On June 4, 2021 Provectus (OTCQB: PVCT) reported that preliminary full study data from the Company’s Phase 1 clinical trial of investigational cancer immunotherapy PV-10 (rose bengal disodium) for the treatment of neuroendocrine tumors (NET) metastatic to the liver (mNET) refractory to somatostatin analogs (SSAs) and peptide receptor radionuclide therapy (PRRT) (NCT02693067) is be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2021 Annual Meeting, held June 4-8 online (Press release, Provectus Biopharmaceuticals, JUN 4, 2021, View Source [SID1234583575]).

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Highlights from the mNET Presentation at ASCO (Free ASCO Whitepaper) 2021:

Baseline and disease characteristics
12 patients; 50% male; median age of 66 years (range 47-79)
Primary tumor sites: 7 small bowel (58%), 2 pancreas (17%), 1 caecal (8%), and 2 unknown (17%)
NET grades: 5 Grade 1 (42%) and 7 Grade 2 (58%)
Refractory to SSA and PRRT; symptomatic progressive disease
PV-10 treatment summary
Median of 1 hepatic NET lesion injected (range 1-4); median of 1 injection cycle (range 1-4); 8 patients (75%) received 1 PV-10 treatment
Safety
Mild-to-moderate post-procedure pain reported by most patients
Grade 3 photosensitivity reaction in 1 patient, Grade 3 elevation of hepatic enzymes in 1 patient, and carcinoid flare in 2 patients
Injected lesion efficacy (RECIST 1.1)
42% partial response (PR) and 42% objective response rate (ORR)
Patient-level efficacy (RECIST 1.1)
83%a disease control rate (DCR)
Progression-free survival (PFS): median 9.2 months (range 1.0-41.8)
Overall survival (OS): median 22.5 months (range 5.5-41.8); 6 patients (50%) undergoing response follow-up at the data cut-off of April 30, 2021
Immune response
Upregulation of NK cells and activated CD4+ T cells was observed in peripheral blood collected 7 and 28 days post-PV-10 injection
Biomarkers and quality of life (QOL)
Chromogranin A levels remained stable in 10 patients (83%)
QOL assessments showed stable or improved carcinoid symptoms and global health status in most patients
a Typographical error on the poster

A copy of the poster is available on Provectus’ website at View Source

This clinical trial, a single-center study at The Queen Elizabeth Hospital (TQEH) in Adelaide, Australia that completed enrollment in 2020, is led by Tim Price, MBBS, DHlthSc (Medicine), FRACP, Head of Clinical Oncology Research and Chair of the combined Hematology and Medical Oncology Unit at TQEH and Clinical Professor in the Faculty of Medicine at the University of Adelaide. The primary endpoint of the trial is safety. Secondary endpoints include ORR of injected target and measurable bystander lesions, target lesion somatostatin receptor expression, and biochemical response. Disease response assessments are conducted by independent review using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Six patients in the first cohort each received one percutaneously-administered injection of PV-10 to one target lesion per treatment cycle. Patients in the six-person second cohort can receive PV-10 injections of multiple lesions per cycle.

Dominic Rodrigues, Vice Chair of the Company’s Board of Directors, said, "The vast majority of patients with neuroendocrine cancer present with liver metastases, and their prognosis is poor. PV-10 treatment of these hepatic tumors in heavily pre-treated patients resulted in durable systemic clinical benefit and evidence of immunotherapeutic activity in an otherwise immunologically cold tumor type."

Mr. Rodrigues added, "Provectus’ PV-10 development program for visceral hepatic tumors, led by more recent clinical study of neuroendocrine cancer and uveal melanoma, has not elicited any safety concerns and provided encouraging evidence of local and systemic response and disease control in refractory patient populations. Numerous liver metastases of defined tumor types have been treated in this program, including hepatoma, colorectal, lung, pancreatic, ovarian, cutaneous melanoma, breast, neuroendocrine, and uveal melanoma."

About PV-10

Intralesional (IL) administration of PV-10 for the treatment of solid tumor cancers can yield immunogenic cell death within hours of tumor injection, and induce tumor-specific reactivity in circulating T cells within days.1,2,3 This IL PV-10-induced functional T cell response may be enhanced and boosted in combination with immune checkpoint blockade (CB).4 In CB-refractory advanced cutaneous melanoma, IL PV-10 may restore disease-specific T cell function, which may also be prognostic of clinical response. IL PV-10 has been administered to over 450 patients with cancers of the skin and of the liver. It is administered under visual, tactile or ultrasound guidance to superficial malignancies, and under CT or ultrasound guidance to tumors of the liver. Systemic administration of PV-10 is also undergoing preclinical study as prophylactic and therapeutic treatments for refractory and high-risk adult solid tumor cancers, and as a treatment for relapsed and refractory blood cancers.

