On November 20, 2024 Pathios Therapeutics ("Pathios"), a biotech company focused on the development of first-in-class therapies for cancer, reported dosing of the first patient in the initial module of a Phase 1/2 clinical trial evaluating PTT-4256, the company’s investigational first-in-class GPR65 inhibitor (Press release, Pathios Therapeutics, NOV 20, 2024, View Source [SID1234648522]). PTT-4256 is an internally discovered, oral, highly potent, and selective small molecule inhibitor of the pH-sensing GPR65.

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The RAISIC-1 trial (Relief of Acidic Immune Suppression in Cancer) is a modular multi-part, multi-arm open-label study being conducted in Australia. The study’s first module is designed to evaluate the safety, tolerability, preliminary efficacy and pharmacokinetics of PTT-4256 monotherapy in patients with a range of advanced solid tumours. Subsequent modules will explore the potential of PTT-4256 in specific tumour types, including in combination with different standards of care.

"The transition of our first-of-its-kind GPR65 Inhibitor in immunooncology into the clinic represents a significant milestone for our company and is a validation of the promise of this approach and of the hard work of the entire Pathios team," said Paul G. Higham, Chief Executive Officer of Pathios. "This multi-module trial has been carefully designed to provide a range of valuable data on PTT-4256 that will be critical to our continued clinical advancement of the program. In addition to important safety, tolerability and pharmacokinetic findings, this clinical trial includes investigating the activity of this novel target and mechanism in humans for the first time through measuring disease response and exploring links to biomarkers designed to elucidate the consequences of target engagement."

Pathios is pursuing this novel immunooncology approach which focuses on counteracting the immunosuppressive polarization of immune cells, blocking a ubiquitous cancer immune evasion pathway through the targeting of GPR65, an acid sensing a G protein-coupled receptor that has been shown to foster immunosuppressive polarization of immune cells. GPR65 is exclusively expressed on immune cells and is associated with driving the immunosuppressive immune cell phenotype in the tumour microenvironment (TME) that prevents immune-mediated killing of cancer cells.

Pathios’ human genetic analysis demonstrates that reductions in GPR65 function are associated with significantly improved survival across a range of solid tumour types, positioning it as a unique immunooncology target for therapeutic intervention. Preclinical data for PTT-4256 have demonstrated that the compound possesses excellent drug-like properties and impressive monotherapy anti-tumour activity.

The RAISIC-1 trial is being run by the Australian-based team at Pathios Therapeutics Pty Ltd, in partnership with key Australian clinical trial sites and collaborators, contract research organisations and M:M Bio Pty Ltd, part of the global Molecule to Medicine (MTM) ecosystem of companies. The study has been approved by the applicable Australian Ethics Committees and is being conducted under the Australian Therapeutic Goods Administration’s (TGA’s) Clinical Trial Notification (CTN) scheme. It has been registered on the World Health Organisation recognised clinical trial registry ClinicalTrials.gov with trial identifier NCT06634849.

On November 20, 2024 Pasithea Therapeutics Corp. (NASDAQ: KTTA) ("Pasithea" or the "Company"), a clinical-stage biotechnology company developing PAS-004, a next-generation macrocyclic MEK inhibitor, for the treatment of neurofibromatosis type 1 (NF1) and other cancer indications, reported that the external Safety Review Committee recommended proceeding to cohort 4, 15mg capsule, without modifications (Press release, Pasithea Therapeutics, NOV 20, 2024, View Source [SID1234648521]). This recommendation was based on the absence of any dose limiting toxicities (DLT’s). In addition, no rash was observed in any of the first 9 patients who received PAS-004. The Company has decided to add a cohort 4b to the trial, which will consist of 3 additional patients and introduce an alternate formulation which is intended for commercial use.

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Dr. Tiago Reis Marques, Chief Executive Officer of Pasithea stated, "We are pleased to observe that as we continue to dose escalate, we have not yet seen rash emerge. Rash is a common adverse event (AE) that is observed at low doses with competitor MEK inhibitors and may lead to the high discontinuation rate in real world practice. In addition, we are excited to dose patients with our potential commercial formulation."

The Phase 1 clinical trial is a multi-center, open-label, dose escalation 3+3 study design to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy of PAS-004 in patients with MAPK pathway driven advanced solid tumors with a documented RAS, NF1 or RAF mutation, or patients who have failed BRAF/MEK inhibition (NCT06299839).

PAS-004 Demonstrates a Differentiated MEK Inhibitor Profile

Unlike first-generation MEK inhibitors for the treatment of NF1 that require twice-daily dosing (BID) and exhibit short half-lives (<8 hours), PAS-004 has the potential to achieve prolonged target inhibition and once-daily dosing (QD) due to its long half-life of approximately 70 hours. As disclosed previously, the PK profile shows consistent plasma levels at steady-state, as reflected by a low Cmax to Cmin ratio, potentially reducing the risks for Cmax-related toxicity. These findings provide a compelling rationale for the advancement of PAS-004 into clinical trials for both the treatment of cutaneous and plexiform neurofibromas in NF1, cancer and other MAPK-driven opportunities. The company expects to provide additional trial updates on a periodic basis as the trial progresses.

On November 20, 2024 Novavax presented its corporate presentation (Press release, Novavax, NOV 20, 2024, View Source [SID1234648520]).

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On November 20, 2024 Mural Oncology plc (Nasdaq: MURA), a clinical-stage immuno-oncology company developing novel, investigational engineered therapies targeting cytokine pathways designed to address areas of unmet need for patients with a variety of cancers, reported the publication of previously reported clinical data demonstrating tolerability and antitumor activity from ARTISTRY-1, a phase 1/2 trial of the company’s lead candidate, nemvaleukin alfa (nemvaleukin) (Press release, Mural Oncology, NOV 20, 2024, View Source [SID1234648519]). The paper, titled "Nemvaleukin alfa as monotherapy and in combination with pembrolizumab in advanced solid tumors: the phase 1/2, non-randomized ARTISTRY-1 trial," was published in the Journal for ImmunoTherapy of Cancer (JITC).

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"While immunotherapies have marked a paradigm shift in the treatment of some types of cancers, many patients still face challenges, including lack of response, tolerability issues, or resistance to therapy, and there remains a great deal of unmet clinical need. In the ARTISTRY-1 study, notable antitumor activity of nemvaleukin was observed in both monotherapy and combination therapy. What was most striking were the durable and complete responses in platinum-resistant ovarian cancer, which does not usually respond to immunotherapy. These clinical data provide a solid foundation for Mural’s ongoing late-stage trials," said Ulka Vaishampayan, MD, Professor, Internal Medicine, Division of Hematology/Oncology at the University of Michigan and the paper’s lead author.

Nemvaleukin is a novel, engineered fusion protein designed to leverage the antitumor effects of the IL-2 pathway while mitigating aldesleukin’s toxicity. ARTISTRY-1 was a three-part, open-label, phase 1/2 study evaluating the safety, tolerability, and efficacy of both nemvaleukin monotherapy and combination therapy with pembrolizumab. The study was conducted at 32 sites in seven countries, with 286 patients with advanced solid tumors enrolled and treated from July 2016 to March 2023.

ARTISTRY-1 is the foundation of Mural’s two ongoing potentially registrational trials, with data readouts expected in late Q1/early Q2 2025 for platinum-resistant ovarian cancer (PROC) and Q2 2025 for mucosal melanoma.

Key Findings:

As previously reported, nemvaleukin was generally well tolerated and demonstrated promising antitumor activity alone and in combination with pembrolizumab across heavily pretreated patients with advanced solid tumors. Robust expansion of CD8+ T cells and natural killer (NK) cells, with minimal expansion of regulatory T (Treg) cells were observed following treatment, thus supporting the design hypothesis of nemvaleukin.

