Ivonescimab in Combination with Chemotherapy Approved in China by NMPA for 2L+ EGFRm NSCLC based on HARMONi-A Clinical Trial: Positive Trend Observed in Overall Survival towards Ivonescimab Plus Chemotherapy

Separate & Distinct from HARMONi-2 Announcement, HARMONi-A Showed Clinically Meaningful and Statistically Significant Benefit: PFS Hazard Ratio of 0.46 

For Subset of Patients Previously Receiving 3^rd Generation EGFR-TKI: PFS Hazard Ratio of 0.48

5.6% Treatment Discontinuation of Ivonescimab due to Adverse Events vs. 2.5% Treatment Discontinuation of Placebo

HARMONi-A to be Featured in Oral Presentation at ASCO 2024 Today, May 31, 2024 at 4:57pm CT

HARMONi-A Manuscript Published in JAMA

HONG KONG, May 31, 2024 /PRNewswire/ — Akeso, Inc. (the Company, Akeso, 9926.HK) announced that, on May 24, 2024,  Akeso received marketing authorization in China from the National Medical Products Administration (NMPA). The approval is based on the positive dataset associated with HARMONi-A, a single region, multi-center, Phase III study conducted in China sponsored by Akeso.

HARMONi-A evaluated ivonescimab combined with platinum-doublet chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated, locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) who have progressed after treatment with an EGFR tyrosine kinase inhibitor (TKI) against placebo plus platinum-doublet chemotherapy. This is a clinical setting with a patient population where PD-1 monoclonal antibodies have previously been unsuccessful in Phase III global clinical trials. The Phase III HARMONi-A study provides further evidence supporting the differentiated mechanism of action of ivonescimab, a PD-1 / VEGF bispecific antibody evidencing cooperative binding characteristics.

This data and trial are separate and distinct from the Phase III HARMONi-2 trial in locally advanced or metastatic NSCLC whose tumors have positive PD-L1 expression (PD-L1 TPS >1%), which was covered in a separate announcement. For clarity, the data in this release is with respect to the HARMONi-A trial.

Clinically Meaningful Efficacy
Progression free survival (PFS), the primary endpoint of the study, was significantly improved in the ivonescimab plus chemotherapy arm (HR 0.46; 95% CI: 0.34 – 0.62; p<0.001), representing a 54% reduction in the risk of disease progression compared to chemotherapy. Median PFS for ivonescimab plus chemotherapy was 7.1 months (95% CI: 5.9 – 8.7), as compared to 4.8 months (95% CI: 4.2 – 5.6) for placebo plus chemotherapy. In addition, for the subgroup of patients receiving a 3^rd generation TKI (e.g., osimertinib or other locally approved 3^rd generation TKIs), patients experienced a reduced risk of disease progression of 52% (HR: 0.48; 95% CI: 0.35 – 0.66). The PFS benefit was demonstrated across all clinical subgroups.

While not yet mature, overall survival (OS) analyses performed on request of the NMPA trended positively for ivonescimab plus chemotherapy vs. chemotherapy alone: after 10.2 months of median follow-up, the hazard ratio (HR) was 0.72 (95% CI: 0.48 – 1.09). An additional analysis performed after approximately 17.6 months of median follow-up showed a hazard ratio of 0.80 (95% CI: 0.59 – 1.08). Both overall survival curves appear to demonstrate clear separation between the two arms of the trial and show a trend in improvement of survival towards ivonescimab plus chemotherapy.

Overall response rate (ORR) was 50.6% (95% CI: 42.6% – 58.6%) for those receiving ivonescimab plus chemotherapy vs. 35.4% (95% CI: 28.0% – 43.3%) for those receiving chemotherapy alone. Ivonescimab plus chemotherapy usage resulted in a disease control rate (DCR) – those who either responded or were considered to have stable disease under RECIST 1.1 criteria – of 93.1% (95% CI: 88.0% – 96.5%) vs. 83.2% (95% CI: 76.5% – 88.6%) for those receiving placebo plus chemotherapy.

mFU = median follow-up; NE = not estimable; mFU is 7.89 months unless otherwise noted above

