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Primmune Therapeutics Presents New Clinical Data from Phase 1 Study Evaluating PRTX007 in Healthy Volunteers at the 2023 American Association for Cancer Research (AACR) Annual Meeting

On April 18, 2023 Primmune Therapeutics, a biotech company harnessing the power of the innate immune system to treat solid tumors in the advanced cancer setting and for the clearance of human papillomavirus and related pre-cancerous cervical lesions, reported new clinical data from a first-in-human, Phase 1 study evaluating PRTX007, an orally administered prodrug of a novel, small molecule toll-like receptor 7 (TLR7)-specific agonist, at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Orlando, Florida (Press release, Primmune Therapeutics, APR 18, 2023, View Source [SID1234630257]).

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The study was a first-in-human, Phase 1, single-center, prospective, randomized, double-blind, placebo-controlled study with 9 single-ascending dose (SAD) cohorts and 4 multiple-ascending dose (MAD) cohorts where PRTX007 was administered orally to adult HVs. In addition to assessing the clinical safety and tolerability of PRTX007, the study was designed to evaluate the pharmacokinetics of PRTX007 and identify the specific active dosing range for use in future cancer studies.

Consistent with interim results from the Phase 1 study, data show that PRTX007 was well-tolerated and expressed a favorable safety profile in all of the analyzed cohorts, with no serious adverse events (AEs) or AEs at or above grade 3. Every other day (QOD) dosing in the 750mg cohort demonstrated stable systemic induction of the innate and adaptive immune responses, with significant increases in CD8+ T cells and NK cell activation (CD38+ markers) observed from pretreatment to end of dosing in all HVs. There were no systemic increases in proinflammatory factors observed for any dose range in the Phase 1 study. Both the clinical characteristics and unique pattern of immune induction by PRTX007 support its use in combination with immune checkpoint inhibitors.

"These Phase 1 results set the stage for PRTX007 to enable long-term continuous immune induction in combination with other therapeutic modalities including checkpoint inhibitors and as a single agent," said James Appleman, Ph.D., Co-Founder and Chief Scientific Officer at Primmune Therapeutics. "PRTX007 was shown to activate innate and downstream adaptive immune responses without significant increases in circulating proinflammatory cytokines, demonstrating its potential to deliver the therapeutic benefit that patients need while avoiding dose-limiting adverse events. The Primmune team is encouraged by our positive Phase 1 data and we look forward to the ongoing clinical development of PRTX007."

Presentation details:

Title: Activation of Innate and Adaptive Immune Response with a Clinical Stage TLR7 Agonist Prodrug PRTX007
Presenting Author: Curtis Scribner, M.D., Chief Medical Officer, Primmune
Abstract Number: CT180
Poster Board: 12
Session Title: First-in-Human Phase I Clinical Trials 2
Session Date and Time: Tuesday, April 18, 9:00 a.m. ET to 12:30 p.m. ET
Location: Orange County Convention Center, Poster Section 45

Additional highlights from the poster presentation include:

PRTX007 demonstrated a favorable safety profile when administered orally to all 9 SAD and 4 MAD cohorts tested.
Most AEs were mild and not dose-related, with no instances of dose modification or discontinuation due to treatment-related AEs throughout the study. The most common drug-related AE was headache, seen across both treated and placebo groups independent of dose.
PRTX007 demonstrated well-controlled expression of interferon-stimulated genes (ISGs) independent of dose, without significant increases in circulating IFNs. There was no increase in expression or circulating levels of proinflammatory cytokines (e.g., TNFα, IL-6, IL-1β).
CD8+ T cells and NK cell activation (CD38+ markers) increased markedly from pretreatment to end of dosing in all HVs.
These data justify further exploration of PRTX007 as a potential cancer therapeutic. Primmune plans to conduct a future study evaluating PRTX007 in combination with a checkpoint inhibitor across the active doses identified in the Phase 1 study for the potential treatment of solid tumors.

