LAG3

Multi-centre trial evaluating efti in combination with pembrolizumab and chemotherapy in patients with non-small cell lung cancer reaches enrolment target of approximately 50 evaluable patientsData updates from INSIGHT-003 are expected in 2025 and beyond SYDNEY, AUSTRALIA, Jan. 06, 2025 (GLOBE NEWSWIRE) -- Immutep Limited (ASX: IMM; NASDAQ: IMMP) (“Immutep” or “the Company”), a clinical-stage biotechnology company developing novel LAG-3 immunotherapies for cancer and autoimmune disease, today announces that patient enrolment has been completed in the investigator-initiated INSIGHT-003 trial. INSIGHT-003 is evaluating eftilagimod alpha (efti) in combination with the anti-PD-1 therapy, KEYTRUDA® (pembrolizumab) and doublet chemotherapy as first line treatment for patients with advanced or metastatic non-squamous non-small cell lung cancer (1L NSCLC). The Phase I trial has reached its enrolment target of approximately 50 evaluable patients across multiple clinical sites in Germany led by the Frankfurt Institute of Clinical Cancer Research IKF. First Overall Survival results from INSIGHT-003 were reported on 14 November 2024, showing mature data in patients with a minimum follow-up of 22 months (N=21) achieved a median Overall Survival of 32.9 months and a 24-month Overall Survival rate of 81.0%1. These results compare favourably to the 22.0-month median OS and 24-month OS rate of 45.5% from a registrational trial of anti-PD-1 and doublet chemotherapy in non-squamous 1L NSCLC regardless of PD-L1 expression.2 Additional data updates from INSIGHT-003 are expected in 2025 and beyond. For more information on the trial, please visit clinicaltrials.gov (NCT03252938). About INSIGHT-003INSIGHT-003 is an investigator-initiated study conducted by the Frankfurt Institute of Clinical Cancer Research IKF and several other German centres. 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 evaluating a triple combination therapy in first line non-small cell lung cancer patients consisting of efti administered subcutaneously in conjunction with an existing approved standard-of-care combination of anti-PD-1 therapy (pembrolizumab) and chemotherapy (carboplatin and pemetrexed) delivered intravenously. The trial will assess the safety, tolerability, and initial efficacy of the combination. About ImmutepImmutep is a clinical-stage biotechnology company developing novel LAG-3 immunotherapy for cancer and autoimmune disease. We are pioneers in the understanding and advancement of therapeutics related to Lymphocyte Activation Gene-3 (LAG-3), and our diversified product portfolio harnesses its unique ability to stimulate or suppress the immune response. Immutep is dedicated to leveraging its expertise to bring innovative treatment options to patients in need and to maximise value for shareholders. For more information, please visit www.immutep.com. 1. Data cutoff - 15 October 20242. Shirish Gadgeel et al., Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non–Small-Cell Lung Cancer. JCO 38, 1505-1517(2020). DOI:10.1200/JCO.19.03136 KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Australian Investors/Media:Catherine Strong, Sodali & Co.+61 (0)406 759 268; catherine.strong@sodali.com U.S. Media:Chris Basta, VP, Investor Relations and Corporate Communications+1 (631) 318 4000; chris.basta@immutep.com

On December 16, Merck announced on its official website that it has officially stopped the development of the anti-TIGIT antibody Vibostolimab and the anti-LAG-3 antibody Favezelimab. This decision marks the end of Merck's years of effort in the field of immune checkpoint inhibitors. Two days later, on December 18, Merck announced its new strategic direction by reaching a collaboration agreement with domestic company Hansoh Pharmaceutical. According to the agreement, Merck will obtain global exclusive licensing rights for Hansoh’s oral small molecule GLP-1 receptor agonist HS-10535, while Hansoh will retain control of the drug in the Chinese market. The total amount of this collaboration is as high as $2 billion. This series of business adjustments reflects Merck's concerns about the impending patent cliff for its main product, Pembrolizumab (Keytruda). At the same time, these adjustments provide clues about future competitive focuses for innovative pharmaceutical companies. Vibostolimab, which Merck has discontinued, is an antibody drug targeting the TIGIT site. TIGIT is an inhibitory receptor expressed on T cells and NK cells, belonging to the immunoglobulin superfamily. Vibostolimab aims to block the TIGIT signaling pathway to enhance the body's immune response against tumor cells. Although TIGIT is regarded as a potential therapeutic target, Merck and several other pharmaceutical companies like Roche have conducted long-term development in this area but have not achieved success. Vibostolimab faced failures in multiple clinical trials, including the KeyVibe-002 trial in patients with metastatic non-small cell lung cancer (NSCLC) and studies in high-risk melanoma patients. Similarly, Merck's other drug Favezelimab is an antibody drug targeting the LAG-3 site, aiming to restore the effector function of T cells. Despite several clinical studies, including the Phase III KEYFORM-007 study in PD-L1 positive microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients, Favezelimab also failed to meet its primary endpoint, leading Merck to decide to terminate its clinical development program. After abandoning Vibostolimab and Favezelimab, Merck's next research focus shifts to the oral small molecule GLP-1 receptor agonist HS-10535. GLP-1 related products, as weight loss drugs, hold significant appeal for pharmaceutical companies. Novo Nordisk and Eli Lilly have already reaped substantial profits from their GLP-1 products. Merck began its layout in the GLP-1 project back in 2010, but has yet to successfully launch a product. This collaboration with Hansoh Pharmaceuticals may provide Merck with an opportunity to break through in this field. Currently, the oral Semaglutide tablet (Rybelsus) is the only marketed oral GLP-1 drug, utilizing SNAC technology to facilitate transcellular absorption through the gastric mucosa. Eli Lilly’s Orforglipron is leading the field of oral GLP-1 receptor agonists, while domestic companies such as Heng Rui Medicine's HRS-7535 and Wenshan Medicine's VCT220 are also actively developing. With the impending expiration of the Keytruda patent, Merck is under pressure to find its next blockbuster. Despite setbacks in the research of TIGIT, LAG-3, and GLP-1 targets, Merck's bet on oral GLP-1 small molecule drugs may provide it with a chance to overtake competitors.

After multiple clinical failures, it’s finally the end of the road for Merck’s TIGIT program. The company is dropping development of its anti-TIGIT candidate vibostolimab after two more Phase 3 studies of a fixed-dose combination with Keytruda ended in disappointment. Merck is also discontinuing a separate LAG-3 targeting antibody asset called favezelimab, which it was also testing alongside Keytruda, according to a company release Tuesday. The pipeline cuts mean Merck won’t be able to stave off generic competition for its blockbuster PD-1 medicine by launching fixed-dose combinations with other targeted therapies, Leerink analysts wrote Tuesday. They added that the drugmaker will instead have to focus on converting patients to a subcutaneous formulation of Keytruda, which could launch as soon as next year. The decision to nix vibostolimab was made after two trials of the drug plus Keytruda in certain patients with non-small cell lung cancer — KeyVibe-003 and KeyVibe-007 — met prespecified futility criteria for the overall survival primary endpoint. These flops add to a spate of late-stage disappointments earlier this year in small cell lung cancer and skin cancer . The company is also axing the KeyVibe-006 test of vibostolimab plus Keytruda and chemoradiotherapy in stage 3 NSCLC, which is still enrolling, according to clinicaltrials.gov. Merck did not offer much explanation of what drove the most recent failures, but the Leerink analysts said TIGIT/PD-1 combinations tend to have high levels of toxicity that can lead to patients discontinuing treatment, making it difficult to establish a long-term survival benefit. Merck is not the only drugmaker that has struggled with developing TIGITs. Last month, Roche’s candidate tiragolumab plus its PD-L1 drug Tecentriq missed the OS primary endpoint in a registrational NSCLC test. But there’s still potential for TIGIT drugs that are Fc-incompetent because they could have better safety, the Leerink analysts said. These include Gilead and Arcus’ domvanalimab and Compugen’s COM902. Elsewhere, Merck stopped enrollment in the Phase 3 KEYFORM-008 trial of a fixed-dose combination of favezelimab and Keytruda in certain patients with relapsed or refractory classical Hodgkin lymphoma as it ended the broader KEYFORM development program. The company said the decision was not driven by safety concerns. In September, the favezelimab regimen failed a separate study in metastatic colorectal cancer.