On September 16, 2021 Bridge Biotherapeutics (KQ288330), a clinical-stage biotech company, reported that an ePoster presenting pre-clinical data of BBT-176,[1] will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 (ePoster identifier:1365TiP) (Press release, Bridge Biotherapeutics, SEP 16, 2021, View Source [SID1234587849]).

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At the virtual event, the pre-clinical data and the trial design of the ongoing phase 1/2 clinical study for BBT-176 in non-small cell lung cancer (NSCLC) patients will be presented via an ePoster.

BBT-176, which is currently in the dose escalation phase of the phase 1/2 study, was designed to inhibit the signaling pathway of epidermal growth factor receptors (EGFR) with C797S triple mutations acquired after progression on third-generation EGFR inhibitors such as osimertinib.

The in vitro data from engineered Ba/F3 cells and the in vivo data from patient-derived xenografts confirmed that BBT-176 is efficacious in NSCLC with C797S EGFR mutations. As can be seen from the presented in vitro assay, compared to osimertinib, BBT-176 is potent against EGFR double mutations such as Del19/C797S (DC) and L858R/C797S (LC) as well as triple mutations such as Del19/T790M/C797S (DTC) and L858R/T790M/C797S (LTC). Also, a dose-dependent anti-tumor effect has been confirmed in patient-derived cell (PDC)-xenograft mice models harboring Del19/T790M/C797S (DTC) triple mutations.

In addition, BBT-176 showed in vivo efficacy leading to brain metastases inhibition in triple-mutant mice models, using the IVIS imaging platform. The brain metastases are found in approximately 20% of patients with stage IV NSCLC.

Encouraged by the non-clinical data demonstrating tumor regression efficacy in NSCLC with EGFR mutations, the first-in-human (FIH) study of BBT-176 was designed and patient dosing began in April 2021 under the IND of the U.S. and the Republic of Korea. Additional clinical trial sites in the U.S. to evaluate the efficacy and safety in diversified racial and ethnic groups particularly Caucasian patients are expected to open by the end of this year.

Once the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) are determined, the company will initiate enrollment for the dose expansion cohort in the U.S. and the Republic of Korea. In parallel with the clinical development of BBT-176, the company will also continue to expand its NSCLC solutions, utilizing precision medicine accompanied by companion diagnostic devices.

"We are proud to present the exploratory efficacy data from our pre-clinical studies for BBT-176, our first-ever oncology pipeline, to both European and international oncologists," and "by accelerating our development of 4th generation EGFR TKIs, we will try our best to address the unmet medical needs of patients with NSCLC," stated Dr. Sang Yoon Lee, Chief Medical Officer of Bridge biotherapeutics.

The copy of the ePoster presented at the ESMO (Free ESMO Whitepaper) 2021 is available at: https://bit.ly/2YLgsw4.

On September 16, 2021 Ayala Pharmaceuticals, Inc. (NASDAQ: AYLA), a clinical-stage oncology company focused on developing and commercializing small molecule therapeutics for patients suffering from rare and aggressive cancers, reported new preliminary clinical data from the 6mg cohort of its ongoing Phase 2 ACCURACY trial of AL101 for the treatment of recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) harboring Notch-activating mutations (Press release, Ayala Pharmaceuticals, SEP 16, 2021, View Source [SID1234593999]). The data is being presented at the 2021 ESMO (Free ESMO Whitepaper) Virtual Congress as an ePoster. In a separate ePoster presentation, Ayala presented new preclinical results evaluating the potential of AL101 in combination with approved cancer therapies for dual targeting of ACC tumours.

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"ACC is an orphan disease with no approved therapies and patients with Notch mutations have a more aggressive disease course and poorer survival outcomes as compared to patients with Notch wild-type. R/M ACC remains a significant area of unmet need, and I am encouraged by the preliminary results that AL101 monotherapy has demonstrated to-date. Coupled with new preclinical data showing that AL101 in combination with approved targeted therapies could potentially treat a greater proportion of ACC tumors, regardless of Notch mutations, it will be exciting to see how AL101 may be developed as a viable treatment option for R/M ACC patients," said Alan L. Ho, M.D., Ph.D., Medical Oncology, Memorial Sloan Kettering Cancer Center and Lead Investigator in The ACCURACY Trial. "While these results are still preliminary, the safety profile of AL101 and the disease control rate of 70% are promising indicators in this incredibly difficult to treat patient population."

