On March 21, 2024 Mabwell (688062.SH), an innovation-driven biopharmaceutical company with entire industry chain, reported "Mtoxin Payload Applied in IDDC ADC Platform Significant Increases Therapeutic Index and Overcome MultiDrug Resistance in Various Tumor" as poster presentation from March 12 to 15, 2024 at the 14th World ADC London (Press release, Mabwell Biotech, MAR 21, 2024, View Source [SID1234641356]). The development of several ADC drugs under the capabilities of IDDC, a next generation ADC technology platform, was demonstrated.

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Evolutions of conjugation technologies, new release structures, and multiple mechanism payloads have prompted the development of ADC field. However, further improving drug delivery and overcoming drug resistance are urgent problems for the next generation of ADC drugs. Mabwell has independently developed IDDC technology and novel payload Mtoxin. The study results show:

1. DARfinity produces site-specific conjugated drugs with DAR 4 as the main component (DAR 4 ≥ 95%).

2. IDconnect enhances plasma stability and payload transfer efficiency of ADC drugs (40% increase from control group).

3. LysOnly technology enhances tumor-specific release capacity of ADC drugs and reduces off-target effects.

4. Mtoxin has good tumor penetration, bystander killing effect and anti-multidrug resistance.

5. ADC drugs developed based on IDDC and Mtoxin have good pharmacodynamic and safety characteristics, especially in the DXd-resistant multidrug resistance model.

Summary

IDDC is a clinically validated site-specific conjugation technology with good homogeneity, efficacy, and safety advantages. In addition, the novel payload Mtoxin (MF6) has good pharmacodynamics, bystander killing efficacy, and anti-multidrug resistance.

Novel ADC Drugs Developed Based on IDDC Platform

The IDDC platform has been validated in multiple drugs under study.

9MW2821 – novel Nectin-4-targeting ADC:
For the indication of urothelial carcinoma, 9MW2821 is the first Nectin-4 ADC developed by a Chinese company to enter phase III clinical studies, making it the second globally in terms of progress. 9MW2821 is also the first therapeutic drug with the same target in the world to disclose clinical efficacy data for indications of cervical cancer and esophageal carcinoma. It has been granted Fast Track Designation by the U.S. Food and Drug Administration (FDA) for the treatment of advanced, recurrent, or metastatic esophageal squamous cell carcinoma.

7MW3711 – novel B7-H3-targeting ADC:
Clinical trials have been conducted for 7MW3711 for the indication of advanced solid tumors in China, and it has received FDA approval to conduct clinical trials for patients with advanced malignant solid tumors.

9MW2921 – novel Trop-2-targeting ADC:
Clinical trials have been conducted for 9MW2921 for the indication of advanced solid tumors in China.

On March 21, 2024 4SC AG (4SC, FSE Prime Standard: VSC) reported its financial results for the financial year ended 31 December 2023, presenting all material reporting period developments and providing an outlook for 2024 (Press release, 4SC, MAR 21, 2024, View Source [SID1234641355]). The full report is available at 4SC’s website.

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Jason Loveridge, Ph.D., CEO of 4SC, commented: "2023 was a real breakout year for 4SC, culminating with the filing of our MAA for resminostat (Kinselby) with the EMA in February 2024. This represents a very significant step forward for 4SC and was a great achievement for our team. It further de-risks our resminostat program and will assist our ongoing efforts to not only bring this important treatment to patients, but also commercialise the asset and create value for shareholders."

Key highlights of 2023
4SC had a very busy year in 2023, with key achievements summarized below, and further detail provided in respective press releases.

