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Replicate Bioscience Presents Preclinical srRNA Data at the American Association for Cancer Research Annual Meeting 2023

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.

Genprex Collaborators Report Positive Preclinical Data With NPRL2 Gene Therapy Utilizing Non-Viral ONCOPREX® Nanoparticle Delivery System in Non-Small Cell Lung Cancer at the 2023 AACR Annual Meeting

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.

"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.

Fusion Pharmaceuticals Announces Presentation of Preclinical Data Supporting FPI-2059 and Leading Targeted Alpha Therapy Platform at AACR Annual Meeting

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.

"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.

Innovent Announces Overall Survival Results of Phase 2 Study of Pemazyre® (pemigatinib) in Chinese Patients with Advanced Cholangiocarcinoma Presented at AACR Annual Meeting 2023

On April 19, 2023 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high quality medicines for the treatment of oncology, autoimmune, metabolic, ophthalmology and other major diseases, reported that the overall survival (OS) results of the Phase 2 study of pemigatinib in Chinese patients with advanced cholangiocarcinoma (CCA) were presented today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Abstract CT153) (Press release, Innovent Biologics, APR 19, 2023, View Source [SID1234630324]).

This study (CIBI375A201, NCT04256980) is a Phase 2, open-label, multi-center, single-arm study to evaluate the efficacy and safety of pemigatinib – a selective fibroblast growth factor receptor (FGFR) inhibitor – in Chinese patients with unresectable, advanced/recurrent or metastatic cholangiocarcinoma with FGFR2 fusion/rearrangement that failed to prior systemic therapy, which is a bridging study of the FIGHT-202 study (INCB 54828-202, NCT08924376).

As of data cutoff date (Dec 28, 2022), 31 subjects with documented FGFR2 fusion or arrangement were enrolled and received pemigatinib 13.5mg QD on a 2 weeks on/1 week off schedule until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision.

Among 30 efficacy evaluable subjects (1 participant excluded due to inadequate FGFR2 aberrant frequency), the median follow-up was 25.6 months (95% CI, 23.0-25.8), the median OS was 23.9 months (95% CI, 15.2-NC) with 16 (53.3%) OS events.
Estimated OS rates at 12 months, 18 months and 24 months were 73.3% (95% CI, 53.7%-85.7%), 66.5% (95% CI, 46.7%-80.4%), and 41.4% (95% CI, 22.4%-59.4%), respectively.
As previously reported, there were no clinically or statistically significant differences in safety outcomes with extended follow up of this study.
Dr. Hui Zhou, Senior Vice President of Innovent, stated: "This bridging study aimed to evaluate and validate the efficacy and safety of pemigatinib in Chinese patients with recurrent or metastatic cholangiocarcinoma with FGFR2 fusion or rearrangement, and previously efficacy and safety data was presented at the ESMO (Free ESMO Whitepaper) Congress 2021. These updated OS results demonstrate the encouraging and durable survival benefit of pemigatinib in Chinese patients. Pemigatinib provides an important treatment option for eligible Chinese cholangiocarcinoma patients. Innovent has an ongoing phase 3 study of pemigatinib as first line therapy for cholangiocarcinoma. We will conduct in-depth clinical development of pemigatinib to explore potential treatments in other indications as well. We are looking forward to providing novel therapies for more cancer patients in the future."

About Advanced Cholangiocarcinoma and FGFR2 Rearrangement

Cholangiocarcinoma is a malignant tumour originated from biliary epithelium cells and it is categorized as intrahepatic or extrahepatic based on anatomical location of origin. The incidence of cholangiocarcinoma has been increasing progressively over the past decade. Surgery is the first line treatment for patients with resectable disease. However, most cholangiocarcinomas have been in advanced and/or metastatic status at diagnosis and lost the chance for surgical resection. The treatment options for patients who relapse after surgery or have advanced / metastatic disease are limited and the recommended therapy method is systemic chemotherapy with gemcitabine plus cisplatin, which has a medium overall survival of less than a year.

Aberrant signaling through FGFR resulting from gene amplification or mutation, chromosomal translocation, and ligand-dependent activation of the receptors has been demonstrated in multiple types of human cancers. Fibroblast growth factor receptor signaling contributes to the development of malignancies by promoting tumor cell proliferation, survival, migration, and angiogenesis. Results from early clinical studies of selective FGFR inhibitors, including pemigatinib, have shown a tolerable safety profile for the class and preliminary signs of clinical benefit in participants with FGF/FGFR alterations.

