TL895 / EMD Serono, Telios Pharma - LARVOL DELTA

TL-895, a Highly Selective, Covalent Inhibitor of Bruton's Tyrosine Kinase (BTK), Sensitizes Myeloproliferative Neoplasm (MPN)-Blast Phase Stem Cells to Navtemadlin By Targeting Intrinsic Dysregulated MDM2/p53 and NF-Κb Pathways and Disrupting the Protective Tumor Microenvironment (TME) (ASH 2023) - P1/2, P2 | "Our results indicate that BTKi therapy might increase susceptibility of MPN-BP SC to MDM2i therapy, by upregulating p53 activity and dampening NF-κB signaling, and also by disrupting protective TME interactions that sustain MPN-BP SC. This novel combination merits further clinical investigation in advanced phase MPN."

Biomarker • IO biomarker • Tumor microenvironment • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • ATF3 • BCL2L1 • BTG2 • CD34 • CDK1 • CDKN1A • DDB2 • EIF4EBP1 • ETV6 • KRAS • MDM2 • PTPRC • S100A10 • WT1

A Phase (Ph) 2 Study of TL-895, a Highly Selective, Novel Covalent BTK Inhibitor (BTKi), in Patients (pts) with Treatment-Naïve (TN) and Relapsed/Refractory (R/R) BTKi-Naïve Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) (ASH 2023) - P1/2 | "Treatment with TL-895 resulted in rapid clearance of leukemic compartments, particularly in TN pts, leading to earlier and deeper responses than expected with monotherapy BTKi. In R/R pts with a very high frequency of del17p/TP53MUT, remissions have been durable. With a very low incidence of AEs typical of less selective BTKi (e.g., AFib, major hemorrhage, rash and headache), TL-895 has the potential to be a best-in-class backbone BTKi."

Clinical • Anemia • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Hypertension • Infectious Disease • Leukemia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Novel Coronavirus Disease • Oncology • Otorhinolaryngology • Pneumonia • Respiratory Diseases • Richter's Syndrome • Sinusitis • Small Lymphocytic Lymphoma • Thrombocytopenia

EFFECT OF NOVEL AGENTS ON THE MECHANISM OF FIBROCYTE-MEDIATED INDUCTION OF MYELOFIBROSIS (EHA 2024) - "6%, while themeans for the Ruxolitinib, Navitoclax, TL-895, Parsaclisib, and Navtemadlin groups were 49. In vitro experiments demonstrated that the novel agents examined in this studyeffectively inhibited monocyte differentiation into fibrocytes and reduced certain profibrotic cytokinelevels in the culture supernatant. Further investigation into these mechanisms is anticipated to provideinsights into the antifibrotic mechanisms underlying the action of these novel agents."

Hematological Disorders • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • CCL2 • CCL22 • CSF1 • CXCL1 • IFNG • IL13 • IL18 • IL1R1 • IL4 • IL6 • IL7 • TNFA

Study of TL-895 in Subjects With Myelofibrosis or Indolent Systemic Mastocytosis (clinicaltrials.gov) - P2 | N=121 | Recruiting | Sponsor: Telios Pharma, Inc. | Trial primary completion date: Dec 2023 ➔ Jun 2025

Trial primary completion date • Myelofibrosis

Preclinical evidence for the effective use of TL-895, a highly selective and potent second-generation BTK inhibitor, for the treatment of B-cell malignancies. (PubMed, Sci Rep) - "TL-895 significantly inhibited tumor growth in the Mino MCL xenograft model and in 5/21 DLBCL PDX models relative to vehicle controls. These findings demonstrate the potency of TL-895 for BTK and its efficacy in models of B-cell lymphoma despite its refined selectivity."

Journal • Preclinical • Burkitt Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Evaluation of TL-895, A Novel Bruton’s Tyrosine Kinase Inhibitor (BTKi), On Oncogenic Janus Kinase 2-V617F (JAK2VF) Signaling (DGHO 2023) - P1b/2, P2 | "Treatment with the JAK1/2 inhibitor, ruxolitinib (rux) is limited by loss of response and blast phase transformation, underscoring a need for novel therapies... Murine 32D or BaF3- JAK2 WT and JAK2 VF were treated for 4h or overnight with TL-895, ibrutinib (ibr), or rux and evaluated by Western blot... JAK2 VF dependent BTK signalling promoted cell adhesion and chemotaxis. TL-895 potently inhibited BTK signaling to reduce cell adhesion and SDF1α-mediated chemotaxis in JAK2 VF cells. These data suggest that TL-895 could inhibit the interactions of JAK2 VF myeloblasts with their microenvironment and may improve patient outcomes in MF, a hypothesis that is currently being evaluated in the clinic (NCT04655118, NCT05280509, NCT04640532)."

Myelofibrosis • Oncology • ICAM1 • RAC1 • VCAM1

Orphan Designation: Treatment of myelofibrosis (FDA) - Date Designated: 08/31/2023

Orphan drug • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

MS200662_0001: Phase I/II, FIH, Dose Escalation Trial of TL-895 and Expansion of TL-895 Monotherapy and Combination Therapy With Navtemadlin in Tx-Naïve and R/R CLL/SLL Subjects (clinicaltrials.gov) - P1/2 | N=130 | Active, not recruiting | Sponsor: Telios Pharma, Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Monotherapy • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

A MECHANISTIC ABSORPTION AND PHARMACOKINETIC MODEL OF COVALENT BTK INHIBITOR TL-895: INFLUENCE OF FOOD AND ACID REDUCING AGENTS (EHA 2023) - P1 | "Physiological factors underlying higher exposure of TL-895 with fed administration were inferred from a MA-PBPKmodel. Simulations revealed dose linear increases in exposure with fed administration were aided by higher intestinal bile salt concentrations under fed conditions. Absorption was precipitation-limited under fasted conditions."

PK/PD data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Myelofibrosis • Oncology

FOOD AND ACID REDUCING AGENT EFFECTS ON PHARMACOKINETICS (PK) AND PHARMACODYNAMICS (PD) OF THE COVALENT BRUTON TYROSINE KINASE INHIBITOR (BTKI) TL-895 IN HEALTHY SUBJECTS (EHA 2023) - " TL-895-204 is an open-label, 4 period study (N=26): Arm A (Reference) 150 mg TL-895 - low fat meal ( LFM ) (PK/PD); B - high fat meal ( HFM ) (PK); C - LFM and -10h, +2h staggered steady state (SS) famotidine (20 mg BID, PK); D - LFM and SS omeprazole (40 mg QD, PK/PD). TL-895 had appropriate PK for a covalent BTKI, with a short t 1/2 , long PD effect, and dose-proportional PK. Food increased AUC and decreased PK variability, regardless of meal type, TL-895 is given with food. At 300 mg TL-895, BTK occupancy was similar in fed vs fasted states, with saturable maximum BTK occupancy only incrementally higher than 150 mg."

Clinical • PK/PD data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Myelofibrosis • Oncology

TRIAL IN PROGRESS: AN OPEN-LABEL, GLOBAL, MULTICENTER, PHASE 1B/2 STUDY OF TL-895, A BRUTON'S TYROSINE KINASE INHIBITOR (BTKI), ADDED TO RUXOLITINIB (RUX) IN PATIENTS (PTS) WITH MYELOFIBROSIS (MF) (EHA 2023) - P1b/2 | "TL-895-209 is an ongoing clinical trial evaluating the novel BTK/BMX inhibitor TL-895 added to rux in MF pts who are JAKi-naïve or have suboptimal response to rux. Myelofibrosis, IL-8, Ruxolitinib, Thrombocythemia"

Clinical • P1/2 data • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia • Thrombocytosis • BMF • CXCL8 • JAK1

TL-895, A FIRST-IN-CLASS, COVALENT BRUTON TYROSINE KINASE INHIBITOR (BTKI) FOR THE TREATMENT OF MYELOFIBROSIS (MF) PATIENTS (PTS) WITH SEVERE THROMBOCYTOPENIA (PLATELETS (PLTS) <50 K/UL) (EHA 2023) - P1b/2 | "In MF pts with severe TCP, TL-895 provided clinically meaningful improvements in TSS and plt counts that wereassociated with reductions in IL-8. This is the first clinical proof-of-concept for BTKi in the treatment of MF and supports further investigation in a recently commenced randomized, double blind, placebo-controlled Ph 2b study. Thrombocytopenia, IL-8, Myelofibrosis, Bone Marrow Fibrosis"

Clinical • Anemia • Fatigue • Hematological Disorders • Immunology • Myelofibrosis • Pain • Thrombocytopenia • CD34 • CXCL8

EFFECT OF TL-895, A NOVEL BRUTON’S TYROSINE KINASE INHIBITOR (BTKI), ON ONCOGENIC JANUS KINASE 2-V617F (JAK2VF) SIGNALING (EHA 2023) - P1b/2, P2 | "While the JAK1/2 inhibitor ruxolitinib (rux) can control symptoms and improve splenomegaly, treatment is often limited by loss of response, adverse events, and blast phase transformation (Palandri 2019)... Murine 32D or BaF3 cells ectopically expressing human JAK2 WT and JAK2 VF were treated for 4h or overnight with TL-895, ibrutinib (ibr), or rux... Increased adhesion and aberrant chemotaxis contribute to MF pathogenesis. The BTK pathway, which plays a key role promoting cell adhesion and chemotaxis, was activated by JAK2-mediated signals and the chemokine SDF1α. TL-895 potently inhibited BTK signaling to reduce cell adhesion and SDF1α-mediated chemotaxis in JAK2 VF cells."

Myelofibrosis • Oncology • ICAM1 • RAC1 • VCAM1

CHARACTERIZATION OF TL-895: A NOVEL BRUTON TYROSINE KINASE INHIBITOR (BTKI) IN CLINICAL DEVELOPMENT FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND MYELOFIBROSIS (MF) (EHA 2023) - P1/2, P2 | "TL-895, a highly selective, novel BTKi demonstrated potent inhibition of cell activation, proinflammatory signaling, migration and cytokine production in lymphoid and myeloid cells. In pts with CLL and MF, the 150mg BID doseachieved complete and sustained BTK occupancy throughout the dosing interval, despite faster BTK resynthesis in myeloid cells. TL-895 holds therapeutic promise by modulating key signaling nodes of cell activation, reducing stromal support, and downregulating proinflammatory cytokines in pts with CLL and MF."

Clinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Myelofibrosis • Oncology • CCL4 • CD34 • CD69 • CXCL12 • CXCL8 • EGFR • ERBB4 • IL1B • IL6 • JAK2 • NF-κβ

MS200662_0001: Phase I/II, FIH, Dose Escalation Trial of TL-895 and Expansion of TL-895 Monotherapy and Combination Therapy With Navtemadlin in Tx-Naïve and R/R CLL/SLL Subjects (clinicaltrials.gov) - P1/2 | N=130 | Recruiting | Sponsor: Telios Pharma, Inc. | Active, not recruiting ➔ Recruiting | N=80 ➔ 130 | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Combination therapy • Enrollment change • Enrollment open • Monotherapy • Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

TL-895 and KRT-232 Study in Acute Myeloid Leukemia (clinicaltrials.gov) - P1b/2 | N=18 | Active, not recruiting | Sponsor: Telios Pharma, Inc. | Recruiting ➔ Active, not recruiting | N=70 ➔ 18

Enrollment change • Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • TP53

Study of TL-895 Combined With Ruxolitinib in JAKi Treatment-Naïve MF Subjects and Subjects With MF Who Have a Suboptimal Response to Ruxolitinib (clinicaltrials.gov) - P1b/2 | N=70 | Recruiting | Sponsor: Telios Pharma, Inc. | Initiation date: Oct 2022 ➔ Jun 2022

Trial initiation date • Myelofibrosis

Phase I/II, first in human trial with M7583, a Bruton’s tyrosine kinase inhibitor (BTKi), in patients with B cell malignancies (ESMO 2018) - P1/2; "M7583 has been well tolerated with evidence of clinical benefit at all the doses investigated. M7583 appears to have a favorable benefit: risk profile."

Clinical • P1/2 data • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Indolent Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma

Study of TL-895 in Subjects With Myelofibrosis (clinicaltrials.gov) - P2 | N=149 | Recruiting | Sponsor: Telios Pharma, Inc. | Trial completion date: Jun 2024 ➔ Dec 2025 | Trial primary completion date: Jun 2022 ➔ Dec 2023

Trial completion date • Trial primary completion date • Myelofibrosis

MS200662_0001: Phase I/II, First in Human, Dose Escalation Trial of TL-895 in Subjects With R/R CLL/SLL and Expansion in Treatment Naïve CLL/SLL Subjects and Subjects With R/R CLL/SLL (clinicaltrials.gov) - P1/2 | N=80 | Active, not recruiting | Sponsor: Telios Pharma, Inc. | Trial completion date: Feb 2024 ➔ Dec 2024

Trial completion date • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

Study of TL-895 Combined With Ruxolitinib in JAKi Treatment-Naïve MF Subjects and Subjects With MF Who Have a Suboptimal Response to Ruxolitinib (clinicaltrials.gov) - P1b/2 | N=70 | Recruiting | Sponsor: Telios Pharma, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Myelofibrosis

TL-895 and KRT-232 Study in Acute Myeloid Leukemia (clinicaltrials.gov) - P1b/2 | N=70 | Recruiting | Sponsor: Telios Pharma, Inc. | Trial completion date: Jun 2024 ➔ Nov 2025 | Trial primary completion date: Jun 2022 ➔ Nov 2024

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • TP53

Phase 1b/2 Study of TL-895 Combined with Ruxolitinib in JAKi Treatment-Naïve MF Subjects and Subjects with MF who have a Suboptimal Response to Ruxolitinib I.b/II. fázisú ruxolitinibbel kombinált TL-895 vizsgálat Janus-kináz-gátló (JAKi) kezelésben még nem részesült vagy ruxolitinibre szuboptimális választ adó, myelofibrosi (clinicaltrialsregister.eu) - P1/2 | N=70 | Ongoing | Sponsor: Telios Pharma, Inc.

New P1/2 trial • Hematological Malignancies • Myelofibrosis • Oncology

Phase I/II, First in Human, Dose Escalation Trial of TL-895 in Subjects With R/R CLL/SLL and Expansion in Treatment Naïve CLL/SLL Subjects and Subjects With R/R CLL/SLL (clinicaltrials.gov) - P1/2 | N=80 | Active, not recruiting | Sponsor: Telios Pharma, Inc. | Recruiting ➔ Active, not recruiting | N=58 ➔ 80

Enrollment change • Enrollment closed • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

A Phase I/II, First in Human Trial of the Bruton's Tyrosine Kinase Inhibitor M7583 in Patients with B-Cell Malignancies (ASH 2018) - P1/2; "Conclusion s: Clinical benefit was observed with M7583 across the doses investigated and was well tolerated in patients with refractory/resistant B cell malignancies. These outcomes indicate a favorable benefit:risk profile for M7583."

Clinical • P1/2 data • Biosimilar • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology