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).

Please see full Prescribing Information.

On December 09, 2024 Immune-Onc Therapeutics, Inc. ("Immune-Onc"), a private clinical-stage biopharmaceutical company advancing novel therapies in immunology and oncology by targeting myeloid cell inhibitory receptors, reported updated data from its Phase 1b expansion cohort evaluating IO-202, a first-in-class anti-LILRB4 antibody, in combination with azacitidine (AZA) in patients with chronic myelomonocytic leukemia (CMML) (Press release, Immune-Onc Therapeutics, DEC 9, 2024, View Source [SID1234648950]). These new findings were highlighted in an oral presentation at the 2024 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, California.

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The updated results from this trial in hypomethylating agent-naïve CMML showed that IO-202, in combination with AZA, achieved a complete remission (CR) rate of 50.0% and an overall response rate (ORR) of 66.7% among the 18 efficacy evaluable patients based on the International Working Group (IWG) 2023 response criteria for higher-risk myelodysplastic syndromes.1 Further analysis revealed that efficacy favors patients with high LILRB4 expression, who achieved a CR rate of 83.3% (5/6) and an ORR of 100% (6/6). Responses were observed in patients across all subgroups, including those with proliferative disease, elevated blast counts, unfavorable mutations, and high symptom scores. These findings underscore the potential of IO-202 to address an important unmet need in CMML, where the only approved treatment with hypomethylating agents yields modest CR rates of 7-17%.2

There is a critical need for innovative therapies for CMML, as no new treatments with a novel mechanism of action have been approved in over 30 years. The prognosis for CMML patients remains poor, with a median survival of less than three years. Allogenic hematopoietic cell transplant (HCT) is the only potentially curative option, yet fewer than 15-20% of patients are eligible to undergo HCT. As a novel agent, IO-202 demonstrates promising clinical benefits, addressing a significant unmet need.

In this study, treatment with IO-202 in combination with AZA enabled 38.9% of the patients to successfully bridge to HCT. Additionally, four out of six transfusion-dependent patients became transfusion-independent. IO-202 is well-tolerated at the preliminary recommended Phase 2 dose (60 mg/kg followed by 30 mg/kg every two weeks​) among 21 safety-evaluable patients. No dose-limiting toxicities were reported.

"These results represent a positive advance in the treatment of CMML, a disease with very limited options and poor outcomes," said Gabriel N. Mannis, M.D., IO-202 Phase 1 investigator and associate professor of medicine, division of hematology, Stanford Cancer Institute, Stanford University. "The favorable correlation between LILRB4 expression and treatment response underscores the contribution of IO-202 to efficacy consistent with its mechanism of action. Achieving a 50% complete response rate overall—and an 83% complete response rate in patients with high LILRB4 expression—demonstrates the potential of IO-202 as a highly impactful therapy. Additionally, the ability to bridge nearly 40% of patients to transplant and help most transfusion-dependent patients achieve independence offers new hope for improving outcomes in this challenging disease."

"We are encouraged by the promising clinical activity and tolerability of IO-202 in this trial," said Charlene Liao, Ph.D., chief executive officer of Immune-Onc. "These data support a pivotal study to evaluate IO-202 in combination with azacitidine as a frontline treatment for hypomethylating agent-naïve CMML. We look forward to working closely with regulators to bring this potentially life-changing therapy to patients."

ABOUT CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML)

CMML is a rare form of blood cancer, with an overall incidence of 0.35 cases per 100,000 population in the United States.3 CMML is characterized by persistent elevation of peripheral blood monocytes (≥0.5×109/L; monocytes ≥10% of white blood cell count) for over three months, accompanied by dysplastic features in the bone marrow.4,5 The only FDA-approved therapies currently available for CMML are hypomethylating agents, such as azacitidine, which achieve a complete response rate of just 7-17%.2

ABOUT LILRB4 (also known as ILT3)

LILRB4, also known as ILT3, is an immune-modulatory transmembrane protein found on monocytes and monocyte-derived cells. LILRB4 is expressed on certain hematologic cancer cells, such as myelomonocytic leukemia blasts, and on certain pathogenic cells involved in autoimmunity and inflammatory processes.

