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Overview of Select Oncology Drug Product Candidates

ISB 2001 TREAT^TM  Trispecific antibody

• ISB 2001 is a first-in-class T cell-engaging antibody that targets BCMA and CD38 on multiple myeloma cells. It is a trispecific antibody based on IGI’s proprietary BEAT^®platform, allowing maximal flexibility and excellent manufacturability of full-length multispecific antibodies.

• ISB 2001 combines three proprietary Fab antigen-binding arms, each targeting a different antigen, with one arm binding to the epsilon chain of CD3 on T cells, and the other two binding BCMA and CD38 on multiple myeloma cells. Its Fc domain was fully silenced to suppress Fc effector functions.
• ISB 2001 redirects CD3+ T lymphocytes to kill tumor cells expressing low to high levels of both BCMA and CD38. With two different tumor-associated antigens instead of one, ISB 2001 is expected to be more resistant to antigen escape associated with treatment of multiple myeloma patients.
• The preclinical data package for ISB 2001 which may be viewed at this linkshows:
  • Increased killing of tumor cells across variable levels of expression of both BCMA and CD38 compared to teclistamab, alnuctamab and EM-801
  • Higher potency in vitrowhen compared to the combination of daratumumab and teclistamab
  • Superior cytotoxicity over teclistamab in ex vivoassays with Multiple Myeloma cells from patients at different stages of progression of the disease Superior efficacy over teclistamab in in vivo models with low level of expression of CD38 and BCMA demonstrating 100% complete responses
• At the recent AACR Annual Meeting 2024, an oral presentation showcased the results of ISB 2001 anti-myeloma activity in bone marrow aspirates from patients who were either newly diagnosed or suffer from r/r MM following multiples lines of treatment, including patients relapsing after CD38 and BCMA targeted therapies. ISB 2001 demonstrated superior cytotoxicity relative to teclistamab in the samples of patient relapsing from CD38 and BCMAtargeted immunotherapies.
• In April 2023, Ichnos received approvals from HREC in Australia and the FDA to initiate a Phase 1 first-in-human study of ISB 2001 for the treatment of relapsed/refractory multiple myeloma  In April 2024, IGI received approval from DCGI to expand the clinical Phase 1 study into India. This phase 1 study is divided into a dose escalation part and a dose expansion part, with the latter being designed to meet the goals of FDA Project Optimus.
• First patient was dosed in November 2023 and dose escalation is ongoing in Australia and US, with faster patient enrolment than projected.
• First participant in India was dosed in July 2024.
• In July 2023, Ichnos received Orphan Drug Designation from the FDA for ISB 2001 for the treatment of multiple myeloma.
• The bulk drug substance is manufactured in La Chaux-de-Fonds, Switzerland.

ISB 1442 (CD38 x CD47 BEAT^® bispecific antibody)

• This first-in-class biparatopic bispecific antibody targeting CD38 and CD47 was generated by scientists in IGI’s laboratories in Lausanne at the Biopole life sciences campus.
• ISB 1442 is designed to kill CD38-expressing tumor cells through inhibition of the CD47-SIRPαaxis to increase antibody-dependent cellular phagocytosis (ADCP) and enhance antibody-dependent cellular cytotoxicity (ADCC) as well as complement-dependent cytotoxicity (CDC).
• After receiving approval from the HREC in Australia, the U.S. Food and Drug Administration and the Drug Controller General of India, a Phase 1 / 2 first-in-human dose-finding study of ISB 1442 in relapsed/refractory multiple myeloma is now actively enrolling patients in the dose escalation phase in all three countries.
• IGI is also considering the potential development of ISB 1442 in acute myeloid leukemia (AML).
• The preclinical data package for ISB 1442, which may be viewed at this link, shows:
  • Higher potency in vitro for ISB 1442 relative to daratumumab in CD38 high/low tumor models as measured by a multiple antibody-dependent mechanisms of action killing assay
  • Higher tumor growth inhibition for ISB 1442 than daratumumab in CD38 high and low preclinical in vivo xenograft models
  • Low on-target off-tumor binding with ISB 1442 compared to anti-CD47 mAb (hu5F9), is anticipated to result in lower red blood cell depletion in clinic, and potentially a better therapeutic index than anti-CD47 bivalent monoclonal antibodies
  • Additional information on preclinical models in other hematologic malignancies were presented at the 2022 ASH Annual Meeting in December. Specifically, data showed  the rationale for advancing to a clinical study in relapsed/refractory AML (link). ISB 1442 induces killing, including ADCP and ADCC, in AML cell lines in multiple in vitro assays. ISB 1442 also showed superior activity to daratumumab in AML cell lines having intermediate or low CD38 expression.

• ISB 1442 was granted Orphan Drug Designation for multiple myeloma by the FDA in February 2023.
• The bulk drug substance is manufactured in IGI’s manufacturing plan in La Chaux-de-Fonds, Switzerland.
• Additional information on the ongoing Phase 1 was presented at the2023 ASH Annual Meeting. Overall, treatment of low grade (1 or 2) CRS and mostly resolved within one day. No neurotoxicity events have been observed to date. No signal infections or anemia. https://www.hematology.org/meetings/annual-meeting/abstracts
  • Proof of Mechanism in patients was declared based on increasedmacrophage-related markers among the other biomarkers changes observed.
  • Dose escalation is ongoing.

ISB 1342 (CD38 x CD3 BEAT^® bispecific antibody)

• A Phase 1, open-label, dose-escalation, first-in-human study of ISB 1342 in patients with relapsed/refractory multiple myeloma
  • The study has been paused due to pipeline strategic reprioritization and the asset is available for licensing in oncology (proof-of-mechanism and proof-of-concept have been established in RRMM, with acceptable immunogenicity on par with other bispecifics) as well as autoimmune indications, observations of depletion of B cells with the CD38 targeting has been observed during the clinical trial.
  • The Database has been locked and all sites closed by Q2, 2024. The Clinical Study Report is targeted for Q4, 2024.
  • The first partial response in this study was observed in Cohort 109 intravenous (dose level 8 µg/kg) and additional two partial responses were observed in Cohort 110 intravenous (dose level 16 µg/kg). The responses are supported by translational data, where higher T-cell activation has been observed with increasing doses.
• The primary objectives of the Phase 1 study are to:
  • Determine maximum tolerated dose and/or recommended Phase 2 dose of ISB 1342 (Part 1 dose escalation).
  • Assess the anti-myeloma activity of ISB 1342 according to the International Myeloma Working Group response criteria (Part 2 dose expansion).
• Clinical safety remains on par with earlier results presented in a poster session at the 2023 American Society of Hematology (ASH) Annual Meeting in December (link) with data cut-off October 27, 2023:
  • Observed CRS events were moderate and manageable with supportive care
  • No increased risk of infection has been observed
  • Proof-of-Mechanism with evidence of T-cell activation was noted following treatment with ISB 1342
  • Further dose-escalation (to 32 and 64 μg/kg) is warranted based on the manageable safety profile, anti-myeloma activity observed, and supported by PK profile as well as T-cell activation biomarkers.

• ISB 1342 was granted Orphan Drug Designation for multiple myeloma by the U.S. Food and Drug Administration.
• The bulk drug substance is manufactured in IGI’s manufacturing plant in La Chaux-de-Fonds, Switzerland.

Casitas B-lineage lymphoma b (Cbl/b) program

• Casitas B-lineage lymphoma b (Cbl/b) is an E3 ubiquitin ligase that has been identified as a key inhibitor of T and NK cells activation in the absence of CD28 co-stimulation, regulate immune cells activity in PD-1, CTLA4, TIGIT etc positive cells.  As an intracellular master regulator, Cbl/b inhibition may lead to robust immune cells activation in suppressed tumor microenvironment and induce strong single agent activity.

• GRC 65327 is the provisional clinical candidate. It has been identified as a novel nanomolar potent, selective, and orally bioavailable candidate with intuitive medicinal chemistry and computational chemistry approaches.

• IND-enabling studies are near completion.  The analytical method development and validation for the drug substance is completed, and tech transfer planned by end of Aug.  Raw material procurement activities underway.  A capsule formulation feasibility and dissolution (50 mg to 250 mg) trials are completed.  A feasibility trial for a backup capsule formulation is ongoing.  Confirmation on final capsule strengths to be manufactured at R&D is awaited from the DMPK team to load batches of required strengths on stability to support Phase 1 submission to the Drugs Controller General of India (DCGI).

• The submission to the DCGI is planned at the end of CY24 and the FIH trial is expected to start in early 2025 and enroll patients with relapsed/refractory solid tumor indications.

• An abstract on the preclinical assessment of GRC 65327 is accepted for poster presentation in the 39th Annual Meeting of the Society of Immunotherapy of Cancer (SITC), Nov 2024 in Houston, USA.

Autoimmune Diseases

IGI has two monoclonal antibody drug product candidates addressing autoimmune diseases in the pipeline. To enhance the company’s focus on oncology, future development of both assets are overseen by out-licensing partners.

The first asset, ISB 880, an anti-IL-1RAP antagonist, was licensed to Almirall, S.A. in December 2021. The initiation of dosing in a Phase 1 study of ISB 880/ALM27134 was announced by Almirall in September 2022.

The second antibody, ISB 830 (telazorlimab) and its follow-on molecule ISB 830-X8, was licensed to Astria Therapeutics in October 2023. Telazorlimab is an OX40 antagonist that successfully completed a Phase 2b study in moderate to severe atopic dermatitis in 2021. Both compounds have potential across a range of autoimmune diseases.