TOP1

First anti-Claudin-1 antibody-drug conjugate (ADC) to enter the clinic Phase 1/2 clinical trial in patients expected to start Q1 2025 BASEL, Switzerland I October 02, 2024 I Alentis Therapeutics (“Alentis”), the clinical-stage biotechnology company developing treatments for Claudin-1 positive (CLDN1+) tumors and organ fibrosis, announced today that the U.S. Food & Drug Administration (FDA) cleared an IND application for ALE.P02, an anti-CLDN1 ADC with a tubulin inhibitor payload. A Phase 1/2 clinical trial in patients with CLDN1+ squamous tumors is expected to start during the first quarter of 2025. “ ADCs have shown great potential in the treatment of cancer, ” said Luigi Manenti, Chief Medical Officer of Alentis. “ Squamous cancers originating in the head and neck, cervix, esophagus and lung are characterized by high CLDN1 expression, and ALE.P02 provides a first-in-class opportunity for these patients who need new therapies after first-line treatment fails. ” “ Anti-CLDN1 ADCs are exciting because they address the urgent need for novel targets in the ADC space, ” added Tony Mok, Professor of Clinical Oncology at the Chinese University of Hong Kong . “ ALE.P02 is particularly promising for squamous cancers, including HNSCC and NSCLC, where CLDN1 is often overexpressed. The unmet medical need in these indications is significant, and I look forward to the results of the Phase 1/2 study. ” Dr. Roberto Iacone, Chief Executive Officer of Alentis said, “ ALE.P02, entering the clinic, marks a significant advancement in our oncology pipeline. We can maximize our development plan by leveraging insights from human clinical trials of lixudebart (ALE.F02), used as the backbone antibody for Alentis’ ADCs.” Dr. Iacone added,“ For our second ADC program, ALE.P03, with its topoisomerase I inhibitor payload, we plan to initiate a first-in-human clinical trial in 2025. ” About ALE.P02 ALE.P02 is a first-in-class ADC designed by linking a tubulin inhibitor, a potent cancer drug, to our antibody that specifically targets a unique CLDN1 epitope exposed on cancer cells. This combination could be a powerful new tool to fight the many squamous cancers that overexpress CLDN1 with less toxicity than traditional cancer drugs. About Alentis Therapeutics Alentis Therapeutics, the CLDN1 company, is a clinical-stage biotech developing breakthrough treatments for CLDN1+ tumors and organ fibrosis. CLDN1 is a previously unexploited target that plays a key role in the pathology of cancer and fibrotic disease. Alentis is the leading company pioneering anti-CLDN1 antibodies and ADCs to modify and reverse the course of disease. Alentis was founded based on ground-breaking research in the laboratory of Prof. Thomas Baumert, MD at the University of Strasbourg and the French National Institute of Health and Medical Research (Inserm). Alentis is headquartered at the pharma-biotech hub in Basel, Switzerland with an R&D subsidiary in Strasbourg, France and clinical operations in the US. Visit www.alentis.ch SOURCE: Alentis Therapeutics

Based on DESTINY-Breast06 Phase III trial which demonstrated a statistically significant and clinically meaningful progression-free survival benefit for ENHERTU If approved, AstraZeneca and Daiichi Sankyo’s ENHERTU will be the first HER2 directed therapy and ADC for patients prior to receiving chemotherapy for metastatic breast cancer ENHERTU also granted Breakthrough Therapy Designation in the US for this patient population WILMINGTON, DE, USA I October 01, 2024 I AstraZeneca and Daiichi Sankyo’s supplemental Biologics License Application (sBLA) for ENHERTU ® (fam-trastuzumab deruxtecan-nxki) has been accepted and granted Priority Review in the US for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (IHC 0 with membrane staining) breast cancer who have received at least one endocrine therapy in the metastatic setting based on positive results from the DESTINY-Breast06 Phase III trial which compared ENHERTU to chemotherapy. The Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions or enhancing patient compliance. The Prescription Drug User Fee Act date, the FDA action date for their regulatory decision, is anticipated during the first quarter of 2025. ENHERTUwas also recently granted Breakthrough Therapy Designation (BTD) by the FDA in this setting. BTD accelerates the development and regulatory review of potential new medicines intended to treat a serious condition and address a significant unmet medical need. HR-positive, HER2-negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers. 1 Despite being classified as HER2-negative, many of these tumors still carry some level of HER2 expression. 2 It is estimated that up to 85-90% of tumors historically classified as HR-positive, HER2-negative may be HER2-low or HER2-ultralow. 