On December 10, 2024 Syntara Limited (ASX:SNT), a clinical-stage drug development company, reported positive interim data from its ongoing Phase 2 clinical trial evaluating SNT-5505 (200 mg BID) in combination with ruxolitinib (RUX) for the treatment of myelofibrosis (MF) (Press release, Syntara, DEC 10, 2024, View Source [SID1234649009]). The interim results2 suggest that SNT-5505 has potential as a breakthrough therapy for MF and are being presented today at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting (ASH) (Free ASH Whitepaper). Further interim data will be released in 1H 2025 and final data in 2H 2025.

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The interim data suggests that SNT-5505 compares favourably thus far to other drugs being trialled for MF demonstrating excellent tolerability and improvements in symptoms and spleen volume that increase over time.

This is in line with the anticipated disease modifying effects of a pan-LOX inhibitor that works to improve the bone marrow microenvironment and inhibits a growth factor receptor (PDGFR-b) that regulates cell expansion and division. This is encouraging, particularly given the trial patient population with a suboptimal response to existing standard of care and a high disease burden. Despite long prior RUX usage, most patients had high symptom scores and enlarged spleens at their entry into the trial.

Highlights2:

At 12 weeks of treatment, 46% of evaluable patients3 achieved a 50% improvement in Total Symptom Score (TSS50) which improved to 80% at 38 weeks of treatment. TSS50 is a standard efficacy endpoint used as the primary endpoint in MF clinical trials.
30% of evaluable patients4 achieved a spleen volume reduction (SVR) of 25% and 20% achieved an SVR of 35%. Both levels are considered clinically meaningful, with SVR35 a typical endpoint used in MF clinical trials.
Patient symptoms and spleen volume continued to improve over the duration of the interim data which is a novel finding that differentiates SNT-5505 from MF drugs on market and in later stages of development. It highlights the potential of SNT-5505 to be used in combination with JAK inhibitors to change the long-term outcomes for MF patients.
SNT-5505 is safe & well tolerated with no treatment related serious adverse events noted at this interim stage – viewed together with the excellent safety profile seen in the earlier monotherapy study⁵ this is emerging as another key differentiator to MF drugs on the market and in development.
After receiving data from a subset of patients reaching 52 weeks of treatment by March 2025, the company intends to discuss with the FDA the trial design for a pivotal Phase 2c/3 study. Concurrently, the company will also engage with potential global and regional partners.
The open-label study, which aims to assess the safety and efficacy of SNT-5505 over 52 weeks, has enrolled 16 patients with intermediate-2 or high-risk MF to date, with data extracted for use at ASH (Free ASH Whitepaper) on 14 November 2024:

13 patients had reached 12-week visit
8 patients had reached 24-week visit
5 patients had reached 38-week visit
Patients enrolled had a median RUX exposure of 3.2 years and a median baseline symptom score of 23, indicative of a high disease burden.

Professor Claire Harrison, Professor of myeloproliferative neoplasms at Guy’s and St Thomas’ NHS Foundation Trust, commented:

"This interim data confirms the excellent safety profile of SNT-5505 and also suggests that the mechanism of SNT-5505 may exert a long-term effect on the disease, with both symptoms and spleen volume continuing to improve as we now see patients on drug for 9 months. This hasn’t been seen before with this class of drug and holds potential for real long-term benefits for MF patients. I look forward to seeing the data mature in the coming months to confirm these important early findings."

