On April 16, 2023 As a global innovative biopharmaceutical company, Henlius reported that it is committed to offering high-quality, affordable and innovative biopharmaceuticals to patients worldwide with 5 products launched in China (Press release, Henlius Biopharmaceuticals, APR 16, 2023, View Source [SID1234630134]). Leveraging the differentiated competitive edges of its products, Henlius adopts meticulous management model and precise market strategies to optimize the commercialization layout and further extend its market reach. In the first quarter of 2023, Henlius’revenue climbed 97.2% to RMB995.7 million. With expanding sales of its flagship products including HANQUYOU and HANSIZHUANG, the company has shown continous revenue growth.

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HANQUYOU Continues to Soar

In the first quarter of 2023, Henlius’ core anti-tumour product HANQUYOU (trastuzumab, trade name in Europe: Zercepac, trade name in Australia: Tuzucip and Trastucip) extended its strong momentum, soaring by 66.7%, to RMB538.6 million.

HANQUYOU, indicated for the treatment of HER2-positive breast cancer and gastric cancer, is the first product sold and promoted in Chinese mainland by the company’s in-house commercialisation team. The 150mg/60mg dual dosage and preservative-free formulation of HANQUYOU sets it apart, leading clinical practices and providing a personalized and cost-effective treatment option for breast cancer patients of any weight. In 2022, the 24,000L production capacity of Songjiang First Plant was approved to commence the commercial production of HANQUYOU, being a driving force behind the production increase and the accerlerated commercialisation of HANQUYOU. Furthermore, Henlius continues to expand the sales network of HANQUYOU. As at the end of 2022, the copany had more than 550 sales agents for HANQUYOU, with the goal of penetrating the Chinese mainland markets with efficiency far exceeding the industry average.

HANQUYOU is the first China-developed mAb approved both in China and Europe. It was approved for commercialisation by the European Commission (EC) and NMPA in July 2020 and August 2020, respectively. In February 2023, the Biologics License Application (BLA) for HANQUYOU has been accepted by the U.S. Food and Drug Administration (FDA), which will further expand the product’s footprint in major markets of biologics in the U.S. and Europe. In addition, Henlius has aggressively pursued international commercialization of HANQUYOU, actively collaborating with global partners to bring its therapeutics to patients in the United States, Canada, Europe, and other emerging markets, covering about 100 countries and regions. Up to now, HANQUYOU has launched in over 30 countries and regions, including the United Kingdom, France, Germany, Switzerland, Australia, Finland, Spain, Singapore, Argentina and Saudi Arabia.

HANSIZHUANG Sees Unbated Growth

In the first quarter of 2023, the company’s first innovative product, HANSIZHUANG (serplulimab) achieved a domestic sales revenue of RMB249.8 million. Notably, HANSIZHUANG realized a monthly sales of over RMB100 million in March 2023 in Chinese mainland, starting a new stage of its sales growth as well as providing strong momentum for the product’s commercialization.

HANSIZHUANG was launched in China in March 2022，and has been approved for 3 indications including MSI-H solid tumour, squamous non-small cell lung cancer (sqNSCLC) and extensive stage small cell lung cancer (ES-SCLC) so far. As the world’s first anti-PD-1 monoclonal antibody (mAb) for the first-line treatment of SCLC, HANSIZHUANG set a record for SCLC immunotherapy with a median OS (overall survival) of 15.8 months. With its outstanding quality and clinical efficacy, HANSIZHUANG has earned wide recognitions from the market and has seen rapid sales uptick. At the beginning of the product’s commercialisation, an amazing "Henlius speed" has been demonstrated in the first deliveries and the first prescriptions of HANSIZHUANG, which also indicated the company’s strong commercial operation and execution. As of the end of 2022, its sales team has been expanded to approximately 400 people. With a rich experience in oncology and meticulous management model, the team has covered over 23,000 healthcare providers from nearly 1000 domestic hospitals. Looking forward, the company will continue to accelerate the market coverage and penetration of HANSIZHUANG in the areas of lung cancer, gastrointestinal and gynecological tumours.

