C4 Therapeutics Presents Cemsidomide Phase 1 Data at the American Society for Hematology (ASH) Annual Meeting that Demonstrated Potential to Become Best-in-Class IKZF1/3 Degrader

On December 7, 2024 C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company dedicated to advancing targeted protein degradation science, reported clinical data from the ongoing Phase 1 trial of cemsidomide, an orally bioavailable small molecule degrader of IKZF1/3, at the ASH (Free ASH Whitepaper) Annual Meeting (Press release, C4 Therapeutics, DEC 8, 2024, View Source [SID1234648865]). Presentations included a poster highlighting results for cemsidomide in combination with dexamethasone in multiple myeloma, and an oral presentation delivering initial results for cemsidomide as a monotherapy for non-Hodgkin’s lymphoma. These presentations reinforce the potential of cemsidomide to become a backbone therapy of choice in both multiple myeloma and non-Hodgkin’s lymphoma where IKZF1/3 degradation is warranted.

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C4T designed cemsidomide to be a more potent and selective degrader of IKZF1/3 with unique pharmacokinetic properties, with the goal to improve the therapeutic index to treat multiple myeloma and non-Hodgkin’s lymphoma—both alone and in combination with other therapeutic agents in these therapeutic areas.

"Cemsidomide continues to deliver clinical data demonstrating its potential to be used in both multi-refractory patients and as part of combination therapies across all lines of treatment for a significant number of patients with multiple myeloma or non-Hodgkin’s lymphoma," said Len Reyno, M.D., chief medical officer of C4 Therapeutics. "We look forward to leveraging today’s data to inform clinical development strategies in both multiple myeloma and non-Hodgkin’s lymphoma that has the potential to unlock the value of cemsidomide for patients in need of innovative therapies across treatment lines."

Multiple Myeloma (MM)
At the ASH (Free ASH Whitepaper) Annual Meeting, C4T presented safety and anti-myeloma data demonstrating cemsidomide has the potential to become a best-in-class IKZF1/3 degrader used as a backbone therapy of choice for patients with multiple myeloma where IKZF1/3 degradation is warranted. These data support the future development of cemsidomide across treatment lines in combination with other anti-myeloma agents.

As of the data cutoff date of October 11, 2024, a total of 47 patients received cemsidomide in combination with dexamethasone across four dose levels (50 µg dosed Monday, Wednesday, Friday (MWF); 37.5 µg dosed once daily (QD); 62.5 µg QD; 75 µg QD). Patients were heavily pretreated, receiving a median of six prior therapies. All patients (100 percent) were triple-class exposed, defined as exposure to one or more immunomodulatory agents, one or more proteasome inhibitors, and one anti-CD38 antibody. Thirty-three patients (70 percent) received prior BCMA directed therapy. Thirty-one patients (66 percent) received prior CAR-T or T-cell engager therapy.

Safety: Cemsidomide in combination with dexamethasone was well tolerated.

As of the data cutoff date, 47 patients were evaluable for safety.
The most common adverse events (AEs) Grade 3 or above were neutropenia (n=18), anemia (n=10) and infections (n=8). No patients discontinued therapy due to neutropenia.
No patients experienced a treatment emergent adverse event that led to dose reduction.
The maximum tolerated dose has not yet been identified. Enrollment is currently ongoing at the 100 µg QD dose level.
Anti-myeloma activity: Cemsidomide in combination with dexamethasone demonstrated anti-myeloma activity across a broad range of doses, highlighting a wide therapeutic range.

As of the data cutoff, 42 patients were evaluable for anti-myeloma activity.
Across all dose levels, cemsidomide in combination with dexamethasone achieved a 26 percent ORR and a 40 percent clinical benefit rate (CBR).
At the highest dose level explored to date (75 µg QD), cemsidomide achieved a 36 percent ORR and a 45 percent CBR.
At the two highest dose levels evaluated to date (62.5 µg QD and 75 µg QD), 62 percent of patients remained on therapy as of the data cutoff date.
Binod Dhakal, M.D., M.S., associate professor of medicine, Medical College of Wisconsin, Division of Hematology, presented a poster highlighting the MM results. He commented: "The data presented at the ASH (Free ASH Whitepaper) Annual Meeting demonstrate cemsidomide in combination with dexamethasone is active and well-tolerated over a range of doses in a heavily pretreated, relapsed/refractory multiple myeloma patient population—including a majority of patients who have received T-cell directed therapies who are challenging to treat. I look forward to cemsidomide’s continued development as a potential new treatment option for patients in the evolving myeloma landscape."

C4T has identified 75 µg QD as a target dose for various dexamethasone combination regimens; as dose escalation continues, higher doses may also be considered. For immune-based combination strategies, C4T believes doses lower than 75 µg QD will be optimal based on anti-myeloma activity and immune activation observed in the previously disclosed monotherapy data set.

C4T has identified the following next steps in cemsidomide MM development:

Complete Phase 1 dose escalation trial in MM to establish go forward doses
Initiate initial combination trials
Engage regulatory authorities on registrational path
Non-Hodgkin’s Lymphoma (NHL)
At the ASH (Free ASH Whitepaper) Annual Meeting, C4T also presented safety and anti-lymphoma data that reinforce C4T’s belief that IKZF1/3 degradation remains relevant in lymphoma. Based on the emerging anti-lymphoma signal demonstrated in patients with PTCL, C4T believes cemsidomide could be further developed in areas of high unmet need.

