On April 11, 2022 Debiopharm, (www.debiopharm.com/debiopharm-international/) an oncology and infectious disease focused biopharmaceutical company based in Switzerland, reported data releases on 3 investigational products including Debio 0123 (Selective WEE1 inhibitor), clinical exploratory results for xevinapant (IAP inhibitor), and 2 Multilink technology posters (antibody drug conjugate linker) at the 2022 Annual American Association for Cancer Research (AACR) (Free AACR Whitepaper) meeting in New Orleans, Louisiana (Press release, Debiopharm, APR 11, 2022, View Source [SID1234612008]). The AACR (Free AACR Whitepaper) conference serves as the focal point of the cancer research community to gather together and share advances in oncology science. Debiopharm and their partners’ poster presentations represent scientific progress in the research of these compounds leveraging novel modes of action and new delivery methods in development to treat cancer types with high unmet needs.

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"Scientific cancer research is evolving quickly, bringing us the insights needed to better develop safer and more effective anti-tumor therapies. Our ultimate vision is to translate these findings into meaningful outcomes for patients in future clinical settings," explained Carolina Haefliger, Head of Translational Medicine at Debiopharm.

AACR 2022 Poster Sessions

Compound

Title

Date and Time

N°

Debio 0123

The WEE1 inhibitor Debio 0123
enhances the efficacy of standard
of care DNA Damaging agents in
lung cancer models

Tue, April 12th,
9:00am-12:30pm

Section 5

#4894

Multilink technology

A novel antibody drug conjugate
linker enabling production of ADCs
with high drug to antibody ratios
and fast payload release for improved efficacy

Mon, April 11th,
1:30-5:00pm

Section 21

#4882

Multilink technology
(combined with Genome & Co’s Antibody)

The antibody-drug conjugate GENA-111
conjugated to auristatin F shows
therapeutic potency in BCAM positive epithelial cancer

Mon, April 11th,
1:30-5:00pm

Section 21

#1716

xevinapant
(rights under Merck KGaA, Darmstadt, Germany)

The IAP antagonist xevinapant in combination
with high-dose cisplatin chemoradiotherapy
induces NF-kB and apoptotic pathway biomarkers
in patients with high-risk, locally advanced
squamous cell carcinoma of the head and neck

Tue, April 12th,

1:30-5:00pm

Section 33

#603

About Debio 0123
Debio 0123 is an inhibitor of WEE1 kinase, a key regulator of the G2/M and S phase checkpoints, activated in response to DNA damage, allowing cells to repair their DNA before resuming their cell cycle. WEE1 inhibition, particularly in combination with DNA damaging agents, induces DNA breaks leading to the accumulation of DNA damage. In conjunction with abrogation of other checkpoints such as those of the G1 phase of the cell cycle, the compound pushes the cells through cycle without DNA repair, promoting mitotic catastrophe and inducing apoptosis of cancer cells.

About Multilink
Multilink is a new cleavable linker platform suited for multidrug attachment and compatible with any conjugation technology to produce ADCs with high DAR (drug-to-antibody ratio), allowing the loading of multiple payloads on an antibody for an enhanced therapeutic effect. This highly effective and well-tolerated linker platform is available for use of other specialty biotech or pharmaceutical companies to generate a proprietary, clinical-stage ADCs.

About xevinapant
Xevinapant, now exclusively licensed to Merck for product development and commercialization, is a potential first-in-class potent, oral, small-molecule inhibitor of IAPs (Inhibitor of Apoptosis Proteins). In preclinical studies, xevinapant restored sensitivity to apoptosis in cancer cells, thereby depriving them of one of their major resistance mechanisms to anticancer therapy. Currently in phase III clinical research, in a randomized, placebo-controlled phase II study, xevinapant has demonstrated preliminary evidence of efficacy in combination with chemoradiotherapy (CRT) in patients with high-risk locally advanced squamous cell carcinoma of the head and neck (LA SCCHN), with a clinically significant and sustained clinical activity and an acceptable safety profile compared with CRT alone.

