sonrotoclax (BGB-11417)

P=N/A, N=47, Not yet recruiting, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

P2, N=100, Active, not recruiting, BeiGene | Recruiting --> Active, not recruiting

P1/2, N=260, Recruiting, BeiGene | Phase classification: P1b/2 --> P1/2 | Trial completion date: Aug 2025 --> Feb 2028 | Trial primary completion date: Dec 2023 --> Feb 2028

P1/2, N=126, Active, not recruiting, BeiGene | Recruiting --> Active, not recruiting | Trial primary completion date: Nov 2024 --> Apr 2025

P2, N=87, Not yet recruiting, BeiGene

P1/2, N=170, Not yet recruiting, BeiGene

The combination of venetoclax (ven), the first-generation BCL2 inhibitor, and ibrutinib, a BTK inhibitor, has efficacy in CLL. Other secondary endpoints include investigator (INV)-assessed PFS, CRR-INV, uMRD4 rate by flow cytometry, ORR-IRC and -INV, DOR-IRC and -INV, patient-reported outcomes, and safety and tolerability. Recruitment is ongoing.

P1, N=30, Recruiting, BeiGene | Not yet recruiting --> Recruiting

P2, N=102, Not yet recruiting, French Innovative Leukemia Organisation

P1, N=30, Not yet recruiting, BeiGene

P2, N=47, Not yet recruiting, Shanghai Jiao Tong University School of Medicine

P2, N=30, Not yet recruiting, Tianjin Medical University Cancer Institute and Hospital

P1, N=64, Active, not recruiting, BeiGene | Trial completion date: May 2024 --> Apr 2026 | Trial primary completion date: May 2024 --> Apr 2026

P2, N=97, Recruiting, BeiGene | N=72 --> 97 | Trial primary completion date: Nov 2024 --> Apr 2025

Zanubrutinib, a next-generation BTK inhibitor, significantly improved PFSand had a more tolerable safety profile, including fewer cardiac adverse events, vs ibrutinib in a randomized,head-to-head study of patients with CLL/SLL (Brown et al. N/A

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

Background: The combination of venetoclax (ven), the first-generation BCL2 inhibitor, and ibrutinib, a BTK inhibitor, has demonstrated efficacy in patients with CLL (Wierda et al. Other secondary endpoints include PFS as assessed by investigator (INV); CRR by INV; rate of uMRD4 based on flow cytometry; overall response rate by IRC and INV; duration of response by IRC and INV; patient-reported outcomes; and safety and tolerability. Recruitment is ongoing.

P2, N=66, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

P1, N=64, Active, not recruiting, BeiGene | Recruiting --> Active, not recruiting

P3, N=640, Recruiting, BeiGene | Not yet recruiting --> Recruiting

P1/2, N=167, Recruiting, BeiGene | Phase classification: P1b/2 --> P1/2

P1/2, N=122, Recruiting, BeiGene | Phase classification: P2 --> P1/2

P1, N=537, Recruiting, BeiGene | Phase classification: P1a/1b --> P1

Sonrotoclax (BGB-11417) is a next-generation BH3 mimetic which binds and inhibits BCL2 with a potency >10x that of venetoclax in biochemical assays. These data confirm sonrotoclax monotherapy had a tolerable safety profile across all doses tested and encouraging antitumor activity in patients with MZL. Two patients had laboratory TLS following the initial doses that resolved. No clinical TLS were observed, indicating that TLS can be mitigated with current measures, including revised ramp-up.

We therefore aimed to investigate the prevalence and pattern of BAX-mutated CH across different hematological and non-hematological neoplasms in response to BCL2 inhibitor therapy (both venetoclax and BGB-11417)...We assessed a cohort of pts with metastatic breast cancer who received venetoclax in combination with tamoxifen (mBEP; Lok, Cancer Discover 2019), and detected BAX variants from peripheral blood samples in 5/16 (31%) pts (median age 66) after a median duration of 20 (range 13–44) months on venetoclax...In summary, the emergence of BAX-mutated CH appears to be a generalized phenomenon of adaptive hematopoiesis that occurs across both hematological and non-hematological malignancy settings as well being observed with other BCL2 inhibitors consistent with a therapeutic class effect. Further research is needed to understand the contribution of this phenomenon to the subsequent development of clinically relevant hematological abnormalities and its implications for future therapeutic resistance.