"The preliminary safety and efficacy data from the 6mg cohort of our ongoing ACCURACY trial of AL101 highlights a favourable profile. We are pleased to see that AL101’s safety profile continues to be tolerable and manageable, providing us with potential dosing flexibility as we continue to advance our development plans," said Gary Gordon, M.D., Ph.D., Chief Medical Officer of Ayala. "We continue to see strong potential for AL101 to transform the treatment landscape for R/M ACC patients with Notch mutations and we look forward to reporting additional clinical data in 2022."

Preliminary Safety and Efficacy Data from 6mg Cohort of ACCURACY Phase 2 Trial:
Ayala presented new preliminary 6mg data from its ongoing ACCURACY Phase 2 clinical trial evaluating the safety and efficacy of AL101 monotherapy for the treatment of patients with R/M ACC harboring Notch-activating mutations. The Phase 2 ACCURACY clinical trial is an open-label, single-arm, multi-center study to assess the clinical activity of AL101 using radiographic assessments of patients with R/M ACC demonstrating disease progression within 6 months prior to dosing.

As of July 9, 2021, all 42 patients enrolled in the 6mg cohort were treated and evaluable for safety and 33 were evaluable for efficacy.

Efficacy:
All evaluable patients were assessed for efficacy for a best response by investigators using RECIST 1.1 criteria.

Disease control rate (DCR) (defined as partial response and stable disease) was 70% (23/33 patients).
Partial responses (PR) were observed in 3 patients (9%).
Stable disease (SD) was observed in 20 patients (61%).
Progressive disease (PD) was observed in 8 patients (24%).
Two patients were determined to be evaluable per protocol but their scans were not available for analyses.
Study is ongoing with several patients remaining on drug as of the cutoff date.
Safety:
AL101 6mg QW treatment in patients with R/M ACC was well tolerated with manageable side effects consistent with those observed in the 4mg QW cohort with no new adverse events (AEs) specific to the 6mg cohort.

Most common treatment-related (TR) AEs of any grade were diarrhea (76%), fatigue (48%), nausea (41%), hypophosphatemia (29%), vomiting (26%) and decreased appetite (26%).
Treatment-related diarrhea was common and occurred in 32 patients (76%) and most were grades 1 and 2. Treatment-related serious diarrhea occurred in 6 patients (14%).
Serious TRAEs were reported in 31% of patients with treatment-emergent AEs leading to discontinuation in 26% of patients.
Two patients experienced a grade 4 TRAE: one patient experienced a seizure and one patient experienced drug-induced liver injury.
Four treatment-emergent patient deaths occurred (10%), one of which was assessed by the investigator to be treatment related.
Ayala plans to report additional data from the ACCURACY study in 2022.

"Our new preclinical study evaluating the potential of improved efficacy of AL101 in combination with approved targeted therapies represents a promising potential approach for additive or synergistic activity of gamma secretase inhibition when combined with various mechanisms of action," said Roni Mamluk, Ph.D., Chief Executive Officer of Ayala. "We observed stronger tumor growth inhibition in ACC PDX models with Notch pathway genes downregulated regardless of mutational status in the combination arm of the study, as compared to AL101 monotherapy. Based on these results, we believe there is a strong rationale for a combination therapy approach to treating ACC, in addition to other cancer indications in which Notch is dysregulated. We look forward to the further development of AL101 in Notch dysregulated tumors, both as monotherapy and in combination."

Preclinical Results of AL101 Combined with Other Drugs for Dual Targeting of Notch Dysregulated Tumors:
In this preclinical study evaluating the potential of combination therapy of AL101 in PDX models of ACC, Ayala compared the differential gene expression of ACC tumors versus normal matched tissue regardless of Notch activation status. Combination compounds were selected based on determination of the pathways that are implicated with approved oncology therapies, including inhibitors of Bcl2, HDAC, FGFR & CDK4/6. Based on a comparison of AL101 alone, each approved drug alone, and the combination of each drug with AL101, Ayala observed additive or synergistic activity of AL101 combined with agents of various mechanisms of action. AL101 in combination demonstrated significant tumor growth inhibition, including regressions, compared to each drug alone, showing significant benefit with dual targeting of Notch and other dysregulated pathways. Additionally, the study indicated that crosstalk between signaling pathways may increase the efficacy of AL101 in R/M ACC regardless of Notch mutational status. These preclinical results demonstrated a compelling rationale for potential expansion to a larger portion of ACC patients and to additional cancer indications.

