On October 23, 2024 Circle Pharma, a clinical-stage biopharmaceutical company dedicated to discovering and developing a new generation of macrocycle therapies, reported that preclinical data from its lead candidate, CID-078, a first-in-class oral macrocycle cyclin A/B RxL inhibitor, has been selected for a late-breaking poster presentation at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics, also known as the Triple Meeting (Press release, Circle Pharma, OCT 23, 2024, View Source;utm_medium=rss&utm_campaign=circle-pharmas-first-in-class-oral-macrocycle-cyclin-a-b-rxl-inhibitor-cid-078-preclinical-data-highlighted-at-the-36th-eortc-nci-aacr-symposium [SID1234647334]). The symposium is taking place from October 23-25, 2024, in Barcelona, Spain.

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Poster presentation details are below:

Author: Wang et al.
Title: CID-078, a First-in-Class Oral Macrocycle Cyclin A/B RxL Inhibitor, Demonstrates Anti-Tumor Activity in ESF-driven Cancers
Abstract Number: PB-515
Session Title: Late breaking posters
Date and Time: October 23, 2024 (6 a.m. EST/12 p.m. CEST) to October 25, 2024 (11 a.m. EST/5 p.m. CEST)

The digital poster can be viewed here.

The pre-clinical data shows CID-078 demonstrated single-agent tumor activity across tumor cell line and in vivo models with dysregulated cell cycle (CDK-RB-E2F) function. Notably, tumor regressions were observed in small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), and triple-negative breast cancer (TNBC) preclinical models. Within specific indications, CID-078 single agent activity was correlated with RB1 mutation, high E2F target, or G2M checkpoint hallmark pathway scores. The cumulative pre-clinical data suggests that CID-078 holds promise as a monotherapy for patients with these cancers. A multi-center phase 1 clinical trial (NCT06577987) is currently enrolling patients..

About CID-078, Circle Pharma’s Cyclin A/B RxL Inhibitor Program

CID-078 is an orally bioavailable macrocycle with dual cyclin A and B RxL inhibitory activity that selectively targets tumor cells with oncogenic alterations that cause cell cycle dysregulation. In biochemical and cellular studies, Circle Pharma’s cyclin A/B RxL inhibitors have been shown to potently and selectively disrupt the protein-to-protein interaction between cyclins A and B and their key substrates and modulators, including E2F (a substrate of cyclin A) and Myt1 (a modulator of cyclin B). Preclinical studies have demonstrated the ability of these cyclin A/B RxL inhibitors to cause single-agent tumor regressions in multiple in vivo models. A multi-center phase 1 clinical trial (NCT06577987) is currently enrolling patients.

On October 23, 2024 Circio Holding ASA’s (the "Company") reported outstanding convertible bonds as issued to Atlas Special Opportunities, LLC ("Atlas") under the Investment Agreement entered into between Atlas and the Company in March 2023 (Press release, Circio, OCT 23, 2024, View Source [SID1234647333]).

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Atlas has, by a notice of conversion, requested conversion of convertible bonds with a nominal value of NOK 500,000 which, pursuant to the bond terms, are convertible into 833,333 new shares in the Company at a conversion price of NOK 0.6.

The Company’s share capital will accordingly be increased by NOK 499,999.80 by the issuance of 833,333 new shares upon completion of the conversion by registration of the share capital increase in the Norwegian Register of Business Enterprises (Nw.: Foretaksregisteret). Following the conversion, the Company’s total share capital will be NOK 15,211,804.20 divided into 25,353,007 shares, each with a nominal value of NOK 0.60.

On October 23, 2024 Bicycle Therapeutics plc (NASDAQ: BCYC), a pharmaceutical company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle) technology, reported the presentation of the first human imaging data validating the potential of MT1-MMP as a novel target in the treatment of cancer and demonstrating the positive properties of Bicycle Radionuclide Conjugates (BRC) for radiopharmaceutical use, as well as preclinical data demonstrating optimized BRC radioisotope delivery at the European Association of Nuclear Medicine (EANM) 2024 Congress in Hamburg, Germany (Press release, Bicycle Therapeutics, OCT 23, 2024, View Source [SID1234647331]).

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"Since our founding, our goal at Bicycle Therapeutics has been to leverage the power of our platform in areas where we can have the most impact for patients. Over the years, we have built a robust pipeline of oncology therapies that includes targeted drug conjugates, immuno-oncology agents and now, radiopharmaceuticals," said CEO Kevin Lee, Ph.D. "The exciting data presented at EANM underscore the potential of our Bicycle Radionuclide Conjugates to deliver a range of isotopes to novel cancer targets. Through our strategy of pursuing novel targets with first-in-class potential and selecting the isotope that best aligns with the target biology and indication, we have an opportunity to potentially broaden the use of radiopharmaceuticals to diagnose and treat cancer."

In line with Bicycle Therapeutics’ radiopharmaceuticals strategy, the company selected tumor antigen EphA2 as its second BRC target and signed a letter of intent with leading isotope technology company Eckert & Ziegler to put in place an agreement to supply a range of radioisotopes and develop and manufacture BRC molecules. Bicycle Therapeutics, through its internal pipeline of wholly owned molecules and strategic collaborations with industry and academic leaders in the field, aims to be at the forefront of the development of next-generation radiopharmaceutical therapies. Bicycle molecules have ideal properties for radioisotope delivery due to their low molecular weight, high selectivity and affinity for their intended target and rapid systemic clearance.

"The data presented at EANM demonstrate how our Bicycle platform is a powerful tool for de novo identification of high-quality binders to important cancer targets. We believe the ability to optimize the biodistribution properties of our molecules, significantly reducing kidney retention while retaining rapid, selective uptake in tumors, position Bicycle Radionuclide Conjugates as a potentially best-in-class approach for targeted radionuclide therapy," said Michael Skynner, Ph.D., chief technology officer of Bicycle Therapeutics. "MT1-MMP is the first target for radiopharmaceutical development that we are pursuing given its expression in many solid tumors such as non-small cell lung cancer, esophageal and triple negative breast cancer."

EANM 2024 Congress Data Highlights

During an oral presentation, the German Cancer Consortium (DKTK) presented first human imaging data for a BRC targeting MT1-MMP. They focused on a case study in a 65-year-old male diagnosed with advanced pulmonary adenocarcinoma, the most common type of non-small cell lung cancer, in the lung and lymph nodes confirmed by endobronchial ultrasound (EBUS) biopsy. The patient received fluorine-18-labelled FDG-PET/CT imaging, and two weeks later received MT1-MMP PET/CT imaging up to one hour post injection of the gallium-68-labelled BRC tracer.

Both scans revealed multiple lymph node metastases and bone metastases in the sternum. MT1-MMP imaging demonstrated tracer uptake in the primary tumor in the lung and lymph node and bone metastases, consistent with FDG imaging. Additionally, the MT1-MMP BRC tracer showed renal excretion, with all other organs showing only negligible tracer uptake. Clear imaging contrast was also observed at early time points.

In an e-poster, Bicycle Therapeutics presented preclinical data demonstrating the suitability of Bicycle molecules to deliver indium to tumors in vivo due to their favorable properties, including specific tumor uptake, rapid tumor penetration and rapid renal elimination. Additionally, imaging showed how the biodistribution profile of BRCs can be optimized to maintain high tumor uptake and retention while significantly reducing kidney uptake and retention. These data build on the body of preclinical data the company has published in this area demonstrating the use of Bicycle molecules to effectively deliver various radioisotopes, such as lutetium and lead, to tumors.

Altogether, the data presented at EANM validate the potential of MT1-MMP as a novel target in the treatment of cancer, demonstrate the translatability of BRC preclinical data and highlight the potential of Bicycle molecules for targeted radionuclide therapy.

The e-poster, "Bicycle Radionuclide Conjugates for radioisotope delivery to solid tumors," is available in the Publications section of the Bicycle Therapeutics website.

Conference Call Details

Bicycle Therapeutics will host a conference call and webcast today, Oct. 23, at 8 a.m. ET to review the first human imaging data and outline the company’s radiopharmaceuticals strategy. To access the call, please dial 833-816-1408 (U.S.) or +1-412-317-0501 (international) and ask to join the Bicycle Therapeutics call. A live webcast and replay of the conference call will be accessible in the Investor section of the Company’s website at www.bicycletherapeutics.com.

On October 23, 2024 Aulos Bioscience, an immuno-oncology company working to revolutionize cancer care through development of potentially best-in-class IL-2 therapeutics, reported data and analyses used to determine dose selection for Phase 2 expansion cohorts in a Phase 1/2 clinical trial of its lead candidate, AU-007 (Press release, Aulos Bioscience, OCT 23, 2024, View Source [SID1234647330]). The data and evaluations of pharmacodynamics, pharmacokinetics, safety and clinical efficacy were presented as a poster at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain.

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The results continue to affirm AU-007’s unique profile among interleukin-2 (IL-2) therapeutics, showing regulatory T cell (Treg) reduction, and demonstrating that deeper drops in peripheral Treg counts were associated with longer progression-free survival (PFS) outcomes in patients from the Phase 1 and Phase 2 portions of the AU-007 trial, across a range of dose levels, tumor types and lines of therapy. Additionally, increases in interferon-gamma and effector T cells (Teffs) were observed with escalating subcutaneously administered aldesleukin (recombinant human IL-2) dose levels.

"These data point to a correlation between deeper reductions in Tregs and better clinical outcomes, which differentiates AU-007 from all other IL-2 therapeutics in development," said Aron Knickerbocker, Aulos Bioscience’s president and chief executive officer. "We’re also excited about AU-007’s ability to increase Teffs and natural killer cells. These findings, combined with a mild and tolerable safety profile, further validate our belief in AU-007’s potential as a best-in-class IL-2 therapeutic for solid tumor cancers. We look forward to presenting new Phase 2 clinical efficacy and safety data, particularly in melanoma and renal cell carcinoma, later this year."

Created by Biolojic Design, AU-007 is the first human IgG1 monoclonal antibody designed by leveraging artificial intelligence to enter a human clinical trial. The antibody’s novel mechanism of action is to bind precisely to IL-2 instead of IL-2 receptors. By binding only to the portion of IL-2 that binds to CD25, AU-007 prevents IL-2 from binding to high-affinity IL-2 receptors on Tregs, vasculature and eosinophils, and redirects IL-2 to medium-affinity receptors on Teffs and natural killer (NK) cells. This allows Teffs and NK cells to expand and kill tumor cells.

Safety data presented at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium demonstrate manageable toxicity for AU-007 and low-dose, subcutaneous aldesleukin, with no vascular leak syndrome or pulmonary edema at all dose levels evaluated. Additionally, the AU-007 pharmacokinetic data show characteristics typical of an IgG1-LALA monoclonal antibody, with no evidence of neutralizing anti-drug antibody (ADA) activity and an approximate half-life of more than 15 days. No clear trends were observed in safety or efficacy data to determine if a single loading dose or multiple loading doses of aldesleukin would lead to better outcomes, and clinical investigation is ongoing in the Phase 2 dose expansion cohorts to determine the optimal dosing schedule.

Based on these results, researchers will evaluate dosing regimens of 9 mg/kg for AU-007 every two weeks (Q2W) and 135K IU/kg subcutaneous aldesleukin administered either on a single loading dose schedule or a Q2W multiple dose schedule in the Phase 2 expansion cohorts. The Phase 2 expansion portion of the trial is currently ongoing in renal cell carcinoma (RCC), melanoma and non-small cell lung cancer (NSCLC) evaluating these two dosing regimens.

The poster, "PB452: Determination of the phase 2 dose of AU-007, an AI-designed human monoclonal antibody that redirects IL-2 to T effector cells," (Abstract 464) is available to meeting registrants as an electronic poster on the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium’s online platform. It will be presented live in the poster session "New therapies in immuno oncology" on Friday, October 25, 2024, 9:00 a.m.-3:00 p.m. CEST in the Exhibition Hall.

The poster presentation is also available on the Aulos Bioscience website in the Abstracts and Publications section.

To learn more about the AU-007 clinical trial program, please visit ClinicalTrials.gov (identifier: NCT05267626). For patients and providers in the U.S., please visit www.solidtumorstudy.com. For patients and health professionals in Australia, please visit www.solidtumourstudy.com.

About AU-007
AU-007 is a human IgG1 monoclonal antibody designed by leveraging artificial intelligence that is highly selective to the CD25-binding portion of IL-2. With a mechanism of action unlike any other IL-2 therapeutic in development, AU-007 redirects IL-2 to reinforce anti-tumor immune effects. This is achieved by preventing IL-2, either exogenous or secreted by effector T cells, from binding to trimeric receptors on regulatory T cells while still allowing IL-2 to bind and expand effector T cells and NK cells. This prevents the negative feedback loop caused by other IL-2-based treatments and biases the immune system toward activation over suppression. AU-007 also prevents IL-2 from binding to CD25-containing receptors on eosinophils, as well as vasculature and pulmonary endothelium, which may significantly reduce the vascular leak syndrome and pulmonary edema associated with high-dose IL-2 therapy.

