On April 19, 2023 IDEAYA Biosciences, Inc. (NASDAQ: IDYA), a precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported achievement of First-Patient-In in the Phase 1 clinical trial evaluating IDE161 (NCT 05787587) and release of a poster presentation profiling IDE161 at AACR (Free AACR Whitepaper) 2023 (Press release, Ideaya Biosciences, APR 19, 2023, View Source [SID1234630329]). IDE161 is a potent, selective, small-molecule inhibitor of PARG, a novel and mechanistically-differentiated target in the same clinically validated pathway as poly (ADP-ribose) polymerase (PARP).

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"We are excited to clinically investigate IDE161 as a potential first-in-class synthetic lethality treatment for cancer patients with homologous recombination deficiencies (HRD). We believe IDE161 may be impactful for ER+ / Her2- breast cancer patients with HRD, as well as for patients having ovarian cancer and other solid tumors with HRD, for whom current treatment options are limited," said Dr. Darrin M. Beaupre, M.D., Ph.D., Chief Medical Officer, IDEAYA Biosciences. "Based on its preclinical tolerability profile, IDE161 may also be suitable for evaluation with several distinct classes of combination agents, providing multiple paths to demonstrate patient benefit in these populations," continued Dr. Beaupre.

Dr. Timothy Yap, M.D., Ph.D., Associate Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston, the site which dosed the first patient, is a leading principal investigator for the Phase 1 clinical trial evaluating IDE161.

IDEAYA’s Phase 1 clinical trial will evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic properties and preliminary efficacy of IDE161 as monotherapy in patients having tumors with homologous recombination deficiency (HRD). The clinical protocol includes dose escalation in solid tumors with HRD. Subject to selection of an expansion dose, the company is planning expansion in cohorts for patients having HRD tumors in breast cancer, ovarian cancer, and a basket of other solid tumors. The breast cancer cohort will focus on estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (Her2-) tumors with HRD, which represent approximately 10% to 14% of breast cancer patients.

IDEAYA is planning to present a poster with preclinical data profiling IDE161 at the 2023 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) on Wednesday, April 19, 2023:

Abstract 6093: "IDE161, a potential first-in-class clinical candidate PARG inhibitor, selectively targets Homologous-Recombination-Deficient and PARP inhibitor resistant breast and ovarian tumors" (Abed, M. et al.)
Date/Time: Wednesday April 19, 2023 at 9:00 am – 12:30 pm ET
Session / Location: Molecular/Cellular Biology and Genetics, Targeting DNA Damage Response and Novel Pathways; Poster Section 13, Poster Board 1
The IDE161 abstract is available online at View Source in connection with the 2023 Annual Meeting of AACR (Free AACR Whitepaper), and the poster will be available online at View Source following the presentation.

An updated corporate presentation, reflecting updates from AACR (Free AACR Whitepaper) 2023 for IDE161 (PARG), as well as for IDE397 (MAT2A), co-published with Amgen, and Werner Helicase, co-published with GSK, will also be available on the IDEAYA website at its Investor Relations page: View Source

IDEAYA owns or controls all commercial rights in IDE161, subject to certain economic obligations under its exclusive, worldwide license with Cancer Research UK and University of Manchester.

On April 19, 2023 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported that James Porter, Ph.D., Chief Executive Officer, and Alexandra Balcom, Chief Financial Officer, will participate in a fireside chat during the Stifel 2023 Virtual Targeted Oncology Days on Wednesday, April 26, 2023, at 1:30 p.m. ET (Press release, Nuvalent, APR 19, 2023, View Source [SID1234630328]).

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A live webcast will be available in the Investors section of the company’s website at www.nuvalent.com, and archived for 30 days following the presentation.

On April 19, 2023 Replicate Bioscience, a company pioneering novel self-replicating RNA (srRNA) technology for use in infectious disease, oncology, autoimmune disease, and more, reported new preclinical data underscoring the strength of Replicate’s srRNA platform and its potential for oncology applications at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Press release, Replicate Bioscience, APR 19, 2023, View Source [SID1234630327]).

