On April 3, 2024 TransCode Therapeutics, Inc. (NASDAQ: RNAZ), the RNA oncology company committed to more effectively treating cancer using RNA therapeutics, reported financial results for 2023 and recent business progress (Press release, TransCode Therapeutics, APR 3, 2024, View Source [SID1234641817]).

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"We believe 2023 was extremely productive and pivotal for TransCode. We are proud to have advanced our lead therapeutic candidate, TTX-MC138, into the clinic as a first-in-class drug candidate against metastatic cancer. The year was highlighted by preliminary clinical results from our Phase 0 clinical trial with radiolabeled TTX-MC138," said Tom Fitzgerald, interim CEO and CFO of TransCode. "Further, despite very challenging financial markets, we raised over $25 million in equity financings, streamlined our operations for higher efficiency, and signed two strategic collaborations aimed at demonstrating the value of our TTX platform in additional applications. We also continued to achieve other important milestones, with the ultimate objective of fulfilling the promise of RNA therapeutics for oncology applications. We now look forward to our Phase 1 clinical trial of TTX-MC138 which, subject to FDA authorization, is planned to begin in mid-2024."

Key Highlights (2023 and Q1 2024)

· IRB approval for FDA-cleared first-in-human Phase 0 clinical trial with TTX-MC138.
· First patient dosed and preliminary clinical results with radiolabeled TTX-MC138 in the Phase 0 clinical trial.
· Signed a co-research agreement with Debiopharm to develop nucleic acid therapeutics for cancer treatment.
· Signed a joint research and development agreement with Akribion Genomics to develop a CRISPR-derived technology platform for cancer treatment.
· Raised over $25 million in equity financings in an extremely challenging financial environment.
· Refocused our development strategy, prioritizing advancing TTX-MC138 into a Phase 1 clinical trial and reducing cash burn.
· Appointed CFO Tom Fitzgerald as interim CEO and director Philippe Calais as Executive Chairman following the resignation of Michael Dudley as CEO.
· Appointed Daniel Vlock, M.D., as Chief Medical Officer (part-time).
· Regained compliance with Nasdaq’s stockholders’ equity requirement.
· Presented TransCode technology at leading cancer conferences including San Antonio Breast Cancer Symposium, AACR (Free AACR Whitepaper), OTS, and TIDES Europe.

TTX-MC138

· Reported preliminary clinical results suggesting delivery of TTX-MC138 to metastatic lesions in a patient with breast cancer metastatic to lungs, bone, and liver.
· Reported positive preclinical results in a model of glioblastoma showing successful delivery and pharmacodynamic activity in brain tumors.
· Reported positive preclinical results in a model of metastatic pancreatic adenocarcinoma showing 50% inhibition of metastatic progression compared to standard-of-care chemotherapy.
· Received second Orphan Drug Designation from FDA, for TTX-MC138 in pancreatic cancer.

TTX-siPDL1

· Reported positive preclinical results in pancreatic cancer, showing extended survival relative to standard-of-care chemotherapy.

TTX-RIGA

· Reported successful completion of animal studies in a model of melanoma showing arrest of secondary tumor progression.

2024 Corporate and R&D Objectives

With what we expect will be a very exciting year ahead, our 2024 corporate goals, none of which are assured, are to strengthen our organization while raising sufficient capital to continue to advance our research. We will also seek to expand collaborations with strategic partners to further enhance the value of our pipeline.

2024 will also be a critical year for the clinical development of TTX-MC138 and our preclinical portfolio, as we seek to:

· Initiate a Phase 1 clinical trial with TTX-MC138 in patients with advanced solid tumors as soon as we obtain FDA authorization and relevant institutional review board approvals from investigational sites.
· Report preliminary results from the planned Phase 1 trial later this year.
· Publish preclinical results in the second half of the year supporting TTX-MC138 in glioblastoma and pancreatic cancer, TTX-siPDL1 in pancreatic cancer, and TTX-RIGA in melanoma.
· Continue preclinical studies for therapeutic candidates TTX-mRNA and TTX-CRISPR.
· Advance existing strategic partnerships and sign others around TransCode’s TTX delivery platform, TTX-CRISPR, TTX-siRNA, TTX-MC138, and TTX-mRNA candidates.
· Further develop an exploratory test for miRNA-10b.
· If capital resources permit, initiate CMC development to support future IND-enabling studies with TTX-siPDL1 or TTX-RIGA candidates.

2023 Financial Highlights (amounts are approximate)

· Cash was $2.8 million on December 31, 2023, compared to $4.97 million on December 31, 2022.
· Research and development expenses were $12.3 million in 2023 compared to $10.2 million in 2022.
· General and administrative expenses were $7.2 million in 2023 compared to $8.4 million in 2022.
· Operating loss was $19.4 million in 2023 compared to $18.6 million in 2022.

Financial Guidance

TransCode expects that its cash of approximately $2.8 million as of December 31, 2023, together with approximately $6.2 million in net proceeds received from the sale of common stock and warrants in a January 2024 registered direct offering, will be sufficient to fund planned operations into late third quarter or early fourth quarter of 2024.

On April 4, 2024 Novartis reported updated overall survival (OS) results from a pre-planned analysis at approximately 75% information fraction demonstrates an OS hazard ratio less than 1.0 (HR<1.0) in the intent-to-treat (ITT) population unadjusted for cross-over (Press release, Novartis, APR 3, 2024, View Source [SID1234641784]).

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Radiographic progression free survival (rPFS) and other secondary efficacy endpoints are consistent with previous interim analysis results presented in 2023.

With an additional 8 months of follow-up, Pluvicto safety profile remains consistent with previous interim analyses presented in 2023.

Full results will be presented at an upcoming medical congress.

Novartis confirms plans to file in H2 2024.

On April 3, 2024 Conformation-X Therapeutics, LLC, an immune-oncology focused drug development company, reported that it has closed an oversubscribed funding tranche of $3.65M, bringing the total raised since inception to over $13.5M (Press release, Conformation-X Therapeutics, APR 3, 2024, View Source [SID1234641761]). The company unveiled its lead assets by disclosing successful ex vivo and in vivo proof-of-concept studies for its HHLA2 and IL18BP programs, marking critical milestones in the cancer drug development process.

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Drawing inspiration from the fundamental role of protein conformations in disease biology and drug efficacy, Conformation-X applies unparalleled precision to developing novel immune checkpoint inhibitors. The company is creating a comprehensive portfolio of differentiated therapeutics addressing cancer mechanisms that have eluded existing treatments.

"The limitations of current checkpoint therapies are evident, as they don’t fully target the diverse spectrum of mechanisms associated with non-responsiveness and treatment resistance," said Dr. Ali H. Munawar, CEO of Conformation-X Therapeutics.

Despite the pivotal role of PD-1/PD-L1 inhibitors in cancer immunotherapy, several peer-reviewed clinical studies have shown that the overall response rate across various cancers remains at or below 20%. Patients facing resistance to conventional checkpoint therapies encounter a range of challenges. This includes tumors that inherently possess low immunogenicity, are less likely to trigger an immune response, and immune exclusion, which restricts immune cells from the tumor microenvironment (TME). Moreover, complex genetic landscapes featuring oncogenic drivers and epigenetic modifications further contribute to immune evasion and influence treatment outcomes.

Dr. Munawar added, "We are committed to pioneering alternative therapeutic options for these patients by targeting novel biology and molecular pathways. The successive rounds of funding are a testament to our investors’ confidence in the innovation and rigor behind our efforts."

The recent capital infusion accelerates the company towards translational studies of its lead asset and facilitates the expansion of its pipeline. The company’s pipeline encompasses diverse drug target classes, extending beyond the current landscape of immune checkpoints to include novel soluble and epigenetic checkpoints while continuing to innovate within the B7-family of receptors.

"Achieving selective therapeutic targeting of HHLA2 demonstrates our team’s profound understanding of its intricate structure-function relationship and the critical role that HHLA2 plays in tumor immune evasion. Our work highlights the strength of Conformation-X’s drug discovery platform," said Dr. Stephen Weeks, Sr. Director of Structural Biology and Biophysics.

