On June 2, 2023 Vigeo Therapeutics, a clinical-stage immuno-oncology company pioneering novel cancer therapies, reported new data from its Phase I/II expansion study evaluating single-agent activity of VT1021 in patients with recurrent glioblastoma (rGBM) (Press release, Vigeo Therapeutics, JUN 2, 2023, View Source [SID1234632407]). The data will be presented by Dr. David Peereboom of Cleveland Clinic in a poster discussion session tomorrow, June 3, 2023, from 4:30 – 6:00 PM at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting being held June 2 – June 6, 2023 in Chicago, IL.

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VT1021 is a first-in-class compound that, by binding to MDSCs, induces the expression of thrombospondin-1 (Tsp-1) in the tumor microenvironment (TME). Tsp-1 blocks the CD47 immune checkpoint and engages CD36 to induce tumor cell apoptosis, inhibit angiogenesis, activate cytotoxic T cells (CTL), and reprogram macrophages from the M2 to M1 phenotype.

In a phase I/II clinical study in solid tumors (NCT03364400) VT1021 demonstrated promising single-agent clinical activity against recurrent glioblastoma. Among 22 evaluable subjects with rGBM, 3 had a complete response (CR), 1 had a partial response (PR), and 6 had stable disease (SD) with an average study duration of over 120 days. One subject continues to receive VT1021 treatment and has been on study for almost 3 years with no remaining measurable lesion. Historically, rGBM patients have a response rate of less than 5% and a median progression free survival of 48 days.

Confirming the role of VT1021 in altering the tumor microenvironment, immune profiling of the GBM patients on the study showed beneficial and sustained changes in CTL parameters and PD-L1+ MDSCs that correlated with response. Specifically, CR/PR subjects showed decreases in PDL1+ MDSCs along with an increase in total CTLs, proliferating CTLs, and CTL/Treg ratio. In contrast, SD and PD subjects exhibited no change or decrease in these three CTL parameters.

"The demonstration of the effect of VT1021 on the tumor immune microenvironment and the correlation with clinical outcome are encouraging signs in the development of new therapies for GBM patients" said Dr. David Peereboom of Cleveland Clinic. "To further advance VT1021 as a therapy for GBM, Vigeo is studying the potential of VT1021 in both newly diagnosed and recurrent subjects in an ongoing phase II/III clinical study (NCT03970447)" said Dr. Jing Watnick, COO and co-founder of Vigeo Therapeutics.

Presentation

Title: Immune profiling in patients with glioblastoma treated with VT1021 in a phase I/II expansion study.
Date & Time: Saturday June 3, 2023 from 4:30PM – 6:00 PM
Abstract Session: Central Nervous System Tumors
Abstract: 409504
Location: Board # 378
Presenter: David M. Peereboom, MD Professor of Medicine, Cleveland Clinic

About VT1021
Vigeo’s lead asset, VT1021, is a first-in-class dual-modulating compound that blocks the CD47 immune checkpoint and activates CD36, which induces apoptosis in tumors and endothelial cells, and increases the M1:M2 macrophage ratio. VT1021 achieves these biological effects via stimulation of thrombospondin-1 (Tsp-1). The goal of these dual-modulating effects is conversion of immuno-suppressive, or "cold," tumors that that are associated with poor response to immuno-oncology agents, to immuno-stimulated, or "hot," tumors that are more susceptible to attack from the body’s immune system. Vigeo is developing VT1021 as a therapeutic agent across a range of cancers, with a current focus on solid tumors.

On June 2, 2023 EpicentRx, Inc. ("EpicentRx"), a leading-edge, clinical-stage biopharmaceutical company, reported clinical progress updates for two lead oncology treatment candidates, RRx-001 and AdAPT-001, at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held June 2-6, 2023, in Chicago, IL and virtually (Press release, EpicentRx, JUN 2, 2023, View Source [SID1234632406]).

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The company presented study design details for the Phase 2b KEVLARx study of RRx-001, which received FDA Fast Track designation for the treatment of severe oral mucositis based on data from the previous Phase 2a PREVLAR study. The company also presented promising first-in-human data for its transforming growth factor beta (TGFβ) trap vector, AdAPT-001.

