On December 8, 2024 CStone Pharmaceuticals ("CStone", HKEX: 2616), an innovation-driven biopharmaceutical company focused on the research and development of anti-cancer therapies, reported the presentation of the latest clinical data for CS5001, an anti-ROR1 ADC and one of the leading assets in CStone Pipeline 2.0, at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, CStone Pharmaceauticals, DEC 8, 2024, View Source [SID1234648881]). These data highlight the compound’s potential as a treatment for lymphoma.

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Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an embryonic tyrosine kinase-like molecule implicated in multiple pathways promoting oncogenic signaling. ROR1 is overexpressed at high frequency in hematological malignancies and in a broad spectrum of solid tumors while lower or absent in normal tissues, which makes ROR1 an attractive anti-cancer therapy target. CS5001 is so far the first anti-ROR1 ADC known to show clinical anti-tumor activity in both solid tumors and lymphomas.

Dr. Jason Yang, CEO, President of R&D, and Executive Director at CStone, commented,"We are very encouraged that CS5001 continues to demonstrate potent anti-tumor activity and manageable safety and tolerability in the ongoing clinical study. The data presented at ASH (Free ASH Whitepaper) further validate CS5001’s potential, particularly as a monotherapy for patients with advanced lymphomas, most of whom had failed at least 3 prior lines of therapy. We observe encouraging anti-tumor activity in both HLs and NHLs, especially the ORR of 76.9% among the 13 evaluable patients with advanced B-cell lymphoma at DL8 (125 μg/kg). As we move forward with our Phase 1b study, we will further evaluate and optimize the dose. Given CS5001’s initial efficacy in both aggressive and indolent lymphomas, we are confident in its broad clinical potential and significant market competitiveness. We remain committed to accelerate the clinical development of CS5001 in bringing this novel therapy to lymphoma patients as soon as possible."

Patient baseline characteristics

A total of 33 patients with advanced B-cell lymphoma were enrolled, including 17 diffuse large B-cell lymphoma (DLBCL), 11 HLs, 2 follicular lymphoma (FL), 1 mantle cell lymphoma (MCL), 1 marginal zone lymphoma (MZL), and 1 high-grade B-cell lymphoma (HGBCL).

Among them, 84.8% were Asian, and the rest were non-Asian. 81.8% of the patients had received at least 3 prior lines of systemic anti-tumor therapy. In the DL8 cohort, patients who had previously received CART and hematopoietic stem cell transplantation therapy each accounted for over 20%.

Safety and tolerability

Dose escalation has been completed and no DLT has been reported up to DL10 so far.

Efficacy Results

CS5001 demonstrated encouraging anti-tumor activity in B-cell lymphomas, with an ORR of 48.4% across all dose levels; a notably higher ORR of 76.9% was observed at DL8 (125 μg/kg) among 13 evaluable patients.

Hodgkin Lymphoma (HL): objective responses were observed from effective dose of DL5 (50 μg/kg) and above, including 3 complete responses (CRs) and 3 partial responses (PRs) among 10 evaluable patients at DLs 5-9 (ORR: 60.0%). 2 CRs and 1 PR were observed at DL8 (125 μg/kg) among 3 evaluable patients.
Non-Hodgkin Lymphoma (NHL): objective responses were observed from effective dose of DL7 (100 μg/kg) and above, including 3 CRs (2 DLBCL and 1 MCL) and 6 PRs (3 DLBCL, 1 MZL, 1 HGBC and 1 FL) among 16 evaluable patients at DLs 7-9 (ORR: 56.3%). A notably higher ORR of 70.0% was observed at DL8 (125 μg/kg) among 10 evaluable patients.
The global multicenter Phase 1 trial of CS5001 are currently in progress in the United States, Australia, and China. Dose escalation has been completed. Backfilling at DL8 (125 μg/kg) or DL9 (156μg/kg) is still ongoing. A Phase 1b dose-expansion study with potential for registration across multiple tumor types is expected to be initiated soon.

Conference Call and Webcast

CStone will host a conference call and webcast to discuss this announcement on December 9, 2024, at 10:00 AM Beijing Time.

The conference call can be accessed via this link: View Source

About CS5001 (ROR1 ADC)

CS5001 is a clinical-stage antibody-drug conjugate ("ADC") targeting ROR1 (receptor tyrosine kinase-like orphan receptor 1). CS5001 has been uniquely designed with proprietary tumor-cleavable linker and pyrrolobenzodiazepine ("PBD") prodrug. Only after reaching the tumor, the linker and prodrug are cleaved to release the PBD toxin, resulting in lethal DNA cross-links in cancer cells. The use of the linker plus PBD prodrug effectively helps address the toxicity associated with traditional PBD payloads, leading to a better safety profile. CS5001 has demonstrated complete tumor suppression in several preclinical cancer models and demonstrated favorable serum half-life and pharmacokinetic characteristics. CS5001 is a promising candidate drug with precision treatment potential in both hematologic tumors and malignant solid tumors. Additionally, CS5001 utilizes site-specific conjugation for a precise drug antibody ratio of which enables homogeneous production and large-scale manufacturing.

In October 2020, CStone signed a licensing agreement with LigaChem Biosciences, Inc. (LCB) for the development and commercialization of CS5001 which was originally generated by collaboration of LCB and ABL Bio, both South Korea-based leading biotech companies. Under the agreement, CStone obtains the exclusive global right to develop and commercialize CS5001 outside the Republic of Korea.

Preliminary data from the first-in-human study presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting demonstrated that CS5001 is well-tolerated and exhibits encouraging anti-tumor activity across various dose levels in patients with heavily pre-treated advanced solid tumors and lymphomas.

On December 7, 2024 bluebird bio, Inc. (Nasdaq: BLUE) reported updated data from patients with beta-thalassemia who require regular blood transfusions treated with betibeglogene autotemcel (beti-cel, approved commercially as ZYNTEGLO) in clinical studies (Press release, bluebird bio, DEC 7, 2024, View Source [SID1234648864]). The data was presented today at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

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"Updated follow-up data of up to 10 years showed that patients treated with beti-cel in clinical trials experienced durable transfusion independence and normal or near-normal hemoglobin, regardless of genotype and age, and a continued favorable safety profile", said Richard Colvin, M.D., Ph.D., chief medical officer, bluebird bio. "We are deeply grateful for the ongoing commitment of our investigators, patients, and study participants. Our collective efforts are not only advancing the field of gene therapy but also providing new hope and possibilities for individuals with severe genetic diseases."

"Data at ASH (Free ASH Whitepaper) demonstrate the durability of beti-cel through 10 years of long-term follow-up, giving additional confidence in that the transformational outcomes observed in parent studies are sustained over time," said Alexis Thompson, MD, MPH, Chief of the Division of Hematology at Children’s Hospital of Philadelphia, which is a Qualified Treatment Center for ZYNTEGLO. "These long-term data demonstrate beti-cel’s continued positive impact on iron management outcomes over time, which can help inform treatment decisions by clinicians who are now using this therapy in the real-world setting."

Betibeglogene Autotemcel (beti-cel) Gene Addition Therapy results in durable Hemoglobin A (HbA) Production with up to 10 Years of Follow-Up in Participants with Transfusion-Dependent β-Thalassemia (Poster #2194)

Long-term outcomes with beti-cel in adult and pediatric patients with TDT were presented in a poster session. The data focused on 63 adult and pediatric study participants who had received beti-cel in a Phase 1/2 or Phase 3 study. Two participants had 10 years of follow-up, and 51 (81.0%) participants had 5 or more years of follow-up. Additionally, iron status was assessed in study participants who achieved TI and discontinued chelation therapy. Results showed that majority of participants treated with beti-cel achieved TI. All participants achieved platelet and neutrophil engraftment. Specific findings showed:

Of 63 patients, 52 (90.2% in Phase 3 studies and 68.2% in Phase 1/2 studies) achieved TI. All except one patient maintained TI through last follow-up. The median weighted average hemoglobin during TI was 10.2 mg/dL for Phase 1/2 studies and 11.2 mg/dL for Phase 3 studies. Achievement and maintenance of TI and median weighted average hemoglobin were similar across ages and genotypes.
Study participants treated with beti-cel who achieved and maintained TI demonstrated effective restoration of iron homeostasis over time and reduced iron management burden. Among participants who achieved TI, improvements in serum ferritin and liver iron concentration were sustained through month 60. 28/37 (75.7%) study participants who achieved TI in Phase 3 studies are no longer undergoing iron chelation therapy.
Both adult and pediatric health-related quality of life scores (HRQoL) remained above the normative population mean up to 60 months. All 26 participants who achieved TI and completed a questionnaire reported an overall benefit with beti-cel.
The safety profile was consistent with known side effects of hematopoietic stem cell collection and the busulfan conditioning regimen. None of the study participants had a fatal event. No beti-cel–related serious adverse events were reported more than 2 years after infusion through last follow-up. No malignancies, insertional oncogenesis or vector-derived replication-competent lentivirus were reported in any study participants.
Beti-cel was approved by the FDA in August 2022 and is commercially available in the United States as ZYNTEGLO.

About ZYNTEGLO (betibeglogene autotemcel) or beti-cel

ZYNTEGLO is a first-in-class, one-time ex-vivo LVV gene therapy approved for the treatment of beta-thalassemia in adult and pediatric patients who require regular red blood cell transfusions. ZYNTEGLO works by adding functional copies of a modified form of the beta-globin gene (βA-T87Q-globin gene) into a patient’s own hematopoietic (blood) stem and progenitor cells to enable the production of a modified functional adult hemoglobin (HbAT87Q). Once a patient has the βA-T87Q-globin gene, they have the potential to increase ZYNTEGLO-derived adult hemoglobin (HbAT87Q) and total hemoglobin to normal or near normal levels that can eliminate the need for regular red blood cell (RBC) transfusions.

Indication

ZYNTEGLO is indicated for the treatment of adult and pediatric patients with beta-thalassemia who require regular red blood cell (RBC) transfusions.

Important Safety Information

Delayed Platelet Engraftment

Delayed platelet engraftment has been observed with ZYNTEGLO treatment. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia; 15% of patients had ≥ Grade 3 decreased platelets on or after Day 100.

Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise.

Risk of Neutrophil Engraftment Failure

There is a potential risk of neutrophil engraftment failure after treatment with ZYNTEGLO. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 500 cells/microliter obtained on different days by Day 43 after infusion of ZYNTEGLO. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with ZYNTEGLO, provide rescue treatment with the back-up collection of CD34+ cells.

Risk of Insertional Oncogenesis

There is a potential risk of LVV mediated insertional oncogenesis after treatment with ZYNTEGLO.

Patients treated with ZYNTEGLO may develop hematologic malignancies and should be monitored lifelong. Monitor for hematologic malignancies with a complete blood count (with differential) at Month 6 and Month 12 and then at least annually for at least 15 years after treatment with ZYNTEGLO, and integration site analysis at Months 6, 12, and as warranted.

In the event that a malignancy occurs, contact bluebird bio at 1 833-999-6378 for reporting and to obtain instructions on collection of samples for testing.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of ZYNTEGLO. The dimethyl sulfoxide (DMSO) in ZYNTEGLO may cause hypersensitivity reactions, including anaphylaxis.

Anti-retroviral and Hydroxyurea Use

Patients should not take prophylactic HIV anti-retroviral medications or hydroxyurea for at least one month prior to mobilization, or for the expected duration for elimination of the medications, and until all cycles of apheresis are completed. If a patient requires anti-retrovirals for HIV prophylaxis, then confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells.

Interference with Serology Testing

Patients who have received ZYNTEGLO are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a false-positive test for HIV. Therefore, patients who have received ZYNTEGLO should not be screened for HIV infection using a PCR‑based assay.

Adverse Reactions

The most common non-laboratory adverse reactions (≥20%) were mucositis, febrile neutropenia, vomiting, pyrexia, alopecia, epistaxis, abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus. The most common Grade 3 or 4 laboratory abnormalities (>50%) include neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia.

Drug Interactions

Drug-drug interactions between iron chelators and the myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of conditioning. The prescribing information for the iron chelator(s) and the myeloablative conditioning agent should be consulted for the recommendations regarding co-administration with CYP3A substrates.

Some iron chelators are myelosuppressive. After ZYNTEGLO infusion, avoid use of these iron chelators for 6 months. If iron chelation is needed, consider administration of non-myelosuppressive iron chelators. Phlebotomy can be used in lieu of iron chelation, when appropriate.

Pregnancy/Lactation

Advise patients of the risks associated with conditioning agents, including on pregnancy and fertility. ZYNTEGLO should not be administered to women who are pregnant, and pregnancy after ZYNTEGLO infusion should be discussed with the treating physician.

ZYNTEGLO is not recommended for women who are breastfeeding, and breastfeeding after ZYNTEGLO infusion should be discussed with the treating physician.

Females and Males of Reproductive Potential

A negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before ZYNTEGLO administration.

Women of childbearing potential and men capable of fathering a child should use an effective method of contraception (intra uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of ZYNTEGLO.

Advise patients of the option to cryopreserve semen or ova before treatment if appropriate.

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.

On December 7, 2024 HanX Biopharmaceuticals reported presented poster presentations at the 2024 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting , held in San Diego, CA, USA, December 7–10 : " A Phase IB Clinical Trial INVESTIGATING the Safety, Tolerability, and Pharmacokinetics of HX009," and " A Novel BsAb Dual Targeting PD-1xCD47 in Patients with EBV+ Non-Hodgkin Lymphoma (NHL) (Press release, HanX Biopharmaceuticals, DEC 7, 2024, View Source [SID1234655963]).

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HX009 is a clinical-stage investigational anti-PD-1 and anti-CD47 bifunctional large molecule cancer immunotherapy independently developed by Hans-Eti. Two Phase I single-agent dose-escalation trials in solid tumors and one in lymphoma have been successfully completed in Australia and China. Single-agent data demonstrated favorable safety and tolerability, with single-agent anti-tumor efficacy observed in multiple indications, including lymphoma. Existing data support advancement to Phase II and combination trials. The company is currently conducting multicenter Phase II trials in multiple clinical indications. This poster presentation reported data from the ongoing Phase IB lymphoma program in the EBV+ NHL subgroup. HX009 demonstrated a favorable safety profile at a single dose of 10 mg/kg Q2W . Preliminary efficacy assessment in 14 patients with refractory/relapsed EBV+ NHL showed three partial responses and four sustained-release (SD) outcomes.

Dr. Henry Li, CEO/CSO of Hans Ait , and Dr. Zhang Lei, CMO, attended this year’s annual meeting and said, "We are very pleased to have the opportunity to report the results of this study to everyone at this annual meeting. Currently, there is no unified standard treatment for EBV+NHL. In clinical practice, the treatment of EBV+ and EBV- basically uses similar drugs with poor efficacy. In this clinical trial, we have observed that HX009 monotherapy can cause objective remission, suggesting the therapeutic potential of HX009 in this indication. We look forward to rapidly advancing this clinical trial and providing patients with new treatment options as soon as possible."

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.