On December 9, 2024 Sumitomo Pharma America, Inc. (SMPA) reported new clinical data supporting further development of nuvisertib, an investigational small molecule being researched for the treatment of relapsed/refractory myelofibrosis (MF), and enzomenib, an investigational oral small molecule being researched for relapsed/refractory acute leukemia, at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (Press release, Sumitomo Pharmaceuticals, DEC 9, 2024, View Source [SID1234648938]).

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Preliminary data presented from the ongoing Phase 1/2 study of nuvisertib monotherapy (N=74) in patients with relapsed/refractory MF show nuvisertib was well tolerated with no dose-limiting toxicities (DLTs). Preliminary data in evaluable patients showed clinical activity including spleen volume reduction (SVR25 of 22.2%), symptom reduction (TSS50 of 44.4%), and bone marrow fibrosis (47.8% patients) and hemoglobin (25% patients) and platelet count (27.6% patients) improvement. Additional data presented show nuvisertib treatment led to significant cytokine modulation (e.g. EN-RAGE, IL-18, MIP-1β, and adiponectin) over time correlating with spleen and symptom responses. The global study has been expanded to evaluate nuvisertib add-on to ruxolitinib, the first approved Janus-associated kinase (JAK) inhibitor, and in combination with momelotinib, a recently approved JAK inhibitor for MF patients with anemia, to assess safety and potential clinical activity.

New preliminary clinical and translational data from the enzomenib Phase 1/2 study were also presented at the conference by Dr. Joshua Zeidner from the University of North Carolina. The safety population included 84 total patients with acute leukemia, most of whom (94%, 79/84) had acute myeloid leukemia (AML). The study population was diverse, with 47.6% non-white (40/84), and also heavily pre-treated, with a median of 3 prior regimens.

In these patients, enzomenib was administered twice daily in continuous 28-day study cycles at dose levels from 40 mg BID up to 300 mg BID. Enzomenib was well tolerated with low overall rates of drug-related adverse events and no dose limiting toxicity (DLT) reported. Differentiation syndrome was reported in 10.7% of patients but did not result in patient deaths nor did it require permanent discontinuations of enzomenib.

Also presented were clinical activity results from the dose optimization cohorts at the dose levels of 200 mg BID and 300 mg BID. The data included results from all patients with KMT2A rearrangement (KMT2Ar) or NPM1 mutation (NPM1m) who had received at least one dose of enzomenib and who had not received a menin inhibitor previously.

In 23 patients with KMT2Ar, the Objective Response Rate (ORR) using ELN 2017 criteria was 65.2% (15/23) and the proportion to achieve CR+CRh was 30.4% (7/23). In the subset of patients with KMT2Ar to receive 300 mg BID (n = 15), the ORR was 73.3% (11/15) and CR+CR was 40% (6/15). In the 17 total patients with NPM1 mutation (NPM1m) who received 200 mg BID or 300 mg BID, the ORR was 58.8% (10/17) and the proportion to achieve CR+CRh was 47.1% (8/17). The 400 mg BID dose optimization cohort is ongoing, with 21 patients enrolled as of the clinical cut-off and data planned for presentation at a future conference.

These encouraging clinical activity results combined with an excellent safety profile suggest that enzomenib may play an important role in the treatment of patients with relapsed/refractory acute leukemia with KMT2A rearrangement or NPM1 mutation.

"These data signal growing momentum in our oncological pipeline and an important milestone in our development of new treatments for relapsed/refractory MF and acute leukemia," said Tsutomu Nakagawa, Ph.D., President and Chief Executive Officer of SMPA. "With these promising results in hand, we remain committed to advancing nuvisertib and enzomenib as we believe our investigational therapies may have the potential to improve the lives of patients living with these critical cancers who do not respond to currently available therapeutics."

MF is a rare type of blood cancer that is characterized by the buildup of fibrous tissue in the bone marrow, which can affect the production of blood cells. This buildup is caused by a dysregulation in the JAK signaling pathway. MF is a serious and rare disease with 0.7 new cases per 100,000 people worldwide each year.4

Leukemia is a type of cancer that forms in blood-forming tissue, characterized by the uncontrolled growth of blood cells, usually white blood cells, in the bone marrow. Acute leukemia, a form of leukemia, requires immediate treatment as blood cells multiply rapidly leading to a sudden onset of symptoms.1 Approximately 30% of AML patients have NPM1 mutations2 and 5-10% of AML patients have KMT2A (MLL) rearrangements.3

"Patients and families living with incurable cancers of MF and AML are in need of new treatment options – and we are encouraged by the promising clinical activity for both nuvisertib and enzomenib," said Jatin Shah, M.D., Chief Medical Officer, Oncology, SMPA. "This additional preliminary data reinforces the strong potential for PIM1 inhibition in myelofibrosis, and for menin inhibitors in acute leukemia."