As of the data cutoff date of October 11, 2024, a total of 23 patients received cemsidomide monotherapy across five dose levels (25 µg MWF; 50 µg MWF QD; 37.5 µg QD; 62.5 µg QD; 100 µg QD). Patients were heavily pretreated, receiving a median of three prior therapies. Seventeen patients had refractory progressive PTCL and six patients had refractory progressive B-cell lymphoma.

Safety: Cemsidomide monotherapy was well tolerated and additional dose finding is ongoing.

As of the data cutoff, 23 patients were evaluable for safety.
The most common AEs Grade 3 or above were neutropenia (n=11), infections (n=6), febrile neutropenia (n=4) and anemia (n=4). No patients discontinued therapy due to neutropenia.
At this time, the maximum tolerated dose has not been defined. Two dose-limiting toxicities occurred at the 100 µg QD dose level. As a result, a 75 µg QD cohort was opened to refine the understanding of dose and safety in the NHL population; this cohort is currently enrolling patients. Escalation above 75 µg QD may be explored pending the outcome of the cohort.
Anti-lymphoma activity: Cemsidomide monotherapy demonstrated anti-lymphoma activity across a broad range of doses.

As of the data cutoff, 21 patients were evaluable for efficacy, 16 of which had PTCL.
Cemsidomide displays a differentiated pharmacokinetic profile with an approximate two-day half-life and an ability to induce rapid and potent degradation of IKZF1/3.
Across all dose levels explored, cemsidomide achieved a 38 percent ORR and 19 percent CMR rate.
In patients with PTCL, cemsidomide achieved a 44 percent ORR and 25 percent CMR rate.
Steve Horwitz, M.D., lymphoma specialist and cellular therapist, Memorial Sloan Kettering Cancer Center, delivered an oral presentation highlighting the NHL results at the ASH (Free ASH Whitepaper) Annual Meeting. He commented: "I am pleased to share the first clinical data on monotherapy cemsidomide in non-Hodgkin’s lymphoma, which demonstrated its well-tolerated safety profile and compelling anti-lymphoma activity. These initial data are encouraging, particularly in PTCL where relapsed/refractory patients lack effective targeted therapies. We believe these Phase 1 monotherapy data demonstrate that cemsidomide is well suited for further development in earlier lines of treatment and in combination with other anti-lymphoma agents."

C4T has identified the following next steps in cemsidomide NHL development:

Complete Phase 1 dose escalation trial and identify go forward dose
Initiate expansion cohort for PTCL
Engage regulatory authorities on registrational path
C4T Webcast for Analysts and Investors
C4T will host an investor webcast today December 8, 2024, at 5 pm EST. To join the webcast, please visit this link or the "Events & Presentations" page of the Investors section on the company’s website at www.c4therapeutics.com. A replay of the webcast will be archived and available following the event.

About Cemsidomide
Cemsidomide is an investigational, orally bioavailable small-molecule degrader designed to be a more potent and selective degrader of IKZF1/3, transcription factors that drive multiple myeloma (MM) and non-Hodgkin’s lymphomas (NHL), with unique pharmacokinetic properties. Clinical data has shown that cemsidomide is well-tolerated. In MM, cemsidomide displays evidence of anti-myeloma activity and immunomodulatory effects. In NHL, cemsidomide displays evidence of anti-lymphoma activity. More information may be accessed at www.clinicaltrials.gov (identifier: NCT04756726).

About IKZF1/3
IKZF1 (Ikaros) and IKZF3 (Aiolos) are transcription factors that directly regulate the activity of IRF4, a transcription factor that regulates downstream immune cell differentiation. Aberrant IRF4 is associated with both lymphoma and multiple myeloma proliferative T, B and plasma cell populations. Down regulation of IRF4 promotes the death of both myeloma and lymphoma cells.

About Multiple Myeloma
Multiple myeloma (MM) is a rare blood cancer affecting plasma cells. Approximately 36,000 people in the United States are diagnosed with MM each year. Despite advances in treatment, multiple myeloma remains incurable. Treatment combinations include IKZF1/3 degraders, which are established backbone therapies, across lines of therapy.

About non-Hodgkin’s Lymphoma
Non-Hodgkin’s lymphoma (NHL) is one of the most common cancers in the United States. NHL forms in cells of the immune system called lymphocytes. In the United States, approximately 80,000 people are diagnosed with NHL each year. IKZF1/3 degraders are used across NHL subtypes.

Agios Presents Positive Results from Phase 3 ENERGIZE-T Study of Mitapivat at ASH 2024 and Provides Regulatory Update on Mitapivat

On December 8, 2024 Agios Pharmaceuticals, Inc. (Nasdaq: AGIO), a leader in cellular metabolism and pyruvate kinase (PK) activation pioneering therapies for rare diseases, reported positive results from the Phase 3 ENERGIZE-T study investigating mitapivat, an oral, small molecule PK activator, in adults with transfusion-dependent alpha- or beta-thalassemia (Press release, Agios Pharmaceuticals, DEC 8, 2024, View Source [SID1234648861]). These findings were shared in an oral presentation (abstract #409) at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, California.

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Thalassemia is a rare inherited blood disorder caused by genetic mutations that lead to a reduced production of healthy hemoglobin, compromising red blood cell development, health and survival, and resulting in chronic anemia. Patients with thalassemia often experience a range of debilitating complications, both from the disease itself and as secondary effects of common management strategies such as blood transfusions and iron chelation therapy, including organ damage, stroke, and other serious health issues.