Monotherapy:

10% overall response rate (ORR) with nemvaleukin monotherapy (7/68; 95% CI 4 to 20), with all seven confirmed partial responses (melanoma, n=4; renal cell carcinoma, n=3).
33.3% ORR in patients with mucosal melanoma, with two partial responses (one confirmed, one unconfirmed) in six evaluable patients. All responders had been on prior CPI therapy and progressed.
Combination therapy:

13% ORR with nemvaleukin and pembrolizumab (19/144; 95% CI 8 to 20), with five confirmed complete responses and 14 confirmed partial responses. Six responses were in PD-(L)1 inhibitor-approved and five in PD-(L)1 inhibitor-unapproved tumor types.
21% ORR in patients with PROC: Notably, there were three confirmed responses (two complete, one partial) in 14 evaluable patients with PROC, which does not normally respond to immunotherapy and for which there are no approved immunotherapies. Additionally, there was one unconfirmed partial response.
Durable, stable disease for greater than 6 months was observed in patients with cervical cancer, bladder cancer, non-small-cell lung cancer, PROC, and endometrial cancer.
Safety and Tolerability:

Nemvaleukin was administered in an outpatient setting throughout treatment and had a manageable safety profile, with a low rate (4%) of discontinuation due to adverse events.
Most common grade 3-4 treatment-related adverse events (TREAs) were neutropenia and anemia.

On November 20, 2024 Lineage Cell Therapeutics, Inc. (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing allogeneic cell therapies for unmet medical needs, reported that it entered into definitive agreements with certain healthcare focused institutional investors and with Broadwood Partners, L.P. ("Broadwood"), an affiliate of Neal Bradsher, a member of Lineage’s board of directors, for the purchase and sale of up to an aggregate of 39,473,688 of Lineage’s common shares and accompanying warrants (the "common warrants") to purchase an aggregate of up to 39,473,688 of Lineage’s common shares at a combined purchase price of $0.76 per common share and accompanying common warrant, in a registered direct offering (Press release, Lineage Cell Therapeutics, NOV 20, 2024, View Source [SID1234648518]). Each common warrant will be exercisable for one common share at an exercise price of $0.91 per common share and will be exercisable commencing six months following their date of issuance and will expire on the earlier of (a) the three-year anniversary of the initial exercise date, and (b) the 90th day following the date of the public disclosure of the intent to advance OpRegen (also known as RG6501) into a multi-center phase 2 or 3 clinical trial which includes a control or comparator arm, or if the date of such public disclosure occurs prior to the initial exercise date of the common warrants, the 90th day following the initial exercise date. However, the common warrants that may be issued to Broadwood will not be exercisable until the later of (i) their date of issuance, which will be the date shareholder approval is obtained, and (ii) the six-month anniversary of the date of issuance of the common warrants to the unaffiliated institutional investors in the offering.

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

The offering of the securities to the unaffiliated institutional investors is expected to close on or about November 21, 2024, subject to the satisfaction of customary closing conditions. The offering of the securities to Broadwood is expected to close upon obtaining shareholder approval to satisfy applicable NYSE American rules and to the satisfaction of customary closing conditions.

Lineage expects to receive $24 million in aggregate gross proceeds from the offering with respect to the investments by the unaffiliated institutional investors, and approximately $6 million in aggregate gross proceeds from the offering with respect to the investment by Broadwood, in each case, before deducting the placement agent’s fees and other offering expenses payable by Lineage. The potential additional gross proceeds to Lineage from the common warrants, if fully exercised on a cash basis, will be approximately $36 million. No assurance can be given that Lineage will obtain the shareholder approval required to satisfy applicable NYSE American rules in order to sell the securities in the offering to Broadwood or that any of the common warrants will be exercised. Lineage currently plans to use the net proceeds from the offering for working capital and general corporate purposes, including research and development expenses and capital expenditures.

The securities described above are being offered and sold by Lineage in a registered direct offering pursuant to a "shelf" registration statement on Form S-3 (File No. 333-277758) filed with the Securities and Exchange Commission (the "SEC") on March 7, 2024, and which was declared effective by the SEC on May 14, 2024. The offering of the securities in the registered direct offering is being made only by means of a base prospectus and a prospectus supplement that forms a part of the effective registration statement. A final prospectus supplement and the accompanying base prospectus relating to the offering will be filed with the SEC and will be available on the SEC’s website at www.sec.gov. Electronic copies of the final prospectus supplement and the accompanying base prospectus may also be obtained, when available, from 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].