About enzomenib (DSP-5336)
Enzomenib (DSP-5336) is an investigational small molecule inhibitor of the menin and mixed-lineage leukemia (MLL) protein interaction. Menin is a scaffold nuclear protein which plays key roles in gene expression and protein interactions involved in many biological pathways, including cell growth, cell cycle, genomic stability, and hematopoiesis.5,6 In preclinical studies, enzomenib has shown selective growth inhibition in human acute leukemia cell lines with KMT2A (MLL) rearrangements or NPM1 mutations.5,7 Enzomenib reduced the expression of the leukemia-associated genes HOXA9 and MEIS1, and increased the expression of the differentiation gene CD11b in human acute leukemia cell lines with MLL rearrangements and NPM1 mutation.8,9 The safety and efficacy of enzomenib is currently being clinically evaluated in a Phase 1/2 dose escalation/dose expansion study in patients with relapsed or refractory acute leukemia (NCT04988555). The FDA granted Orphan Drug Designation for enzomenib for the indication of acute myeloid leukemia in June 2022. The FDA granted Fast Track Designation for enzomenib for the indication of relapsed or refractory acute myeloid leukemia with MLLr or NPM1m in June 2024. The PMDA granted Orphan Drug Designation for enzomenib for the indication of relapsed or refractory acute myeloid leukemia with MLLr or NPM1m in September 2024.

About nuvisertib (TP-3654)
Nuvisertib (TP-3654) is an oral investigational selective inhibitor of PIM1 kinase, which has shown potential antitumor and antifibrotic activity through multiple pathways, including induction of apoptosis in preclinical models.10,11 Nuvisertib was observed to inhibit proliferation and induce apoptosis in murine and human hematopoietic cells expressing the clinically relevant JAK2V617F mutation.10 Nuvisertib alone and in combination with ruxolitinib showed white blood cell and neutrophil count normalization, and also reduced spleen size and bone marrow fibrosis in JAK2V617F and MPLW515L murine models of myelofibrosis.11 The safety and efficacy of nuvisertib is currently being clinically evaluated in a Phase 1/2 study in patients with intermediate and high-risk myelofibrosis (NCT04176198). The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation for nuvisertib for the indication of myelofibrosis in May 2022. The PMDA granted Orphan Drug Designation for nuvisertib for the indication of myelofibrosis in November 2024.

On December 9, 2024 TransThera Sciences Nanjing, Inc. (the "TransThera") reported the poster presentation at the 2024 European Society For Medical Oncology (ESMO) (Free ESMO Whitepaper) Asia Congress to discuss the clinical study of tinengotinib in combination with atezolizumab (Tecentriq) in biliary tract carcinoma (BTC) (Press release, TransThera Biosciences, DEC 9, 2024, View Source [SID1234648937]).

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Title: Tinengotinib (TT-00420) in Combination with Atezolizumab in Chinese Patients with Biliary Tract Carcinoma (BTC): Efficacy and Safety Results from a Phase Ib/II Study

Poster number: 140P

Immune-checkpoint inhibitor (ICI) combined with chemotherapy have been approved as first-line therapy for BTC. However, no standard of care has been established after first-line treatment and the survival of the patients is short, there is a huge unmet clinical need. Tinengotinib is a novel multi-kinase inhibitor. It may play a role of synergistic effect when combined with ICI. The efficacy and safety data of tinengotinib in combination with atezolizumab in Chinese BTC patients has been explored in a phase Ib/II study.

Results:

As of September 26, 2024, a total of 31 heavily pretreated advanced BTC patients were enrolled and treated with tinengotinib plus atezolizumab. 71.0% were priorly treated with at least one immunotherapy.

Promising efficacy:

A total of 20 intrahepatic cholangiocarcinoma patients were efficacy evaluable. The objective response rate (ORR) and disease control rate (DCR) were 25.0% and 80.0%, the median progression free survival (mPFS) reached 8.77 months and the 12-month overall survival (OS) rate was 70.1%.
A total of 28 cholangiocarcinoma patients were efficacy evaluable. The ORR and DCR were 25.0% and 75.0%, the mPFS reached 5.72 months and the 12-month OS rate was 64.8%.
All 31 BTC patients were efficacy evaluable. The ORR and DCR were 22.6% and 74.2%, the mPFS reached 4.11 months and the 12-month OS rate was 61.8%.
Similar efficacy was observed regardless of prior ICI(s) therapy.
Good safety and tolerability:

No DLT was observed in the dose escalation phase.
The combination therapy was generally well tolerated in heavily pre-treated BTC patients.
These encouraging results suggest the combination therapy may have synergistic effect in treating some solid tumor such as BTC, and support the further exploration to evaluate the safety and efficacy of tinengotinib plus ICI in BTC patients who were previously treated with or without ICI therapy.

