On March 6, 2023 AstraZeneca and Daiichi Sankyo reported positive high-level results from an analysis of the ongoing DESTINY-PanTumor02 Phase II trial showed that met the prespecified target for objective response rate (ORR) and demonstrated durable response across multiple HER2-expressing advanced solid tumours in heavily pretreated patients (Press release, AstraZeneca, MAR 6, 2023, View Source [SID1234628222]).

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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.

The DESTINY-PanTumor02 Phase II trial is evaluating the efficacy and safety of Enhertu in patients with locally advanced, unresectable, or metastatic previously treated, HER2-expressing solid tumours not eligible for curative therapy, including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, and rare cancers. The primary endpoint of the trial is investigator-assessed confirmed ORR and investigator-assessed duration of response (DoR) is a key secondary endpoint.

The data will be presented at an upcoming medical meeting and shared with global regulatory authorities.

HER2 is a tyrosine kinase receptor protein expressed on the surface of various tissue cells throughout the body and is involved in normal cell growth.1,2 In some cancer cells, HER2 expression is amplified or the cells have activating mutations.1,3 While HER2-directed therapies have been used to treat breast, gastric and lung cancers, more research is needed evaluating their potential role in treating other HER2-expressing tumour types.2,4-6

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said, "Enhertu has already demonstrated its potential to improve outcomes for patients with HER2-targetable breast, gastric and lung cancers, and these positive initial results in other tumour settings with significant unmet need are very encouraging. The DESTINY-PanTumor02 results mark an important step forward in our understanding of the potential role of Enhertu across multiple HER2-expressing tumour types."

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said, "The clinically meaningful responses seen in the DESTINY-PanTumor02 trial reaffirm our belief in the potential of Enhertu across multiple HER2-expressing cancers. The results seen so far across multiple cohorts of the trial will inform next steps of our broad development programme as we look to bring this important medicine to as many patients as quickly as possible."

The safety profile observed in patients treated with Enhertu in the DESTINY-PanTumor02 trial was consistent with that seen in other trials of Enhertu with no new safety signals identified.​

Notes

DESTINY-PanTumor02
DESTINY-PanTumor02 is a global, multicentre, multi-cohort, open-label Phase II trial evaluating the efficacy and safety of Enhertu (5.4mg/kg) for the treatment of HER2-expressing tumours, including biliary tract cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer and rare tumours.

The primary efficacy endpoint of DESTINY-PanTumor02 is confirmed ORR as assessed by investigator. Secondary endpoints include DoR, disease control rate, progression-free survival, overall survival, safety, tolerability and pharmacokinetics.

DESTINY-PanTumor02 has enrolled 268 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 more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a (or one or more) 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 the results from the DESTINY-Breast03 trial.

Enhertu (5.4mg/kg) is approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in-situ hybridisation [ISH]-) 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 from the DESTINY-Breast04 trial.

Enhertu (5.4mg/kg) is approved under accelerated approval in the US for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer whose tumours have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/kg) is approved in more than 30 countries for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial and/or DESTINY-Gastric02 trial.

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

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.

On March 6, 2023 Cantex Pharmaceuticals, Inc., a clinical-stage pharmaceutical company focused on developing transformative therapies for cancer and other life-threatening medical conditions, and Baptist Health Miami Cancer Institute, part of Baptist Health Cancer Care, the largest cancer program in South Florida, reported that the U.S. Food and Drug Administration (FDA) has issued a "Study May Proceed" letter for the Miami Cancer Institute’s investigator initiated clinical trial to assess the safety and effectiveness of azeliragon combined with stereotactic radiosurgery in patients with brain metastases (Press release, Cantex, MAR 6, 2023, View Source [SID1234628221]).

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"Brain metastases are a devastating diagnosis for many people in their cancer journey," said Rupesh Kotecha, M.D., the principal investigator of the trial and Chief of Radiosurgery in the Department of Radiation Oncology and Director of the Central Nervous System Metastasis program at Miami Cancer Institute. "At Miami Cancer Institute, we are fortunate in that we have the latest radiotherapy technologies used to treat brain metastases. Stereotactic radiosurgery allows the radiation oncologist to deliver an intense, precisely targeted dose of radiation to tumor cells inside the brain while sparing healthy surrounding tissues including the brain itself, arteries, nerves and other important structures. Typically, patients receive corticosteroids along with the treatment to reduce the risk of peri-tumoral edema and inflammation. The clinical trial of azeliragon, with its differentiated mechanism of action, will offer patients a unique approach to the treatment of brain metastases that may protect against inflammation as well as potentiate radiation response in the tumor. This clinical trial represents a novel way of enhancing the effectiveness of radiation therapy of cancer."

