pediatric and adult patients with R/R or newly diagnosed AML or MPAL harboring either NPM1m, KMT2Ar, or NUP98r alterations. Patients ≥12 years of age with these molecular subtypes who were not candidates for high-intensive chemotherapy were eligible to enroll in the newly diagnosed cohort.

At data cutoff (November 10, 2025), 21 newly diagnosed patients had been enrolled. The median age was 70 years (range: 60-83). 67% (14/21) had NPM1m and 33% (7/21) had KMT2Ar AML.

High rates of response, MRD negativity, and HSCT were observed among NPM1m and KMT2Ar AML patients who received the all-oral combination. The ORR was 86% (18/21) and the complete remission (CR) rate was 76% (16/21). The MRD negativity rate by flow cytometry was 100% (18/18) among responders. 33% (7/21) of patients proceeded to HSCT after receiving the combination, with 57% (4/7) having resumed revumenib as post-HSCT maintenance at the data cutoff.

With a median follow-up of 9 months, the median overall survival (OS) and event-free survival (EFS) were not reached.

The combination was generally well tolerated. The most common (>20%) Grade ≥3 treatment-emergent adverse events (TEAEs) were febrile neutropenia (48%), thrombocytopenia (33%), and neutropenia (24%). There was no treatment-emergent QTc prolongation above Grade 2. Two (10%) patients had Grade 3 treatment-emergent differentiation syndrome (DS) which promptly resolved with steroids. There was no treatment-emergent DS above Grade 3.

Results from Phase 1 trial of revumenib with intensive chemotherapy in patients with newly diagnosed KMT2Ar or NPM1m AML (SNDX-5613-0708) (Abstract #3425)

Preliminary data were reported from the Phase 1, multi-center, open-label, dose-escalation and dose-expansion trial of revumenib in combination with intensive chemotherapy (SNDX-5613-0708). Adults with newly diagnosed KMT2Ar, NPM1m, or NUP98r AML who were candidates for intensive chemotherapy were eligible to enroll. The primary endpoints were the occurrence of dose-limiting toxicities (DLTs) and safety. The secondary endpoints were PK parameters. Exploratory endpoints included the rate of CR, CRc, ORR, and MRD negative CR.

At the data cutoff (September 30, 2025), 30 patients had been enrolled and treated across two revumenib dose levels (DL1: revumenib 110 or 220 mg q12hr with/without strong CYP3A4i; DL2: 160 or 270 mg q12hr with/without strong CYP3A4i). The median age was 49 years (range: 19-71). 63% (19/30) had KMT2Ar and 37% (11/30) had NPM1m.

The safety profile of the combination was consistent with the profile for intensive chemotherapy alone. The most common treatment-related adverse events (TRAEs) of any Grade were decreases in neutrophil count (31%), anemia (23%), nausea (23%), and vomiting (23%) in DL1, and anemia (18%) in DL2. No cases of DS were reported. No events of QTc prolongation above Grade 3 were reported. The rates of TEAEs leading to revumenib reductions or discontinuations were low at 7% and 13%, respectively. One DLT of Grade 3 QTc prolongation was reported in DL1 in a patient taking several concomitant medications that can also prolong the QTc interval. This patient discontinued revumenib during Cycle 1; of note, at the end of Cycle 1, the patient had achieved MRD-negative CR and proceeded to HSCT.

The early data show encouraging clinical activity with the combination. Across both dose levels combined, the ORR was 96% (25/26), CRc rate was 92% (24/26), CR rate was 69% (18/26), and MRD negative CR rate was 86% (12/14) among patients with MRD results available. Data will continue to mature, and responses could deepen further with longer follow-up, particularly in DL2.

Time to count recovery was rapid and similar at both dose levels. The median time to neutrophil (≥1,000 cells/μL) recovery among CRc responders was 29 days in both DL1 and DL2 in Cycle 1. The median time to platelet (≥100,000 cells/μL) recovery among CRc responders was 28 days and 29 days in DL1 and DL2, respectively, in Cycle 1.

Syndax Investor Event

The Company will host an investor event on Monday, December 8, 2025, at 7:00 a.m. ET to discuss key Revuforj and Niktimvo data presented at the 67th ASH (Free ASH Whitepaper) Annual Meeting. The live audio webcast and accompanying slides for the event may be accessed through the Events & Presentations page of the Company’s website or directly through the meeting link here.

For those unable to join the live webcast, a replay will be available on the Investors section of the Company’s website at www.syndax.com for a limited time.

About Revuforj (revumenib)

Revuforj (revumenib) is an oral, first-in-class menin inhibitor that is FDA approved for the treatment of relapsed or refractory (R/R) acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation as determined by an FDA-authorized test in adult and pediatric patients one year and older. Revuforj is also indicated for the treatment of R/R acute myeloid leukemia (AML) with a susceptible nucleophosmin 1 (NPM1) mutation in adult and pediatric patients one year and older who have no satisfactory alternative treatment options.