About Adenoid Cystic Carcinoma (ACC)

ACC is a rare malignancy of the secretory glands including salivary glands, accounting for about 10% of all salivary gland tumors with an annual incidence of 3,400 in the U.S. There is currently no approved standard of care for patients with recurrent/metastatic ACC. Patients with locoregional disease undergo surgery and radiation therapy, with recurring disease treated by chemotherapy. ACC is an immunologically "cold" tumor that is refractory to chemotherapy, with a recurrence rate of about 60% after initial surgery. The Notch pathway has been determined to be an oncogenic driver of ACC and its dysregulation plays a key role in tumorigenesis and correlates with a distinct pattern of metastasis and a poor prognosis.

About AL101

AL101 is an investigational small molecule Gamma Secretase Inhibitor (GSI) that is designed to potently and selectively inhibit Notch 1, 2, 3 and 4, and is currently being evaluated in two Phase 2 clinical studies, ACCURACY and TENACITY, in patients with adenoid cystic carcinoma (ACC) and in patients with triple negative breast cancer (TNBC), respectively. AL101 is designed to inhibit the expression of Notch gene targets by blocking the final cleavage step by the gamma secretase required for Notch activation. Ayala obtained an exclusive, worldwide license to develop and commercialize AL101 from Bristol-Myers Squibb Company in November 2017. AL101 was granted U.S. FDA Fast Track Designation and Orphan Drug Designation for the treatment of ACC.

On September 16, 2021 MacroGenics, Inc. (NASDAQ: MGNX), a biopharmaceutical company focused on developing and commercializing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported results from Cohort A Part 1 of the Phase 2/3 MAHOGANY clinical trial of margetuximab (Press release, MacroGenics, SEP 16, 2021, View Source [SID1234587802]). MARGENZA (margetuximab-cmkb) is approved in HER2+ metastatic breast cancer and is being investigated as a potential first-line treatment for patients with HER2+ gastric cancer (GC) or gastroesophageal junction (GEJ) cancer in combination with a checkpoint inhibitor, with or without chemotherapy. The dataset is available in a poster titled "Margetuximab With Retifanlimab in HER2+, PD-L1+ First-Line Unresectable/Metastatic Gastroesophageal Adenocarcinoma (GEA): MAHOGANY Cohort A" (Poster #1379P) at the 2021 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Conference taking place September 16-21, 2021.

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The efficacy data and safety cutoff dates were July 19, 2021 and August 3, 2021, respectively. In Cohort A Parts 1 and 2, the efficacy and safety of combining margetuximab and retifanlimab (investigational anti-PD-1 monoclonal antibody licensed to Incyte by MacroGenics) is planned to be evaluated in approximately 100 patients whose tumors are HER2+ at the 3+ level by immunohistochemical (IHC) staining, PD-L1+ (combined positive score ≥1%) and non-microsatellite instability-high (non-MSI-H). A pre-specified interim analysis assessing efficacy and safety was conducted on the first 40 non-MSI-H patients enrolled in Part 1. These data support advancement to Part 2 with plans to enroll approximately 60 additional response-evaluable non-MSI-H patients.

A total of 43 HER2 3+ and PD-L1+ patients were enrolled in Cohort A Part 1 and received margetuximab 15 mg/kg plus retifanlimab 375 mg/kg administered intravenously every three weeks. Twenty-five patients (58%) had gastric cancer and 18 patients (42%) had gastroesophageal junction cancer; 36 patients (84%) had metastatic disease at study entry.

MAHOGANY Cohort A Interim Analysis

Anti-tumor activity was observed in patients treated with margetuximab plus retifanlimab in MAHOGANY Cohort A after the first scan. Tumor shrinkage was observed in 32 of 41 patients (78%) with at least one post-baseline target lesion measurement. Twenty-one of 40 response-evaluable patients achieved an objective response (53%, 95% confidence interval (CI): 36%-69%), including four confirmed complete responses and 17 confirmed partial responses. The number of confirmed responders by independent assessment exceeded the prespecified futility boundary for the trial, and enrollment is proceeding to Cohort A Part 2.