P3, N=640, Not yet recruiting, BeiGene

P2, N=85, Recruiting, BeiGene | Not yet recruiting --> Recruiting

P2, N=85, Not yet recruiting, BeiGene

Among 52 patients with hematological malignancies the maximum tolerated dose (MTD) was not reached and no clinical TLS was observed.20 In this study of 22 evaluable patients with RR CLL there was an overall response rate (ORR) of 63.6% (14/22).20 A larger study of 114 patients with RR CLL evaluated lisaftoclax in combination with either the Bruton's tyrosine kinase inhibitor (BTKi) acalabrutinib or the anti CD20 monoclonal antibody rituximab (NCT04215809)...In CLL an overall response rate (ORR) to BGB-1147 of 100% as monotherapy was observed among 8 patients with RR disease.25 In 12 patients with RR MM, the ORR to BGB-1147 in combination with dexamethasone varied from 0–68% depending on the dose cohort.26 In combination with azacytidine in AML the ORR to BGB-11417 was 74% among those with treatment naïve (TN) disease (n=20/27) and 65% (n=13/20) in the cohort with RR disease.27 BGB-11417 monotherapy in 23 patients with RR NHL demonstrated responses in 2 patients with diffuse large B cell lymphoma (DLBCL) and one patient with marginal zone lymphoma (MZL).28 In 11 patients with RR MCL treated with BGB-11417 in combination with zanubrutinib there was a 55% (6/11) ORR.28 S55746 is a potent BAX/BAK dependent BCL2 inhibitor administered orally.18,29 Developed by Servier, it has been tested in phase I studies in CLL, NHL and AML. In a study of S55746 among 37 patients with RR NHL, no dose limiting toxicities (DLT) or TLS was observed after a medium duration of treatment of 42 days.30 FCN-338 is another orally available selective BCL2 inhibitor developed by Fochon currently undergoing phase I testing in RR CLL.18,31 Clinical outcomes with this drug are yet to be publicly reported...More recently navitoclax has been tested in RR myelofibrosis (MF) in combination with ruxolinitib with evidence of clinical response to the combination.35 AZD0466 by Astrazeneca is a nanomedicine potent dual BCL2/ BCLxL inhibitor that mediates BAX/BAK induced apoptosis36,37 and is administered intravenously...Among 9 patients reported undergoing testing for RR hematological malignancy the DLT had not yet been reached.38 Pelcitoclax or APG1252 by Ascentage is a more recent BAX/BAK dependent dual BCL2 and BCLxL inhibitor18,39,40 currently in phase I trials in RR NHL (NCT05186012)...There are multiple emerging BCL2 inhibitors currently undergoing clinical trial testing in hematological malignancies, and it remains too early to appreciate the differential efficacy and toxicity profiles that these agents may carry compared with venetoclax. It is hoped that the results seen with venetoclax can be improved upon across a raft of disease groups over the coming years.

These results demonstrated that BGB-11417 monotherapy was well tolerated at all tested doses up to 640 mg/d, with no dose-dependent toxicity increase. BGB-11417 monotherapy showed promising initial efficacy results in R/R CLL/SLL, with pts achieving responses at lower dose levels. Lymphoma, Chronic lymphocytic leukemia, BCL2, Hematological malignancy

BGB-11417 is a novel Bcl-2 inhibitor that is more potent and selective than venetoclax. Initial data show an encouraging safety profile and evidence of efficacy for BGB-11417 in NHL, MCL, and WM cohorts. MTD was not reached at highest dose (640 mg QD). All low-grade TEAEs and grade ≥3 neutropenia were manageable.

BGB-11417, a Bcl-2 inhibitor, is more potent and selective than venetoclax. BGB-11417 plus dexamethasone was generally well-tolerated in patients with R/R MM harbouring t(11;14) at doses ≤640 mg. Efficacy data are forthcoming. Recruitment is ongoing in the US, Australia, and New Zealand; the BGB-11417, dexamethasone, and carfilzomib combination arm will open in the future.

Background: Bcl-2 inhibitors are effective for treating chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL); however, the emergence of resistance limits their utility. Preliminary data show BGB-11417 (monotherapy and combination with zanubrutinib) is well-tolerated. Grade ≥3 neutropenia was uncommon and manageable. TLS rates are low.

No abstract available

P2, N=98, Recruiting, BeiGene | Not yet recruiting --> Recruiting

Preliminary findings suggest that BGB-11417 has promising efficacy and is tolerable at ≤640 mg as monotherapy and ≤160 mg combined with zanubrutinib. Dose escalation continues as MTD has not been reached. Enrollment is ongoing; data for Waldenström macroglobulinemia and treatment-naïve CLL/SLL are forthcoming.

Preliminary fi ndings suggest that BGB-11417 has promising effi cacy and is tolerable at 640 mg as monotherapy and 160 mg combined with zanubrutinib. Dose escalation continues as MTD has not been reached. Enrollment is ongoing; data for Waldenström macroglobulinemia and treatment-naïve CLL/SLL are forthcoming.

Bcl-2 is a well-validated target for B cell malignancies as demonstrated by a selective Bcl-2 inhibitor venetoclax approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML). Our efforts may provide the opportunity to develop a novel Bcl-2 inhibitor which presents more benefits in CLL patients as well as other Bcl-2 mediated malignancies. BGB-11417 is currently undergoing phase1/2 clinical assessment in monotherapy or combination.

