On September 20, 2023 Protara Therapeutics, Inc. (Nasdaq: TARA), a clinical-stage company developing transformative therapies for the treatment of cancer and rare diseases, reported that dosing is now underway in its Phase 1b/2 ADVANCED-2 trial evaluating intravesical instillation of TARA-002, the Company’s investigational cell-based therapy, for the treatment of high-grade non-muscle invasive bladder cancer (NMIBC) patients with Bacillus Calmette-Guérin (BCG)-naïve and BCG-unresponsive carcinoma in situ (CIS) (Press release, Protara Therapeutics, SEP 20, 2023, View Source [SID1234635283]). In addition, dosing is progressing in the ongoing ADVANCED-EXP trial started earlier this year with preliminary results expected in the first half of 2024.

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"The ADVANCED-2 trial in NMIBC is an exciting opportunity to build on the favorable anti-tumor and safety data of TARA-002 presented earlier this year," said Tom Jayram, M.D., Director, Advanced Therapeutics Center, Urology Associates, P.C., TN and study investigator for the ADVANCED-2 trial. "There is significant need for new intravesical approaches for NMIBC, which can recur and progress to invasive disease with current treatments. This trial looks at the potential clinical benefit of TARA-002 as a possible new therapy for NMIBC, across both BCG-naïve and BCG-unresponsive patient populations."

The initiation of this trial follows the positive results of the ADVANCED-1 clinical trial of TARA-002 presented in April 2023 at the American Urological Association Annual Meeting. In the dose-escalation component of that study, TARA-002 was generally well tolerated and anti-tumor activity was observed, including tumor regression in all three evaluable patients with CIS, including one heavily pre-treated BCG-unresponsive patient who achieved a complete response (CR).

"Following positive preliminary results from the ADVANCED-1 trial, we are pleased to have dosed the first patient in the ADVANCED-2 trial," said Jathin Bandari, M.D., Chief Medical Officer of Protara Therapeutics. "We believe TARA-002 has the potential to play a meaningful role in the NMIBC treatment landscape and look forward to progressing the trial in parallel with our ongoing ADVANCED-1EXP study."

ADVANCED-2 (NCT05951179) is a Phase 1b/2 open-label trial evaluating intravesical TARA-002 in up to 102 patients with CIS (± Ta/T1) who are BCG-naïve (N=27) and BCG-unresponsive (N=75). Trial subjects will receive an induction with or without a reinduction course of six weekly intravesical instillations of TARA-002, followed by a maintenance course of three weekly installations every three months in the BCG-unresponsive cohort.

The ongoing ADVANCED-1EXP trial is a Phase 1b open-label expansion trial evaluating intravesical TARA-002 in 12 CIS patients, including BCG-naïve, BCG-unresponsive, and BCG-inadequately treated patients.

About TARA-002

TARA-002 is an investigational cell therapy in development for the treatment of NMIBC and of LMs, for which it has been granted Rare Pediatric Disease Designation by the U.S. Food and Drug Administration. TARA-002 was developed from the same master cell bank of genetically distinct group A Streptococcus pyogenes as OK-432, a broad immunopotentiator marketed as Picibanil in Japan and approved in Taiwan by Chugai Pharmaceutical Co., Ltd. Protara has successfully shown manufacturing comparability between TARA-002 and OK-432.

When TARA-002 is administered, it is hypothesized that innate and adaptive immune cells within the cyst or tumor are activated and produce a strong immune cascade. Neutrophils, monocytes, and lymphocytes infiltrate the abnormal cells and various cytokines, including interleukins IL-2, IL-6, IL-8, IL-10, IL-12, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha are secreted by immune cells to induce a strong inflammatory reaction and destroy the abnormal cells.

About Non-Muscle Invasive Bladder Cancer

Bladder cancer is the 6th most common cancer in the United States, with NMIBC representing approximately 80% of bladder cancer diagnoses. Approximately 65,000 patients are diagnosed with NMIBC in the United States each year. NMIBC is cancer found in the tissue that lines the inner surface of the bladder that has not spread into the bladder muscle.