In January 2023, the company’s pre-authorisation eligibility request to the European Medicines Agency (EMA) for resminostat in cutaneous T-cell lymphoma was accepted. During its meeting in December 2022, the CHMP agreed, on the basis of the documentation provided, that resminostat was eligible to submit an application for European Union Marketing Authorisation according to the centralized procedure as detailed in Regulation (EC) No 726/2004.
In May 2023, 4SC announced topline data from its pivotal RESMAIN study, confirming resminostat had successfully met the primary endpoint in the study, demonstrating a statistically significant improvement in progression free survival in CTCL patients of 97.6%, with a risk reduction of 38% compared to placebo. The study confirmed the already well-known safety profile of resminostat.
Also in May 2023, the company submitted its letter of intent to file for Marketing Authorization for resminostat in CTCL and requested the appointment of a rapporteur with the EMA.
In June 2023, the EMA notified 4SC that it had accepted its Letter of Intent to Submit a Marketing Authorization Application (MAA) and rapporteurs would be appointed. The EMA also notified 4SC that its nominated trade name for resminostat – Kinselby – had been accepted by its Name Review Group (NRG).
In September 2023, RESMAIN study investigator, Professor Dr. Rudolf Stadler (University Hospital Johannes Wesling, Minden, Germany) presented positive new data from the pivotal RESMAN study at the EORTC Cutaneous Lymphoma Tumour Group Annual Meeting. The presented findings showed that maintenance therapy with resminostat is now clinically proven to postpone disease progression in advanced CTCL, which he expected, would lead to a significantly change in current clinical practice. Additional analyses established that patients receiving resminostat showed a clinically meaningful improvement in median "total" PFS (defined from the start of the last prior therapy to disease progression) of 24.3 months, compared to 14.9 months for those in the placebo group. Additionally, there was a significant delay in the development of new, or worsening of existing, skin tumours.
Also in September 2023, the US Food and Drug Administration (FDA) granted 4SC’s application for Orphan Drug Designation for resminostat for the treatment of CTCL.
In October 2023, the EMA granted Orphan Drug Designation for resminostat for the treatment of CTCL.
In December 2023, the Management Board of 4SC AG announced that the company had incurred a cumulative loss amounting to more than half of its share capital and pursuant to Section 92 (1) German Stock Corporation Act (AktG) would convene a general meeting. The meeting took place on 7 February 2024.
Business outlook for 2024
4SC’s future success, or failure, as a company is closely linked to the outcome of the company’s marketing authorization application for resminostat, an orally administered class I, IIb and IV histone deacetylase (HDAC) inhibitor that is in development as a maintenance therapy in CTCL.

Resminostat demonstrated significant benefit as maintenance therapy in the RESMAIN pivotal study – prolonging the period patients remain stable without progression and study results were published in May and September 2023. Given these data were positive, 4SC subsequently filed with the EMA for marketing approval for resminostat for the treatment of CTCL in Europe in February 2024. Filings for the UK and Switzerland are in preparation and, in addition, a pre-New Drug Application (NDA) meeting request was also submitted to the FDA in February 2024. In Japan, Yakult Honsha Co., Ltd. (Yakult Honsha) is responsible for filing the marketing authorization application for resminostat.

In 2024, 4SC expects to focus its resources on addressing questions from the EMA with respect to its MAA for resminostat as well as obtaining and assessing feedback from the USA FDA on 4SC’s pre-NDA submission. In addition, 4SC continues to hold discussions with potential partners in the pharmaceutical industry regarding the commercialization of its resminostat program with the assistance of a global investment bank.

Cash balance development in full year 2023 and financial forecast
4SC’s cash balance/funds were at €8,321 thousand on 31 December 2023. The average monthly operating cash burn in 2023 was €792 thousand, which was slightly lower than the forecast range of between €800 thousand and €1,100 thousand forecast for 2023. This is the result of later payments for agreed milestones in existing contracts for clinical trials. Taking into account the current financial planning and the intended operating activities, the Management Board estimates that current funds should be sufficient to finance 4SC for at least the next 12 months of operations.

Whilst 4SC’s funds of €8,321 thousand at the end of 2023 represent a solid cash position entering 2024, it is also clear that the funding environment for biotech companies deteriorated significantly in 2023 and as such management remains cautious as to 4SC’s ability to raise additional funds through further capital measures and to generate income with business partners. To address this risk, 4SC entered into a second loan agreement in the first quarter of 2024 with its largest shareholder giving the Company access to a further €3.5 million in available funding. For 2024, 4SC is expecting an average monthly use of cash from operations of between €600 thousand and €900 thousand.

