Immutep Limited (Immutep), a biotechnology company, engages in developing novel Lymphocyte Activation Gene-3 (LAG-3) related immunotherapies for cancer and autoimmune disease.
The company’s lead clinical candidate is eftilagimod alpha (‘efti’ or ‘IMP321’) for the treatment of different types of cancers. Efti is a soluble LAG-3Ig fusion protein that is a first-in-class antigen-presenting cell (APC) agonist designed to capitalize on LAG-3’s unique ability to drive the adaptive and innate immune s...
Immutep Limited (Immutep), a biotechnology company, engages in developing novel Lymphocyte Activation Gene-3 (LAG-3) related immunotherapies for cancer and autoimmune disease.
The company’s lead clinical candidate is eftilagimod alpha (‘efti’ or ‘IMP321’) for the treatment of different types of cancers. Efti is a soluble LAG-3Ig fusion protein that is a first-in-class antigen-presenting cell (APC) agonist designed to capitalize on LAG-3’s unique ability to drive the adaptive and innate immune systems against cancer. Efti binds to and activates antigen presenting cells via MHC II molecules 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 that further boost the immune system’s ability to fight cancer. Efti’s favourable safety profile enables various combinations, including with anti-PD-[L]1 immunotherapy and/or chemotherapy.
As part of the company’s late-stage clinical development strategy for efti, Immutep is preparing to commence TACTI-004, which is a registrational Phase III trial in combination with an anti-PD-1 therapy and chemotherapy in 1st line non-small cell lung cancer (NSCLC). In addition, the company is conducting a Phase IIb trial of efti in combination with an anti-PD-1 therapy in 1st line head and neck squamous cell carcinoma (HNSCC) called TACTI-003 (NCT04811027). The company is also conducting an integrated Phase II/III trial evaluating efti in combination with standard-of-care paclitaxel for the treatment of metastatic breast cancer (MBC), called AIPAC-003 (NCT05747794).
Efti is also being evaluated as part of a combination therapy with an immune checkpoint inhibitor in 1st and 2nd line non-small cell lung carcinoma, as well as 2nd line head and neck squamous cell carcinoma in the ongoing Phase II clinical trial, called TACTI-002 (NCT03625323) and in two separate investigator-initiated trials: the first is a Phase I trial platform in a variety of solid tumors called INSIGHT (NCT03252938) and the second, a Phase II trial evaluating efti in combination with radiotherapy and pembrolizumab in soft tissue sarcoma, called EFTISARC-NEO.
Efti has completed a Phase IIb clinical trial as a chemo-immunotherapy combination for metastatic breast cancer termed AIPAC (NCT02614833), and a Phase I combination therapy trial in metastatic melanoma termed TACTI-mel (NCT02676869).
IMP701 is licensed to and being developed by Novartis for the treatment of cancer. IMP731 was previously licensed to a major pharmaceutical company and is now being transferred back to Immutep. Immutep is also developing an agonist of LAG-3 (IMP761) for autoimmune disease.
Efti (IMP321) Clinical Development Program
TACTI-mel
Efti has been utilized in multiple clinical trials in combination with immune checkpoint inhibitors, including anti-PD-1 and anti-PD-L1 immunotherapies. The first such trial was initiated during fiscal 2016 called Two ACTive Immunotherapeutics in melanoma (TACTI-mel), a Phase I study on efti’s effectiveness in enhancing immune responses to PD-1 inhibitors in melanoma patients. The primary purpose of the TACTI-mel trial, which had a study group of up to 24 patients, was to determine safety and dosage levels for combining the two products in future trials. In December 2016, the company announced first clinical data from its TACTI-mel Phase I clinical trial for efti combined with PD-1 checkpoint inhibitor pembrolizumab (KEYTRUDA®) in melanoma cancer. The results confirmed that efti is safe and well tolerated at the first dose level of 1 mg, paving the way for 6 mg dosage. In January 2017, it commenced recruitment for the second cohort of six patients for the TACTI-mel melanoma trial, which was fully recruited by March 2017.
After reporting additional encouraging interim data regarding the efficacy and safety of efti combined with pembrolizumab (KEYTRUDA®), in March 2018 the company expanded the clinical trial to include a fourth cohort (Part B) of six patients evaluating dosing of efti at 30mg in combination with pembrolizumab. In May 2018, interim data for the initial three cohorts (Part A) yielded an overall response rate of 61% when the response rates from the initial four cycles of pembrolizumab monotherapy are used, and an overall rate response (ORR) of 33% measured from the start of the combination therapy when efti was added at cycle five of pembrolizumab. Two complete responses according to RECIST were reported from the trial, out of 18 patients. Full recruitment of the expanded TACTI-mel trial was reached in August 2018, bringing the participation number to 24 patients.
