On April 8, 2022 Theseus Pharmaceuticals, Inc. (NASDAQ: THRX) (Theseus or the Company), a clinical-stage biopharmaceutical company focused on improving the lives of cancer patients through the discovery, development and commercialization of transformative targeted therapies, reported preclinical data characterizing next-generation pan-variant EGFR inhibitors that will be detailed in a live poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2022 Annual Meeting, being held April 8-13, 2022 in New Orleans, Louisiana (Press release, Theseus Pharmaceuticals, APR 8, 2022, View Source [SID1234611790]). The poster highlights advanced lead compounds for use in non-small cell lung cancer (NSCLC) that have been observed to potently inhibit the kinase activity, both in vitro and in vivo, of all major single-, double-, and triple-mutant EGFR variants, including T790M and C797S, with selectivity over wild-type EGFR and the ability to penetrate the central nervous system (CNS).

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"Up to half of all non-small cell lung cancer tumors are driven by activating mutations (single-mutants) in EGFR and up to 90 percent of those mutations are found in exons 19 and 21. Furthermore, as patients progress through lines of treatment, a substantial percentage of patients’ tumors may develop one or more additional EGFR mutations (double- and triple-mutants) that cause resistance to treatment," said William Shakespeare, Ph.D., President of Research and Development at Theseus. "At Theseus, we have developed a series of potent and selective, single molecule, fourth-generation EGFR inhibitors that are designed to inhibit all major classes of EGFR activating and resistance mutations that contribute to later-line clonal heterogeneity in patients who have been failed by current approved therapies. We are finalizing preclinical studies to characterize our lead compounds and look forward to designating a development candidate in the third quarter of this year."

The preclinical data presented at AACR (Free AACR Whitepaper) demonstrates that pan-variant EGFR inhibition of all major single-, double-, and triple-mutants, including T790M and C797S, with selectivity over wild-type, is achievable with a single molecule. Detailed findings show that:

Theseus’ lead compounds potently inhibited all major single-, double-, and triple-mutant EGFR variants in vitro, demonstrating cellular IC50 values between 2-12 nM.
Lead compounds displayed favorable selectivity over wild-type EGFR, with ratios between 11- to 88-fold.
An advanced lead compound demonstrated tumor regressions in mice against variants associated with both 1st and 2nd line osimertinib clinical failure – i.e., C797S double- and triple-mutants – at well-tolerated doses.
This lead compound also demonstrated a brain:plasma ratio consistent with predicted activity against CNS metastatic disease.
Studies to further characterize lead compounds are under way, with additional data expected to be presented at a scientific conference in the second half of 2022.

Presentation details:

Poster Title: Discovery of potent and selective next-generation EGFR inhibitors with activity against single, double, and triple mutant EGFR variants including T790M and C797S

Poster Number: 3342

Presenter: Wei-Sheng Huang, Ph.D., Vice President of Chemistry

Session Date and Time: Live presentation on Tuesday, April 12TH, 1:30pm – 5pm CT

About NSCLC
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 2.2 million cases of lung cancer diagnosed in 2020. Up to half of NSCLC patients have tumors that are driven by activating mutations in the epidermal growth factor receptor (EGFR) and up to 90 percent of those mutations are found in exons 19 and 21. [Most] patients’ tumors, in response to treatment, develop one or more additional EGFR mutations, causing resistance and rendering current therapies ineffective.

On April 8, 2022 Arcellx, Inc. (NASDAQ: ACLX), a biotechnology company reimagining cell therapy through the development of innovative immunotherapies for patients with cancer and other incurable diseases, reported the presentation of preclinical data utilizing its novel ARC-SparX platform for ACLX-002, a CD123-targeted universal CAR-T cell therapy for relapsed or refractory Acute Myelogenous Leukemia (AML) and high-risk myelodysplastic syndrome (MDS) (Press release, Arcellx, APR 8, 2022, View Source [SID1234611789]). The data show that ACLX-002 completely regressed disseminated MOLM14 and MV4-11 tumors in a schedule and dose-dependent manner without the aid of alloreactivity and performs similarly to a traditional CD123-targeting D-domain based CAR. Additionally, ACLX-002 completely regresses multiple cell line and patient-derived AML xenografts.

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"There are limited treatment options for AML and MDS patients as heterogeneity is known to be a major challenge for targeted therapeutics in this patient population," said Rami Elghandour, Arcellx’s chairman and chief executive officer. "Our ARC-SparX platform is designed to allow for controllability and adaptability, to potentially reduce toxicities that are often associated with serious dose-limiting adverse events and to overcome tumor heterogeneity. These ACLX-002 preclinical data provide the scientific rationale to move forward with initiating a Phase 1 clinical trial and our ambition to deliver a meaningful treatment option for these patients. We look forward to starting this study in the second half of this year."

The data are being presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting taking place April 8-13, 2022. Presentation details are as follows:

The poster can be accessed through the AACR (Free AACR Whitepaper) Annual Meeting program or the company’s corporate website www.arcellx.com/pipeline-focus-area/#scientific-publications

About the ARC-SparX Platform Technology
The ARC-SparX platform is designed to allow for controllability and adaptability, to potentially reduce toxicities that are often associated with serious dose-limiting adverse events and to overcome tumor heterogeneity. It is a modular therapy which utilizes a universal ARC-T cell combined with an off the shelf SparX protein to separate the tumor-recognition and tumor-killing functions. SparX (soluble protein antigen-receptor X-linkers) proteins utilize our D-Domain technology engineered to recognize antigens on the surface of diseased cells and flags those cells for detection by the ARC-T (Antigen Receptor Complex-T) cells. ARC-T cells express a D-Domain-based CAR engineered to specifically recognize a unique TAG in the SparX protein. ARC-T cells are dosed separately and only activated to kill the target cell when they encounter a SparX protein bound to the target antigen thus are controlled through SparX dose modulation. Arcellx has developed a collection of SparX proteins that bind different antigens on the surface of diseased cells. Multiple SparX proteins with different antigen specificity can be administered to potentially address antigen heterogeneity or antigen escape that contribute to relapsed and refractory disease.

On April 8, 2022 Omega Therapeutics (NASDAQ: OMGA) (Omega), a development-stage biotechnology company pioneering the first systematic approach to use mRNA therapeutics as a new class of programmable epigenetic medicines by leveraging its OMEGA Epigenomic Programming platform, reported that it will present preclinical data highlighting the potential of its lead Omega Epigenomic Controller, OTX-2002, to regulate overexpression of the c-Myc (MYC) oncogene in models of hepatocellular carcinoma (HCC) in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022, taking place in New Orleans, Louisiana, April 8-13, 2022 (Press release, Omega Therapeutics, APR 8, 2022, View Source [SID1234611786]).

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"Despite its essential role in a broad range of cancers, MYC has remained undruggable to date," said Thomas McCauley, Ph.D., Chief Scientific Officer of Omega Therapeutics. "However, we believe that targeting the MYC gene pre-transcriptionally within its Insulated Genomic Domain (IGD), and epigenetically tuning it using our epigenomic controller, could overcome the challenges that have limited previous technologies including small molecules, antisense oligos and siRNA. We believe that these data strongly support OTX-2002’s ability to tune and restore MYC expression to a normal range and demonstrate the broader potential of our Epigenomic Programming platform to tackle previously intractable diseases. We are excited to continue advancing OTX-2002 into clinical trials and look forward to filing an Investigational New Drug application in the first half of this year."

Key findings

A single dose of OTX-2002 induced durable changes in the epigenetic profile of the MYC gene
OTX-2002 reduced MYC mRNA expression and protein levels over approximately 2 weeks in vitro
Downregulation of MYC in multiple HCC cell lines resulted in significant loss in viability of MYC-addicted cancer cells while sparing normal cells
In murine xenograft HCC models, OTX-2002 significantly reduced tumor growth and was well-tolerated
Cumulatively, these data support the filing of an Investigational New Drug application with the U.S. Food and Drug Administration for the clinical development of OTX-2002 in the first half of 2022.

The poster can be viewed on the Omega website at View Source

About OTX-2002

OTX-2002 is a first-in-class Omega Epigenomic Controller in development for the treatment of hepatocellular carcinoma (HCC). OTX-2002 is designed to modulate levels of c-MYC (MYC) expression by utilizing targeted mRNA-expressed proteins to mediate epigenetic regulation while potentially overcoming MYC autoregulation. The MYC oncogene is associated with aggressive disease in up to ~70% of patients with HCC. Omega is currently evaluating OTX-2002 in Investigational New Drug (IND)-enabling studies.

On April 8, 2022 Kazia Therapeutics Limited (NASDAQ: KZIA; ASX: KZA), an oncology-focused drug development company, reported new preclinical data demonstrating the activity of paxalisib in two forms of childhood brain cancer with very high unmet medical need (Press release, Kazia Therapeutics, APR 8, 2022, View Source [SID1234611784]).

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This data is the subject of three abstracts presented at the Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), held in New Orleans, LA, from April 8 – 13, 2022.

Two abstracts by scientists working in the laboratory of Assistant Professor Jeffrey Rubens at Johns Hopkins University in Baltimore, MD, describe the use of paxalisib as a backbone therapy in a childhood brain cancer known as atypical teratoid / rhabdoid tumours (AT/RT). This is the first time that data exploring paxalisib in this form of brain cancer has been presented, and it opens an important new potential indication for the drug.

The third abstract, from a different team of scientists at Johns Hopkins University, led by Associate Professor Eric Raabe and Dr Katherine Barnett, showed evidence of strong synergy between paxalisib and another class of cancer therapies in a model of diffuse intrinsic pontine glioma (DIPG). Paxalisib has previously shown evidence of activity in this disease, both as monotherapy and in combination with several types of cancer therapy, and the new data further validates its potential in this very challenging disease.

Key Points

AT/RT is a rare brain cancer that predominantly affects infants and young children. There are no FDA approved drugs for AT/RT and existing therapeutic options are very limited. Fewer than one in five patients survive more than two years from diagnosis.
Data from Professor Rubens’ laboratory shows that the PI3K pathway is commonly activated in AT/RT, and that treatment with paxalisib alone is active in preclinical models of the disease. Moreover, combination with either RG2822, an HDAC inhibitor, or TAK580, a MAPK inhibitor, appears to substantially extend survival when compared to monotherapy treatment.
DIPG is a rare brain cancer that is typically seen in young children and adolescents. There are no FDA approved drugs, and average life expectancy from diagnosis typically averages around ten months.
Previous data from several teams of researchers, and particularly from Professor Matt Dun’s team at the Hunter Medical Research Institute, has shown that paxalisib is highly active in DIPG and combines synergistically with several cancer drugs.
Data from Drs Raabe and Barnett and colleagues identifies an additional novel treatment combination, with the HDAC inhibitor RG2833, which exhibits evidence of strong synergy in a preclinical model of DIPG.
Kazia CEO, Dr James Garner, added, "This is very promising data, and we are grateful to the team at Johns Hopkins for this important and encouraging research. Paxalisib is already the subject of an ongoing phase II clinical trial in DIPG and diffuse midline gliomas (NCT05009992) and this new data suggests potential wider applications for the drug in childhood brain cancers. We look forward to working with the Johns Hopkins team, and with other partners and advisors, to explore these opportunities further."

Summary of Abstracts

SESSION OPO.CL02.01 – Pediatric Cancer: Clinical Investigations

April 8, 2022 – 12:00pm-1:00pm

Abstract 5225 – The PI3K inhibitor Paxalisib combines with the novel HDAC1/3 inhibitor RG2833 to improve survival in mice bearing orthotopic xenografts of atypical teratoid/rhabdoid tumors
Tyler Findlay, Kristen Malebranche, Charles Eberhart, Eric Raabe, Jeffrey Rubens.
Johns Hopkins School of Medicine, Baltimore, MD

Abstract 5226 – The PI3K inhibitor Paxalisib combines synergistically with the pan-Raf inhibitor TAK580 (DAY 101) to extend survival in orthotopic xenograft models of atypical teratoid/rhabdoid tumors
Kristen Malebranche, Tyler Findlay, Charles Eberhart, Eric Raabe, Jeffrey Rubens.
Johns Hopkins School of Medicine, Baltimore, MD

SESSION PO.ET04.01 – Identification of Molecular Targets

April 13, 2022 – 9:30am-12:30pm

Abstract 3987 / 9 – Brain penetrant HDAC and PI3K/mTOR inhibitors synergize to induce DIPG cell death
Katherine Barnett, Hyuk Jean Kwon, Orlandi Novak, Charles Eberhart, Eric Raabe.
Johns Hopkins Hospital, Baltimore, MD

On April 8, 2022 Bantam Pharmaceutical, a drug discovery and development company targeting selective modulation of mitochondrial dynamics in cancer, reported that it will present new data on its lead drug candidate BTM-3566 at AACR (Free AACR Whitepaper) 2022 taking place the 8th-13th of April in New Orleans (Press release, Bantam Pharmaceutical, APR 8, 2022, View Source [SID1234611783]). The data demonstrate that BTM-3566 co-opts a specific mitochondrial quality control pathway to induce apoptosis in cell lines, xenografts and patient-derived xenograft (PDX) models of Diffuse Large B-cell Lymphoma (DLBCL).

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The poster presentation on Wednesday, April 13th highlights the robust in vivo activity of BTM-3566, including complete and durable regressions in 6 out of 9 PDX models with a 100% response rate across a range of difficult to treat DLBCL tumors. Equally important, BTM-3566 acts through a novel mechanism of action with activity across multiple genomic and phenotypic subtypes of DLBCL, suggesting this represents an impactful treatment option for patients progressing on existing standard-of-care agents. Emerging data characterizing the responses and dependency on expression of a mitochondrial protein will also be presented.

The abstract is available now on the AACR (Free AACR Whitepaper) website.

Michael Stocum, CEO of Bantam Pharmaceutical, commented: "We are excited to be presenting this new data at AACR (Free AACR Whitepaper). Together with our academic collaborators, we continue enhancing our understanding of the novel mechanism of BTM-3566 and its capacity to induce apoptosis in cancer cells. We expect to file an Investigational New Drug (IND) application for BTM-3566 this quarter (2Q 2022) and are prepared to initiate clinical trials later this year. Our IND and pre-clinical data are generating significant enthusiasm with oncologists as we advance toward the clinic."

Title: BTM-3566 co-opts mitochondrial quality control pathways to induce apoptosis, and complete tumor regression in DLBCL cell lines, xenografts and PDX models

About BTM-3566

BTM-3566 is an orally-available novel small molecule compound with broad anti-cancer activity in hematologic and solid tumors, initially focused on Diffuse Large B-cell Lymphomas (DLBCL). BTM-3566’s anti-cancer mechanism of action is unique and differentiated from other therapeutics, disrupting mitochondrial function in tumor cells to induce apoptosis (cell death). An IND application for BTM-3566 in B-cell malignancies is being completed for submission in Q2 2022.