About Tinengotinib

Tinengotinib is an internally discovered, global phase III multi-kinase inhibitor that exerts antitumor effects by targeting FGFRs and VEGFRs, mitotic kinases Aurora A/B and Janus kinases (JAK). Ongoing clinical trials in the US and China have revealed the potential of tinengotinib to be efficacious in various solid tumors. It was granted the Orphan Drug Designation (ODD) and Fast Track Designation (FTD) by the FDA for the treatment of CCA, the Breakthrough Therapy Designation (BTD) by NMPA in China, the Orphan Drug Designation (ODD) for the treatment of biliary tract cancer by EMA.

On December 9, 2024 AbbVie (NYSE: ABBV) reported new results from two ongoing clinical trials evaluating epcoritamab, a CD3xCD20 bispecific T-cell-engaging antibody administered subcutaneously, in adult patients with diffuse large B-cell lymphoma (DLBCL) at the 66th Annual Meeting and Exposition of the American Society of Hematology (ASH) (Free ASH Whitepaper) (Press release, AbbVie, DEC 9, 2024, View Source [SID1234648936]).

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Arm 1 of the Phase 1b/2 EPCORE NHL-2 multi-arm trial evaluates fixed-duration investigational epcoritamab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated high-risk DLBCL patients (n=46) with International Prognostic Index (IPI) scores of 3 to 5 (Abstract #581).1 Results from this arm of the study showed an overall response rate (ORR) of 100% and a complete response (CR) rate of 87%. Among complete responders, an estimated 83% remained in remission after two years. Separately, three-year follow-up results from the Phase 2 EPCORE NHL-1 trial (Abstract #4480),2 evaluating epcoritamab monotherapy in challenging-to-treat adult patients (n=157) with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) after two or more lines of systemic therapy showed that among the 41% of patients who achieved a CR, an estimated 52% were still responding at three years (median CR duration: 36.1 months).

DLBCL is the most common type of non-Hodgkin’s lymphoma (NHL) worldwide, accounting for approximately 25-30% of all NHL cases.3,4 In the U.S., there are approximately 25,000 new cases of DLBCL diagnosed each year.5 DLBCL can arise in lymph nodes as well as in organs outside of the lymphatic system, occurs more commonly in the elderly and is slightly more prevalent in men.6,7 DLBCL is a fast-growing type of NHL, a cancer that develops in the lymphatic system and affects B-cell lymphocytes, a type of white blood cell. For many people living with DLBCL, their cancer either relapses, which means it may return after treatment, or becomes refractory, meaning it does not respond to treatment. Although new therapies have become available, treatment management can remain a challenge.6,8

"The results from these epcoritamab studies help provide confidence in our ongoing Phase 3 trials and highlight our commitment to advancing treatment standards for this challenging type of cancer," said Mariana Cota Stirner, M.D., Ph.D., vice president, therapeutic area head for hematology, AbbVie. "We remain dedicated to exploring epcoritamab both as a monotherapy and in combination with other therapies for earlier lines of treatment, as well as establishing it as a core therapy across B-cell malignancies."

EPCORE NHL-2 Results in First-Line DLBCL (Abstract #581)
The EPCORE NHL-2 trial enrolled 46 evaluable patients considered to have high-risk DLBCL, identified by International Prognostic Index (IPI) scores of 3 to 5, a range associated with poor long-term outcomes. The IPI is a key tool used by oncologists to predict the prognosis of aggressive B-cell lymphomas.9 At screening, 35% of patients (n=16) had bulky disease (>10 cm), and 21% (n=6/28) had double-hit/triple-hit DLBCL, which are aggressive subtypes caused by major genetic mutations.

A minimal residual disease (MRD) analysis from blood samples (n=33) showed that 91% of patients achieved MRD negativity, indicating no detectable disease as defined by ctDNA.10

The most common treatment-emergent adverse events (TEAEs) were neutropenia (70%), anemia (69%), cytokine release syndrome (CRS 60%), fatigue (49%), nausea (47%), pyrexia (42%), and injection-site reaction (40%). Four patients (9%) discontinued epcoritamab due to TEAEs; fatal TEAEs occurred in two patients (COVID-19 and septic shock). CRS events were mostly low grade (45% Grade 1, 11% Grade 2, 4% Grade 3) and mainly occurred after the first full dose. All CRS cases resolved, and none led to discontinuation. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in two patients (one Grade 1; one Grade 2) and resolved in a median of 2.5 days without leading to discontinuation.