About PRTX007
PRTX007, Primmune’s lead clinical development candidate, is designed to provide well-tolerated, controlled, long-term stimulation of the innate immune response while also potentiating long-term effective innate and adaptive immune responses. PRTX007 administration uniquely activates plasmacytoid dendritic cells (pDCs), leading to a systemic immune poly-IFN response without stimulating production of NF-κB-driven proinflammatory factors like IL-6, TNFα or IL-1β. Activated pDCs directly deliver interferons to target cells by paracrine transfer. Conceptually, this is equivalent to administering a therapeutically effective cocktail of all Type I/III IFNs while avoiding the associated side effects and adverse events. Furthermore, PRTX007 administration leads to systemic activation of anti-tumor effector CD8+ T cells and NK cells. PRTX007 is being rapidly advanced towards clinical trials for solid tumors in the advanced cancer setting and for clearing human papillomavirus-transformed pre-cancerous cervical lesions.

Precision BioSciences Announces Late-Breaking Abstract of Preclinical In Vivo Gene Editing Research Selected for Oral Presentation at the American Society of Gene & Cell Therapy 26th Annual Meeting

On April 18, 2023 Precision BioSciences, Inc. (Nasdaq: DTIL), a clinical stage gene editing company developing ARCUS-based ex vivo allogeneic CAR T and in vivo gene editing therapies, reported that a late-breaking abstract featuring preclinical data from its PBGENE-DMD program for the potential treatment of Duchenne muscular dystrophy (DMD), was selected for an oral presentation at the American Society of Gene & Cell Therapy (ASGCT) (Free ASGCT Whitepaper) 26th Annual Meeting being held May 16-20, 2023 in Los Angeles, CA (Press release, Precision Biosciences, APR 18, 2023, View Source [SID1234630256]).

"ARCUS nucleases have been shown to be exceptionally versatile for complex gene editing approaches, including large gene excisions. The goal of the PBGENE-DMD program is to utilize a pair of ARCUS nucleases, delivered by a single AAV, that are designed to excise an approximately 500,000 base pair mutation "hot spot" region from the dystrophin gene in order to make a variant of the dystrophin protein that is functionally competent," said Jeff Smith, Chief Research Officer of Precision BioSciences. "We look forward to the upcoming ASGCT (Free ASGCT Whitepaper) presentation highlighting new data from Precision’s DMD gene editing program."

The abstract will be publicly accessible through the ASGCT (Free ASGCT Whitepaper) website at View Source beginning on May 2, 2023.

Presentation Details:

Title: ARCUS-Mediated Excision of the "Hot Spot" Region of the Human Dystrophin Gene for the Treatment of Duchenne Muscular Dystrophy (DMD)
Date and Time: Friday, May 19, 2023, 10:15 AM – 12:00 PM
Session Title: Late-breaking Abstracts 2
Session Room: Concourse Hall 152 & 153

About ARCUS

ARCUS is a proprietary genome editing technology discovered and developed by scientists at Precision BioSciences. It uses sequence-specific DNA-cutting enzymes, or nucleases, that are designed to either insert (knock-in), excise (knock-out), or repair DNA of living cells and organisms. ARCUS is based on a naturally occurring genome editing enzyme, I-CreI, that evolved in the algae Chlamydomonas reinhardtii to make highly specific cuts in cellular DNA and stimulate gene insertion at the cut site by homologous recombination. Precision’s platform and products are protected by a comprehensive portfolio including nearly 100 patents to date.

Phio Pharmaceuticals Presents Preclinical Data Demonstrating Synergy-Enhanced in vivo Anti-Tumor Efficacy of PD-1/CTLA-4 Dual-Targeting INTASYL

On April 18, 2023 Phio Pharmaceuticals Corp. (Nasdaq: PHIO), a clinical stage biotechnology company whose proprietary INTASYL RNAi platform technology is designed to make immune cells more effective in killing tumor cells, reported that in vivo data from a mouse model of colon cancer demonstrates target synergy-enhanced anti-tumor efficacy from a novel dual-targeting mouse PD-1 and CTLA-4 of an INTASYL coformulation (Press release, Phio Pharmaceuticals, APR 18, 2023, View Source [SID1234630255]).

