On September 14, 2024 Indian Council of Medical Research (ICMR) reported to have formalized Memorandum of Agreements (MoAs) with multiple sponsors under its Network of Phase 1 Clinical Trials (Press release, Aurigene Discovery Technologies, SEP 14, 2024, View Source [SID1234646855]). The agreements mark a ground-breaking entry into First-in-Human Clinical Trials for four promising molecules. These include collaborative research over a small molecule for multiple myeloma with Aurigene Oncology Limited, partnering for Zika vaccine development with Indian Immunologicals Limited, coordinating seasonal Influenza virus vaccine trial with Mynvax Private Limited, and CAR-T cell therapy advancement study for a new indication of chronic lymphocytic leukemia with ImmunoACT. This initiative is a crucial step towards establishing India as a leader in the clinical development of pharmaceutical agents.

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Union Health and Family Welfare Minister, Shri J P Nadda, commended the strategic collaboration between ICMR and prominent industry and academic partners, emphasizing it as a key milestone in the pursuit of affordable and accessible cutting-edge treatments for all citizens. He noted that this initiative positions India to emerge as a global leader in healthcare innovation.

Dr. Rajiv Bahl, Secretary, Department of Health Research & Director General, ICMR, emphasized the transformative potential of the project, stating, "This collaboration reflects our commitment to advancing clinical research in India through strategic public-private partnerships. Establishing Phase 1 clinical trial infrastructure is a key component in fostering the development of indigenous molecules and cutting-edge treatments. Our vision is to expand this network further, ensuring that India continues to lead in the development of innovative and affordable healthcare solutions."

Dr. Bahl also highlighted the broader impact of ICMR’s initiatives, such as the Network for Phase 1 Clinical Trials, INTENT Network, and MedTech Mitra, aligning with the government’s vision of a "Viksit Bharat" (Developed India). He cited ICMR’s pivotal role in development of Covaxin in collaboration with Bharat Biotech as a testament to the organization’s commitment to affordable and accessible healthcare for all.

The ICMR Network for Phase 1 Clinical Trials comprises four strategically located institutions across India—KEMH & GSMC, Mumbai; ACTREC, Navi Mumbai; SRM MCH&RC, Kattankulathur; and PGIMER, Chandigarh—supported by a Central Coordinating Unit at ICMR Headquarters, New Delhi. This network is designed to build and enhance India’s capacity to conduct early-phase clinical trials, supported by robust infrastructure and dedicated manpower at each trial site, ensuring smooth and effective operations.

The signing of these agreements reinforces the strong partnerships ICMR has cultivated with key industry players. It underscores the institute’s dedication to building a robust clinical trial ecosystem in India, fostering capacity to develop new drugs from early-phase trials through to marketing, thereby reducing dependency on international resources, and ultimately driving the mission of affordable, high-quality healthcare for all.

On September 14, 2024 BioCity reported interim clinical results on the safety and efficacy of its first-in-class antibody-drug conjugate (ADC) BC3195 targeting CDH3 (P-Cadherin) in a Phase I clinical trial at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024 (Press release, Biocity Biopharmaceutics, SEP 14, 2024, View Source [SID1234646828]).

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As of the data cut-off date (August 10, 2024), BC3195 demonstrated impressive antitumor activity in patients with advanced non-small cell lung cancer (NSCLC) with an ORR of 36.4% (4 of 11 patients). The ORR was 80% (4 of 5 patients) in NSCLC with epidermal growth factor receptor mutations (EGFRmut). BC3195 demonstrated manageable safety and tolerability, as well as favorable pharmacokinetic characteristics. Dose optimization and further patient accrual in NSCLC, breast cancer, and other types of CDH3-expressing cancers are ongoing. Clinical trial information: NCT05957471.

Thirty-four patients (median age, 59.5; male, 64.7%) have been enrolled at the date of data cut-off, with 3 patients each enrolled at BC3195 dose levels of 0.3, 0.6, 1.2, and 1.8 mg/kg as an intravenous (IV) infusion every 3 weeks (Q3W), 21 patients enrolled at the 2.4 mg/kg IV Q3W dose level, and 1 patient enrolled at the 1.2 mg/kg IV weekly dose level.