EPCORE NHL-1 Results in Third-Line LBCL (Abstract #4480)
Three-year follow-up results from the Phase 2 EPCORE NHL-1 trial evaluated epcoritamab monotherapy in 157 patients with R/R LBCL after two or more lines of prior therapy and showed that epcoritamab continues to deliver durable responses in challenging-to-treat patients. Additional data results include:

The ORR was 59%, and CR was 41%. Median duration of response was 20.8 months (95% CI, 13.0-32.0) and median duration of CR was 36.1 months (95% CI, 20.2 to not reached [NR]).
A MRD analysis from blood samples (n=119) showed that 45.4% of patients achieved MRD negativity, as defined by ctDNA.11
The most common TEAEs were CRS (51%; 32% Grade 1, 16% Grade 2, 3% Grade 3), fatigue (25%), and pyrexia (25%); CRS rates remained unchanged since prior reports. Fatal TEAEs were reported in 20 patients; 10 patients had Grade 5 COVID-19 (including COVID-19 pneumonia). 73% of patients who received epcoritamab for two or more years did not experience a Grade 3 or higher infection after two years (median follow-up after two years: 12.3 months). Incidence of Grade 3 or higher cytopenias was highest (27%) during the first eight weeks of treatment and rates were within 0-13% in subsequent 12-week time periods up to week 144. Immunoglobulin G levels decreased by a median of ~20% after the start of epcoritamab treatment (baseline median, 540.0 mg/dL) and remained stable over time.

"More first-line treatments for diffuse large B-cell lymphoma are needed, especially for patients with aggressive disease markers that may impact the efficacy of current standard first-line therapies," said Lorenzo Falchi, M.D., Lymphoma Specialist, Department of Medicine, Memorial Sloan Kettering Cancer Center. "The durable responses observed in the study suggest significant potential for this first-line epcoritamab-based combination."

Epcoritamab (approved under the brand name EPKINLY in the U.S. and Japan, and TEPKINLY in the EU) has received regulatory approval in certain lymphoma indications in several territories. Use of epcoritamab + R-CHOP in first-line DLBCL is not approved in the U.S. or in the EU or in any other territory. The safety and efficacy of epcoritamab for use as a combination therapy in DLBCL have not been established.

About the EPCORE NHL-2 Trial
EPCORE NHL-2 is a Phase 1b/2 open-label interventional trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics/biomarkers, immunogenicity, and preliminary efficacy of epcoritamab as a monotherapy and in combination with other standard of care agents in patients with B-cell non-Hodgkin’s lymphoma (B-NHL). The trial consists of two parts: Part 1 (Dose Escalation) and Part 2 (Dose Expansion). The primary objective of Part 1 is safety, and it includes Arms 1-5 and Arm 10. Part 2 includes all 10 arms (Arm 1-10) and the primary goal of all arms, except Arm 7, is preliminary efficacy. The primary endpoint was overall response rate (ORR) based on best overall response per Lugano criteria. MRD negativity was assessed as a secondary endpoint.

Arm 1 of the trial is epcoritamab plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‑CHOP) in adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL). More information on this trial can be found at View Source (NCT: 04663347).

About the EPCORE NHL-1 Trial
EPCORE NHL-1 is an open-label, multicohort, single-arm, Phase 1/2 trial of epcoritamab in participants with relapsed or refractory large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL). The trial was conducted at 88 sites across 15 countries and consisted of three parts: a Phase 1 first-in-human, dose escalation part; a Phase 2a expansion part; and a Phase 2a dose optimization part. More information on this trial can be found at View Source (NCT: 03625037).

About Epcoritamab
Epcoritamab is an IgG1-bispecific antibody created using Genmab’s proprietary DuoBody technology and administered subcutaneously. Genmab’s DuoBody-CD3 technology is designed to direct cytotoxic T cells selectively to elicit an immune response toward target cell types. Epcoritamab is designed to simultaneously bind to CD3 on T cells and CD20 on B cells and induces T-cell-mediated killing of CD20+ cells.12 Epcoritamab is being co-developed by Genmab and AbbVie as part of the companies’ oncology collaboration. The companies share commercial responsibilities in the U.S. and Japan, with AbbVie responsible for further global commercialization. Both companies will pursue additional international regulatory approvals for the investigational R/R FL indication and additional approvals for the R/R DLBCL indication. Genmab and AbbVie continue to evaluate the use of epcoritamab as a monotherapy, and in combination, across lines of therapy in a range of hematologic malignancies. This includes five ongoing Phase 3, open-label, randomized trials including a trial evaluating epcoritamab as a monotherapy in patients with R/R DLBCL compared to investigators choice chemotherapy (NCT04628494), a trial evaluating epcoritamab in combination with R-CHOP in adult patients with newly diagnosed DLBCL (NCT05578976), a trial evaluating epcoritamab in combination with rituximab and lenalidomide (R2) in patients with R/R FL (NCT05409066), a trial evaluating epcoritamab in combination with rituximab and lenalidomide (R2) compared to chemoimmunotherapy in patients with previously untreated FL (NCT06191744), and a trial evaluating epcoritamab in combination with lenalidomide compared to chemotherapy infusion in patients with R/R DLBCL (NCT06508658). The safety and efficacy of epcoritamab have not been established for these investigational uses.