In November 2018, Immutep presented new interim data from the TACTI-mel trial, which were reconfirmed with more mature data in March 2019. Its reported efficacy data from Part A was encouraging and supportive of previously disclosed response rates. The first efficacy data from Part B of the trial was also reported in November 2018, where the combination treatment is administered to patients from the beginning of cycle 1, day 1 of pembrolizumab treatment. In October 2019, Immutep reported final efficacy data from the TACTI-mel trial. Deep and durable responses were observed with 56% and 66% of patients showing tumor shrinkage in Parts A and B, respectively.
TACTI-002
Following the end of FY24, in August 2024, Part A of the TACTI-002 Phase II trial remains ongoing, and has already shown efti is enabling deep, durable responses for patients regardless of PD-L1 expression with a favorable safety profile in line with anti-PD-1 monotherapy. Exceeding expectations, median Overall Survival (OS) has reached 35.5 months in NSCLC patients expressing PD-L1 (patients with a Tumor Proportion Score (TPS) of >1%) and 23.4 months in patients with low PD-L1 expression (TPS 1-49%). Encouragingly, OS has not yet been reached in patients with high PD-L1 expression (TPS >50%). These patients continue to be followed.
TACTI-003
TACTI-003 is a 1:1 randomized, controlled clinical study in approximately 154 1st line HNSCC patients to evaluate the safety and efficacy of efti in combination with pembrolizumab, compared to pembrolizumab alone.
In September 2024, Immutep announced positive efficacy and safety results from the TACTI-003 Phase IIb trial evaluating eftilagimod alpha (efti) in combination with MSD’s anti PD-1 therapy KEYTRUDA (pembrolizumab) as first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma patients (1L HNSCC). In patients with any PD-L1 expression (CPS >1), efti in combination with KEYTRUDA outperformance is largest in CPS >20 with 31.0% ORR (34.5% ORR including partial response after data cut-off) versus 18.5% ORR for KEYTRUDA. Efti in combination with KEYTRUDA led to a high durability of response of 17.5 months in patients with any PD-L1 expression and combination continues to have favorable safety profile. Statistically significant increase in absolute lymphocyte count biomarker seen in the efti in combination with KEYTRUDA arm shows efti’s biological activity in a randomized setting.
TACTI-004
Immutep is preparing to commence TACTI-004, its Phase III trial of efti in combination with an anti-PD-1 therapy in 1st line NSCLC. In June 2024, Immutep entered into its third and most important collaboration with Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside the United States and Canada) for its upcoming registrational Phase III trial in non-small cell lung cancer called TACTI-004. In July 2024 Immutep announced that positive feedback had been received from multiple agencies, concluding preparatory work for TACTI-004 which is planned to enrol ~750 patients. The FDA feedback from this Type C meeting, along with feedback previously received from the Paul-EhrlichInstitut (‘PEI’) and the Spanish Agency for Medicines and Health Products (‘AEMPS’), concludes the preparatory regulatory interactions for the design of this registrational trial.
EFTISARC-NEO
In September 2022, Immutep announced it would support the evaluation of Efti in a new cancer setting, soft tissue sarcoma, aligning with its strategy to expand the application of Efti into a broader range of cancer indications in a capital efficient manner. In September 2024, Immutep announced that it would present new data from the EFTISARC-NEO Phase II investigator-initiated trial of efti in combination with radiotherapy plus KEYTRUDA (pembrolizumab) for patients with soft tissue sarcoma (STS) at the Connective Tissue Oncology Society 2024 Annual Meeting on 14 November.
INSIGHT-004
In July 2017, Immutep announced its collaboration partner, the Institute of Clinical Cancer Research, Krankenhaus Nordwest GmbH in Frankfurt Germany (“IKF”), had received the regulatory and ethical approvals for the clinical trial investigating efti in new settings, called “INSIGHT”. The investigator-initiated INSIGHT clinical trial was designed to explore different routes of administration of efti in solid tumors.
In June 2021, Immutep reported positive final results from INSIGHT-004 at the ASCO 2021 Annual Meeting showing promising activity signals from efti in combination with avelumab in a variety of solid cancers, primarily gastrointestinal. Overall, 41.7% (6/12) of patients responded to the therapy and 50% (6/12) showed disease control. Importantly, efti continued to be well tolerated. These encouraging results are supportive of further clinical evaluation of this new combination, efti plus anti-PD-L1 therapy.