Notable safety findings include:

All patients in the dose escalation stage of the study were evaluable for dose-limiting toxicity (DLT). One patient had Grade 3 pharyngitis, considered a DLT, following treatment with BC3195 2.4 mg/kg IV Q3W.
Rash, stomatitis and liver function abnormalities were the main adverse events (AEs). Most episodes of rash and stomatitis occurred in the first cycle and were manageable.
Fourteen (41.2%) patients experienced Grade≥3 treatment-related adverse events (TRAEs). Grade ≥3 TRAEs experienced by more than 2 patients include stomatitis (23.5%), neutropenia (8.8%), and rash(8.8%).
Notable efficacy findings include：

Five patients, including 4 NSCLC patients and 1 breast cancer patient had confirmed PRs following treatment with BC3195 2.4 mg/kg IV Q3W.
Of 11 NSCLC patients treated at the 2.4mg/kg IV Q3W dose level, 10 patients had reductions in tumor volume including 4 patients with confirmed PRs and 6 patients with stable disease (SD) as their best response. At 2.4 mg/kg IV, the ORR and disease control rate (DCR) were 36.4% and 90.9%, respectively.
Four of 5 (80%) patients with EGFRm NSCLC had confirmed PRs.
Among the 30 patients who were evaluable for tumor response, no complete response (CR) nor partial response (PR) were reported in BC3195 dose levels up to 1.8 mg/kg IV Q3W.
Based on the promising clinical results already achieved with BC3195, BioCity will continue to collaborate with global researchers to advance the clinical development of this first-in-class ADC.

About BC3195

BC3195 is currently the only ADC targeting CDH3(P-Cadherin) in clinical development globally. In preclinical studies, BC3195 binds to membrane CDH3 with strong affinity and is efficiently internalized. BC3195 is designed with a clinically validated, cleavable linker and payload (vc-MMAE) allowing for the destruction of targeted cancer cells, as well as surrounding cells, which is known as the bystander effect. In animal models, BC3195 demonstrated a favorable safety profile and robust antitumor activity with tumor growth inhibition ≥100% in some animals bearing well established cancers.

BC3195 is currently undergoing concurrent Phase I dose optimization and dose expansion in China and the US. BC3195 demonstrated a manageable safety profile and favorable PK characteristics, significant antitumor activity with confirmed PRs observed across multiple tumor types.

On September 14, 2024 Medigene AG (Medigene or the "Company", FSE: MDG1, Prime Standard), an oncology platform company focused on the research and development of T cell receptor (TCR)-guided therapies for the treatment of cancer, reported updates for its T cell receptor (TCR) library targeting the Kirsten rat sarcoma viral oncogene homolog (KRAS) and also highlighted advancements of its UniTope and TraCR technology, which serves as a universal system for tagging and tracking recombinant TCRs (rTCRs) across multiple modalities, including T cell receptor engineered T cell (TCR-T) therapies, at the ESMO (Free ESMO Whitepaper) Congress 2024 taking place in Barcelona from September 13-17, 2024 (Press release, MediGene, SEP 14, 2024, https://www.pressetext.com/news/20240914005 [SID1234646624]).

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The presented posters " Advancing a multi-dimension KRAS mutation-specific T cell receptor (TCR) library with a 3S TCR targeting the G12D mutation to address large global patient populations " and " UniTope & TraCR – Universal tagging and tracking system for TCR-T cells integrated directly in the TCR constant region " will be made available after the conference on Medigene’s website:View Source