EPKINLY (epcoritamab-bysp) U.S. INDICATIONS & IMPORTANT SAFETY INFORMATION

What is EPKINLY?
EPKINLY is a prescription medicine used to treat adults with certain types of diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, or follicular lymphoma (FL) that has come back or that did not respond to previous treatment after receiving 2 or more treatments. EPKINLY is approved based on patient response data. Studies are ongoing to confirm the clinical benefit of EPKINLY. It is not known if EPKINLY is safe and effective in children.

Important Warnings—EPKINLY can cause serious side effects, including:

Cytokine release syndrome (CRS), which is common during treatment with EPKINLY and can be serious or life-threatening. To help reduce your risk of CRS, you will receive EPKINLY on a step-up dosing schedule (when you receive 2 or 3 smaller step-up doses of EPKINLY before your first full dose during your first cycle of treatment), and you may also receive other medicines before and for 3 days after receiving EPKINLY. If your dose of EPKINLY is delayed for any reason, you may need to repeat the step-up dosing schedule.
Neurologic problems that can be life-threatening and lead to death. Neurologic problems may happen days or weeks after you receive EPKINLY.
People with DLBCL or high-grade B-cell lymphoma should be hospitalized for 24 hours after receiving their first full dose of EPKINLY on day 15 of cycle 1 due to the risk of CRS and neurologic problems.

Tell your healthcare provider or get medical help right away if you develop a fever of 100.4°F (38°C) or higher; dizziness or lightheadedness; trouble breathing; chills; fast heartbeat; feeling anxious; headache; confusion; shaking (tremors); problems with balance and movement, such as trouble walking; trouble speaking or writing; confusion and disorientation; drowsiness, tiredness or lack of energy; muscle weakness; seizures; or memory loss. These may be symptoms of CRS or neurologic problems. If you have any symptoms that impair consciousness, do not drive or use heavy machinery or do other dangerous activities until your symptoms go away.

EPKINLY can cause other serious side effects, including:

Infections that may lead to death. Your healthcare provider will check you for signs and symptoms of infection before and during treatment and treat you as needed if you develop an infection. You should receive medicines from your healthcare provider before you start treatment to help prevent infection. Tell your healthcare provider right away if you develop any symptoms of infection during treatment, including fever of 100.4°F (38°C) or higher, cough, chest pain, tiredness, shortness of breath, painful rash, sore throat, pain during urination, or feeling weak or generally unwell.
Low blood cell counts, which can be serious or severe. Your healthcare provider will check your blood cell counts during treatment. EPKINLY may cause low blood cell counts, including low white blood cells (neutropenia), which can increase your risk for infection; low red blood cells (anemia), which can cause tiredness and shortness of breath; and low platelets (thrombocytopenia), which can cause bruising or bleeding problems.
Your healthcare provider will monitor you for symptoms of CRS, neurologic problems, infections, and low blood cell counts during treatment with EPKINLY. Your healthcare provider may temporarily stop or completely stop treatment with EPKINLY if you develop certain side effects.

Before you receive EPKINLY, tell your healthcare provider about all your medical conditions, including if you have an infection, are pregnant or plan to become pregnant, or are breastfeeding or plan to breastfeed. If you receive EPKINLY while pregnant, it may harm your unborn baby. If you are a female who can become pregnant, your healthcare provider should do a pregnancy test before you start treatment with EPKINLY and you should use effective birth control (contraception) during treatment and for 4 months after your last dose of EPKINLY. Tell your healthcare provider if you become pregnant or think that you may be pregnant during treatment with EPKINLY. Do not breastfeed during treatment with EPKINLY and for 4 months after your last dose of EPKINLY.

In DLBCL or high-grade B-cell lymphoma, the most common side effects of EPKINLY include CRS, tiredness, muscle and bone pain, injection site reactions, fever, stomach-area (abdominal) pain, nausea, and diarrhea. The most common severe abnormal laboratory test results include decreased white blood cells, decreased red blood cells, and decreased platelets.