Disease control was achieved in 29 of 40 patients (73%, CI: 56%-85%) and the median duration of response was 10.3 months (range: 2.1 – 14.5 months, CI: 4.6 months – not evaluable (NE)). Median progression-free survival (PFS) was 6.4 months by independent assessment (CI: 6.0 months – NE); median overall survival (OS) was not yet reached. At both 12 and 18 months, OS was 85% (CI: 63%-95%).

Antitumor activity was comparable to historical data from the experimental arm of the Trastuzumab for Gastric Cancer (ToGA) study (trastuzumab + chemotherapy; n=294; objective response rate (ORR) of 47%; median duration of response (DOR) of 6.9 months)1 and initial data from the control arm (placebo + trastuzumab + chemotherapy) of the KEYNOTE‐811 study (ORR of 52%; median DOR of 9.5 months).2

The safety analysis of all 43 patients treated with margetuximab plus retifanlimab suggests the combination was well tolerated in the study population. The most common TRAEs were fatigue (21% Grade 1-2, 0% Grade ≥3), infusion-related reaction (19% Grade 1-2, 0% Grade ≥3), rash (19% Grade 1-2, 0% Grade ≥3), diarrhea (16% Grade 1-2, 2% Grade 3), and pruritus (16% Grade 1-2, 0% Grade ≥3). A total of nine Grade 3 TRAEs were reported in eight patients (19%); no Grade 4 TRAEs were observed. Eight serious TRAEs were reported in seven patients. Infusion-related reactions considered as adverse events (AEs) of special interest occurred in six patients.

Treatment-emergent AEs of Grade 3 occurred in 18 of 43 patients (42%) of patients. Three of 43 patients (7%) discontinued therapy due to immune-related AEs: renal dysfunction (Grade 3), hepatitis (Grade 3), and diabetic ketoacidosis (Grade 1); no AEs led to death.

Safety data from MAHOGANY compare favorably to the experimental arm of ToGA in which overall Grade 3-4 AEs were 68% and the treatment-related mortality was 3%.1 Initial results from KEYNOTE-811 data presented at the 2021 ASCO (Free ASCO Whitepaper) Annual Meeting indicated that AEs of Grade 3-5 occurred in 57.1% of patients in the experimental arm (pembrolizumab + trastuzumab + chemotherapy) and in 57.4% of patients in the control arm, AEs leading to death occurred in 3.2% vs 4.6%, and AEs leading to discontinuation of any study drug occurred in 24.4% vs 25.9% of patients, respectively. Despite limitations of cross-study comparisons, regimens containing chemotherapy may have clinically relevant safety differences compared to the chemotherapy-free regimen in MAHOGANY Cohort A.

"We are excited to share our results from the interim analysis of Part 1 of the MAHOGANY Cohort A study at ESMO (Free ESMO Whitepaper)," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "This study is designed to support potential registration of margetuximab in combination with other agents for patients with gastric or gastroesophageal junction cancer as part of our strategy to advance margetuximab in HER2+ cancer. The findings suggest the combination of margetuximab and retifanlimab may potentially provide a chemotherapy-free option as a first-line treatment for patients whose tumors are positive for both HER2 and PD-L1. We are pleased these data support the protocol’s prespecified advancement into Part 2 of MAHOGANY Cohort A. We plan to discuss these results and future development of the combination in an upcoming scheduled meeting with the FDA."

ESMO Presentation
MacroGenics’ Cohort A Part 1 MAHOGANY Study poster presentation is available for on-demand viewing on the ESMO (Free ESMO Whitepaper) website and on the "Events & Presentations" page on MacroGenics’ website at View Source

The MAHOGANY Study Design

MAHOGANY (NCT04082364) is a Phase 2/3 clinical trial in two cohorts designed to evaluate margetuximab in combination with a checkpoint inhibitor, with or without chemotherapy, as a potential first-line treatment for patients with advanced or metastatic HER2+ GEJ/GC.