On April 3, 2024 Agilent Technologies Inc. (NYSE: A), a global leader in life sciences and diagnostics, reported its participation in the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (AACR) (Free AACR Whitepaper). At the meeting, which will take place from April 5 to 10, 2024, in San Diego, CA, Agilent will highlight new cell analysis, genomics, digital pathology, and companion diagnostics solutions (Press release, Agilent, APR 3, 2024, View Source [SID1234641760]).

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Featured products and solutions that play a crucial role in advancing cancer research and diagnostics, will include:

Agilent NovoCyte Opteon Spectral Flow Cytometer – The Agilent NovoCyte Opteon Spectral Flow Cytometer, is an advanced solution in spectral flow cytometry. This user-friendly system allows simultaneous analysis of multiple markers and offers flexibility in designing multiple marker panels. With configurations ranging from 3 to 5 lasers and support for up to 70 high-quality detectors, the NovoCyte Opteon promises enhanced research capabilities for scientists and researchers.
Agilent Avida – Agilent Avida’s new cutting-edge target enrichment solutions enable simultaneous DNA and methylation profiling from a single sample. The proprietary Avida technology maintains original sample quality and quantity, supporting advanced applications such as liquid biopsy and multiomics capabilities for targeted next-generation sequencing (NGS). Researchers gain accelerated access to genetic and epigenetic data from limited samples, propelling cancer biology and clinical insights. The high-performance and streamlined workflows offer outstanding fidelity, turnaround time, and ease of use.
Agilent SureSelect Cancer Custom panels – Agilent SureSelect Cancer Custom panels offer the ability to add new and emerging biomarkers, including tumor mutational burden (TMB) and microsatellite instability (MSI), to custom tumor genomic profiling assays. These custom NGS cancer panels are designed quickly and easily using Agilent SureDesign 8.0, an intuitive probe design software powered by machine learning. These custom cancer panels extend the SureSelect Cancer product portfolio and underscore Agilent’s commitment to advancing precision oncology.
Agilent SureSelect CD CiberMed Tissue and SureSelect CD CiberMed Heme panels – Agilent announces a new partnership with CiberMed. This company aims to simplify cellular profiling and biomarker discovery with its digital cytometry software, iSort. The new Agilent SureSelect CD CiberMed Tissue and SureSelect CD CiberMed Heme panels enable a combined SureSelect and iSort workflow to offer a cellular profiling solution from bulk RNA-Seq data with enhanced sensitivity, accuracy, and robustness.
"Agilent continues to direct strategic focus toward the battle against cancer. Our comprehensive portfolio encompasses groundbreaking technologies, from cell analysis to genomics, digital pathology, and companion diagnostics," stated Bob McMahon, interim president of Agilent’s Diagnostics and Genomics Group. "These innovations empower scientists, clinicians, and researchers worldwide to ignite discoveries and enhance patient outcomes."

Agilent will also host two joint events with key collaborators. The first with SomaLogic, now part of StandardBioTools on Sunday, April 7 at 1:30 pm. The focus of this symposium is cancer understanding and care. Presenters Marc Gunter from Imperial College London and Karl Smith-Byrne from Oxford University will discuss their utilization of SomaLogic’s SomaScan Platform. They will delve into discovering novel causes and biomarkers of cancer within a large-scale prospective cohort.

The second symposium on Sunday, April 7 at 3:30 pm will focus on novel technologies for precision medicine. Caroline Germa, CMO from Transcenta Therapeutics will present on how the use of Claudin 18.2 IHC assay informed Transcenta Therapeutics’ Osemitamab program, and Bellal Moghis from Agilent will discuss Agilent’s new Avida targeted sequencing.

In addition, Agilent will feature partnerships with BostonGene and CiberMed at the Agilent booth (#1531). AACR (Free AACR Whitepaper) attendees can also explore multiple Agilent research posters and over 50 additional customer posters highlighting Agilent instruments and solutions. For more details about these events, visit the Agilent booth.