Key points from the interim data2:

Safety and tolerability:
SNT-5505, in combination with a stable dose of RUX, was safe and well tolerated. There were no treatment related serious adverse events (SAEs) attributed to SNT-5505.
Substantial symptom relief observed over time:
At Week 12 – 46% (6/13) of evaluable patients3 achieved a ≥50% reduction in Myelofibrosis Symptom Assessment Form Total Symptom Score (TSS50), a benchmark for clinical response recognised by regulatory authorities such as the FDA.
At Week 38 – 80% (4/5) of evaluable patients achieved a TSS50.
Spleen volume reductions in the majority of patients:
82% (9/11) of evaluable patients3 experienced stable or reduced spleen volume with no dosage adjustments in RUX.
30% (3/10) of evaluable patients achieved an SVR25 and 20% (2/10) achieved an SVR35 with indications that patients were improving further at later timepoints.
Notably, spleen reductions over the period of the interim data were achieved in patients despite significant duration (>2 years) prior RUX exposure with many on low daily doses (≤20 mg/day).
80% (4/5) of evaluable patients showed further reductions in spleen volume from Week 24 to Week 38 which is a novel finding that differentiates SNT-5505 from other treatments on market and in development.
Haematological parameters remain stable:
Haemoglobin levels and platelet counts were generally stable across the cohort, with few major haematological toxicities reported.
One (of 2) transfusion dependent patients showed reduced transfusion requirements (approximately 70% reduction from baseline) over the period of the interim data.
Syntara CEO Gary Phillips added:

"A well tolerated drug that produces increasing and durable benefit the longer patients stay on is an exciting prospect and would differentiate SNT-5505 from other MF drugs on the market and in development. The changes in symptom score seen in the interim data at 9 months, albeit from a relatively small cohort of patients, suggests a superiority to other drugs that have been trialled in this patient group and are particularly important given the emphasis that the FDA and other regulatory bodies place on this measure. We will continue to analyse the data coming in, and anticipate requesting feedback from the FDA on the next stage of clinical development in Q2 2025 when we will have a number of patients with 12 months of treatment data."

Of the 16 enrolled patients, 12 patients were continuing to receive treatment as of the ASH (Free ASH Whitepaper) data cut off. Subsequent to the data cut off, a further three patients discontinued after receiving 6 months of therapy. No discontinuations for adverse events were considered related to SNT-5505 treatment. This level of discontinuations in clinical trials is consistent with a patient group with a high disease burden.

The Phase 2 trial has been designed to evaluate SNT-5505 in combination with RUX in patients with intermediate-2 or high-risk MF. Patients must have been on RUX for at least 12 weeks (stable dose for ≥8 weeks) before enrolling and be symptomatic. The study is being conducted across 19 sites in Australia, South Korea, Taiwan, and the USA, and the last patient visit is expected in July 2025.

On December 10, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in discovering, developing, and commercializing therapies to address global unmet medical needs primarily for malignancies, reported that it has released the latest clinical data of lisaftoclax (APG-2575) as a monotherapy or in combinations in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), in a Poster Presentation at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, taking place in San Diego, CA, the United States (Press release, Ascentage Pharma, DEC 10, 2024, View Source;ascentage-pharmas-bcl-2-inhibitor-lisaftoclax-in-combinations-demonstrates-potential-clinical-benefit-in-patients-with-prior-exposure-to-venetoclax-302327542.html [SID1234649008]). Dr. Matthew Davids, from Dana-Farber Cancer Institute in the US, is the principal investigator of the study.

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The ASH (Free ASH Whitepaper) Annual Meeting is one of the largest gatherings of the international hematology community, bringing together the most cutting-edge scientific research and latest data of investigational therapies that represent leading scientific and clinical advances in the global hematology field. Garnering growing interest from the global research community, results from multiple clinical and preclinical studies on four of Ascentage Pharma’s drug candidates (olverembatinib, lisaftoclax, APG-2449, and APG-5918) have been selected for presentations, including two Oral Reports, at this year’s ASH (Free ASH Whitepaper) Annual Meeting.

These data once again highlighted the therapeutic magnitude of Ascentage Pharma’s Bcl-2 selective inhibitor lisaftoclax, as a monotherapy and in combinations, in patients with relapsed/refractory (R/R) CLL/SLL, particularly the clinical benefit of lisaftoclax in combination with acalabrutinib in patients with prior exposure to venetoclax, including those who progressed on or were intolerant/refractory to venetoclax. Furthermore, no drug-drug interactions (DDIs) or new safety signals were observed in patients treated with lisaftoclax monotherapy or combinations.