In follicular lymphoma the most common side effects of EPKINLY include injection site reactions, CRS, COVID-19, tiredness, upper respiratory tract infections, muscle and bone pain, rash, diarrhea, fever, cough, and headache. The most common severe abnormal laboratory test results include decreased white blood cells and decreased red blood cells.

These are not all of the possible side effects of EPKINLY. Call your doctor for medical advice about side effects. You are encouraged to report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch or to Genmab US, Inc. at 1-855-4GENMAB (1-855-443-6622).

Please see Full Prescribing Information and Medication Guide, including Important Warnings.

Globally, prescribing information varies; refer to the individual country product label for complete information.

On December 9, 2024 Rgenta Therapeutics, a clinical-stage biotechnology company pioneering the development of a new class of oral small molecules targeting RNA for oncology and neurological disorders, reported the presentation of preclinical data demonstrating anti-tumor activity of RGT-61159, a potent, selective oral small molecule inhibitor of MYB, a master oncogene in human malignancies (Press release, Rgenta Therapeutics, DEC 9, 2024, View Source [SID1234648935]). The data, which are being presented at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition being held December 7-10, 2024, in San Diego, CA, support the development of RGT-61159 as a potential treatment for acute myeloid leukemia (AML).

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"As demonstrated by the data being presented at ASH (Free ASH Whitepaper), RGT-61159 leads to the elimination of MYB RNA and protein in cancer cells and results in significant anti-tumor activity," said Simon Xi, Ph.D., co-founder and chief executive officer of Rgenta. "Importantly, RGT-61159 is active in a range of AML models harboring the most prevalent genetic alterations found in patients that often lead to resistance to current treatments. These data support our plans to extend our clinical development of RGT-61159 beyond our existing programs in solid tumors, adenoid cystic carcinoma (ACC) and colorectal cancer (CRC), and into hematologic malignancies such as AML."

RGT-61159 is a potent, selective oral small molecule inhibitor of the MYB oncogene that functions by inducing the inclusion of a cryptic exon into MYB RNA transcripts, resulting in the activation of the nonsense mediated decay pathway and promoting MYB mRNA depletion and thus, MYB protein degradation. The data presented at ASH (Free ASH Whitepaper) demonstrate that RGT-61159 potently eliminates MYB RNA and protein in a dose-dependent manner in AML cancer cell lines. As a single agent, RGT-61159 showed significant anti-tumor activity in several AML cell line-derived xenograft (CDX) models that harbor the most prevalent genetic alterations found in patients. In addition, RGT-61159 driven MYB inhibition led to a robust, dose-dependent increase in the differentiation markers CD11b and CD14 on the surface of THP-1 AML cells and the reduction of master oncogenes such as MYC and BCL2 across a broad panel of AML cell lines, providing a strong rationale for its development as a treatment for patients with AML.

"Genomic analyses of different AML cell lines treated with RGT-61159 shed further light on key oncogenes including BCL2 and MYC that are significantly regulated by MYB inhibition and further demonstrate RGT-61159’s anti-tumor activity of leukemic cells is driven by inhibition of MYB signaling," said Travis Wager, Ph.D., co-founder, president and chief scientific officer. "These data also confirm the role of MYB as a convergent dependency across AML tumors and highlight the potential of RGT-61159, a best-in-class MYB inhibitor, as a novel therapeutic approach to address this malignancy."

About RGT-61159
RGT-61159 is an orally available small molecule designed to specifically modulate splicing of the transcription factor MYB resulting in the inhibition of the oncogenic MYB protein production, which has the potential to induce cell death of the cancer cells overexpressing MYB protein. MYB acts as a master regulator of cell proliferation, self-renewal, and differentiation processes and its aberrant expression has been demonstrated in multiple forms of human cancer including adenoid cystic carcinoma (ACC), acute myeloid leukemias (AML), T-cell acute lymphoblastic leukemias (T-ALL), colorectal cancer (CRC), small cell lung cancer (SCLC) and breast cancer. Rgenta is evaluating RGT-61159 in an ongoing multi-center, open-label Phase 1a/b clinical trial in patients with advanced relapsed or refractory ACC or CRC. The Phase 1a/b study is designed to evaluate safety, tolerability, pharmacokinetics and target engagement and clinical efficacy of RGT-61159 in patients with ACC or CRC. Additional information about the Phase 1a/b clinical trial can be accessed at ClinicalTrials.gov (NCT06462183).