Cohort A is designed as a single arm study to test margetuximab plus retifanlimab (previously known as MGA012 and INCMGA00012), an investigational anti-PD-1 monoclonal antibody, in patients with HER2+ and PD-L1+ tumors. The primary outcome measure for efficacy is ORR per Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

Cohort B is designed as a randomized trial to test margetuximab plus a checkpoint inhibitor in combination with chemotherapy compared to standard of care therapy of trastuzumab with chemotherapy in patients with HER2+ tumors irrespective of PD-L1 expression. Patients randomized to one of two experimental arms containing a checkpoint inhibitor will receive either retifanlimab or tebotelimab (previously known as MGD013), an investigational DART molecule targeting PD-1 and LAG-3. The primary outcome measure for efficacy is OS.

The Phase 2/3 clinical trial is being conducted at clinical sites globally, in collaboration with Zai Lab, the company’s regional partner in Greater China. For additional information about the MAHOGANY study, please visit View Source

About Gastric and Gastroesophageal Junction Cancer

Cancer of the stomach (gastric cancer, GC), or the gastroesophageal junction (GEJ) where the esophagus joins the stomach, is collectively known as gastroesophageal adenocarcinoma and is the fifth most common tumor type worldwide. Both GC and GEJ cancer are often diagnosed at an advanced stage and therefore have very poor prognosis, with a 5-year survival of 5-20%. Chemotherapy is the standard of care for first-line therapy and may be combined with trastuzumab for the approximately 20% of patients whose tumors are HER2+.

About Margetuximab

MARGENZA (margetuximab-cmkb) is approved in HER2+ metastatic breast cancer and is being investigated as a potential first-line treatment for patients with HER2+ GC or GEJ cancer in combination with a checkpoint inhibitor, with or without chemotherapy. Margetuximab is an Fc-engineered monoclonal antibody that targets the HER2 oncoprotein. HER2 is expressed by tumor cells in breast, gastroesophageal and other solid tumors. Through MacroGenics’ Fc Optimization technology, margetuximab has been engineered to enhance the engagement of the immune system.

Margetuximab is also being evaluated in combination with tebotelimab (PD-1 × LAG-3 bispecific DART molecule) in various HER2+ tumors (NCT03219268). MacroGenics is partnered with Zai Lab for the development and commercialization of margetuximab in Greater China. For more information, please visit www.clinicaltrials.gov.

About Retifanlimab

Retifanlimab is an investigational, humanized, proprietary anti-PD-1 monoclonal antibody being developed for use as monotherapy as well as in combination with other potential cancer therapeutics. Retifanlimab was licensed to Incyte Corporation in 2017 under an exclusive global collaboration and license agreement. MacroGenics retains the right to develop its pipeline molecules with retifanlimab. Incyte is pursuing development of retifanlimab monotherapy in four potentially registration-directed trials for patients with MSI-high endometrial cancer, Merkel cell carcinoma, anal cancer and non-small cell lung cancer. Incyte and MacroGenics are each conducting multiple studies of retifanlimab in combination with other agents.

About Tebotelimab

Tebotelimab is an investigational, first-in-class bispecific DART molecule designed to provide co-blockade of PD-1 and LAG-3 for the potential treatment of a range of solid tumors and hematological malignancies.

On September 16, 2021 BeyondSpring Pharmaceuticals (the "Company" or "BeyondSpring") (NASDAQ: BYSI), a global pharmaceutical company focused on the development of innovative cancer therapeutics, reported new positive data on plinabulin from its chemotherapy-induced neutropenia (CIN) prevention program with three poster presentations at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2021 Congress taking place from September 16-21, 2021 (Press release, BeyondSpring Pharmaceuticals, SEP 16, 2021, View Source;utm_medium=rss&utm_campaign=beyondspring-pharmaceuticals-announces-new-positive-data-on-plinabulin-from-its-chemotherapy-induced-neutropenia-prevention-program-at-the-european-society-for-medical-oncology-2021-congress [SID1234587817]). Plinabulin, the Company’s first-in-class lead asset, in combination with G-CSF for the prevention of chemotherapy-induced neutropenia (CIN) is currently under U.S. and China regulatory review with an FDA PDUFA date of November 30, 2021. The posters will be made available for viewing on the ESMO (Free ESMO Whitepaper) website starting on September 16 at 8:30 a.m. CEST and will remain available on the ESMO (Free ESMO Whitepaper) website throughout the entire duration of the Congress.

