On April 12, 2021 Jubilant Therapeutics Inc. , a biopharmaceutical company developing oral, small molecule modulators to meet unmet medical needs in oncology and autoimmune diseases, reported preclinical data from two programs investigating the company’s PRMT5 inhibitor and PD-L1 inhibitor as anticancer agents will be unveiled today in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021, which will be held virtually from Nov. takes place until April 15 , 2021 (Press release, Jubilant Therapeutics, APR 12, 2021, View Source;pgid=1475&pressid=449 [SID1234577941]) .

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"We are pleased to announce these important data from our PRMT5 and PD-L1 programs that demonstrate efficacy and tolerability in preclinical models," said Syed Kazmi, President and Chief Executive Officer of Jubilant Therapeutics Inc. "Our oral PRMT5 inhibitor has good plasma and sustained brain exposure resulting in potent target inhibition, tumor growth delay, and a survival benefit in both xenografts and orthotopic brain models . Our shorter half-life oral anti-PDL1 immunotherapeutics are an attractive alternative to current intravenous antibody therapies, especially in the maintenance phase, with the potential to limit immune-mediated toxicities and side effects through innovative dosage approaches while maintaining class-based broad anti-tumor efficacy. We look forward to continuing our work on these programs as we see great potential for treating various types of cancer. "

A link to the e-posters listed below is available on the AACR (Free AACR Whitepaper) website.

Title: Novel Small Molecular Weight PRMT5 Inhibitors for the Treatment of Cancer
Poster Number: 1128
Date and Time: April 10 , 2021 at 8:30 a.m. Eastern Daylight Time (EDT)
Session Title: Epigenetic Targets
Speaker: Dhanalakshmi Sivanandhan, et al.

Title: Novel Small Molecular Weight Inhibitors of PD-L1 / PD-1 Interaction
Poster Number: 1630
Date and Time: April 10 , 2021 at 8:30 a.m. Eastern Daylight Time (EDT)
Session Title: Immune Checkpoints
Speaker (r ): Dhanalakshmi Sivanandhan, et al.

The overexpression of PRMT5, which has been demonstrated in various types of cancer such as lymphatic cancer, lung cancer, breast cancer, glioblastoma, gastric cancer, etc., is considered to be an important factor in tumorigenicity due to its repressive function on the expression of tumor suppressor genes. The most important highlights from an evaluation that examined the inhibition of tumor growth by the PRMT5 inhibitor JBI-778 in various cancer cell lines as well as in glioblastoma are as follows:

JBI-778 is a potent PRMT5 inhibitor that acts selectively against other PRMTs;
JBI-778 is a potent PRMT5 inhibitor that acts selectively against other PRMTs;
This orally administered small molecule demonstrated anti-tumor activity in a mantle cell lymphoma model with an ED50 of <10 mg / kg and complete inhibition of tumor growth (97%) at a dose of 50 mg / kg; and
JBI-778 demonstrated sustained exposure of the brain and significant inhibition of tumor growth in an orthotopic glioblastoma model, resulting in a significant survival benefit.
JBI-778 is currently being investigated for the treatment of a variety of cancers and IND-approved studies have begun.

PD-L1 expression is an immune evasion mechanism that is exploited by many cancers, including melanoma, non-small cell lung cancer, and breast cancer, that enables cancer to progress and metastasize. Key findings from the PD-L1 / PD-1 Study, which examined the ability of JBI-1527 to inhibit PD-L1 and restore T cell proliferation and function, included:

JBI- 1527 is a potent, selective inhibitor of PD-L1, which induces the dimerization of the protein and thereby reduces the PD-L1-induced suppression of T-cell activation;
The inhibitor shows a similar modulation of cytokines as pembrolizumab in the BioMAP assay and competes with the anti-PD-L1 blocking antibody, suggesting a similar binding site on PD-L1; and
In syngeneic CT-26 and MC38-hPD-L1 models, the small molecule showed a strong inhibition of tumor growth, comparable to anti-PD-L1 mAb / atezolizumab, and was well tolerated.
Studies to further evaluate JBI-1527 and other substances are ongoing.

On April 12, 2021 PharmAbcine Inc. (KOSDAQ: 208340ks), a clinical-stage biotech company focusing on the development of antibody therapeutics, reported that the company presented an e-poster featuring the non-clinical data of PMC-309 at American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting taking place virtually (Press release, PharmAbcine, APR 12, 2021, View Source [SID1234577940]).

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PMC-309, one of the company’s first immuno-oncology drug candidates, is a monoclonal IgG (Immunoglobulin G) that targets human VISTA (V-domain Ig Suppressor of T cell Activation), an immune checkpoint regulator. VISTA is found overexpressed on MDSC (Myeloid-Derived Suppressor Cells) and M2 macrophages both of which are immunosuppressive cells found abundantly around TME (Tumor Microenvironment).

The presentation highlighted that PMC-309 inhibits VISTA pathway on immunosuppressive cells and increases T cell activities in in vitro settings and shows potent anti-tumor effects in in vivo studies.

The in vitro studies confirmed that PMC-309 inhibits VISTA interaction and promotes T cell activation. PMC-309 blocked the VISTA pathway with its partner molecules such as VSIG3 (V-Set and Immunoglobulin domain containing 3), PSGL1 (P-selectin glycoprotein ligand-1) and other VISTA. In addition, there was a rise in the level of IFN-y, a pro-inflammatory cytokine, which indicates that PMC-309 enhanced T cell activities.

In in vivo studies, the test subjects administered with PMC-309 in both hPBMC (human Peripheral Blood Mononuclear Cell) engrafted mouse model and human VISTA Knock-In mouse model showed notable tumor growth inhibition. PMC-309 also showed a possible synergistic effect when used in combo with an anti-PD1 antibody because the combination of two antibodies demonstrated significantly improved tumor growth inhibition.

"Our non-clinical studies revealed PMC-309’s unique binding mechanism and its anti-tumor effect," said Dr. Jin-San Yoo, CEO of PharmAbcine. "The study results add to our confidence that PMC-309 can be a promising immunotherapeutic strategy in both mono and combo therapies for patients who do not respond to other immuno-oncology drugs."

Dr. Yoo also added, "We plan to initiate the IND (Investigational New Drug)-enabling studies and evaluate the potential toxicity risk this year. We expect PMC-309 to enter a clinical stage in 2022."

The e-poster presentation is currently available on the AACR (Free AACR Whitepaper) website. The details of the presentation are as follows:

Title: PMC309, a highly selective anti-VISTA antibody enhances T cell activation through blocking the interaction of T cells and myeloid derived suppressor cells (MDSC)
Session category/title: Immunology/Immune Checkpoints
Abstract number: 1116
Poster number: 1626
Presentation Type: E-poster with audio presentation

On April 12, 2021 GT Biopharma, Inc. (NASDAQ: GTBP), a clinical stage immuno-oncology company focused on developing innovative therapeutics based on the Company’s proprietary NK cell engager (TriKE) protein biologic technology platform, reported additional interim results from its GTB-3550 TriKE first-in-human Phase I/II clinical trial for the treatment of high-risk myelodysplastic syndromes (MDS) and refractory/relapsed acute myeloid leukemia (AML) (Press release, GT Biopharma, APR 12, 2021, View Source [SID1234577939]).

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Additional results show GTB-3550 TriKE monotherapy is able to rescue the patient’s otherwise exhausted/inhibited/non-functional endogenous NK cell population and target direct killing of the patient’s AML and MDS cancer cells without the need for the co-administration addition of supplemental progenitor-derived or autologous/allogenic engineered NK cells.

GTB-3550 TriKE monotherapy has demonstrated clinical benefit in very hard to treat relapsed/refractory AML and high-risk MDS cancer patients by significantly reducing cancer cell (blast) levels and, in some cases, ending transfusion dependency with patients becoming eligible for bone marrow transplant.

The ability to use GTB-3550 in a monotherapy setting is a significant competitive and therapeutic advantage, and a major cost savings compared to the co-administration of drug/cell therapy combination regimens. GTB-3550 TriKE therapy requires no patient pre-treatment regimens such as myeloablative chemotherapy, and is well tolerated with no signs of cytokine release syndrome (CRS) or other toxicities suggesting GTB-3550 could be used to treat patients earlier in the disease process, whereas complicated and expensive combination drug/cell therapy regimens are expected to be used as late-stage or salvage therapies after all other therapeutic options have been exhausted.

