On April 18, 2023 Immunocore Holdings plc (Nasdaq: IMCR), a commercial-stage biotechnology company pioneering the development of a novel class of T cell receptor (TCR) bispecific immunotherapies designed to treat a broad range of diseases, including cancer, infectious diseases and autoimmune conditions, reported four posters with KIMMTRAK (tebentafusp-tebn) data in HLA-A*02:01 patients with metastatic uveal melanoma (mUM), at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Press release, Immunocore, APR 18, 2023, View Source [SID1234630241]).

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"KIMMTRAK is now approved in over 30 countries and delivering benefit to hundreds of patients. The Phase 3 trial data presented at AACR (Free AACR Whitepaper) confirms that ctDNA reduction from tebentafusp is strongly associated with survival benefit," said David Berman, Head of Research and Development of Immunocore. "We are also proud to share the almost 4-year follow-up from the Phase 2 trial, which now represents the largest and longest follow-up on survival and safety from any TCR therapy to date."

Circulating tumor DNA (ctDNA) reduction by week 9 was observed in 88% of mUM patients treated as first-line (Phase 3 trial) and 71% in previously treated patients (Phase 2 trial); in both trials, this reduction was associated with longer overall survival (OS). ctDNA clearance was also higher in first-line patients (37%) compared to second-line patients (13%). ctDNA clearance in the Phase 3 trial was associated with 84% 1-year OS. In both trials, the association between ctDNA reduction and longer OS was also observed in patients with best RECIST response of progressive disease (PD), indicating that RECIST responses underestimate tebentafusp’s clinical benefits, and that ctDNA may be a better predictor of long OS than radiographic response.

The final analysis from the Phase 2 trial in previously treated mUM, after 46 months of follow-up, showed a median OS of 16.8 months – consistent with previous data updates. The landmark OS rates from the trial were approximately double historical rates in this patient population, as reported in two meta-analyses1,2. Later in 2023, the Company intends to provide an OS update from the Phase 3 trial. At the time of primary analysis in 2020, the median OS was 21.7 months for patients treated with KIMMTRAK, versus 16.0 months for those treated with investigator’s choice.

1 Rantala ES, Hernberg M, Kivela TT. Overall survival after treatment for metastatic uveal melanoma: a systematic review and meta-analysis. Melanoma Res. 2019; 29:561-568.
2 Khoja L, Atenafu EG, Suciu S, et al. Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study. Ann Oncol. 2019; 30:1370-1380

The third poster provides a pooled analysis from 3 clinical trials in 12 mUM patients with orbital disease. Tebentafusp demonstrated preliminary signals of activity in intra-ocular lesions, supporting KIMMTRAK’s use in patients with unresectable uveal melanoma.

The fourth poster shares in vitro data potentially explaining how tebentafusp may lead to OS benefit even in tumors with heterogenous gp100 expression.

Poster details

Title: Early ctDNA reduction is associated with better overall survival in the Ph 3 trial of tebentafusp in previously untreated metastatic uveal melanoma
Presenting author: Ryan Sullivan
Session: Liquid Biopsies: Circulating Nucleic Acid and Circulating Tumor Cells 1

Title: Long-term survival follow-up of tebentafusp in previously treated metastatic uveal melanoma
Presenting author: Joe Sacco
Session: Phase II Clinical Trials 2

Title: Evidence of tumor response in orbital lesions treated with tebentafusp in metastatic uveal melanoma patients
Presenting author: Marcus Butler
Session: Late breaking research: clinical research 1/ Endocrinology

Title: Melanoma patients with high and low target-expression can benefit from TCR-CD3 bispecifics through direct and indirect mechanisms of tumor control
Presenting author: Esra Güç
Session: Combination Immunotherapies 2

About KIMMTRAK
KIMMTRAK is a novel bispecific protein comprised of a soluble T cell receptor fused to an anti-CD3 immune-effector function. KIMMTRAK specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma. This is the first molecule developed using Immunocore’s ImmTAC technology platform designed to redirect and activate T cells to recognize and kill tumor cells. KIMMTRAK has been approved for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma in the United States, European Union, Canada, Australia, and the United Kingdom.