In the ENERGIZE-T trial, mitapivat demonstrated a statistically significant reduction in transfusion burden compared to placebo in patients with transfusion-dependent alpha- or beta-thalassemia, achieving its primary endpoint. Additionally, the ENERGIZE-T study met all the key secondary endpoints, with mitapivat demonstrating a statistically significant reduction in additional measures of transfusion reduction response compared to placebo. In June 2024, Agios also presented positive results from the Phase 3 ENERGIZE study, which evaluated mitapivat in adults with non-transfusion-dependent alpha- or beta-thalassemia.

"Treatment options for patients with transfusion-dependent thalassemia are extremely limited, and transfusions carry serious risks, such as iron overload, infections and immune reactions. There is a significant need for alternative treatments to manage this debilitating disease," said Maria Domenica Cappellini, M.D., professor, Internal Medicine, University of Milan, Italy. "The strong Phase 3 ENERGIZE-T results build on the positive findings from the Phase 3 ENERGIZE study in patients with non-transfusion-dependent alpha- or beta-thalassemia presented earlier this year, pointing to mitapivat as a potential transformative advancement in thalassemia care."

Phase 3 ENERGIZE-T Study Results
ENERGIZE-T is a Phase 3, double-blind, randomized, placebo-controlled and multicenter 48-week study. A total of 258 patients were enrolled in the study worldwide, with 171 patients randomized to mitapivat 100 mg twice-daily (BID) and 87 patients randomized to matched placebo.

The study’s primary endpoint of transfusion reduction response (TRR) was defined as a ≥50% reduction in transfused red blood cell (RBC) units with a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through Week 48 compared with baseline. A TRR was achieved by 30.4% (n=52/171) of patients in the mitapivat arm compared to 12.6% (n=11/87) of patients in the placebo arm (2-sided p=0.0003).

Additionally, mitapivat demonstrated statistically significant reductions in transfusion burden compared with placebo as measured by the three key secondary endpoints of transfusion reduction response reflective of durability of response up to 36 weeks during the 48-week double-blind period. The key secondary endpoint TRR2, defined as a ≥50% reduction in transfused RBC units in any consecutive 24-week period through Week 48 compared with baseline, was achieved in 13.5% (n=23/171) versus 2.3% (n=2/87) of patients in the mitapivat and placebo arms, respectively (2-sided p=0.0003). The key secondary endpoints TRR3 and TRR4 were defined as a ≥33% and ≥50% reduction in transfused RBC units, respectively, from Week 13 through Week 48 compared with baseline. TRR3 was achieved in 14.6% (n=25/171) versus 1.1% (n=1/87) of patients in the mitapivat and placebo arms, respectively (2-sided p<0.0001), and TRR4 was achieved in 7.6% (n=13/171) versus 1.1% (n=1/87) of patients in the mitapivat and placebo arms, respectively (2-sided p=0.0056).

The results for the primary and key secondary endpoints were not driven by any of the individual prespecified subgroups, including but not limited to genotype and baseline transfusion burden, highlighting the overall robustness of the efficacy results.

Further, 17 patients (9.9%) in the mitapivat arm compared with one patient (1.1%) in the placebo arm achieved the secondary endpoint of transfusion independence (transfusion-free for 8 or more consecutive weeks through Week 48). Three patients in the mitapivat arm did not receive any transfusions during the 48-week double-blind period.

Overall, during the 48-week double-blind period, incidence of adverse events (AEs) was similar across the mitapivat and placebo arms. The proportion of patients with any treatment-emergent adverse events (TEAEs) was 90.1% (n=155) in patients on mitapivat and 83.5% (n=71) in patients on placebo. The most frequent TEAEs that occurred in at least 10% of patients on mitapivat were headache, upper respiratory tract infection, initial insomnia, diarrhea and fatigue. Serious treatment-emergent adverse events were reported in 11.0% (n=19) and 15.3% (n=13) of patients on mitapivat and placebo, respectively; 2.3% (n=4) and 1.2% (n=1), respectively, were considered treatment-related. There were 5.8% (n=10) of patients on mitapivat and 1.2% (n=1) on placebo with TEAEs leading to treatment discontinuation. The TEAEs leading to discontinuation of mitapivat, each of which occurred in one patient, were diarrhea, paresthesia oral, concurrent anxiety and insomnia, initial insomnia, supraventricular tachycardia, fatigue, hypertransaminasemia, hepatitis C, hepatic cancer, and renal mass. The TEAE that led to discontinuation of the one patient on placebo was blood creatine phosphokinase increased.

Mitapivat Thalassemia Regulatory Next Steps
Currently, there are no disease-modifying therapies approved to treat the full spectrum of patients with thalassemia across transfusion requirements and genotypes. The standard of care for thalassemia remains centered on supportive care to address symptoms through transfusions, splenectomy, and/or iron chelation therapy, none of which address the underlying pathophysiology of the disease.

Based on the favorable benefit-risk profile observed in both the Phase 3 ENERGIZE and ENERGIZE-T studies, Agios filed regulatory applications for mitapivat (PYRUKYND) for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia with the U.S., European Union, Kingdom of Saudi Arabia and United Arab Emirates health authorities.

The Phase 3 ENERGIZE and ENERGIZE-T trials enrolled a total of 452 patients reflective of the real-world thalassemia population. The results demonstrated that mitapivat improves hemolytic anemia and quality-of-life related measures, as measured by significant reductions in transfusion burden and significant improvements in hemoglobin and fatigue.