On April 3, 2024 Asher Biotherapeutics, a biotechnology company developing precisely-targeted immunotherapies for cancer, autoimmune, and infectious diseases, reported the publication of two manuscripts in Cancer Discovery, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), detailing the design of AB248 and reviewing preclinical data supporting its development as a potentially best-in-class interleukin-2 (IL-2) therapy (Press release, Asher Biotherapeutics, APR 3, 2024, View Source [SID1234641759]). The papers were authored by Asher Bio scientists and collaborators at The Netherlands Cancer Institute (NKI), respectively, and published online in Cancer Discovery on April 2, 2024.

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"We are delighted to announce the publication of preclinical data on AB248, our lead product candidate for the treatment of solid tumors, in a prestigious cancer research and medicine journal", said Andy Yeung, Chief Technology Officer of Asher Bio. "These co-published manuscripts are the culmination of several years of great collaboration between Asher Bio scientists and our academic co-founders, Dr. Ton Schumacher, of NKI, and Dr. Robert Schreiber, of Washington University School of Medicine, alongside our collaborator, Dr. Daniela Thommen, of NKI."

"With AB248, we set out to solve a major limitation of existing immune-based medicines – namely, the significant off-target effects that come from acting on multiple cell types simultaneously", commented Ivana Djuretic, Chief Scientific Officer of Asher Bio. "AB248 was designed to potently and selectively activate CD8+ T cells, which are responsible for driving anti-tumor activity, while avoiding NK cells and Tregs, which can act as a pharmacological sink, contribute to toxicities, and suppress the immune system more broadly. Preclinical data from the Asher Bio, Schreiber and Thommen labs together reinforce the power of AB248’s highly differentiated profile, showing an unprecedented level of selectivity for CD8+ T cells, as well as enhanced anti-tumor activity and improved tolerability, and further support the evaluation of AB248 in our ongoing Phase 1a/1b trial."

Preclinical Data Suggest AB248 Offers Improved Therapeutic Index and CD8+ T Cell Selectivity

In the first publication entitled, "CD8+ T cell-targeted IL-2 promotes robust effector T cell responses to mediate potent anti-tumor immunity," lead author Dr. Kelly Moynihan, Ph.D., Senior Director and Project Team Leader at Asher Bio, described the rationale for, and the design of, AB248, and reviewed nonclinical data suggesting AB248 offers an improved therapeutic index compared to broadly acting IL-2-based therapies.

While high dose IL-2 therapy is approved for the treatment of certain cancers, its clinical use is limited due to life-threatening toxicities. A next generation of IL-2 therapies, "not-α" IL-2s, were subsequently introduced to mitigate some of the liabilities associated with high dose IL-2 through binding the IL-2 α receptor, such as potent regulatory T cell (Treg) stimulation and vascular leak syndrome (VLS). To-date, however, these "not-α" IL-2 have not demonstrated a meaningful improvement in clinical efficacy and, while VLS appears mitigated, significant toxicities still occur. In preclinical studies, natural killer (NK) cells were responsible for toxicities following treatment with a not-α IL-2 therapy but did not contribute to anti-tumor activity. Asher Bio hypothesized that the therapeutic index of an IL-2 therapy could be improved by selectively targeting CD8+ T cells – which are critical effectors of antitumor immunity – while avoiding other cell types, such as non-specific, innate NK cells and immunosuppressive Treg cells.

Asher Bio systematically evaluated the properties needed for effective cis-targeting to CD8+ T cells and generated AB248, a CD8+ T cell selective IL-2. AB248 recapitulates key features of IL-2 biology, including induction of proliferation and enhancement of effector function, but does so selectively in CD8+ T cells across a wide range of concentrations in vitro and in vivo, with over 500-fold preference for CD8+ T cells compared to other cell types. Preclinical data demonstrate the potential of a CD8+ T cell selective IL-2 to improve the therapeutic index of IL-2 and support the advancement of AB248 into the clinic:

– In preclinical mouse models, a single dose of AB248’s murine surrogate (CD8-mIL2) demonstrated strongly improved anti-tumor activity and reduced toxicity compared to untargeted not-α IL-2 variants.

– Further, CD8-mIL2 drastically increased the number and function of tumor antigen specific T cells and induced a "better effector" population, with a signature consistent with high polyfunctionality and low exhaustion.