About Phase 2 IMCgp100-102 Trial
IMCgp100-102 (NCT02570308) was an open-label, multi-center, single-arm trial of the safety and efficacy of tebentafusp in patients with previously treated mUM. The trial included 127 HLA-A*02:01+ 2L+ mUM patients, treated with tebentafusp at the recommended Phase 2 dose of 68mcg following intra-patient dose escalation of 20 mcg (week 1) and 30 mcg (week 2). The primary endpoint was overall response rate (ORR), with secondary objectives being overall survival (OS) and safety in 127 patients who had enrolled after progressing on one or more prior therapies.

About Phase 3 IMCgp100-202 Trial
IMCgp100-202 (NCT03070392) is a randomized pivotal trial that evaluated overall survival (OS) of KIMMTRAK compared to investigator’s choice (either pembrolizumab, ipilimumab, or dacarbazine) in HLA-A*02:01-positive adult patients with previously untreated mUM. KIMMTRAK demonstrated an unprecedented OS benefit with a Hazard Ratio (HR) in the intent-to-treat population favoring KIMMTRAK, HR=0.51 (95% CI: 0.37, 0.71); p< 0.0001, over investigator’s choice (82% pembrolizumab; 13% ipilimumab; 6% dacarbazine).

IMPORTANT SAFETY INFORMATION

Cytokine Release Syndrome (CRS), which may be serious or life-threatening, occurred in patients receiving KIMMTRAK. Monitor for at least 16 hours following first three infusions and then as clinically indicated. Manifestations of CRS may include fever, hypotension, hypoxia, chills, nausea, vomiting, rash, elevated transaminases, fatigue, and headache. CRS occurred in 89% of patients who received KIMMTRAK with 0.8% being grade 3 or 4. Ensure immediate access to medications and resuscitative equipment to manage CRS. Ensure patients are euvolemic prior to initiating the infusions. Closely monitor patients for signs or symptoms of CRS following infusions of KIMMTRAK. Monitor fluid status, vital signs, and oxygenation level and provide appropriate therapy. Withhold or discontinue KIMMTRAK depending on persistence and severity of CRS.

Skin Reactions

Skin reactions, including rash, pruritus, and cutaneous edema occurred in 91% of patients treated with KIMMTRAK. Monitor patients for skin reactions. If skin reactions occur, treat with antihistamine and topical or systemic steroids based on persistence and severity of symptoms. Withhold or permanently discontinue KIMMTRAK depending on the severity of skin reactions.

Elevated Liver Enzymes

Elevations in liver enzymes occurred in 65% of patients treated with KIMMTRAK. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total blood bilirubin prior to the start of and during treatment with KIMMTRAK. Withhold KIMMTRAK according to severity.

Embryo-Fetal Toxicity
KIMMTRAK may cause fetal harm. Advise pregnant patients of potential risk to the fetus and patients of reproductive potential to use effective contraception during treatment with KIMMTRAK and 1 week after the last dose.

The most common adverse reactions (≥30%) in patients who received KIMMTRAK were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting. The most common (≥50%) laboratory abnormalities were decreased lymphocyte count, increased creatinine, increased glucose, increased AST, increased ALT, decreased hemoglobin, and decreased phosphate.

For more information, please see full Summary of Product Characteristics (SmPC) or full U.S. Prescribing Information (including BOXED WARNING for CRS).

On April 18, 2023 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:​HCM; HKEX:​13) reported that its New Drug Application ("NDA") for fruquintinib in combination with paclitaxel for the treatment of second-line advanced gastric or gastroesophageal junction adenocarcinoma in China has been accepted for review by the China National Medical Products Administration ("NMPA") (Press release, Hutchison China MediTech, APR 18, 2023, View Source [SID1234630240]).

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Dr. Michael Shi, Head of R&D and Chief Medical Officer of HUTCHMED said, "The NMPA acceptance of our NDA for fruquintinib is a positive step towards addressing the significant unmet medical need for gastric cancer patients. Gastric cancer is one of the most common cancers globally, with the highest incidence and mortality rates found in Asian populations. China alone accounts for over 40% of all new gastric cancer cases in the world. Despite recent advancement in the first line setting, there are few treatments available for patients whose disease progressed on initial therapy. Fruquintinib has demonstrated clinically meaningful benefit for patients in the Phase III FRUTIGA study, and we are excited by the possibility of providing a potential new oral treatment option for patients in China."