The primary and all the key secondary efficacy endpoints were met, demonstrating the efficacy of mitapivat compared with placebo in the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia.
Overall, the incidence of AEs was similar for patients on mitapivat and patients on placebo. There were 4.7% (n=14) of patients on mitapivat and 0.7% (n=1) of patients on placebo with TEAEs leading to treatment discontinuation across the two studies.
Two of 301 patients (0.66%) on mitapivat experienced AEs of hepatocellular injury within the first six months of exposure leading to treatment discontinuation. Liver tests improved following discontinuation of mitapivat. Based on the data from the ENERGIZE and ENERGIZE-T studies, Agios included, in its regulatory applications, hepatocellular injury as an important potential risk of mitapivat in patients with thalassemia and proposed monthly monitoring of liver tests for the first six months of treatment with mitapivat. In addition, mitapivat clinical trial protocols across all indications have been updated to incorporate similar monitoring.
"Informed by the robust data from both the Phase 3 ENERGIZE and ENERGIZE-T trials, we believe mitapivat has demonstrated an overall favorable benefit-risk profile in all subtypes of thalassemia, a disease where patients face debilitating challenges and have limited or no treatment options," said Sarah Gheuens, M.D., Ph.D., chief medical officer and head of R&D at Agios. "We are confident that this comprehensive data package will highlight mitapivat’s effectiveness in treating patients with thalassemia with the convenience of an oral medication. We look forward to collaborating with regulators with the goal of bringing this novel therapy to patients with thalassemia as quickly as possible."

Investor Event at ASH (Free ASH Whitepaper) 2024
Agios will host a live and webcast investor event with the company’s leadership team and medical experts. The event will take place on Monday, December 9, in San Diego, starting at 7:00 a.m. PT (10:00 a.m. ET). The webcast will be accessible on the Investors section of the company’s website (www.agios.com) under the "Events & Presentations" tab. The archived webcast will be available on the company’s website approximately two hours after the event.

About PYRUKYND (mitapivat)
PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States, and for the treatment of PK deficiency in adult patients in the European Union.

IMPORTANT SAFETY INFORMATION
Acute Hemolysis: Acute hemolysis with subsequent anemia has been observed following abrupt interruption or discontinuation of PYRUKYND in a dose-ranging study. Avoid abruptly discontinuing PYRUKYND. Gradually taper the dose of PYRUKYND to discontinue treatment if possible. When discontinuing treatment, monitor patients for signs of acute hemolysis and anemia including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath.

Adverse Reactions: Serious adverse reactions occurred in 10% of patients receiving PYRUKYND in the ACTIVATE trial, including atrial fibrillation, gastroenteritis, rib fracture, and musculoskeletal pain, each of which occurred in 1 patient. In the ACTIVATE trial, the most common adverse reactions including laboratory abnormalities (≥10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia.

Drug Interactions:

Strong CYP3A Inhibitors and Inducers: Avoid concomitant use.
Moderate CYP3A Inhibitors: Do not titrate PYRUKYND beyond 20 mg twice daily.
Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers. If there are no alternatives, adjust PYRUKYND dosage.
Sensitive CYP3A, CYP2B6, CYP2C Substrates Including Hormonal Contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index.
UGT1A1 Substrates: Avoid concomitant use with substrates that have narrow therapeutic index.
P-gp Substrates: Avoid concomitant use with substrates that have narrow therapeutic index.
Hepatic Impairment: Avoid use of PYRUKYND in patients with moderate and severe hepatic impairment.

Please see full Prescribing Information and Summary of Product Characteristics for PYRUKYND.

Galapagos Announces Encouraging New Results from Ongoing Phase 1/2 Study of CD19 CAR T-Cell Therapy, GLPG5101, in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

On December 7, 2024 Galapagos NV (Euronext & NASDAQ: GLPG) reported additional data from the ongoing Phase 1/2 ATALANTA-1 study of its CD19 CAR T-cell therapy, GLPG5101 (Press release, Galapagos, DEC 7, 2024, View Source [SID1234648899]). The results, featured in an oral presentation at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, demonstrate an encouraging efficacy and safety profile in patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL). Most patients in the study received GLPG5101 as a fresh, fit, stem-like, early memory CD19 CAR T-cell therapy, with a median vein-to-vein time of seven days.

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"Shorter vein-to-vein time can lead to improved patient outcomes and remains an important unmet need in CAR-T therapy," said Marie José Kersten, MD, ATALANTA-1 Principal Investigator and Professor of Hematology at the Department of Hematology at Amsterdam University Medical Center. "I am impressed by the latest data on GLPG5101, which demonstrate a promising efficacy and safety profile. With a median vein-to-vein time of just seven days, GLPG5101 has the potential to offer speed and scheduling flexibility, comparable to off-the-shelf therapies."

"CAR-T therapies are highly personalized treatments that currently undergo a time-intensive manufacturing process taking multiple weeks to months. For many patients with rapidly progressing cancers, every day counts, and treatment delays can be detrimental," said Jeevan Shetty, MD, Head of Clinical Development Oncology at Galapagos. "We are steadfast in our commitment to bring innovation to cell therapies to address the most significant medical challenges. Our latest data at ASH (Free ASH Whitepaper) strongly support the feasibility of our innovative decentralized cell therapy manufacturing platform in delivering fresh, fit cells with a median vein-to-vein time of just seven days, driving positive patient outcomes."