Cantex’s azeliragon is an orally administered small molecule, taken as a pill once daily, that is being studied as a treatment for glioblastoma, brain metastases, and other cancers. Azeliragon inhibits interactions of the receptor for advanced glycation end products (known as RAGE) with certain ligands, including HMGB1 and S100 proteins in the cancer microenvironment. S100A9, a protein released from cells within the microenvironment of brain metastasis, binds to RAGE receptors on the surface of cancer cells, making them resistant to the effectiveness of radiation treatments. Azeliragon blocks the interaction of S100A9 with RAGE, potentially restoring sensitivity to radiation therapy. In addition, interaction of RAGE with proteins that bind to it, trigger inflammatory responses, which may worsen brain swelling associated with radiation therapy. The Miami Cancer Institute’s investigator-initiated trial is designed to determine whether azeliragon, when administered in combination with stereotactic radiosurgery, can prevent or eliminate the need for a powerful steroid, dexamethasone, to control brain swelling as well as improve the effectiveness of radiation therapy to treat brain metastases.

Brain metastases occur when cancer spreads from their original location. Brain metastases are the most common type of cancer in the brain, with over 150,000 people each year developing brain metastasis from their primary cancer (most commonly lung and breast cancer).

"We are excited to receive FDA authorization to proceed with this trial. With this approval, Cantex expands the cancer indications for which azeliragon is being investigated, including glioblastoma, breast cancer, and pancreatic cancer, furthering our work to better understand azeliragon as a treatment of very aggressive and difficult to treat cancers," said Stephen G. Marcus, M.D., Chief Executive Officer of Cantex. "The team of renowned oncologists at Miami Cancer Institute is committed to expanding innovative, cutting-edge tools for cancer treatment as indicated by their interest in RAGE inhibition and treatment of brain metastases."

Cantex recently announced that the FDA had provided the company with a "Study May Proceed" letter to assess azeliragon for the treatment of glioblastoma, the most common primary brain cancer. Azeliragon was also recently granted FDA Orphan Drug Designation for the treatment of glioblastoma.

About Azeliragon
Azeliragon, previously known as TTP488, is an orally active, small molecule, antagonist of the receptor for advanced glycation end products (RAGE) licensed by Cantex from vTv Therapeutics Inc. (NASDAQ:VTVT). vTv Therapeutics discovered azeliragon and carried out phase 3 clinical trials for Alzheimer’s disease. Although these trials did not demonstrate efficacy in Alzheimer’s disease, clinical safety data from these trials, involving over 2000 patients dosed for periods up to 18 months, indicate that azeliragon is very well tolerated. A broad range of evidence suggests that RAGE—ligand interactions play a critical role in cancer and its complications as well as in a range of inflammatory diseases.

On March 6, 2023 Lantern Pharma Inc. (NASDAQ: LTRN), a clinical-stage biopharmaceutical company using its proprietary RADR artificial intelligence (AI) and machine learning (ML) platform to transform the cost, pace, and timeline of oncology drug discovery and development, reported that it has formed a wholly-owned subsidiary, Starlight Therapeutics Inc. ("Starlight"), to develop drug candidate LP-184’s central nervous system (CNS) and brain cancer indications – including glioblastoma (GBM), brain metastases (brain mets.), and several rare pediatric CNS cancers (Press release, Lantern Pharma, MAR 6, 2023, View Source [SID1234628220]). Starlight will refer to the molecule LP-184, as it is developed in CNS indications, as "STAR-001". Combined, STAR-001’s targeted treatment indications are estimated to represent an annual global market potential of approximately $6.0 billion (USD) and over 500,000 global cases each year.

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Starlight plans on establishing a leading CNS oncology franchise to develop the unique drug candidate STAR-001 for some of the most malignant and unaddressed primary and secondary CNS cancers. The programs being developed by Starlight were born from the analysis of billions of oncology-focused data points and by using Lantern’s AI platform, RADR. STAR-001’s powerful anti-tumor mechanism of action, synthetic lethality, and collaborations with internationally recognized institutions, including the Kennedy Krieger Institute at Johns Hopkins and the Greehey Children’s Cancer Research Institute at UT Health – San Antonio, make it well positioned to advance in targeted and efficient clinical development programs. Starlight intends to pursue human clinical trials for multiple CNS indications starting in late 2023, building on prior IND-enabling studies and the Phase 1 clinical testing that will be conducted by Lantern.

"The formation of Starlight allows Lantern to put extreme focus on advancing STAR-001 through targeted clinical trials and dedicate increased time, resources, and personnel to progress one of the most promising drug candidates for CNS cancer patients in decades," stated Panna Sharma, Lantern’s CEO and President. "Additionally, establishing Starlight as a wholly-owned subsidiary will increase the potential to partner with other biopharma companies who are looking to develop a franchise in CNS cancers and to further accelerate the progression of STAR-001 towards changing patient outcomes in this devastating set of diseases," continued Sharma. "Since our initial discovery, in which we used large-scale, multi-omic network analysis from our RADR AI platform, to validate that GBM was sensitive to LP-184 and that LP-184 had excellent blood-brain barrier permeability, our team has found, validated, and published on several additional pediatric and adult brain cancers that have shown early promise to LP-184, now STAR-001, in CNS cancers," stated Sharma. "Our portfolio of opportunities and pipeline in CNS cancers has grown five-fold and includes multiple indications lacking any accepted standard-of-care. We believe that by focusing our efforts via Starlight Therapeutics we can accelerate and deepen our commitment to the CNS cancer patient community, while also creating the potential for meaningful additional upside for our investors," concluded Sharma.

STAR-001 is a unique blood-brain barrier permeable small molecule that utilizes its powerful mechanism of action, synthetic lethality, to exploit common vulnerabilities in CNS cancers with DNA damage repair (DDR) deficiencies. The anti-tumor potential of STAR-001 has been demonstrated across an extensive number of in-vitro and in-vivo CNS cancer models, including GBM, brain mets., and atypical teratoid rhabdoid tumors (ATRT), and has been presented at leading conferences and publications including, the Society for Neuro-Oncology annual meeting, the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, and the Frontiers in Drug Discovery Journal. Highlights of STAR-001’s promising preclinical results from these presentations and publications are included below:

Pharmacokinetic studies have shown STAR-001 to have 2X the bioavailability in brain tumors, compared to normal brain tissue, and to have 2X the bioavailability in brain tumors compared to the bioavailability of temozolomide (TMZ), the GBM standard-of-care (SOC) agent. Additional details from these experiments can be found here.
In mice implanted with subcutaneous GBM cell-derived xenograft (CDX) tumors from models of the two major GBM subtypes, known as MGMT methylated and MGMT unmethylated, STAR-001 treatment resulted in 107% tumor growth inhibition in both tumor types. In these experiments, 75% of mice with tumors from the MGMT unmethylated GBM model and 30% of mice with tumors from the MGMT methylated GBM model were entirely tumor-free after STAR-001 treatment. Additional details from these experiments can be found here.
STAR-001 has the potential for combination with the FDA-approved agent spironolactone to enhance STAR-001’s anti-tumor potency. In in-vitro GBM models with different MGMT methylation states, STAR-001 treatment with spironolactone significantly decreased STAR-001’s IC50 by 3-6X, resulting in IC50s in the low nanomolar range of 34-94nM. Additional details from these experiments can be found here.
STAR-001 has been demonstrated to have nanomolar potency in brain mets. cell lines that originated from non-small cell lung cancer, melanoma, and breast cancer (HER2- and Triple Negative). Additional details from these experiments can be found here.
STAR-001 treatment of mice implanted with ATRT CDX tumors, at either 2 mg/kg or 4 mg/kg doses (I.V.), showed near complete tumor growth inhibition between 82-91%, respectively. Additional details from these experiments can be found here.
Based on STAR-001’s demonstrated anti-tumor potential in CNS cancers, the FDA has granted STAR-001 Orphan Drug Designations (ODD) for malignant gliomas (including GBM) and ATRT. Additionally, STAR-001 was granted a Rare Pediatric Disease Designation for ATRT, which occurs in 60-70 pediatric patients a year in the US.

Starlight’s clinical development strategy will initially focus on progressing STAR-001 through early-stage clinical trials for adult recurrent high-grade gliomas (HGGs), including GBM. There have been no effective single-agent treatment options approved for GBM in nearly two decades. The current GBM standard-of-care agent, TMZ, is ineffective in MGMT unmethylated patients, who represent over 65% of all GBM patients. Starlight is planning several additional clinical programs for STAR-001 including adult and pediatric CNS cancers and combination regimens.

Commencing in mid-2023, Lantern is anticipating a Phase 1A basket trial for LP-184 (STAR-001), in a range of solid tumors including: recurrent brain cancers (including GBM and HGGs), metastatic CNS cancers (brain mets.), pancreatic cancer, and solid tumors with DDR deficiencies. The clinical development of STAR-001 in CNS cancers beyond the Phase 1A trial will be conducted exclusively by Starlight. Following the launch of Starlight, Lantern will continue to advance LP-184’s preclinical and clinical development for non-CNS indications (including pancreatic cancer and other solid tumors) and will also provide AI-driven bioinformatic and computational biology support to Starlight.

On March 6, 2023 Virion Therapeutics, LLC, a clinical-stage biotech company focused on the development of novel, adaptable, and accessible CD8+ T cell-based technologies focused on cancers and infectious diseases, reported data of a genetically encoded checkpoint modifier-based immunotherapy, which enhances CD8+ T cell activation, in a fast-growing preclinical tumor model at the ESMO (Free ESMO Whitepaper) Target Anticancer Therapies Congress in Paris France (Press release, Virion Biotherapeutics, MAR 6, 2023, View Source [SID1234628219]).

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Top line results, following a single intramuscular injection of this novel immunotherapy include:

Enhanced immune responses (10- to 15-fold) to oncogenic antigens
At study completion, 100% survival (n=30/30), 100% initial tumor clearance (n=30/30), and 93% of animals were tumor free (n=28/30)
In contrast, all mice treated with a control vaccine experienced rapid tumor growth and death by Day 30 (n=20)
These results were durable and reproducible across multiple treatment groups and studies
"Glycoprotein D (gD), when genetically expressed as a fusion protein with antigen(s) of choice, enhances, broadens, and prolongs CD8+ T cell responses. In this preclinical model of fast-growing HPV-16-associated tumors, a gD-based immunotherapy against HPV-16 provided incredibly strong protection against tumor growth and death," said Hildegund Ertl, MD, Professor, Vaccine & Immunotherapy Center, at The Wistar Institute in Philadelphia PA and Scientific Co-Founder of Virion Therapeutics. "Targeting different checkpoints of early T cell activation represents a novel approach to overcoming T cell impairments during tumor progression and these data further support its potential application, alone or in combination with other checkpoint inhibitors, for a wide range of cancers."

"These preclinical oncology data demonstrated treatment responses which were profound, durable, and reproducible – and show clear differentiation to any other immunotherapy or vaccine in development. We are excited to be advancing our checkpoint modifier pipeline, not only with IND-enabling activities for our oncology program, but also, VRON-0200, for chronic HBV, which is heading to the clinic this summer," said Andrew Luber, Pharm.D., President, and chief executive officer of Virion.

Presentation Details

Presentation Title: "Therapeutic vaccination with HPV-16 proteins fused into a checkpoint modifier or early T cell activation protects against HPV-associated tumors in a preclinical model." Poster #36P

Abstract Number: 277

Presenting Author: Sue Currie, PhD

Presentation Date: March 6, 2023

The above presentation is available via the ESMO (Free ESMO Whitepaper) TAT meeting website, View Source, and on Virion’s website at View Source

About Genetically Encoded Checkpoint Modifiers (gCPM)

Virion is developing a series of novel gCPMs which act at different stages of T cell activation. The lead gCPM, glycoprotein D (gD), works by blocking an inhibitory signal of early activation (e.g., BTLA/CD160), thereby allowing a co-stimulatory signal to predominate (e.g., LIGHT) – the resultant CD8+ T cells that are induced to the target antigen(s) are enhanced, broadened and prolonged and they are more resistant to becoming impaired over time. This novel mechanism of early checkpoint modification that acts locally at the onset of the immune response has shown promising therapeutic efficacy in several settings, including animal models of fast and slow growing tumors, with viral or human cancer antigens, in young and older animals, and when inserted into DNA or adenovirus vaccine delivery platforms (both human and chimpanzee).

On March 6, 2023 Phanes Therapeutics, Inc., a clinical stage biotech company focused on innovative drug discovery and development in oncology, reported that it has entered into a research collaboration with Xyphos Biosciences, Inc. an Astellas Company (Press release, Phanes Therapeutics, MAR 6, 2023, View Source [SID1234628218]). The collaboration will leverage Phanes’ proprietary technology platforms, PACbody and SPECpair, in the evaluation of cell therapies in oncology.

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Under the terms of the agreement, Phanes will receive a technology access payment and further collaborative research support. The details of the financial terms were not disclosed.

"We are delighted to have the opportunity to collaborate with Xyphos," said Dr. Ming Wang CEO of Phanes. "PACbody and SPECpair allow construction of native IgG-like bispecific antibodies and production of the molecules using the conventional manufacturing process for monoclonal antibodies. The lead molecule Phanes made using these technologies has entered Phase 1 clinical study. With the bispecific antibody technology platforms we have built, Phanes is well positioned to make important impacts in cell therapies."