Multiple trials of revumenib are ongoing or planned across the treatment landscape, including in combination with standard of care therapies in newly diagnosed patients with NPM1m or KMT2Ar AML.

Revumenib was previously granted Orphan Drug Designation for the treatment of AML, ALL and acute leukemias of ambiguous lineage (ALAL) by the U.S. FDA and for the treatment of AML by the European Commission. The U.S. FDA also granted Fast Track designation to revumenib for the treatment of adult and pediatric patients with R/R acute leukemias harboring a KMT2A rearrangement or NPM1 mutation and Breakthrough Therapy Designation for the treatment of adult and pediatric patients with R/R acute leukemia harboring a KMT2A rearrangement.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME, QTc PROLONGATION, and TORSADES DE POINTES

Differentiation syndrome, which can be fatal, has occurred with Revuforj. Signs and symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and renal dysfunction. If differentiation syndrome is suspected, immediately initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

QTc prolongation and Torsades de Pointes have occurred in patients receiving Revuforj. Correct hypokalemia and hypomagnesemia prior to and during treatment. Do not initiate Revuforj in patients with QTcF > 450 msec. If QTc interval prolongation occurs, interrupt, reduce, or permanently discontinue Revuforj.

WARNINGS AND PRECAUTIONS

Differentiation Syndrome: Revuforj can cause fatal or life-threatening differentiation syndrome (DS). Symptoms of DS, including those seen in patients treated with Revuforj, include fever, dyspnea, hypoxia, peripheral edema, pleuropericardial effusion, acute renal failure, rash, and/or hypotension.

In clinical trials, DS occurred in 60 (25%) of 241 patients treated with Revuforj at the recommended dosage for relapsed or refractory acute leukemia. Among those with a KMT2A translocation, DS occurred in 33% of patients with acute myeloid leukemia (AML), 33% of patients with mixed-phenotype acute leukemia (MPAL), and 9% of patients with acute lymphoblastic leukemia (ALL); DS occurred in 18% of patients with NPM1m AML. DS was Grade 3 or 4 in 12% of patients and fatal in 2 patients. The median time to initial onset was 9 days (range 3-41 days). Some patients experienced more than 1 DS event. Treatment interruption was required for 7% of patients, and treatment was withdrawn for 1%.

Reduce the white blood cell count to less than 25 Gi/L prior to starting Revuforj. If DS is suspected, immediately initiate treatment with systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours in adults or dexamethasone 0.25 mg/kg/dose IV every 12 hours in pediatric patients weighing less than 40 kg) for a minimum of 3 days and until resolution of signs and symptoms. Institute supportive measures and hemodynamic monitoring until improvement. Interrupt Revuforj if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids, or earlier if life-threatening symptoms occur such as pulmonary symptoms requiring ventilator support. Restart steroids promptly if DS recurs after tapering corticosteroids.

QTc Interval Prolongation and Torsades de Pointes: Revuforj can cause QT (QTc) interval prolongation and Torsades de Pointes.

Of the 241 patients treated with Revuforj at the recommended dosage for relapsed or refractory acute leukemia in clinical trials, QTc interval prolongation was reported as an adverse reaction in 86 (36%) patients. QTc interval prolongation was Grade 3 in 15% and Grade 4 in 2%. The heart-rate corrected QT interval (using Fridericia’s method) (QTcF) was greater than 500 msec in 10%, and the increase from baseline QTcF was greater than 60 msec in 24%. Revuforj dose reduction was required for 7% due to QTc interval prolongation. QTc prolongation occurred in 21% of the 34 patients less than 17 years old, 35% of the 146 patients 17 years to less than 65 years old, and 46% of the 61 patients 65 years or older. One patient had a fatal outcome of cardiac arrest, and one patient had non-sustained Torsades de Pointes.

Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to and throughout treatment with Revuforj. Perform an electrocardiogram (ECG) prior to initiation of Revuforj, and do not initiate Revuforj in patients with QTcF >450 msec. Perform an ECG at least once weekly for the first 4 weeks and at least monthly thereafter. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring may be necessary. Concomitant use with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation.

Interrupt Revuforj if QTcF increases >480 msec and <500 msec, and restart Revuforj at the same dose twice daily after the QTcF interval returns to ≤480 msec
Interrupt Revuforj if QTcF increases >500 msec or by >60 msec from baseline, and restart Revuforj twice daily at the lower-dose level after the QTcF interval returns to ≤480 msec
Permanently discontinue Revuforj in patients with ventricular arrhythmias and in those who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia
Embryo-Fetal Toxicity: Revuforj can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Revuforj and for 4 months after the last dose of Revuforj.