Intratumoral administration of the PD-1/CTLA-4 INTASYL improved tumor control compared to either single targeting formulation, at an identical total dose. The dual-targeting formulation was well tolerated.

"The synergistic effects of dual inhibition of PD-1 and CTLA-4 in enhancing tumor response are clinically recognized, however, a high rate of immune-related adverse events limits the utility of systemic use of this combination of products," said Dr. Mary Spellman, Phio’s Acting Chief Medical Officer. "Intratumoral administration of dual-targeting PD-1/CTLA-4 INTASYL may provide an effective treatment option, with an improved safety profile."

Presentation Details:

Poster Title:

INTASYL self-delivering RNAi therapeutic dual targeting PD-1 and CTLA-4
provides synergistic antitumor efficacy in the treatment of murine colon cancer
in vivo

Session Date and Time:

Tuesday, April 18, 2023 from 1:30 PM – 5:00 PM EST

Phio Pharmaceuticals Announces $2 Million Registered Direct Offering Priced At-the-Market Under Nasdaq Rules

On April 18, 2023 Phio Pharmaceuticals Corp. (Nasdaq: PHIO), a clinical stage biotechnology company whose proprietary INTASYL RNAi platform technology is designed to make immune cells more effective in killing tumor cells, reported that it has entered into a definitive agreement for the issuance and sale of an aggregate of 353,983 of its shares of common stock at a purchase price of $5.65 per share in a registered direct offering priced at-the-market under Nasdaq rules (Press release, Phio Pharmaceuticals, APR 18, 2023, View Source [SID1234630254]). In a concurrent private placement, Phio has also agreed to issue and sell unregistered Series A warrants to purchase up to an aggregate of 353,983 shares of common stock and unregistered Series B warrants to purchase up to an aggregate of 353,983 shares of common stock. The offering is expected to close on or about April 20, 2023, subject to the satisfaction of customary closing conditions.

Logo – View Source

H.C. Wainwright & Co. is acting as the exclusive placement agent for the offering.

Each series of warrants will have an exercise price $5.40 per share and become exercisable immediately upon issuance. The Series A warrants have a term of five and one-half years from the date of issuance and the Series B warrants have a term of eighteen months from the date of issuance.

The gross proceeds to the Company from the offering are expected to be approximately $2 million, before deducting the placement agent’s fees and other offering expenses payable by Phio. Phio currently intends to use the net proceeds from the offering for the development of its immuno-oncology programs, working capital and general corporate purposes.

The shares of common stock offered in the registered direct offering (but excluding the unregistered warrants offered in the concurrent private placement and the shares of common stock underlying such unregistered warrants) are being offered and sold by the Company pursuant to a "shelf" registration statement on Form S-3 (Registration No. 333-256100), including a base prospectus, previously filed with the Securities and Exchange Commission (SEC) on May 13, 2021 and declared effective by the SEC on May 21, 2021. The offering of the shares of common stock to be issued in the registered direct offering are being made only by means of a prospectus supplement that forms a part of the registration statement. A final prospectus supplement and an accompanying base prospectus relating to the registered direct offering will be filed with the SEC and will be available on the SEC’s website located at View Source Electronic copies of the final prospectus supplement and accompanying base prospectus may also be obtained by contacting H.C. Wainwright & Co., LLC at 430 Park Avenue, 3rd Floor, New York, NY 10022, by phone at (212) 856-5711 or e-mail at [email protected].

The offer and sale of the unregistered warrants described above are being made in a transaction not involving a public offering and have not been registered under Section 4(a)(2) of the Securities Act of 1933, as amended (the "Securities Act") and/or Rule 506(b) of Regulation D promulgated thereunder and, along with the shares of common stock underlying such unregistered warrants, have not been registered under the Securities Act or applicable state securities laws. Accordingly, the unregistered warrants and underlying shares of common stock may not be reoffered or resold in the United States except pursuant to an effective registration statement or an applicable exemption from the registration requirements of the Securities Act and such applicable state securities laws.