On September 20, 2023 Orionis Biosciences, a privately held life sciences company with an integrated drug discovery and chemical biology platform, reported a multi-year collaboration with Genentech, a member of the Roche Group, to discover novel small molecule medicines for challenging targets in major disease areas, including oncology and neurodegeneration (Press release, Orionis Biosciences, SEP 20, 2023, View Source [SID1234635282]).

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Orionis’s Allo-Glue platform utilizes multiple unique approaches to discover drug-like small molecules against disease targets that have remained elusive to traditional discovery approaches. The platform integrates a suite of proprietary chemical biology technologies, including biological assays, computational analyses, chemical libraries and automated processes for high throughput discovery, rational design and optimization of small molecules that promote or induce interactions of proteins in living cells. This includes molecular glues that can promote interactions leading to either target degradation (through virtually any ligase) or modulation of target function, via either direct or allosteric mechanisms. Both target-centric and ligase-driven discovery paradigms are enabled and leveraged in a synergistic manner in the company’s overall approaches to molecular glue discovery.

Under the terms of the agreement, Orionis will be responsible for the discovery and optimization of molecular glues for Genentech’s designated targets, while Genentech will be responsible for subsequent later-stage preclinical, clinical development, regulatory filing, and commercialization of such small molecules. Orionis will receive an upfront payment of $47 million and is eligible for development milestone payments, as well as commercial and net sales milestone payments that could exceed $2 billion and a tiered royalty upon sale of collaboration products.

"Molecular glues represent one of the most exciting recent developments in small-molecule drug discovery. We are thrilled to collaborate with Genentech, a company long known for its world-class science and trailblazing medicines, to make use of technological innovations that we have systematically evolved over the past years to unlock novel target space with such drug modalities" said Nikolai Kley, Co-Founder and CEO of Orionis Biosciences. "We could not be more excited about the potential for this pioneering collaboration to lead to impactful new treatment paradigms."

Riccardo Sabatini, Orionis Chief Data Scientist, added, "It is exciting to see how synergies created by the integration of our biological, chemical and computational technologies are being leveraged for the discovery and design of molecular glues."

"Molecular glue degraders are an exciting modality to target disease-related proteins that have proven challenging with more traditional treatment modalities," said James Sabry, Global Head, Roche Pharma Partnering. "For patients with unmet needs, this offers a new therapeutic approach to modulate major disease drivers. This collaboration enables us to apply the concept of targeted protein degradation to discover and develop medicines for patients with serious and life-threatening diseases."

On September 20, 2023 Nerviano Medical Sciences S.r.l. (NMS), a member of NMS Group S.p.A. and a clinical stage biotech, discovering and developing innovative therapies for the treatment of cancer, reported the publication of preclinical data on NMS-P945 (link to article), its novel protease-cleavable thienoduocarmycin derivative payload-linker, with DNA damaging properties, in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Nerviano Medical Sciences, SEP 20, 2023, View Source [SID1234635281]).

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The manuscript describes preclinical studies on NMS-P945 conjugated to trastuzumab as biological proof-of-concept for the novel NMS payload-linker. Published data now show that NMS-P945, has superior physicochemical features for ADC production compared to other duocarmycin based payload-linkers. Trastuzumab-NMS-P945 ADC is highly active in vitro and in vivo with "bystander effect" to be active in heterogeneous tumors, triggering features potentiating tumor cell recognition by the immune system and with potent activity in chemoresistant tumors. As a result of the reported features, NMS-P945 represents a highly effective, innovative, DNA damaging payload-linker for the creation of novel, next generation ADCs. Hugues Dolgos, PharmD, Chief Executive Officer of NMS S.r.l. and NMS Group S.p.A. commented "I am excited about our first peer reviewed publication of NMS-P945, our first innovative payload designed to enhance ADC efficacy versus products armed with MMAE and deruxtecan payloads. I am convinced that this publication will accelerate the initiation of novel projects in partnership with biotech and pharma worldwide".

On September 20, 2023 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) has accepted for priority review a new supplemental Biologics License Application (sBLA) seeking approval for KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with external beam radiotherapy (EBRT) plus concurrent chemotherapy, followed by brachytherapy (also known as concurrent chemoradiotherapy) as treatment with definitive intent for newly diagnosed patients with high-risk locally advanced cervical cancer (Press release, Merck & Co, SEP 20, 2023, View Source [SID1234635280]). The sBLA is based on data from the KEYNOTE-A18 trial, also known as ENGOT-cx11/GOG-3047, in which KEYTRUDA plus concurrent chemoradiotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to concurrent chemoradiotherapy alone. If approved, this would be Merck’s third approved indication in cervical cancer and first in an earlier stage of the disease. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of January 20, 2024.

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"The standard of care for patients with locally advanced cervical cancer has not changed in more than two decades, and the majority of patients will experience recurrence or progression of their disease," said Dr. Gursel Aktan, vice president, global clinical development, Merck Research Laboratories. "If approved, KEYTRUDA will be the first immunotherapy available for patients with newly diagnosed high-risk locally advanced cervical cancer. We are committed to working closely with the FDA to bring KEYTRUDA to these patients who are in need of additional treatment options."

In the U.S., KEYTRUDA has two approved indications in cervical cancer: in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (Combined Positive Score [CPS] ≥1) as determined by an FDA-approved test; and as a single agent, for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

About KEYNOTE-A18/ENGOT-cx11/GOG-3047

KEYNOTE-A18, also known as ENGOT-cx11/GOG-3047, is a randomized, double-blind Phase 3 trial (ClinicalTrials.gov, NCT04221945) sponsored by Merck and conducted in collaboration with the European Network for Gynaecological Oncology Trial (ENGOT) groups and the GOG Foundation, Inc. (GOG) evaluating KEYTRUDA in combination with EBRT plus concurrent chemotherapy (cisplatin), followed by brachytherapy (also known as concurrent chemoradiotherapy) compared to placebo plus concurrent chemoradiotherapy for the treatment of newly diagnosed high-risk (stage 1B2-2B with lymph node-positive disease, and stage 3-4A with and without lymph node-positive disease per FIGO 2014) locally advanced cervical cancer where patients are treated with definitive intent. The primary endpoints are PFS and overall survival, and secondary endpoints include complete response rate, objective response rate and safety. The trial enrolled 1,060 patients who were randomized to receive:

KEYTRUDA (200 mg intravenously [IV]) on Day 1 of each three-week cycle (Q3W) for five cycles followed by KEYTRUDA (400 mg by IV) on Day 1 of each six-week cycle (Q6W) for an additional 15 cycles plus concurrent chemoradiotherapy (cisplatin 40 mg/m2 by IV once per week [QW] for five or six weeks plus EBRT followed by brachytherapy with minimum total radiotherapy dose of 80 Gray Units [Gy] for volume-directed and 75 Gy for point-directed given with the total duration of radiation treatment not to exceed 50 days [with an extension to a maximum of 56 days for unforeseen delays]); or
Placebo plus concurrent chemoradiotherapy (cisplatin 40 mg/m2 by IV QW for five or six weeks plus EBRT followed by brachytherapy with minimum total radiotherapy dose of 80 Gy for volume-directed and 75 Gy for point-directed given with the total duration of radiation treatment not to exceed 50 days [with an extension to a maximum of 56 days for unforeseen delays]).

On September 20, 2023 IN8bio, Inc. (Nasdaq: INAB), a leading clinical-stage biopharmaceutical company focused on innovative gamma-delta T cell therapies, reported William Ho, CEO and co-founder, will participate in a panel presentation at the 2023 Cantor Fitzgerald Global Healthcare Conference on Wednesday, September 27, 2023, at 8:35 a.m. ET (Press release, In8bio, SEP 20, 2023, View Source [SID1234635279]).

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The Cantor Fitzgerald presentation will be available live and as a replay on IN8bio’s website at https://bit.ly/3F1WEaQ.