In March 2023, the European Medicines Agency (EMA) has validated the Marketing Authorization Application(MAA) for HANSIZHUANG for the first-line treatment of ES-SCLC. Another patient has also been dosed in a head-to-head bridging trial of HANSIZHUANG versus first-line standard of care atezolizumab for ES-SCLC in the U.S. The company also plans to submit a Biologics License Application (BLA) for HANSIZHUANG in the U.S. in 2024. Meanwhile, the company continues to explore the combination therapies between HANSIZHUANG and self-developed products such as HANBEITAI, HLX07 (anti-EGFR mAb), HLX26 (anti-LAG-3 mAb), HLX208 (BRAF V600E small molecule inhibitor) and HLX60 (anti-GARP mAb) to provide better therapies for the patients, more than 10 clinical trials on immuno-oncology combination therapies are in progress in a wide variety of indications.

Looking forward, Henlius will continue to delve into the area of oncology, auto-immune and other diseases. While maximizing the commercial value of biosimilars at home and abroad, Henlius will actively explore innovation drugs and tackle unmet clinical needs by leveraging its in-house R&D capabilities supplemented by external cooperation and license-in, so as to consolidate the best-in-class capabilities of "integrated research, manufacturing and commercialisation", and achieve steady development as a larger, international and more profitable Biopharma to provide more affordable and better therapies for patients worldwide.

On April 16, 2023 Accent Therapeutics, a biopharmaceutical company developing breakthrough, oncology-focused small molecule therapies that target RNA-modifying proteins (RMPs), reported data supporting DHX9 inhibition as a novel cancer treatment approach at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 in Orlando, Florida (Press release, Accent Therapeutics, APR 16, 2023, View Source [SID1234630133]).

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DHX9 is a multifunctional DEAH-box RNA helicase which has been reported to play important roles in replication, transcription, translation, and RNA splicing – critical processes that contribute to maintenance of genomic stability. Microsatellite instable (MSI) tumors exhibiting defective mismatch repair (dMMR) show a strong dependence on DHX9, making the helicase an attractive target for oncology drug discovery.

"Accent is advancing the compelling and growing body of evidence linking RMPs to cancer pathobiology and demonstrating their untapped potential for addressing cancers with high unmet clinical need. Our systematic analysis of the RMP landscape has revealed several promising precision oncology targets, including DHX9. The data presented at AACR (Free AACR Whitepaper) illustrate strong proof-of-concept supporting DHX9 inhibition as a promising approach to addressing MSI tumors and validate the overall utility of RMPs as a compelling target class for oncology drug development," said Robert A. Copeland, Ph.D., President, Founder, and Chief Scientific Officer of Accent Therapeutics. "We are pleased with our rapid progress advancing from target identification to promising therapeutic programs and look forward to bringing these therapies closer to patients."

The data presented at the meeting provide compelling support for targeted inhibition of DHX9 as a novel therapeutic modality in MSI colorectal cancer (CRC) and describe the first identification of potent and selective small molecule inhibitors of DHX9 that demonstrate tumor cell killing in both in vitro and in vivo preclinical cancer models.

Informed by a proprietary crystal structure of human DHX9, Accent used structural considerations to design selective small molecule inhibitors of the protein and developed a robust assay suite to characterize inhibitor activity. Data from xenograft models demonstrate that oral administration of one such compound, ATX968, was well tolerated in vivo and induced durable tumor regression during the 28-day treatment period, with minimal tumor regrowth observed within a 28-day post treatment window. Dose dependent changes in biomarkers of DHX9 inhibition, such as circular RNA induction – which can be measured in peripheral blood, indicate a promising pharmacokinetic (PK)/pharmacodynamic (PD) profile and further validate DHX9 as a promising new oncology target.

"Our DHX9 program is one in a portfolio of high impact, RNA-modifying targets that Accent is pursuing with novel, oncology-focused small molecules," said Shakti Narayan, Ph.D., J.D., Chief Executive Officer of Accent. "This progress is a testament to our team’s ability to leverage deep insights into cancer biology and structure-based drug development to deliver new precision oncology therapies with transformative potential."