3,4 Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “While endocrine therapies are widely used in the initial treatment of HR-positive metastatic breast cancer, most patients see limited benefit with additional lines of treatment, and subsequent chemotherapy is often associated with poor response rates and outcomes. The results from DESTINY-Breast06 show thatENHERTUhas the potential to evolve the current HR-positive treatment landscape and become the first targeted treatment for patients with HER2-low or HER2-ultralow expression following endocrine therapy.” Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: “This Priority Review highlights the potential to expand the existing indication of ENHERTU in HER2-low metastatic breast cancer to include use in an earlier disease setting as well as in a broader patient population that includes HER2-ultralow. We look forward to working closely with the FDA with the goal of bringing ENHERTU to more patients as quickly as possible.” The sBLA is based on data from the DESTINY-Breast06 Phase III trial presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and recently published in The New England Journal of Medicine . In the trial, ENHERTU reduced the risk of disease progression or death by 37% by blinded independent central review (BICR) versus chemotherapy (hazard ratio [HR] 0.63; 95% confidence interval [CI]: 0.53-0.75; p< 0.0001) in the overall trial population. Median PFS was 13.2 months with ENHERTUcompared to 8.1 months with chemotherapy. Results were consistent between patients with HER2-low expression and HER2-ultralow expression. In the primary endpoint analysis of patients with HER2-low expression, ENHERTU showed a median PFS of 13.2 months compared to 8.1 months for chemotherapy (HR 0.62; 95% CI 0.51-0.74; p<0.0001). In a prespecified exploratory analysis of patients with HER2-ultralow expression, ENHERTU showed a median PFS of 13.2 months versus 8.3 months, respectively (HR 0.78; 95% CI 0.50-1.21). The safety profile of ENHERTU in DESTINY-Breast06 was consistent with previous clinical trials of ENHERTUin breast cancer with no new safety concerns identified. ENHERTU is a specifically engineered HER2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialized by AstraZeneca and Daiichi Sankyo. ENHERTUis already approved in more than 65 countries, including the US, for patients with HER2-low metastatic breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial. Indications ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with: Please see accompanying full Prescribing Information , including Boxed WARNINGS, and Medication Guide. Notes Breast cancer and HER2 expression Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide. 5 More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally. 5 While survival rates are high for those diagnosed with early breast cancer, only approximately 30% of patients who are diagnosed with or who progress to metastatic disease are expected to live five years after their diagnosis. 1 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including breast cancer. 6 Patients with high levels of HER2 expression (IHC 3+ or 2+/ISH+) are classified as HER2-positive and treated with HER2-directed therapies, representing approximately 15-20% of all breast cancers. 7 Historically, tumors that were not classified as HER2-positive were classified as HER2-negative. 2 HR-positive, HER2-negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers. 1 Despite being classified as HER2-negative, many of these tumors still carry some level of HER2 expression. 2 It is estimated that 60-65% of HR-positive, HER2-negative breast cancers are HER2-low and an additional 25% may be HER2-ultralow. 3,4 Endocrine therapies are widely used in the early lines of treatment for HR-positive metastatic breast cancer; however, after two lines of treatment, further efficacy from endocrine therapy is often limited. 8 The current standard of care following endocrine therapy is chemotherapy, which is associated with poor response rates and outcomes. 8-11 Prior to the approval of ENHERTU in HER2-low metastatic breast cancer post chemotherapy based on the DESTINY-Breast04 trial, there were no targeted therapies approved specifically for patients with HER2-low expression. There are no targeted therapies specifically approved for patients with HER2-low expression prior to chemotherapy or for patients with HER2-ultralow expression. 