On March 21, 2024 Phio Pharmaceuticals Corp. (Nasdaq: PHIO), a clinical stage biotechnology company whose proprietary INTASYL siRNA gene silencing technology is designed to make immune cells more effective in killing tumor cells, reported it is presenting new data about INTASYL on March 21st (Press release, Phio Pharmaceuticals, MAR 21, 2024, View Source [SID1234641354]). The event is scheduled to take place at the 10th Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Conference (ITOC10), which will be held in Munich, Germany from March 21-23, 2024.

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The poster, Enhancing NK cell cytotoxicity against tumor cells with a novel self-delivering RNAi compound targeting Cbl-b, reveals new preclinical data demonstrating the potential of treatment with INTASYL self-delivering siRNA Compound PH-905, formerly known as Compound 27547, to improve function of natural killer (NK) cells. The data reveals a consistent silencing of Cbl-b mRNA, which has been shown to limit NK cell activation. Cytotoxic activity of NK cells against K562 (Chronic Myelogenous Leukemia) cancer cells was also increased. By reducing the expression of Cbl-b, INTASYL promotes NK cell activation and proliferation. These preclinical data demonstrate the potential of INTASYL Compound PH-905 to improve Adoptive Cell Therapy (ACT) by targeting and silencing Cbl-b. This may result in a more effective cell therapy for hematological malignancies.

"These data underscore the versatility and potential of Phio’s INTASYL siRNA technology," said Phio’s President & CEO Robert Bitterman. "It offers a strategy to enhance the effectiveness of ACT therapies in hematological malignancies."

The preclinical data demonstrate the following:

INTASYL self-delivering RNAi compound PH-905 effectively targets and silences Cbl-b in primary NK cells without negative impact on their viability.
Silencing of Cbl-b results in increased proliferation of primary NK cells.
INTASYL silencing of Cbl-b in primary NK cells enhanced their functional cytotoxicity towards tumor cells.
Silencing of Cbl-b leads to enhanced fitness of NK cells through increased expression of CD98 and CD25, potentially improving NK metabolism and promoting activation in response to IL-2.
INTASYL compound PH-905 may be used to improve the anti-tumor response of NK cells to provide a more effective cell therapy for cancer treatment.
Presentation Details are as follows:
Title: Enhancing NK cell cytotoxicity against tumor cells with a novel self-delivering
RNAi compound targeting Cbl-b
Poster Number: P01.03
Topic: 01.Emerging concepts / New Agents
Presenting Author: Melissa Maxwell
Date and Time: 18:00 hrs Thursday, March 21, 2024
18:00-19:00 hrs Friday, March 22, 2024
Location: Ludwig Maximilian University Campus Großhadern,
Lecture Room 3, Marchioninistrasse 15
81377 Munich, Germany

On March 21, 2024 Turnstone Biologics Corp. ("Turnstone" or the "Company") (Nasdaq: TSBX), a clinical-stage biotechnology company developing a differentiated approach to treat and cure patients with solid tumors by pioneering selected tumor-infiltrating lymphocyte (Selected TIL) therapy, reported financial results for the fourth quarter and full year ended December 31, 2023, and provided recent business highlights (Press release, Turnstone Biologics, MAR 21, 2024, View Source [SID1234641352]).

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"2023 marked a transformative year for Turnstone Biologics in which we transitioned into a publicly traded company and continued to advance our pipeline through clinical development. We are encouraged by the increasing momentum in the TIL landscape that paves the way for next-generation approaches like our Selected TIL therapy, which is designed to create a TIL product with a significantly greater population of potent tumor-reactive T cells, which we believe is the key to extending their therapeutic potential to high unmet medical needs in solid tumors beyond melanoma," said Sammy Farah, M.B.A., Ph.D., Turnstone’s President and Chief Executive Officer. "In 2024, we look forward to generating clinical data that potentially highlights the differentiation of our platform and supports further development of our lead asset, TIDAL-01, which is currently being evaluated in Phase 1 studies in patients with colorectal cancer, head and neck squamous cell carcinoma, breast cancer, uveal melanoma, and cutaneous melanoma. We remain on-track to share initial clinical data for TIDAL-01 in mid-2024 and we believe we are well-positioned for another year of meaningful progress for our organization."