INSIGHT-003
In June 2021, Immutep announced it had signed an agreement to commence a new Phase I trial, called INSIGHT-003, to evaluate the combination of lead product candidate eftilagimod alpha (‘efti’ or ‘IMP321’) in conjunction with an existing approved standard of care therapy consisting of a chemotherapy agent and an anti-PD-1 therapy. INSIGHT-003 is an investigator-initiated trial conducted by IKF and will be run as an amendment to the protocol of the ongoing INSIGHT trial as the third arm (Stratum C) with Prof. Dr. Salah-Eddin Al-Batran as lead investigator.
In October 2023, at the ESMO Congress, encouraging efficacy and tolerability data were presented, including a robust ORR of 71.4% and a DCR of 90.5%. Notably, the median OS has not yet been reached, while the median Progression-Free Survival (PFS) was 10.1 months.
In the challenging PD-L1 TPS <50% patient population, encompassing both low (TPS 1-49%) and negative (TPS <1%) PD-L1 patients, the triple combination therapy achieved a notable 70.6% response rate and a median PFS exceeding 10 months. This PD-L1 TPS <50% group constitutes about 70% of the overall NSCLC patient population and represents a significant area of unmet medical need. The strong ORR observed in this trial compares favorably with results from an independent registrational trial of anti-PD-1 and doublet chemotherapy, which reported a response rate of 40.8% in a similar patient population.
INSIGHT-005
INSIGHT-005 is an open-label trial evaluating the safety and efficacy of efti in combination with BAVENCIO (avelumab) in up to 30 patients with metastatic urothelial carcinoma. In January 2024, the first patient was enrolled and safely dosed in the trial following receipt of regulatory approvals. Recruitment is continuing.
AIPAC
In fiscal 2016, Immutep started Active Immunotherapy PAClitaxel (AIPAC), a Phase IIb study on efti’s effectiveness in treating metastatic breast cancer. The primary purpose of the AIPAC trial, which had a study group of 227 patients in the randomized part of the study and 15 patients for the safety run-in (242 patients in total), was to determine the clinical benefit of efti in terms of Progression-Free Survival as the primary clinical endpoint and a number of secondary endpoints such as Overall Survival in this patient population.
AIPAC-003
AIPAC-003 is an integrated Phase II/III trial evaluating efti in combination with standard-of-care paclitaxel for the treatment of metastatic HER2- neg/low HR+ breast cancer and triple-negative breast cancer, which together account for approximately 78% of breast cancer cases. The Phase II portion of the study will take place at clinical sites across Europe and the United States. The trial includes an open-label lead-in of up to 12 patients dosed at 90mg efti, which will be followed by a randomized (1:1) portion of the Phase II study consisting of up to 58 evaluable patients who will receive 30mg efti or 90mg efti to determine the optimal biological dose in combination with paclitaxel.
In October 2024 the last patient for the Phase II portion was dosed. The Phase II enrolled 65 metastatic hormone receptor positive (HR+), HER2-negative/low, or triple-negative breast cancer patients who exhausted endocrine therapy including cyclin-dependent kinase 4/6 (CDK4/6) inhibitors.
IMP761 Preclinical Development
In April 2024, Immutep entered into an agreement with the Centre for Human Drug Research (CHDR), a world-class institute in Leiden, the Netherlands specializing in innovative early-stage clinical drug research, to perform Immutep’s first-in-human clinical study of IMP761. CHDR will use its unique challenge model that enables insights into IMP761’s pharmacological activity early in clinical development. In August 2024, Immutep received regulatory clearance from the ethics and competent authority in the Netherlands to initiate the trial which will be a single and multiple ascending dose, placebo-controlled, double-blind, Phase I study. The first subject has been successfully dosed.
IMP731 Clinical Development
A third key product candidate of Immutep is IMP731, a depleting antibody that removes T cells involved in autoimmunity. The product candidate was acquired through the company’s acquisition of Immutep S.A.S. (formerly known as Immutep S.A.) in December 2014. The development of IMP731 was licensed to GlaxoSmithKline (GSK) under a license and research collaboration agreement dated December 2010 between Immutep S.A.S. and GSK.
GSK terminated the license and research collaboration agreement effective from May 30, 2024. All development and commercialization rights to the product candidate have reverted to Immutep. GSK is completing the transfer of the candidate and all related data and intellectual property to Immutep. There has been no material impact on the Company’s financial statements due to the termination. As a depleting antibody, IMP731 has a different mode of action compared to that of Immutep’s other LAG3 products in development in oncology and autoimmune diseases. Immutep will examine the data returned from GSK and explore options for further developing and commercializing this asset.
IMP701 Clinical Development
The fourth key product candidate of Immutep is IMP701, an antagonist (blocking) antibody targeting the LAG-3 molecule with potential application in the treatment of cancer. It is designed to block the negative signal in cytotoxic T cells, which may stop T cells from responding to the cancer. The product candidate was acquired through the company’s acquisition of Immutep S.A.S. in December 2014.
The development of IMP701 was licensed to CoStim Pharmaceuticals under an exclusive license and collaboration agreement dated September 2012 between Immutep and CoStim. Under the license, CoStim has the exclusive development right of IMP701, in consideration for the obligation to fund all the development costs and to make milestone and royalty payments to Immutep S.A.S. In February 2014, CoStim became a wholly owned subsidiary of Novartis, but the obligations of the Agreement remained with CoStim.
Novartis presented two posters on LAG525 at ESMO 2021. One poster included data from its PLATForM Phase II study of novel spartalizumab combinations in melanoma, concluding that patients with LAG-3+ melanoma may be more likely to respond to spartalizumab + ieramilimab (LAG525) treatment.
Novartis also presented data from its Phase II, open-label, 3-arm study, in patients with advanced TNBC regardless of PD-L1 status progressing after adjuvant or 1 prior line of systemic therapy for metastatic disease, but who had not received an immune checkpoint inhibitor, where patients were randomized 1:1:1 to LAG525 + spartalizumab, LAG525 + spartalizumab + carboplatin, or LAG525 + carboplatin. As no arms met the proof of preliminary efficacy PPE criteria, no further investigation is planned for this study.
Novartis continued to evaluate ieramilimab in multiple cancer indications during fiscal year 2024 and retains the candidate in its development portfolio.
Intellectual Property
As of June 30, 2024, Immutep owns, co-owns, or in-licenses 16 patent families relating to its development candidates efti, IMP701, IMP731 and IMP761. As of June 30, 2024, the company also owns trademark registrations for IMMUTEP in Australia, United States, Europe, China, and Japan. In fiscal year 2024, Immutep has continued to build its patent portfolio with the addition of 10 new patents.
In particular, Immutep was granted eight patents for efti in the fiscal year, spanning key geographies. New patents covering efti in combination with chemotherapy or anti-PD-1 therapy were granted in Europe, Korea, and Brazil. In addition, patents directed to Immutep’s binding assay for determining MHC Class II binding activity were granted in Brazil, Canada, India, Macao, and Russia. The assay is used in the characterisation of efti in GMP-grade manufacturing.
In addition, the Australian and Japanese Patent Office each granted a new patent protecting IMP761. These two new patents follow the grant of similar patents in other territories.
In January 2024, Immutep entered into a research collaboration agreement with Monash University to progress joint investigations into the structure of LAG-3 and how it interacts with its main ligand, MHC Class II. This work is being led by Professor Jamie Rossjohn at Monash University and Immutep’s CSO, Dr Frederic Triebel. The agreement extends Immutep’s previous research collaboration agreements with Monash University signed in 2017 and 2020.
In June 2024, Immutep signed an exclusive License Agreement with Cardiff University, granting the company the rights to develop and commercialize next-generation anti-LAG-3 small molecules. This agreement builds on years of collaboration between Immutep and Cardiff University’s expert team. The goal of the program is to create an orally available small molecule anti-LAG-3 treatment that offers a more cost-effective alternative to the existing anti-LAG-3 monoclonal and bi-specific antibodies on the market or in clinical development. Several promising compounds that block LAG-3 have been identified in collaboration with the world leading scientists at Cardiff University.
Government Regulations
The company’s ongoing research and development, clinical, regulatory, commercial, and manufacturing activities of pharmaceutical products are subject to extensive regulation by numerous governmental authorities, including in Australia, principally the Therapeutics Goods Administration, or TGA; in the United States, principally the Food and Drug Administration, or FDA; and in Europe, principally the European Medicines Agency, or EMA and local competent authorities, human research ethic committee (HREC), ethics committees (ECs), institutional research boards (IRBs) and other regulatory authorities at federal, state or local levels. The company, along with its third-party contractors, is required to navigate the various preclinical, clinical, and commercial approval and post-approval requirements of the governing regulatory agencies of the countries in which it wishes to conduct studies or seek approval or licensure of product candidates.
When conducting clinical trials in the EU, the company must adhere to the provisions of either the European Union Clinical Trials Directive (Directive 2001/20/EC) or the European Union Clinical Trials Regulation (Regulation 536/2014), which is directly applicable in all EU member states. In Europe, the clinical trial directive is being phased out and is to be replaced by the clinical trial Regulation.
Research and Development
The company’s research and development expenses for the fiscal year 2024 is A$41.55 million.
History
Immutep Limited was incorporated in 1987. The company was formerly known as Prima BioMed Ltd and changed its name to Immutep Limited in 2017.
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