ABOUT IO-202

IO-202 is a first-in-class IgG1 antibody with specific, high-affinity binding to LILRB4 and depletes LILRB4 positive cells via antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. As such, IO-202 is a targeted therapy with broad potential in blood cancers and autoimmune and inflammatory diseases.

IO-202 has completed the dose escalation part of the first-in-human, multicenter, open-label Phase 1 study in the U.S., and the data was presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress in 2023. This Phase 1 trial has advanced to the dose expansion stage to evaluate IO-202 in combination with azacitidine (NCT04372433) in patients with newly diagnosed chronic myelomonocytic leukemia (CMML) who have not received any hypomethylating agents (HMA).

The U.S. Food and Drug Administration granted IO-202 Fast Track Designations for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) and relapsed or refractory CMML, respectively. The FDA has also granted IO-202 Orphan Drug Designations for the treatment of AML and CMML, respectively.

On December 9, 2024 Ichnos Glenmark Innovation (IGI), a global fully integrated clinical-stage biotech company developing multispecifics in oncology, reported first-time clinical data from the early dose-escalation portion of its Phase 1 study of ISB 2001 for the treatment of relapsed or refractory multiple myeloma (RRMM) (Press release, Ichnos Sciences, DEC 9, 2024, View Source;utm_medium=rss&utm_campaign=igi-presents_first-clinical_data_from-phase-1-study_of_trispecific_treat_antibody_isb-2001_showing_high_overall-response_rate_orr_with_durable_responses_and_favorable_safety_profile_in_pa [SID1234648903]). ISB 2001 is an investigational trispecific TREAT antibody for the treatment of RRMM that targets BCMA and CD38 on myeloma cells and CD3 on T cells. Initial results from 20 patients treated as of October 1, 2024, demonstrated an overall response rate (ORR) of 75% (15/20) across all doses tested (0.005 to 1.2 mg/kg), with a stringent complete remission (sCR) and complete remission (CR) rate of 20%. The ORR was 83% among the 18 patients treated at active doses (0.05 mg/kg and higher doses), including sCR/CR rate of 22%. The safety profile was mild with good tolerability, comparing favorably with first-generation 1+1 bispecifics.

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The data were presented today during an oral session at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, CA.

"The data presented today on ISB 2001 highlight its remarkable effectiveness as a novel trispecific-antibody T cell engager," said Professor Hang Quach, M.D., Professor of Haematology at the University of Melbourne and Director of Haematology at St Vincent’s Hospital Melbourne. "These results are among the most impressive I have seen in this patient population. ISB 2001 has the potential to revolutionize the treatment landscape for heavily pretreated patients with multiple myeloma who have exhausted currently approved therapies."

ISB 2001 was designed to enhance avidity with two binders targeting distinct myeloma-associated antigens – even at low expression levels – while offering improved safety compared to first-generation bispecific antibodies. IGI is developing ISB 2001 to meet the critical needs of RRMM patients, who have received prior T-cell directed therapies (including CAR-T cells and bispecifics).

"Early data based on only 20 patients are encouraging. ISB 2001 showed high clinical responses in a heavily pretreated and advanced patient population. Combined with a favorable safety and tolerability profile, these findings suggest ISB 2001 could represent a major advance in the treatment of RRMM in the future," said Lida Pacaud, M.D., Chief Medical Officer at IGI. "We are excited to advance the development of ISB 2001 by completing dose-escalation and moving swiftly into the dose-expansion part of the trial to establish the recommended Phase 2 dose and optimal dosing schedule."

ISB 2001 Phase 1 Dose Escalation Study Design

The Phase 1, first-in-human, open-label study is evaluating the safety and anti-myeloma activity of ISB 2001 in patients with RRMM (NCT05862012). The study is enrolling patients with RRMM who have been treated with immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies and are refractory to, or intolerant of, established therapies known to provide clinical benefit in multiple myeloma. Patients with prior CAR-T cell therapies, bispecifics and/or prior BCMA targeted agents were eligible.

The study is being conducted in two parts: dose escalation and dose expansion. This dataset comes from patients treated in the dose escalation at six sites in the United States and Australia.