The abstract is available online as part of the annual meeting’s Proceedings supplement in AACR (Free AACR Whitepaper)’s journal, Cancer Research, and the presentation will be archived on the Accent Therapeutics website, www.accenttx.com.

Presentation details are as follows:

Title: Targeting DHX9 Inhibition as a Novel Therapeutic Modality in Microsatellite Instable Colorectal Cancer
Authors: Jennifer Castro, Matthew H. Daniels, Chuang Lu, David Brennan, Deepali Gotur, Young-Tae Lee, Kevin Knockenhauer, April Case, Jie Wu, Shane M. Buker, Julie Liu, Brian A. Sparling, E. Allen Sickmier, Stephen J. Blakemore, P. Ann Boriack-Sjodin, Kenneth W. Duncan, Scott Ribich, Robert A. Copeland
Accent Therapeutics, Lexington, MA
Abstract Number: 1136
Session Category: Experimental and Molecular Therapeutics
Session Title: Innovative Therapeutic Approaches
Session Date and Time: Sunday, April 16, 2023 3:00 – 5:00 PM ET
Session Location: Room W331, Orange County Convention Center, Orlando, Florida

About DHX9
DHX9 is a multifunctional DEAH-box RNA helicase which has been reported to play important roles in replication, transcription, translation, RNA splicing and RNA processing which contribute to DHX9’s role in maintenance of genomic stability. Overexpression of DHX9 has been observed in multiple cancer types, including colorectal cancer (CRC). In addition, microsatellite instable (MSI) tumors exhibiting defective mismatch repair (dMMR) show a strong dependence on DHX9, making this helicase an attractive target for oncology drug discovery.

On April 16, 2023 Telix Pharmaceuticals Limited (ASX: TLX, Telix, the Company) reported successful preclinical development of radiolabelled olaratumab, an antibody licensed from Eli Lilly and Company (Lilly) (Press release, Telix Pharmaceuticals, APR 16, 2023, View Source [SID1234630132]). Telix has demonstrated proof-of-concept (PoC) of using olaratumab to selectively deliver both diagnostic and therapeutic radiation to tumours as a radiopharmaceutical moiety and has produced a candidate for clinical translation. Telix will now progress to first-in-human clinical studies based on these highly encouraging results.

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In April 2022, Telix secured the exclusive worldwide rights to develop and commercialise radiolabelled forms of olaratumab for the diagnosis and treatment of human cancers.[1] Olaratumab was originally developed as a naked (non-radiolabelled) monoclonal antibody targeting Platelet Derived Growth Factor Receptor Alpha (PDGFRα), a target expressed in multiple tumour types. Olaratumab has a well-established clinical safety profile, a favourable toxicology dataset and advanced manufacturing package in relation to Lilly’s development program, which Telix expects to be able to leverage for future development as a radiopharmaceutical drug product.

Telix’s initial development PoC has focused on a rare type of cancer known as Soft Tissue Sarcoma (STS). External beam radiation is a key part of the standard of care for STS, which may therefore be a suitable clinical target for novel radionuclide therapy, particularly for alpha-emitting radionuclides. The ability of olaratumab to target PDGFRα in the STS tumour microenvironment makes it a highly novel and high-potential radiopharmaceutical candidate.

Telix has now completed its preclinical evaluation, with results sufficiently encouraging to advance development toward initial human clinical trials, in line with planned R&D expenditure for 2023/24. The agent has been assigned formal candidate status in Telix’s development pipeline (to be denoted as TLX300-CDx/TLX300 for the diagnostic/patient selection tool and therapeutic, respectively). Specifically, these studies have shown that olaratumab can be bioconjugated with multiple chelators (including Telix’s proprietary DFO-squaramide chelator), radiolabelled with zirconium-89 (89Zr) for imaging by Positron Emission Tomography (PET) and used to demonstrate specific delivery of radiation to STS cancer cells to show proof of concept in xenograft tumour mouse models. Furthermore, olaratumab radiolabelled with therapeutic radionuclide payloads has demonstrated in vivo efficacy with significant reduction in tumour volumes in relevant disease models, even after administration of a single dose. The Company is preparing to publish preliminary findings.

Telix Chief Scientist, Dr Michael Wheatcroft stated, "Building on Telix’s proven track record in acquiring and developing novel radiopharmaceutical assets, it is extremely pleasing to demonstrate the adaptation of this traditional biologic agent for future potential use as a targeted radiopharmaceutical. TLX300 will initially be evaluated in a first-in-human clinical study that is designed to inform both the potential efficacy (dosimetry) and safety profile of this research candidate as a therapeutic, demonstrating the development advantage of a theranostic approach."

About Soft Tissue Sarcoma (STS)

Soft tissue sarcoma is a complex disease that encompasses a diverse group of relatively rare cancers, with more than 50 histological subtypes. In the United States (U.S.), it is estimated that 13,040 new cases and 5,150 deaths were caused by STS in 2019, representing 0.75% of overall cancer incidence and 0.84% of overall cancer mortality.[2] In Europe, nearly 23,600 new STS cases rose annually, and the crude incidence rate was 4.7 per 100,000.[3] Approximately 39,900 new STS cases occurred nationwide in China in 2019, accounting for 1.05% of overall cancer incidence.[4] The crude incidence rate was 2.91/100,000 and generally increased with age. Standard treatment for soft tissue sarcoma includes surgery, radiation therapy and/or chemotherapy. For patients with advanced, unresectable, or metastatic disease, treatment typically involves chemotherapy with single agents (e.g., doxorubicin) or anthracycline-based combination regimens. However, the prognosis for these patients remains poor, with treated patients with metastatic disease having a median overall survival of around 12–18 months.[5]

About olaratumab

Olaratumab (previously marketed under the brand name, Lartruvo) was originally developed as a monoclonal antibody targeting PDGFRα. Olaratumab was granted "Accelerated Approval" in the U.S. and "Conditional Approval" in the EU based on Phase II trial data which showed a 1-year survival benefit in patients with STS, when given in combination with standard chemotherapy. Olaratumab was voluntarily withdrawn from the market by Lilly following the failure of the Phase III ANNOUNCE clinical trial, in which olaratumab did not improve survival for patients.

On April 16, 2023 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high quality medicines for the treatment of oncology, autoimmune, metabolic, ophthalmology and other major diseases, reported that the final analysis results of ORIENT-15, the Phase 3 study evaluating sintilimab in combination with chemotherapy for the first-line treatment of esophageal squamous cell carcinoma (ESCC) were released in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Abstract CT075) (Press release, Innovent Biologics, APR 16, 2023, View Source [SID1234630131]).

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As of data cutoff date (August 28, 2022), a total of 690 patients were randomly assigned and received treatment, and the median follow-up was 32.2 months.

Sintilimab plus chemotherapy significantly improved the median overall survival (mOS) over placebo plus chemotherapy with a 33.9% reduction in risk of death (HR 0.661; P<0.0001) and a 4.6-month improvement in mOS (17.4 vs 12.8 months) in all randomized patients (the ITT population); and 36.5% reduction in risk of death (HR 0.635; P=0.0001) and a 3.9-month improvement in mOS (18.4 vs 14.5 months) in PD-L1 positive patients (defined as combined positive score [CPS] ≥10).

Estimated OS rates at 12 and 24 months for sintilimab plus chemotherapy versus chemotherapy alone in all randomized patients were 64.0% vs 53.5% and 41.4% vs 22.9%, respectively.

The safety profile of sintilimab in this study was consistent with that observed in previously reported studies of sintilimab, and no additional safety signals were identified for the combination of sintilimab and chemotherapy with approximate 16 months of extended follow-up.

The principal investigator of the ORIENT-15 study, Prof. Shen Lin from Peking University Cancer Hospital and Institute, stated, "More than half of new and fatal cases of esophageal cancer in the world occur in China every year. Esophageal cancer is the fifth most commonly diagnosed cancer and the fourth leading cause of death from cancer in China, and squamous cell carcinoma is the predominant histologic type[i]. The interim analysis of ORIENT-15 met all endpoints, and sintilimab in combination with chemotherapy has been approved by the NMPA to be a first-line treatment option for patients with advanced ESCC. In addition, this new indication of sintilimab has been included in the updated China National Reimbursement Drug List (NRDL), benefiting broader patient groups. In this final analysis, sintilimab in combination with chemotherapy demonstrated continued significant OS benefits, further supporting the use of sintilimab plus chemotherapy as a standard of care for first-line treatment in these patients."

Dr. Hui Zhou, Senior Vice President of Innovent, stated, "The approval of immunotherapy has significantly improved the clinical benefits of standard treatments in patients with advanced esophageal squamous cell carcinoma. According to the results of interim analysis, sintilimab plus chemotherapy has been approved by NMPA. We are also pleased that this indication of sintilimab has been included in the NRDL, making sintilimab the only PD-1 inhibitor for the first-line treatment of five high-incidence cancer types included in the NRDL. In this final analysis, the continued significant OS benefits have been verified in advanced ESCC patients with an acceptable safety profile over time, and further demonstrated that sintilimab as a first-line treatment option will benefit ESCC patients in China."

About the ORIENT-15 Study

ORIENT-15 is a global randomized, double-blind, multicenter Phase 3 clinical study evaluating sintilimab in combination with chemotherapy, compared to placebo in combination with chemotherapy, for the first-line treatment of unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ClinicalTrials.gov, NCT03748134). At the time of interim analysis, a total of 659 eligible patients (of the planned 676 estimated participants) were enrolled and randomly assigned into the experimental group or control group in a 1:1 ratio. The primary endpoints were overall survival (OS) in all randomized patients and OS in PD-L1 positive (defined as CPS ≥10) patients[ii].

About Esophageal Squamous Cell Carcinoma (ESCC)

Esophageal cancer (EC) is one of the most common malignant tumors worldwide that begins in the inner layer (mucosa) of the esophagus, which connects the throat to the stomach. Based on GLOBOCAN 2020 estimates, approximately 600,000 new cases of esophageal cancer are diagnosed and approximately 540,000 deaths result from the disease worldwide each year[iii]. Esophageal cancer is the seventh most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwideiii. More than half of new and fatal cases of esophageal cancer in the world occur in Chinai. In China, it is estimated there were approximately 320,000 new cases of esophageal cancer diagnosed and approximately 300,000 deaths resulting from the disease in 2020i. Esophageal cancer is the fifth most commonly diagnosed cancer and the fourth leading cause of death from cancer in China, where it has a five-year survival rate of only 30%i.

The two main types of esophageal cancer are squamous cell carcinoma (SCC) and adenocarcinoma. In China, SCC is the predominant histologic type, accounting for more than 90% of all esophageal cancer[iv]. In the past, first-line standard systemic therapy was chemotherapy based on platinum drugs for unresectable locally advanced, recurrent or metastatic ESCC, which calls for more effective first-line treatment options. Several PD-1 inhibitors have been approved as first-line treatment in combination with chemotherapy[v]，[vi].

About Sintilimab

Sintilimab, marketed as TYVYT (sintilimab injection) in China, is a PD-1 immunoglobulin G4 monoclonal antibody co-developed by Innovent and Eli Lilly and Company. Sintilimab is a type of immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells[vii]. Innovent is currently conducting more than 20 clinical studies of sintilimab to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials.

In China, sintilimab has been approved and included in the National Reimbursement Drug List (NRDL) for all six indications. The updated NRDL reimbursement scope of TYVYT (sintilimab injection) include:

For the treatment of unresectable locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma;
For the treatment of unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma;
For the treatment of unresectable locally advanced or metastatic non-squamous non-small cell lung cancer lacking EGFR or ALK driver gene mutations;
For the treatment of unresectable locally advanced or metastatic squamous non-small cell lung cancer;
For the treatment of unresectable or metastatic hepatocellular carcinoma with no prior systematic treatment;
For the treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy.
Innovent currently has the regulatory submission for sintilimab in combination with bevacizumab biosimilar and chemotherapy for EGFR-TKI failed EGFR-mutated non-squamous NSCLC under review in the China’s NMPA.

Additionally, two clinical studies of sintilimab have met their primary endpoints:

Phase 2 study of sintilimab monotherapy as second-line treatment of esophageal squamous cell carcinoma;
Phase 3 study of sintilimab monotherapy as second-line treatment for squamous NSCLC with disease progression following platinum-based chemotherapy.

On April 16, 2023 Abbisko (Stock Code: 2256.HK) reported the results of five latest preclinical studies at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting (Press release, Abbisko Therapeutics, APR 16, 2023, View Source [SID1234630130]).

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These include its self-developed CSF-1R inhibitor Pimicotinib (ABSK021), which has been recognized as a breakthrough therapy in China and the United States, and ABSK112, a next-generation of EGFR Exon20 inhibitor that may become the best-in-class to overcome resistance mutations, and a next-generation of the latest preclinical and translational research progress of the FGFR4 inhibitor ABSK012 and FGFR inhibitor ABSK121 that overcome drug-resistant mutations, and the next-generation KRAS inhibitor ABSK071.

Abbisko presented the following posters at the AACR (Free AACR Whitepaper) Annual Meeting:

Medicine

Title

Abstract Number

ABSK021

A potent and selective small molecule inhibitor of CSF-1R ABSK021 demonstrates strong efficacy in preclinical models of osteosarcoma

LB329

ABSK112

Discovery and characterization of ABSK112, a next-generation and potential best-in-class EGFR Exon20 mutant inhibitor with superior selectivity and brain penetration ability

LB327

ABSK012

Discovery & characterization of a next-generation FGFR4 inhibitor overcoming resistant mutations

LB328

ABSK121

Discovery and characterization of a next-generation FGFR inhibitor overcoming FGFR resistant mutations

LB317

ABSK071

A next-generation KRASG12C inhibitor ABSK071 demonstrated broad synergy with other therapeutic agents in KRASG12C mutated cancer models

LB316

Title: A potent and selective small molecule inhibitor of CSF-1R ABSK021 demonstrates strong efficacy in preclinical models of osteosarcoma
Abstract Number: LB329
Research Background：
Osteosarcoma is the most common primary malignant bone tumor in children and young adults. Surgery combined with multimodal chemotherapy remains as the standard treatment for osteosarcoma patients. However, patients with osteosarcoma metastasis have a five-year survival rate of less than 30%, and their long-term outcomes have not improved over the last 30 years, representing a high unmet medical need. CSF-1/CSF-1R signaling is crucial for the survival, function, proliferation and differentiation of myeloid lineage cells, including osteoclasts and monocytes/macrophages. Targeting CSF-1R either on tumor cells or tumor-associated macrophages has been reported to limit osteosarcoma progression in preclinical models. ABSK021, an oral, highly potent and selective small molecule inhibitor of CSF-1R, showed significant anti-tumor activity and favorable safety profile in patients with advanced tenosynovial giant cell tumor in phase 1b trial. We demonstrated the treatment potential of ABSK021 for osteosarcoma patients through a series of preclinical in vitro and in vivo experiments, as well as human osteosarcoma profiling.
Result：
ABSK021 has strong inhibition of CSF-1R activity and corresponding anti-tumor activity in preclinical osteosarcoma models. High prevalence of CSF-1R expression was also found in osteosarcoma patients, suggesting great potential of utilizing ABSK021 as a novel therapy to treat osteosarcoma patients in clinic.

Title: ABSK112, a potential best-in-class EGFR exon 20 mutant Inhibitor with excellent selectivity and brain penetration
Abstract Number: LB327
Research Background：
EGFR Exon20 mutations are clinically validated oncogenic alterations including a wide spectrum of mutations occurring in lung cancer and various other cancer types. Although several EGFR Exon20 inhibitors have reached clinical stage or received approval, there still leave large room for improvement in safety and efficacy, likely due to their limited selectivity against wild-type EGFR or other kinases, suboptimal mutation coverage, and lack brain penetrating ability. Herein, we have discovered a novel and next-generation EGFR Exon20 mutation inhibitor, ABSK112. It showed high selectivity over wild-type EGFR and other kinases, as well as a more comprehensive coverage over majority of EGFR Exon20 mutations in comparison with other EGFR Exon20 inhibitors.
Result：
ABSK112 is a leading next-generation EGFR Exon20ins inhibitor with improved selectivity over wild-type EGFR and strong brain penetrating ability. It shows superior in vivo efficacy in various EGFR Exon20ins xenograft models, and broader spectrum of mutation coverage than clinical stage competitors.