Highlights from the first nine patients treated with GTB-3550 TriKE include:

Up to 63.7% Reduction in Bone Marrow Blast Levels Resulting in Clinical Benefit
Restores Patient’s Endogenous NK Cell Function, Proliferation and Immune Surveillance
No Progenitor-derived or Autologous/Allogenic Cell Therapy Required
No Cytokine Release Syndrome Observed
3 out of the last 5 Patients Treated Respond (25mcg/kg/day to 100mcg/kg/day therapeutic dose range)
"We believe GTB-3550 TriKE sets a new standard for NK cell engager therapies due to the incorporation of Interleukin 15 (IL-15) directly in the protein backbone. The flexibility and versatility of our TriKE platform allows us to change the cancer cell targeting moiety of TriKE to attack different cancers while maintaining the core NK cell activation, proliferation and persistence attributes of the molecule," said Anthony J. Cataldo, GT Biopharma’s Chairman and Chief Executive Officer. "The TriKE is a true monotherapy, unlike all other NK cell technologies in development. The novel TriKE uniquely does not need any outside NK cell manufacturing or combination drugs, to supplement or assist. Further, the TriKE does not require pre-conditioning of the patient’s immune system. These supplemental requirements of competitive technologies add tremendous cost to an already costly therapeutic approach. Everything the TriKE does happens with no outside assistance whatsoever. We believe the TriKE’s clinical data is demonstrating exactly that, opening the door to a significantly more cost-effective off-the-shelf therapeutic."

About High-Risk Myelodysplastic Syndromes
MDS is a rare form of bone marrow-related cancer caused by irregular blood cell production within the bone marrow. As a result of this irregular production, MDS patients do not have sufficient normal red blood cells, white blood cells and/or platelets in circulation. High-risk MDS is associated with poor prognosis, diminished quality of life, and a higher chance of transformation to acute myeloid leukemia. Approximately 40% of patients with high-risk MDS transform to AML, another aggressive cancer with poor outcomes.

About Acute Myeloid Leukemia
Acute myeloid leukemia is a type of cancer in which the bone marrow makes abnormal myeloblasts (a type of white blood cell), red blood cells, or platelets. According to the National Cancer Institute (NCI), the five-year survival rate is about 35% in people under 60 years old, and 10% in people over 60 years old. Older people whose health is too poor for intensive chemotherapy have a typical survival of five to ten months. AML accounts for roughly 1.8% of cancer deaths in the United States.

About GTB-3550 TriKE
GTB-3550 is the Company’s first TriKE product candidate being initially developed for the treatment of AML and MDS, and other CD33+ hematologic cancers. GTB-3550 is a single-chain, tri-specific scFv recombinant fusion protein conjugate composed of the variable regions of the heavy and light chains of anti-CD16 and anti-CD33 antibodies and a modified form of Interleukin 15 (IL-15). The natural killer (NK) cell-stimulating cytokine human IL-15 portion of the molecule provides a self-sustaining signal that activates NK cells and enhances their ability to kill. We intend to study GTB-3550 in CD33 positive leukemias such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and other CD33+ hematopoietic malignancies.

About GTB-3550 TriKE Clinical Trial
Patients with CD33+ malignancies (primary induction failure or relapsed AML with failure of one reinduction attempt or high-risk MDS progressed on two lines of therapy) age 18 and older are eligible (NCT03214666). The primary endpoint is to identify the maximum tolerated dose (MTD) of GTB-3550 TriKE. Correlative objectives include the number, phenotype, activation status and function of NK cells and T cells.

On April 12, 2021 Innovent Biologics, Inc. ("Innovent", HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of cancer, metabolic, autoimmune and other major diseases, reported with Eli Lilly and Company ("Lilly",NYSE: LLY) that the results of the Phase 3 ORIENT-3 study were released today in an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Innovent Biologics, APR 12, 2021, View Source [SID1234577938]).