Dr. Matthew S. Davids commented, "Lisaftoclax continues to demonstrate very strong efficacy in multiple patient subgroups, including those who previously progressed on venetoclax or BTK inhibitors. The drug also has excellent tolerability and the convenience of a daily dose ramp-up to reach the target effective dose. Based on the promising early phase results, the GLORA global registrational study has now launched and is actively enrolling."

"Results released at this year’s ASH (Free ASH Whitepaper) Annual Meeting reaffirmed the therapeutic potential of lisaftoclax in CLL/SLL," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "In China, a New Drug Application (NDA) for lisaftoclax has already been accepted and granted the Priority Review designation by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA), potentially leading lisaftoclax to become the second Bcl-2 inhibitor approved anywhere in the world. In the US, a global registrational Phase III study that was cleared by the US Food and Drug Administration (FDA) is currently underway. Fulfilling our mission of addressing unmet clinical needs in China and around the world, we will expedite the global clinical development of our key drug candidates such as lisaftoclax to bring more safe and effective therapies to patients as soon as possible."

Highlights of the data this study reported at ASH (Free ASH Whitepaper) 2024 are as below:

Lisaftoclax (APG-2575) Demonstrates Activity and Safety When Given With Accelerated Ramp-up and Then Combined With Acalabrutinib or Rituximab in Patients (pts) With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Including Those With Prior Exposure to Venetoclax
Format: Poster Presentation
Abstract#: 4614
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III

Highlights:

Background: Bcl-2 inhibition with venetoclax (ven) was a major advance in CLL treatment, but the 5-week dose ramp-up to mitigate the risk of tumor lysis syndrome (TLS) and DDIs challenge treatment optimization. Lisaftoclax is an investigational, oral Bcl-2i with a short half-life, allowing it to be ramped-up on a daily schedule.

Introduction: This poster presents updated clinical data of lisaftoclax alone or combined with acalabrutinib or rituximab in patients with treatment-naïve (TN), R/R, or prior ven-treated CLL/SLL.

Enrolled Patients and Study Methods:

From March 20, 2020, to June 27, 2024, 176 patients were enrolled: 46 in monotherapy and 39 and 91 in the rituximab and acalabrutinib combination cohorts, respectively; 87.5% (154/176) of patients were R/R and 12.5% (22/176) were TN. The median (range) age was 63 (34-80) years; 67% were male; 25.6% had del(17p) and/or TP53 mutation.
Median (range) duration of treatment with lisaftoclax was 16.5 (1-54; monotherapy), 24 (3-39; rituximab), and 27 (1-43; acalabrutinib) cycles. Fourteen (9%) patients relapsed on or were intolerant /refractory to prior treatment with ven. Their median (range) age was 65 (51-78) and 79% were male. 50% of those patients had del (17p), 36% had the TP53 mutation, 64% had del (11q), 38% had a complex karyotype (≥ 3 abnormalities), and 92% had unmutated IGHV.
Patients were treated with a rapid 4- to 6-day daily ramp-up of lisaftoclax from 20 mg to a target dose of 400, 600, or 800 mg, receiving daily oral lisaftoclax alone or, plus continuous acalabrutinib or 6 cycles of rituximab in 28-day cycles, starting on Cycle 1 Day 8 (C1D8) until disease progression, complete response by C24, or unacceptable toxicity.
Efficacy Results:

The ORR for lisaftoclax plus acalabrutinib in 87 patients was 98%, and the median duration of response (DOR; 95% CI, 31-NE) and median progression-free survival (PFS; 95% CI, 34-NE) of responders were not reached.