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"Taken together, the results of these studies demonstrate the activity, versatility, and durability of Replicate’s srRNA vectors and their potential for treating cancer," said Zelanna Goldberg, M.D., Chief Medical Officer at Replicate, and poster presenter. "Our srRNAs are designed to produce higher bioactivity at low doses compared to linear mRNA therapeutics. These unique characteristics enable flexible co-administration with existing therapies and better tolerability. We are pleased to share these promising results with the oncology community and look forward to advancing our programs towards clinical trials."

The poster presented today by Dr. Goldberg, titled "A self-replicating RNA precision medicine approach to overcoming resistance to endocrine therapy in ER+ breast cancer," underscores the therapeutic potential of Replicate’s lead immuno-oncology candidate, RBI-1000, to address acquired resistance mutations, a major factor behind the clinical failure of existing endocrine therapy.

RBI-1000 encodes high frequency, clinically characterized pervasive and predictable acquired resistance mutations found in estrogen-receptor expressing breast cancer, representing about 80% of all ER+ breast cancers. RBI-1000 primes T cells to respond to these mutations as they arise and is designed to act synergistically with standard of care treatments.
In a mouse model expressing the targeted acquired resistance mutations, RBI-1000 successfully primed CD4+ and CD8+ T cells leading to significant tumor growth inhibition and improved survival at a 100-fold lower dose than linear mRNA approaches in other tumor models.
"This study contributes to our growing body of preclinical data indicating that when coupled with a standard of care therapy, RBI-1000 forces tumors into a lose-lose situation and ultimately, destruction," said Parinaz Aliahmad, Ph.D., head of Research and Development at Replicate. "Our team is proud to pave the way in unlocking broader applications for RNA to realize therapeutic breakthroughs for large and diverse patient populations."

The second poster, titled "A self-replicating RNA precision medicine approach to therapeutic protein delivery of narrow therapeutic index biomolecules," was presented on April 17 by Dr. Goldberg. The study is the first demonstration of Replicate’s srRNAs to encode multiple biotherapeutic molecules in a single vector backbone for better bioactivity at lower doses than linear mRNA approaches. Multiple encoded proteins also allow for durable tumor immunotherapy, and applications such as the expression of cytokines, other biologics, protein replacement, or secreted proteins.

RBI-2000 encodes two distinct proteins on one RNA strand: one multimeric protein to promote generation of new immune cells, and another monomeric to prevent sterile inflammation, aberrant angiogenesis, and tumor invasiveness. RBI-2000 utilizes a novel self-replicating RNA vector with an enhanced pharmacokinetic profile and pharmacodynamic effects at very low doses capable of controlling tumors as a monotherapy or in combination with checkpoint inhibition.
Mice who had complete responses were rechallenged with tumor cells at 70 days post-treatment and successfully rejected the challenge, indicating robust immunological memory.

On April 19, 2023 Genprex, Inc. ("Genprex" or the "Company") (NASDAQ: GNPX), a clinical-stage gene therapy company focused on developing life-changing therapies for patients with cancer and diabetes, reported that its research collaborators presented positive preclinical data for the NPRL2 gene (also known as the TUSC4 gene) (Press release, Genprex, APR 19, 2023, View Source [SID1234630326]). The studies used the Company’s non-viral ONCOPREX Nanoparticle Delivery System in KRAS/STK11 mutant anti-PD1 resistant metastatic human non-small cell lung cancer (NSCLC) humanized mouse models and were presented at the 2023 American Association of Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, which took place from April 14-18, 2023 in Orlando, Florida.

