On May 26, 2021 Kintara Therapeutics, Inc. (Nasdaq: KTRA) ("Kintara" or the "Company"), a biopharmaceutical company focused on the development of new solid tumor cancer therapies, reported that the VAL-083 treatment arm in the Global Coalition for Adaptive Research (GCAR) registrational Phase 2/3 clinical trial for glioblastoma multiforme (GBM) has been activated in 15 U.S. sites as of May 14, 2021 (Press release, Kintara Therapeutics, MAY 26, 2021, View Source [SID1234580633]).

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The trial, titled GBM AGILE (Glioblastoma Adaptive Global Innovative Learning Environment), is a patient-centered, adaptive platform trial for registration evaluating multiple therapies for patients with newly-diagnosed and recurrent GBM. Since January 2021, GCAR has accelerated the pace of clinical site activation with increased awareness in the medical community of Kintara’s arm of the study. GCAR plans to enroll 150-200 patients in the Kintara arm of the study at 30 sites in the U.S. and Canada with potential to increase this total to 40 clinical trial centers.

"The entire Kintara team is enthused by the pace at which our treatment arm is being activated in the study," commented Saiid Zarrabian, Kintara’s Chief Executive Officer. "With 15 sites already active, including prestigious centers such as Memorial Sloan Kettering, Henry Ford Cancer Institute, Columbia University Irving Cancer Research Center, Emory University Winship Cancer Institute, and the University of Florida, we are delighted to witness GCAR’s exceptional clinical trial execution capabilities that drew us to participate in this exciting and highly efficient registrational study."

Key GBM AGILE Highlights for VAL-083

Only therapeutic agent currently being evaluated in all three GBM patient subtypes: newly-diagnosed methylated MGMT; newly-diagnosed unmethylated MGMT; and recurrent

May accelerate VAL-083’s time to pivotal trial completion and potential regulatory submission by up to 18 months

Cost-effective opportunity to advance VAL-083 due to the GBM AGILE study’s expense sharing protocol
GBM AGILE is an international, innovative platform trial designed to more rapidly identify and confirm effective therapies for patients with GBM through response adaptive randomization and a seamless Phase 2/3 design. The trial, conceived by over 130 key opinion leaders, is conducted under a master protocol allowing multiple therapies, or combinations of therapies, from different pharmaceutical partners to be evaluated simultaneously. With its innovative design and efficient operational infrastructure, data from GBM AGILE can be used as the foundation for a new drug application and biologics license application submissions and registrations to the FDA and other health authorities.

Kintara’s VAL-083 is a "first-in-class," small molecule bifunctional alkylating agent that crosses the blood-brain barrier. VAL-083 is independent of the MGMT resistance mechanism and has been assessed in over 40 Phase 1 and Phase 2 clinical trials in multiple indications sponsored by the U.S. National Cancer Institute (NCI). Published pre-clinical and clinical data indicate that VAL-083 has activity against a range of tumor types, including lung, brain, cervical, ovarian tumors and hematologic (blood) cancers. VAL-083 has been granted Orphan Drug Designation for GBM by the FDA and EMA and has also been granted Orphan Drug Designations for medulloblastoma and ovarian cancer by the FDA. In addition, the FDA granted Fast Track Designation for VAL-083 in recurrent GBM. VAL-083 is approved as a cancer chemotherapeutic in China for the treatment of chronic myelogenous leukemia and lung cancer. VAL-083 has not been approved for any indications outside of China.

On May 26, 2021 TransThera Biosciences Co. Ltd. ( "TransThera" ), a clinical stage biotechnology company dedicated to developing innovative therapeutics across oncology, cardiovascular, and inflammatory diseases with major unmet medical needs globally and in China, reported that it has entered into a collaboration agreement with Roche to explore the combination of TT-00420 and atezolizumab for the treatment of patients in China with gastrointestinal ("GI") tract cancers (Press release, TransThera Biosciences, MAY 26, 2021, View Source [SID1234580649]). The Investigational New Drug application of the combination therapy has been recently approved by China National Medical Products Administration (NMPA).