"What patients need is not the ‘same old, same old’ but potentially well-tolerated, novel therapies like RRx-001 and AdAPT-001 that work differently to harm diseases, not the patients with these diseases," said Tony Reid, Chief Executive Officer of EpicentRx. "With a growing body of data and our recent FDA Fast Track Designation of RRx-001 and positive Phase 1 data for AdAPT-001, EpicentRx is well positioned to move our pipeline forward and demonstrate success in additional disease indications."

RRx-001 UPDATES

Following the positive announcement of the Phase 2a PREVLAR study, EpicentRx received U.S. Food and Drug Administration (FDA) Fast Track designation, which expedites the development and review process for RRx-001. The FDA also gave regulatory approval for the company to initiate a follow-on, multicenter, randomized Phase 2b study of RRx-001. Details about this study, called KEVLARx, were provided today at ASCO (Free ASCO Whitepaper) (Abstract 416822). Data from the previous PREVLAR trial showed that pretreatment with only 4 doses of RRx-001, prior to the start of chemotherapy and radiation, which is easy and convenient for both physicians and patients, delayed the onset, lessened the severity, and shortened the duration of severe oral mucositis (SOM) in patients with locally advanced head and neck cancer.

RRx-001 is a small molecule inflammasome NLRP3/KEAP1 inhibitor with tumor-targeted cytotoxicity and healthy tissue cytoprotective properties being developed as a companion therapy to current oncology treatments. The protective properties of RRx-001 have been demonstrated with irinotecan, cisplatin, carboplatin, and etoposide treatment in solid tumors in Phase 2 studies.

AdAPT-001 IMMUNOTHERAPY UPDATES

EpicentRx also presented data from the first-in-human (FIH) trial of AdAPT-001, which carries a TGF-β trap that binds to and eliminates the pathologic cytokine, TGF-β, in tumors. Data from this FIH trial showed that AdAPT-001 (Abstract 2550) is well tolerated with promising single agent activity that includes 3 partial responses, and 5 patients with prolonged stable disease of 6 months or more.

On June 2, 2023 MEDSIR reported the positive results of the PHERGain trial (Press release, MedSIR, JUN 2, 2023, View Source [SID1234632405]). This study is the first to use an adaptive design that tailors treatment in the neoadjuvant/adjuvant setting of patients with HER2-positive early breast cancer. The main objective of this trial was to assess the feasibility of a chemotherapy-free strategy based on a dual HER2 blockade with trastuzumab and pertuzumab through a positron emission tomography (PET)-based, pathologic complete response response(pCR)-adapted strategy.

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PHERGain is a randomized, controlled phase 2 clinical trial that involved 356 early-stage HER2-positive breast cancer patients from 45 centers in seven European countries. It was sponsored by MEDSIR, a company dedicated to advancing clinical research in oncology, and led by scientific investigators Dr. Javier Cortés, Dr. Antonio Llombart-Cussac, and Dr. José Pérez. The first primary endpoint was the pCR rate in patients with PET response included in group B, whose positive results were published in 2021 in Lancet Oncology.

The results of the second primary endpoint, 3-year invasive disease-free survival in all patients assigned to group B, have been presented at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) congress. Overall, 95.4% of patients who followed this chemotherapy de-escalation strategy using PHERGain’s adaptive design remained cancer-free after three years of follow-up from breast cancer surgery. This is especially relevant because around 30% of these patients did not receive chemotherapy without compromising patient’s outcome. Among this latter group, 98.9% remained cancer-free after three years of follow-up from breast cancer surgery.

"This study offers a potential future therapeutic option that enables a significant reduction of toxicity and an improvement in quality of life for this patient population without reducing efficacy", explains Dr. Cortés. In addition, the most relevant finding "is that 99% of the subgroup who received anti-HER2 therapy without chemotherapy have not presented a recurrence of the disease after three years of follow-up".

"These results bring us closer to the end of chemotherapy in a significant percentage of patients with this type of tumor," explains Dr. Llombart-Cussac, "It is critical to design more efficient strategy-based clinical trials with adaptive designs to bring effective therapies to patients in the shortest amount of time."

