MS-553 / MingSight Pharma - LARVOL DELTA

Overcoming BTK Inhibitor Resistance in Chronic Lymphocytic Leukemia by Targeting PKCβ. (PubMed, Blood Cancer Discov) - "By inhibiting PKCβ, MS-553 blocks B-cell receptor signaling and WNT/β-catenin and NF-κB functions, thereby inducing apoptosis in BTK inhibitor-resistant cells. See related article by Gordon et al., p. XX ."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • CTNNB1 • PRKCB

MS-553 Therapy Inhibits BCR Signaling and Increases Survival Dependence on BCL-2 in BTK-Inhibitor Resistant CLL (ASH 2023) - P1/2 | "B-cell receptor (BCR) signaling pathway inhibitors and B-cell lymphoma-2 (BCL-2) antagonist venetoclax (Ven) have transformed the treatment of chronic lymphocytic leukemia (CLL), including in high-risk patients with 17p deletion and/or TP53 mutations and complex karyotype...Patients who progress on BTKi including ibrutinib (ibr) often receive Ven but eventually relapse, underscoring an urgent need for new treatment strategies...Overall, our data provides clear evidence that MS-553 inhibits BCR signaling in vitro and in patients on MS-553 therapy. It also provides a rationale for combinations with Ven as a treatment partner based on its ability to increase survival dependence on BCL-2."

IO biomarker • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Leukemia • Lymphoma • Metabolic Disorders • Oncology • ANXA5 • BCL2 • BCL2L1 • MCL1 • PLCG2 • PRKCB • TP53

PKCβ inhibitor MS-553 displays preclinical efficacy in both treatment-naïve and BTK inhibitor-resistant Chronic Lymphocytic Leukemia. (PubMed, Blood Cancer Discov) - "MS-553 reduced BCR and Wnt/β-catenin signaling, overcame stromal cell mediated protection, and synergized with venetoclax in CLL samples. Furthermore, MS-553 delayed disease progression and prolonged survival in the Eµ-MTCP1 murine model of CLL. Collectively our results demonstrate that selective inhibition of PKCβ has the potential to overcome BTKi-resistant CLL."

Journal • Preclinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • PRKCB

The PKC-β Inhibitor MS-553 Displays Preclinical Efficacy in BTK Inhibitor Resistant Chronic Lymphocytic Leukemia (ASH 2023) - P1/2 | "Our data demonstrate the efficacy of the PKCβ inhibitor MS-553 in preclinical models of CLL including that with BTK mutations conferring BTKi resistance. These findings support continued preclinical and clinical investigation of MS-553 in CLL, and the phase 1 trial of this agent is currently underway (NCT03492125) (Blachly et al., 2022)."

IO biomarker • Preclinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BCL2 • CCL3 • CCND1 • CCND2 • CD40 • CTNNB1 • MYC • NFKBIA • PLCG2 • PRKCB

MS-553 in Diabetic Retinopathy Patients With Central Involved Macular Edema (clinicaltrials.gov) - P1 | N=45 | Recruiting | Sponsor: Shenzhen MingSight Relin Pharmaceuticals Co., Ltd. | Trial completion date: Jul 2025 ➔ Dec 2026 | Trial primary completion date: Jun 2025 ➔ Oct 2026

Trial completion date • Trial primary completion date • Diabetes • Diabetic Macular Edema • Diabetic Retinopathy • Macular Edema • Metabolic Disorders • Ophthalmology • Retinal Disorders • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus

A Phase Ib Study of the Selective PKC-β Inhibitor MS-553 in Patients With Refractory or Relapsed CLL/SLL (clinicaltrials.gov) - P1/2 | N=12 | Not yet recruiting | Sponsor: MingSight Pharmaceuticals, Inc | Trial completion date: Dec 2027 ➔ Dec 2028 | Initiation date: Jul 2025 ➔ Jul 2026 | Trial primary completion date: Sep 2027 ➔ Sep 2028

Trial completion date • Trial initiation date • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

New Targets and Drugs on the Horizon in Chronic Lymphocytic Leukemia (SOHO 2025) - P1, P1/2 | "12 Treatment planning for patients with " double refractory " CLL — CLL that is resistant to a covalent BTKi and venetoclax — is a relatively novel but emerging scenario in the clinic...Noncovalent (Reversible) BTK Inhibitors In the BRUIN-321 phase 3 randomized trial of pirtobrutinib monotherapy versus the control arm of the investigator's choice between idealisib plus rituximab or bendamustine plus rituximab, pirtobrutinib had improved PFS (14 vs 8.7 months, Hazard ratio [HR] 0.54, P = 0.0002) and a superior time to next treatment or death compared to the control arm (24 vs 10.9 months, HR 0.37, P < 0.0001)...Nemtabrutinib is another noncovalent BTKi under clinical investigation, demonstrating an overall response rate (ORR) of 36.4% in CLL patients in the phase 1 study (n = 22 patients)...23,24 Thus far, data for three orally administered BTK degraders — NX-2127, NX-5948 and BGB-16673 23–25— have been presented, and there are ongoing clinical..."