Manageable Safety Profile
Ivonescimab demonstrated an acceptable and manageable safety profile. The most common treatment related adverse events (TRAEs), both all grades and Grade 3 or higher, were hematological, laboratory count-based events: white blood cell count decreases, anemia, neutrophil count decreases, and platelet count decreases. There were nine patients (5.6%) who discontinued ivonescimab due to TRAEs compared to four patients (2.5%) who discontinued placebo due to TRAEs. Grade 3 or higher immune-related adverse events occurred in 6.2% of patients receiving ivonescimab plus chemotherapy and 2.5% of patients receiving placebo plus chemotherapy. Grade 3 or higher VEGF-related adverse events between the two arms were similar (3.1% vs. 2.5%, respectively); there were no Grade 3 bleeding or arterial thrombotic events in the ivonescimab plus chemotherapy arm. No TRAEs resulted in the death of a patient in either arm in this Phase III study.

Summit Therapeutics continues to enroll in the HARMONi clinical trial, a multi-regional Phase III study evaluating ivonescimab plus platinum-doublet chemotherapy vs. placebo plus platinum-doublet chemotherapy with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with a 3^rd generation EGFR TKI. HARMONi will analyze patients enrolled in North America, China, and Europe. HARMONi intends to include all patients from the HARMONi-A trial who previously received a 3^rd generation TKI – representing approximately 276 patients (85%) of the HARMONi-A trial. The planned total enrollment for the Phase III multi-regional HARMONi trial is approximately 420 patients, which Summit intends to complete enrolling during the second half of 2024.

HARMONi-A data will be presented by Dr. Li Zhang, Sun Yat-Sen University Cancer Center, at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL today at 4:57pm CT.

In addition to the HARMONi-A oral presentation, there will be a poster featuring Phase II clinical trial data for ivonescimab in combination with chemotherapy in front-line biliary tract cancer presented on Saturday, June 1, 2024.

About the ASCO 2024 Data
Presentation Title: Ivonescimab combined with chemotherapy in patients with EGFR-mutant non-squamous non-small cell lung cancer who progressed on EGFR-TKIs treatment: a randomized, double-blind, multi-center, phase 3 trial (HARMONi-A study)

ASCO Abstract No.: 8508

Session Date & Time: Friday, May 31 at 4:57pm CT

Poster Title: The safety and efficacy of ivonescimab in combination with chemotherapy as first-line treatment for advanced biliary tract cancer

ASCO Abstract No.: 4095

Session Date & Time: Saturday, June 1 at 1:30PM CT

About Ivonescimab
Ivonescimab, known as SMT112 in Summit’s license territories, the United States, Canada, Europe, and Japan, and as AK112 in China and Australia, is a novel, potential first-in-class investigational bispecific antibody combining the effects of immunotherapy via a blockade of PD-1 with the anti-angiogenesis effects associated with blocking VEGF into a single molecule. Ivonescimab displays unique cooperative binding to each of its intended targets with higher affinity when in the presence of both PD-1 and VEGF.

This could differentiate ivonescimab as there is potentially higher expression (presence) of both PD-1 and VEGF in tumor tissue and the tumor microenvironment (TME) as compared to normal tissue in the body. Ivonescimab’s tetravalent structure (four binding sites) enables higher avidity (accumulated strength of multiple binding interactions) in the tumor microenvironment with over 18-fold increased binding affinity to PD-1 in the presence of VEGF in vitro, and over 4-times increased binding affinity to VEGF in the presence of PD-1 in vitro.¹ This tetravalent structure, the intentional novel design of the molecule, and bringing these two targets into a single bispecific antibody with cooperative binding qualities have the potential to direct ivonescimab to the tumor tissue versus healthy tissue. The intent of this design, together with a half-life of 6 to 7 days,¹ is to improve upon previously established efficacy thresholds, in addition to side effects and safety profiles associated with these targets. 

Ivonescimab was discovered by Akeso Inc. (HKEX Code: 9926.HK) and is currently engaged in multiple Phase III clinical trials. Over 1,600 patients have been treated with ivonescimab in clinical studies globally. Summit has begun its clinical development of ivonescimab in non-small cell lung cancer (NSCLC), commencing enrollment in 2023 in two Phase III clinical trials, HARMONi and HARMONi-3.

HARMONi is a Phase III clinical trial which intends to evaluate ivonescimab combined with chemotherapy compared to a placebo plus chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with a third-generation EGFR TKI (e.g., osimertinib).

