On March 11, 2024 Autolus Therapeutics plc (Nasdaq: AUTL), a clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies, reported a publication in Blood Cancer Journal entitled ‘Dual T-cell constant β chain (TRBC)1 and TRBC2 staining for the identification of T-cell neoplasms by flow cytometry (Press release, Autolus, MAR 11, 2024, View Source [SID1234641026]).’

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Diagnosing leukemic T-cell malignancies poses challenges due to their resemblance to reactive T-cells. In the paper published by Pedro Horna of Mayo Clinic in collaboration with Autolus, the authors introduce a unique approach for identifying T-cell neoplasms by flow cytometry1. This method adopts the recently described monoclonal antibodies targeting TRBC1 and TRBC22, 3, to assess for TRBC-restriction as a surrogate of clonality. The strategy mirrors the routine and broadly adopted analysis of kappa and lambda immunoglobulin chain restriction for the identification of B-cell malignancies.

This innovative and simple strategy to detect clonal expansion of T-cells by flow cytometry has the potential to facilitate the development of more comprehensive diagnostic panels that can be seamlessly integrated into existing screening protocols, obviating the need for separate T-cell clonality assessments. Autolus is working with world leading flow cytometry companies, including Beckman Coulter Life Sciences, BD (Becton, Dickinson and Company) and Thermo Fisher Scientific, in order to enable the development and distribution of diagnostic panels based on these unique TRBC1 and TRBC2 antibodies.

Advancements in diagnostic approaches for T-cell malignancies, coupled with the development of TRBC1 and TRBC2-directed CAR T cell therapeutics4, may contribute to the improvement of therapeutic strategies in this area of unmet clinical need.

1. Horna et al, Dual T-cell constant β chain (TRBC)1 and TRBC2 staining for the identification of T-cell neoplasms by flow cytometry. Blood Cancer J. 14, 34 (2024). | doi: 10.1038/s41408-024-01002-0

2. Maciocia et al, Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies. Nat Med 23, 1416–1423 (2017) | doi: 10.1038/nm.4444

3. Ferrari et al, Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies. Nat Commun 15, 1583 (2024) | doi: 10.1038/s41467-024-45854-3

4. Cwynarski et al, First in human study of AUTO4, a TRBC1-Targeting CAR T cell therapy in refractory T cell lymphoma. Hematol Oncol 41, 80–81 (2023) | doi: 10.1002/hon.3163_44

On March 11, 2024 Theriva Biologics (NYSE American: TOVX), a diversified clinical-stage company developing therapeutics designed to treat cancer and related diseases in areas of high unmet need, reported that Company’s Management will provide a corporate update and participate in one-on-one meetings at the BIO-Europe Spring Conference, to be held in Barcelona, Spain from March 18-20, 2024 (Press release, Theriva Biologics, MAR 11, 2024, View Source [SID1234641024]).

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BIO-Europe Spring Conference
Format: Corporate presentation and one-on-one meetings
Presentation Date: Monday, March 18, 2024
Presentation Time: 3:00pm CET
Presentation Location: Room 133/134, Barcelona International Convention Centre (CCIB)

On March 11, 2024 Sonnet BioTherapeutics Holdings, Inc. ("Sonnet" or the "Company") (NASDAQ:SONN), a clinical-stage company developing targeted immunotherapeutic drugs, reported that the first Phase 1b/2a clinical trial of SON-080 was cleared to proceed to Phase 2 after review by the independent DSMB (Press release, Sonnet BioTherapeutics, MAR 11, 2024, View Source [SID1234641023]). This study (SB211, NCT05435742) is being conducted at two sites in Australia in patients with persistent CIPN using a new proprietary version of recombinant human Interleukin-6 (rhIL-6), which required confirmation of safety before continued development in Phase 2. Many drugs cause peripheral nerve damage; patients with CIPN experience discomfort that can result in persistent, unbearable pain that may limit chemotherapeutic treatment.