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GI tract cancers represent one of the most challenging unmet medical needs in China. A lack of effective therapy calls for an emergent need for novel drug development. TT-00420, a unique small molecule kinase inhibitor, has demonstrated preliminary clinical benefits in Cholangiocarcinoma patients and other GI cancer patients in Phase I study. In addition to its targeted therapy attribute, TT-00420 also showed synergistic effect to modulate tumor microenvironment, rendering it a potential partner to checkpoint inhibitors for hard-to-treat solid tumors. Taken together, compelling pre-clinical and clinical data warrant the clinical development of TT-00420 in combination with atezolizumab.

"We are grateful to partner with Roche to tackle the challenge of GI tract cancers affecting people in China. GI cancers represent a huge unmet medical need and we are very excited about the potential of TT-00420 in this field. We are hoping to provide better options for GI cancer patients through the collaboration with Roche in the future", commented by Dr. Peng Peng, Vice President of TransThera in charge of the oncology pipeline development.

About TT-00420

TT-00420 is a highly innovative clinical stage spectrum-selective kinase inhibitor that exerts anti-tumor effects by targeting tumor cells and improving the tumor microenvironment. A large number of preclinical studies have found that TT-00420 has an excellent inhibitory effect on triple-negative breast cancer, cholangiocarcinoma and other malignant tumors. In September 2018, TT-00420 was approved by the US FDA for the first human clinical trial; in February 2019, it was approved by China’s NMPA for human clinical trials; and on November 7 of the same year, TT-00420 was granted the "Orphan Drug Designation" status (ODD) by FDA for the treatment of cholangiocarcinoma. On November 28, 2020, it was again approved by the US FDA targeting the clinical trial of new indication for cholangiocarcinoma. In March 2021, TransThera announced the completion of a phase I dose escalation clinical trial in China and the United States.

On May 26, 2021 Lyell Pharmaceuticals reported that it filed for an initial public offering (IPO) with plans to raise $150 million (Press release, Lyell Immunopharma, MAY 26, 2021, View Source [SID1234583252]). The preclinical biotech raked in $493 million in a Series C round on March 12, 2020.

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The company, which isn’t expected to enter the clinic until possibly in 2022, is working to make cell therapies work in solid tumors. So far, cell therapies such as CAR-T have been effective in hematologic cancers but have been far less successful in solid tumors. They are also working to prevent relapses caused by T-cell exhaustion.

In March, the company completed the construction of its $65 million LyFE Manufacturing Center in Bothell, Washington. The facility is 70,000 square feet and holds cell process equipment and manufacturing processes needed to expand and reengineer immune cells obtained from patients.

"This manufacturing center represents crucial infrastructure for our upcoming clinical trials and will be able to scale to meet our cell therapy manufacturing needs as we grow," said Stephen Hill, chief technical operations officer of Lyell.

"Manufacturing is integral to the actual design and performance of new cell therapies, so we have made large investments to build leading edge capabilities in this area. LyFE is a paperless facility that has digital manufacturing integrated into the operation. We believe the ability to capture and analyze data in real time will ultimately lead to better and safer cell therapies for patients."

In September 2020, Lyell inked a research partnership with Orca Bio to combine Orca’s precision purification T-cell technology with Lyell’s T-cell biology expertise to focus on solid tumor cell therapies. Orca has developed T-cell therapies for blood diseases as well as developed an ultra-fast, clinically compatible cell sorter dubbed OrcaSort.

"Lyell Immunopharma is focused on developing curative T-cell therapies for solid tumor cancers by defining starting cell preparations and modulating T-cells, so they are functional in the immunosuppressive tumor microenvironment," said Nick Restifo, executive vice president of Research for Lyell, at the time. "This collaboration with Orca Bio provides the potential to more efficiently define starting cell preparations, which I believe could lead to more effective T-cell therapies."

The company’s lead asset is a CAR (chimeric antigen receptor) that targets ROR-1, a receptor tyrosine kinase present in various cancers with abnormal expression. Lyell and other biotech companies believe that silencing ROR-1 will prevent cancer metastasis. They expect early clinical trials to be on triple-negative breast cancers and non-small cell lung cancer (NSCLC).

They won’t be alone, although their approach appears to be unique. In 2020, Merck acquired VelosBio for an antibody-drug conjugate (ADC) against ROR-1. And the same year, Boehringer Ingelheim bought NBE-Therapeutics to partner on an ADC. ADCs are antibodies directed against a target, in this case ROR-1, linked to a toxic drug, which is more precisely directed to the target.

Lyell’s approach would be to collect T-cells from the patients, engineer them to attack ROR-1, and reinfuse them back into the patient. In its filing, the company wrote, "We are applying our Gen-R and Epi-R technology platforms to our lead CAR program, LYL797, which is expected to be an intravenous (IV) administered CAR-T cell product candidate targeting ROR1. If successful, we anticipate expanding into other ROR1+ cancers with a lower incidence of ROR1 expression, including potentially hormone receptor positive (HR+) breast cancer, ovarian and other solid tumors. We expect to submit an IND for LYL797 in the first quarter of 2022."

GlaxoSmithKline holds 14% of Lyell. According to the filing, GSK is "developing a New York esophageal squamous cell carcinoma 1 (NY-ESO-1) TCR T-cell product candidate, NY-ESO-1C259, currently in pivotal development. We are collaborating with them to potentially enhance this clinical-stage product candidate with Gen-R and Epi-R. Preclinical efforts and IND-enabling studies are underway. We anticipate GSK will conduct initial clinical trials with the enhanced product candidate in synovial sarcoma and multiple other solid tumor indicates. We anticipate an IND submission in the first half of 2022."

In total, the company hopes to submit four Investigational New Drug (IND) applications in 2022.

On May 26, 2021 Mersana Therapeutics, Inc. (NASDAQ:MRSN), a clinical-stage biopharmaceutical company focused on discovering and developing a pipeline of antibody-drug conjugates (ADCs) targeting cancers in areas of high unmet medical need, reported that Anna Protopapas, President and Chief Executive Officer, will present at the Jefferies Virtual Healthcare Conference on Wednesday, June 2, 2021 at 11:00 a.m. ET (Press release, Mersana Therapeutics, MAY 26, 2021, View Source [SID1234580602]).

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A live webcast of the presentation will be available on the Investors & Media section of Mersana’s website at www.mersana.com.

On May 26 2021 Aptevo Therapeutics Inc. ("Aptevo") (NASDAQ:APVO), a clinical-stage biotechnology company focused on developing novel immuno-oncology therapeutics based on its proprietary ADAPTIR and ADAPTIR-FLEX platform technologies, reported positive results from the Company’s Phase 1 dose escalation trial evaluating lead ADAPTIR candidate, APVO436, for the treatment of acute myeloid leukemia and myelodysplastic syndromes (AML/MDS) (Press release, Aptevo Therapeutics, MAY 26, 2021, View Source [SID1234580634]). APVO436 was generally well tolerated and demonstrated a favorable side effect profile, including the absence of severe or prolonged neutropenia, an often serious condition associated with CD123-targeting therapies. Further, APVO436 showed encouraging single agent activity and a promising benefit to risk profile in patients with relapsed, advanced stage AML.

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The Phase 1 dose escalation study, conducted at leading cancer centers across the United States (US), as listed in www.clinicaltrials.gov as NCT03647800, enrolled 46 patients with AML or myelodysplastic syndromes, each of whom received escalated intravenous infusions of APVO436 ranging in dose from 0.3 micrograms to 60 micrograms. The long half-life of APVO436 enabled its administration over short infusion times. The study met its primary endpoint – identification of an active dose level for advanced studies. The Company plans to submit the data for publication later this year.

AML is the most common form of adult acute leukemia with >20,000 estimated new cases and >10,000 deaths in the United States (US) for 2021 (SEER Program, www.seer.cancer.gov).

The therapeutic landscape for leukemias is rapidly evolving in the era of personalized medicine but development of new drugs capable of killing chemotherapy resistant leukemia cells that can be used to improve the efficacy of standard of care induction and consolidation regimens remains an unmet medical need.

Unlike the potency of chemotherapy drugs, the clinical activity of bispecific antibodies in leukemia patients is often not "dose-linear," so a higher dose may potentially be less effective than a much lower dose. Likewise, the most effective concentrations are frequently not concentrations that are achieved at the highest tolerated dose levels. This is because these antibodies can be captured by normal cells, including T-cells that bind to the CD3 directed portion of the bispecific antibody. In order to avoid such a "sink effect", a dose level needs to be carefully identified at which the likelihood of excessive binding to normal cells in blood and bone marrow is very low. That is to say, an optimal dose needs to be identified at which leukemia cells are selectively killed without causing severe neutropenia, a complication reported for CD123-targeting drugs that can lead to life-threatening infections and sepsis. Therefore, the contemporary strategy in clinical development of bispecific antibodies is to identify a biologically optimal dose level, ideally a dose level much lower than the maximum tolerated dose level. Importantly, the APTEVO study 5001 has met the primary endpoint of its Part 1, identifying Cohort 6 dose as an active dose level for advanced studies of APVO436, also known as the recommended Phase 2 dose (RP2D).

"We observed, as preliminary signs of clinical activity both stabilization of leukemia as well as complete remissions," reported Dr. Fatih Uckun, leukemia expert and Chief Clinical Advisor, who is coordinating the APVO436 clinical development program. Of seven evaluable relapsed AML patients treated in Cohort 6, four showed stabilization of their leukemias. Of those four patients with disease stabilization, three patients lived 246+ days, 261+ days, and 281+ days, respectively and one progressed after a month. Two relapsed AML patients, who experienced stabilization of their leukemia, achieved a partial remission (PR) and subsequently a complete remission (CR). No partial or complete remissions have been observed at APVO436 dose levels either lower or higher than the Cohort 6 dose level. Therefore, APVO436 will be used at the Cohort 6 dose level in Part 2 of the study.

"We are very pleased to see lead ADAPTIR platform candidate, APVO436, progress in the clinic. APVO436 has demonstrated the potential to address a significant unmet need for patients with AML and provide the foundation for new and more effective multi-modality standard of care regimens that offer renewed hope for leukemia patients," said Jane Gross, PhD, the Chief Scientific Officer for Aptevo.

One of the most significant and frequent side effects associated with the use of bispecific, T-cell engaging antibodies are neurologic toxicities. Neurological toxicities may be severe, life-threatening, or fatal. Serious neurologic toxicity has not been a frequent complication associated with APVO436 treatments in this study. Another potential complication associated with treatment using bispecific, T-cell engaging antibodies is a systemic inflammatory syndrome known as Cytokine Release Syndrome (CRS). CRS has occurred in some patients and has been managed using the generally recommended standard CRS treatments. In Cohort 6, of 9 AML/MDS patients evaluable for toxicity, 2 patients developed a Grade 1 CRS and one patient developed a transient Grade 3 CRS related to APVO436 which resolved with routine clinical management.

CD123, although highly expressed on AML blasts, is also expressed on normal bone marrow hematopoietic stem cells and myeloid progenitor cells that give rise to the infection-fighting white blood cells. Therefore, treatment platforms targeting CD123 have been associated with a prolonged and profound decrease of white blood cell counts, known as severe neutropenia, and infections, especially pneumonias. This side effect caused by CD123 targeting overlaps with the blood count lowering side effects of standard chemotherapy drugs is among the main hurdles impeding the desired incorporation of CD123 targeting drugs into contemporary frontline as well as second-line standard of care treatment regimens. Notably, Aptevo researchers discovered that APVO436 does not cause severe or prolonged neutropenia at doses that resulted in complete remissions. None of the 46 patients treated with APVO436 developed severe or prolonged neutropenia as a side effect of the drug.

"This finding will inform the clinical development path for APVO436, as a novel drug candidate for blood cancers," stated Dr. Uckun. "AML patients are in urgent need of active new drugs capable of destroying leukemia cells without causing profound neutropenia. We will diligently advance the clinical development of APVO436 and evaluate its potential clinical impact for leukemia patients." Dr. Uckun added.

"We are pleased to report progress in the clinical development of our ADAPTIR platform candidate, APVO436," said Marvin White, President and CEO of Aptevo. "We remain confident about the breakthrough potential of APVO436 and look forward to sharing interim data from Part 2 of our study later this year. The scientific data from multiple studies so far suggest tremendous therapeutic potential for the APVO436 ADAPTIR platform and provides the foundation for our optimism regarding the potential commercialization of APVO436.",