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"We’re pleased to present additional positive data at this year’s ESMO (Free ESMO Whitepaper) Congress to show that the Grade 4 neutropenia endpoint is correlated with clinically meaningful endpoints in a meta-analysis with >7000 patients in various cancer and various chemotherapy. This adds to our existing body of data in CIN prevention, a critically important indication for cancer patients," said Dr. Ramon Mohanlal, executive vice president, R&D, and chief medical officer at BeyondSpring Pharmaceuticals. "Over the last few years, plinabulin has continued to show its potential in preventing this life-threatening side effect of chemotherapy, and we remain committed to bringing this therapy to patients in need globally as we eagerly await November’s PDUFA date."

A summary of the data can be found below:

Severe Neutropenia (Grade 4, Gr4N) as a Population-Based Predictor for Adverse Clinical Outcome of Chemotherapy Induced Neutropenia (CIN). Poster #3574.

Ramon Mohanlal, M.D., Ph.D., executive vice president, R&D, chief medical officer, BeyondSpring Pharmaceuticals

The meta-analysis dataset included data from 36 published world literature (n > 7000) in various cancers and chemotherapy as well as the plinabulin CIN program including all 105 and 106 CIN studies (n=496).
Correlations of exponential equations between rate of febrile neutropenia (FN), duration of severe neutropenia (DSN) and absolute neutrophil count (ANC) nadir were statistically significant (p<0.0001) and in agreement with each other.
Grade 4 neutropenia (Gr4N) is a valid binary predictor of CIN outcomes, and a 65% Gr4N threshold depicts low vs. high CIN outcome risk.
Prediction of Febrile Neutropenia (FN), Hospitalization (Hosp) Rates, and Infection (Inf) Rates in Chemotherapy-Induced Neutropenia (CIN) Patients (pts) Treated with the Plinabulin and Pegfilgrastim Combination (Plin+Peg) using a Meta-Analysis (MA)-based Tool. Poster # 3627.

Stephan Ogenstad, Ph.D., founder and president of Statogen Consulting LLC, North Carolina

In the PROTECTIVE-2 Phase 3 trial, the combination of plinabulin and pegfilgrastim had superior efficacy in preventing Gr4N versus pegfilgrastim alone; Gr4N of 68% in the combination vs. Gr4N of 86% for pegfilgrastim alone, p = 0.0015.
Based on the meta-analysis detailed above in n>7000 patients, the reduction in Gr4N frequency from 86% in pegfilgrastim alone to 68% in the combination is predicted to result in a statistically significant and clinically meaningful reduction (approximately 50% reduction) in key clinically relevant CIN outcomes including mean DSN, FN rate, mean ANC nadir, hospitalization rate and infection rate (all p<0.0001), if used in an "all chemotherapy and all cancers" setting.
Impact of Adding Plinabulin to Pegfilgrastim for the Prevention of Chemotherapy Induced Neutropenia (CIN), on Patient Quality of Life (QoL). Poster# 3857.

Douglas W. Blayney, M.D., professor of medicine (oncology), Stanford Medicine

The physical wellbeing (in particular, pain and energy levels) of patients receiving plinabulin and pegfilgrastim was significantly less impacted by TAC compared to those receiving pegfilgrastim alone.
In addition, patients receiving plinabulin and pegfilgrastim recovered to their pre-chemotherapy physical wellbeing levels more rapidly and experienced less deterioration in their QoL over the duration of the 4-cycle trial.
About Plinabulin

Plinabulin, BeyondSpring’s lead asset, is a selective immunomodulating microtubule-binding agent (SIMBA), which is a potent antigen presenting cell (APC) inducer. It is a novel, intravenous infused, patent-protected, NDA stage asset for CIN prevention and a Phase 3 anti-cancer candidate for non-small cell lung cancer (NSCLC). Plinabulin triggers the release of the immune defense protein, GEF-H1, which leads to two distinct effects: first is a durable anticancer benefit due to the maturation of dendritic cells resulting in the activation of tumor antigen-specific T-cells to target cancer cells, and the second is early-onset of action in CIN prevention after chemotherapy by boosting the number of hematopoietic stem/progenitor cells (HSPCs). It is being developed as a "pipeline in a drug" in multiple cancer indications.

On September 16, 2021 Shasqi, a clinical-stage biotechnology company developing precision activated oncology therapeutics with its proprietary Click Activated Protodrugs Against Cancer (CAPAC) platform, reported that interim data from its Phase 1 clinical study of SQ3370 in advanced sarcomas and other solid tumors, as well as additional non-clinical data at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, being held virtually on September 16-21, 2021 (Press release, Shasqi, SEP 16, 2021, View Source [SID1234587835]).