About Acute Myeloid Leukemia (AML)
AML is a blood cancer that starts in the bone marrow, begins to make large numbers of abnormal cells, is characteristically fast growing, and moves quickly into the blood. AML is the most common type of acute leukemia in adults, and it accounts for about 10% of all new blood cancers each year. In the United States, there are about 20,000 new cases of AML per year. The average age of people diagnosed with AML is 68 years old, and while it is uncommon in people under 45, it can occur in adolescents and children. While complete remission can be achieved in up to 70% of patients with newly diagnosed AML, prognosis remains poor with only approximately 32% of patients that remain alive 5 years after diagnosis. Allogeneic hematopoietic cell transplantation (HCT) remains the only potentially curative strategy for most patients. Up to 40% of patients relapse after allogeneic HCT, and 5-year overall survival (OS) rates for these patients are low, approximately 30–40%.

On December 9, 2024 Taiho Oncology, Inc., reported results of two studies focused on oral therapies for patients with myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasm (MPN), at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, Dec. 7-10, 2024, in San Diego (Press release, Taiho, DEC 9, 2024, View Source [SID1234648934]).

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Findings from a Phase 1 dose escalation trial of ASTX030, an investigational combination of azacitidine and cedazuridine, were shared with attendees during an oral presentation. In addition, results of a real-world study comparing clinical outcomes with INQOVI (decitabine and cedazuridine) tablets, an oral hypomethylating agent (HMA), versus intravenous (IV) or subcutaneous (SC) decitabine and azacitidine, respectively, were shared in a poster presentation.

Azacitidine and decitabine are HMAs. Following oral administration, HMAs are rapidly degraded by cytidine deaminase, resulting in poor oral bioavailability. Cedazuridine is a cytidine deaminase inhibitor, with the potential to increase the bioavailability of HMAs.

"We’re pleased to join hematology scientific leaders at the ASH (Free ASH Whitepaper) meeting to share data on oral HMAs for patients living with complications from MDS," said Harold Keer, MD, PhD, Chief Medical Officer, Taiho Oncology. "When administered at home, HMAs such as ASTX030 and INQOVI may potentially reduce the toll of time toxicity many patients with cancer experience and may help them to manage this disease long-term as a chronic condition."

Oral Presentation: Results of Phase 1 Open-Label Dose Escalation and Expansion Trial of ASTX030 (Oral Azacitidine + Cedazuridine)

This Phase 1 trial aimed to determine the optimal dose and formulation of ASTX030 to achieve oral azacitidine area under the curve (AUC) exposures comparable to SC azacitidine.

The trial enrolled 88 patients with MDS and MDS/MPN overlap syndromes, including chronic myelomonocytic leukemia (CMML), who received a median of seven cycles of treatment with ASTX030. Six combinations of azacitidine (60–144 mg) and cedazuridine (20–100 mg) doses were evaluated in the dose escalation portion of the trial, and two ASTX030 dose combinations (136 mg of azacitidine with 20 mg of cedazuridine and 144 mg of azacitidine with 20 mg of cedazuridine) were evaluated in the dose-expansion portion.

Pharmacokinetic data showed that 20 mg of cedazuridine sufficiently prevented azacitidine from degradation during first pass in the digestive tract and liver resulting in enhanced azacitidine bioavailability, achieving AUC exposures comparable to SC azacitidine, and the dose combination of 140 mg azacitidine/20 mg cedazuridine was recommended for evaluation in Phase 2.

The clinical efficacy results were consistent with parenteral azacitidine. The median overall survival was 29.5 months, with overall response rate of 56% (11% complete response, 0% partial response, 34% marrow complete response, 10% hematologic improvement), 27% stable disease, 2% progressive disease and 15% not evaluable.

Treatment emergent adverse events (TEAEs) were reported in 100% of participants, with 86% experiencing an AE of grade 3 or higher and 9% discontinuing treatment due to an AE. The most common TEAEs of grade 3 or higher were related to myelosuppression. Gastrointestinal AEs also reflected a similar safety profile to that typically associated with SC azacitidine. There was one dose-limiting toxicity that was possibly related to the study drug — a case of prolonged grade 4 neutropenia.

"These results are promising, as they demonstrate the potential of this novel oral therapy to reduce the treatment burden for people with MDS," said Guillermo Garcia-Manero, MD, professor of Leukemia at The University of Texas MD Anderson Cancer Center and the study’s lead investigator. "We look forward to soon sharing the results of a recently completed Phase 2 study of ASTX030 and are planning a Phase 3 trial of the compound."

Real-World Use Patterns and Outcomes for MDS Patients Treated with INQOVI or IV/SC HMA

The real-world study evaluated HMAs use patterns and clinical outcomes in adults with MDS who received first-line treatment with either INQOVI or a similar HMA administered subcutaneously or intravenously. Real-world treatment outcomes among MDS patients were gathered through the ConcertAI real-world electronic health records database.