12 DESTINY-Breast06 DESTINY-Breast06 is a global, randomized, open-label, Phase III trial evaluating the efficacy and safety ofENHERTU (5.4 mg/kg) versus investigator’s choice of chemotherapy (capecitabine, paclitaxel or nab-paclitaxel) in patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) or HER2-ultralow (defined as IHC 0 with membrane staining) advanced or metastatic breast cancer. Patients in the trial had no prior chemotherapy for advanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastatic setting. Patients were also eligible if they had received one prior line of endocrine therapy combined with a CDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of starting 1st-line treatment or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months. HER2 status in the trial was confirmed by central laboratory and was performed on an archival tumor sample obtained at the time of initial metastatic diagnosis or later. If archival tissue was not available, a fresh tissue sample was required. The primary endpoint is PFS in the HR-positive, HER2-low patient population as measured by BICR. Key secondary endpoints include PFS by BICR in the overall trial population (HER2-low and HER2-ultralow), OS in the HER2-low patient population and OS in the overall trial population. Other secondary endpoints include ORR, DOR, time to first subsequent treatment or death, time to second subsequent treatment or death and safety. DESTINY-Breast06 enrolled 866 patients (n=713 for HER2-low and n=153 for HER2-ultralow) randomized at multiple sites in Asia, Europe, Australia, North America and South America. For more information about the trial, visit ClinicalTrials.gov . ENHERTU (fam-trastuzumab deruxtecan-nxki) ENHERTU (fam-trastuzumab deruxtecan-nxki) is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, ENHERTUis the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. ENHERTU (5.4mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+ or in-situ hybridization [ISH]+) breast cancer who have received a prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial. ENHERTU (5.4mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial. ENHERTU (5.4mg/kg) is approved in more than 45 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ENHERTU (6.4mg/kg) is approved in more than 45 countries worldwide for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 , DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Full approval in China for this indication will depend on whether a randomized controlled confirmatory clinical trial can demonstrate clinical benefit in this population. ENHERTU (5.4mg/kg) is approved in the US for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02 , DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication in the US may be contingent upon verification and description of clinical benefit in a confirmatory trial. ENHERTU development program A comprehensive global clinical development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2-targetable cancers. Trials in combination with other anti-cancer treatments, such as immunotherapy, also are underway. Daiichi Sankyo collaboration AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan in July 2020 , except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan. AstraZeneca in breast cancer Driven by a growing understanding of breast cancer biology, AstraZeneca is starting to challenge, and redefine, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need – with the bold ambition to one day eliminate breast cancer as a cause of death. AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumor environment. With ENHERTU (fam-trastuzumab deruxtecan-nxki), a HER2-directed antibody drug conjugate (ADC), AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in previously treated HER2-positive and HER2-low metastatic breast cancer and are exploring its potential in earlier lines of treatment and in new breast cancer settings. In HR-positive breast cancer, AstraZeneca continues to improve outcomes with foundational medicines goserelin and aims to reshape the HR-positive space with first-in-class AKT inhibitor, capivasertib, and next-generation SERD and potential new medicine camizestrant. AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan, in this setting. PARP inhibitor olaparib is a targeted treatment option that has been studied in early and metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with MSD (Merck & Co., Inc. in the US and Canada) continue to research olaparib in these settings and to explore its potential in earlier disease. To bring much-needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is evaluating the potential of datopotamab deruxtecan alone and in combination with immunotherapy durvalumab, capivasertib in combination with chemotherapy, and durvalumab in combination with other oncology medicines, including olaparib and ENHERTU. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 125 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on social media @AstraZeneca . References SOURCE: AstraZeneca

In the ADC renaissance of the last few years, Japan’s venerable pharma company Daiichi Sankyo has won many of the headlines. But if MediLink Therapeutics has its way, Chinese biotechs will cement the treatments’ dominance in oncology — and prove that China’s new generation of drugmakers can truly compete on the global stage. MediLink has raised $120 million in funding and counts BioNTech and Roche as partners. The Suzhou-based company is at the forefront of a dealmaking wave in which multinational pharma companies have increasingly looked to China as a source of early drug candidates. And MediLink’s licensing deals with multinational pharmas are a bright spot amid growing US-China tensions that have cast a chill over much of the local industry’s work with US companies. The biotech, founded in 2020, came on the scene just as “nearly every pharma was looking for ADCs” again after the drugs had fallen out of favor a decade prior, said Jiaqiang Cai, MediLink’s co-founder and chief scientific officer. That wasn’t always the case. Cai previously worked at Sichuan Kelun-Biotech, which began pursuing ADCs in 2013 after the FDA approval of Roche’s Kadcyla sparked an ADC me-too frenzy in China. While he believed Kelun had a me-better molecule, at 2019’s JP Morgan conference in San Francisco, everyone turned him down for meetings to talk about licensing deals. They saw no future in ADCs, and “nobody believed everything we did in China at that time,” he said. A few months later, Merck came calling after AstraZeneca’s up to $7 billion ADC deal with Daiichi Sankyo stunned the industry. Merck licensed Kelun’s TROP2 ADC and eventually inked two more deals for other programs, each with billions of dollars in potential milestones. By then, Cai had left to work for another domestic pharma company in Shanghai. But Tony Xue, his former ADC partner at Kelun, wondered if they could repeat the success with a new startup and a new platform. “Kelun’s technology is actually very good for TROP2. But for many other targets, [it’s] probably too unstable, and also [the] potency is too high,” Cai said. That fine balance of delivering enough chemotherapy to kill cancer without poisoning the rest of the body has long been the key challenge for ADCs. MediLink works with a version of the standard antibody-linker-payload combo that is stable in healthy tissue and doesn’t require internalization of the antibody — meaning its cancer-killing drugs can be unleashed outside the cell, removing some barriers to efficacy. The concept isn’t new. But the way MediLink turned it into reality is emblematic of the fast, iterative engineering that’s helped many Chinese startups get ahead in the drug discovery race. The tiny team led by Xue, Cai and COO Joey Xiao came up with six different ideas of how to structure the payload-linker complex, then hired a CRO to test them all in parallel. They got to work in December 2020. Three months later, in February 2021, they had a molecule that met their criteria. And in June of that year, optimization was complete. “During six months, they made 200 molecules for us. And only six chemists,” he said. Roche made MediLink the first partner for its Shanghai R&D group, and sees the startup “as a fast-growing China biotech with R&D expertise and proprietary ADC platform technology, including differentiated TOP1 inhibitor payload and linker,” a spokesperson for the Swiss drugmaker said. There can be downsides to speed: MediLink and BioNTech’s HER3 ADC was placed on a clinical hold by regulators earlier this year after patient deaths were deemed related to treatment. The serious toxicity arose as MediLink expanded the patient cohort in a short period of time. “We moved too fast,” Cai told Endpoints. But he said the companies also reacted swiftly to pause enrollment and notify regulators. They ended up adjusting the dose, and the hold was lifted in August . With money from the out-licensing deals, MediLink has been able to grow its team to almost 180 people, even though it hasn’t raised any new venture funding since closing a $70 million Series B in 2022. With many of MediLink’s assets already claimed by a partner (before BioNTech and Roche, it also struck deals with Zai Lab, Harbour BioMed and Henlius) the company’s leaders are hoping to keep some candidates in-house before considering more deals, which Cai said would likely happen at a later phase. “For anything you try to license out, you need to get the idea earlier than others, and then you have something other people don’t have,” he said. When asked about concerns that promising data from Chinese patients wouldn’t translate in trials outside the country, Cai noted that the much higher body weight for US patients could skew the pharmacokinetics, and different dose settings may be required in different countries. “I believe eventually it will work,” he said. Key investors: LYFE Capital, Qiming Venture Partners, Legend Capital, Loyal Valley Capital, Apricot Capital, C&D Emerging Capital, Highlight Capital Find the full list of 2024 Endpoints 11 winners here .