On April 10, 2023 Totus Medicines, a clinical stage biotechnology company fueled by its breakthrough Accel platform, reported it will be presenting four posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, regarding its lead program, TOS-358, the first highly specific, covalent PI3Kα inhibitor (Press release, Totus Medicines, APR 10, 2023, View Source [SID1234629925]). Totus has created the Accel Platform that, for the first time ever, can search, map, and decode billions of drug molecules across multiple cellular targets in a single experiment. This has allowed Totus to identify candidate molecules in months, not years, and rapidly advance these molecules toward the clinic. Notably, the Accel Platform enabled discovery of TOS-358 at an unprecedented pace. TOS-358 was discovered in under 4 months and received IND approval in ~2 years from original screening.

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TOS-358 represents the first highly specific covalent inhibitor of PI3Kα, which is mutated in ~15% of all cancers (Breast, Colorectal, Lung, Bladder, etc.). However, the therapeutic benefit of current molecules is limited by two key problems. Firstly, current non-covalent PI3Kα inhibitors cannot achieve continuous >95% target pathway inhibition, which is required for anti-tumor efficacy. Secondly, high doses of current non-covalent PI3Kα inhibitors are non-specific and inhibit other PI3K isoforms at effective doses. This leads to toxicity such as hyperglycemia and GI toxicity. TOS-358 represents the first ever highly specific covalent molecule targeting PI3Kα that can achieve durable, near 100% inhibition of PI3Kα activity and avoid these safety issues in preclinical studies.

Totus will outline three key points at AACR (Free AACR Whitepaper) to support TOS-358 as the best-in-class PI3Kα inhibitor:

Despite claims indicating 80% inhibition is sufficient, PI3Kα-mutant tumors consistently require >95% inhibition to induce significant anti-tumor effects, and TOS-358 can uniquely achieve this level of inhibition.

Common pathway feedback mechanisms re-activate PI3Kα in most cell lines and render non-covalent approaches ineffective. TOS-358 can uniquely block these feedback mechanisms and retain >95% inhibition over time.

PI3Kα-WT inhibition alone does not induce significant hyperglycemia or metabolic dysfunction. Previous non-covalent molecules (Alpelisib) inhibit both PI3Kα and other off-target (PI3Kβ) leading to significant toxicities. TOS-358 does not cause significant metabolic dysfunction due to its highly specific ability to target PI3Kα.
Based on these studies, we outline the best-in-class status of TOS-358 due to its unique ability to achieve >95% inhibition of PI3Kα with limited side effects leading to unprecedented monotherapy efficacy in preclinical models.

"We’re thrilled to be presenting several posters at AACR (Free AACR Whitepaper) that demonstrate the preclinical efficacy, safety, and differentiation of TOS-358, the world’s first covalent inhibitor of PI3Kα in clinical development," said Neil Dhawan, CEO and co-founder of Totus Medicines. "We’ve come a long way, fast, and are looking forward to sharing our findings with the broader cancer research community, which we believe will redefine the cancer community’s understanding of PI3Kα targeting."

The poster presentations are listed below and the full abstracts will be available on the AACR (Free AACR Whitepaper) and Totus Website.

A study to evaluate the safety and tolerability of the covalent phosphoinositide-3-kinase (PI3K)-alpha Inhibitor, TOS-358, in adult subjects with select solid tumors
Abstract number: CT249
Date and Time: Tuesday April 18 at 1:30 PM – 5:00 PM ET

Development and validation of a pharmacodynamic (PD) assay for TOS-358, the first covalent inhibitor of PI3Kα in clinical development
Abstract number: 2249
Date and Time: Monday, April 17 at 9:00 AM – 12:30 PM ET

Inhibition of wild-type PI3Kα signaling is required for durable efficacy in PI3Kα mutant cancer cells due to robust re-activation of wild-type PI3Kα signaling
Abstract number: 4946
Date and Time: Tuesday, April 18 at 1:30 PM – 5:00 PM ET

TOS-358, a first-in-class covalent PI3Kα inhibitor, demonstrates superior efficacy and does not induce significant hyperglycemia at efficacious doses in multiple animal models
Abstract number: 4945
Date and Time: Tuesday, April 18 at 1:30 PM – 5:00 PM ET

