NVG-111 / Novalgen - LARVOL DELTA

Encouraging long-term efficacy and safety from first-in-human phase 1 study of time-limited NVG-111 in relapsed/refractory CLL and MCL (ASH 2025) - P1 | "Targeting this compartment may offer a path to deeperand more durable remission.NVG-111 is a novel, humanised, first-in-class bispecific T-cell engager (TCE) that binds ROR1 and CD3.Similar in size to blinatumomab, NVG-111 is designed to redirect cytotoxic T cells to eliminate ROR1-expressing tumour cells, including CISCs...Fourteen ROR1-positive participants (CLL, n=11; MCL, n=3) received NVG-111 either asmonotherapy (n=5) or with ibrutinib (n=9)... NVG-111, a first-generation ROR1-targeting bispecific TCE, shows encouraging and durableanti-tumour activity in relapsed/refractory CLL and MCL, with a safety profile consistent with itsmechanism. Despite limited treatment, outcomes compare favourably with those of continuouslyadministered next-generation BTK inhibitors in R/R CLL. These long-term follow-up data support clinicalproof of concept for selective ROR1 targeting via bispecific TCEs."

Clinical • First-in-human • IO biomarker • P1 data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Neutropenia • ATM • CD8 • NOTCH1 • ROR1 • TP53

MODULE 5: Chimeric Antigen Receptor (CAR) T-Cell Therapy and Other Novel Strategies for CLL (ASH 2024) - "This program is supported by educational grants from AstraZeneca Pharmaceuticals LP, BeiGene Ltd and Eli Lilly.Biological rationale for the investigation of CD19- directed CAR T-cell therapy for CLL Published efficacy and safety findings with lisocabtagene maraleucel (liso-cel) for R/R CLL from the Phase I/II TRANSCEND CLL 004 trial FDA approval of liso-cel for CLL previously treated with a BTK inhibitor and a Bcl-2 inhibitor; current clinical role and optimal patient selection Early findings with other CAR T-cell-based approaches (eg, liso-cel in combination with ibrutinib, brexucabtagene autoleucel, rapcabtagene autoleucel) for heavily pretreated CLL Antitumor activity observed with bispecific antibody therapy (eg, epcoritamab, NVG-111, LAVA-051) for CLL, including in patients with Richter's transformation Other promising agents and strategies under investigation for CLL"

Chronic Lymphocytic Leukemia • Oncology • Richter's Syndrome

MODULE 5: Promising Investigational Agents and Strategies (ASH 2023) - "Supported by educational grants from AstraZeneca Pharmaceuticals LP, BeiGene Ltd, Bristol Myers Squibb, and Lilly. Biological rationale for the investigation of CD19-directed chimeric antigen receptor T-cell therapy for patients with CLL Published and emerging findings with lisocabtagene maraleucel (liso-cel) monotherapy in the Phase I/II TRANSCEND CLL 004 trial; rates of complete response compared to historical controls Early findings with liso-cel in combination with ibrutinib for heavily pretreated CLL Mechanism of action of nemtabrutinib; early efficacy and safety data with nemtabrutinib for R/R CLL and ongoing Phase III evaluation for treatment-naïve disease Antitumor activity observed with bispecific antibody therapy, such as epcoritamab or NVG-111, among patients with CLL, including those with Richter's transformation Other promising agents and strategies under investigation for CLL"

Oncology • Richter's Syndrome

NVG-222: A First-in-Class Autoregulating Half-Life Extended ROR1xCD3 T Cell Engager Heralding a New Class of Safer Drugs (ASH 2023) - P1 | "Results Selected AR peptides were exposed to a range of proteases present in circulation or in the tumour microenvironment and showed a specific and threshold-dependent sensitivity to granzyme B. A first prototype of an AR TCE was engineered from NVG-111, a ROR1xCD3 TCE in clinical development (NCT04763083), and showed uncompromised cytotoxic potency in vitro with an EC50 in the pM range. Conclusion Our AR platform technology has the potential to improve the therapeutic index of immunotherapies leading to improved safety and efficacy outcomes. This technology has been applied to our next generation ROR1-targeting TCE NVG-222, which is in IND-enabling studies with the aim of beginning clinical development for hematological and solid malignancies in 2024."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • Solid Tumor • Targeted Protein Degradation • GZMB • ROR1