"We are excited about our expanding library of mKRAS-specific rTCRs targeting different mutations and HLA allotypes, aiming to broaden treatment options and improve outcomes for patients with difficult-to-treat solid tumors," said Dolores Schendel, CSO at Medigene AG. "Our lead KRAS G12D candidate, enhanced by the costimulatory switch protein (CSP) PD1-41BB, has shown very promising T cell functionality. By overcoming the challenges of the tumor microenvironment that have hindered the effectiveness of TCR-T therapies, we are confident that this program could offer best-in-class efficacy and safety. We are expanding our TCR library and also incorporating new proprietary technologies into our End-to-End (E2E) Platform, including UniTope & TraCR, a universal detection system for any rTCR across various modalities like TCR-T therapies, TCR-guided T cell engagers therapies, and TCR-NK cell therapies. Direct integration of the UniTope tag guarantees 100% co-expression of a unique identifier in a rTCR sequence and provides a significant advancement over current methods for detection of rTCRs in TCR-guided therapeutics. UniTope and TraCR will help us streamline quality control and provide precise data for determining the correct drug dosage for TCR-T therapies."

Advancing a multi-dimension KRAS mutation-specific T cell receptor (TCR) library with a 3S TCR targeting the G12D mutation to address large global patient populations

The first data presented showcased recent advancements in the expansion of the Company’s KRAS library, using a high-throughput approach to develop optimal affinity TCRs targeting the mKRAS G12D neoantigen in the context of HLA-A*11 via Medigene’s proprietary E2E Platform. Further in vitro studies characterized the lead TCR candidate in terms of specificity, sensitivity, and safety (3S) while incorporating the PD1-41BB CSP. TCR-expressing T cells, when stimulated by mKRAS G12D-positive tumor cells, showed increased interferon gamma (IFNγ) release. Reduced cancer cell survival was observed when mKRAS G12D-positive tumor cell lines from various origins were exposed to T cells co-expressing the rTCR mKRAS G12D-HLA-A*11 and PD1-41BB CSP. These effects were specific to mKRAS G12D, with no impact on wild-type KRAS cells. The TCR demonstrated an excellent safety profile, with no off-target toxicity against an extensive panel of healthy cell types. Finally, in vitro data showed that co-expression of PD1-41BB CSP enhanced and sustained T cell function in an rTCR-specific manner, with gated activation that only occurred when the specific peptide-HLA complex was present on target cells, and not through PD-L1 expression alone.

UniTope & TraCR – Universal tagging and tracking system for TCR-T cells integrated directly in the TCR constant region

The second poster displayed the Company´s recently introduced universal TCR tagging and tracking combination technology UniTope & TraCR. Bioinformatic alignment of T cell receptor beta variable sequences enabled a six-amino-acid peptide (UniTope) to be predicted that is not found in natural TCR beta chains and has low immunogenicity. In parallel, an antibody was developed to specifically target this short amino acid peptide (TraCR) and further in vitro experiments demonstrated that TCR-T cells containing the UniTope sequence exhibited similar effects to those of TCR-T cells without the UniTope sequence. Integration of the UniTope sequence in a rTCR guarantees 100% co-expression of the tag and provides a significant advancement over current methods of detection of rTCRs in TCR-guided therapeutics.

In vitro studies confirmed that insertion of UniTope did not alter expression or functionality of rTCRs. In addition, safety assessments confirmed that UniTope-modified rTCRs displayed the same high safety profile as un-modified rTCRs with respect to lack of recognition and killing of 16 healthy cell types.

On September 14, 2024 Sutro Biopharma, Inc. (Sutro or the Company) (NASDAQ: STRO), a clinical-stage oncology company pioneering site-specific and novel-format antibody drug conjugates (ADCs), reported updated data from the ongoing Phase 1b study of luveltamab tazevibulin (luvelta) in combination with bevacizumab for patients with epithelial ovarian cancer (EOC) in a poster presentation at the 2024 European Society For Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in Barcelona, Spain (Press release, Sutro Biopharma, SEP 14, 2024, View Source [SID1234646623]).

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In this study, luvelta plus bevacizumab has demonstrated encouraging antitumor activity in patients with late-stage ovarian cancer irrespective of Folate Receptor-α (FRα) expression, including patients with no FRα expression, and prior bevacizumab treatment, with an overall response rate of 35%. These early data in combination may offer a non-biomarker driven approach to treat patients with EOC. The expansion phase of the study is ongoing at the recommended phase 2 dose (RP2D) of luvelta (4.3 mg/kg) in combination with bevacizumab (15 mg/kg) with an additional 23 patients enrolled to date; initial data is expected in the first half of 2025.