About Pemazyre (pemigatinib)

Pemazyre (pemigatinib) is a selective, oral inhibitor of FGFR isoforms 1, 2 and 3. In December 2018, Innovent and Incyte entered into a strategic collaboration for three clinical-stage product candidates discovered by Incyte, including pemigatinib. Under the terms of the agreement, Innovent has received the rights to develop and commercialize the three assets in Mainland China, Hong Kong, Macau and Taiwan.

In April 2020, the U.S. Food and Drug Administration (FDA) approved Pemazyre (pemigatinib) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement as detected by an FDA-approved test. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). In August 2022, Pemazyre is also approved in the U.S. for the treatment of adults with relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with FGFR1 rearrangement.

Pemazyre is approved and marketed by Innovent in Mainland China, Hongkong and Taiwan, for the treatment of adults with locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or rearrangement as confirmed by a validated diagnostic test that have progressed after at least one prior line of systemic therapy.

Pemazyre is a trademark of Incyte Corporation. Pemazyre is marketed by Incyte in the United States, Europe and Japan.

Actinium Presents Data Demonstrating Actimab-A’s Potential Use Against Solid Tumors by Selectively Depleting Immunosuppressive MDSCs, a Key Component of the Tumor Microenvironment, at the AACR Annual Meeting

On April 19, 2023 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) (Actinium or the Company), a leader in the development of targeted radiotherapies, reported the first ever data demonstrating the utility of Actimab-A to depleted myeloid derived suppressor cells (MDSCs), which are ubiquitously present within the solid tumor microenvironment as well as blood cancers (Press release, Actinium Pharmaceuticals, APR 19, 2023, View Source [SID1234630323]). The new data were showcased in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2023 Annual Meeting, which is being held April 14 – 19, 2023 in Orlando, Florida.

Sandesh Seth, Actinium’s Chairman and CEO, said, "Significant research and development activities are being applied to understanding the complex biological activities within the tumor microenvironment in order to generate better treatment responses and patient outcomes. MDSCs are recruited to sites of chronic inflammation, such as the tumor microenvironment, where they exert immunosuppressive effects including inhibition of immune responses mediated by T cells, B cells, and NK cells. At Actinium, we believe Actimab-A can play an important role in the tumor microenvironment by depleting MDSCs, which express CD33, in a targeted manner. In doing so, Actimab-A can mitigate a major immunosuppressive contributor and potentially improve response rates as well as the duration of responses for a wide array of immunotherapies. With the substantial number of immunotherapies in development or currently in clinical use, we see multiple opportunities to synergize with immunotherapies such as checkpoint inhibitors and T and NK cell therapies. These data are an important step forward and we are excited to continue development of Actimab-A for MDSC depletion and beyond."

Highlights from the AACR (Free AACR Whitepaper) poster titled, "Targeting myeloid-derived suppressor cells with actinium-225 lintuzumab, a CD33 antibody radioconjugate to enhance antitumor immunity", include:

Actimab-A demonstrated efficient depletion of ex vivo human MDSCs derived from colorectal and lung cancer patient samples in vitro in addition to an in vivo humanized mouse model of Non-Small Cell Lung Cancer

Colorectal cancer blood MDSCs treated with Actimab-A were more effectively cleared (p<0.01) compared to depletion by Mylotarg, a CD33-targeted antibody-drug conjugate, highlighting the powerful cytotoxicity and potential therapeutic benefit of radiotherapy compared to naked antibodies or ADCs

Flow cytometry data confirmed an upregulation of CD33+ MDSCs in both lung and colorectal cancer patient samples compared to healthy donor controls. Following Actimab-A treatment in mice, a specific and robust depletion of ex vivo CD33+ MDSCs was observed

These results suggest that targeted blockade of MDSC activity via treatment with Actimab-A can alleviate their pro-tumorigenic and immunosuppressive activities to bolster the efficacy of immunotherapy such as checkpoint inhibitors.
The poster will be available on the presentations page of Actinium’s investor relations page of its website: View Source