The new ATALANTA-1 data are summarized below:
The ongoing ATALANTA-1 study included updated data on patients with mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). As of the April 25, 2024, data cut-off, 49 patients received CD19 CAR T-cell therapy infusion, and safety and efficacy results were available for 45 patients and 42 patients, respectively.

High objective response rates (ORR) and complete response rates (CRR) were observed in the pooled Phase 1 and Phase 2 efficacy analysis set, split by indication:
In patients with MCL, all 8 of 8 efficacy-evaluable patients responded to treatment (ORR and CRR 100%).
In patients with MZL, FL, objective and complete responses were observed in 20 of 21 efficacy-evaluable patients (ORR and CRR 95%).
In patients with DLBCL, 9 of 13 efficacy-evaluable patients responded to treatment (ORR 69%), with 7 patients achieving a complete response (CRR 54%). Of the 7 patients with DLBCL who received the higher dose, 6 responded to treatment (ORR 86%) with 5 achieving a complete response (CRR 71%).
Of the 15 minimal residual disease (MRD)-evaluable patients with a complete response, 12 patients (80%) achieved MRD negativity and remained in complete response at data cut-off.
The median study follow-up was 3.3 months for FL and DLBCL with a range of 0.9-21.2 months, and 4.4 months for MCL with a range of 1-24.4 months.
GLPG5101 showed an encouraging safety profile, with the majority of Grade ≥ 3 treatment emergent adverse events being hematological. One case of CRS Grade 3 was observed in Phase 1 and one case of ICANS Grade 3 was observed in Phase 2.
96% of patients (47 of 49) received an infusion with fresh, fit, stem-like early memory CD19 CAR T-cell therapy, with 91.5% (43 of 47) achieving a vein-to-vein time of seven days, thereby avoiding cryopreservation, and eliminating the need for bridging therapy.
Strong and consistent in vivo CAR-T expansion levels and products consisting of stem-like, early memory phenotype T cells were observed in all doses tested.
About the ATALANTA-1 study (EudraCT 2021-003272-13)

ATALANTA-1 is an ongoing Phase 1/2, open-label, multicenter study to evaluate the safety, efficacy and feasibility of decentralized manufactured GLPG5101, a CD19 CAR-T product candidate, in patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL). GLPG5101 is a second generation anti-CD19/4-1BB CAR-T product candidate, administered as a single fixed intravenous dose. The primary objective of the Phase 1 part of the study is to evaluate the safety and preliminary efficacy to determine the recommended dose for the Phase 2 part of the study. Secondary objectives include assessment of efficacy and feasibility of decentralized manufacturing of GLPG5101. The dose levels that were evaluated in Phase 1 are 50×106 (DL1), 110×106 (DL2) and 250×106 (DL3) CAR+ viable T cells. The primary objective of the Phase 2 part of the study is to evaluate the objective response rate (ORR), while the secondary objectives include complete response rate (CRR), duration of response, progression free survival, overall survival, safety, pharmacokinetic profile, and the feasibility of decentralized manufacturing. Each enrolled patient will be followed for 24 months.

Beam Therapeutics Announces New Data from BEACON Phase 1/2 Clinical Trial of BEAM-101 in Sickle Cell Disease at American Society of Hematology (ASH) Annual Meeting

On December 7, 2024 Beam Therapeutics Inc. (Nasdaq: BEAM), a biotechnology company developing precision genetic medicines through base editing, reported new safety and efficacy data from its BEACON Phase 1/2 clinical trial of BEAM-101 in patients with sickle cell disease (SCD) with severe vaso-occlusive crises (VOCs) (Press release, Beam Therapeutics, DEC 7, 2024, View Source [SID1234648891]). The data were featured today in the press program for the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego and will be presented in an oral session on Sunday, Dec. 8, 2024, at 10 a.m. PT.

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Consistent with Beam’s previously announced data, updated data from seven patients treated with investigational base-editing therapy BEAM-101 demonstrated robust and durable increases in fetal hemoglobin (HbF) and reductions in sickle hemoglobin (HbS), rapid neutrophil and platelet engraftment, and normalized or improved markers of hemolysis. No VOCs were reported post-engraftment. A summary of the results from the ongoing clinical study is provided below.

"These initial data from the BEACON trial are very encouraging and highlight the potential of BEAM-101 to deliver meaningful clinical benefits to patients with severe sickle cell disease," said Matthew M. Heeney, M.D., associate chief of hematology at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. "The data from the first seven patients demonstrate the ability for BEAM-101 to dramatically modify the hemoglobin profile to express a majority of protective fetal hemoglobin. All patients mobilized efficiently and had rapid engraftment with a low number of neutropenic days. I look forward to the continued maturation of the data to provide further insights into the long-term benefits of BEAM-101 for people living with sickle cell disease."

"It’s an honor to share the initial results from BEACON with the hematology community at the ASH (Free ASH Whitepaper) Annual Meeting, where there is broad recognition of the significant burden that sickle cell disease places on patients and their families," said John Evans, chief executive officer of Beam. "We believe these early data for BEAM-101 are a testament to the potential of our base-editing technology to provide a differentiated option for sickle cell patients, having demonstrated a robust increase in fetal hemoglobin of >60%, a decrease in hemoglobin S to <40% and resolution of anemia in all patients. Additionally, the data from our ESCAPE nongenotoxic conditioning program – to be presented on Sunday – highlight our commitment to expanding access to treatment by decreasing the burden and complications patients potentially face when undergoing transplantation. We look forward to continuing to rapidly advance both programs for patients with sickle cell disease."