"We are encouraged by these results achieved with luvelta in combination with bevacizumab, which may offer the opportunity to benefit ovarian cancer patients regardless of FRα expression," said Jane Chung, Sutro’s President and Chief Operating Officer. "We have already seen promising antitumor activity with luvelta as a monotherapy treatment and we believe these combination data support our goal to deliver effective therapies to more patients living with cancer. We look forward to sharing initial results from our expansion phase in the first half of 2025."

ESMO Poster Presentation Highlights:

18 patients were enrolled; one patient remains on treatment.
Luvelta plus bevacizumab demonstrated encouraging antitumor activity in 17 RECIST evaluable patients:
At the RP2D (4.3 mg/kg), an Objective Response Rate (ORR) of 56% (5/9) was observed; no (0/6) patients had a response at 3.5 mg/kg and 50% (1/2) of patients had a response at 5.2 mg/kg.
An ORR of 35% (6/17) was observed in the overall population with a median duration of response of 9.3 months.
In patients with ≥25% FRα expression, an ORR of 44% (4/9) was observed; in patients with <25% FRα expression, an ORR of 29% (2/7) was observed.
No new safety signals were observed compared with either agent alone; consistent with previous reported luvelta safety results, the most common adverse event was neutropenia.
The Presentation will be accessible through the News & Events page of the Investor Relations section of the company’s website at www.sutrobio.com.

About Luveltamab Tazevibulin
Luveltamab tazevibulin, abbreviated as "luvelta" and formerly known as STRO-002, is a FRα-targeting antibody-drug conjugate (ADC) designed to treat a broad range of patients with ovarian cancer, including those with lower FRα-expression who are not eligible for approved treatment options targeting FRα. Developed and manufactured with Sutro’s cell-free XpressCF platform, luvelta is a homogeneous ADC with four hemiasterlin cytotoxins per antibody, precisely positioned to efficiently deliver to the tumor while ensuring systemic stability after dosing. REFRαME-O1, a Phase 2/3 registration-directed study for patients with platinum-resistant ovarian cancer is ongoing. The Company has additional ongoing trials in patients with endometrial cancer, non-small cell lung cancer, and in combination with bevacizumab in patients with ovarian cancer. The Company expects to initiate REFRαME-P1, a Phase 2/3 registration-directed study for patients with CBF/GLIS2 acute myeloid leukemia, a rare subtype of pediatric cancer, in the second half of 2024. The U.S. Food and Drug Administration (FDA) has granted luvelta a Fast Track designation for Ovarian Cancer, as well as Orphan and Rare Pediatric Disease designations for CBF/GLIS2 Pediatric AML.

On September 14, 2024 BioInvent International AB, a biotech company focused on the discovery and development of novel and first-in-class immune-modulatory antibodies for cancer immunotherapy, and Transgene, a biotech company that designs and develops virus-based immunotherapies for the treatment of cancer, reported new initial data from their ongoing Phase 2/2a study on the multifunctional oncolytic virus BT-001, demonstrating antitumor activity in patients with refractory solid tumors (Press release, BioInvent, SEP 14, 2024, https://www.bioinvent.com/en/press/bioinvent-and-transgenes-oncolytic-virus-bt-001-shows-promising-antitumor-activity-ongoing [SID1234646619]). The data presented today at the 2024 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Meeting, showed that BT-001 induced tumor regression in patients unresponsive to prior anti PD(L)-1 treatment, both as a monotherapy and in combination with MSD’s (Merck & Co., Inc., Rahway, NJ, USA) anti-PD-1 therapy KEYTRUDA (pembrolizumab).
Preliminary translational data suggest that BT-001 replicates in the tumor where the payloads are expressed with undetectable systemic exposure. BT-001 alone or in combination with pembrolizumab was well tolerated and showed first signs of efficacy with clinical responses in 2 of 6 refractory patients when given in combination with pembrolizumab. BT-001 treatment turned "cold" tumors to "hot" inducing T cell infiltration, a higher M1/M2 ratio, and a shift to PD(L)-1 positivity in the tumor microenvironment.