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"We are pleased to have these positive data that support the therapeutic potential of our non-viral delivery system, which is being used in our current REQORSA clinical oncology programs, presented before some of the world’s leading cancer researchers," said Rodney Varner, President and Chief Executive Officer at Genprex. "The use of the ONCOPREX Nanoparticle Delivery System to deliver the NPRL2 tumor suppressor gene positions Genprex to expand our clinical pipeline with a new drug candidate."

"The preclinical data also provide further evidence that the ONCOPREX Nanoparticle Delivery System has the ability to be successful using genes other than the TUSC2 gene that we are already using in clinical trials with REQORSA," stated Varner. "These compelling outcomes give us further confidence in the potentially broad-based application of our non-viral delivery system, which may provide a multitude of potential pipeline opportunities in the future."

Genprex’s ONCOPREX Nanoparticle Delivery System, is a novel non-viral approach utilizing lipid nanoparticles to deliver tumor suppressor genes that have been deleted during the course of cancer development. The platform allows for the intravenous delivery of various tumor suppressor genes, and potentially other genes, to achieve a therapeutic affect without the risk of toxicity often associated with viral delivery systems.

Featured Genprex-supported posters presented at AACR (Free AACR Whitepaper) 2023 include:

Event: Americal Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting
Session Category: Immunology
Session Title: Combination Immunotherapies 2
Location: Section 22
Session Date and Time: Tuesday, April 18 from 1:30-5:00 p.m. ET
Title: "NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic human NSCLC in a humanizedmouse model"
Presenters: Jack A. Roth, MD, The University of Texas MD Anderson Cancer Center
Poster Board Number: 23
Abstract Presentation Number: 5120

The abstract entitled, "NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic human non-small cell lung cancer (NSCLC) in a humanized mouse model," is available on the AACR (Free AACR Whitepaper) website. The presentation reported results from this study, which investigated the antitumor immune responses to NPRL2 gene therapy on anti-PD1 resistant KRAS/STK11 mutant NSCLC in a humanized mouse model. In the study, humanized mice were treated with NPRL2 gene therapy, immunotherapy pembrolizumab (Keytruda), or the combination. A dramatic antitumor effect was mediated by NPRL2 treatment, whereas pembrolizumab was ineffective. A significant antitumor effect was also found in non-humanized NSG mice, although the antitumor effect was greater in humanized mice, suggesting that the immune response played a role in inducing antitumor activity.

The study data suggest that NPRL2 gene therapy induces antitumor activity on KRAS/STK11 mutant anti-PD1 resistant tumors through DC mediated antigen presentation and cytotoxic immune cell activation.

A KRAS mutation occurs in approximately 25% of patients with NSCLC, and one study found that KRAS/STK11 combination mutations were found in approximately 6.5% of NSCLC patients.

"These data are encouraging because they not only validate Genprex’s non-viral oncology platform to deliver a variety of tumor suppressor genes, but they also provide further evidence of the important role that tumor suppressor genes play in cancer, particularly NSCLC," said Mark Berger, MD, Chief Medical Officer at Genprex. "KRAS is the most frequent oncogene mutated in NSCLC, and KRAS mutations are often associated with resistance to drug therapyi. Targeting KRAS/STK11 mutant NSCLC with the NPRL2 gene, and potentially with anti-PD1 as well, may provide therapeutic potential for this group of lung cancer patients."

Genprex currently has three clinical trials evaluating the Company’s lead drug candidate, REQORSA Immunogene Therapy (quaratusugene ozeplasmid) in lung cancer. The Acclaim-1 clinical trial, which received FDA Fast Track Designation, is an open-label, multi-center Phase 1/2 clinical trial evaluating REQORSA in combination with Tagrisso (osimertinib) in patients with late-stage NSCLC with activating epidermal growth factor receptor ("EGFR") mutations whose disease progressed after treatment with Tagrisso. The Acclaim-2 clinical trial, which received FDA Fast Track Designation, is an open-label, multi-center Phase 1/2 clinical trial evaluating REQORSA in combination with Keytruda (pembrolizumab) in patients with late-stage NSCLC whose disease progressed after treatment with Keytruda. The Acclaim-3 clinical trial, expected to open for enrollment by the end of the third quarter of 2023, is an open-label, multi-center Phase 1/2 clinical trial evaluating REQORSA in combination with Tecentriq (atezolizumab) in patients with extensive-stage small-cell lung cancer (SCLC) who did not develop tumor progression after receiving Tecentriq and chemotherapy as an initial treatment.