On June 2, 2023 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) and Zymeworks Inc. (Nasdaq: ZYME) reported positive pivotal trial data, including new data on progression-free survival (PFS), from the Phase 2b HERIZON-BTC-01 trial of the bispecific antibody zanidatamab in previously treated HER2-amplified biliary tract cancers (BTC) (Press release, Jazz Pharmaceuticals, JUN 2, 2023, View Source [SID1234632404]). The data were featured as an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, and the results were concurrently published in The Lancet Oncology. The abstract (4008) was also selected to be included in the 2023 Best of ASCO (Free ASCO Whitepaper) program, which will be held this summer following the ASCO (Free ASCO Whitepaper) Annual Meeting.

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For the trial’s primary endpoint, data from 80 patients with HER2-amplified BTC (defined as in situ hybridization [ISH] positive and immunohistochemistry [IHC] 2+ or 3+) demonstrated a confirmed objective response rate (cORR) of 41.3% [95% confidence interval (CI): 30.4, 52.8] with a Kaplan Meier (KM) estimated median duration of response (DOR) of 12.9 months. The KM estimated median PFS was 5.5 months [95% CI: 3.7, 7.2] with a range of 0.3 to 18.5 months.

"With a confirmed ORR of 41.3 percent, median DOR of 12.9 months and median PFS of 5.5 months, these results for zanidatamab are a significant step forward for second-line treatment of HER2-amplified BTC, where current chemotherapy treatments have been reported to provide only a 5 to 15 percent ORR and median PFS of 1.4 to 4 months," said Shubham Pant, M.D., professor of Gastrointestinal Medical Oncology and Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center. "The HERIZON-BTC-01 trial advances an exciting field of oncology research where we can leverage next-generation sequencing on BTC patients to understand genomic markers of the disease and choose the appropriate targeted therapies for these patients."

"We are thrilled to deliver an oral presentation on the pivotal HERIZON-BTC-01 study results demonstrating zanidatamab’s meaningful clinical benefit and tolerable safety profile in patients with HER2-amplified BTC," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals. "We are committed to advancing this program as rapidly as possible to potentially transform the lives of patients in critical need, with the goal of delivering a chemotherapy-free option that is the first-and-only therapy that targets HER2-amplified BTC."

Trial Results

Results of the pivotal HERIZON-BTC-01 trial (NCT04466891) indicate that the HER2-targeted, bispecific antibody zanidatamab demonstrates rapid, durable responses with a manageable safety profile in patients with treatment-refractory HER2-amplified BTC.

The trial evaluated zanidatamab (20 mg/kg IV every 2 weeks) in patients with HER2-amplified, locally advanced unresectable or metastatic BTC (gallbladder cancer, intra-/extra-hepatic cholangiocarcinoma) who had received prior gemcitabine-containing therapy. Patients with prior HER2-targeted therapy use were excluded from the trial. All patients were required to have HER2 status confirmed with tissue samples by a central lab. Patients (n=87) were assigned into two cohorts based on tumor IHC status: Cohort 1 (n=80) included patients who were IHC 2+/3+ (HER2-amplified) and Cohort 2 (n=7) included patients who were IHC 0/1+. Tumors were assessed every 8 weeks per RECIST v1.1. The primary endpoint was cORR by independent central review (ICR) in Cohort 1, with secondary endpoints including other efficacy and safety outcomes.

In Cohort 1, cORR was 41.3% [95% CI: 30.4, 52.8] with the KM estimated DOR of 12.9 months (range of 1.5 – 16.9+) by ICR assessment with a median study follow-up time of 12.4 months (range of 7 – 24). The response was more than double the historical response rates of 5 to 15%1,2 reported for second-line standard of care chemotherapy in patients with BTC. The median PFS in Cohort 1, which is new data presented at ASCO (Free ASCO Whitepaper) 2023, was 5.5 months [95% CI: 3.7, 7.2], with a range of 0.3 to 18.5 months. Current chemotherapy treatments have shown to provide a median PFS of 1.4 – 4 months in patients with BTC.1,2

Among the 33 responding patients at the data cutoff (October 10, 2022), 16 patients (49%) had ongoing responses and 27 patients (81.8%) had a DOR of ≥16 weeks. The median time to first confirmed response was 1.8 months (range, 1.6 – 5.5).

Cohort 1 (n=80)

Confirmed Objective Response Rate, % (95% CI)

41.3 (30.4, 52.8)

Confirmed Best Objective
Response, n (%)

Complete Response

1 (1.3)

Partial Response

32 (40)

Stable Disease

22 (27.5)

Progressive Disease

24 (30)

Disease Control Rate, (95%, CI)

68.8 (57.4, 78.7)

Progression Free Survival

Median months: 5.5 (0.3 – 18.5)

Duration of Response Greater than, or Equal to, 16
Weeks

27

Time to First Response

Median months: 1.8 (1.6 – 5.5)

No responses were observed in Cohort 2.

Zanidatamab demonstrated a manageable and tolerable safety profile, with two of the 87 patients (2.3%) experiencing adverse events (AEs) leading to treatment discontinuation. There were no Grade 4 AEs and no deaths were treatment-related. The most common AEs were diarrhea and infusion-related reactions, which were predominately low-grade, reversible and manageable with routine supportive care.

The HERIZON-BTC-01 trial is ongoing and some secondary outcome measures, including overall survival, are not yet mature.

The abstract is available to conference registrants on the ASCO (Free ASCO Whitepaper) conference website here. (Abstract Number 4008).

Webcast Information

Jazz Pharmaceuticals will host a webcast today, Friday, June 2, 2023, at 6:45 p.m. CT / 7:45 p.m. ET / 12:45 a.m. IST (June 3) to provide a review of the zanidatamab BTC data presented at the 2023 ASCO (Free ASCO Whitepaper) Annual Meeting. Dr. Shubham Pant, M.D., who is presenting the zanidatamab BTC findings at ASCO (Free ASCO Whitepaper), will provide an overview of the data. Dr. Pant is a professor in the Department of Gastrointestinal Medical Oncology with a joint appointment in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center.

Interested parties may register for the call in advance here or via the Investors section of the Jazz website at www.jazzpharmaceuticals.com. To ensure a timely connection, it is recommended that participants register at least 15 minutes prior to the scheduled webcast.

A replay of the webcast will be available via the Investors section of the Jazz website at www.jazzpharmaceuticals.com.

About Zanidatamab
Zanidatamab is an investigational bispecific antibody, based on Zymeworks’ Azymetric platform, that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients. Zymeworks, along with collaborators Jazz and BeiGene, Ltd. (BeiGene), are developing zanidatamab in multiple clinical trials as a targeted treatment option for patients with solid tumors that express HER2.

The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for zanidatamab in patients with previously treated HER2 gene-amplified biliary tract cancers (BTC), and two Fast Track designations for zanidatamab: one as a single agent for refractory BTC and one in combination with standard of care chemotherapy for first-line GEA. Additionally, zanidatamab has received Orphan Drug designations from FDA for the treatment of BTC and GEA, as well as Orphan Drug designation from the European Medicines Agency for the treatment of gastric cancer. Zanidatamab was also granted Breakthrough Therapy designation from the Center for Drug Evaluation (CDE) in China.

About Biliary Tract Cancers
Biliary tract cancers (BTC), including gallbladder cancer and cholangiocarcinoma, account for approximately <1% of all adult cancers and are often associated with a poor prognosis.3,4 Globally, more than 210,000 people are diagnosed with BTC every year5 and most patients (> 65%) are diagnosed with tumors that cannot be removed surgically. The human epidermal growth factor receptor 2 (HER2) is a well-validated target for anti-tumor therapy in other cancers. About 5% to 19% of patients with BTC have tumors that express HER26 and may be positioned for potential benefit from HER2-targeted therapy. Currently no HER2-targeted therapy has been approved for the treatment of BTC.

On June 2, 2023 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, metabolic, autoimmune, ophthalmology and other major diseases, reported that the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) has granted Breakthrough Therapy Designation (BTD) for olverembatinib for the treatment of patients with succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST) who had received first-line treatment (Press release, Innovent Biologics, JUN 2, 2023, View Source [SID1234632403]).

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Results from an ongoing Phase 1b/2 study of olverembatinib in China showed an impressive clinical benefit rate (CBR) of 93.8% in patients with this subtype of GIST. Based on these promising results, the study was selected for presentations at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting for two consecutive years[1].

Olverembatinib is the first and only third-generation BCR-ABL inhibitor approved in China for the treatment of adult patients with tyrosine kinase inhibitors (TKI)-resistant chronic-phase chronic myeloid leukemia (CML-CP) or accelerated-phase CML (CML-AP) harboring the T315I mutation as confirmed by a validated diagnostic test. Olverembatinib is jointly commercialized in China by Ascentage Pharma and Innovent Biologics.

This marks the second BTD granted to olverembatinib by the CDE, with the first one granted in March 2021 for the treatment of patients with CML-CP resistant and/or intolerant to first- and second-generation TKIs. A New Drug Application (NDA) for the first BTD indication was accepted by the NMPA in July 2022 and subsequently granted Priority Review designation that will support a full approval of olverembatinib.

Dr. Hui Zhou, Senior Vice President of Innovent stated:" We are glad to see the NMPA grants another BTD for olverembatinib, marking a major milestone in its clinical development and demonstrating its therapeutic potentials beyond hematologic malignancies. We look forward to more good news of olverembatinib that allow more patients to benefit from this novel drug as soon as possible."

NMPA Breakthrough Therapy Designation is intended to facilitate and expedite the development and review of an investigational drug to treat a serious disease or condition when preliminary clinical evidence indicates that the drug has demonstrated substantial improvement over current therapies. The BTD will not only qualify a drug candidate to receive status for rapid review by the CDE, but it will also allow the sponsor to obtain timely advice and communication from the CDE to accelerate the approval and launch to address the unmet clinical need of patients at an accelerated pace. Click here for the published list of drugs which have been granted BTD by NMPA.

About Gastrointestinal Stromal Tumor (GIST)

GIST is a type of malignancy that arises in mesenchymal tissues of the gastrointestinal tract, and most patients with GIST harbor KIT or PDGFRA mutations. The introduction of TKIs has significantly improved the prognosis of these patients. However, patients with SHD-deficient GIST, a rare subtype of GIST, still have considerable unmet medical needs. It is known to the research community that patients with SDH-deficient GIST are commonly insensitive to existing TKIs. Although patients with early-stage localized disease can benefit from surgical treatment, most of them eventually experience relapse[2]-[6]. At present, there is no standard of care for patients with relapsed or advanced SDH-deficient GIST, whose 5-year event-free survival (EFS) is only 24%[2]-[6].

About Olverembatinib

Developed by Ascentage Pharma with support from the National Major New Drug Discovery and Manufacturing Program in China, the orally active, third-generation BCR-ABL inhibitor olverembatinib is the first China-approved third-generation BCR-ABL inhibitor targeting drug-resistant chronic myeloid leukemia (CML). Olverembatinib can effectively target a spectrum of BCR-ABL mutants, including the T315I mutation.

In November 2021, olverembatinib was granted a conditional approval through the Priority Review process by the China National Medical Products Administration (NMPA) for the treatment of adult patients with tyrosine kinase inhibitor (TKI)-resistant chronic-phase CML (CML-CP) or accelerated-phase CML (CML-AP) harboring the T315I mutation as confirmed by a validated diagnostic test. Subsequently, Olverembatinib was included into the China 2022 National Reimbursement Drug List (NRDL) for the approved indication. In March 2021, olverembatinib was granted a Breakthrough Therapy Designation (BTD) by the CDE for the treatment of patients with CML-CP who are resistant and/or intolerant of first- and second-generation TKIs.

In overseas, olverembatinib was cleared by the US FDA in July 2019 to directly enter a Phase Ib study. Since 2018, the clinical results of olverembatinib have been selected for oral presentations at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meetings for five consecutive years, and was nominated for "Best of ASH (Free ASH Whitepaper)" in 2019. To date, olverembatinib has been granted one Fast Track Designation (FTD) and four Orphan Drug Designations (ODDs) from the US Food and Drug Administration (FDA) for the treatment of CML, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and gastrointestinal stromal tumour (GIST); and one Orphan Designation from the European Medicines Agency (EMA) of the European Union for the treatment of CML.

In July 2021, Ascentage Pharma (6855.HK) and Innovent Biologics (1801.HK) reached the agreement regarding the joint development and commercialization of olverembatinib in China.

*Olverembatinib has not been approved for any indication in the U.S.