The NDA is supported by data from the FRUTIGA study, a randomized, double-blind, Phase III study in China to evaluate fruquintinib combined with paclitaxel compared with paclitaxel monotherapy, for second-line treatment of advanced gastric cancer.

In China, fruquintinib is approved under the brand name ELUNATE and is included in the China National Reimbursement Drug List ("NRDL"). HUTCHMED markets fruquintinib in China in partnership with Eli Lilly and Company.

In March 2023, HUTCHMED and Takeda Pharmaceutical Company Limited (TSE:4502, NYSE:TAK) closed an exclusive license agreement to further the global development, commercialization and manufacture of fruquintinib outside China.

About the Phase III FRUTIGA Trial

FRUTIGA is a randomized, double-blind, Phase III study in China to evaluate fruquintinib combined with paclitaxel compared with paclitaxel monotherapy, for second-line treatment of advanced gastric cancer. The study enrolled approximately 700 patients. Its dual-primary endpoints were progression-free survival ("PFS") and overall survival ("OS"). The trial met the PFS endpoint at a statistically and clinically meaningful level. While there was an improvement in median OS, the OS endpoint was not statistically significant per the pre-specified statistical plan. Fruquintinib also demonstrated a statistically significant improvement in secondary endpoints including objective response rate (ORR), disease control rate (DCR) and duration of response (DoR). The safety profile of fruquintinib in FRUTIGA was consistent with previously reported studies. Additional details may be found at clinicaltrials.gov, using identifier NCT03223376.

About Gastric Cancer

Gastric cancer is a cancer that starts in the stomach. It is the fifth most common cancer worldwide, estimated to have caused approximately 770,000 deaths in 2020.1 In China, an estimated 478,000 people were diagnosed with gastric cancer and 373,000 people will have died from gastric cancer in 2020.2

About Fruquintinib

Fruquintinib is a highly selective and potent oral inhibitor of vascular endothelial growth factor receptor ("VEGFR") -1, -2 and -3. VEGFR inhibitors play a pivotal role in blocking tumor angiogenesis. Fruquintinib was designed to improve kinase selectivity with the intention of minimizing off-target toxicities, improving tolerability and providing more consistent target coverage. Fruquintinib has been generally well tolerated in patients to date and is being investigated in combinations with other anti-cancer therapies.

Fruquintinib was approved for marketing by the NMPA in September 2018 and commercially launched in China in November 2018 under the brand name ELUNATE for the treatment of patients with metastatic colorectal cancer ("CRC") who have been previously treated with fluoropyrimidine, oxaliplatin and irinotecan, including those who have previously received anti-VEGF therapy and/or anti-epidermal growth factor receptor (EGFR) therapy (RAS wild type). It has been included in the NRDL since January 2020.

The safety and efficacy of fruquintinib for the following investigational uses have not been established and there is no guarantee that it will receive health authority approval or become commercially available in any country for the uses being investigated.

Filing of a rolling submission of NDA to the U.S. Food and Drug Administration ("FDA") was completed in March 2023. Submissions to the European Medicines Agency (EMA) and the Japan Pharmaceuticals and Medical Devices Agency (PMDA) are expected to be completed in 2023. The submission to the FDA is supported by positive results from FRESCO-2 study, a global double-blind, placebo-controlled, Phase III study in 691 patients with refractory metastatic CRC.3 Additional details of the study may be found at clinicaltrials.gov, using identifier NCT04322539.

HUTCHMED is also developing fruquintinib for the treatment of multiple solid tumor cancers in combination with PD-1 monoclonal antibodies for the treatment of endometrial and other solid tumors.

On April 18, 2023 Genprex, Inc. ("Genprex" or the "Company") (NASDAQ: GNPX), a clinical-stage gene therapy company focused on developing life-changing therapies for patients with cancer and diabetes, reported that independent researchers recently presented preclinical data on the tumor suppressor gene, TUSC2, reporting that it functions as a novel tumor suppressor for glioblastoma (Press release, Genprex, APR 18, 2023, View Source [SID1234630239]). TUSC2 is the tumor suppressor gene that is reexpressed in tumors using REQORSA Therapy treatment, Genprex’s lead drug candidate. Genprex has no affiliation with these researchers.

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The independent researchers presented their abstract, titled, "Investigating TUSC2 for its tumor suppressive functions in glioblastoma and its role in gliomagenesis," at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting on April 17. The abstract reports TUSC2 protein expression, but not mRNA expression, to be significantly decreased in glioblastoma as compared to normal brain. TUSC2 protein is destabilized in glioblastoma due to polyubiquitination by E3 ligase, neural precursor cell-expressed developmentally downregulated gene 4 (NEDD4), and degradation by the proteasome. The researchers determined that NEDD4 targets TUSC2 on lysine residue K71.

The researchers also reported that TUSC2 overexpression reduced colony formation and neurosphere formation and promoted apoptosis of glioblastoma cells in vitro, and suppressed tumor growth in vivo. Further, glioblastoma cells with CRISPR-mediated knockout (KO) of TUSC2 were highly aggressive in vitro and in vivo, demonstrating the role of TUSC2 as a novel tumor suppressor for glioblastoma.

In the study, researchers performed immunoprecipitation-mass spectrometry analysis to identify TUSC2-interacting proteins in both normal human astrocytes and glioblastoma cell lines. Results showed 95 and 88 TUSC2-interacting proteins in astrocytes and glioblastoma cell lines respectively, and 27 proteins were found to interact with TUSC2 in both astrocytes and glioblastoma.

"This research supports the growing body of studies evaluating TUSC2 as a target in oncology, and potentially an effective treatment, for many types of cancer," said Rodney Varner, Chairman, President and Chief Executive Officer of Genprex. "We are encouraged by the increasing number of research institutions and independent researchers producing positive data on TUSC2, which provide additional support for REQORSA and its therapeutic potential against cancers."

REQORSA Therapy is currently in development for the treatment of non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). REQORSA consists of the TUSC2 gene expressing plasmid encapsulated in non-viral nanoparticles made from lipid molecules (the Company’s ONCOPREX Nanoparticle Delivery System) with a positive electrical charge. REQORSA is injected intravenously and specifically targets cancer cells, taking advantage of leaky tumor vascularity, increased tumor pinocytosis, and attraction of positively charged lipid nanoparticles to negatively charged cancer cells. REQORSA is designed to deliver the functioning TUSC2 gene to cancer cells while minimizing their uptake by normal tissue.

According to the National Brain Tumor Society, glioblastoma is one of the most complex, deadly, and treatment-resistant cancers. More than 13,000 Americans were expected to receive a glioblastoma diagnosis in 2022. Glioblastoma accounts for 49.1 percent of all primary malignant brain tumors. There have only been five drugs and one device ever approved by the U.S. Food and Drug Adminstration for the treatment of glioblastoma.

Other independent researchers and studies have found that TUSC2 therapy may benefit other types of cancer, including head and neck, breast (including triple-negative breast cancer), renal cell (kidney), thyroid, and soft tissue sarcoma, as well as NSCLC and SCLC. For more information and additional studies supporting TUSC2, please refer to our Bibliography Page.

On April 18, 2023 Genmab A/S (Nasdaq: GMAB) reported that worldwide net trade sales of DARZALEX (daratumumab), including sales of the subcutaneous (SC) product (daratumumab and hyaluronidase-fihj, sold under the tradename DARZALEX FASPRO in the U.S.), as reported by Johnson & Johnson were USD 2,264 million in the first quarter of 2023 (Press release, Genmab, APR 18, 2023, View Source [SID1234630238]). Net trade sales were USD 1,191 million in the U.S. and USD 1,072 million in the rest of the world. Genmab receives royalties on the worldwide net sales of DARZALEX, both the intravenous and SC products, under the exclusive worldwide license to Janssen to develop, manufacture and commercialize daratumumab.

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On April 18, 2023 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a clinical stage pharmaceutical company with a growing pipeline, including Phase 2 clinical programs, for hard-to-treat tumors and viruses, reported that positive preclinical data regarding the Company’s next-generation anthracycline, Annamycin, was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023, taking place April 14-19, 2023, at the Orange County Convention Center in Orlando, FL (Press release, Moleculin, APR 18, 2023, View Source [SID1234630237]). This research was sponsored by the Company.

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The poster titled, Exploration of Annamycin Organotropism to Target Primary and Metastatic Liver Cancers was presented by Rafal Zielinski, Ph.D., Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center as part of the Experimental and Molecular Therapeutic Session "Novel Antitumor Agents, PI3K/AKT Inhibitors, Proteasome Inhibitors, and Topoisomerases". The poster outlined results from the analysis of the pharmacokinetics of two formulations of Annamycin, liposome formulated drug product (L-ANN) and free Annamycin (ANN), in the liver in comparison with doxorubicin (DOX) and to determine its tumoricidal potential in a hepatocellular carcinoma (HCC) model in situ and in experimental models of liver metastasis.

"Annamycin has continued to demonstrate in preclinical models promising results in hard-to-treat tumors. We are pleased with the findings from these preclinical models in HCC, the most common type of primary liver cancer that is responsible for more than 12,000 deaths per year in the US. The high antitumor activity seen preclinically with Annamycin is very encouraging and provides validation for expanded studies to assess activity in different tumor liver metastasis models as well as HCC models," commented Walter Klemp, Chairman and Chief Executive Officer of Moleculin.

Annamycin is the Company’s next-generation anthracycline that has been designed to be non-cardiotoxic (unlike currently prescribed anthracyclines) and has been shown in animal models to accumulate in the lungs at up to 30-fold the level of doxorubicin (a commonly prescribed anthracycline), as well as demonstrating the ability to avoid the multidrug resistance mechanisms that typically limit the efficacy of doxorubicin and other currently prescribed anthracyclines.

The levels of ANN and DOX in plasma and tissue homogenates were assessed using LC/MS. The antitumor efficacy of L-ANN was studied using HEPA 1-6 hepatocellular carcinoma models (subcutaneous, orthotopic, and experimental liver metastatic models) as well as CT26 colon cancer and MIA PaCa-2 pancreatic cancer liver metastasis models.

Data Highlights:

ANN exhibited significantly higher accumulation in the liver parenchyma when compared to DOX (6-fold higher AUC values).

Researchers observed clear inhibition of the subcutaneous tumor growth after systemic (IV) administration of L-ANN.

Increased liver uptake of the drug had a direct effect on activity of the drug in vivo. Remarkable activity of L-ANN was observed in orthotopic models. Significant inhibition of the tumor growth and extension of the survival of L-ANN treated mice vs. vehicle-receiving animals was observed in HEPA 1-6 models (median survival 29.5 vs 50 days (p<0.0001) and 28 vs 59 days (p<0.0001), respectively).

L-ANN treatment resulted in dramatic increase in survival (median survival >407 days) in the CT26 colon cancer experimental metastasis model. In a separate experiment, significant delay in tumor progression was also observed in pancreatic cancer (MIA PaCa-2) liver metastasis model.

Annamycin is currently being evaluated in ongoing clinical trials for the treatment of STS lung metastases and AML. For more information about the ongoing trials, please visit clinicaltrials.gov and reference identifiers NCT04887298 and NCT05319587, respectively. Unless specifically noted otherwise, references to "Annamycin" refer to the liposome formulated form of the drug.

About Annamycin

Annamycin is the Company’s next-generation anthracycline that has been shown in animal models to accumulate in the lungs at up to 30-fold the level of doxorubicin. Importantly, Annamycin has also demonstrated a lack of cardiotoxicity in multiple early-stage human clinical trials, including ongoing trials for the treatment of acute myeloid leukemia (AML) and STS lung metastases. For that reason, although additional data will be necessary, the Company believes Annamycin may not face the same usage limitations imposed on doxorubicin, one of the most common currently approved anthracyclines. Annamycin is currently in development for the treatment of AML and STS lung metastases and the Company believes the drug may have the potential to treat additional indications.