On April 19, 2023 Fusion Pharmaceuticals Inc. (Nasdaq: FUSN), a clinical-stage oncology company focused on developing next-generation radiopharmaceuticals as precision medicines, reported the presentation of preclinical data that provide further support of its clinical stage FPI-2059, a neurotensin receptor 1 (NTSR1) targeted alpha therapy (TAT), and additional preclinical development programs (Press release, Fusion Pharmaceuticals, APR 19, 2023, View Source [SID1234630325]). The Company presented these data in three poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting.

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"These data highlight the strong scientific rationale supporting clinical development of FPI-2059, demonstrating that targeting NTSR1 with the tumor killing power of actinium-225 has the potential to induce suppression in solid tumors. We are pleased to be progressing FPI-2059 in our ongoing Phase 1 study," said Fusion Chief Scientific Officer Christopher Leamon, Ph.D. "With our discovery platform, the Fusion team has quickly and efficiently developed TATs for various targets and progressed to multiple clinical programs. The data presented on exploratory targets, such as EGFRvIII and TEM-1, show the ability of our TATs to impact hard to treat cancers."

Data from preclinical studies of FPI-2059, a small molecule TAT designed to deliver actinium-225 to tumor sites expressing NTSR1, a protein expressed in gastrointestinal, prostate, pancreatic ductal adenocarcinoma (PDAC) and multiple other cancers, were presented in a poster presentation titled, "NTSR1-targeted alpha therapeutic [Ac-225]-FPI-2059 induces growth inhibition in a preclinical colorectal tumor model". Outcomes of the study demonstrate robust FPI-2059 tumor uptake and dose-dependent tumor growth inhibition and therapeutic efficacy in a preclinical colorectal tumor model. These data provide further evidence supporting the clinical development of FPI-2059, which is currently being evaluated in a Phase 1 study for the treatment of solid tumors expressing NTSR1.

Data from additional preclinical studies highlight the potential of tumor endothelial marker 1 (TEM-1) and epidermal growth factor receptor variant 3 (EGFRvIII) as targets for actinium-225 labelled TATs. In sarcoma xenograft models, TEM-1-targeted alpha therapy demonstrates strong dose-dependent and target level-dependent efficacy with no apparent toxicity. In glioblastoma multiforme (GBM) models, EGFRvIII-targeted alpha therapy demonstrates therapeutic efficacy as a single agent and in combination with standard of care. Further, EGFRvIII-targeted alpha therapy demonstrates efficacy in models with both leaky and intact blood-brain tumor barriers, suggesting that even low tumor uptake has potential anti-tumor effect.

Copies of the poster presentations can be found at: View Source following the conclusion of the AACR (Free AACR Whitepaper) Annual Meeting.

About FPI-2059

FPI-2059 is a small molecule radiopharmaceutical targeting neurotensin receptor 1 (NTSR1) which is overexpressed in multiple solid tumors, including pancreatic ductal adenocarcinoma, colorectal, squamous cell carcinoma head & neck, gastric, Ewings sarcoma, and neuroendocrine differentiated prostate. FPI-2059 is based upon a compound previously referred to as IPN-1087 and 3BP-227 that had previously been studied in investigator sponsored studies and a Phase 1 clinical trial as a beta-emitting radiopharmaceutical. Fusion acquired the asset in 2021 and converted it to an alpha emitting radiopharmaceutical using actinium-225. The diagnostic analogue which uses indium-111 in place of actinium-225 is referred to as FPI-2058.