Of 2,101 enrolled patients, 405 were treated with INQOVI and 1,696 with IV or SC azacitidine or decitabine.

Patients receiving INQOVI had a numerically longer median real-world overall survival (rwOS) compared to those treated with IV/SC HMA (23.2 versus 19.0 months) and lower risk of death, although the differences were not statistically significant.

Notably, median acute myeloid leukemia (AML)-free survival was 16.5 months with INQOVI versus 13.3 months with IC/SC HMAs (p=0.009). Furthermore, in a Cox-adjusted model, patients treated with INQOVI had a 16% lower risk of AML transformation or death (HR=0.84; 95% CI: 0.73–0.98; p=0.027) compared with those treated with IV or SC HMAs.

Those who received INQOVI prolonged the time to next treatment: 9.4 months, versus 7.4 months for those in the IV/SC cohort (p<0.001). Patients who received INQOVI were 18% less likely than their study counterparts receiving IV/SC HMAs to receive a next treatment (HR=0.82; 95% CI: 0.71–0.94; p=0.004).

"This real-world study is among the first and largest to examine clinical outcomes in patients treated for MDS with either first-line INQOVI or an intravenous or subcutaneous hypomethylating agent," said Tehseen Salimi, MD, MHA, Senior Vice President and Head of Medical Affairs, Taiho Oncology. "In addition to demonstrating comparable overall survival between the two treatment options, this study identified some potentially exciting unique signals of efficacy in patients who took INQOVI. These results highlight the potential value of this compound as an alternative to parenteral hypomethylating agents."

INDICATIONS AND IMPORTANT SAFETY INFORMATION

INDICATIONS

Decitabine and cedazuridine, marketed under the brand name INQOVI, is indicated for treatment of adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Myelosuppression: Fatal and serious myelosuppression can occur with INQOVI. Based on laboratory values, new or worsening thrombocytopenia occurred in 82% of patients, with Grade 3 or 4 occurring in 76%. Neutropenia occurred in 73% of patients, with Grade 3 or 4 occurring in 71%. Anemia occurred in 71% of patients, with Grade 3 or 4 occurring in 55%. Febrile neutropenia occurred in 33% of patients, with Grade 3 or 4 occurring in 32%. Myelosuppression (thrombocytopenia, neutropenia, anemia, and febrile neutropenia) is the most frequent cause of INQOVI dose reduction or interruption, occurring in 36% of patients. Permanent discontinuation due to myelosuppression (febrile neutropenia) occurred in 1% of patients. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS.

Fatal and serious infectious complications can occur with INQOVI. Pneumonia occurred in 21% of patients, with Grade 3 or 4 occurring in 15%. Sepsis occurred in 14% of patients, with Grade 3 or 4 occurring in 11%. Fatal pneumonia occurred in 1% of patients, fatal sepsis in 1%, and fatal septic shock in 1%.

Obtain complete blood cell counts prior to initiation of INQOVI, prior to each cycle, and as clinically indicated to monitor response and toxicity. Administer growth factors and anti-infective therapies for treatment or prophylaxis as appropriate. Delay the next cycle and resume at the same or reduced dose as recommended.

Embryo-Fetal Toxicity: INQOVI can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise patients to use effective contraception during treatment and for 6 months (females) or 3 months (males) after last dose.

ADVERSE REACTIONS

Serious adverse reactions in > 5% of patients included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%). Fatal adverse reactions included sepsis (1%), septic shock (1%), pneumonia (1%), respiratory failure (1%), and one case each of cerebral hemorrhage and sudden death.

The most common adverse reactions (≥ 20%) were fatigue (55%), constipation (44%), hemorrhage (43%), myalgia (42%), mucositis (41%), arthralgia (40%), nausea (40%), dyspnea (38%), diarrhea (37%), rash (33%), dizziness (33%), febrile neutropenia (33%), edema (30%), headache (30%), cough (28%), decreased appetite (24%), upper respiratory tract infection (23%), pneumonia (21%), and transaminase increased (21%). The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were leukocytes decreased (81%), platelet count decreased (76%), neutrophil count decreased (71%), and hemoglobin decreased (55%).

USE IN SPECIFIC POPULATIONS

Lactation: Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with INQOVI and for 2 weeks after the last dose.

Renal Impairment: No dosage modification of INQOVI is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] of 30 to 89 mL/min based on Cockcroft-Gault). Due to the potential for increased adverse reactions, monitor patients with moderate renal impairment (CLcr 30 to 59 mL/min) frequently for adverse reactions. INQOVI has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease (ESRD: CLcr <15 mL/min).

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