ADVERSE REACTIONS

Fatal adverse reactions occurred in 9 (4%) patients who received Revuforj, including 4 with sudden death, 2 with differentiation syndrome, 2 with hemorrhage, and 1 with cardiac arrest.

Serious adverse reactions were reported in 184 (76%) patients. The most frequent serious adverse reactions (≥10%) were infection (29%), febrile neutropenia (20%), bacterial infection (15%), differentiation syndrome (13%), and hemorrhage (11%).

The most common adverse reactions (≥20%) including laboratory abnormalities, were phosphate increased (51%), hemorrhage (48%), nausea (48%), infection without identified pathogen (46%), aspartate aminotransferase increased (44%), alanine aminotransferase increased (40%), creatinine increased (38%), musculoskeletal pain (37%), febrile neutropenia (37%), electrocardiogram QT prolonged (36%), potassium decreased (34%), parathyroid hormone intact increased (34%), alkaline phosphatase increased (33%), diarrhea (29%), bacterial infection (27%), triglycerides increased (27%), phosphate decreased (25%), differentiation syndrome (25%), fatigue (24%), edema (24%), viral infection (23%), decreased appetite (20%), and constipation (20%).

DRUG INTERACTIONS

Drug interactions can occur when Revuforj is concomitantly used with:

Strong CYP3A4 inhibitors: reduce Revuforj dose
Strong or moderate CYP3A4 inducers: avoid concomitant use with Revuforj
QTc-prolonging drugs: avoid concomitant use with Revuforj. If concomitant use is unavoidable, obtain ECGs when initiating, during concomitant use, and as clinically indicated. Withhold Revuforj if the QTc interval is >480 msec. Restart Revuforj after the QTc interval returns to ≤480 msec
SPECIFIC POPULATIONS

Lactation: advise lactating women not to breastfeed during treatment with Revuforj and for 1 week after the last dose.

Pregnancy and testing: Revuforj can cause fetal harm when administered to a pregnant woman. Verify pregnancy status in females of reproductive potential within 7 days prior to initiating Revuforj.

Infertility: based on findings in animals, Revuforj may impair fertility. The effects on fertility were reversible.

Pediatric: monitor bone growth and development in pediatric patients.

Geriatric: no overall differences were observed in the effectiveness of Revuforj between patients who were 65 years and older, and younger patients. Compared to younger patients, the incidences of QTc prolongation and edema were higher in patients 65 years and older.

To report SUSPECTED ADVERSE REACTIONS, contact Syndax Pharmaceuticals at 1-888-539-3REV or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see Full Prescribing Information, including BOXED WARNINGS.

(Press release, Syndax, DEC 8, 2025, View Source [SID1234661273])

On December 8, 2025 Incyte (Nasdaq:INCY) reported updated clinical data from two Phase 1 studies evaluating the safety, tolerability and efficacy of INCA033989, a first-in-class mutant calreticulin (mutCALR)-targeted monoclonal antibody, as a treatment for patients with mutCALR-expressing myeloproliferative neoplasms (MPNs). These data, which are featured in oral presentations at the 2025 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando (Session 634, Publication #1024; Session 631, Publication #71), focus on the dose escalation portion of the studies in patients with essential thrombocythemia (ET) harboring a CALR mutation who are resistant or intolerant to at least one cytoreductive therapy.

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"The compelling efficacy and safety data presented today at the 2025 ASH (Free ASH Whitepaper) Annual Meeting provide additional evidence of the potential for INCA033989 to provide disease modification for high-risk ET patients harboring a CALR mutation," said Pablo J. Cagnoni, M.D., President, Head of Research and Development, Incyte. "We are proud to be advancing a portfolio of novel targeted therapies, including INCA033989, that could offer a mutation-specific treatment for patients with mutCALR-expressing MPNs."

Results presented today evaluate the safety and efficacy of INCA033989 in patients with ET, as measured by hematologic response and reduction in mutCALR variant allele frequency (VAF), and build upon previously announced data presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2025 Congress.

The new results (data cut-off September 25, 2025) demonstrate rapid and durable normalization of platelet counts across all dose levels in patients with ET treated with INCA033989 (n=55), with optimal responses at higher doses. Of note, most (90%) ET patients treated with starting doses of 400 to 2,500 mg (n=30) INCA033989 achieved a hematologic response. Of those, 83.3% achieved a complete hematologic response (CHR), defined as platelet count ≤400 × 109/L and leukocytes <10 × 109/L, and nearly half (46.4%) achieved a durable (≥12 weeks) CHR. Among patients treated at lower doses (24 to 250 mg, n=25), 88% achieved a hematologic response, with 68% achieving a CHR and of those 44% achieving a durable CHR.