Title: Discovery & characterization of a next-generation FGFR4 inhibitor overcoming resistant mutations
Abstract Number: LB328
Research Background：
Aberrant activation of FGF19-FGFR4 signaling pathway plays an essential role in the tumorigenesis of Hepatocellular carcinoma (HCC) and FGFR4 inhibitors have shown preliminary efficacy in recent clinical trials for patients with FGF19 overexpression. However, the observed responses only lasted a few months before tumors relapse. Acquired FGFR4 resistant mutations were found in ~30% of FGFR4 inhibitor responsive patients. Similar FGFR4 mutations haven also been found de novo in about 7-10% of Rhabdomyosarcoma (RMS) and ER-treated invasive lobular carcinoma patients. First generation FGFR4 inhibitors have minimal activity against these de novo or acquired resistant mutations. Therefore, next-generation of FGFR4 inhibitors are needed to overcome these resistant FGFR4 mutations to provide better treatment options for patients. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a next-generation small molecule FGFR4 inhibitor, ABSK012, and demonstrated its strong activities against de novo and acquired resistant FGFR4 mutations while retaining inhibition for wild-type FGFR4.
Result：
ABSK012, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR4 inhibitor overcoming FGFR4 mutations resistant to first-generation inhibitors. Its superior preclinical profile supports its fast-track development into clinic.

Title: Discovery and characterization of a next-generation FGFR inhibitor overcoming FGFR resistant mutations
Abstract Number: LB317
Research Background：
FGFRs play important roles in cancer development and inhibition of FGFR could disrupt tumor cell proliferation and growth. Four selective FGFR inhibitors have been approved (erdafitinib, pemigatinib, infigratinib, and futibatinib) and several others are in clinical development. Unfortunately upon treatment with these first-generation FGFR inhibitors, acquired resistance often develops and is frequently associated with the emergence of secondary FGFR2/3 kinase domain mutations. Therefore, selectively targeting FGFR2/3 as well as their resistant mutations may render a second-generation treatment approach for the refractory/relapsed patients. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a novel, next-generation, and highly selective FGFR inhibitor, ABSK121. This novel inhibitor demonstrated robust anti-tumor activity in FGFR-dependent tumor models with strong activities against not only de novo but also acquired resistant mutations.
Result：
ABSK121, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR inhibitor with great potency against resistant FGFR mutations. Its superior profile supports fast-track preclinical and clinical development.

Title: A next-generation KRASG12C inhibitor ABSK071 demonstrated broad synergy with other therapeutic agents in KRASG12C mutated cancer models
Abstract Number: LB316
Research Background：
KRAS is frequently mutated in human cancers, including pancreatic (~90%), colorectal (~35%), and lung cancer (~25%). The KRASG12C mutation (single amino acid substitution of cysteine for glycine at position 12) accounts for ~14% of lung cancer, ~4% of colorectal cancer, and ~2% of pancreatic cancer. Currently, two covalent KRASG12C inhibitors, namely sotorasib (AMG-510) and adagrasib (MRTX-849), have been approved as monotherapy to treat locally advanced or metastatic NSCLC with KRASG12C mutation through accelerated approval process.
Despite the beneficial effects of KRASG12C inhibitors in clinic for certain patients, the limited antitumor efficacy in most patients and potential drug resistance are major concerns. A next-generation inhibitor with better inhibitory activity may improve anti-tumor efficacy. Combination with other therapeutic agents may also improve the single-agent activity of KRASG12C inhibitors. These approaches could both overcome the limitations of sotorasib and adagrasib and provide additional benefits to patients.
Result：
ABSK071 is a next-generation KRASG12C inhibitor with greater activity and anti-tumor efficacy in vitro and in vivo. It also demonstrated broad synergistic effects with a large set of targeted agents and immuno-oncology agents, indicating its strong potential in combinatory therapy in treating a wider range of KRASG12C-dependent cancers.