On June 5, 2022 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 the preliminary data of IBI351 (GFH925) (KRASG12C inhibitor) from dose escalation portion of a phase I clinical trial (NCT05005234) at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Innovent Biologics, JUN 5, 2022, View Source [SID1234615592]).

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Phase I dose-escalation study of IBI351 (GFH925) monotherapy in patients with advanced solid tumors

Poster Presentation, Abstract #: 3110

IBI351(GFH925) is a novel, irreversible covalent inhibitor of KRASG12C mutation. The NCT05005234 study presented was a first-in-human study conducted in China to evaluate the safety, tolerability and efficacy of IBI351 monotherapy in patients with advanced solid tumors who failed or intolerant to standard of care treatment. As data cutoff (15 April 2022), 31 subjects were enrolled in the study, including 25 patients with non-small cell lung cancer, 5 colorectal cancer and 1 pancreatic cancer. Approximately 30% patients received 3 lines or above prior systemic anticancer therapy. The highlights of the study results were as follows:

Of 21 patients (including 16 non-small cell lung cancer and 5 colorectal cancer) having at least 1 tumor assessment per RECISTv1.1, 9 achieved PR, with investigator assessed ORR 42.9% and DCR 81%.
Of 12 patients with NSCLC treated at/above doses of 700mg once daily, 6 achieved PR, with investigator assessed ORR 50% and DCR 83.3%.
Of 5 CRC patients, 2 achieved PR, with investigator assessed ORR 40% and DCR 60%.
As data cutoff, IBI351 was well tolerated. No DLT was reported and MTD was not reached. Treatment-related adverse events (TRAEs) occurred in 93.5% (29/31) patients and the most common TRAEs were anemia, transferase increased, bilirubin increased, vomiting and diarrhea. The majority of the TRAEs were grade 1-2 with 12.9% (4/31) of patients reporting grade 3 TRAEs. There were no grade 4-5 TRAEs or TRAEs led to treatment discontinuation.
Favorable safety and tolerability and promising antitumor activity of IBI351 monotherapy were observed in previously-treated advanced non-small cell lung cancer and colorectal cancer harboring KRASG12C mutation. As data cutoff, dose escalation is still ongoing. More data will be presented at the future medical meeting.

Professor Yi-Long Wu from Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, stated: "KRASG12C mutation occurs in about 2~4% of non-small cell lung cancer and 2.5% of colorectal cancer in China, and no KRASG12C inhibitor was approved yet in China. IBI351 is a novel, irreversible covalent inhibitor of KRASG12C mutation. The preliminary data shows the favorable safety and promising activity of IBI351 (GFH925) monotherapy in KRAS G12C mutated advanced solid tumor. We look forward to more positive clinical data from this study. "

Dr. Hui Zhou, Senior Vice President of Innovent, stated: "We are pleased to present our clinical development updates at the 2022 ASCO (Free ASCO Whitepaper), and that IBI351 monotherapy demonstrated encouraging efficacy and safety data in phase I dose-escalation study. We are working to advancing into late stage clinical development to explore the potential of IBI351 in monotherapy and combo-therapy. We hope to benefit more cancer patients as we are exploring next-generation immunotherapies."

To learn more about Innovent’s R&D updates and activities at 2022 ASCO (Free ASCO Whitepaper), please visit View Source

About IBI351/GFH925 (KRASG12C Inhibitor)

Discovered by GenFleet Therapeutics, GFH925 (Innovent R&D code: IBI351) is a novel, orally active, potent KRASG12C inhibitor designed to effectively target the GTP/GDP exchange, an essential step in pathway activation, by modifying the cysteine residue of KRASG12C protein covalently and irreversibly. Preclinical cysteine selectivity studies demonstrated high selectivity of IBI351 towards G12C. Subsequently, IBI351 effectively inhibits the downstream signal pathway to induce tumor cells’ apoptosis and cell cycle arrest. In September 2021, Innovent and GenFleet Therapeutics entered into an exclusive license agreement for the development and commercialization of IBI351 in China (including mainland China, Hong Kong, Macau and Taiwan) with additional option-in rights for global development and commercialization.

On June 5, 2022 AstraZeneca reported that Detailed positive results from the pivotal DESTINY-Breast04 Phase III trial showed that Enhertu (trastuzumab deruxtecan) demonstrated superior and clinically meaningful progression-free survival (PFS) and overall survival (OS) in previously treated patients with HER2-low (immunohistochemistry (IHC) 1+ or IHC 2+/in-situ hybridisation (ISH)-negative) unresectable and/or metastatic breast cancer with hormone receptor (HR) positive or HR-negative disease versus standard of care physician’s choice of chemotherapy (Press release, AstraZeneca, JUN 5, 2022, View Source [SID1234615560]). Results will be presented during the Plenary Session today at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, and have been simultaneously published in The New England Journal of Medicine.

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Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

In the primary endpoint analysis for DESTINY-Breast04, Enhertu demonstrated a 49% reduction in the risk of disease progression or death versus physician’s choice of chemotherapy in patients with HER2-low metastatic breast cancer with HR-positive disease (PFS hazard ratio [HR] 0.51; 95% confidence interval [CI]: 0.40-0.64; p<0.001). A median PFS of 10.1 months was seen in patients treated with Enhertu compared to 5.4 months with chemotherapy, as assessed by blinded independent central review (BICR).

Results also showed a 36% reduction in the risk of death with Enhertu compared to chemotherapy in patients with HR-positive disease (OS HR 0.64; 95% CI: 0.48-0.86; p=0.003) with a median OS of 23.9 months with Enhertu versus 17.5 months with chemotherapy, meeting a key secondary endpoint of the trial.

Additionally, data showed consistent efficacy for Enhertu in the overall trial population of patients with HER2-low metastatic breast cancer with HR-positive or HR-negative disease and across levels of HER2 expression (IHC 1+ and IHC 2+/ISH-). In the key secondary endpoint analysis of PFS by BICR in all patients, a similar 50% reduction in the risk of disease progression or death was observed between Enhertu and chemotherapy (PFS HR 0.50; 95% CI: 0.40-0.63; p<0.001). Results also showed a 36% reduction in the risk of death with Enhertu compared to chemotherapy (OS HR 0.64; 95% CI: 0.49-0.84; p=0.001) with a median OS of 23.4 months for Enhertu versus 16.8 months with chemotherapy.

Shanu Modi, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, US and Principal Investigator for the trial, said: "The results of DESTINY-Breast04 show for the first time that a HER2-directed therapy can provide a survival benefit to patients with low HER2 expression, indicating we must reconsider the way we categorise patients with metastatic breast cancer. The efficacy seen with Enhertu also reinforces the potential to establish a new standard of care for more than half of all patients with breast cancer currently categorised as having HER2-negative disease, but who actually have tumours with low HER2 expression."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca said: "Today’s results represent a pivotal moment demonstrating the potential for Enhertu to redefine the treatment of HER2-targetable cancers. DESTINY-Breast04 validates targeting the lower end of the spectrum of HER2 expression, since Enhertu reduced the risk of disease progression or death across all types of patients in the trial by half, and reduced the risk of death by over a third. We must now evolve the way we classify and treat metastatic breast cancer to ensure these patients are effectively diagnosed and treated."

Ken Takeshita, Global Head, R&D, Daiichi Sankyo said: "As innovative research organisations, extending the survival for patients is one of our primary goals as we seek to identify potentially new treatment options for patients with metastatic breast cancer. These potentially practice-changing data show that DESTINY-Breast04 takes us one step closer to achieving this goal, as Enhertu is the first HER2-directed medicine to demonstrate a survival benefit in patients with HER2-low metastatic breast cancer. We are honoured by the recognition these important findings are receiving at one of the world’s most prominent oncology meetings as well as in one of the leading medical journals."

Summary of results: DESTINY-Breast04

table data
CI, confidence interval; CBR, clinical benefit rate; DCR, disease control rate; DoR, Duration of Response; HR, hazard ratio; NE, not evaluable; ORR, overall response rate; OS, overall survival; PFS, progression-free survival
i For the primary end point (PFS in the HR-positive cohort) and key secondary end points (PFS among all patients and OS in the HR-positive cohort and among all patients), the HR status is based on data collected with the use of the interactive web-response and voice-response system at the time of randomisation, which includes patients who were mis-stratified. For the other end points, HR status is based on data from the electronic data capture that was corrected for mis-stratification
ii As assessed by BICR
iii ORR is (Complete Response + Partial Response)
iv CBR is Complete Response + Partial Response + Stable Disease (≥ 6 months)
v DCR is (Complete Response + Partial Response + Stable Disease)

In an exploratory analysis of patients with HR-negative disease (n=58), median PFS was 8.5 months with Enhertu versus 2.9 months with chemotherapy (PFS HR 0.46; 95% CI: 0.24-0.89) and median OS was 18.2 months with Enhertu versus 8.3 months with chemotherapy (OS HR 0.48; 95% CI: 0.24-0.95).

The safety profile of Enhertu was consistent with previous clinical trials with no new safety concerns identified. The most common Grade 3 or higher treatment-emergent adverse events were neutropenia (13.7%), anaemia (8.1%), fatigue (7.5%), leukopenia (6.5%), thrombocytopenia (5.1%), and nausea (4.6%).

Interstitial lung disease (ILD) or pneumonitis rates were consistent with that observed in late-line HER2-positive breast cancer trials of Enhertu with a lower rate of Grade 5 ILD observed, as determined by an independent adjudication committee. The majority (10%) were primarily low Grade (Grade 1 or 2) with five Grade 3 (1.3%), no Grade 4 and three Grade 5 (0.8%) events reported.

Notes

Breast cancer and HER2 expression
Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.1 More than two million cases of breast cancer were diagnosed in 2020 with nearly 685,000 deaths globally.1

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including breast, gastric, lung and colorectal cancers, and is one of many biomarkers expressed in breast cancer tumours.2 HER2 expression is currently defined as either positive or negative, and is determined by an IHC test which measures the amount of HER2 protein on a cancer cell, and/or an ISH test which counts the copies of the HER2 gene in cancer cells.2,3 HER2-positive cancers are defined as IHC 3+ or IHC 2+/ISH+, and HER2-negative cancers are currently defined as IHC 0, IHC 1+ or IHC 2+/ISH-.2

Approximately half of all patients with breast cancer have tumours with a HER2 IHC score of 1+, or 2+ in combination with a negative ISH test, a level of HER2 expression not currently eligible for HER2-targeted therapy.4-7 Low HER2 expression occurs in both HR-positive and HR-negative disease.8

HER2 testing is routinely used to determine appropriate treatment options for patients with metastatic breast cancer. Targeting the lower range of expression in the HER2 spectrum may offer another approach to delay disease progression and extend survival in patients with metastatic breast cancer.9 Currently, patients with low HER2 expression with HR-positive tumours have limited treatment options following progression on endocrine (hormone) therapy.10 Few targeted options are available for those who are HR-negative.11

DESTINY-Breast04
DESTINY-Breast04 is a global, randomised, open-label, registrational Phase III trial evaluating the efficacy and safety of Enhertu (5.4mg/kg) versus physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) in patients with HR-positive or HR-negative HER2-low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomised 2:1 to receive either Enhertu or chemotherapy.

The primary endpoint of DESTINY-Breast04 is PFS in patients with HR-positive disease based on blinded independent central review (BICR). Key secondary endpoints include PFS based on BICR in all randomised patients (HR-positive and HR-negative disease), OS in patients with HR-positive disease and OS in all randomised patients (HR-positive and HR-negative disease). Other secondary endpoints include PFS based on investigator assessment, objective response rate based on BICR and on investigator assessment, duration of response based on BICR and safety.

DESTINY-Breast04 enrolled approximately 557 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

Enhertu
Enhertu is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

Enhertu (5.4mg/kg) is approved in the US and Israel for the treatment of adult patients with unresectable or metastatic HER2-positive 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 results from the DESTINY-Breast03 trial.

Enhertu (5.4mg/kg) is also approved in approximately 40 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial.

Enhertu (6.4mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

Enhertu development programme
A comprehensive development programme is underway globally, evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Regulatory applications for Enhertu are currently under review in China, Europe, Japan and several other countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2 based regimen based on the results from the DESTINY-Breast03 trial.

Enhertu was granted Breakthrough Therapy Designation in the US for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-negative) 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 of the DESTINY-Breast04 trial. Patients with hormone receptor (HR) positive breast cancer should additionally have received or be ineligible for endocrine therapy.

Enhertu is also currently under review in the US for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumours have a HER2 (ERBB2) mutation and who have received a prior systemic therapy, based on the DESTINY-Lung01 trial, and in Europe for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior anti-HER2-based regimen based on the DESTINY-Gastric01 and DESTINY-Gastric02 trials.

Daiichi Sankyo collaboration
Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as Daiichi Sankyo] and AstraZeneca entered into a global collaboration to jointly develop and commercialise Enhertu (a HER2-directed ADC) in March 2019, and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. 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 tumour environment.

AstraZeneca aims to continue to transform outcomes for HR-positive breast cancer with foundational medicines Faslodex (fulvestrant) and Zoladex (goserelin) and the next-generation oral selective oestrogen receptor degrader (SERD) and potential new medicine camizestrant.

PARP inhibitor Lynparza (olaparib) is a targeted treatment option that has been studied in HER2-negative 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 Lynparza in metastatic breast cancer patients with an inherited BRCA mutation and are exploring new opportunities to treat these patients earlier in their disease.

Building on the initial approvals of Enhertu, a HER2-directed ADC, in previously treated HER2-positive metastatic breast cancer, AstraZeneca and Daiichi Sankyo are exploring its potential in earlier lines of treatment and in new breast cancer settings.

To bring much-needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is testing immunotherapy Imfinzi (durvalumab) in combination with other oncology medicines, including Lynparza and Enhertu, evaluating the potential of AKT kinase inhibitor, capivasertib, in combination with chemotherapy, and collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan.

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 catalyse 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.

On June 5, 2022 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, and IASO Biotherapeutics ("IASO Bio"), a clinical-stage biopharmaceutical company engaged in discovering, developing, and manufacturing innovative cell therapies and antibody products, reported that the China National Medical Products Administration (NMPA) has formally accepted the New Drug Application (NDA) for Equecabtagene Autoleucel (Innovent R&D code: IBI326，IASO Bio R&D code: CT103A) , a fully human anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy for the treatment of relapsed and/or refractory multiple myeloma (R/R MM) (Press release, Innovent Biologics, JUN 5, 2022, View Source [SID1234615593]).

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Equecabtagene Autoleucel is the first CAR-T therapy in China that is self-developed with proprietary whole-process product development and the first BCMA-targeting CAR T-cell therapy in China with its NDA formally accepted by the NMPA. It is an innovative therapy co-developed by IASO Bio and Innovent. In February 2021, Equecabtagene Autoleucel was granted "Breakthrough Therapy Designation" by the NMPA.

The acceptance of NDA is based on data from a single-arm, open-label, multi-center phase 1/2 study（NCT05066646）being conducted in China. Study results showed that Equecabtagene Autoleucel has excellent safety and efficacy profiles, low immunogenicity given a fully-human scFv, robust expansion and prolonged persistence in vivo. It will potentially offer a breakthrough treatment option for patients with R/R MM. The data from the phase 1/2 clinical study of Equecabtagene Autoleucel was presented in an oral presentation at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Abstract #547) and the updated data was accepted as an oral presentation at the 27th Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper)（EHA）Virtual Meeting (Abstract #S187) , held on June 9-12, 2022.

"Multiple Myeloma (MM) is the second-most-common hematologicmalignancy. Although the survival in MM patients has been dramatically extended to 7-10 years on average with recent drug development, the disease is still incurable and relapse or refractory after standard therapies is common for most MM patients. The later lines of treatment the patients are receiving, the shorter of survival time for those patients. Usually, the median progression-free survival of MM patients who had received at least third-line of prior therapy is only 3-6 months, and the overall survival time is less than 1 year. In recent years, there have been some encouraging breakthroughs in drugs and therapeutic interventions for the treatment of MM. The most exciting progress is BCMA CAR-T cell immunotherapy." said the two principal investigators at the primary study sites – Prof. Lugui Qiu, MD, from the Chinese Academy of Medical Science Hematology Hospital and Prof. Chunrui Li, MD, PhD, from Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology. "At the 63rd Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in 2021, we reported the results of the clinical study on Equecabtagene Autoleucel injection. The study was conducted in 14 clinical centers and enrolled 79 patients with MM who had received at least third-line of prior therapy. Of the 79 patients, the overall response rate(ORR) was 94.9% and the complete response/stringent complete response (CR/sCR) rate was 58.2%. These study results showed that Equecabtagene Autoleucel has excellent safety and efficacy profiles. In addition, Equecabtagene Autoleucel also demonstrated favorable efficacy in patients with extramedullary multiple myeloma and patients who had received prior CAR-T therapy. These results suggest that Equecabtagene Autoleucel is potentially a new and effective immunotherapy treatment option for patients with multiple myeloma. We hope that Equecabtagene Autoleucel can be launched in China soon, bringing long-term benefits to patients."

Dr. Yongjun Liu, President of Innovent, said, "We are glad about the NDA acceptance of Equecabtagene Autoleucel, a product candidate co-developed by Innovent and IASO Bio, and it will potentially to be the domestic first approved and launch-to-market BMCA CAR-T therapy for multiple myeloma. In the clinical studies, Equecabtagene Autoleucel demonstrated impressive efficacy and favorable safety profiles. We hope that this breakthrough therapy could be approved in the near future and we will actively coordinate with all parties including the government authorities, hospitals, commercial insurance and charity funds to bring benefit to more multiple myeloma patients.

"IASO Bio currently has more than 10 innovative pipeline products under development. Equecabtagene Autoleucel is China’s first domestically developed CAR T-cell therapy with global intellectual property rights and the first BCMA-targeting CAR T-cell therapy with its NDA formally accepted by the NMPA. This is a significant milestone for IASO Bio. IASO Bio’s over 100,000 ft² manufacturing facility in Nanjing, which has end-to-end manufacturing capability that covers the entire CAR-T production process, received its drug manufacturing license earlier this year, will be the future commercial production site for Equecabtagene Autoleucel." said Wen (Maxwell) Wang, M.D., Ph.D., Chief Executive Officer and Chief Medical Officer of IASO Bio.

"In 2018, Professor Jianfeng Zhou of Tongji Hospital，Tongji Medical College led a team of clinicians and biologists to initiate clinical study of the world’s first fully-human BCMA CAR T-Cell therapy (Equecabtagene Autoleucel) for the treatment of multiple myeloma. The first patient of the study has maintained strict complete remission (sCR) for over 40 months." Maxwell added, "Many thanks to Professor Jianfeng Zhou for his unremitting efforts to promote the development of novel cell therapies and provide the impetus for the continuous innovation of CAR-T therapy. We look forward to the commercialization of Equecabtagene Autoleucel to bring hope to more multiple myeloma patients."

Innovent and IASO Bio are actively advancing the clinical development of Equecabtagene Autoleucel. In February 2022, it was granted "Orphan Drug Designation (ODD)"by the Office of Orphan Products Development (OOPD) of the U.S. Food and Drug Administration (FDA). In January 2022, IASO Bio and Innovent have jointly granted non-exclusive commercial rights of the fully-human BCMA CAR construct used in Equecabtagene Autoleucel to Sana Biotechnology (NASDAQ: SANA), a company focused on creating and delivering engineered cells as medicines, for use in its in vivo gene therapy and ex vivo hypoimmune cell therapy applications. Sana’s clinical and commercial development could further enhance the potential value of IBI326, benefitting a broader patient population. In addition to multiple myeloma, the NMPA has accepted IND application of Equecabtagene Autoleucel for the new expanded indication of Neuromyelitis Optica Spectrum Disorder (NMOSD).

About Multiple Myeloma (MM)

In the United States, MM accounts for nearly 2% of new cancer cases, and more than 2% of all cancer-related deaths. According to Frost & Sullivan, the number of new MM cases in the United States rose from 30,300 in 2016 to 32,300 in 2020 and is expected to increase to 37,800 by 2025. Additionally, the total number of patients diagnosed with MM increased from 132,200 in 2016 to 144,900 in 2020 and is expected to rise to 162,300 by 2025. In China, the number of new MM cases rose from 18,900 in 2016 to 21,100 in 2020 and is expected to increase to 24,500 by 2025. The total number of patients diagnosed with MM in China increased from 69,800 in 2016 to 113,800 in 2020 and is expected to rise to 182,200 by 2025.

On June 5, 2022 BioNTech SE (Nasdaq: BNTX, "BioNTech") reported initial data from an ongoing investigator-initiated first-in-human Phase 1 study evaluating the safety and tolerability of the mRNA-based individualized neoantigen specific immunotherapy (iNeST) autogene cevumeran (also known as BNT122, RO7198457) in combination with anti-PD-L1 immune checkpoint inhibitor atezolizumab and chemotherapy in patients with resected pancreatic ductal adenocarcinoma (PDAC) (Press release, BioNTech, JUN 5, 2022, View Source [SID1234615561]). Feasibility of the process of profiling each patient’s tumor to inform individualized vaccine design and on-demand manufacturing of iNeST in a clinically relevant timeframe was confirmed. The preliminary results showed a favorable safety profile as well as encouraging signs of clinical activity. The data have been presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ("ASCO") Annual Meeting 2022 by Vinod Balachandran, M.D., at Memorial Sloan Kettering Cancer Center. Autogene cevumeran is the lead candidate from BioNTech’s iNeST platform, which is jointly developed together with Genentech, a member of the Roche Group, in multiple solid tumor indications.

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The data presented at the ASCO (Free ASCO Whitepaper) Annual Meeting include a total of 19 patients who underwent surgery and received atezolizumab. 16 out of these 19 patients (84%) received autogene cevumeran at 9.4 weeks (median; 95% CI 9–10) after surgery. The preliminary data readout from these 16 vaccinated patients revealed that autogene cevumeran in combination with atezolizumab was well-tolerated. Only 1 of 16 patients (6%) developed a vaccine-related Grade 3 fever and hypertension, no other Grade 3 or higher adverse events were observed. In addition, the treatment induced de-novo, neoantigen-specific T cell response in half (8/16) of these patients from undetectable levels to large fractions of all blood T cells (median 2.9%). At an early median follow-up of 18 months, patients with de-novo immune response (n=8) had a significantly longer recurrence-free survival (RFS) as compared to those without vaccine-induced immune responses (n=8) (median not reached vs. 13.4 months, HR 0.08, 95% CI 0.01-0.4, P = 0.003). Based on these data, BioNTech and Genentech are planning a randomized study to further evaluate the efficacy and safety of autogene cevumeran in combination with atezolizumab and chemotherapy in patients with resected PDAC.

"With only under 5 percent of patients responding to current treatment options, PDAC is one of the highest unmet medical need cancers. We are committed to take up this challenge by leveraging our long-standing research in cancer vaccinology and are trying to break new ground in the treatment of such hard-to-treat tumors," said Prof. Özlem Türeci, M.D., Co-Founder and Chief Medical Officer at BioNTech. "The results of this Phase 1 study are encouraging. We look forward to further evaluating these early results in a larger randomized study."

The investigator-initiated, single-center, Phase 1 trial (NCT04161755) was designed to evaluate the treatment of the companies’ individualized immunotherapy candidate autogene cevumeran in combination with the anti-PDL-1 immune checkpoint inhibitor atezolizumab as an add-on to the standard-of-care regimen with adjuvant chemotherapy mFOLFIRINOX in patients with resected PDACs. The primary objective of the study is to assess the safety. Secondary objectives include the efficacy of the treatment measured as the 18-month RFS, the immunogenicity as well as the feasibility of the treatment regimen.

"Pancreatic cancer remains one of the deadliest cancers as it is resistant to all treatments, including immunotherapies. Conventional thinking has been that, as pancreatic cancers have few mutations, the immune system is unlikely to recognize mutation-derived neoantigens," said Vinod Balachandran, M.D., surgeon-scientist at Memorial Sloan Kettering Cancer Center and Principal Investigator of the study. "Our research, and now the results from this study show that the immune system can recognize neoantigens in pancreatic cancer, and that we can use mRNA vaccines to stimulate T cells to recognize neoantigens in pancreatic cancer patients. We now look forward to further investigating these results in a larger randomized trial."

BioNTech’s iNeST platform previously demonstrated encouraging results with a tolerable safety profile of autogene cevumeran as single agent and in combination with atezolizumab in a heterogenous patient population with advanced and heavily pretreated solid tumors. In a Phase1a/b trial autogene cevumeran revealed robust CD8+ and CD4+ T cell responses and a manageable safety profile (NCT03289962). In October 2021, BioNTech announced that the first patient was dosed in a randomized Phase 2 trial (NCT04813627) of autogene cevumeran in the adjuvant treatment of post-operative circulating tumor DNA (ctDNA) positive, surgically resected colorectal cancer. BioNTech and Genentech are also conducting a Phase II proof-of-concept study, which is designed to evaluate autogene cevumeran plus pembrolizumab in the first-line treatment of advanced melanoma (NCT03815058).

The abstract is available under the following link:
Title: Phase I Trial of adjuvant autogene cevumeran, an Individualized mRNA Neoantigen Vaccine, for Pancreatic Ductal Adenocarcinoma

Poster: 172
Abstract: 2516
About resected pancreatic ductal adenocarcinoma (PDAC)
PDAC is amongst the leading causes of cancer-related deaths in the United States with ~90% of patients dying within two years of their diagnosis. A combination of surgical removal and systemic cytotoxic chemotherapy has shown to improve clinical outcomes, however, even with surgical resection, the relapse rate remains high, and the 5-year overall survival is only approximately 20% in patients who undergo surgery followed by adjuvant chemotherapy (ACT) and only 10% in those who do not receive ACT. Thus, there is a high unmet medical need for novel therapies for patients with resected PDAC. The individualized Neoantigen Specific immunoTherapy (iNeST) candidate autogene cevumeran (also known as BNT122, RO7198457) provides a novel treatment strategy aimed to induce de-novo immune responses against cancer-specific neoantigens, recognize residual cancer cells and to prevent relapse.

About iNeST (individualized Neoantigen Specific immunoTherapy)
iNeST immunotherapies are individualized cancer therapies tailored to a specific patient’s tumor. They contain unmodified, pharmacologically optimized mRNA encoding up to 20 patient-specific neoantigens, identified using real-time next generation sequencing and bioinformatic neoantigen discovery. Neoantigens are proteins that are produced by cancer cells that differ from the proteins produced by healthy cells and are recognized by immune cells. The mRNA is encapsuled in BioNTech’s proprietary intravenous RNA-lipoplex delivery formulation which is designed to enhance stability as well as enable targeted delivery to dendritic cells. By analyzing each patient’s tumor, BioNTech is able to identify the cancer mutations that may act as neoantigens. Each individual cancer vaccine encodes for neoantigen candidates with the highest likelihood to help the immune system to recognize the cancer. For this purpose, BioNTech has developed a first of its kind, on-demand manufacturing process, following Good Manufacturing Practice (GMP) conditions.

An iNeST Fact Sheet and images from the iNeST manufacturing process are available in the media materials section on BioNTech’s website at this link.

On June 5, 2022 InnoCare Pharma (HKEX: 09969), a leading biotech company, reported that Professor Zhanguo Li, the leading PI, has presented latest data of BTK inhibitor orelabrutinib for the treatment of Systemic Lupus Erythematosus (SLE) at the just-concluded EULAR 2022 European Congress of Rheumatology (Press release, InnoCare Pharma, JUN 5, 2022, View Source [SID1234615577]). The abstract was selected as late-breaking oral presentation.

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Late-breaking Oral Presentation:

Orelabrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), for the treatment of SLE: results of a randomized, double-blind, placebo-controlled, phase Ib/IIa dose-finding study
Abstract Number: LB0005

The study is aimed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), preliminary efficacy and biomarkers of orelabrutinib in patients with mild to moderate SLE who received standard of care therapy.

The study randomized 60 patients with 55 patients who completed 12-week treatment. Baseline disease characteristics were generally balanced across treatment groups. Orelabrutinib was generally well tolerated in patients with SLE.

The plasma exposure of orelabrutinib (AUC and Cmax) was proportionally increased with doses. Nearly complete BTK occupancy was achieved at all dose levels, and the occupancy lasted for 24 hours.

In all evaluable patients, the SLE Response Index (SRI)-4 response rates at week 12 were 50.0%(7/14), 61.5%(8/13) and 64.3%(9/14) in patients treated with orelabrutinib at 50mg, 80mg and 100mg respectively, compared with 35.7%(5/14) in patients treated with placebo, which indicated a trend of dose-dependent improvement.

Among the small cohort of subgroup of patients with SLEDAI-2K≥8 at screening, SRI-4 response occurred in 70%(7/10), 70%(7/10) and 66.7%(6/9) of patients who received orelabrutinib at 50mg, 80mg and 100mg, respectively, compared with 30%(3/10) who received placebo.

A biological signal of reduced proteinuria, anti-dsDNA and IgG, total B cells and increased complements C4 were also observed following orelabrutinib administration.

Professor Zhanguo Li said, "Orelabrutinib was generally well tolerated in patients with SLE. We are encouraged by the preliminary results suggesting trends in efficacy and supporting further studies in longer-term trials and larger cohorts of SLE patients."

More information can be found at EULAR official website.

About Orelabrutinib

Orelabrutinib is a highly selective BTK inhibitor developed by InnoCare for the treatment of cancers and autoimmune diseases.

On Dec. 25 2020, orelabrutinib received conditional approval from the China National Medical Products Administration (NMPA) in two indications: the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL), and the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL). At the end of 2021, orelabrutinib was included into National Reimbursement Drug list to benefit more lymphoma patients.

In addition to the approved indications, multi-center, multi-indication clinical trials are underway in the US and China with orelabrutinib as monotherapy or in combination therapies.

Orelabrutinib was granted as Breakthrough Therapy Designation for the treatment of r/r MCL by U.S. Food and Drug Administration (FDA).

In addition, orelabrutinib is also being evaluated in global phase II studies for the treatment of Multiple Sclerosis (MS), and clinical trials for the treatment of SLE, Primary Immune Thrombocytopenia (ITP) and Neuromyelitis Optica Spectrum Disorder (NMOSD) in China.