Additionally, molecular responses were frequent, rapid, durable and correlated with hematologic responses seen with INCA033989 monotherapy. A reduction in mutCALR VAF from baseline occurred in 96.2% of ET patients with ≥1 post-baseline VAF measurement, with approximately half (52%) achieving a ≥25% best reduction in VAF and nearly one third (31%) achieving a ≥50% best reduction in VAF. Reduction in mutCALR VAF was observed within three to six months and has maintained over time in most patients, with deeper and more consistent mutCALR VAF reductions observed at higher doses of INCA033989.

Exploratory analyses in a subset of ET patients showed that INCA033989 reduced circulating mutCALR-positive hematopoietic stem and progenitor cells (HSPC) and mutCALR-positive platelet producing cells called megakaryocytes (MK) in the bone marrow, and improved MK hyperplasia. Together, these findings demonstrate the disease-modifying activity of INCA033989 in patients with mutCALR-expressing ET.

The safety analysis (n=55) showed that INCA033989 was well tolerated across all dose cohorts (24 to 2,500 mg), with no dose-limiting toxicities observed. Only one (1) patient discontinued treatment due to treatment emergent adverse events (TEAEs). One (1) dose reduction and one (1) infusion interruption due to TEAEs were reported, and a maximum tolerated dose was not reached. Fifty-three (53) patients across the dose cohorts reported a TEAE, thirty-six (36) of which were treatment related. The most common TEAEs were fatigue (30.9%), headache (27.3%), upper respiratory tract infection (27.3%) and anemia (20%). Grade >3 anemia and/or neutropenia TEAEs (>1 patient) occurred in five (5) patients (3.6% and 7.3%, respectively). No Grade ≥3 thrombocytopenia TEAEs were observed.

"Approximately 25 to 35 percent of ET patients have mutCALR-expressing ET, yet current treatments are broadly myelosuppressive, not mutant targeted and have limited efficacy in reducing mutCALR allele frequency," said John Mascarenhas, M.D., Professor of Medicine at the Icahn School of Medicine at Mt. Sinai and Director, Center of Excellence for Blood Cancers and Myeloid Disorders, The Tisch Cancer Institute. "These emerging data suggest that INCA033989 could offer a novel treatment approach by selectively targeting mutCALR in a way that enables rapid and durable hematologic responses, while maintaining safety and tolerability for ET patients who are resistant or intolerant to prior cytoreductive therapy. I’m encouraged by these findings and the potential for INCA033989 to redefine treatment paradigms for patients with ET."

INCA033989 was recently granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with ET harboring a Type 1 CALR mutation who are resistant or intolerant to at least one cytoreductive therapy. Incyte plans to develop INCA033989 for patients with Type 1 and non-Type 1 CALR mutations and, following discussions with regulatory agencies, plans to initiate a registrational program evaluating patients with ET with a Type 1 or non-Type 1 CALR mutation who are resistant or intolerant to at least one cytoreductive therapy in the first half of next year.

More information regarding the 2025 ASH (Free ASH Whitepaper) Annual Meeting can be found on the ASH (Free ASH Whitepaper) website: View Source

About Essential Thrombocythemia
Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm (MPN) characterized by persistently elevated platelet counts due to abnormal blood cell production in the bone marrow. People living with ET are at increased risk for blood clots and bleeding and a proportion of patients may progress over time to myelofibrosis or acute leukemia.

About Mutations in Calreticulin (mutCALR)
Calreticulin (CALR) is a protein involved in the regulation of cellular calcium levels and normal protein folding. Somatic, or non-inherited, DNA mutations in the CALR gene (mutCALR) can result in abnormal protein function and lead to the development of myeloproliferative neoplasms (MPNs),1 a closely related group of clonal blood cancers in which the bone marrow functions abnormally, overproducing blood cells.2,3 Among two types of MPNs, essential thrombocythemia (ET) and myelofibrosis (MF), mutCALR drives 25-35% of all cases.2,3

Incyte is at the forefront of developing novel therapies for patients with mutCALR ET or MF that target only malignant cells, sparing normal cells, including INCA033989, a first-in-class, mutCALR-specific therapy.

About the INCA033989 Trial Program
The clinical trial program for INCA033989 includes two multicenter, open-label Phase 1 studies, INCA33989-101 (NCT05936359) and INCA33989-102 (NCT06034002). The studies are evaluating the safety, tolerability and efficacy of INCA033989 in ~455 adult (≥18 years old) patients with mutCALR-expressing myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET) and myelofibrosis (MF).

The primary endpoint of the studies is measured by the number of participants with dose limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs) and the number of participants with TEAEs leading to dose modification or discontinuation. Secondary endpoints include response rates, mean change of ET total symptom score, percentage of MF patients achieving spleen volume reduction, MF patient anemia response, mean change in disease-related allele burden and various pharmacokinetics measures.

For more information on the studies, please visit: View Source and View Source

(Press release, Incyte, DEC 8, 2025, View Source [SID1234661289])