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ORIENT-3 is a randomized, open-label, Phase 3 clinical trial evaluating TYVYT (sintilimab injection) versus docetaxel as a second-line treatment for advanced or metastatic squamous non-small cell lung cancer (sqNSCLC). A total of 290 patients whose cancer had progressed following first-line treatment with platinum-based chemotherapy were enrolled. Based on the primary analysis population (280 patients, excluding patients on the docetaxel arm who received immunotherapy prior to disease progression), TYVYT (sintilimab injection) demonstrated a statistically significant improvement in overall survival (OS) compared to docetaxel, meeting the pre-specified primary endpoint. The median OS was 11.79 months for patients on the TYVYT (sintilimab injection) arm and 8.25 months for those on the docetaxel arm (HR=0.74, 95% CI: 0.56-0.96, P=0.02489). The median progression-free survival (PFS) as assessed by investigators was 4.30 months versus 2.79 months (HR=0.52, 95% CI: 0.39-0.68, P<0.00001), and the confirmed objective response rate (ORR) was 25.5 percent versus 2.2 percent (P<0.00001), respectively. Safety was consistent with previous studies of TYVYT (sintilimab injection), and no new safety signals were identified.

Professor Yuankai Shi, principal investigator of ORIENT-3, Associate Dean of Cancer Hospital, Chinese Academy of Medical Sciences and Chairman of Cancer Foundation of China, stated: "Lung cancer is the leading cause of cancer death globally, of which non-small cell lung cancer accounts for 80 to 85 percent. In the past few decades, drug development of non-small cell lung cancer has mainly focused on nonsquamous non-small cell lung cancer, while drug development of squamous non-small cell lung cancer has been slower due to its unique epidemiological, histopathological and molecular characteristics. In China, specifically, the approved options for second-line immunotherapy to treat squamous non-small cell lung cancer are even more limited. The ORIENT-3 study showed that the anti-PD-1 monoclonal antibody sintilimab significantly improved overall survival for the second-line treatment of squamous non-small cell lung cancer patients, which is of great clinical value. We hope that the positive results of ORIENT-3 can help more squamous non-small cell lung cancer patients."

"TYVYT (sintilimab injection) was the first anti-PD-1 inhibitor included in the New Catalogue of the National Reimbursement Drug List in 2019," said Dr. Hui Zhou, Vice President of Medical Science and Strategy Oncology of Innovent. "In August 2020, the NMPA accepted a new indication application for TYVYT (sintilimab injection) in combination with chemotherapy for first-line treatment of squamous NSCLC. In the ORIENT-3 study, sintilimab as second-line monotherapy demonstrated a significantly improved survival benefit for patients with advanced squamous non-small cell lung cancer, and we look forward to the potential approval of this indication, to help more patients with this type of lung cancer."

"We are excited about these results, showing TYVYT (sintilimab injection) significantly improved overall survival in this patient population. This study underscores the joint commitment from Lilly and Innovent to provide innovative treatment options to patients with lung cancer," said Dr. Wang Li, Senior Vice President of Lilly China and Head of Lilly China Drug Development and Medical Affairs. "We would like to thank the patients, the investigators, the clinical trial centers and our colleagues from Innovent that are involved in the study. We look forward to working together to potentially bring this new treatment option to people in China with squamous non-small cell lung cancer."

About Squamous NSCLC

Lung cancer is a malignancy with the highest morbidity and mortality in China. NSCLC accounts for about 80 to 85 percent of lung cancer. Approximately 70 percent of people with NSCLC have locally advanced or metastatic NSCLC at initial diagnosis, rendering many of those patients with no chance of radical resection. Meanwhile, even after radical surgery, patients still have a high chance of recurrence and eventually die from disease progression. About 30 percent of people in China with non-small cell lung cancer have tumors of the squamous subtype and there are limited approved second-line therapies for these patients. Therefore, there remains a huge unmet medical need in China.

About the ORIENT-3 Trial

ORIENT-3 is a randomized, open-label, multi-center, Phase 3 clinical trial to evaluate the efficacy and safety of TYVYT (sintilimab injection) as second-line therapy for advanced or metastatic sqNSCLC (ClinicalTrials.gov, NCT 03150875). The primary endpoint is overall survival (OS). The secondary endpoints include progression-free survival (PFS) as assessed by investigators based on RECIST v1.1, objective response rate (ORR) and safety profile.

A total of 290 patients were enrolled in ORIENT-3 and randomized in a 1:1 ratio to receive either TYVYT (sintilimab injection) 200mg or docetaxel every three weeks. The patients received treatment until radiographic disease progression, unacceptable toxicity or any other conditions that require treatment discontinuation.

About TYVYT (Sintilimab Injection)

TYVYT (sintilimab injection), an innovative drug with global quality standards jointly developed in China by Innovent and Lilly, has been granted marketing approval by the NMPA (National Medical Products Administration) for the treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy, and is included in the 2019 Guidelines of Chinese Society of Clinical Oncology for Lymphoid Malignancies. In February 2021, TYVYT (sintilimab injection) was approved by the China NMPA in combination with pemetrexed and platinum chemotherapy as first-line therapy for the treatment of nonsquamous non-small cell lung cancer. TYVYT (sintilimab injection) was included in the National Reimbursement Drug List (NRDL) in November 2019 as the first PD-1 inhibitor and the only PD-1 included in the list in that year.

Currently TYVYT (sintilimab injection) has three supplemental New Drug Applications ("sNDA") under review by the NMPA. In August 2020, the NMPA accepted the sNDA for TYVYT (sintilimab injection) in combination with gemcitabine and platinum chemotherapy as first-line therapy in squamous NSCLC. In January 2021, the NMPA accepted the sNDA for TYVYT (sintilimab injection) in combination with BYVASDA (bevacizumab injection) as first-line therapy in Hepatocellular Carcinoma (HCC) and the sNDA for TYVYT (sintilimab injection) as second-line therapy in squamous NSCLC. Besides, in May 2020, TYVYT (sintilimab injection) monotherapy met the primary endpoint of overall survival in the Phase 2 ORIENT-2 study as second-line therapy in patients with advanced or metastatic esophageal squamous cell carcinoma.

TYVYT (sintilimab injection), 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. Innovent is currently conducting more than 20 clinical studies with TYVYT (sintilimab injection) to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials. Meanwhile, Innovent is conducting clinical research studies on TYVYT (sintilimab injection) worldwide.

On April 12, 2021 Antengene Corporation Limited ("Antengene", SEHK: 6996.HK), a leading innovative biopharmaceutical company dedicated to discovering, developing, and commercializing global first-in-class and/or best-in-class therapeutics in hematology and oncology, reported preclinical data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021, which demonstrated the synergistic effect of the combination of ATG-010 (selinexor, XPO1 inhibitor) and ATG-008 (onatasertib, mTORC1/2 inhibitor) for the treatment of triple-hit diffuse large B-cell lymphoma (DLBCL) (Press release, Antengene, APR 12, 2021, View Source [SID1234577937]).

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#1380: Synergistic effect of the combination of XPO1 and mTORC1/2 inhibition for the treatment of triple-hit DLBCL
Results from this study demonstrated potent in vitro and in vivo anti-tumor efficacy and synergy with the combination of ATG-010 and ATG-008, including strong synergistic activities in the triple-hit DLBCL cell line. Meanwhile, in the DLBCL circulating tumor cell-derived explants (CDX) model, the combination of ATG-010 and ATG-008 also showed enhanced tumor growth inhibition and synergism.

The single agent oral XPO1 inhibitor, ATG-010, is a first-in-class and only-in-class selective inhibitor of nuclear export (SINE) compound, approved by the US Food and Drug Administration (FDA) for the treatment of patients with DLBCL after at least two prior therapies. ATG-008 is a dual mTORC1/2 kinase inhibitor, which has shown preclinical and clinical activity in treating DLBCL. Antengene is currently developing a clinical study to investigate the combination of ATG-010 and ATG-008 in relapsed or refractory DLBCL (the MATCH trial).

The preclinical data showed:

ATG-008 and ATG-010 both inhibit the growth of the DLBCL cell line in vitro.
ATG-008 combined with ATG-010 enhanced the growth inhibition of triple-hit DLBCL cells.
ATG-008 combined with ATG-010 showed in vitro synergism in triple-hit DLBCL cells.
ATG-008 combined with ATG-010 showed in vivo synergism in CDX of the triple-hit DLBCL cell line.
Dr. Jay Mei, Founder, Chairman and CEO of Antengene, commented: "ATG-010 has been approved for the treatment of relapsed or refractory DLBCL, whilst ATG-008 has shown early clinical activity in the same disease. Using in vitro and in vivo DLBCL models, we found that ATG-010 combined with ATG-008 at certain concentrations could achieve amplified anti-tumor activity in triple-hit DLBCL. The strong synergism of the ATG-010 plus ATG-008 combination suggests a promising therapeutic strategy for the treatment of patients with DLBCL, including triple-hit disease where significant unmet medical needs exist, that we are looking forward to exploring in the MATCH trial."