HARMONi-3 is a Phase III clinical trial which is designed to evaluate ivonescimab combined with chemotherapy compared to pembrolizumab combined with chemotherapy in patients with first-line metastatic squamous NSCLC.

Ivonescimab is an investigational therapy that is not approved by any regulatory authority in Summit’s license territories, including the United States and Europe. Ivonescimab was approved for marketing authorization in China in May 2024.

About Lung Cancer
Lung cancer is believed to impact approximately 600,000 people across the United States, United Kingdom, Spain, France, Italy, Germany, and Japan.² NSCLC is the most prevalent type of lung cancer and represents approximately 80% to 85% of all incidences.³ Among patients with non-squamous NSCLC, approximately 15% have EGFR-sensitizing mutations in the United States and Europe.⁴ Patients with squamous histology represent approximately 25% to 30% of NSCLC patients.⁵

About Akeso 
Akeso (HKEX: 9926.HK) is a leading biopharmaceutical company committed to the research, development, manufacturing and commercialization of the world’s first or best-in-class innovative biological medicines. Founded in 2012, the company has created a unique integrated R&D innovation system with the comprehensive end-to-end drug development platform (ACE Platform) and bi-specific antibody drug development technology (Tetrabody) as the core, a GMP-compliant manufacturing system and a commercialization system with an advanced operation mode, and has gradually developed into a globally competitive biopharmaceutical company focused on innovative solutions.

With fully integrated multi-functional platform, Akeso is internally working on a robust pipeline of over 50 innovative assets in the fields of cancer, autoimmune disease, inflammation, metabolic disease and other major diseases, with 19 drug candidates in the clinical stage ，including 8 multispecific antibodies. Akeso has successfully promoted the commercialization of three innovative biological drugs, and marketing applications of multiple indications are submitted for 4 new drugs. 安尼可®, approved for marketing in August 2021, is currently the only differentiated PD-1 monoclonal antibody that applies the IgG1 subtype with modified Fc-nulldomain. 开坦尼® (PD-1/CTLA-4 bi-specific antibody, Cadonilimab injection) has been granted marketing approval in June 2022, making it the world’s first bi-specific antibody drug for tumor immunotherapy and the first bi-specific antibody new drug in China.In May 2024,依达方® (PD-1/VEGF bi-specific antibody,Ivonescimab injection) ，the first-in-class PD-1/VEGF bi-specific antibody  independently developed by the Company, has been granted marketing approval for the treatment of epidermal growth factor receptor (“EGFR”) mutated locally advanced or metastatic non-squamous non-small cell lung cancer (“nsq-NSCLC”) ,making it the world’s first approved PD-1/VEGF bi-specific antibody. The drug had been granted three Breakthrough Therapy Designations for the treatment of lung cancer by the Center for Drug Evaluation (CDE) .In December 2022, a license agreement with total potential deal value of USD5 billion, plus a low double-digit royalty of product net sales in the authorized countries of the new drug, 依达方®, set a new record in overseas licensing for the transaction amount of an single innovative drug in China.

Through efficient and breakthrough R&D innovation, Akeso always integrate superior global resources, develop the first-in-class and best-in-class new drugs, provide affordable therapeutic antibodies for patients worldwide, and continuously create more commercial and social values so as to become a global leading biopharmaceutical enterprise.

¹ Zhong, et al, SITC 2023
² American Cancer Society: www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html. Accessed April 2024; World Health Organization: International Agency for Research on Cancer, Globocan data by country (UK, Spain, France, Italy, Germany); Japan National Cancer Registry.  
³ Schabath MB, Cote ML. Cancer Progress and Priorities: Lung Cancer. Cancer Epidemiology, Biomarkers & Prevention. (2019). 
⁴ About EGFR-Positive Lung Cancer | Navigating EGFR (lungevity.org).
⁵ Schabath MB, Cote ML. Cancer Progress and Priorities: Lung Cancer. Cancer Epidemiology, Biomarkers & Prevention. (2019).

Source : Ivonescimab in Combination with Chemotherapy Approved in China by NMPA for 2L+ EGFRm NSCLC based on HARMONi-A Clinical Trial: Positive Trend Observed in Overall Survival towards Ivonescimab Plus Chemotherapy

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