On April 11, 2022 Kintara Therapeutics, Inc. (NASDAQ: KTRA) ("Kintara" or the "Company"), a biopharmaceutical company focused on the development of new solid tumor cancer therapies, reported that it has presented data at the 2022 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Kintara Therapeutics, APR 11, 2022, View Source [SID1234612007]).

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Data Presentation:

Track 24: Experimental and Molecular Therapeutics

Session PO.ET02.01 – Mechanisms of Drug Action 1

1843 / 15 – Dianhydrogalactitol (VAL-083) for the Treatment of Glioblastoma Multiforme (GBM): Impact of Glucose Transporters for Crossing the Blood Brain Barrier (BBB)

(Presentation Time: Monday, April 11, 2022 – 1:30 p.m. to 5:00 p.m. CT)

Enhanced drug concentrations of VAL-083 in the brain and GBM brain tumors in comparison to circulating plasma concentrations have been observed in human clinical trials. Most therapeutic agents targeting brain tumors have very limited access to primary brain tumors due to the protective nature of the BBB that limits access for most chemical structures.

VAL-083 shares structural and molecular similarities to glucose including low molecular weight and high water solubility. Glucose transporters, in particular GLUT1, are overexpressed by the BBB since the brain requires very high concentrations of glucose for metabolism. Laboratory studies presented at the meeting assessed whether glucose transporters are involved in the ability of VAL-083 to cross the BBB.

Three glucose transporters were studied in vitro including SGLT1, SGLT2 and GLUT1. For all three transporters VAL-083 was not a substrate for these active transport systems. This suggests that VAL-083 may be crossing the BBB by passive diffusion rather than facilitated active transport.

VAL-083 has some physical chemical parameters that differ from glucose. These include increased lipophilicity (log P) and a significantly lower polar surface area (PSA) (lower surface charge) which may allow for relatively unencumbered passive diffusion across the lipid cell membranes of the BBB as well as GBM tumor cells. This independence for the need for specific active drug transporters may help to explain the enhanced drug concentrations of VAL-083 observed clinically in GBM.

"These results are extremely important," said Dennis Brown, Ph.D., Kintara’s Chief Scientific Officer. "We thought that since there were numerous structural similarities between VAL-083 and glucose that perhaps a specialized glucose transporter could explain the favorable brain concentration demonstrated clinically for VAL-083. It appears that other molecular features like PSA and log P may account for the very unique pharmacologic properties we are observing. This suggests that the clinical pharmacokinetics of VAL-083 would result in less inter- and intra-patient variability in CNS penetration and, therefore, greater precision of drug dosing to the brain.

On April 11, 2022 Linnaeus Therapeutics, Inc. (Linnaeus), a privately held clinical-stage biopharmaceutical company focused on the development and commercialization of novel small-molecule oncology therapeutics, reported that the laboratory of Gary Schwartz, MD at Columbia University Irving Medical Center presented new findings from his research team at the 2022 AACR (Free AACR Whitepaper) Annual Meeting (Press release, Linnaeus Therapeutics, APR 11, 2022, View Source [SID1234612004]).

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The poster was entitled, "G protein-coupled estrogen receptor-1 agonist LNS8801 induces mitotic arrest and cell death in uveal melanoma cells" and was led by Grazia Ambrosini, PhD, a research scientist in Dr. Schwartz’s lab (Abstract 1852).

Ambrosini and colleagues have demonstrated that LNS8801 has potent anti-cancer activities in models of uveal melanoma cells. Treatment with LNS8801 resulted in inhibition of proliferation and depletion of c-Myc and phospho-RB proteins. The inhibition of proliferation was associated with a G2/M cell cycle block through the disruption of microtuble dynamics and mitotic spindle formation. LNS8801 treatment also resulted in the inhibition of migration and induction of cell death. LNS8801 had potent effects in an in vivo xenograft model of uveal melanoma, resulting in the inhibiton of tumor growth.