On October 23, 2024 Aprea Therapeutics, Inc. (Nasdaq: APRE) ("Aprea", or the "Company"), a clinical-stage biopharmaceutical company focused on precision oncology through synthetic lethality, reported that preliminary safety results on its WEE1 inhibitor APR-1051 are highlighted in a poster being presented today at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics, taking place in Barcelona, Spain (Press release, Aprea, OCT 23, 2024, View Source [SID1234647329]).

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The results are from ACESOT-1051, a first-in-human Phase 1 study assessing the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent APR-1051 in advanced solid tumors harboring cancer-associated gene alterations.

The dose escalation part of the study (Part 1) is currently ongoing and is expected to include up to 39 patients with advanced solid tumors. Oral APR-1051 is being administered once daily for 28-day cycles. A total of 8 cohorts are planned, evaluating doses of 10 mg to 150 mg once daily. So far, patients have been enrolled in single patient Cohorts 1, 2 and 3, evaluating subtherapeutic doses of 10 mg, 20 mg and 30 mg, respectively.

Preliminary results

Data are available on two of three patients, with a cutoff date of October 7, 2024

Preliminary results demonstrate that APR-1051 is safe and well-tolerated with no hematologic toxicity
Hemoglobin, hematocrit, and platelet counts were stable or increased slightly during the first treatment cycle
There were no signs of neutropenia, with white blood cells and neutrophils trending up for both patients during the first treatment cycle
All adverse events (AEs) recorded were Grade 1 and 2, with one Grade 1 AE (abdominal distention) possibly related to APR-1051
No QT prolongation has been observed
Three patients have been dosed to date with data available on two of these. One had disease progression at 49 days, a second withdrew following 36 days of treatment and dosing is ongoing in the third patient.
"These preliminary data from our ongoing Phase 1 study are encouraging, showing that APR-1051 is safe and well-tolerated," said Philippe Pultar, MD, Senior Medical Advisor and Lead of WEE1 Clinical Development at Aprea. "APR-1051 has been designed to be selective for WEE1, without the off-target inhibition of PLK or QT prolongation reported for other molecules in this class. We expect to confirm this favorable safety profile as we move to higher doses in the ACESOT-1051 trial. We are excited to explore the full therapeutic benefits of APR-1051, which has best in class potential, and hope to generate preliminary efficacy data from the study during 2025."

APR-1051 targets WEE1 kinase, an enzyme involved in the DNA damage response pathway. Based on preclinical studies, Aprea believes that APR-1051 may solve liabilities associated with other WEE1 inhibitors and is differentiated based on: 1) molecular structure; 2) selectivity for WEE1 versus off-target inhibition of the polo-like kinase, or PLK, family of kinases; 3) potentially improved pharmacokinetic (PK) properties; and 4) potential absence of QT prolongation at doses that significantly inhibit WEE1. No head-to-head studies with APR-1051 have been conducted.

Active enrollment in ACESOT-1051 is ongoing at three sites in the U.S. (NEXT Oncology locations in San Antonio and Dallas, and The University of Texas MD Anderson Cancer Center) with planned additional sites.

Anthony Tolcher M.D., Founder of Next Oncology commented, "The preliminary findings from ACESOT-1051 are promising and we are encouraged by the minimal toxicity in the patients treated so far. WEE1 kinase is a validated oncology target and represents an opportunity for therapeutic intervention in patients who otherwise have poor prognosis and no effective treatments today. We look forward to further exploring APR-1051’s potential and are excited to recruit additional patients as the study progresses."

ACESOT-1051 Study Design

ACESOT-1051 (A Multi-Center Evaluation of WEE1 Inhibitor in Patients with Advanced Solid Tumors, APR-1051) is a focused biomarker-driven study designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent APR-1051 in advanced solid tumors harboring cancer-associated gene alterations. Oral APR-1051 will be administered once daily for 28-day cycles. The study consists of two parts: Part 1 is dose escalation and is expected to enroll up to 39 patients with advanced solid tumors. The first three dose levels are using accelerated titration followed by Bayesian Optimal Interval (BOIN) design for the remaining dose levels; Part 2 (up to 40 patients) is designed for dose optimization, with the goal of selecting the Recommended Phase 2 Dose (RP2D). For more information, refer to Clinicaltrials.gov: NCT06260514.

A copy of the poster will be available on Aprea’s corporate website today. Three additional posters will be available at the conclusion of the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Friday, October 25, 2024.