On April 10, 2023 Ultima Genomics, Inc. and Genome Insight, Inc. have signed an agreement to collaborate to bring affordable whole genome sequencing solutions to cancer patients (Press release, Ultima Genomics, APR 10, 2023, https://www.prnewswire.com/news-releases/ultima-genomics-and-genome-insight-collaborate-to-bring-affordable-whole-genome-sequencing-to-cancer-patients-301792800.html [SID1234629924]). As part of the agreement, Genome Insight will join the early access program for Ultima’s high-throughput NGS instrument platform, the UG 100, and develop an optimized version of its whole genome bioinformatics solution for Ultima’s sequencing technology. The combination of Genome Insight’s proprietary bioinformatics with Ultima’s low-cost sequencing will make whole genome sequencing an affordable reality for cancer patients.

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Although cancer is a disease caused by alterations to the genome, conventional NGS approaches typically use targeted panels that examine only a small fraction of this information. Insights into the whole genome can expand the understanding of cancer biology and provide important information for physicians in formulating a treatment strategy for each patient. Genome Insight’s proprietary bioinformatics platform translates a cancer patient’s genome into medically meaningful insights. Optimizing this platform for Ultima’s high-throughput, low-cost sequencing architecture will enable delivery of curated whole genome sequencing reports to patients and physicians at a very low cost – even cheaper than conventional NGS panels.

"We are excited to partner with Ultima to bring affordable whole genome sequencing to cancer patients," said Young Seok Ju, CEO of Genome Insight. "The ability to analyze the entire genome at a low cost is a game-changer in cancer treatment, and we are proud to be at the forefront of this revolution. This collaboration is an important step towards our vision of using whole genome sequencing to improve patient outcomes."

"We founded Ultima Genomics to help overcome the tradeoffs scientists and clinicians are forced to make between the breadth, depth and frequency with which they use genomic information," said Gilad Almogy, CEO of Ultima Genomics. "Genome Insight’s focus on whole genome sequencing is a perfect example of this, and we are excited to collaborate on this development."

On April 10, 2023 CTRL Therapeutics Inc., a biotechnology company developing a next-generation cell therapy platform for solid tumors, reported a $10M seed financing led by General Catalyst with participation from Intermountain Health, FACIT and other investors (Press release, CTRL Therapeutics, APR 10, 2023, View Source [SID1234629923]).

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"The field of cell therapy has been limited by the lack of tools to isolate and expand tumor-reactive cells that are efficacious against solid tumors." said Shana Kelley, Ph.D., Founder and Chief Technology Officer at CTRL Therapeutics. "This funding enables further optimization and validation of our proprietary technology platform and expansion of our team to support our mission to deliver curative therapies for all individuals living with cancer."

CTRL Therapeutics is leveraging a next-generation platform with the potential to address the challenges of existing cell therapy technologies by extracting circulating tumor-reactive lymphocytes (cTRLs) from blood. It builds on the advantages of tumor-infiltrating lymphocyte (TIL) therapies while providing greater efficacy by improving the immune-phenotype, quality and consistency of therapeutic cells harvested. This method may enable broader patient access by avoiding invasive and costly surgery, while delivering superior cost-effectiveness and simplified manufacturing.

The company’s approach is highlighted in a landmark publication featured in Nature Biomedical Engineering, titled "Isolation of tumor-reactive lymphocytes from peripheral blood via microfluidic immunomagnetic cell sorting." The study validates CTRL’s high-throughput cell processing platform to harvest tumor-reactive immune cells from the blood, which exhibited significant levels of antitumor activity when tested against solid tumors in mice.

"CTRL combines high impact, pioneering science that harnesses natural biology with experienced leadership that is well versed in platform optimization and clinical development," said Elena Viboch, Partner at General Catalyst. "We are excited to partner with the CTRL team to propel the development of next-generation cellular therapy for solid tumors, and to ultimately bring accessible, safe and effective therapeutics to patients affected by cancer.

On April 10, 2023 Sumitomo Pharma Oncology, Inc., a clinical-stage company focused on novel cancer therapeutics, reported the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation for TP-1287, an investigational oral CDK9 inhibitor, for the treatment of Ewing sarcoma (Press release, Sumitomo Pharmaceuticals, APR 10, 2023, View Source [SID1234629922]).

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"We are delighted to have received this designation for TP-1287 which underscores the need for additional treatment options for patients with Ewing sarcoma," said Patricia S. Andrews, Chief Executive Officer and Global Head of Oncology, Sumitomo Pharma Oncology, Inc. "We recognize the unmet need for novel treatments in this disease state and are excited to contribute to the advancement of this research with the goal of helping to improve patient outcomes."

The FDA’s Orphan Drug Designation is granted to investigational therapies addressing rare medical diseases or conditions that affect fewer than 200,000 people in the United States.1 Ewing sarcoma is a rare type of cancer that occurs in bones or in the soft tissue around the bones. The disease occurs when a cell develops changes in its DNA that cause the cell to multiply quickly, resulting in a tumor of abnormal cells that is capable of invading and destroying healthy body tissue. The abnormal cells can break away and metastasize throughout the body. Ewing sarcoma can occur at any age, but it is more likely to occur in children and teenagers.2

"TP-1287 exhibits potent inhibition of intracellular kinases including CDK9. Inhibition of CDK9 leads to downregulation of key antiapoptotic proteins such as MCL-1, which in turn has been shown to inhibit tumor growth in preclinical models of hematologic malignancies and several tumor types,"3-6 detailed Jatin J. Shah, M.D., Chief Medical Officer of Sumitomo Pharma Oncology, Inc.

TP-1287 was also granted Rare Pediatric Disease Designation from the FDA for the treatment of Ewing sarcoma. A rare pediatric disease is one that is serious or life-threatening in which the serious or life-threatening manifestations primarily affect patients from birth to 18 years old.7

TP-1287 is currently being evaluated in a Phase 1, first-in-human study of oral TP-1287 in patients with advanced metastatic or progressive solid tumors who are refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition, which is being conducted in the United States. To learn more about the study and eligibility for enrollment, visit clinicaltrials.gov (NCT03604783).

This is the fourth Orphan Drug Designation Sumitomo Pharma Oncology, Inc. has received in the last year. DSP-5336, the company’s proprietary investigational small molecule inhibitor against the binding of menin and mixed-lineage leukemia (MLL) protein, was granted Orphan Drug Designation for the treatment of acute myeloid leukemia (NCT04988555). TP-3654, the company’s proprietary investigational oral inhibitor of PIM kinases, was granted Orphan Drug Designation for the treatment of myelofibrosis (NCT04176198). DSP-0390, an investigational emopamil-binding protein (EBP) inhibitor, was also granted Orphan Drug Designation for the treatment of brain cancer (NCT05023551). These designations showcase the strength and diversity of SMP Oncology’s pipeline and commitment to oncology research and development.

About TP-1287
TP-1287 is an investigational oral phosphate prodrug of the CDK9 inhibitor alvocidib.8 TP-1287 is hydrolyzed enzymatically to yield alvocidib.8,9 Alvocidib binds at the ATP-binding site of CDK9, stopping phosphorylation by CDK9.3 This binding prevents productive transcription and causes reduction of messenger RNA (mRNA) in genes such as c-MYC and MCL-1.3 Downregulation of c-MYC and MCL-1 transcription leads to apoptosis in a variety of tumor cells.3 TP-1287 is currently being evaluated in a Phase 1, open-label, dose-escalation, dose-expansion, safety, pharmacokinetics and pharmacodynamic study, with a purpose of determining the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral TP-1287 in patients with advanced metastatic or progressive solid tumors who are refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition (NCT03604783).

On April 10, 2023 Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) will report its first quarter 2023 financial results on Monday, May 1, 2023 after the financial markets close (Press release, Vertex Pharmaceuticals, APR 10, 2023, View Source [SID1234629921]). The company will host a conference call and webcast at 4:30 p.m. ET. To access the call, please dial (877) 270-2148 (U.S.) or +1(412) 902-6510 (International) and reference the "Vertex Pharmaceuticals First Quarter 2023 Earnings Call."

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The conference call will be webcast live and a link to the webcast can be accessed through Vertex’s website at www.vrtx.com in the "Investors" section. To ensure a timely connection, it is recommended that participants register at least 15 minutes prior to the scheduled webcast. An archived webcast will be available on the company’s website.