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SB211 is studying a low dose of rhIL-6 that has an amino acid sequence identical to the native molecule. The trial targets serum levels similar to those induced with moderate exercise, which triggers the natural healing of nerves, muscle, and bone. As a pleiotropic cytokine, native IL-6 participates in several physiological processes, including tissue repair, glucose homeostasis, and the innate immune response at lower levels, but it can result in acute pathological inflammation at higher serum levels. Preclinical models of CIPN and DPN show that low dose rhIL-6 has the potential to stimulate nerve regrowth to re-establish normal sensations, thereby reducing pain and normalizing some of the physiological conditions that had deteriorated due to nerve degeneration. Early versions of rhIL-6, including Serono’s atexakin alfa and others, have been tested in hundreds of patients with cancer, diabetes, idiopathic aplastic anemia, or in healthy controls, showing a maximum tolerated dose of 10 µg/kg three times a week (TIW). However, fever, nausea, and vomiting were prominent at doses over 2 µg/kg TIW. Study SB211 was designed in Phase 1b to show safety using lower doses in CIPN with up to about 1 µg/kg of Sonnet’s new version of IL-6 (SON-080) given subcutaneously TIW for twelve weeks.

The protocol required DSMB to review the unblinded safety and tolerability of SON-080 in the first nine patients in SB211. While the data is still blinded to the rest of the team and we do not have access to the responses by group, the initial safety profile mimics that seen in prior studies with lower doses of exogenous rhIL-6. The most prominent symptoms in SB211 included injection site reactions (redness, bruising, pain, or itching) that resolved within a few days, as well as fatigue, body aches, or nausea that were mostly mild with some symptoms that were moderate. One patient developed severe fatigue and withdrew from the study after one month. All adverse events were transient and reversible. The DSMB concluded that the symptoms were tolerable in the initial patients and the study could proceed to Phase 2. The unblinded safety data from two dose levels of SON-080 compared to placebo are expected during the second half of 2024.

"Completion of the Phase 1b portion of SB211 is an important milestone for Sonnet in the Company’s quest to bring a potentially groundbreaking treatment forward for peripheral neuropathies, where there’s a large unmet need," said Pankaj Mohan, Ph.D., Sonnet Founder and Chief Executive Officer. "This trial was designed to initially bridge the large atexakin alfa historical safety database in cancer patients and then to study the neuroprotective and neuro-regenerative effects of SON-080 in Phase 2 in a neurotherapy indication. Owing to the larger market opportunity of the DPN indication, we have received greater potential partnering interest in this indication." Dr. Mohan further added, "The inhibition of IL-6 release in diabetic patients, even after moderate exercise, suggests there is tremendous disease modifying potential for the application of rhIL-6 in DPN. Given the high prevalence of neuropathy in diabetes and the commensurate industry interest in this market, we have prioritized DPN as the best potential indication for Phase 2 development. We have initiated a partnering process to move the asset forward towards commercialization."

"Interleukin-6 has been extensively studied in cancer patients in the past, so the use of SON-080 in CIPN was expected to provide a similar adverse event profile at low doses," said Richard Kenney, M.D., Sonnet’s Chief Medical Officer. "The preclinical models showing improvements in nerve function and histology suggest possible benefits in humans with various types of peripheral neuropathy due to cancer and diabetes. This approach is a unique way to actually treat the underlying causes of peripheral neuropathy with rhIL-6, rather than trying to mask the symptoms. Further, given the business priorities, SB211 CIPN development will be placed on hold and the data will be leveraged to initiate a Phase 2 study in the much larger DPN indication."

About the SB211 Phase 1b/2a Trial

The SB211 study is primarily designed to evaluate the safety, PK, PD, and initial efficacy of two dose levels of SON-080 compared to placebo. The drug is self-administered three times a week, subcutaneously, in patients with CIPN lasting at least 3 months after chemotherapy. The study is being conducted at multiple sites in Australia, in a blinded fashion, comparing SON-080 to placebo. The primary endpoint explores the safety and tolerability of SON-080, with key secondary endpoints intended to measure PK, PD, and immunogenicity. Preliminary efficacy is being explored using standardized pain questionnaires over the course of the trial.

On March 11, 2024 Ribometrix, a biotechnology company developing small molecule therapeutics that modulate RNA biology, reported that it will present two posters with preclinical data highlighting advancements across two distinct modalities at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Ribometrix, MAR 11, 2024, View Source [SID1234641022]).

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The posters will show in vivo anti-tumor efficacy of Ribometrix’s lead candidate targeting the RNA-binding protein eIF4E in combination with standard-of-care across multiple indications, and the Company’s discovery of small molecules that directly bind a complex RNA structure within the c-MYC mRNA in cells, and demonstrate a reduction in c-MYC protein levels.

These new data support the potential for Ribometrix’s RNA-modulating approach to enable drugging well-validated therapeutic targets, including eIF4E and c-MYC, that are currently intractable to traditional small molecule approaches.

Presentation Details:

Abstract Title: Development of novel eIF4E inhibitors to potently and selectively suppress tumor growth across multiple indications

Abstract: 682 / 28
Presenter: Matthew Friedersdorf, Ph.D., Associate Director, Translational Medicine at Ribometrix

Session: PO.ET09.05 – Novel Antitumor Agents 2
Date: Saturday, April 7, 2024

Time: 1:30pm – 5:00pm CT

Abstract Title: Leveraging an RNA-targeting platform for the discovery of cell-active c-MYC mRNA-binding small molecules

Abstract: 680 / 26
Presenter: Katie Warner, SVP of RNA Biology at Ribometrix
Session: PO.ET09.05 – Novel Antitumor Agents 2
Date: Saturday, April 7, 2024

Time: 1:30pm – 5:00pm CT

At the time of presentation, Ribometrix’s posters will be made available on the "Publications" page of the "News" section of its website.

About eIF4E

Eukaryotic translation initiation factor 4E (eIF4E) is a crucial regulatory component of mRNA translation. It selectively promotes pro-oncogenic protein synthesis in response to activation of multiple tumor signaling pathways. Many pro-oncogenic signaling pathways require eIF4E activity to promote tumor growth. Clinically, eIF4E activity is elevated in many kinds of tumor and it is typically associated with poor prognosis. Thus, targeting eIF4E has the potential to enhance anti-cancer activity when given in combination with standard-of-care. Additionally, eIF4E is also central to many resistance mechanisms, therefore eIF4E inhibition has the potential to overcome drug resistance and re-sensitize tumors to anti-cancer therapies. Ribometrix is developing eIF4E inhibitors as a promising therapeutic strategy to inhibit oncogene expression to enhance efficacy in combination with other therapies and overcome resistance to targeted anti-cancer therapies.

About c-MYC

c-MYC is a well-validated oncogene with broad anti-cancer potential, as c-MYC expression is dysregulated in more than 50% of cancers and a key regulator in nearly every aspect of the oncogenic process. c-MYC has remained intractable to traditional small molecule drug discovery, primarily due to its lack of a defined small molecule binding pocket. By targeting the c-MYC mRNA with small molecules, Ribometrix is bypassing the "undruggable" challenges to successfully reduce c-MYC protein levels and develop a novel anti-cancer therapeutic for c-MYC-driven cancers.

On March 11, 2024 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported financial results and operational updates for the quarter and year ended December 31, 2023 (Press release, ORIC Pharmaceuticals, MAR 11, 2024, View Source [SID1234641021]).

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"We’ve made significant progress over the past year as we presented initial positive data readouts across our three clinical programs, ORIC-114, ORIC-944 and ORIC-533, demonstrating their potential as best-in-class cancer therapeutics," said Jacob M. Chacko, M.D., president and chief executive officer. "We strengthened our balance sheet with the completion of two PIPE financings totaling $210 million from top-tier healthcare specialist funds and prioritized our clinical pipeline around ORIC-114 and ORIC-944. We are building on the momentum generated in 2023 with multiple clinical milestones planned through the first half of 2025 as we advance two programs towards the initiation of registrational studies in the second half of 2025."