Among patients who received lisaftoclax plus acalabrutinib, 14 have relapsed on or were intolerant/refractory to prior treatment with ven. Their median (range) cycles of treatment were 16 (3-25), the ORR was 86%, the median PFS was not reached (11.3-NE), the 12-month PFS rate was 84%, and the 18-month PFS rate was 73%.
Among patients who received lisaftoclax plus acalabrutinib, 9 were refractory to ven. Their median (range) cycles of treatment were 16 (3-25), the ORR was 89%. The median PFS was not reached (NE-NE), the 12-month PFS rate was 89%, and the 18-month PFS rate was 89%.
Safety Results:

Incidence and severity of TEAEs were similar across cohorts.
Common (≥20%) any-grade TEAEs in all cohorts combined were infection (107 [61%]), neutropenia (67 [38%]), anemia (51 [29%]), diarrhea (51 [29%]), and thrombocytopenia (38 [22%]). Grade ≥ 3 treatment-emergent AEs (TEAEs；≥10%) were neutropenia in 15 (33%), 11 (28%), and 27 (30%) patients; infection in 13 (28%), 4 (10%), and 14 (15%) patients; and anemia in 8 (17%), 4 (10%), and 11 (12%) patients in monotherapy, rituximab, and acalabrutinib combination cohorts, respectively.
Lisaftoclax, alone or in combination, demonstrated a favorable safety profile and a rate of clinical tumor lysis syndrome (TLS) of 1.1%. No DDIs or new safety signals were observed in patients who received lisaftoclax in combination with acalabrutinib or rituximab.
Conclusions: The presented data suggest that lisaftoclax combined with acalabrutinib was active in patients with TN or R/R CLL, with a reported 98% ORR and a median DOR that was not reached at 22.3 months of median follow-up. Lisaftoclax combined with acalabrutinib was also effective for patients with prior ven exposure, including those who progressed on or were intolerant/refractory to ven. In this updated analysis with longer follow-up, no DDIs or new safety findings were observed in TN or R/R CLL/SLL patients treated with lisaftoclax monotherapy or combinations. Patients with prior ven exposure continue to be accrued in order to further evaluate this promising signal. A global registrational phase III study is recruiting.

*Lisaftoclax is an investigational drug that has not been approved in any country and region.

On December 10, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in discovering, developing, and commercializing therapies to address global unmet medical needs primarily for malignancies, reported that it has released the latest clinical data from a global study of its novel drug candidate, olverembatinib (HQP1351), in patients with heavily pretreated chronic myeloid leukemia (CML), in a Poster Presentation at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, taking place in San Diego, CA, the United States (Press release, Ascentage Pharma, DEC 10, 2024, View Source;1-5-year-follow-up-data-from-a-global-study-of-olverembatinib-reaffirms-potential-in-overcoming-resistanceintolerance-to-ponatinib-or-asciminib-302327550.html [SID1234649007]). Prof. Hagop Kantarjian, MD, and Prof. Elias Jabbour, MD, from the Department of Leukemia, The University of Texas MD Anderson Cancer Center, are the principal investigators of the study.

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The ASH (Free ASH Whitepaper) Annual Meeting is one of the largest gatherings of the international hematology community, bringing together the most cutting-edge scientific research and latest data of investigational therapies that represent leading scientific and clinical advances in the global hematology field. Garnering growing interest from the global research community, results from multiple clinical and preclinical studies on four of Ascentage Pharma’s drug candidates (olverembatinib, lisaftoclax, APG-2449, and APG-5918) have been selected for presentations, including two Oral Reports, at this year’s ASH (Free ASH Whitepaper) Annual Meeting. Furthermore, this is the seventh consecutive year for studies of olverembatinib to be selected for Oral Reports at the meeting.

After releasing the preliminary results from the global study of olverembatinib in an Oral Report at ASH (Free ASH Whitepaper) 2022 and the updated results from a larger patient sample at ASH (Free ASH Whitepaper) 2023, this year Ascentage Pharma presented the 1.5-year follow-up data in patients with heavily pretreated CML-CP. In the latest data, olverembatinib showed strong, durable and consistent antileukemic activity, the ability to overcome resistance/intolerance to the third-generation tyrosine kinase inhibitor (TKI) ponatinib or the allosteric STAMP inhibitor asciminib, as well as favorable tolerability in patients with heavily pretreated CML-CP.

