Efti is Immutep’s proprietary soluble LAG-3 clinical stage candidate that is a first-in-class antigen presenting cell (APC) activator for the treatment of cancer, capitalising on LAG-3’s unique characteristics to stimulate both innate and adaptive immunity. Through its high affinity for a subset of MHC II ligands, efti binds to and activates antigen presenting cells leading to expansion and proliferation of CD8+ (cytotoxic) T cells, CD4+ (helper) T cells, dendritic cells, NK cells, and monocytes. It also upregulates the expression of key biological molecules like IFN-ƴ and CXCL10 that further boost the immune system’s ability to fight cancer.

Efti is under evaluation for a variety of solid tumours including non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), and HER2–neg/low metastatic breast cancer. Its favourable safety profile enables various combinations, including with anti-PD-[L]1 immunotherapy and/or chemotherapy. Efti has received Fast Track Designation in 1st line HNSCC and in 1st line NSCLC from the United States Food and Drug Administration (FDA).

EOC Pharma has the exclusive development rights for efti in the territory of Greater China (namely mainland China, Hong Kong SAR, Macao SAR, and Taiwan). Immutep received a $1 million milestone from EOC Pharma in January 2018 and is eligible to receive additional milestone payments and sales-based royalties.

Immutep retains development rights for efti in all other countries worldwide and has the option of out-licensing it for further geographic territories.

TACTI-003

TACTI-003 is a randomised, controlled Phase IIb clinical trial in 1st line head and neck squamous cell carcinoma (HNSCC). The study is evaluating efti in combination with MSD’s KEYTRUDA® (pembrolizumab) as a 1st line therapy in metastatic or recurrent HNSCC patients with PD-L1 negative and PD-L1 positive (CPS ≥1) tumours. It will enroll approximately 154 patients and will take place across Australia, Europe and the United States of America in up to 35 clinical sites.

The study will evaluate the safety and efficacy of efti in combination with pembrolizumab, compared to pembrolizumab alone in 1st line metastatic or recurrent HNSCC patients with PD-L1 positive (CPS ≥1) tumours (cohort A), and determine the efficacy and safety of efti plus pembrolizumab in patients with PD-L1 negative tumours (CPS <1) (cohort B). According to the current plans, about 130 patients in cohort A will be randomised 1:1 to receive either efti plus pembrolizumab or pembrolizumab alone. Subjects in cohort B (up to 24 patients) will receive a combination of efti and pembrolizumab. The primary endpoint of the study is Overall Response Rate (ORR) according to RECIST 1.1. Secondary endpoints include Overall Survival (OS) and Progression Free Survival (PFS). For more information about the Phase IIb trial, visit clinicaltrials.gov (NCT04811027).

AIPAC-003

AIPAC-003 is an integrated Phase II/III trial to evaluate eftilagimod alpha (“efti”) in combination with paclitaxel for the treatment of metastatic HER2-neg/low breast cancer (MBC) and triple-negative breast cancer, an aggressive cancer with limited treatment options. The Company and the US Food and Drug Administration (FDA) agreed to the trial design, which also incorporates feedback from Scientific Advice meetings with the European Medicines Agency (EMA).

As a first-in-class soluble LAG-3 protein targeting MHC Class II ligands on antigen-presenting cells (APC), efti is uniquely positioned to improve clinical outcomes from standard-of-care chemotherapy. Its activation of APCs (e.g., dendritic cells, monocytes) triggers a broad immune response that includes significant increases in cytotoxic CD8+ T cells armed with chemo-induced tumour antigens to target cancer. This synergy was demonstrated by the AIPAC Phase IIb trial’s encouraging efficacy and safety. Unlike the prior AIPAC trial that administered efti + paclitaxel on different days and stopped chemotherapy at six months, patients will receive same-day administration of efti + paclitaxel that can continue until disease progression in AIPAC-003.

The trial has an open-label lead-in component of 6 to 12 patients to test 90mg efti dosing in combination with paclitaxel driven by efti’s excellent safety profile, along with the FDA’s Project Optimus initiative in oncology. This will be followed by a randomized (1:1) portion of the Phase II consisting of up to 58 patients that will receive 30mg efti or 90mg efti to determine the optimal biological dose in combination with paclitaxel. Depending on the Phase II results, potential regulatory actions and resources, a randomized, double-blinded, placebo-controlled Phase III portion will then follow. The Phase III will have overall survival as the primary endpoint and may include a specific patient population. For more information about the trial, visit clinicaltrials.gov (NCT05747794).

TACTI-002

TACTI-002 (Two ACTive Immunotherapies) is being conducted in collaboration with Merck & Co., Inc., Rahway, NJ, USA (known as “MSD” outside the United States and Canada). The study is evaluating the combination of eftilagimod alpha (efti) with MSD’s anti-PD-1 therapy KEYTRUDA® (pembrolizumab) in patients with first & second line non-small cell lung cancer (NSCLC), and second line head and neck squamous cell carcinoma (HNSCC). Recruitment was completed in November 2021.

The trial is a Phase II, Simon’s two-stage, non-comparative, open-label, single-arm, multi-centre clinical study that is taking place in study centres across Australia, Europe, and the US.