Preliminary ISB 2001 Phase 1 Dose Escalation Results

The early portion of the trial is evaluating the safety and anti-myeloma activity of ISB 2001. Twenty heavily pretreated patients with RRMM were enrolled as of October 1, 2024. These patients had received a median of 6 prior lines of therapy. Six patients (30%) had extra-medullary plasmacytomas, and 4 of the 12 patients assessed (33%) had high cytogenetic risk. Five (25%) patients were triple-refractory, 14 (70%) were penta-exposed, 2 (10%) were penta-refractory and 13 (65%) were refractory to the last therapy prior to study entry. About half of patients (n=9) had received bispecific antibodies, with other prior therapies including anti-BCMA targeted therapies (n=8), and CAR-T cell therapies (n=2).

ISB 2001 showed a favorable safety profile in patients with heavily pretreated RRMM. No dose-limiting toxicity was detected, and no adverse events led to treatment discontinuation. Grade 1 CRS was observed in 13 patients (65%), and only 2 patients (10%) experienced Grade 2. The median duration of CRS was 2 days (range: 1–8). No immune cell-associated neurotoxicity syndrome (ICANS) was observed. Injection site reactions were reported in 10 patients (50%), all Grade 1. Grade 3 infections were reported in 3 patients (15%).

In the 20 heavily pretreated patients, the ORR was 75% across all dose levels.

Responses to ISB 2001 at active doses (0.05 mg/kg or higher) were durable and deepened over time:

The ORR was 83% among the 18 patients which included stringent Complete Responses (sCRs) in 3 patients (17%), Complete Response in 1 patient (6%), Very Good Partial Responses (VGPRs) in 9 patients (50%), and Partial Responses (PRs) in 2 patients (11%).
The median time to first objective response was 36 days (range: 29–99).
16 patients (80%) remain on treatment at data cutoff.
Dose-proportional PK with long half-life of over 10 days and low immunogenicity (2/20 patients, 10% across all doses tested) support exploring less-frequent dosing than weekly subcutaneous administration.

T cell activation, proliferation and soluble BCMA reduction were observed in most patients at effective doses.

Potential Opportunity for ISB 2001

ISB 2001 was developed using IGI’s proprietary BEAT protein platform, which combines TCR interface-based heavy chain pairing and universal light chain technology to create multispecific antibodies. This innovative design can increase binding to tumor cells while minimizing on-target, off-tumor side effects and/or boost immune cell activity against tumor cells by triggering multiple signals.

"While there have been significant advancements in treatments for relapsed/refractory multiple myeloma, many patients still experience relapse. IGI designed ISB 2001 to offer a therapeutic option to patients who have previously received T-cell directed therapies including first-gen bispecific and CAR-T cell therapies." said Cyril Konto, M.D., President and CEO of IGI. "These results further validate IGI’s BEAT technology which addresses the stability and engineering bottlenecks that previously hindered the large-scale production of bispecific and multispecific antibodies."

On December 9, 2024 Theratechnologies Inc. ("Theratechnologies" or the "Company") (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, reported data from Part 3 (dose optimization, weekly dosing schedule) of its ongoing Phase 1b trial of sudocetaxel zendusortide (TH1902) – the company’s lead investigational peptide drug conjugate (PDC) – in patients with advanced ovarian cancer (Press release, Theratechnologies, DEC 9, 2024, View Source [SID1234648919]). Based on results demonstrating favorable tolerability and signals of efficacy, the Medical Review Committee, which includes study investigators and external experts, has unanimously recommended continued evaluation and exploration of higher doses.

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"We are encouraged by the tolerability and preliminary efficacy data for sudocetaxel zendusortide seen thus far in this part of the Phase 1 study, which was designed to explore dose optimization utilizing a weekly dosing schedule in a population of heavily pre-treated ovarian cancer patients," commented Christian Marsolais, Ph.D., Senior Vice President and Chief Medical Officer at Theratechnologies. "These latest results add to the growing body of evidence that our novel PDC technology can deliver a toxic payload into cancer cells with little impact on non-cancerous tissues and we believe there could be further clinical implications at a higher dose."

A total of 13 patients with advanced ovarian cancer who progressed despite prior platinum-based and taxane chemotherapy were enrolled in two Arms in Part 3 of the Phase 1b trial. Seven patients were enrolled in Arm A and received a 1.75-mg/kg/week dose of sudocetaxel zendusortide on a weekly infusion, three-weeks-on/one-week-off schedule every 28 days. The six patients enrolled in Arm B received a 2.5-mg/kg/week dose on the same schedule.

Investigators observed no dose-limiting toxicities in either arm. Although there were no responses observed in the five Arm A participants that comprised the per-protocol (PP) set, there was encouraging evidence of activity observed in three of the six patients enrolled in the Arm B PP set, including one patient with a complete resolution of a liver lesion. Those three Arm B patients also experienced significant reductions in the CA-125 ovarian tumor marker as well as significant tumor shrinkage, including two patients with more than a 25% reduction in tumor size. Additionally, Arm B participants in the PP set received a mean of 10.25 weeks of treatment compared to a mean of 7.6 weeks of treatment in patients treated on Arm A. All patients in Arm B received at least two cycles of treatment, with some completing up to four cycles (on-treatment range: 4-18 weeks).

The Company received permission from the U.S. Food and Drug Administration (FDA) in 2023 to amend the initial Phase 1b clinical trial protocol based on results from Parts 1 and 2, which utilized every-3-week dosing. For Part 3, the protocol was amended to explore dosing weekly for three weeks, followed by a one-week break and shifted the focus to patients with ovarian cancer. At the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting earlier this year, Theratechnologies presented an updated analysis from Parts 1 and 2 of the study, in which sudocetaxel zendusortide induced durable disease stabilization (up to 45 weeks) lasting beyond treatment completion in several patients with a variety of solid tumors. The ASCO (Free ASCO Whitepaper) presentation also highlighted early signals of efficacy observed in female cancers (ovarian cancer, endometrial cancer, triple-negative breast cancer [TNBC]), as well as a manageable safety profile when sudocetaxel zendusortide was dosed at 300mg/m2 given once every 3 weeks with few Grade 3 adverse events (AEs).

"The latest data from Part 3 of the Phase 1 trial build on a compelling body of preclinical and translational evidence of antitumor activity with sudocetaxel zendusortide," said Ira Winer, M.D., Ph.D., FACOG, a member of the Gynecologic Oncology and Phase 1 Clinical Trials Multidisciplinary Teams at Karmanos Cancer Center and Professor of Oncology at Wayne State University School of Medicine in Detroit, MI. "While this is a small sample of patients, it is not often that we see promising signs of efficacy, combined with favorable safety and tolerability data, in this patient population with advanced disease. We therefore recommend and encourage continued investigation with further dose escalation for this agent."

In addition to the Phase 1b clinical trial results, there is also an extensive body of preclinical data demonstrating the flexibility of the Company’s SORT1+ Technology platform when conjugated with different toxic payloads. With a significant portion of the clinical trial data to date now available, Theratechnologies will accelerate its search for a partner to advance its oncology program.

About Sudocetaxel Zendusortide (TH1902) and SORT1+ Technology

Sudocetaxel zendusortide is a first-of-its-kind sortilin receptor (SORT1)-targeting PDC, and the first compound to emerge from the Company’s broader licensed oncology platform. A new chemical entity, sudocetaxel zendusortide employs a cleavable linker to conjugate (attach) a proprietary peptide to docetaxel, a well-established cytotoxic chemotherapeutic agent used to treat many cancers. The FDA granted Fast Track designation to sudocetaxel zendusortide as a single agent for the treatment of all sortilin-positive recurrent advanced solid tumors that are refractory to standard therapy.

Theratechnologies has established the SORT1+ Technology platform as an engine for the development of PDCs that target SORT1, which is expressed in multiple tumor types. SORT1 is a "scavenger" receptor that plays a significant role in protein internalization, sorting, and trafficking. Expression of SORT1 is associated with aggressive disease, poor prognosis, and decreased survival. It is estimated that SORT1 is expressed in 40% to 90% of endometrial, ovarian, colorectal, triple-negative breast (TNBC), and pancreatic cancers, making this receptor an attractive target for anticancer drug development.

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%.