P2, N=98, Not yet recruiting, BeiGene

However, 10–50% of newly diagnosed patients with AML may not respond to venetoclax and HMA or LDAC, and 3–15% patients may not respond to venetoclax with intensive or non-intensive chemotherapy.1–6 In addition, up to 40% of responding patients may relapse with low rates of response of 20% to salvage therapy and poor overall survival of 2 months after relapse.7 Clinical and biological factors associated with primary and acquired resistance to venetoclax include secondary AML, monocytic differentiation, complex cytogenetics, mutations in TP53, BAX, dependence on other anti- apoptotic proteins, altered metabolism of nicotinamide, fatty acids, and oxidative phosphortylation.3,8–14 Several novel inhibitors of BCL-2 are currently being tested in clinic, including BGB 11417, APG-2575, LP-108 and others...There is strong pre-clinical rationale for targeting MCL-1 alone as well as in conjunction with BCL-2 inhibition in AML.15 Recently several selective and highly potent MCL-1 inhibitors have entered pre-clinical and clinical development including S63845, AZD5991, AMG397, and others. Questions remain regarding the therapeutic window of these inhibitors given the important physiologic role of MCL-1 in vital organs and early reports of cardiac adverse events from the AMG176 phase 1 trial.15,16 Multiple pre-clinical studies have expectedly shown synergism between BCL- 2 and MCL-1 inhibition making it a promising path for clinical development of these agents.17,18 Multifactorial challenges in design of specific MCL-1 inhibitors also led to interest in compounds which downregulate MCL-1 expression. Cyclin dependent kinase (CDK) inhibitors including alvocidib, dinaciclib, voruciclib are in various stages of evaluation. Although addition of alvocidib to intensive chemotherapy improved response rates but failed to improve event-free or overall survival.19 Novel CDK inhibitors are currently in early phase trials including AZD4573, CYC065, TG02-101, and others. Inhibition of Nedd8 activating enzyme has complex repercussions for the intrinsic apoptotic pathway with eventual increase in Noxa leading to MCL-1 neutralization.20 Pevonedistat has shown promising early results in AML and myelodysplastic syndrome and is being investigated multiple clinical trials for solid tumors as well. BCL-xL Inhibition Another anti-apoptotic protein BCL-xL had been long recognized as a potential therapeutic target in AML, in particular AML from preceding MPN and AML recurrent post venetoclax failure, but toxicity of earlier inhibitors precluded clinical development.21–23 Recently, AZD0466, a dual BCL-2/xL inhibitor with a favorable therapeutic index and robust activity has been developed and is undergoing pre-clinical development and planned for phase iin hematological malignancies.24 Targeting the Extrinsic Apoptosis Pathway Inhibitor of apoptosis protein (IAP) inhibition: X-linked IAP (XIAP), cellular IAP (cIAP) and survivin have been of long- standing interest in AML. Prior clinical trials with XIAP inhibitor AEG35156, cIAP targeting agent birinapant, and survivin targeting agent LY2181308 have not succeeded in clinc.16,25 ASTX660 is a dual antagonist of XIAP and cIAP which is currently being investigated in phase 1/2 trials in solid tumors and in combination with HMA in relapsed or refractory AML.26,27 TRAIL Agonism Agonists of the TNF-related apoptosis-inducing ligand (TRAIL) receptors have been tested in AML with low response rates.28,29 Previous agents have had limited success in part due to suboptimal clustering of TRAIL receptors.30 Novel antibodies against TRAILR1 and TRAILR2 including an IgM molecule IGM-8444, a tetravalent compound INBRX-109, and HLX56 are currently in phase 1 trials and preclinical data suggests potential synergy with venetoclax.31 FLIP Inhibition FLICE-like inhibitor protein (FLIP or CFLAR) is a key regulator of the death-inducing signaling complex (DISC) involved in the extrinsic apoptotic pathway...This can be augmented by inhibiting p53 degradation via MDM2, which is often upregulated in AML.34 Idasanutlin in combination with venetoclax showed anti- Figure 1 leukemic activity in the dose finding stage in R/R AML.35 Several other inhibitors of MDM2 and dual MDM2/X inhibitors are currently in various stages of pre-clinical and clinical development including HDM-201, KRT-232, BI-9078282, and others.34 Conclusions Opportunities to target the apoptosis machinery in AML has considerably evolved in the last decade. While venetoclax heralded a paradigm shift for patients, we are now faced with challenges in patients who relapse or remain refractory. We have novel clinical stage compounds to methodologically target different facets of the apoptotic pathway and optimize novel combinations with the goal to improve the cure rates in AML patients.

Collectively, BGB-11417 is a potent and highly selective Bcl-2 inhibitor with superior anti-tumor activities compared with venetoclax in preclinical studies. The phase I study of BGB-11417 for treatment of hematological cancers is ongoing.