Fourth Quarter 2023 and Other Recent Highlights

ORIC-114: a brain penetrant, orally bioavailable, irreversible EGFR/HER2 inhibitor

Presented initial data from the Phase 1b dose escalation trial for patients with EGFR or HER2 exon 20 mutated non-small cell lung cancer (NSCLC) at the ESMO (Free ESMO Whitepaper) Congress 2023. Initial data demonstrated potential best-in-class profile in heavily pretreated patients, with 81% of patients having received prior EGFR exon 20 targeted agents and 86% having CNS metastases at baseline. Data from 50 patients showed favorable safety and both systemic and CNS responses, including the first reported systemic and CNS confirmed complete response in a patient with active brain metastases.
Presented preclinical data for ORIC-114 at ESMO (Free ESMO Whitepaper) Congress 2023, demonstrating potent activity across atypical mutations in EGFR, thus expanding the potential eligible patient population.
Expect to initiate dose expansion of Phase 1b trial in multiple cohorts in the first half of 2024 and expect to report updated Phase 1b data in the first half of 2025.
ORIC-944: a potent and selective allosteric inhibitor of PRC2

In January 2024, reported initial Phase 1b monotherapy data in metastatic prostate cancer demonstrating the potential of ORIC-944 as a best-in-class therapeutic, including half-life greater than 10 hours, robust target engagement and well tolerated safety profile, supporting advancement for combination development.
Expect to initiate combination study with AR inhibitor(s) in the first half of 2024 and provide a program update in mid-2024.
ORIC-533: a highly potent, orally bioavailable small molecule inhibitor of CD73

Presented initial data from the Phase 1b trial of ORIC-533 in patients with relapsed/refractory multiple myeloma at the 2023 ASH (Free ASH Whitepaper) Annual Meeting. Initial data demonstrated preliminary evidence of clinical antimyeloma activity and predicted immune effects from preclinical models, as well as a clean safety profile, with only grade 1 and 2 treatment-related events in heavily pre-treated patients.
Expect to complete dose escalation for the Phase 1b trial of ORIC-533 in the first quarter of 2024, and the company plans to pursue strategic partnership for combination studies.
Discovery Pipeline:

Presented preclinical data confirming the therapeutic potential of highly selective PLK4 inhibitors as a synthetic lethal therapy for TRIM37 amplified breast cancers at the 2023 AACR (Free AACR Whitepaper) Annual Meeting.
Advanced ORIC-613, a novel, highly selective PLK4 inhibitor, through IND enabling studies.
Corporate Highlights:

Strengthened cash position with $85 million and $125 million private placement financings from new and existing healthcare specialist funds in June 2023 and January 2024, respectively.
Fourth Quarter and Full Year 2023 Financial Results

Cash, Cash Equivalents and Investments: Cash, cash equivalents and investments totaled $235.0 million as of December 31, 2023. Including the $125.0 million private placement in January 2024, as of January 31, 2024 the Company had $351.8 million (unaudited) in cash, cash equivalents and investments, which is expected to fund the current operating plan into late 2026.

R&D Expenses: Research and development (R&D) expenses were $24.5 million for the three months ended December 31, 2023, compared to $16.3 million for the three months ended December 31, 2022, an increase of $8.2 million. For the year ended December 31, 2023, R&D expenses were $85.2 million compared to $61.7 million for the same period of 2022, an increase of $23.5 million. The increases were due to a net increase in external expenses related to the advancement of product candidates and discovery programs, as well as higher personnel costs.

G&A Expenses: General and administrative (G&A) expenses were $6.9 million for the three months ended December 31, 2023, compared to $5.8 million for the three months ended December 31, 2022, an increase of $1.1 million. The increase was primarily due to higher professional fees and personnel costs. For the year ended December 31, 2023, G&A expenses were $25.6 million compared to $25.1 million for the same period of 2022, an increase of $0.5 million. The increase was primarily due to higher personnel costs.

IPR&D Expenses: Acquired in-process research and development (IPR&D) expenses of $5.0 million for the year ended December 31, 2022, were due to a development milestone payment related to ORIC-114. There were no such expenses for the year ended December 31, 2023.