In connection with the offering and effective upon the closing of the offering, the Company also agreed to amend certain existing warrants to purchase up to an aggregate of 191,619 shares of the Company’s common stock that were previously issued in April 2018 through January 2021 at exercise prices ranging from $26.52 to $2,079.00, such that the amended warrants will have a reduced exercise price of $5.40 per share, at an additional offering price of $0.125 per amended warrant.

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

ORIC Pharmaceuticals Presents Promising Preclinical Data on Two Programs at the 2023 American Association for Cancer Research (AACR) Annual Meeting

On April 18, 2023 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported two preclinical poster presentations at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, ORIC Pharmaceuticals, APR 18, 2023, View Source [SID1234630253]).

"Our presentations at AACR (Free AACR Whitepaper) reflect the excellent preclinical scientific support of our development pipeline," said Lori Friedman, PhD, chief scientific officer. "Preclinical data provided insights into the comprehensive biomarker strategy for ORIC-944, our PRC2 inhibitor in Phase 1 as a monotherapy for metastatic prostate cancer. We are also pleased with the progress of our PLK4 program, with data showing that the exquisite kinase selectivity is key to synthetic lethality in tumor models with high TRIM37."

Presentation details:

ORIC-944: allosteric inhibitor of PRC2
ORIC-944 is a potent, orally bioavailable, highly selective allosteric small molecule inhibitor of PRC2, the complex which tri-methylates histone H3 lysine 27 (H3K27me3) via targeting the embryonic ectoderm development (EED) subunit, and is in early clinical development as a monotherapy for patients with metastatic prostate cancer.

Poster Presentation:

Biomarker strategy for a phase 1 study of ORIC-944, a potent and selective allosteric PRC2 inhibitor, in patients with metastatic prostate cancer

Key findings of the presentation:

Preclinical pharmacology studies in mice showed that ORIC-944 induces dose- and time-dependent H3K27me3 reduction in the skin epidermis, peripheral blood monocytes, and cell free nucleosomes in plasma, with the latter PD modulation being tumor-specific.
Putative PRC2 target genes were identified via time-dependent transcriptional and epigenetic profiling of xenograft tumor models orally dosed with ORIC-944.
These studies and corresponding assay development support the comprehensive biomarker strategy of target engagement and pharmacodynamic biomarkers implemented in the ongoing Phase 1 trial of ORIC-944 in patients with metastatic prostate cancer.
PLK4 Inhibitor Program
The PLK4 inhibitor program is a small molecule therapeutic program intended to address a mechanism of innate resistance found in a subset of breast cancers, specifically a synthetic lethal interaction of polo-like kinase 4 (PLK4) inhibition in tumors bearing a TRIM37 DNA amplification/elevation. A novel, potent, highly selective, orally bioavailable PLK4 inhibitor was selected as a development candidate in the fourth quarter of 2022.

Poster Presentation:

Selective PLK4 inhibition demonstrates synthetic lethality in TRIM37 amplified neuroblastoma and breast cancer models while less selective inhibitors do not

Key findings of the presentation:

ORIC discovered novel, potent, orally bioavailable small molecule inhibitors of PLK4 that are highly selective, including against the closely related aurora kinases and PLK1-3.
ORIC PLK4 selective inhibitors show greater potency in TRIM37 high cancer cell lines relative to low TRIM37 low cell lines, whereas no differential was observed for non-selective inhibitors.
Apoptotic cell death was observed solely in TRIM37 high cancer cells for ORIC PLK4 selective inhibitors, in contrast to non-selective inhibitors which did not show this synthetic lethality.
Using a genetically engineered PLK4 cell line variant (PLK4 G95L) that prevents compound-mediated inhibition of PLK4, selective PLK4 inhibitors lose activity in TRIM37 high G95L cells, confirming on-target cell activity, compared with non-selective inhibitors whose cell potency is not dependent on PLK4 inhibition.
PLK4 inhibition blocks trans-autophosphorylation and PLK4 protein degradation and correlates with cell viability for selective compounds, and not for non-selective inhibitors.
Together these mechanistic data confirm the potential of highly selective PLK4 inhibition as a synthetic lethal therapy for TRIM37 amplified/elevated cancers.