On October 26, 2022 AI Metrics, an early stage AI-enabled, cancer-imaging radiology software company, reported that it has raised $1.26MM in a bridge financing round (Press release, Metrics, OCT 26, 2022, View Source [SID1234622433]). The round was led by an angel fund and several individual investors, many of them leading radiologists.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

AI Metrics was launched in 2019 by Bob Jacobus, Paige Severino, and radiologist and researcher Dr. Andrew Smith. The company has been developing software to more accurately assess cancer treatment effectiveness — leveraging augmented intelligence to improve radiology workflows and deliver detailed updates of therapy progress to oncologists and patients.

"We are excited to have a mix of existing and new investors support AI Metrics, including several radiologists who are attracted to our promising and innovative technology," said Bob Jacobus, CEO. "AI Metrics expanded its investor base with field experts eager to capitalize on what they see as a breakthrough technology coming to market."

AI Metrics plans to invest in R&D resources to continue its quest to help radiologists deliver improved speed, accuracy, consistency, and clarity of patient condition.

On October 26, 2022 Flare Therapeutics, a biotechnology company targeting transcription factors to discover precision medicines for cancer and other diseases, reported that new preclinical data in a poster presentation titled, "Novel inhibitors of the luminal lineage transcription factor peroxisome proliferator-activated receptor gamma (PPARG) durably eradicate tumors in urothelial cancer (UC) animal models" at the 34th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium in Barcelona, Spain (Press release, Flare Therapeutics, OCT 26, 2022, View Source [SID1234622432]). The data presented by Robert Sims, Ph.D., Chief Scientific Officer and Co-founder of Flare, show that FTX-6746, a potent, selective, small molecule PPARG inhibitor (inverse agonist), drives robust PPARG target gene silencing in UC cell lines and drives tumor regression in PPARG-amplified and RXRA-mutant UC xenograft models.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Targeting cell lineage-defined transcription factors with small molecules is a proven and effective therapeutic strategy, as demonstrated by estrogen and androgen receptor therapies for breast and prostate cancers. Our goal is to add PPARG to that list, to potentially enable treatment of urothelial cancers. Leveraging our deep expertise in transcription factor biochemistry, we engineered compounds capable of driving a powerful repressive conformation of PPARG with high specificity, thereby inducing significant pharmacological effects," said Dr. Sims. "In preclinical models, FTX-6746 demonstrated a favorable therapeutic profile, suppressing PPARG target genes with durable tumor regression at well-tolerated doses. We are currently advancing a novel PPARG inhibitor through IND-enabling studies and plan to advance that therapeutic candidate into the clinic in 2023 in locally advanced or metastatic UC."

Data highlights:

FTX-6746 drives an enhanced repressive conformation to overcome UC mutations
FTX-6746 counteracts the activating effects of recurrent PPARG and RXRA missense mutations in preclinical models of UC
FTX-6746 treatment results in robust PPARG target gene silencing in cells (average 50% maximal inhibitor concentration (IC50) ~5 nM); in vitro growth inhibition is preferentially observed in cell lines with activated PPARG signaling
Tumor growth inhibition or regression was observed in PPARG-amplified and RXRA-mutant UC xenograft models, with no tumor regrowth upon cessation of treatment
"Today’s data presentation demonstrates the strength and depth of Flare’s research platform and our teams’ ability to rapidly advance a first in class molecule in precision oncology," said Amit Rakhit, M.D., Chief Executive Officer of Flare Therapeutics. "Flare is poised to transition to a clinical-stage company early next year with our lead molecule in the PPARG program. Given the high unmet medical need with poor survival in advanced stages of disease, novel approaches that provide alternative therapeutic options are needed for people living with bladder cancer."

About Urothelial Cancer

Muscle-invasive UC is a common type of bladder cancer, with about 20,000 individuals diagnosed each year in the United States alone, and significantly higher incidence rates in other regions of the world. This disease has high rates of recurrence and the five-year survival rate is approximately 5% in metastatic cases. The transcription factor peroxisome proliferator-activated receptor gamma (PPARG) is associated with the luminal lineage subtype reflecting approximately 65% of all advanced UC patients. Recurrent genetic alterations in PPARG, including focal amplification, missense mutations, and fusions, as well as hotspot mutations in its binding partner, retinoid X receptor alpha (RXRA) are characteristic of this molecular subtype.