About Rose Bengal Disodium

RBD is 4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein disodium, a halogenated xanthene and Provectus’ proprietary lead molecule. Provectus’ current Good Manufacturing Practices (cGMP) RBD is a proprietary pharmaceutical-grade drug substance produced by the Company’s quality-by-design (QbD) manufacturing process to exacting regulatory standards that avoids the formation of uncontrolled impurities currently present in commercial-grade rose bengal. Provectus’ RBD and cGMP RBD manufacturing process are protected by composition of matter and manufacturing patents as well as trade secrets.

An IL formulation (i.e., by direct injection) of cGMP RBD drug substance, cGMP PV-10, is being developed as an autolytic immunotherapy drug product for solid tumor cancers.

IL PV-10 is also undergoing preclinical study for relapsed and refractory pediatric solid tumor cancers, such as neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma.5,6

A topical formulation of cGMP RBD drug substance, PH-10, is being developed as a clinical-stage immuno-dermatology drug product for inflammatory dermatoses, such as atopic dermatitis and psoriasis. RBD can modulate multiple interleukin and interferon pathways and key cytokine disease drivers.7

Oral formulations of cGMP RBD are undergoing preclinical study for relapsed and refractory pediatric blood cancers, such as acute lymphocytic leukemia and acute myelomonocytic leukemia.8,9

Oral formulations of cGMP RBD are also undergoing preclinical study as prophylactic and therapeutic treatments for high-risk adult solid tumor cancers, such as head and neck, breast, pancreatic, liver, and colorectal cancers.

Different formulations of cGMP RBD are also undergoing preclinical study as potential treatments for multi-drug resistant (MDR) bacteria, such as Gram-negative bacteria.

Topical formulations of cGMP RBD are also undergoing preclinical study as potential treatments for diseases of the eye, such as infectious keratitis

Tumor Cell Lysosomes as the Seminal Cancer Drug Target

Lysosomes are the central organelles for intracellular degradation of biological materials, and nearly all types of eukaryotic cells have them. Discovered by Christian de Duve, MD in 1955, lysosomes are linked to several biological processes, including cell death and immune response. In 1959, de Duve described them as ‘suicide bags’ because their rupture causes cell death and tissue autolysis. He was awarded the Nobel Prize in 1974 for discovering and characterizing lysosomes, which are also linked to each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Building on the Discovery, Exploration, and Characterization of Lysosomes

Cancer cells, particularly advanced cancer cells, are very dependent on effective lysosomal functioning.10 Cancer progression and metastasis are associated with lysosomal compartment changes11,12, which are closely correlated (among other things) with invasive growth, angiogenesis, and drug resistance13.

RBD selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus2,14, external collaborators5, and other researchers15,16,17 have independently shown that RBD triggers each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Cancer Cell Autolytic Death via RBD: RBD-induced autolytic cell death, or death by self-digestion, in Hepa1-6 murine hepatocellular carcinoma (HCC) cells can be viewed in this Provectus video of the process (ethidium homodimer 1 [ED-1] stains DNA, but is excluded from intact nuclei; lysosensor green [LSG] stains intact lysosomes; the video is provided in 30-second frames, with a duration of approximately one hour). Exposure to RBD triggers the disruption of lysosomes, followed by nucleus failure and autolytic cell death. Identical responses have been shown by the Company in HTB-133 human breast carcinoma (which can be viewed in this Provectus video of the process, with a duration of approximately two hours) and H69Ar human multidrug-resistant small cell lung carcinoma. Cancer cell autolytic cell death was reproduced by research collaborators in neuroblastoma cells to show that lysosomes are disrupted upon exposure to RBD.5

Tumor Autolytic Death via RBD: RBD causes acute autolytic destruction of injected tumors (via autolytic cell death), mediating the release of danger-associated molecular pattern molecules (DAMPs) and tumor antigens; release of these signaling factors may initiate an immunologic cascade where local response by the innate immune system may facilitate systemic anti-tumor immunity by the adaptive immune system. The DAMP release-mediated adaptive immune response activates lymphocytes, including CD8+ T cells, CD4+ T cells, and NKT cells, based on clinical and preclinical experience in multiple tumor types. Mediated immune signaling pathways may include an effect on STING, which plays an important role in innate immunity.9

Orphan Drug Designations (ODDs)

ODD status has been granted to RBD by the U.S. Food and Drug Administration for metastatic melanoma in 2006, hepatocellular carcinoma in 2011, neuroblastoma in 2018, and ocular melanoma (including uveal melanoma) in 2019.