To date, more than 35 patients have cleared screening and enrolled in the BEACON Phase 1/2 clinical trial, and of these, 11 patients have been dosed with BEAM-101. As of an Oct. 28, 2024, data cut-off, a total of seven patients with severe SCD were treated with BEAM-101 and included in the safety and efficacy analysis with follow up ranging from 1 to 11 months.

Key highlights include the following:


Rapid and Sustained Increases in Protective Fetal Hemoglobin (HbF): All patients achieved endogenous HbF levels exceeding 60% and reduction in corresponding sickle hemoglobin (HbS) below 40% that was durable. A pancellular distribution of HbF was observed after the elimination of transfused blood.


Robust and Sustained Total Hemoglobin (Hb) Levels: Total hemoglobin levels increased rapidly with resolution of anemia in patients after elimination of the transfused blood.


Efficient Cell Collection and Rapid Engraftment: All patients achieved the minimum target cell dose in either 1 or 2 cycles of mobilization (average: 1.4). The mean time to neutrophil engraftment was 17.1 days (range: 15–21), with a low mean duration of neutropenia (6.3 days). The mean time to platelet engraftment was 19.1 days (range: 11–34).


Normalization of Hemolysis Markers: Key markers of hemolysis, including indirect bilirubin, haptoglobin, lactate dehydrogenase and reticulocytes, normalized or improved in all patients following BEAM-101 treatment.


Safety Profile Consistent with Busulfan and Autologous Hematopoietic Stem Cell Transplantation (HSCT): The safety profile of BEAM-101 was consistent with busulfan conditioning and autologous HSCT. The most common treatment-emergent adverse events (TEAEs) were consistent with busulfan conditioning, including febrile neutropenia, stomatitis and anemia. One patient died four months after BEAM-101 infusion due to respiratory failure that was determined by the investigator to be likely related to busulfan conditioning and deemed unrelated to BEAM-101. No VOCs were reported post-engraftment.

ASH Investor Event Information

Beam will host a live and webcast investor event on Dec. 8, 2024, at 8:00 p.m. PT in San Diego to review the key presentations from this year’s ASH (Free ASH Whitepaper) meeting. The event will be webcast live and can be accessed under "Events & Presentations" in the Investors section of the company’s website at www.beamtx.com. The archived webcast will be available on the company’s website beginning approximately two hours after the event.

About BEAM-101

BEAM-101 is an investigational genetically modified cell therapy for the treatment of severe sickle cell disease (SCD). The one-time therapy consists of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) that have been base-edited in the promotor regions of the HBG1/2 genes and are administered via a hematopoietic stem cell transplant procedure. The BEAM-101 edit is designed to inhibit the transcriptional repressor BCL11A from binding to the promoter without disrupting BCL11A expression, leading to increased production of non-sickling and anti-sickling fetal hemoglobin (HbF) and thus mimicking the effects of naturally occurring variants seen in hereditary persistence of fetal hemoglobin. HbF is the predominant hemoglobin variant during development and early life. The safety and efficacy of BEAM-101 is being evaluated in the ongoing BEACON Phase 1/2 study, an open-label, single-arm, multicenter trial in adult patients with SCD with severe vaso-occlusive crises (VOCs).

Syndax Presents Positive Revuforj® (revumenib) Data in Acute Leukemias from Multiple Trials, Including the SAVE Combination and AUGMENT-101 Trials, at 66th ASH Annual Meeting

On December 7, 2024 Syndax Pharmaceuticals (Nasdaq: SNDX), a commercial-stage biopharmaceutical company developing an innovative pipeline of cancer therapies, reported positive data from multiple trials of Revuforj (revumenib) as a single-agent and in combination with standard of care agents in patients with acute leukemias in oral sessions at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held in San Diego, December 7-10, 2024 (Press release, Syndax, DEC 7, 2024, View Source [SID1234648871]). Revuforj is the Company’s 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 in adult and pediatric patients one year and older.

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"On the heels of the recent approval of Revuforj for R/R acute leukemia with a KMT2A translocation, we are excited to present clinical data highlighting the consistent efficacy and favorable tolerability of this first-in-class therapy, as both a single-agent and in combination with standard of care, in patients with mNPM1 and KMT2Ar acute leukemia," said Michael A. Metzger, Chief Executive Officer. "We are thrilled that our U.S. launch of Revuforj is firmly underway, and we look forward to building on this momentum as we continue to advance our clinical development program which we believe will position us to pursue meaningful label expansion opportunities."

Overview of Revumenib Data Presented in Oral Sessions at 66th ASH (Free ASH Whitepaper) Annual Meeting

Results from Phase 1/2 SAVE Trial of Revumenib in Combination with Venetoclax and Decitabine/Cedazuridine in R/R AML

The Phase 1/2 SAVE trial is an investigator-sponsored trial testing an all-oral regimen of revumenib, venetoclax and the hypomethylating agent (HMA) ASTX727 (decitabine/cedazuridine) in pediatric and adult patients with R/R acute myeloid leukemia (AML) or mixed-lineage acute leukemia (MPAL) harboring either KMT2Ar, NUP98r or mNPM1 alterations. In the previously announced ASH (Free ASH Whitepaper) abstract, data from 26 patients in the SAVE trial were reported (data cutoff [DCO]: July 2024).

