On April 8, 2024 Alterome Therapeutics, Inc., a biopharmaceutical company pioneering the development of next generation, small molecule targeted therapies for the treatment of cancer, reported promising preclinical data from their lead pipeline candidate, ALTA-2618, a mutation-selective inhibitor for AKT1 E17K driven cancers (Press release, Alterome Therapeutics, APR 8, 2024, View Source [SID1234641916]). The data are being presented in a poster presentation on April 8th at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024, taking place in San Diego, CA on April 5-10, 2024.

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ALTA-2618 is an orally bioavailable, mutant-selective, and covalent allosteric inhibitor of AKT1 E17K. AKT1 E17K is a clinically validated oncogene that drives cancers, including breast, endometrial, and prostate cancers. This program is designed for patients with limited treatment options and is expected to begin clinical testing in the next year.

"We’re excited to present data at AACR (Free AACR Whitepaper) featuring Alterome’s lead program, ALTA-2618, the first AKT1 E17K-selective inhibitor. We believe this data provides validation of the strong dependence of certain cancers on this mutation and underscores the high impact a selective inhibitor could achieve with continuous target coverage," said Eric Murphy, Ph.D., co-founder and CEO of Alterome Therapeutics. "This work was an important step forward in Alterome’s mission to discover precise therapies that generate preclinical tumor regressions with improved safety profiles, and supports the advancement of ALTA-2618 into first-in-human clinical trials in 2024."

Key Findings:

ALTA-2618 is the first allosteric & mutant-selective drug for AKT1 E17K driven cancers.
ALTA-2618 has favorable pharmacokinetic properties across multiple preclinical species.
ALTA-2618 is well tolerated with daily oral dosing in tumor-bearing mice.
The compound demonstrated significant anti-tumor effects in clinically-relevant PDX models driven by AKT1 E17K.
No on-target toxicities (e.g., hyperglycemia) are observed with daily ALTA-2618 treatment.
Poster Presentation Details:

Title: Discovery of ALTA-2618, the first allosteric, mutant-selective targeted therapy for AKT1 E17K driven cancers
Session Title: Late-Breaking Research: Experimental and Molecular Therapeutics 2
Date and Time: Monday, April 8 from 1:30 p.m. – 5:00 p.m. PT
Abstract Number: LB173 / 19
Speaker/Lead Author: Tim Sen Wang, Ph.D., Alterome Therapeutics

On April 8, 2024 Boundless Bio (Nasdaq: BOLD), a clinical-stage oncology company interrogating extrachromosomal DNA (ecDNA) biology to deliver transformative therapies to patients with previously intractable oncogene amplified cancers, reported preclinical and clinical pharmacodynamic data on its lead ecDNA-directed therapy (ecDTx), BBI-355, and research on ecDNA-mediated acquired resistance to chemotherapy at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 (Press release, Boundless Bio, APR 8, 2024, View Source;Directed-Therapy-BBI-355-at-the-American-Association-for-Cancer-Research-Annual-Meeting-2024 [SID1234641915]). BBI-355 is a novel, oral, selective inhibitor of checkpoint kinase 1 (CHK1) being studied in the ongoing, first-in-human, Phase 1/2 POTENTIATE clinical trial in patients with oncogene amplified cancers.

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"Extrachromosomal DNA afford unique advantages to tumors, typically rendering existing therapies ineffective and correlating with poor patient outcomes," said Chris Hassig, Ph.D., Chief Scientific Officer of Boundless Bio. "Our first poster presented this year at AACR (Free AACR Whitepaper) demonstrated that BBI-355 overcame ecDNA-mediated targeted therapy resistance in preclinical tumor models by leveraging the enhanced reliance of ecDNA-driven tumor cells on CHK1 for survival. BBI-355 showed substantial antitumor activity, including complete and durable regressions, in preclinical oncogene amplified models.

Dr. Hassig continued, "Today we present preclinical and preliminary clinical pharmacodynamic biomarker assay data that showed detection of CHK1 inhibition-associated replication stress in both patient skin and tumor tissue following administration of BBI-355. In addition, we report a possible role for ecDNA in acquired resistance to chemotherapy observed in preclinical models, extending the potential applicability of ecDNA-directed strategies beyond targeted therapy resistance. We are encouraged by these findings as we continue to advance BBI-355 through the ongoing Phase 1/2 POTENTIATE clinical trial."

Details of the presentations are as follows:

Title: Oral CHK1 inhibitor BBI-355 allows flexibility of dose and schedule with demonstration of monotherapy and combinational antitumor activity in extrachromosomal DNA (ecDNA)-driven oncogene amplified preclinical models
Abstract Number: 613
Session Category: Experimental and Molecular Therapeutics
Session Title: Kinase and Phosphatase Inhibitors 1
Session Date and Time: Sunday Apr 7, 2024, 1:30 PM – 5:00 PM PT
Location: Poster Section 25
Poster Board Number: 23

BBI-355 showed inhibition of CHK1 in a host of tumor cell lines and demonstrated in vivo single agent tumor growth inhibition, including complete tumor regressions, across a range of tumor models representing multiple different oncogene amplifications and tumor types. BBI-355 also demonstrated synergistic tumor growth inhibition, including durable regressions, when combined with targeted therapies across multiple oncogene amplified tumor models.

Title: Preclinical and clinical pharmacodynamic characterization of BBI-355, a novel, orally bioavailable, and selective CHK1 inhibitor being evaluated in the first-in-human Phase 1/2 POTENTIATE clinical trial of patients with cancer harboring oncogene amplifications
Number: 3631
Session Category: Clinical Research
Session Title: Biomarkers in Clinical Trials
Session Date and Time: Monday Apr 8, 2024, 1:30 PM – 5:00 PM PT
Location: Poster Section 40
Poster Board Number: 9

Historically, clinical CHK1 inhibitor programs have lacked effective clinical PD biomarker assays. The findings showed that phosphorylated-CHK1 Ser345 (pCHK1-S345) is a useful pharmacodynamic (PD) biomarker for confirming clinical on-target activity of BBI-355 and could potentially inform the pharmacologically active range of BBI-355 in clinical development. In addition to preclinical data, increased pCHK1-S345 expression by immunohistochemistry in skin biopsies from patients treated with BBI-355 in the ongoing POTENTIATE clinical study were also observed, marking the first, real-time analysis of PD activity from a CHK1 inhibitor in humans.

Title: Extrachromosomal DNA (ecDNA) amplification of multi-drug resistance genes results in acquired resistance to taxane-based chemotherapy
Abstract Number: 5870
Session Category: Experimental and Molecular Therapeutics
Session Title: Mechanisms of Drug Resistance 3
Session Date and Time: Tuesday Apr 9, 2024, 1:30 PM – 5:00 PM PT
Location: Poster Section 24
Poster Board Number: 14

Early insights into the role of ecDNA in driving resistance to paclitaxel, a taxane chemotherapy, are revealed and highlight the importance of ecDNA-directed therapies as a potential treatment option for many patients that have chemotherapy-resistant disease. Chemotherapy remains standard of care for many cancer patients, however, resistance to chemotherapy often develops and has been associated with the emergence of multi-drug resistance (MDR) gene amplification, such as ABCB1. These preclinical findings showed that ecDNA-enabled MDR gene amplification can cause short-and long-term resistance to paclitaxel, potentially driving resistance to chemotherapy in patients and underscoring the broad need for ecDTx for chemotherapy-resistant patient populations.

About BBI-355

Boundless Bio’s lead ecDNA-directed therapy (ecDTx), BBI-355, is a novel, oral, selective inhibitor of checkpoint kinase 1 (CHK1) being studied in the ongoing, first-in-human, Phase 1/2 POTENTIATE clinical trial (NCT05827614) in patients with oncogene amplified cancers. CHK1 is a master regulator of cells’ response to replication stress (RS). RS is elevated in ecDNA-enabled oncogene amplified cancer cells and, because of this, represents a key vulnerability of those cells. BBI-355 was designed to exploit the elevated RS in ecDNA-enabled oncogene amplified cancer cells by disrupting proper CHK1 function in regulating RS and thereby facilitating catastrophic RS to preferentially kill cancer cells relative to healthy cells.

On April 8, 2024 Blue Earth Therapeutics, a Bracco company and emerging leader in the development of innovative next generation therapeutic radiopharmaceuticals, reported results from a series of preclinical analyses designed to identify synergistic combinations of known anticancer drugs with 177Lu-rhPSMA-10.1 radioligand therapy, and from a preclinical efficacy analysis of the lead novel drug combination for the treatment of prostate cancer (Press release, Blue Earth Therapeutics, APR 8, 2024, View Source [SID1234641914]). Results from a systematic in vitro screen identified MEK inhibitor cobimetinib as a lead candidate with potential for synergistic combination with 177Lu-rhPSMA-10.1, and the preclinical efficacy analysis showed enhanced therapeutic effect of this drug combination when compared to the untreated control and to the single agents alone. The data were presented in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 in San Diego, Calif. 177Lu-rhPSMA-10.1, an investigational radiohybrid (rh) Prostate-Specific Membrane Antigen-targeted therapeutic radiopharmaceutical, is the lead candidate in Blue Earth Therapeutics’ oncology development program of next generation therapeutic radiopharmaceuticals.

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"Radioligand therapy targeting PSMA has been shown to be an effective therapy in men with prostate cancer, and we are pleased to share these promising preclinical results from our study of 177Lu-rhPSMA-10.1 drug combinations with the scientific community at the prestigious AACR (Free AACR Whitepaper) Annual Meeting 2024," said David E. Gauden, D.Phil., Chief Executive Officer of Blue Earth Therapeutics. "Combination approaches are of increasing interest among the medical community, as we know tumors are heterogeneous and some prostate cancer cells do not express PSMA. Importantly, these combinations need to avoid overlapping toxicity. Results from this preclinical study presented at AACR (Free AACR Whitepaper) demonstrated a synergistic therapeutic effect between 177Lu-rhPSMA-10.1 and an MEK inhibitor. This may be due to inhibition of the MEK-MAPK pathway during DNA damage response, resulting in radiosensitization of cancer cells to 177Lu-rhPSMA-10.1. Our ongoing Phase 1/2 clinical trial (NCT05413850) is evaluating 177Lu-rhPSMA-10.1 radioligand therapy as a monotherapy in treating men with metastatic castrate resistant prostate cancer, and we may look to evaluate this combination in the clinic in the future."

About the study

More than 150 FDA-approved anticancer drugs were screened in a clonogenic survival assay of 22Rv1 cells using the test drug alone, at a range of concentrations <20 µM to determine the IC50. The results were then compared to incubations of the drug plus 15 MBq/mL 177Lu-rhPSMA-10.1 (2-hour incubation) after 10 days. Five lead candidates were then selected for a focused screen where the impact of 177Lu-rhPSMA-10.1 (0–25 MBq/mL) on the drug IC50 was determined. A synergy score was determined using the zero interaction potency (ZIP) reference model and the multi-dimensional synergy of combinations (MuSyc) platform. Therapeutic efficacy of the lead combination, 177Lu-rhPSMA-10.1 (single 30 MBq iv dose) plus cobimetinib (0.25 mg orally per day for 21 days), was then evaluated in 22Rv1 prostate tumor xenograft models and compared to the single agents alone (n = 8 per group, plus untreated controls). Tumor volume was measured 2 times per week for 69 days. Two-way ANOVA and Tukey’s multiple comparisons test (data analyzed until n = 3 remained per group) and Kaplan-Meier Log-rank survival analyses were performed.

Results

The in vitro screen identified the MEK inhibitor cobimetinib as a lead candidate for synergistic combination with 177Lu-rhPSMA-10.1 across a wide concentration range, with a ZIP synergy score of 13.25% (95% CI ± 2.17) and promising results on MuSyc analysis. The 177Lu-rhPSMA-10.1 plus cobimetinib MEK inhibitor combination significantly suppressed tumor growth in vivo versus untreated controls (from day 13–30; p<0.01) and 177Lu-rhPSMA-10.1 alone (from day 17–30; p<0.001). The median survival in the combination group (49 days) was significantly longer versus the untreated group (23 days; p=0.001) and the group treated with 177Lu-rhPSMA-10.1 alone (36 days; p=0.002).

The results were discussed in a poster presentation, "Evaluation of a synergistic drug combination with 177Lu-rhPSMA-10.1 for prostate cancer: Results of an in vitro screen and in vivo proof of concept study," by Caroline Foxton, Ph.D., Blue Earth Group, Oxford, UK, at the AACR (Free AACR Whitepaper) Annual Meeting 2024 on April 7, 2024. The abstract is available in the online program here .

About Radiohybrid Prostate-Specific Membrane Antigen (rhPSMA)

rhPSMA compounds are referred to as radiohybrid ("rh"), as each molecule possesses three distinct domains. The first consists of a Prostate-Specific Membrane Antigen-targeted receptor ligand which attaches to and is internalized by prostate cancer cells. It is attached to two labelling moieties which may be radiolabeled with diagnostic isotopes such as 18F or 68Ga for PET imaging, or with therapeutic isotopes such as 177Lu or 225Ac for radioligand therapy – enabling the potential for a true theranostic technology. They may play an important role in patient management in the future, and offer the potential for precision medicine for men with prostate cancer. Radiohybrid technology and rhPSMA originated from the Technical University of Munich, Germany. Blue Earth Diagnostics acquired exclusive, worldwide rights to rhPSMA diagnostic imaging technology from Scintomics GmbH in 2018, and therapeutic rights in 2020, and has sublicensed the therapeutic application to its sister company Blue Earth Therapeutics. Blue Earth Therapeutics and Blue Earth Diagnostics work closely on the development of 177Lu-rhPSMA-10.1. Currently, Blue Earth Therapeutics’ rhPSMA compounds have not received regulatory approval.

On April 11, 2024 RenovoRx, Inc. ("RenovoRx" or the "Company") (Nasdaq: RNXT), a clinical-stage biopharmaceutical company developing novel precision oncology therapies based on a local drug-delivery platform, reported the execution of definitive subscription agreements with accredited investors for a private placement which is expected to result in gross proceeds of approximately $11.1 million to RenovoRx, before deducting offering expenses (Press release, Renovorx, APR 8, 2024, View Source [SID1234641913]).

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The proceeds from this financing, in addition to RenovoRx’s previously announced private placement on January 29, 2024 for gross proceeds of approximately $6.1 million, extend the Company’s cash runway into 2026. The financing allows RenovoRx to advance its lead program, the pivotal Phase III TIGeR-PaC clinical trial in locally advanced pancreatic cancer (LAPC), through the second interim readout and towards completion of the trial. The TIGeR-PaC study is an ongoing randomized multi-center study in LAPC using RenovoRx’s proprietary TAMP (Trans-Arterial Micro-Perfusion) therapy platform to evaluate its first product candidate, RenovoGem, a novel oncology drug-device combination product. The study is comparing treatment with TAMP to the current standard of care (systemic intravenous chemotherapy). RenovoRx expects that the second interim analysis for this study will be triggered by the 52nd event in the trial, which is estimated to occur in late 2024.

Proceeds from the financing are also expected to enable the expansion of the TAMP clinical development pipeline into additional cancer indications.

The definite subscription agreements were executed based on the closing price of RenovoRx’s common stock on April 4, 2024, and the private placement is expected to close on April 11, 2024, subject to customary closing conditions. Newbridge Securities Corporation is acting as sole placement agent for the transaction.

Terms of the Private Placement

In connection with the private placement, the Company will issue 7,912,364 shares of common stock, five-year Series A Warrants to purchase an aggregate of up to 7,912,364 shares of common stock, and two-year Series B Warrants, to purchase an aggregate of up to 3,956,182 shares of common stock, with the Series A Warrants and Series B Warrants together constituting 150% warrant coverage. Investors will pay a purchase price of $1.4075 for each share and associated Series A Warrant and Series B Warrant, with such price being at the market for purposes of Nasdaq Stock Market rules. The Series A Warrants and Series B Warrants are each exercisable for $1.22 per share. The Series B Warrants are callable by the Company after 6 months if certain price and volume thresholds are achieved.

The securities being sold in the private placement have not been registered under the Securities Act of 1933, as amended, or state securities laws and may not be offered or sold in the United States absent registration with the SEC or an applicable exemption from such registration requirements. The Company has agreed to file a registration statement with the SEC covering the resale of the shares and the shares underlying the Series A Warrants and Series B Warrants issuable in connection with the private placement.

This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such jurisdiction.

On April 8, 2024 Tempus, a leader in artificial intelligence and precision medicine, reported that it will present new data along with Pfizer at the AACR (Free AACR Whitepaper) 2024 Annual Meeting (Press release, Tempus, APR 8, 2024, View Source [SID1234641912]). The abstract, titled "Analysis of HER2 prevalence by RNA expression across solid tumors," found that by correlating HER2 protein levels by IHC/ISH and ERBB2 mRNA levels by NGS in tumors of patients with locally advanced/metastatic (LA/m) breast and gastric cancer, RNA expression in several solid tumors apart from breast or gastric cancer may correspond to HER2 IHC≥1+. These findings may open up potential therapeutic routes for HER2-directed antibody-drug conjugates in several tumor types.

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In 2022, Seagen (acquired by Pfizer in December 2023) engaged Tempus to investigate cohorts of patients with HER2 RNA expression. As part of the collaboration, Tempus’ computational and real-world evidence teams helped provide insights on the prevalence of HER2 expression in select solid tumors. Pfizer is leveraging Tempus’ multimodal database to further its HEOR and Translational Science team’s research efforts.

"We’ve been fortunate enough to work alongside the Pfizer team as they expand their understanding of HER2 expression in solid tumors, which outside of breast and gastric cancers, has not been previously well described," said Ryan Fukushima, Chief Operating Officer of Tempus. "For this specific study, we were able to tap into our existing database and analyze 4,500 de-identified records to support their research."