Intellectual Property

Provectus’ IP includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the process by which cGMP RBD and related halogenated xanthenes are produced, avoiding the formation of previously unknown impurities that exist in commercial-grade rose bengal in uncontrolled amounts. The requirement to control these impurities is in accordance with International Council on Harmonisation (ICH) guidelines for the manufacturing of an injectable pharmaceutical. US patent numbers are 8,530,675, 9,273,022, and 9,422,260, with expirations ranging from 2030 to 2031.

The Company’s IP also includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the combination of RBD and CB (e.g., anti-CTLA-4, anti-PD-1, and anti-PD-L1 agents) for the treatment of a range of solid tumor cancers. US patent numbers are 9,107,887, 9,808,524, 9,839,688, and 10,471,144, with expirations ranging from 2032 to 2035; US patent application numbers include 20200138942 (i.e., 16/678,133), which has been allowed.

On June 4, 2021 Alkermes plc (Nasdaq: ALKS) reported new data from its ARTISTRY clinical development program for nemvaleukin alfa (nemvaleukin), Alkermes’ novel, investigational engineered interleukin-2 (IL-2) variant immunotherapy. The data are being presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, taking place virtually June 4-8, 2021, and in an investor webcast presentation hosted by the company (Press release, Alkermes, JUN 4, 2021, View Source [SID1234583574]).

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The presentations include updated efficacy and safety data from ARTISTRY-1, an ongoing phase 1/2 study investigating intravenous (IV) nemvaleukin, which showed anti-tumor activity of IV nemvaleukin monotherapy in checkpoint inhibitor (CPI)-experienced melanoma and renal cell carcinoma (RCC) patients, and anti-tumor activity of IV nemvaleukin in combination with pembrolizumab in a range of difficult-to-treat tumors, including in CPI-unapproved tumor types, and in CPI-approved tumor types among both CPI treatment-naïve and pretreated patients. Durable and deepening responses have been observed with IV nemvaleukin, as monotherapy or in combination with pembrolizumab, in platinum-resistant ovarian cancer (PROC) and mucosal melanoma. Treatment-related adverse events (AEs) were mostly transient and manageable and the maximum tolerated dose had not yet been reached.

Alkermes’ presentations also include data from ARTISTRY-2, an ongoing phase 1/2 study evaluating subcutaneous (SC) nemvaleukin. Findings include a pharmacodynamic response and safety profile that support the recommended phase 2 dose (RP2D), and encouraging early signs of anti-tumor activity in PROC.

"Intravenous nemvaleukin’s observed single-agent activity in melanoma and renal cell carcinoma, and combination activity in both PD-1/L1 unapproved and approved tumor types, support its potential to be a treatment option for a range of difficult-to-treat cancers," said Valentina Boni, M.D., Ph.D., Lead Investigator, ARTISTRY-1 and Medical Oncologist Principal Investigator START Madrid at Centro Integral Oncológico Clara Campal. "In the ARTISTRY-1 trial, the durable and deepening responses observed in PROC and mucosal melanoma are particularly encouraging as these patients have limited treatment options."

"ARTISTRY-1 and ARTISTRY-2 have yielded important clinical data that will guide and serve as the foundation for future clinical evaluation of nemvaleukin. As the data have evolved, we have seen new objective responses in a range of tumors, and improvements upon certain previously reported responses, which provide additional support for nemvaleukin’s potential utility," said Craig Hopkinson, M.D., Chief Medical Officer and Executive Vice President of Research & Development at Alkermes. "We are proud to participate in the important dialogue at this year’s Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and are committed to the development of medicines that seek to improve treatment outcomes for people affected by cancer, particularly cancers for which there are limited or no treatment options currently available."

Data highlights from the ASCO (Free ASCO Whitepaper) poster presentations and the company’s investor presentation include:

ARTISTRY-1, IV Nemvaleukin Monotherapy Cohort
The ARTISTRY-1 monotherapy cohort included CPI-experienced patients with melanoma and renal cell carcinoma. Data are as of March 19, 2021 unless otherwise noted:

Melanoma monotherapy cohort: Among 30 total evaluable patients, 24 continued on study, including 13 patients who rolled over to a combination cohort evaluating nemvaleukin in combination with pembrolizumab.
Metastatic mucosal melanoma: 2 out of 6 patients achieved a partial response (PR) (one unconfirmed). The patient with the confirmed PR demonstrated a durable, deepening response and had been on treatment for 74 weeks.
Cutaneous melanoma: 2 out of 18 evaluable patients achieved a PR (one unconfirmed, one awaiting confirmation), as of May 3, 2021.
Stable disease (SD) was observed in 21 patients.
RCC monotherapy cohort: Among 20 evaluable patients, 12 continued on study, including 6 who rolled over to a combination cohort.
2 patients achieved a PR (one awaiting confirmation as of May 3, 2021) and SD was observed in 10 patients.
ARTISTRY-1, IV Nemvaleukin in Combination with Pembrolizumab
The combination cohorts in ARTISTRY-1 included: patients with PD-1/L1 unapproved tumor types; patients with PD-1/L1 approved tumor types (PD-1/L1 pretreated and PD-1/L1 treatment naïve); patients in tumor-specific cohorts; and patients who rolled over from monotherapy cohorts. Data are as of May 3, 2021:

Among the total 100 evaluable patients in the combination cohorts, 19 objective responses were observed.
Out of the 14 evaluable patients with ovarian cancer enrolled in the PD-1/L1 unapproved cohort, there was 1 complete response (CR), 3 PRs (one unconfirmed) and 6 had SD. As of the data cut, 3 of the 4 patients with objective responses had been on treatment for more than a year and continued on therapy.
Out of the 4 evaluable patients with cervical cancer enrolled in the PD-1/L1 approved cohort, 2 achieved a PR (one awaiting confirmation). As of the data cut, 3 out of the 4 evaluable patients continued on therapy.
Objective responses were also observed in patients with the following cancers: esophageal, bladder, Hodgkin’s lymphoma, breast, RCC, mucosal melanoma, colorectal, gastric, pancreatic, head and neck, small cell and non-small cell lung.
As of March 19, 2021, treatment-related AEs across the monotherapy and combination cohorts were consistent with expectations based on nemvaleukin’s mechanism of action and were mostly transient and manageable at the IV RP2D of 6 µg/kg. Pyrexia, chills and nausea were the most commonly reported AEs. Transient and asymptomatic neutropenia/neutrophil count decrease were the most commonly reported events of grade ≥3. Nemvaleukin, whether as monotherapy or in combination with pembrolizumab, demonstrated no additive toxicity to that established with pembrolizumab alone.

ARTISTRY-2, SC Nemvaleukin Study
The dose-escalation stage of ARTISTRY-2 evaluated the safety and tolerability of ascending doses of SC nemvaleukin administered once weekly (q7d) or once-every-three-weeks (q21d) as lead-in monotherapy for six weeks, followed by combination with pembrolizumab. The ongoing efficacy-expansion stage of ARTISTRY-2 is examining the safety and efficacy of SC nemvaleukin administered at the RP2D in combination with pembrolizumab in select solid tumors. Data are as of March 19, 2021 unless otherwise noted:

SC 3 mg q7d nemvaleukin was selected as the RP2D for the efficacy expansion stage following its demonstration of pharmacodynamic effects on Natural Killer (NK) cells and CD8+ T cells, with minimal expansion of regulatory T cells (Tregs), and a safety and tolerability profile largely consistent with the anticipated pharmacological effect and that observed with IV nemvaleukin.
Phase 2 expansion cohorts at the RP2D recently opened for enrollment. As of May 3, 2021, one confirmed PR had been observed in a patient with PROC, with a 53% reduction in target lesion and a normalization of CA-125 levels.
The safety profile of SC nemvaleukin was largely consistent with that reported for IV nemvaleukin. The most common AEs were pyrexia, fatigue, chills and injection site reactions. Three dose-limiting toxicities were reported, all in the highest doses evaluated in each dosing regimen (declared as the maximum tolerated dose). No additive toxicity was observed with the addition of pembrolizumab to the SC treatment regimen.

Data from both presentations are available on the ASCO (Free ASCO Whitepaper) website at View Source

Abstract: 2513
Title: ARTISTRY-1: Nemvaleukin Alfa Monotherapy and in Combination With Pembrolizumab in Patients With Advanced Solid Tumors
Presenter: Valentina Boni, M.D., Ph.D., Medical Oncologist and Principal Investigator, START Madrid at Centro Integral Oncológico Clara Campal, Madrid, Spain
Presentation Date/Time: The on-demand poster discussion session will take place on June 4, 2021 at 9:00 a.m. ET

Abstract: 2552
Title: Selection of the Recommended Phase 2 Dose (RP2D) for Subcutaneous Nemvaleukin Alfa: ARTISTRY-2
Presenter: Omid Hamid, M.D., Chief of Research and Immunotherapy, The Angeles Clinic and Research Institute
Presentation Date: The poster presentation will be available on-demand to attendees beginning June 4, 2021

Conference Call and Webcast
Alkermes will host a webcast presentation and conference call with accompanying slides for analysts and investors on Friday, June 4, 2021, at 4:00 p.m. ET (9:00 p.m. BST) to discuss the latest data from the ARTISTRY-1 and ARTISTRY-2 clinical trials. The webcast will feature ARTISTRY clinical program investigators, Valentina Boni, M.D., Ph.D., Medical Oncologist and Principal Investigator, START Madrid at Centro Integral Oncológico Clara Campal; and Omid Hamid, M.D., Chief of Research and Immunotherapy, The Angeles Clinic and Research Institute, and members of Alkermes’ management team. The webcast player may be accessed on the Investors section of Alkermes’ website at www.alkermes.com. To participate in the question-and-answer session, please also dial in to the conference call, which may be accessed by dialing +1 877-407-2988 for U.S. callers and +1 201-389-0923 for international callers. A replay of the webcast will be archived on the company’s website for 30 days following the presentation.

About Nemvaleukin Alfa ("nemvaleukin")
Nemvaleukin is an investigational, novel, engineered fusion protein comprised of modified interleukin-2 (IL-2) and the high affinity IL-2 alpha receptor chain, designed to selectively expand tumor-killing immune cells while avoiding the activation of immunosuppressive cells by preferentially binding to the intermediate-affinity IL-2 receptor complex. The selectivity of nemvaleukin is designed to leverage the proven anti-tumor effects of existing IL-2 therapy while mitigating certain limitations.

About the ARTISTRY Clinical Development Program
ARTISTRY is an Alkermes-sponsored clinical development program evaluating nemvaleukin alfa as a potential immunotherapy for cancer. The ARTISTRY program is comprised of multiple clinical trials evaluating intravenous and subcutaneous dosing of nemvaleukin, both as a monotherapy and in combination with the anti-PD-1 therapy KEYTRUDA (pembrolizumab) in patients with advanced solid tumors. Ongoing trials include: ARTISTRY-1, ARTISTRY-2, ARTISTRY-3 and ARTISTRY-6.

On June 4, 2021 Agenus (NASDAQ: AGEN), an immuno-oncology company with an extensive pipeline of checkpoint antibodies, cell therapies, adjuvants, and vaccines designed to activate immune response to cancers and infections, reported data demonstrating the differentiation of balstilimab as an anti-PD-1 antibody as well as data from a Phase 1 clinical trial of AGEN2373, a CD137 agonist antibody, at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2021 from June 4 – 8, 2021 (Press release, Agenus, JUN 4, 2021, View Source [SID1234583573]).

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Agenus submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) on April 19, 2021 for the use of balstilimab in patients with recurrent or metastatic cervical cancer. This submission was based on data from a Phase 2 trial in patients with recurrent or metastatic cervical cancer. These data show a response rate of 20% in PD-L1 positive tumors and an overall response rate of 15%, with a median duration of response of 15.4 months. Balstilimab shows responses across histology subgroups and in populations of patients typically unresponsive to commercially available therapies, such as patients with PD-L1 negative tumors.

Preclinical studies using Agenus’ proprietary R&D VISION platform underscored these observed clinical data. VISION demonstrates that balstilimab may be superior to currently approved anti-PD-1 antibodies such as pembrolizumab and nivolumab. Balstilimab showed superior tumor killing in both PD-L1 positive and PD-L1 negative tumors compared to commercially available anti-PD-1 antibodies in these studies.

"We are encouraged by the initial performance of our VISION platform both for drug discovery and potential therapeutic predictive modeling. It has the potential to bring effective treatments to patients more rapidly," said Steven O’Day, MD, Chief Medical Officer of Agenus. "AGEN2373 continues to show no liver toxicity in the clinic, and we expect the anticipated combination trials to provide potential benefit to patients."

AGEN2373 is a CD137 agonist antibody designed to overcome limitations seen with first-generation CD137 agonist antibodies, particularly the development of liver toxicity. In this first-in-human study of AGEN2373 in patients with advanced solid tumors, no dose limiting toxicities were seen at doses up to 3 mg/kg; notably, no liver toxicity has been observed well above the threshold at which liver toxicity is usually seen with other CD-137 agonist antibodies. Five patients demonstrated stable disease out of 22 patients treated with AGEN2373 monotherapy, with prolonged stable disease observed in three of these patients. AGEN2373 is expected to provide benefit especially in combination therapy, and combination trials are in planning.

Presentation Details:

Abstract title: Differentiated activity profile for the PD-1 inhibitor balstilimab
Abstract number: 5529
Poster Session: Gynecologic Cancer
Presenting author: Cailin Joyce, PhD

Abstract title: Initial findings of the first-in-human Phase I study of AGEN2373, a conditionally active CD137 agonist antibody, in patients (pts) with advanced solid tumors
Abstract number: 2634
Poster Session: Developmental Therapeutics—Immunotherapy
Presenting author: Anthony Tolcher, MD

About balstilimab
Balstilimab is a novel, fully human monoclonal immunoglobulin G4 (IgG4) designed to block PD-1 (programmed cell death protein 1) from interacting with its ligands PD-L1 and PD-L2. PD-1 is a negative regulator of immune activation that is considered a foundational target within the immuno-oncology market. Balstilimab is currently in clinical trials as monotherapy and in combination with Agenus’ anti-CTLA-4, zalifrelimab, in an ongoing Phase 2 study for recurrent/metastatic cervical cancer. A Biologics License Application has been submitted to the U.S. Food and Drug Administration for the use of balstilimab to treat recurrent/metastatic cervical cancer.

About AGEN2373
AGEN2373 is a novel, fully human monoclonal conditionally active CD137 agonist antibody designed to selectively enhance CD137 co-stimulatory signaling in activated immune cells while mitigating side effects associated with systemic activation of CD137. CD137 (4-1BB) is a positive regulator of the immune system that is highly upregulated on activated T cells (adaptive immune cells) and NK cells (innate immune cells). AGEN2373 is currently in a Phase 1 clinical trial against solid tumors.

About VISION
VISION (VIrtual Systems for Immuno-ONcology) is an active learning platform that mimics a patient’s tumor microenvironment and immune system in order to define predictive biomarker signatures. VISION leverages advanced analytics to explore an immense range of drug-biology interactions not possible via traditional processes. Producing informative data feedback loops in real-time, VISION enables quicker validation of drug targets, faster optimized molecule design and drug candidate selection, and personalized treatment regimens based on biomarker signatures.

On June 4, 2021 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported preliminary data from the Company’s Phase 1 dose escalation study of PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies (Press release, Celldex Therapeutics, JUN 4, 2021, View Source [SID1234583572]). These data were presented in a poster session as part of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2021 Annual Meeting taking place June 4-8, 2021.

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These are the first-in-human data of CDX-527, the first candidate developed from Celldex’s bispecific platform which utilizes the Company’s proprietary highly active anti-PD-L1 and CD27 human antibodies to couple CD27 co-stimulation with blockade of the PD-L1/PD-1 pathway.

"We are encouraged by this emerging initial data where we have observed a good safety profile along with promising pharmacodynamic and pharmacokinetic activity, which are important key hurdles for the development of bispecific antibodies," said Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "While we are still early in the dose escalation phase, we are excited to advance into higher dose cohorts and evaluate the data further as the study progresses. We believe this preliminary data provides further validation of our preclinical studies and demonstrates the potential of our bispecific platform to produce next generation candidates."

Summary of preliminary data from ongoing Phase 1 Trial of CDX-527:

As of the data cut-off on April 16, 2021, 11 patients were enrolled in the first 5 dose escalation cohorts, 0.03 mg/kg through 3 mg/kg.

CDX-527 was well tolerated, with no dose-limiting toxicities or treatment related serious adverse events observed.
Pharmacokinetics and receptor occupancy demonstrate good exposure starting at the 1 mg/kg dose and no evidence of significant anti-drug antibodies impact.
Pharmacodynamic parameters demonstrate biological activity consistent with immune activation including: transient increase in pro inflammatory cytokines/chemokines, upregulation of activation marker on T cells and particularly NK cells and a decrease in regulatory T cells.
Patients continue to be enrolled in the dose escalation phase of the trial.
The Phase 1 study is an open label dose-escalation and expansion study (0.03 mg/kg to 10 mg/mg) in 40 patients with advanced or metastatic solid tumors that have progressed during or after standard of care therapy. The study is designed to determine an MTD during the dose-escalation phase and to recommend a dose level for further study in a subsequent expansion phase. The expansion is designed to further evaluate the tolerability, and biologic and anti-tumor effects of selected dose level(s) in specific tumor types. For additional information on this trial (NCT04440943), please visit www.clinicaltrials.gov.

Celldex expects to report additional safety, PK, PD and clinical activity data from this study during 2022.

The poster presented at ASCO (Free ASCO Whitepaper) can be viewed on the "Publications" page of the "Science" section of the Celldex website.

About CDX-527
Celldex’s deep antibody experience and in-house manufacturing capabilities support efficient development of bispecific antibody targets. Targets are selected based on new science as well as their compatibility to be used in bispecific antibody formats with existing Celldex antibody programs. CDX-527, which combines CD27 activation and PD-1 blockade, was the first candidate to enter the clinic from the platform and is currently enrolling patients in a Phase 1 dose escalation study. Celldex is also exploring important targets controlling inflammation and auto-immune pathways.

On June 4, 2021 Sanofi reported that it is partnering with leading groups delivering practice-changing breast cancer research, the Breast International Group (BIG), the European Organization for Research and Treatment of Cancer (EORTC) and the Alliance Foundation Trials (AFT), to initiate a pivotal trial of an oral selective estrogen receptor degrader (SERD) in the adjuvant setting (Press release, Sanofi, JUN 4, 2021, View Source [SID1234583518]). The Phase 3 AMEERA-6 study will evaluate the efficacy and safety of Sanofi’s amcenestrant vs tamoxifen for women with estrogen receptor-positive (ER+) breast cancer who were unable to continue their adjuvant aromatase inhibitor (AI) therapy.

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"Together with our research partners, BIG conducts landmark, practice-changing trials that can have a significant impact on the lives of women with breast cancer," said David Cameron, Chair of the BIG Executive Board. "Adjuvant therapy helps prevent and delay the progression of disease into the later setting. However, current adjuvant therapies, like AIs, can have side effects for some women, which may cause them to discontinue the medication prematurely. Amcenestrant may be a potential option for women in this setting and we look forward to working with Sanofi, EORTC and AFT to investigate this further."

"We look forward to collaborating with these leading academic networks to investigate amcenestrant in the adjuvant setting through AMEERA-6. Based on encouraging data emerging from our ongoing clinical program, we believe that amcenestrant, an investigational oral SERD, has the potential to become a best-in-class oral endocrine backbone therapy," said Peter Adamson, M.D., Global Development Head, Oncology at Sanofi. "Additional treatment options for patients with breast cancer are needed to allow women to remain on adjuvant therapy and decrease their risk of progressive disease."

Amcenestrant is an oral SERD that antagonizes and degrades the estrogen receptor (ER), resulting in inhibition of the ER signaling pathway. Amcenestrant is currently under clinical investigation and its safety and efficacy have not been evaluated by any regulatory authority.

Despite the established clinical efficacy of tamoxifen and AIs in early breast cancer, many patients experience disease recurrence because of resistance to therapy, non-adherence or premature discontinuation of their adjuvant therapy.1 Additional treatment options in the adjuvant setting in early breast cancer are needed to prevent women from developing advanced, incurable disease and could represent a significant treatment advance.

As per the terms of the Pre-Study Agreement, Sanofi will be the sponsor and will provide funding and investigational drug product for the global study. BIG will conduct the study within the BIG network, EORTC will oversee study management and data analysis, as well as the medical management, and AFT will conduct the United States portion of the study. Sanofi will conduct this global study in selected countries outside the geographical scope of the academic networks, as further described in a follow-on agreement under negotiation among the four parties. The protocol is being developed in collaboration with all four parties, including AFT, BIG, EORTC and Sanofi.