IO biomarker • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Leukemia • Lymphoma • Oncology • CD20 • PRKCB • PRKCH • ROR1

A Phase Ib Study of the Selective PKC-β Inhibitor MS-553 in Patients With Refractory or Relapsed CLL/SLL (clinicaltrials.gov) - P1/2 | N=12 | Not yet recruiting | Sponsor: MingSight Pharmaceuticals, Inc

New P1/2 trial • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

MS-553 in Diabetic Retinopathy Patients With Central Involved Macular Edema (clinicaltrials.gov) - P1 | N=45 | Recruiting | Sponsor: Shenzhen MingSight Relin Pharmaceuticals Co., Ltd. | Suspended ➔ Recruiting

Enrollment open • Diabetes • Diabetic Macular Edema • Diabetic Retinopathy • Macular Edema • Metabolic Disorders • Ophthalmology • Retinal Disorders • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus

A Study Of The Selective PKC-β Inhibitor MS- 553 (clinicaltrials.gov) - P1/2 | N=63 | Terminated | Sponsor: MingSight Pharmaceuticals, Inc | N=117 ➔ 63 | Trial completion date: Jun 2024 ➔ Nov 2023 | Recruiting ➔ Terminated | Trial primary completion date: Apr 2024 ➔ Nov 2023; The study is terminated due to major protocol revisions. A new study in CLL patients is planned.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • PRKCB

A Study of MS-553 in Patients With Relapsed or Refractory B-cell Lymphoma (clinicaltrials.gov) - P1/2 | N=8 | Terminated | Sponsor: MingSight Pharmaceuticals, Inc | N=38 ➔ 8 | Trial completion date: Jul 2026 ➔ Nov 2023 | Recruiting ➔ Terminated | Trial primary completion date: Apr 2026 ➔ Nov 2023; The study is terminated due to major protocol revisions.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

MS-553 in Diabetic Retinopathy Patients With Central Involved Macular Edema (clinicaltrials.gov) - P1 | N=45 | Suspended | Sponsor: Shenzhen MingSight Relin Pharmaceuticals Co., Ltd. | Trial completion date: Jan 2024 ➔ Jul 2025 | Recruiting ➔ Suspended | Trial primary completion date: Dec 2023 ➔ Jun 2025

Trial completion date • Trial primary completion date • Trial suspension • Diabetes • Diabetic Macular Edema • Diabetic Retinopathy • Macular Edema • Metabolic Disorders • Ophthalmology • Retinal Disorders • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus

A Study to Investigate the Efficacy and Safety of MS-553 in CLL/SLL (clinicaltrials.gov) - P1/2 | N=13 | Terminated | Sponsor: Shenzhen MingSight Relin Pharmaceuticals Co., Ltd. | N=48 ➔ 13 | Trial completion date: Sep 2025 ➔ Nov 2023 | Recruiting ➔ Terminated | Trial primary completion date: Apr 2024 ➔ Nov 2023; The study is terminated due to major protocol revisions.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

The PKCβ inhibitor MS-553 displays preclinical efficacy in BTK inhibitor resistant Chronic Lymphocytic Leukemia (IWCLL 2023) - P1/2 | "Our data demonstrate the efficacy of the PKCβ inhibitor MS-553 in preclinical models of CLL, including BTK inhibitor resistant disease. These findings support continued preclinical and clinical investigation of MS-553 in CLL, and the phase 1 trial of this agent is currently underway (NCT03492125) [7]."

IO biomarker • Preclinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BCL2 • CCL3 • CCND1 • CCND2 • CD40 • CTNNB1 • MYC • NFKBIA • PLCG2 • PRKCB

CLL Targets Beyond BTKi and Bcl2i (ICLLM 2023) - "1, 2 Treatment of CLL cells with entospletinib, but not other BCR-signaling inhibitors, led to a disruption of BAFF-BCR cross-talk and downmodulation of MCL1 mRNA and protein, thus implicating SYK in transduction of multiple pro-survival signals emanating from the tumor microenvironment.1 Entospletinib has shown promising clinical activity in CLL, alone or in combination with obinutuzumab, including in patients with high-risk disease such as TP53 aberrant.3, 4 The drug is very well tolerated, however its development in CLL has been halted. Meanwhile, we have shown that luxeptinib, a dual SYK/BTK kinase inhibitor, has activity in BTK inhibitor-resistant lymphoid models in vitro.5 Luxeptinib is now being investigated in lcinical trials in hematologic malignancies...The early results of MS-553, a selective PKC-β inhibitor, indicates that this agent is tolerable and effective both as single agent and in combination with venetoclax.8 Proteolysis-targeting chimeras (PROTACs)..."