During the oral session at the ASH (Free ASH Whitepaper) meeting, data from 33 patients were presented (DCO: November 2024). The median age of patients enrolled in the trial was 35 (range 12-81), and 16 patients (49%) had KMT2Ar, 12 patients (36%) had mNPM1, and five patients (15%) had NUP98r. Patients had received a median of three (range: 1-5) prior lines of therapy; 58% had prior venetoclax, 36% had prior hematopoietic stem cell transplantation (HSCT), and 6% had received a prior menin inhibitor.

The all-oral combination resulted in high rates of remission in patients with KMT2Ar, mNPM1, and NUP98r with an overall response rate (ORR)1 of 82% (27/33) and a CR/CRh rate of 48% (16/33). In patients with minimal residual disease (MRD) status available, 65% (17/26) who achieved a response were MRD negative, and among patients who achieved a CR/CRh response, 88% (14/16) were MRD negative. 39% (13/33) of patients proceeded to HSCT following this combination, with 54% (7/13) of patients resuming revumenib post-HSCT.

With a median follow-up of 9.3 months (N=33), the 6-month overall survival (OS) was 68% (95% CI: 47%, 80%); median OS was not reached. The median duration of CR/CRh response was also not reached.

The combination was generally well tolerated in this population. The most common (>20%) Grade 3 or higher treatment-emergent adverse events (TEAEs) were febrile neutropenia (33%) and lung infection (33%). Grade 3 treatment-emergent differentiation syndrome (DS) was observed in one patient (3%), with no Grade 4 or Grade 5 events. Grade 3 treatment-emergent QTc prolongation was observed in two patients (6%) and Grade 4 was observed in one patient (3%) with no Grade 5 events.

"The latest SAVE data show high efficacy and the ability to combine revumenib with venetoclax and hypomethylating agents, which highlights the potential for this combination to become a treatment for patients with acute leukemias that are susceptible to menin inhibition," said Ghayas C. Issa, M.D., Associate Professor of Leukemia at The University of Texas MD Anderson Cancer Center. "In particular, the high rates of overall response, MRD negativity, and HSCT in the R/R cohort are very encouraging, as well as the initial duration of response and overall survival data. These promising data underpin our excitement to expand the SAVE trial to evaluate the combination in newly diagnosed AML patients who are older or unfit for intensive chemotherapy."

Data from Phase 2 Portion of the AUGMENT-101 Trial of Revumenib in R/R KMT2Ar Acute Leukemia

A larger data set with longer follow-up data (DCO: February 2024) from the pivotal Phase 2 portion of the AUGMENT-101 trial of revumenib in R/R KMT2A-rearranged (KMT2Ar) acute leukemia were presented at the 66th ASH (Free ASH Whitepaper) Annual Meeting. This larger efficacy population is comprised of 97 patients, including the 57 patients from the previously reported Phase 2 protocol-defined interim efficacy analysis (DCO: July 2023).

As described in the previously announced ASH (Free ASH Whitepaper) abstract, the CR+CRh rate was 23% (22/97), CRc was 42% (41/97), and ORR was 64% (62/97) among the 97 efficacy evaluable patients. In patients with MRD results available, 61% (11/18) of CR/CRh responders and 58% (21/36) of CRc responders achieved MRD negativity. Of the 62 patients who achieved ORR, 34% (21/62) proceeded to HSCT and nine resumed revumenib post-HSCT.

During the oral session at the ASH (Free ASH Whitepaper) meeting, the Company presented additional data from this larger data set showing that responses were observed across all major subgroups, including heavily pretreated patients, patients with prior venetoclax exposure, and patients of all ages. The updated analyses also show that of the 21 responders who proceeded to HSCT, 67% (14/21) went to transplant in CRc [38% (8/21) in CR/CRh and 29% (6/21) in CRp/CRi] and 33% (7/21) went to transplant in MLFS. Of the patients who proceeded to transplant in CRc and had MRD results available, 82% (9/11) were MRD negative.

Time to response was rapid with a median time to ORR of 1.0 months (range: 0.9-3.1) and median time to CR/CRh of 2.0 months (range: 0.9-4.6). As previously reported, the median duration of CR/CRh was 6.4 months among the 22 CR/CRh responders. Of note, with seven months of additional follow-up, the median duration of CR/CRh extended to 13 months among the 13 CR/CRh responders included in the interim analysis presented at the ASH (Free ASH Whitepaper) Annual Meeting in 2023.

In this larger data set, which includes 116 patients in the safety population, revumenib was generally well tolerated and the safety profile was consistent with the Company’s previously reported data. Treatment-related adverse events (TRAEs) and treatment-emergent adverse events (TEAEs) leading to treatment discontinuation were low at 5% (6/116) and 14% (16/116), respectively. The most common Grade 3 or higher TEAEs were consistent with previously reported data. Grade 3 treatment-emergent DS was observed in 14% (16/116) of patients and one patient (1%) experienced a Grade 4 DS. Grade 3 treatment-emergent QTc prolongation was observed in 13% (15/116) of patients, with no Grade 4 or Grade 5 events. No patients discontinued treatment due to differentiation syndrome, QTc prolongation, or cytopenias.

Initial Results from INTERCEPT Platform Trial of Revumenib as Pre-Emptive Therapy for MRD Positive AML

INTERCEPT is an investigator-sponsored platform trial evaluating the use of novel therapies, including revumenib, to target MRD and early relapse in AML. This proof-of-concept trial is exploring whether targeting MRD in patients with AML may be an effective approach to maintaining patients in first or second remission.