"We are extremely pleased to showcase these data at AACR (Free AACR Whitepaper)," commented Patrick Mooney, MD, CEO of Linnaeus. "These data demonstrate that LNS8801 has activity in preclinical models of uveal melanoma in vitro and in vivo. Importantly, these data are consistent with the clinical data in our on-going studies of LNS8801 in advanced cancer patients. We look forward to sharing some of that data at ASCO (Free ASCO Whitepaper) in June."

About LNS8801
LNS8801 is an orally bioavailable and highly specific and potent agonist of GPER whose activity is dependent on the expression of GPER. GPER activation by LNS8801 rapidly and durably depletes c-Myc protein levels. In preclinical cancer models, LNS8801 displays potent antitumor activities across a wide range of tumor types, rapidly shrinking tumors and inducing immune memory.

In the ongoing clinical study in humans, LNS8801 monotherapy has been safe and well tolerated. Additionally, LNS8801 has demonstrated target engagement, c-Myc protein depletion, and clinical benefit in patients with advanced cancer.

On April 11, 2022 Guardant Health, Inc. (Nasdaq: GH), a leading precision oncology company, reported new data demonstrating the ability of the company’s investigational next-generation Guardant SHIELD multi-cancer assay to accurately detect early-stage cancers (Press release, Guardant Health, APR 11, 2022, View Source [SID1234612001]). This assay is designed to analyze approximately 20,000 epigenomic biomarkers that are informative for detection of a wide range of solid tumors in a single blood test . The data for four cancer types were demonstrated as examples: colorectal, lung, pancreatic and bladder. These cancers alone account for more than 200,000 cancer-related deaths in the U.S. annually.1 In addition, the blood test identified the tumor tissue of origin with high accuracy. These data were presented during an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting.

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Data from the presentation show that the next-generation Guardant SHIELD multi-cancer screening assay achieved sensitivity (detection rates) of 90% (n=692) in stages I and II colorectal cancer (CRC) and 87% (n=55) in stages I and II lung cancer. For more advanced cancer (stages III and IV), sensitivity was 93% (n=582) for CRC and 93% (n=136) for lung cancer. Detection was assessed at 90% specificity (true negative rates) based on a cohort of patients without cancer. This performance is on par with current guideline-recommended screening methods. Current screening options for these cancers, while effective, are limited due to low compliance rates: 66% for CRC and 14% for lung cancer.2,3 A high-performance blood test that can be completed as part of a routine patient workup has the potential to improve screening rates and, ultimately, save more lives.

In addition, the multi-cancer screening assay achieved sensitivity of 73% (n=11) in stages I and II pancreatic cancer and 52% (n=23) in stages I and II bladder cancer. For more advanced cancer (stages III and IV), sensitivity was 84% (n=31) in pancreatic cancer and 85% (n=61) in bladder cancer. Since there is no screening paradigm or diagnostic pathway for these cancers, a specificity threshold of 95% was targeted to reduce false positive rates while ensuring sensitivity is clinically impactful.

Highly accurate tumor tissue of origin prediction is needed when more than one cancer type is evaluated as part of a single assay to help direct patients to the most effective follow up for a positive test. The tumor tissue of origin prediction was evaluated at 98% specificity and correctly identified the tumor tissue of origin in 99% of colorectal, 94% of lung, 88% of bladder, and 86% of pancreatic cancers.

"These positive results show that the next-generation Guardant SHIELD multi-cancer assay provides sensitive detection of early-stage cancers with the ability to identify the tumor tissue of origin with high accuracy," said AmirAli Talasaz, Guardant Health co-CEO. "Presentation of these positive results represents a major step forward in our commitment to offering clinicians and patients a highly sensitive blood-based multi-cancer screening test in select tumor types where we believe cancer screening can save lives."