IO biomarker • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Immune Modulation • Leukemia • Lymphoma • Mantle Cell Lymphoma • Metabolic Disorders • Multiple Myeloma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • Targeted Protein Degradation • CD19 • CD4 • CD8 • IGH • IKZF1 • IKZF3 • NF-κβ • PRKCB • ROR1 • SYK • TP53

Initial Results from a Phase 1/2 Dose Escalation and Expansion Study Evaluating MS-553, a Novel and Selective PKCβ Inhibitor, in Patients with CLL/SLL (ASH 2022) - P1/2 | " The primary objective of the study is to evaluate the safety and tolerability of oral daily continuous MS-553 as monotherapy (Cohort A) in relapsed and refractory patients with CLL/SLL, and in combination with acalabrutinib (Cohort B), or with venetoclax plus an anti-CD20 antibody (Cohort C) in earlier lines of therapy. MS-553 has been generally well tolerated with initial anti-tumor activity seen in this heavily pretreated population. Half of the evaluable patients have shown partial responses. The combination cohorts have shown good initial safety and tolerability."

Clinical • P1/2 data • Acute Kidney Injury • Anemia • Anorexia • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Fatigue • Heart Failure • Hematological Disorders • Nephrology • Neutropenia • Oncology • Pain • Renal Disease • PLCG2 • PRKCB • TP53

A Study Of The Selective PKC-β Inhibitor MS- 553 (clinicaltrials.gov) - P1/2 | N=117 | Recruiting | Sponsor: MingSight Pharmaceuticals, Inc | Trial completion date: Feb 2023 ➔ Jun 2024 | Trial primary completion date: Feb 2023 ➔ Apr 2024

Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

MS-553 in Diabetic Retinopathy Patients With Central Involved Macular Edema (clinicaltrials.gov) - P1 | N=45 | Recruiting | Sponsor: Shenzhen MingSight Relin Pharmaceuticals Co., Ltd. | Trial completion date: Oct 2022 ➔ Jan 2024 | Trial primary completion date: Aug 2022 ➔ Dec 2023

Trial completion date • Trial primary completion date • Diabetes • Diabetic Macular Edema • Diabetic Retinopathy • Macular Edema • Metabolic Disorders • Ophthalmology • Retinal Disorders • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus

A Study of MS-553 in Patients With Relapsed or Refractory B-cell Lymphoma (clinicaltrials.gov) - P1/2 | N=38 | Recruiting | Sponsor: MingSight Pharmaceuticals, Inc

New P1/2 trial • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

MS-553, a Selective PKC-ß Inhibitor Inhibits BCR Signaling and Synergizes with Venetoclax for the Treatment of High Risk CLL (ASH 2022) - "We hypothesized that targeting PKC-β will inhibit BCR signaling downstream of BTK and may offer an effective therapeutic strategy for patients who relapse on ibrutinib. These data provide strong rationale for an ongoing Phase I/II trial that evaluates MS-553 as a single agent and in combination with targeted agents such as venetoclax. Early interim data indicate that MS-553 is safe, tolerable and effective both as a single agent and in combination with venetoclax."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • ANXA5 • BCL2L1 • CTNNB1 • PLCG2 • PRKCB

A Study to Investigate the Efficacy and Safety of MS-553 in CLL/SLL (clinicaltrials.gov) - P1/2 | N=48 | Recruiting | Sponsor: Shenzhen MingSight Relin Pharmaceuticals Co., Ltd. | Not yet recruiting ➔ Recruiting

Enrollment open • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

A Study Of The Selective PKC-β Inhibitor MS- 553 (clinicaltrials.gov) - P1/2 | N=117 | Recruiting | Sponsor: MingSight Pharmaceuticals, Inc | N=47 ➔ 117

Enrollment change • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

A Study to Investigate the Efficacy and Safety of MS-553 in CLL/SLL (clinicaltrials.gov) - P1/2 | N=48 | Not yet recruiting | Sponsor: Shenzhen MingSight Relin Pharmaceuticals Co., Ltd.

New P1/2 trial • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

[VIRTUAL] INITIAL RESULTS OF A PHASE 1 DOSE ESCALATION STUDY EVALUATION OF MS-553, A NOVEL, SELECTIVE INHIBITOR OF PKC-BETA, IN PATIENTS WITH RELAPSED OR REFRACTORY CLL/SLL (EHA 2020) - P1 | "Background Resistance to covalent BTK inhibitors such as ibrutinib and acalabrutinib is an emerging issue that presages a poor clinical outcome. Potent to full inhibition of PKCb signaling during 24 hours of exposure has been demonstrated. Additional dosing of patients including genetic analysis will be completed to further assess MS-553 efficacy in patients with acquired resistance mutations in BTK and PLCG2."

Clinical • P1 data • Chronic Lymphocytic Leukemia • Fatigue • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

[VIRTUAL] Early Results from a Phase 1 Dose Escalation Study Evaluating MS-553, a Novel, Selective Pkcβ Inhibitor, in Relapsed or Refractory CLL/SLL Patients (ASH 2020) - P1 | "Introduction: Resistance to covalent Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib and acalabrutinib is an emerging issue that presages a poor clinical outcome. Although results are preliminary, MS-553 has been generally well tolerated with initial anti-tumor activity seen in this heavily pretreated population. Potent to full inhibition of PKCβ signaling over 24 hours of exposure has been demonstrated. Additional dosing of patients will be completed to further assess MS-553 efficacy in patients with acquired resistance mutations in BTK and PLCG2."

Clinical • P1 data • Anorexia • Chronic Lymphocytic Leukemia • Diabetes • Fatigue • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • PLCG2