Fourth Quarter and Recent Business Highlights

Advancing TIDAL-01 in Multiple Phase 1 Clinical Trials and Expanding of Targeted Solid Tumor Indications. TIDAL-01 employs an unbiased identification and functional screening process to isolate and selectively expand the greatest breadth of tumor-reactive TILs from the patient’s tumor. Turnstone believes TIDAL-01 can expand the utility of TIL therapy to solid tumor types where first-generation TILs have not to date shown objective responses in clinical trials and is pursuing several indications with critical unmet need, potentially enabling meaningful therapeutic differentiation. Recently, Turnstone expanded their trials to evaluate additional solid tumor types in addition to the existing indications of breast cancer and uveal melanoma. The multi-site STARLING trial protocol has been amended to cover head and neck squamous cell carcinoma (HNSCC), and the H. Lee Moffitt Cancer Center and Research Institute sponsored trial has been expanded to include colorectal cancer (CRC) and HNSCC. Turnstone expects to provide an initial clinical update across these trials in mid-2024.

Preclinical Data Presentations at the 2023 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting Support Ongoing Clinical and Preclinical Efforts. In November 2023, Turnstone presented preclinical data on its Selected TIL therapies, including the demonstration of the feasibility of selecting and expanding tumor-reactive TIL as further evidence for the potential of TIDAL-01 as a treatment option for patients with colorectal and gastric cancers. Turnstone also presented on its next Selected TIL program from its development pipeline, TIDAL-02, which seeks to utilize a novel direct selection method, genetically engineered to rapidly select for the greatest breadth of tumor-reactive T cells.

Strengthened Company’s Scientific Advisory Board. In October 2023, Turnstone appointed Jeffrey S. Weber, M.D., Ph.D., to its Scientific Advisory Board. Dr. Weber, a world-renowned thought leader with extensive experience in innovative immunotherapies for solid tumors, currently serves as Deputy Director of the Perlmutter Cancer Center and Co-Director of the Melanoma Research Program at the New York University-Langone Cancer Center.

Fourth Quarter 2023 Financial Results

Cash, Cash Equivalents and Short-Term Investments: As of December 31, 2023, cash, cash equivalents and short-term investments were $94.8 million. The Company expects that the combined cash, cash equivalents and short-term investments will be sufficient to fund its operations into the second quarter of 2025.

Research and Development (R&D) Expenses: R&D expenses for the three months ended December 31, 2023, were $13.6 million, compared to $20.2 million for the same period in 2022. The decrease was due primarily to decreases in pre-clinical and regulatory costs, personnel-related costs, and manufacturing expenses due to the termination of the discovery, collaboration and license agreement entered into on November 7, 2019, with Takeda Oncology for certain viral immunotherapy candidates offset by an increase due to ramp up of TIDAL-01 activities.

General and Administrative (G&A) Expenses: G&A expenses for the three months ended December 31, 2023, were $4.4 million, compared to $4.4 million for the same period in 2022.

Net Loss: Net loss for the three months ended December 31, 2023, was $16.5 million, compared to net loss of $13.7 million for the same period in 2022.

Full Year 2023 Financial Results

Cash, Cash Equivalents and Short-Term Investments: For the full year ended December 31, 2023, cash, cash equivalents and short-term investments were $94.8 million.

Research and Development (R&D) Expenses: R&D expenses for the full year ended December 31, 2023, were $60.5 million, compared to $86.7 million for the prior year period. The decrease was due primarily to decreases in pre-clinical and regulatory and manufacturing expenses due to the termination of the discovery, collaboration and license agreement entered into on November 7, 2019, with Takeda Oncology for certain viral immunotherapy candidates offset by an increase in personnel-related costs and costs due to ramp up of TIDAL-01 activities.

General and Administrative (G&A) Expenses: G&A expenses for the full year ended December 31, 2023, were $17.8 million, compared to $18.2 million for the prior year period. We anticipate that G&A expenses will remain stable as we support public company operations.