The investigational next-generation Guardant SHIELD multi-cancer test aims to detect early-stage cancer where there is a clinical benefit from early detection and treatment. In January 2022, Guardant Health initiated the SHIELD Lung study, a prospective, observational, multi-center basket study designed to enroll individuals undergoing cancer screening across multiple cancer types. The first cohort, or basket, will enroll nearly 10,000 individuals eligible for lung cancer screening and aims to evaluate the performance of the next-generation Guardant SHIELD test to detect lung cancer in high-risk individuals ages 50-80. The study is anticipated to run in approximately 100 centers in the United States and Europe. Additional information about the study is available at clinicaltrials.gov (NCT05117840).

On April 11, 2022 Repare Therapeutics Inc. ("Repare" or the "Company") (Nasdaq: RPTX), a leading clinical-stage precision oncology company, reported that updated data from its ongoing Phase 1/2 TRESR (Treatment Enabled by SNIPRx) clinical trial of RP-3500, a potent and selective oral small molecule inhibitor of ATR (Ataxia-Telangiectasia and Rad3-related protein kinase) for the treatment of solid tumors with specific synthetic-lethal genomic alterations including those in the ATM gene (Ataxia-Telangiectasia mutated kinase) at the 2022 AACR (Free AACR Whitepaper) Annual Meeting (Press release, Repare Therapeutics, APR 11, 2022, View Source [SID1234612000]).

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"We see promising monotherapy data across tumor types, particularly in advanced ovarian cancer where 90% of patients had failed previous treatment with PARP inhibitors and platin based therapy. We are especially pleased with the 25% overall response observed, the clinical benefit rate of 75% and a median PFS of 35 weeks in this heavily pre-treated patient population with a growing unmet need," said Maria Koehler, MD, PhD, Chief Medical Officer of Repare. "These findings, together with anticipated initial data of RP-3500 in combination with PARP inhibitors or gemcitabine expected in the second half of this year, will help us refine our development strategy for this potential best-in-class drug."

The data were featured today at the AACR (Free AACR Whitepaper) Annual Meeting in an oral presentation titled, "Genomic and pathologic determinants of response to RP-3500, an ataxia telangiectasia and Rad3-related inhibitor, in patients with DNA damage repair loss-of-function mutant tumors in the Phase 1/2 TRESR trial" (abstract number CT030).

"The data presented today continue to demonstrate RP-3500’s promising clinical benefit given as monotherapy in patients with solid tumors with multiple genotypes, as predicted by our SNIPRx platform, as well as a potential industry-leading safety and tolerability profile for ATR inhibitors," said Lloyd M. Segal, President and Chief Executive Officer of Repare. "Our comprehensive new dataset shows ATM loss of function as a compelling opportunity to offer durable clinical benefit to patients with genetically defined tumors. Additional results beyond ATM, such as the early efficacy seen in other genotypes involving BRCA1/2, SETD2 and RAD51C alterations, represent substantial validation of our STEP2 platform to identify other synthetic lethalities as we expand TRESR and develop our pipeline of synthetic lethal candidates."

The Company will subsequently host a conference call today, April 11th at 6:30 p.m. Eastern Time to discuss the latest results from the TRESR trial.

Key Initial Findings from the TRESR Phase 1/2 Study:

TRESR is a first-in-human, multi-center, open-label Phase 1/2 dose-escalation and expansion study, designed to establish the recommended Phase 2 dose (RP2D) and schedule, evaluate safety and pharmacokinetics and identify preliminary anti-tumor activity associated with RP-3500, given alone and in combination with talazoparib. The study also examined biomarker responses and their relationship with response to RP-3500 treatment.

The oral presentation described monotherapy Phase 1 (Module 1) results from 120 patients, of which 99 patients were evaluable for efficacy, including 95 patients at RP2D of 160mg and schedule taken weekly for 3 days on/4 days off, and reflecting a data cutoff of 14th February, 2022. Key highlights from the data presented at the 2022 AACR (Free AACR Whitepaper) Annual Meeting include:

RP-3500 monotherapy continues to appear safe and well tolerated. Expectedly, Grade 1-2 anemia was the most common treatment-related adverse event and well controlled in patients. