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."

On April 8, 2024 EpiBiologics, a preclinical stage company advancing new bispecific antibody therapeutics for extracellular protein degradation, reported on its EpiTAC protein degraders in oncology demonstrating robust in vivo anti-tumor activity and survival benefit (Press release, EpiBiologics, APR 8, 2024, View Source [SID1234641911]). EpiTAC bispecific antibodies leverage cell-surface degrader receptors enriched in disease tissue to selectively degrade membrane and extracellular targets and address significant unmet needs.

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These data are being presented this morning at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 in poster presentation #1866, "Discovery of mutation-independent EGFR degrading bispecific antibodies that suppress tumor growth in preclinical tumor models" with Jon Sitrin, Ph.D., Head of Translational Science for EpiBiologics as lead author.

Current cancer treatments targeting EGFR often yield limited benefits due to target-related toxicities and reduced effectiveness in patients with acquired resistance. Recognizing the importance of improving therapeutic outcomes, EpiBiologics tested the efficacy of its novel EpiTACS on this oncogenic driver.

"Our proof-of-concept data demonstrate that EpiTAC activity is greater than standard of care in multiple preclinical tumor models. EpiTAC degradation of EGFR is mutation-independent and can overcome resistance mechanisms. These data motivate us to develop new and clinically meaningful therapies," said Shyra Gardai, Ph.D., Chief Scientific Officer of EpiBiologics.

Poster Presentation Highlights

EpiTACs are bispecific antibodies with a target binding arm and degrader binding arm that together localize degradation of extracellular and membrane targets to disease tissue, sparing normal tissue and increasing efficacy
Novel EpiTACs were rapidly selected and tested using the EpiAtlas of 270+ tumor- and tissue-specific degraders, including transmembrane E3 ubiquitin ligases, chemokine/cytokine receptors and tissue-enriched internalizing receptors
EpiTACs drove robust in vitro tumoricidal activity in colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) models, independent of KRAS or EGFR mutational status
In vivo tumor models demonstrated EpiTACs degraded mutant EGFR and disrupts downstream signaling, suppressing tumor growth and increasing survival beyond osimertinib standard of care
"We believe EpiTACs are a promising new modality, especially for difficult-to-drug targets," said Ann Lee-Karlon, Ph.D., President and CEO of EpiBiologics. "Our modular bispecific antibodies coupled with our EpiAtlas allow us to rapidly screen and manufacture EpiTACs that drive deep anti-tumor responses. We’re committed to advancing EpiTACs for diverse targets in oncology and other disease areas as we move quickly toward the clinic."

On April 8, 2024 AbCellera (Nasdaq: ABCL) reported new data on its T-cell engager (TCE) programs at the American Association for Cancer Research (AACR) (Free AACR Whitepaper)Ⓡ (AACR) (Free AACR Whitepaper) Annual Meeting 2024 at the San Diego Convention Center, with three posters being presented on April 8 and one on April 9. Together, AbCellera’s data demonstrate that it is well-positioned to advance TCEs as a drug class by widening the therapeutic window, enhancing potency, and broadening the accessible target space (Press release, AbCellera, APR 8, 2024, View Source [SID1234641910]).

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"TCEs are among the most promising new modalities in cancer therapy, but limitations in efficacy and safety have been barriers to realizing their potential for solid tumor indications," said Bo Barnhart, Ph.D., VP, Translational Research at AbCellera. "Our data illustrate that we can repeatedly generate TCEs that maximize tumor-cell killing without inducing excessive cytokine release. Reducing the risk associated with CD3 engagement could improve efficacy both by widening the therapeutic window and by creating opportunities to further enhance potency through co-stimulatory modalities."

AbCellera’s poster presentations, which are available for viewing here, describe how AbCellera is:

Widening the therapeutic window: AbCellera’s data describe the generation of TCEs for three solid tumor targets, PSMA, B7-H4, and 5T4, with functional profiles that are differentiated from clinical benchmarks. These molecules were engineered using a specific set of rare CD3-binding antibodies that consistently show potent tumor-cell killing and low cytokine release across multiple targets, demonstrating their potential to expand the therapeutic window across solid tumor indications.

Enhancing potency: TCEs that engage the CD28 costimulatory receptor can enhance T-cell activation, proliferation, and anti-tumor activities, particularly in solid tumors. The data show that AbCellera’s IgG and heavy chain-only CD28-binding antibodies do not display superagonist activity — a property associated with toxicity. Integrating costimulatory building blocks into AbCellera’s TCE repertoire may enable development of molecules with enhanced potency for difficult-to-treat cancers.

Broadening the accessible target space: The target repertoire for TCEs has been restricted to proteins expressed on the surface of cancer cells. Intracellular peptides displayed on MHC class I (pMHCs) would greatly expand the target pool for TCEs. However, development of TCEs against pMHCs has been limited due to the high degree of target specificity required. Data illustrate how AbCellera is unlocking this target class by generating molecules with high specificity for MAGE-A4-pMHC, which showed little to no binding to hundreds of off-target pMHCs.

"Our platform for creating precision TCEs to address indications in cancer and autoimmunity provides a strong foundation for both internal programs and strategic partnerships," said Murray McCutcheon, Ph.D., SVP, Partnering at AbCellera. "We look forward to advancing these programs with the aim of delivering powerful new medicines for patients."