Time Limited Exposure to a ROR1 Targeting Bispecific T Cell Engager (NVG-111) Leads to Durable Responses in Subjects with Relapsed Refractory Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL) (ASH 2023) - P1 | "NVG-111 was administered in combination (N=8) with ibrutinib to subjects who had achieved a partial response to >1 year of ibrutinib therapy, or as monotherapy in subjects that progressed after covalent BTKi/B-cell lymphoma 2 inhibitor (BCL2i) (N=4). These data provide clinical proof of concept for selective targeting of ROR1 with a TCE leading to objective evidence of antitumor activity with encouraging response durability even in CLL patients known to have defective T cell function. The safety profile was consistent with the mechanism of action. Further evaluation of this promising molecule is ongoing."

Clinical • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Fatigue • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology • BCL2 • CD8 • CTCs • IL10 • IL6 • ROR1 • TNFA

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

NovalGen presents NVG-111 clinical data in hematological malignancies in an oral session and preclinical data for next-generation AR T cell engager NVG-222 at the 65th American Society of Hematology Annual Meeting (GlobeNewswire) - P1 | N=90 | NCT04763083 | Sponsor: NovalGen Ltd. | "NovalGen...shared promising findings from the NVG-111-101, a First in Human, Phase I clinical study (NCT04763083), in an oral presentation at the 65th American Society of Hematology Annual meeting, in San Diego, USA. The study showcased positive responses in 58% of evaluable patients with relapsed refractory chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL) across both combination and monotherapy regimens, durable to 24 months. Noteworthy outcomes include a remarkable achievement of MRD4 negativity in peripheral blood, determined by flow cytometry, in 30% of CLL participants. Furthermore, a complete metabolic response (CMR) by Lugano criteria was observed in one of two mantle cell lymphoma participants."

P1 data • Chronic Lymphocytic Leukemia • Mantle Cell Lymphoma

NovalGen announces one oral and one poster presentation at the 65th American Society of Hematology Annual Meeting - P1 | N=90 | NCT04763083 | Sponsor: NovalGen Ltd. | "NovalGen Ltd...announces the online publication of two abstracts submitted to the American Society of Hematology Annual meeting, to be held December 9-12, 2023 in San Diego, USA....Between May 2021 and July 2023 12 subjects (10 males and 2 females, median age 60 years) completed a maximum of 6 cycles of NVG-111 treatment, with all evaluable for toxicity and 11 evaluable for efficacy. Grade 1 or 2 CRS occurred in 58% of subjects, mainly in week 1 cycle 1. Objective clinical responses were observed in 55% of subjects, including two with clear evidence of single agent activity....NovalGen have shown that applying AR to TCEs does not affect the potency, but significantly reduces toxicity in pre-clinical models. Furthermore, modelling from preclinical PK suggests NVG-222 will support dosing once every two weeks in clinic, and is due to enter trials in 2024."

New trial • P1 data • Preclinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

NVG111-101: First in Human Study of NVG-111 in Relapsed/Refractory ROR1+ Malignancies (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: NovalGen Ltd. | Phase classification: P1/2 ➔ P1

Phase classification • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lung Cancer • Lymphoma • Mantle Cell Lymphoma • Melanoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Solid Tumor • ROR1

The use of a transient transfected expression system to deliver high quality bispecific T-cell engager drug product, NVG-111, to the clinic for a fraction of the cost and time associated with the development and use of a producer cell line. (ASCO 2022) - P1/2 | "We established a novel GMP process in 7 months, using transient transfection to manufacture NVG-111 for Phase I/II trials. The process costed less than the more conventional manufacturing approach of using a producer cell line. The strategy offers a rapid, and very efficient way of reaching a first in human study without a trade-off between time, quality and cost."

Preclinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology • ROR1

First-in-Human Phase I Trial of a ROR1 Targeting Bispecific T Cell Engager (NVG-111) in Combination with Ibrutinib or As Monotherapy in Subjects with Relapsed Refractory Chronic Lymphocytic Leukaemia (CLL) and Mantle Cell Lymphoma (MCL) (ASH 2022) - "Early data shows that NVG-111 is generally well tolerated with a predictable and manageable safety profile. Promising evidence of efficacy was observed which appears to be durable in two subjects with MRD4 negative CR. Dose escalation is ongoing in combination or as monotherapy to determine the MTD/RP2D."

Clinical • Combination therapy • Monotherapy • P1 data • Chronic Lymphocytic Leukemia • Fatigue • Hematological Disorders • Hematological Malignancies • Inflammation • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology • Pain • Thrombocytopenia • BCL2 • IL10 • IL6 • ROR1 • TNFA

Pre-Clinical Development of a First in Class Half-Life Extended T Cell Engager Targeting ROR-1 (ASH 2022) - "We have generated a first in class ROR1 targeting half-life extended TCE that maintains the functional and biophysical properties of the clinically promising NVG-111. Our systematic evaluation suggests that careful selection of HLE format is critical for the development of a molecule with good yield, biophysical characteristics and potency. The selected ROR1 HLE-TCE supports weekly administration whilst maintaining potency at sub-nanomolar concentrations, properties which differentiate it from other TCEs in development."

Preclinical • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology • Solid Tumor • ROR1

First-in-human phase I study of a ROR1-targeting bispecific T-cell engager (NVG-111) shows evidence of efficacy in patients with relapsed/refractory CLL and MCL. (ASCO 2022) - P1/2 | "Five patients had CLL, and one had MCL, with all subjects remaining on ibrutinib whilst receiving NVG-111...This did not require tocilizumab or dose interruption except in one patient who developed transient, grade 3 immune effector cell–associated neurotoxicity syndrome-like symptoms (ICANS)... Early data with NVG-111 shows promising efficacy with a predictable and manageable safety profile."

Clinical • P1 data • Chronic Lymphocytic Leukemia • Hematological Disorders • Inflammation • Pain • Thrombocytopenia • ROR1

NovalGen announces one oral and two poster presentations at the American Society of Hematology Annual Meeting (GlobeNewswire) - P1/2 | N=90 | NCT04763083 | Sponsor: NovalGen Ltd. | "Eight subjects had CLL and 2 MCL. NVG-111 was well tolerated. Adverse events (AEs) were largely limited to week 1 of cycle 1 and all were reversible. The most common AEs were Grade 1 or 2 nausea (70%), headaches (60%), and fatigue (50%) and thrombocytopenia (30%). Grade1/2 cytokine release syndrome (CRS) was observed in (40%) of subjects....Objective clinical responses were observed in 66% of subjects and included 2 MRD4 negative clinical remissions (CR)."

P1 data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

NovalGen announces one oral and two poster presentations at the American Society of Hematology Annual Meeting (GlobeNewswire) - "The selected ROR1 HLE-TCE supports weekly administration whilst maintaining potency at sub-nanomolar concentrations, properties which differentiate it from other TCEs in development. Investigational New Drug (IND) enabling studies with NovalGen’s first in class ROR1 targeting HLE-TCE will conclude in 2023, supporting the initiation of a Phase I clinical trial in ROR1 hematological malignancies."

New P1 trial • Preclinical • Oncology

NVG-111 Generates Early Efficacy With Manageable Safety in Relapsed/Refractory CLL, MCL (OncLive) - P1 | N=90 | NCT04763083 | Sponsor: NovalGen Ltd | "The first 3 cohorts featured 1 patient each, and these patients were subjected to accelerated dose titration, with treatment administered daily for 21 days on, 7 days off, in every 28-day cycle. Patients received treatment for 3 cycles, or up to 6 cycles where applicable for each cohort. The patient in cohort 1 received 0.3 μg of intravenous (IV) NVG-111 per day for each cycle. In cohort 2, the patient received 1 μg of IV NVG-111 per day in cycle 1, 3 μg in cycle 2, and 10 μg in cycle 3. The patient in cohort 3 was given 3 μg of IV NVG-111 per day in cycle 1, 10 μg in cycle 2, and 30 μg in cycle 3...No grade 3 or higher AEs or serious AEs were reported. No grade 2 AEs were reported in any patients in cohorts 1, 2, and 3. In cohort 4, all patients experienced multiple grade 1/2 AEs....The biomarker analysis showed that a transient increase in cytokines detected with varying kinetics at all dose levels."

P1 data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A sensitive and robust bioanalytical assay for pharmacokinetic analysis of ROR1xCD3 bispecific T cell engager (NVG-111) in a first-in-human study. (ASCO 2022) - "Development, custom optimization and validation of a highly sensitive MSD-ECLA PK assay has enabled GCLP-compliant measurement of circulating NVG-111 in CLL or MCL patients treated with at least 10µg/day cIV NVG-111."

P1 data • PK/PD data • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Oncology • Solid Tumor • ROR1

Activity and biophysical properties related to clinical evaluation of a first-in-class EHL ROR1xCD3 T Cell Engager. (ASCO 2022) - "NVG-111 has been successfully engineered into an EHL format that increased the molecular size and has the potential to engage in FcRn-mediated recycling. This format maintains functional activity, is stable, and expresses well with a favorable aggregation profile. Further molecular refinements are being actively evaluated in readiness for IND enabling studies."

Clinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • CD69 • ROR1

[VIRTUAL] A First-in-human, Phase 1/2 Study of NVG-111, a Novel ROR1xCD3 Bispecific Antibody, in Patients with Debulked, Relapsed/refractory Chronic Lymphocytic Leukaemia (CLL), Small Lymphocytic Lymphoma (SLL) and Mantle Cell Lymphoma (MCL) (IWCLL 2021) - No abstract available

Clinical • P1/2 data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

NovalGen doses first patient in Phase I study in Chronic Lymphocytic Leukemia & Mantle Cell Lymphoma (PharmiWeb) - “NovalGen…announced that it has dosed the first patient in a Phase I/2 open label study of a first-in-class bispecific antibody T-cell engager, NVG-111, which simultaneously binds CD3 on T-cells and Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1) on tumor cells in patients with Chronic Lymphocytic Leukemia (CLL) & Mantle Cell Lymphoma (MCL). The study, an open-label, multi-centre Phase I/2 trial evaluating the safety, tolerability and clinical efficacy of NVG-111 in patients with CLL and MCL is expected to recruit approximately 90 patients and report initial data in 2021/2022. Recruitment is ongoing in the UK."

Enrollment status • P1/2 data • Trial status • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

[VIRTUAL] NVG-111, a novel ROR1xCD3 bispecific antibody for non-Hodgkin lymphoma. (ASCO 2021) - " NVG-111 demonstrated T cell-dependent cytotoxicity, T cell activation and levels of cytokine release similar in potency to blinatumomab...NVG-111 has progressed to a Phase 1/2 first-in-human study in patients with debulked, relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), the drug given as add-on to ≥2nd line therapy with a Bruton’s tyrosine kinase inhibitor, or venetoclax... NVG-111 shows potent T-cell mediated lymphoma cell cytotoxicity in vitro at concentrations well below those associated with extensive cytokine release . NVG-111 is in an ongoing Phase 1/2 study and may present a novel option for adoptive immunotherapy in patients with non-Hodgkin lymphoma and potentially other cancers."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • ROR1

"Live at #ASCO21 ROR1xCD3 bispecific antibody NVG-111 shows potent cytotoxic response in ROR1+/CD19+ JeKo cells. Phase I/II studies ongoing for NHL" (@Cortellis)

P1/2 data • CD19 • ROR1

First in Human Study of NVG-111 in Chronic Lymphocytic Leukaemia and Mantle Cell Lymphoma (clinicaltrials.gov) - P1/2; N=90; Recruiting; Sponsor: NovalGen Ltd.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • ROR1