As the first approved third-generation BCR-ABL inhibitor in China, olverembatinib has already been approved for the treatment of adult patients with tyrosine kinase inhibitor (TKI)-resistant CP-CML or accelerated-phase (AP-) CML harboring the T315I mutation; and adult patients with CP-CML resistant to and/or intolerant of first- and second-generation TKIs. In January 2024, olverembatinib was cleared by the US Food and Drug Administration (FDA) to enter a global registrational Phase III trial in previously treated adult patients with CML-CP.

Prof. Elias Jabbour commented, "Olverembatinib is a very promising next-generation TKI, and existing data demonstrate its therapeutic ability in patients with resistant/intolerant to ≥2 TKIs CP-CML and above. The high response rate that Olverembatinib has shown in Ponatinib or Asciminib failed patients is encouraging. We continue to recruit for the global Phase III trial examining this novel therapy."

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "The latest data from this global study further demonstrated olverembatinib’s therapeutic potential in patients with drug-resistant CML, including those who had failed prior treatment with ponatinib and asciminib, and once again underscored the drug candidate’s promise in addressing an unmet global clinical need in CML. At Present, a global registrational Phase III study of olverembatinib has been cleared by the US FDA and is already ongoing. We hope, in not too distant future, this innovative drug will become accessible to patients worldwide who are in desperate need of novel therapies. Fulfilling our founding mission of addressing unmet clinical needs in China and around the world, we will expedite the global clinical development of our key drug candidates such as olverembatinib to bring more safe and effective therapies to patients as soon as possible."

Highlights of the data this study reported at ASH (Free ASH Whitepaper) 2024 are as below:

Olverembatinib (HQP1351) Overcomes Resistance/Intolerance to Asciminib and Ponatinib in Patients (pts) with Heavily Pretreated Chronic-Phase Chronic Myeloid Leukemia (CP CML): A 1.5-Year Follow-up Update with Comprehensive Exposure-Response (E-R) Analyses

Format: Poster Presentation

Abstract#: 3151

Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster II

Highlights:

Introduction: New treatment options are needed for patients with CP-CML resistant/intolerant to third-generation (3G) TKI ponatinib and/or asciminib, a specifically targeting the ABL myristoyl pocket (STAMP) inhibitor. Olverembatinib is a well-tolerated TKI with potential to overcome resistance. This update presents efficacy and safety data of olverembatinib in patients with heavily pretreated CP-CML.

Enrolled Patients and Study Methods:

Adults with CP-CML previously treated with ≥2 TKIs and/or a STAMP inhibitor, adequate organ function, and no major molecular response (MMR) were eligible.
As of July 28, 2024, 67 pts with CP-CML were enrolled; median (range) follow-up was 74.3 (0.1-217.1) weeks; median (range) age, 50 (21-80) years; and 38 (56.7%) patients were male.
Patients were randomly allocated to receive olverembatinib at doses of 30, 40, or 50 mg orally every other day (QOD) in 28-day cycles, with stratification based on T315I mutation status. Comprehensive E-R analyses were performed.
Efficacy Results:

No patient had efficacy at baseline. 35 of 60 (58.3%) evaluable patients achieved CCyR and 29/64 (45.3%) achieved MMR. At 12 months, the overall MMR rate was 61.4% (27/44). CCyR was achieved by 66.7% of patients with the T315I mutation vs 54.8% without it, and MMR was achieved by 50.0% vs 43.5%, respectively.
Of 28 cytogenetic response-evaluable patients with ponatinib-failed CP-CML, 15 (53.6%) achieved CCyR. The CCyR rates in patients with prior ponatinib resistance and intolerance were 52.2% (12/23) and 75.0% (3/4), respectively. In the 30 molecular response-evaluable patients who were previously treated with ponatinib, 12 (40.0%) achieved MMR, including 47.8% (11/23) of those with prior resistance and 16.7% (1/6) with intolerance. No patient above had efficacy at baseline.
In evaluable patients with asciminib treatment failure, 37.5% (6/16) achieved CCyR and 30% (6/20) achieved MMR, including a CCyR rate of 30.8% (4/13) and an MMR rate of 26.7% (4/15) in those with prior resistance, and a CCyR rate of 50.0% (1/2) and an MMR rate of 25.0% (1/4) in those with intolerance. No patient had efficacy at baseline.
Safety Results: Among 66 subjects receiving olverembatinib, a total of 62 (93.9%) reported treatment-emergent adverse events (TEAEs) of any grade, with 44 (66.7%) experiencing grade ≥ 3 TEAEs. In addition, 60 (90.9%) patients reported TRAEs of any grade. Common TRAEs (≥20%) were elevated creatine phosphokinase (37.9%), thrombocytopenia (24.2%), and increased alanine aminotransferase (22.7%).

Conclusions: Olverembatinib was well tolerated and showed strong and durable antileukemic activity in patients with heavily pretreated CP-CML. The registrational study is recruiting.

On December 10, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in discovering, developing, and commercializing therapies to address global unmet medical needs primarily for malignancies, reported that it has released the follow-up safety and efficacy data of the company’s investigational Bcl-2 selective inhibitor, lisaftoclax (APG-2575), in combination with azacitidine (AZA) for the treatment of patients with myelodysplastic syndrome (MDS), in a Poster Presentation at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, taking place in San Diego, CA, the United States (Press release, Ascentage Pharma, DEC 10, 2024, View Source;ascentage-pharma-releases-updated-data-of-bcl-2-inhibitor-lisaftoclax-in-mds-that-demonstrates-potential-clinical-benefits-and-favorable-safety-302327621.html [SID1234649006]).

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The ASH (Free ASH Whitepaper) Annual Meeting is one of the largest gatherings of the international hematology community, bringing together the most cutting-edge scientific research and latest data of investigational therapies that represent leading scientific and clinical advances in the global hematology field. Garnering growing interest from the global research community, results from multiple clinical and preclinical studies on four of Ascentage Pharma’s drug candidates (olverembatinib, lisaftoclax, APG-2449, and APG-5918) have been selected for presentations, including two Oral Reports, at this year’s ASH (Free ASH Whitepaper) Annual Meeting.

Thes data underscored the potential clinical benefit and manageable safety of lisaftoclax in combination with AZA in MDS. In the results, the combination regimen demonstrated an overall response rate (ORR) of 75% in patients with treatment-naïve (TN) or relapsed/refractory (R/R) MDS, and no patient withdrew from the study due to intolerable toxicities.

Prof. Jie Jin, the principal investigator of the study from the First Affiliated Hospital, Zhejiang University School of Medicine, noted, "For a long time, there has not been much progress in the treatment of higher-risk MDS and the outcome of the current standard treatment with hypomethylating agents has been disappointing. In patients with MDS, the investigational novel Bcl-2 inhibitor lisaftoclax in combination with AZA has demonstrated clinical benefit and manageable safety that support continued treatment. These observations suggest that the regimen can potentially offer a new standard treatment in MDS."

Prof. Huafeng Wang, the presenter of this study from the First Affiliated Hospital, Zhejiang University School of Medicine, commented, "Patients with higher-risk MDS often have inadequate marrow function and low tolerance for therapeutic agents. The investigational novel Bcl-2 inhibitor lisaftoclax in combination with AZA has shown encouraging clinical benefit, manageable safety, and low suppression on bone marrow function. More importantly, the regimen showed a low rate of treatment-related infections that were mostly mild, and a low rate of mortalities in early treatment, thus overcoming some of the biggest clinical challenges in this patient population."

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "These updated efficacy and safety data of lisaftoclax in combination with AZA are very encouraging as they reaffirmed the therapeutic potential of this novel drug candidate. A global registrational Phase III study of lisaftoclax in combination with AZA for the first-line treatment of MDS is currently ongoing and an NDA for lisaftoclax in R/R chronic lymphocytic leukemia/small lymphocytic lymphoma has already been accepted and granted the Priority Review designation in China. Fulfilling our founding mission of addressing unmet clinical needs in China and around the world, we will expedite the global clinical development of our key drug candidates to bring more safe and effective therapies to patients as soon as possible."

Highlights of the data this study reported at ASH (Free ASH Whitepaper) 2024 are as below:

Lisaftoclax (APG-2575), a Novel BCL-2 Inhibitor, in Combination with Azacitidine in Treatment of Patients with Myelodysplastic Syndrome (MDS)
Format: Poster Presentation
Abstract#: 3202
Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Poster II

Highlights:

Background: Hypomethylating agents (HMAs) remain the standard of care in higher-risk MDS. However, its clinical efficacy is limited, and patients who have failed or are resistant to HMAs have a poor prognosis, leaving them in need of new therapeutic options.

Introduction: Preclinical data have shown that novel investigational Bcl-2 inhibitor lisaftoclax combined with an HMA can synergistically induce apoptosis in cancer cells in AML and MDS. Reported here are the follow-up safety and efficacy data from a Phase Ib/II clinical trial evaluating lisaftoclax combined with azacitidine in adults (≥18 years) with MDS.

Enrolled Patients and Study Methods:

This study enrolled patients with higher-risk MDS (IPSS-R score > 3.5; blasts > 5%), including those with TN or R/R disease. Lisaftoclax at an assigned dose (400, 600, or 800 mg) was administered orally once daily from Days 1 to 14 and combined with azacitidine (75 mg/m2/day) on Days 1 to 7 in repeated 28-day cycles. A daily ramp-up was used before the first cycle to prevent TLS. The primary objectives of the study were to assess the efficacy and safety of the combination regimen in patients with MDS and establish the recommended Phase III dose for lisaftoclax. Complete response (CR) and marrow CR (mCR) rates were evaluated in accordance with 2006 International Working Group (IWG) criteria.
As of July 1, 2024, 49 patients were enrolled: 8 had R/R MDS (lisaftoclax 600 mg [n=5] and 800 mg [n=3]) and 41 had TN MDS (lisaftoclax 400 mg [n=16], 600 mg [n=23], and 800 mg [n=2]). The median (range) age was 66 (22-83) years, and 55.1% of patients were male. IPSS-R risk categories were intermediate (12/49 [24.5%]), high (24/49 [49.0%]), and very high (13/49 [26.5%]). Among the 39 patients with genetic mutational profile data, 9 (23.1%) had TP53 mutations; 11 (28.2%) had TET2 mutations; 10 (25.6%) had ASXL1 mutations; and 10 (25.6%) had RUNX1 mutations. At baseline, 70.8% of patients reported grade ≥ 3 anemia; 54.2% had grade ≥ 3 neutropenia; and 45.8% had grade ≥ 3 thrombocytopenia.
Efficacy Results: In 8 patients with R/R MDS, the median (range) duration of treatment (DOT) was 3.2 (1.2-9.4) months. The ORR (CR[12.5%]+marrow CR[62.5%]) was 75.0% (95% CI, 34.9-96.8). In 40 efficacy-evaluable patients with TN MDS, the median DOT (range) was 4.5 (0.5-12.1) months; the ORR was 77.5% (95% CI, 61.5-89.2); and the CR rate was 25.0% per IWG 2006 criteria. Furthermore, the ORR and CR rate in 23 patients with TN MDS treated with lisaftoclax 600 mg combined with azacitidine were 73.9% and 30.4%, respectively; because these patients had a relatively longer median DOT (6.01 months), we conducted further analyses per IWG 2023 criteria. The composite CR rate (CR2023 = CR [52.2%] + CRL [17.4%]) was 69.6%, and the median time to CR (range) was 2.84 (1.1-8.7) months. Both the median progression-free survival and overall survival rates were not reached.

Safety Results:

Grade ≥ 3 infections were reported in 46.9% of patients, of which 26.5% were treatment related. Treatment delays between cycles due to AEs occurred in 11 (22.4%) patients, with a median delay time (range) of 12 (1-63) days.
A total of 95.9% of patients reported TRAEs, of which 87.8% were grade ≥ 3 AEs and 28.6% were serious AEs. Common grade ≥ 3 hematologic TRAEs included leukocyte count decreased (71.4%), neutropenia (65.3%), thrombocytopenia (65.3%), anemia (20.4%), and febrile neutropenia (12.2%).
Neither 60-day mortality nor TLS was reported.
Conclusions: The clinical data support an emerging role for lisaftoclax in combination with azacitidine for treatment of patients with higher-risk TN or R/R MDS. The combination therapy was efficacious and well tolerated, resulting in no 60-day mortality, few dose modifications, and low infection rates, supporting further clinical development of this combination in patients with higher-risk MDS.

On December 10, 2024 IDEAYA Biosciences, Inc. (Nasdaq:IDYA), a precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported that it has dosed the first patient in the IDEAYA-sponsored Phase 1 trial evaluating the combination of IDE161, the company’s investigational, potential first-in-class, small molecule poly (ADP-ribose) glycohydrolase, or PARG, inhibitor, in combination with Merck’s (known as MSD outside of the US and Canada) anti-PD-1 therapy, KEYTRUDA (pembrolizumab), in endometrial cancer patients with high microsatellite instability (MSI-high) and microsatellite stable(MSS) (Press release, Ideaya Biosciences, DEC 10, 2024, View Source [SID1234649005]).

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"We continue to progress our IDE161 program and are excited to have the first patient dosed evaluating IDE161 in combination with KEYTRUDA in MSI-high and MSS endometrial cancer patients. This trial is part of our overall IDE161 clinical combination strategy that is focused on high conviction rational combinations," commented Dr. Darrin M. Beaupre, M.D., Ph.D., Chief Medical Officer, IDEAYA Biosciences.

"We are continually looking for ways to improve outcomes for patients with MSI-high and MSS endometrial cancer, and PARG has shown promising potential as a precision oncology target in these settings. IDE161 has shown robust anti-tumor activity in preclinical models, and I look forward to evaluating IDE161’s impact on endometrial cancer patients in combination with KEYTRUDA," added Dr. Panos Konstantinopoulos, M.D., Ph.D., Director of Translational Research and attending oncologist in the Division of Gynecologic Oncology at Dana-Farber Cancer Institute, and an Associate Professor of Medicine at Harvard Medical School.

IDE161 is a potential first-in-class inhibitor of poly(ADP-ribose) glycohydrolase (PARG), a novel, mechanistically distinct target in the same clinically validated biological pathway as poly(ADP-ribose) polymerase (PARP). IDE161 has been granted two FDA Fast Track designations in platinum-resistant advanced or metastatic ovarian cancer patients having tumors with BRCA1/2 mutations, and in pretreated advanced or metastatic HR+, Her2-, BRACA1/2 mutant breast cancer.

Under the clinical trial collaboration and supply agreement, Merck will provide KEYTRUDA to IDEAYA, the sponsor of the Phase 1 clinical combination trial. IDEAYA and Merck each retain all commercial rights to their respective compounds, including as monotherapy or as combination therapies.

The safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of IDE161 in combination with KEYTRUDA is being evaluated as an arm in IDE161-001 (NCT05787587), an IDEAYA-sponsored Phase 1 trial of IDE161 in solid tumors. The selection of an initial Phase 1/2 monotherapy expansion dose has been made in a priority tumor type based on adverse event (AE) profile and preliminary clinical efficacy observed.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.