Net Loss: Net loss for the full year ended December 31, 2023, was $55.2 million, compared to net loss of $30.8 million for the prior year period.

On March 21, 2024 Theratechnologies Inc. ("Theratechnologies" or the "Company") (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, reported moving to the next dose level in Part 3 of its Phase 1 clinical trial of sudocetaxel zendusortide in patients with advanced ovarian cancer (Press release, Theratechnologies, MAR 21, 2024, View Source [SID1234641351]). The study’s Medical Review Committee (MRC) has deemed the dose level in the first cohort of patients safe and has approved initiation of the next cohort with an increased dose, in accordance with the updated dose optimization protocol. Study centers are now actively recruiting patients for the second cohort, with one patient already enrolled and treated with the higher dose.

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"We are encouraged by the safety and tolerability of the sudocetaxel zendusortide regimen in the first cohort of six patients in Part 3 of the Phase 1 trial," said trial investigator Ira Winer, M.D., Ph.D., FACOG, a member of the Gynecologic Oncology and Phase 1 Clinical Trials Multidisciplinary Teams at Karmanos Cancer Center and Associate Professor of Oncology at Wayne State University. "We will continue to enroll and monitor patients as we further investigate this novel peptide-drug conjugate in individuals with advanced, platinum-resistant ovarian cancer, a population with high unmet medical need."

Part 3 of the Phase 1 study is intended to assess the optimal dose and schedule of sudocetaxel zendusortide, which is being administered on three consecutive weeks followed by one week of rest on Days 1, 8, and 15 of each 28-day cycle. The dose for the initial six patients was 1.75 mg/kg/dose and the dose for the next cohort of patients is 2.50 mg/kg/dose. The MRC approved initiation of the second cohort following attainment of the threshold of one or less dose-limiting toxicities in the first cohort. The study’s updated protocol defines DLTs as any Grade 3 or greater toxicity, within the first cycle and any worsening of peripheral neuropathy to Grade 3 or 4 within a three-month period.

"Initiation of treatment at the next dose level is an important milestone for Part 3 of the Phase 1 study and will allow us to further characterize sudocetaxel zendusortide as a potentially viable therapy for individuals with advanced ovarian cancer," commented Christian Marsolais, Ph.D., Senior Vice President and Chief Medical Officer at Theratechnologies. "We welcome discussions with potential partners interested in helping to advance development of this novel peptide-drug conjugate."

Theratechnologies completed enrollment of the first cohort of six patients in Part 3 of the Phase 1 trial in February 2024, and dosed the first patient in October 2023. The U.S. Food and Drug Administration (FDA) approved the amended trial protocol in June 2023. Further details about the study design, participation criteria and contact information for the sites can be found at: View Source

About Sudocetaxel Zendusortide (TH1902) and SORT1+ Technology

Sudocetaxel zendusortide is a first-of-its-kind sortilin receptor (SORT1)-targeting peptide-drug conjugate, and the first compound to emerge from the Company’s broader licensed oncology platform. A new chemical entity, sudocetaxel zendusortide employs a cleavable linker to conjugate (attach) a proprietary peptide to docetaxel, a well-established cytotoxic chemotherapeutic agent used to treat many cancers. The FDA granted Fast Track designation to sudocetaxel zendusortide as a single agent for the treatment of all sortilin-positive recurrent advanced solid tumors that are refractory to standard therapy. Sudocetaxel zendusortide is currently being evaluated in a Phase 1 clinical trial.

Theratechnologies has established the SORT1+ Technology platform as an engine for the development of PDCs that target SORT1, which is expressed in multiple tumor types. SORT1 is a "scavenger" receptor that plays a significant role in protein internalization, sorting, and trafficking. Expression of SORT1 is associated with aggressive disease, poor prognosis, and decreased survival. It is estimated that SORT1 is expressed in 40% to 90% of endometrial, ovarian, colorectal, triple-negative breast (TNBC), and pancreatic cancers, making this receptor an attractive target for anticancer drug development.