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Dr. S. Champiat, Medical Oncologist, Head of the Inpatient Unit, Drug Development Department (DITEP) at Institut Gustave Roussy, commented: "The immunological data generated by BT-001 suggest that, as hoped, BT-001 is replicating in the tumor and its payload of transgenes is expressed, with very limited exposure outside of the tumor thereby limiting systemic toxicity. I look forward to additional results from this ongoing study which will provide further evidence of the safety and clinical activity of BT-001 and its potential role as a new therapy for cancer patients with solid tumors."

Transgene and BioInvent are co-developing BT-001, an oncolytic virus developed using Transgene’s Invir.IO platform armed to express GM-CSF and BioInvent’s full-length anti-CTLA-4 monoclonal antibody, to elicit a strong and effective anti-tumoral response in solid tumors.

Alessandro Riva, Chairman and CEO of Transgene, said: "We are pleased to present the first promising clinical data on BT-001 at ESMO (Free ESMO Whitepaper) 2024 which confirm its mechanism of action as a single agent injected intratumorally and importantly demonstrate first signs of anti-tumor activity. Added to its good safety profile alone and in combination with pembrolizumab, BT-001 has the potential to shrink lesions and induce stable disease in refractory patients who may have few other treatment options. We will further explore the safety and efficacy of BT-001 in this development program with our partner BioInvent and report additional data when it becomes available."

Andres McAllister, MD, PhD, Chief Medical Officer at BioInvent International AB, concluded: "We are encouraged by the early clinical results presented at ESMO (Free ESMO Whitepaper) for BT-001, which encodes a potent Treg-depleting recombinant human anti-CTLA-4 antibody generated by our proprietary n-CoDeR and F.I.R.S.T platforms,. This clinical proof of concept confirms our ability to identify antibodies that bind to a selected target but exhibit a differentiated activity, allowing the development of promising new drug candidates such as BT-001."

The abstract and Poster titled: "Initial clinical results of BT-001, an oncolytic virus expressing an anti-CTLA4 mAb, administered as single agent and in combination with pembrolizumab in patients with advanced solid tumors.".

The poster can be accessed at the company’s website https://www.bioinvent.com/en/our-science/scientific-publications.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

About the trial
The ongoing Phase 1/2a (NCT: 04725331) study is a multicenter, open label, dose-escalation trial evaluating BT-001 as a single agent and in combination with pembrolizumab (anti-PD-1 treatment). Patient inclusions are ongoing in Europe (France, Belgium) and the trial has been authorized in the US.
Phase 1 is divided into two parts. In part A, patients with metastatic/advanced tumors receive single agent, intra-tumoral administrations of BT-001. Part B explores the combination of intra-tumoral injections of BT-001 with pembrolizumab. In this part, KEYTRUDA (pembrolizumab) is provided to the trial by MSD (Merck & Co).
Phase 2a will evaluate the combination regimen in several patient cohorts with selected tumor types. These expansion cohorts will offer the possibility of exploring the activity of this approach to treat other malignancies not traditionally addressed with this type of treatment.

About BT-001
BT-001 is an oncolytic virus generated using Transgene’s Invir.IO platform and its patented large-capacity VVcopTK-RR- oncolytic virus, which has been engineered to encode both a Treg-depleting human recombinant anti-CTLA-4 antibody generated by BioInvent’s proprietary n-CoDeR/F.I.R.S.T platforms, and the human GM-CSF cytokine. By selectively targeting the tumor microenvironment, BT-001 is expected to elicit a much stronger and more effective antitumoral response. As a consequence, by reducing systemic exposure, the safety and tolerability profile of the anti-CTLA-4 antibody may be greatly improved.
BT-001 is being co-developed as part of a 50/50 collaboration on oncolytic viruses between Transgene and BioInvent. To know more on BT-001, watch our video here.