– Activity depended both on tumor-resident as well as newly infiltrating T cells on therapy.

– In non-human primates, treatment with AB248 induced potent and selective CD8+ T cell expansion. Treatment was generally well tolerated despite expansion of CD8+ T cells by 20-fold or more.

In summary, AB248 achieved substantial improvements in IL-2’s therapeutic index by selectively targeting all CD8+ T cells without the need to restrict signaling to the tumor site or a single CD8+ T cell subset.

Preclinical Data Support Evaluation of AB248 in Combination with Anti-PD-1 Therapy

In a paper entitled, "CD8-targeted IL-2 unleashes tumor-specific immunity in human cancer tissue by reviving the dysfunctional T cell pool," lead author Paulien Kaptein, Division of Molecular Oncology and Immunology at the NKI, reported new preclinical data supporting the evaluation of AB248 in combination with an immune checkpoint inhibitor in models utilizing ex vivo human tumor tissues from patients.

T cell-based immunotherapies are a groundbreaking approach to treating some cancers. However, a considerable portion of tumors characterized by T cell infiltration remain unresponsive to immune checkpoint blockade (ICB), suggesting a need for novel strategies to restore effector activity in tumor specific T cells. IL-2-based therapies have been identified as a promising strategy for enhancing T cell responses in ICB-resistant tumors. To evaluate this hypothesis, Asher Bio’s collaborators at the NKI performed a comprehensive analysis of T cell reinvigoration following treatment with AB248. Data show:

– Treatment with AB248 broadly armed human intratumoral CD8+ T cells with enhanced effector capacity, specifically enabling reinvigoration of the dysfunctional T cell pool to elicit potent immune activity.

– Tumor-specific T cells underwent broader and qualitatively superior activation with AB248 treatment compared to programmed death-1 (PD-1) blockade.

– AB248 generated an immunological response in tumors that did not show an immunological response to anti-PD-1, suggesting the presence of a tumor-reactive T cell pool targetable by AB248 that is not responsive to PD-1 blockade alone.

– Treatment with AB248 in combination with anti-PD-1 resulted in greater ex vivo responses, supporting the combination of AB248 and anti-PD-1 clinically.

"While immune checkpoint inhibitors are an incredibly powerful tool for treating certain cancers, many tumors don’t respond, underscoring the need for new agents that can reinvigorate exhausted T cells and make them susceptible to PD-1 blockade," said Daniela Thommen, M.D., Ph.D., Group Leader, Department of Molecular Oncology and Immunology at the Netherlands Cancer Institute and senior author on the NKI publication. "New preclinical data published today suggest that treatment with AB248 may stimulate T cells within tumors otherwise resistant to PD-1 therapy, offering a combination strategy that may extend the reach of immuno-oncology regimens across a range of solid tumors. I look forward to initial clinical data from Asher Bio’s ongoing Phase 1a/1b clinical trial, which includes a cohort evaluating AB248 in combination with an anti-PD-1 therapy."

Both publications are now available online through Cancer Discovery: View Source

About AB248

AB248 is a novel CD8+ T cell selective IL-2, generated by fusing a reduced potency IL-2 mutein to an anti-CD8β antibody. It was specifically engineered to selectively and potently activate CD8+ T-cells, while avoiding natural killer (NK) cells, which can act as a pharmacological sink and contribute to toxicity, and regulatory T (Treg) cells, which are immunosuppressive. In preclinical studies, AB248 exhibited an approximately 1,000-fold preference for the activation of CD8+ T cells over NK cells and Tregs. In preclinical murine tumor studies, AB248 demonstrated potent anti-tumor activity both alone and in combination with PD-1 checkpoint blockade in a wide variety of murine tumor models.

Asher Bio is currently evaluating AB248 in a Phase 1a/1b clinical trial, AB248-101. The trial consists of a dose escalation and expansion phase to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of AB248 alone and in combination with pembrolizumab in subjects with locally advanced/metastatic solid tumors who failed prior therapies. Please refer to www.clinicaltrials.gov (NCT05653882) for additional details related to this Phase 1a/1b clinical trial.