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The interim Phase 1 clinical data were presented at the developmental therapeutics virtual poster session:

Abstract Title: Early pharmacokinetic data from a Phase I study of SQ3370 (NCT04106492) in patients with advanced solid tumors provides proof-of-concept for the click chemistry-based CAPAC platform
Presentation Number: 547P
Virtual Poster Session Title: Developmental therapeutics
Link to full poster details here.
The non-clinical data were presented at the basic science virtual poster session:

Abstract Title: Click Activated Protodrugs Against Cancer (CAPAC) Platform Enhances the Safety, Pharmacokinetics, and Antitumor Efficacy of Cancer Therapies in vivo
Presentation Number: 9P
Virtual Poster Session Title: Basic science
Link to full poster details here.
"These early data from our Phase 1 study of SQ3370 provide initial validation for our click chemistry-based platform in humans with an encouraging safety profile," said José M. Mejía Oneto, M.D., Ph.D., Founder and CEO of Shasqi. "Cytotoxic agents remain standard of care for many cancers because they are effective at killing tumor cells. Our platform is designed to enhance the therapeutic benefit of these agents while minimizing toxicity. With this early validation of our platform, we can continue to advance SQ3370 and explore the application of our technology beyond chemotherapies to other standard of care cancer therapies with a limited therapeutic window."

"Conventional chemotherapeutics are not tumor-specific and can lead to toxicity. In this study, which administered up to four times the standard dose of doxorubicin, we showed that SQ3370 has the potential to widen the therapeutic window and improve the safety profile when compared to standard doxorubicin or liposomal doxorubicin," said Vivek Subbiah, M.D., Principal Investigator, Associate Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center. "The early signs of clinical activity without dose limiting toxicities in this group of heavily pretreated patients, some of whom have progressed through standard doxorubicin and other chemotherapies, are encouraging. As the study advances, we will further evaluate the safety and efficacy of higher doses of SQ3370."

The interim Phase 1 results of the first-in-human, dose escalation study of SQ3370 in patients with advanced solid tumors that are refractory/relapsed following or otherwise ineligible for standard of care therapy, were presented in poster format at ESMO (Free ESMO Whitepaper) 2021. Key study findings include:

All nine patients received at least one cycle of SQ3370
Eight out of nine patients had metastatic disease
Escalating doses ranged from 0.38x to 4x the molar equivalent of conventional doxorubicin
Nonclinical and clinical pharmacokinetics (PK) data are consistent, demonstrating more than 50 times higher exposure of doxorubicin in tumor versus plasma
No dose-limiting toxicities (DLT’s) have been observed
The most common treatment emergent adverse events reported were nausea, fatigue, constipation and pyrexia
Five out of eight evaluable patients had a best response of stable disease, including patients who progressed on prior doxorubicin or other prior systemic therapies
Maximum tolerated dose has not yet been reached
SQ3370 dose escalation is ongoing
Non-clinical results on the safety, PK, and antitumor efficacy of Click Activated Protodrugs Against Cancer (CAPAC) Platform in animal models were presented in poster format at ESMO (Free ESMO Whitepaper) 2021. Key findings included:

GLP study in canine models showed that the highest non-severely toxic dose (HNSTD) of SQ3370 was 8.95 mg/kg/cycle. Side effects were dose-dependent and reversible with no evidence of cardiotoxicity
Rat PK modeling shows that doxorubicin exposure in the tumor is >300x higher than plasma
SQ3370 murine models showed antitumor efficacy in multiple tumor types both in injected and non-injected lesions (abscopal effect).
CAPAC and SQ3370:

SQ3370 utilizes Shasqi’s proprietary CAPAC platform, a click chemistry-based approach that activates cancer drugs at a tumor with decreased systemic toxicity. The platform is based on the chemical reaction between an attenuated trans-cyclooctene-modified protodrug and a tetrazine-modified biopolymer. The biopolymer is injected into the target tumor lesion, where it precisely activates an intravenously infused protodrug. Unlike traditional targeted therapies, the CAPAC platform is agnostic to tumor characteristics that can vary from patient to patient, such as biomarker expression and enzymatic activity.