On October 26, 2022 Exscientia plc (Nasdaq: EXAI) reported that new data aimed at enriching for patients that are more likely to respond to its precision-designed CDK7 inhibitor, GTAEXS-617 (‘617) (Press release, Exscientia, OCT 26, 2022, View Source [SID1234622430]). The research confirmed a CDK7-specific pharmacodynamic (PD) biomarker, while revealing potential novel PD markers, and identified an initial novel patient selection gene expression signature that will, in part, be evaluated in its planned Phase 1/2 study. The data are being presented at the 34th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) (ENA 2022) Symposium on Molecular Targets and Cancer Therapeutics, being held October 26-28, 2022, in Barcelona, Spain.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

In this study, researchers leveraged Exscientia’s translational oncology platform, combining AI-based primary cancer tissue profiling with transcriptomics, to understand how cells from diverse patient populations respond to therapy with ‘617. Results demonstrated differential sensitivity in some patient samples, enabling Exscientia to correlate response with individual patient genomic and phenomic profiles. These correlations can then be used to identify which patients are most likely to respond to ‘617 therapy and can be incorporated into upcoming clinical trials.

In addition, the data showed that ‘617 induced less cell death on immune cells than select CDK4/6 and other investigational CDK7 inhibitors, potentially indicating a differentiated clinical safety profile. ‘617 is currently in IND-enabling studies as a potential treatment for transcriptionally addicted cancers.

"We’re excited to highlight new data supporting the power of our translational platform to rapidly assess the activity of new targeted therapies that could lead to improved clinical outcomes for patients," said Gregory Vladimer, VP of Translational Research at Exscientia. "By leveraging our functional precision medicine platform coupled with single cell transcriptomics and AI modeling in primary disease tissue, we believe we are uniquely positioned to enrich studies for patient groups more likely to respond, or not respond, to a therapy, therefore meaningfully improving cancer treatment outcomes for patients."

Poster Presentation Details:
Title: Defining activity and patient selection of a novel CDK7 inhibitor, GTAEXS-617, through AI-supported primary cancer tissue profiling
Poster Session Title: Preclinical Models
Abstract Number: #124
Date/Time: Wednesday, October 26 / 12:00 PM – 8:00 PM CET

GTAEXS-617 is a novel CDK7 inhibitor that has been designed by Exscientia in collaboration with GT Apeiron for high potency, selectivity, bioavailability and safety. CDK7 inhibition combines cell cycle disruption with transcription inhibition, making it an attractive target to overcome common resistance pathways in CDK4/6 inhibition.

Exscientia anticipates submitting a Clinical Trial Application (CTA) by the end of 2022 and initiating a Phase 1/2 clinical trial in multiple solid tumour indications, including ovarian cancer, in the first half of 2023.

The poster is available on Exscientia’s website.

On October 26, 2022 Scorpion Therapeutics, Inc. ("Scorpion"), a pioneering oncology company redefining the frontier of precision medicine through its Precision Oncology 2.0 strategy, reported preclinical proof-of-concept data for STX-721, the Company’s first development candidate from its STX-EGFR-EXON-20 program (Press release, Scorpion Therapeutics, OCT 26, 2022, View Source [SID1234622429]). STX-721 is a next-generation, orally delivered therapy, designed with potential best-in-class selectivity for exon 20 insertion mutations in epidermal growth factor receptors ("EGFR"), a well-known, clinically validated oncogenic driver in non-small cell lung cancer ("NSCLC"). The data will be presented today in a poster session at the European Organisation for Research and Treatment of Cancer, the National Cancer Institute, and the American Association for Cancer Research (AACR) (Free AACR Whitepaper) ("EORTC-NCI-AACR") Symposium 2022 in Barcelona, Spain.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are excited to share the first preclinical data for STX-721, our next-generation, highly-differentiated EGFR exon 20 inhibitor," said Axel Hoos, M.D., Ph.D., Chief Executive Officer of Scorpion. "The discovery and progression of this development candidate in less than two years is further validation of our Precision Oncology 2.0 strategy, designed to exceed the speed, efficiency and quality of traditional target and drug discovery approaches. The data presented at EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) support our selection of STX-721 as our second clinical program, demonstrating potentially best-in-class selectivity that we anticipate will result in a wider therapeutic index and greater efficacy compared to currently marketed therapies and other drug candidates in development. We look forward to submitting an IND application for STX-721 next year, as we aim to transform the lives of thousands of people living with exon 20 insertion mutant EGFR-driven NSCLC who are underserved by existing therapeutics."

NSCLC is the most common form of lung cancer and EGFR mutations are one of the most common mutations in NSCLC. For cancers resulting from an EGFR L858R or exon 19 deletion, osimertinib is a highly selective EGFR mutation-targeting therapy, which achieves a high and durable objective response rate ("ORR") of approximately 80 percent.1 Commercially available therapies for NSCLC patients with EGFR exon 20 insertion mutations have more moderate clinical efficacy (28-40% ORR2,3) and are further limited by significant toxicities associated with the inhibition of wild-type EGFR in healthy tissues such as the skin and GI tract. These toxicities can lead to dose reductions or interruptions which in turn, may reduce the overall efficacy of the treatment.

In the poster presented at EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper), Scorpion scientists will share data from preclinical studies evaluating STX-721 across a broad panel of exon 20 mutant cell lines, with the high selectivity of osimertinib against EGFR T790M mutant cells used as a benchmark for EGFR mutant selectivity. In these studies, STX-721 demonstrated strong EGFR exon 20 mutant potency and selectivity in isogenic Ba/F3 models and human cancer cell lines, as well as signaling and biochemical assays. Importantly, the selectivity of STX-721 for EGFR exon 20 was observed to well exceed that of clinical-stage competitor benchmarks in each of these model systems, while also approaching the selectivity of osimertinib against EGFR L858R and exon 19 deletion mutations.

In addition, STX-721 demonstrated strong in vivo anti-tumor activity across a variety of EGFR and HER2 exon 20 mutant cell line-derived xenograft ("CDX") and patient-derived xenograft ("PDX") models. STX-721 also demonstrated a clear exon 20 genotype-selective in vivo efficacy window in isogenic cancer CDX models, which was not observed with clinical-stage competitor benchmarks. All efficacious and in vivo selective doses of STX-721 were well-tolerated throughout these preclinical studies.

"Leveraging our prowess in covalent drug discovery, a foundational pillar of our drug-hunting platform, we developed an entirely new chemical scaffold for our STX-EGFR-Exon-20 program. This allowed us to overcome the lack of intrinsic selectivity for exon 20 insertion mutations that has hindered most approved or investigational EGFR exon 20 inhibitors and to design a molecule with selectivity comparable to osimertinib, the standard-of-care therapy for patients with L858R or exon 19 deletion," said Darrin Stuart, Ph.D., chief scientific officer of Scorpion Therapeutics. "The data presented at EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) underscore STX-721’s potential to provide a best-in-class option for patients harboring cancers with EGFR exon 20 mutations, and we look forward to advancing our candidate to deliver a transformational therapy to this underserved population."

Based on the data being shared at EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper), Scorpion named STX-721 as the lead development candidate from its STX-EGFR-EXON-20 program in June 2022. STX-721 is currently advancing through preclinical development, with an investigational new drug application submission expected in 2023. Scorpion anticipates advancing STX-721 as a monotherapy and in relevant combinations with approved standard-of-care agents.

The poster presentation is now available here and under "Media" in the News section of Scorpion’s website: View Source

On October 26, 2022 Cyclacel Pharmaceuticals, Inc. (NASDAQ: CYCC, NASDAQ: CYCCP; Cyclacel or the Company), a biopharmaceutical company developing innovative medicines based on cancer cell biology, reported preliminary dose escalation data from its ongoing 065-101 Phase 1/2 clinical study of oral fadraciclib, a cyclin dependent kinase (CDK) 2/9 inhibitor, for the treatment of patients with advanced solid tumors and lymphoma (Press release, Cyclacel, OCT 26, 2022, View Source [SID1234622428]). Of the 18 patients evaluable for response, two out of three T cell lymphoma patients treated achieved partial response and 11 out of 15 patients with various solid tumors achieved stable disease. No dose-limiting toxicities have been observed thus far. Data were presented during a poster presentation at the 34th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) (ENA) Symposium on Molecular Targets and Cancer Therapeutics, which is being held on October 26-28, in Barcelona, Spain.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The findings reported in today’s poster presentation show that oral fadraciclib dosed daily as a single-agent is relatively well tolerated and active in a challenging Phase 1 population," said Mark Kirschbaum, M.D., Senior Vice President and Chief Medical Officer of Cyclacel. "We are encouraged by the antitumor activity observed up to dose level 5 and are now recruiting patients at the sixth dose level of 150mg administered twice daily four out of four weeks. We believe fadraciclib can be safely dosed at these levels that are predicted in target engagement studies to inhibit CDK2 and CDK9. We plan to optimize the dosing schedule and maximize target coverage. Once we determine the recommended Phase 2 dose (RP2D) we can advance into Phase 2 proof of concept stage."

"We are excited by the progress of oral fadraciclib in the 065-101 study. We believe that the combination of daily dosing and dual targeting of both CDK2 and CDK9 at efficacious doses without dose limiting toxicities could potentially result in a competitive product profile for oral fadraciclib," said Spiro Rombotis, President and Chief Executive Officer of Cyclacel. "In our second program with oral CYC140, a differentiated PLK1 inhibitor, we have likewise observed early signs of anticancer activity as a single agent in a Phase 1/2 study in patients with solid tumors and lymphomas. We look forward to reviewing fadraciclib and CYC140 preclinical and clinical data at our upcoming Research & Development Day on Monday, October 31."

Summary of findings:

As of September 30, 2022, 18 evaluable patients were treated with oral fadraciclib as a single agent. Patients were heavily pretreated with various tumor types, including breast, cholangiocarcinoma, gynecological, head & neck, hepatocellular carcinoma, T-cell lymphoma, pancreatic and prostate cancers.

Fadraciclib was well tolerated while escalating from dose levels 1 to 5 (up to and including 100mg BID, Monday-Friday, on week 1-4 in 28-day cycles).

No treatment-related Serious Adverse Events (SAEs), or SUSAR, or Dose-Limiting Toxicities (DLTs) were reported.

Initial anticancer activity was as follows:
Two partial responses (PRs) have been observed in T-cell lymphoma patients, one with CTCL and one with angioimmunoblastic PTCL.
Four patients (with cervical, endometrial, HCC, and ovarian cancers) achieved target lesion reductions.
A patient with pancreatic cancer achieved stable disease for 5 cycles.
Plasma concentration of fadraciclib is dose proportional, crossing the target engagement threshold level for CDK2 and CDK9 with increasing duration at dose levels 4 and 5 after repeated oral administration.

Enrollment continues at dose level 6 (150mg BID, Monday-Friday, on week 1-4 in 28-day cycles).
The ongoing trial is an open-label, multicenter, Phase 1/2 study in adult subjects with advanced solid tumors and lymphoma. Phase 1 explores both schedule and escalating doses of oral fadraciclib as a single-agent in 28-day cycles with a primary objective of identifying maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Once RP2D is established, Phase 2 will enroll patients in seven specific tumor-type groups and a basket cohort, utilizing a Simon two-stage optimal design to evaluate clinical activity. The primary objective of Phase 2 is to achieve proof of concept and determine preliminary efficacy by overall response rate. Safety, pharmacokinetics (PK) and efficacy will be investigated for all subjects. Exploratory objectives are to investigate clinical pharmacodynamics (PD) and pharmacogenomics (PGx) of fadraciclib.

Title: A Phase 1/2, Open-label, Multi-center Study to Investigate the Safety, Pharmacokinetics, and Efficacy of Fadraciclib (CYC065), an Oral CDK2/9 Inhibitor, in Subjects with Advanced Solid Tumors and Lymphoma
Abstract No: 50
Date/Time: Wednesday, October 26, 2022, 12:00 – 20:00 CEST
Location: Exhibition Hall
Session Topic: Molecular Targeted Agents 1
Authors: Sarina Piha-Paul1, Do-Youn Oh2, Elena Garralda3, Maria Vieito3, Ying-Hui Huang4, Mark H. Kirschbaum4, Miguel Villalona-Calero5
1MD Anderson Cancer Center, Texas, US; 2Seoul National University Hospital, Seoul, Korea; 3Vall d’ Hebron Institute of Oncology, Barcelona, Spain; 4Cyclacel, New Jersey, US; 5City of Hope National Medical Center, California, US
The poster can be accessed via the Company’s website at www.cyclacel.com

About Cyclin-Dependent Kinases and Fadraciclib
Cyclin-dependent kinases (CDKs) are critical for cell cycle control and transcriptional regulation. Dysregulated CDKs have been linked to the cancer hallmarks of uncontrolled proliferation and increased cancer cell survival. Fadraciclib, a next generation CDK inhibitor, is a highly selective, potent, orally and intravenously available, inhibitor of CDK2 and CDK9. CDK2 drives cell cycle transitions and CDK9 regulates transcription of genes through phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II (RNAP II). By inhibiting CDK2 and CDK9 fadraciclib causes apoptotic death of cancer cells at sub-micromolar concentrations. Fadraciclib is being tested in a Phase 1/2 trial for the treatment of advanced solid tumors and lymphoma (065-101; NCT#04983810) and a Phase 1/2 trial for the treatment of hematological malignancies (065-102; NCT#05168904).

Preclinical data suggest that fadraciclib may benefit patients with certain cyclin E-addicted or MYC-amplified solid tumors, including certain forms of breast cancer, neuroblastoma, ovarian cancer, uterine serous carcinoma and adult and pediatric hematological malignancies, such as ALL, AML, B-cell lymphoma, CLL, and multiple myeloma. Similarly, to FDA-approved CDK4/6 inhibitors, fadraciclib may be useful in combination with other anticancer drugs, including HER2 inhibitors, such as trastuzumab, or BCL2 inhibitors, such as venetoclax.

In a prior Phase 1 open-label trial (CYC065-01), patients with high copy CCNE (cyclin E), MYC or MCL1 showed sensitivity to intravenously administered, single-agent fadraciclib. A heavily pretreated patient with MCL1 amplified endometrial cancer achieved a radiographically confirmed partial response (PR) after a month and a half on fadraciclib, subsequently achieved CR and continues on treatment with fadraciclib for over three years. An additional patient with cyclin E amplified ovarian cancer achieved stable disease with 29% shrinkage in her target tumor lesions.