Patients participate in one of the following:

• Part A - first line NSCLC, PD-X naïve
• Part B - second line NSCLC, PD-X refractory
• Part C - second line HNSCC, PD-X naïve

TACTI-002 is an all-comer study in terms of PD-L1 status, a well-known predictive marker for response to pembrolizumab monotherapy especially in NSCLC and HNSCC. More information about the trial can be found on Immutep’s website or on ClinicalTrials.gov (Identifier: NCT03625323).

INSIGHT-003

INSIGHT-003 is an investigator-initiated study conducted by the Institute of Clinical Cancer Research IKF at Krankenhaus Nordwest in Frankfurt. It is being run as the third arm (Stratum C) of the ongoing Phase I INSIGHT trial with Prof. Dr. Salah-Eddin Al-Batran as lead investigator. The study is the first evaluating a triple combination therapy consisting of efti in conjunction with an existing approved standard-of-care combination of anti-PD-1 therapy and chemotherapy.

Stratum C reached its enrolment target of 20 patients with advanced non-small cell lung cancer. Patients will receive 30 mg subcutaneous doses of efti every two weeks in conjunction with standard-of-care anti-PD-1 therapy plus chemotherapy. The trial will assess the safety, tolerability, and initial efficacy of the combination. Initial results from the trial were shared at the Society for Immunotherapy of Cancer (SITC) Annual Meeting 2022, which show the triple combination therapy is well-tolerated and provides promising early signals of therapeutic activity in 1L NSCLC patients with an Objective Response Rate (ORR) of 72.7% (8/11) and a Disease Control Rate (DCR) of 90.9% (10/11). Nine patients had a PD-L1 Tumour Proportion Score (TPS) of <50% and this group also reported an encouraging ORR of 66.7% and DCR of 88.9%.

INSIGHT-005

INSIGHT-005 will be an investigator-initiated explorative, open-label study evaluating the safety and efficacy of Immutep’s lead product candidate, efti, in combination with avelumab (BAVENCIO®) in up to 30 patients with metastatic urothelial cancer. INSIGHT-005 is the fifth arm of the investigator-initiated INSIGHT trial, which is being conducted by the Institute of Clinical Cancer Research IKF at Krankenhaus Nordwest in Frankfurt, Germany.

This Phase I trial is Immutep’s second collaboration with Merck KGaA, Darmstadt, Germany, and Pfizer Inc., which builds on the encouraging clinical data previously reported across multiple solid tumour indications in the INSIGHT-004 Phase I study, which was the first combination trial of efti with an anti-PD-L1 drug (avelumab). Here is a summary of the final INSIGHT-004 results:

• Objective Response Rate of 41.7% (5/12) in this all-comer PD-L1 expression trial
• Disease Control was seen in 50% of patients (6/12)
• 75% of patients were still alive in this partly heavily pretreated patient population as of data cut off
• Deep and durable responses in patients with low or no PD-L1 expression and typically IO insensitive indications like gastroesophageal or cervical cancer
• Combination treatment well tolerated with no dose limiting toxicities, building on efti’s strong safety profile.

Under the Agreement, Immutep and Merck KGaA, Darmstadt, Germany will jointly fund the INSIGHT-005 study. The trial will take place in Germany and will be conducted by the Institute of Clinical Cancer Research, Krankenhaus Nordwest (IKF). Avelumab is co-developed and co-commercialised by Merck KGaA, Darmstadt, Germany and Pfizer Inc.

IMP761 is a first-in-class immunosuppressive agonist antibody to LAG-3, which has the potential to address the root cause of autoimmune diseases by specifically silencing autoimmune memory T cells that accumulate at the disease site and which express LAG-3 as an “exhaustion marker” after being repeatedly stimulated with dominant self-peptides.

In early 2019, Immutep reported encouraging pre-clinical results from its studies with IMP761. The in vivo studies showed that IMP761 decreases inflammatory T cell infiltration induced by intra-dermal injection of an antigen. These findings were published in the Journal of Immunology in January 2020. Additional pre-clinical research findings from a juvenile arthritis ex-vivo model were published in Pediatric Research in May 2021. In these studies, IMP761 was shown to decrease effector T cell cytokine secretion.

In December 2022, Immutep announced that a GMP compliant manufacturing process has been established for IMP761. The 200L scale attained by Northway Biotech, an end-to-end biopharmaceutical contract development and manufacturing organisation (CDMO), will ensure supply of IMP761 for IND-enabling studies and ensuing clinical trials.

Our third product candidate is LAG525, an antagonist (blocking) antibody targeting the LAG-3 molecule on T cells with potential applications in the treatment of cancer. It is designed to block the negative signal that may stop T cells from responding to the cancer.

LAG525 is a humanized form of IMP701, a pioneering anti-LAG-3 antibody targeting LAG-3 designed by Immutep that was licensed to CoStim Pharmaceuticals, or CoStim, under an exclusive license and collaboration agreement. In February 2014, CoStim became a wholly owned subsidiary of Novartis.

LAG525 is being evaluated by Novartis in Phase I and Phase II clinical trials for the treatment of cancer. Novartis has full responsibility for the development of the antibody program and Immutep is eligible to receive development-based milestone payments and royalties.

Our fourth product candidate is IMP731 (GSK`781) , a depleting (cytotoxic) antibody that is intended to destroy LAG-3 expressing activated T cells involved in autoimmunity.

IMP731 has been licensed by Immutep to GlaxoSmithKline ("GSK"), under a license and research agreement. This clinical-stage asset is being transitioned back to Immutep as the licensing agreement has been terminated with an effective date of 30 May 2024.