As of the latest data cutoff, 14 patients with MRD relapse (13 with mNPM1 and one with KMT2Ar) were enrolled in the safety cohort and received revumenib. The median age was 56 years; 12 were in first remission and two were in second remission. Prior to starting revumenib treatment, two patients received venetoclax-based treatment and 12 received prior intensive chemotherapy-based treatment as their frontline therapy. In the safety cohort (N=14), the most common (>10%) Grade 3 or higher TEAEs were neutropenia, thrombocytopenia, and QTc interval prolongation. There were no reports of DS, and no Grade 5 events.

Among the 11 efficacy evaluable mNPM1 patients who received revumenib, 54% (6/11) patients had MRD reduction at any time, including 36% (4/11) who achieved MRD negativity. These initial data support the further evaluation of revumenib as a novel approach to targeting MRD relapse.

Copies of the ASH (Free ASH Whitepaper) presentations are available in the Publications and Meeting Presentations section of Syndax’s website.

Syndax Corporate Event

Data presented by the Company at the 66th ASH (Free ASH Whitepaper) Annual Meeting from both the Revuforj (revumenib) and Niktimvo (axatilimab-csfr) clinical programs will be highlighted at the Company’s investor event on Monday, December 9, 2024 at 7:00 a.m. PT/10:00 a.m. ET. The live audio webcast and accompanying slides for the event may be accessed through the Events & Presentations page in the Investors section of the Company’s website or directly through the meeting link here.

For those unable to participate in the conference call or webcast for the event, 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 in adult and pediatric patients one year and older.

Revumenib is in development for the treatment of R/R acute myeloid leukemia (AML) with a nucleophosmin 1 mutation (mNPM1). Positive pivotal data from the AUGMENT-101 trial in this population with revumenib as a monotherapy were recently reported. The Company expects to file a supplemental NDA filing for revumenib in R/R mNPM1 AML in the first half of 2025. Additionally, multiple trials of revumenib in combination with standard-of-care agents in mNPM1 AML or KMT2A-rearranged acute leukemia are ongoing across the treatment landscape, including in newly diagnosed patients.

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

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.

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, and/or hypotension. In clinical trials, DS occurred in 39 (29%) of 135 patients treated with Revuforj. DS was Grade 3 or 4 in 13% of patients and fatal in one. The median time to onset was 10 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: In the clinical trials, QTc interval prolongation was reported as an adverse reaction in 39 (29%) of 135 patients treated with Revuforj. QTc interval prolongation was Grade 3 in 12% of patients. The heart-rate corrected QT interval (using Fridericia’s method) (QTcF) was greater than 500 msec in 8%, and the increase from baseline QTcF was greater than 60 msec in 18%. Revuforj dose reduction was required for 5% of patients due to QTc interval prolongation. QTc prolongation occurred in 16% of the 31 patients less than 17 years old, 33% of the 88 patients 17 years to less than 65 years old, and in 50% of the 16 patients 65 years or older.

Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to 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 4 (3%) patients who received Revuforj, including 2 with differentiation syndrome, 1 with hemorrhage, and 1 with sudden death.

Serious adverse reactions were reported in 99 (73%) patients. The most frequent serious adverse reactions (≥5%) were infection (24%), febrile neutropenia (19%), bacterial infection (17%), differentiation syndrome (12%), hemorrhage (9%), and thrombosis (5%).

The most common adverse reactions (≥20%) including laboratory abnormalities, were hemorrhage (53%), nausea (51%), phosphate increased (50%), musculoskeletal pain (42%), infection (41%), aspartate aminotransferase increased (37%), febrile neutropenia (35%), alanine aminotransferase increased (33%), parathyroid hormone intact increased (33%), bacterial infection (31%), diarrhea (30%), differentiation syndrome (29%), electrocardiogram QT prolonged (29%), phosphate decreased (25%), triglycerides increased (25%), potassium decreased (24%), decreased appetite (24%), constipation (23%), edema (23%), viral infection (23%), fatigue (22%), and alkaline phosphatase increased (21%).

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.

Pediatric: monitor bone growth and development in pediatric patients.

Geriatric: compared to younger patients, the incidences of QTc prolongation and edema were higher in patients 65 years and older.

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

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 WARNING.

About KMT2A-Rearranged Acute Leukemia

Rearrangements of the KMT2A gene (KMT2Ar) give rise to an aggressive form of acute leukemia that is associated with a very poor prognosis and high relapse rates. It is estimated that more than 95% of patients with KMT2Ar acute leukemia have a KMT2A translocation, a type of rearrangement that occurs when part of one chromosome breaks and fuses to a different chromosome.

In KMT2Ar acute leukemias, binding of KMT2A fusion proteins with the protein called menin drives the activation of a leukemogenic transcriptional pathway. Inhibition of the menin-KMT2A interaction has been shown to alter the transcription of multiple genes including differentiation markers. KMT2Ar AML and ALL have a rapid onset and quick progression that makes early identification of a KMT2A rearrangement critical. It is routinely diagnosed through currently available cytogenetic or molecular diagnostic techniques.

About Mutant NPM1 (mNPM1) Acute Myeloid Leukemia (AML)

Mutations in the NPM1 gene are the most common genetic alteration in adult AML and are observed in approximately 30% of cases. Patients with relapsed or refractory mNPM1 AML have a poor prognosis and high unmet need. Similar to KMT2A-rearranged acute leukemia, mNPM1 AML is highly dependent on the expression of specific developmental genes shown to be negatively impacted by inhibitors of the menin-KMT2A interaction. mNPM1 AML is routinely diagnosed through currently available screening techniques. There are currently no approved targeted therapies for mNPM1 AML.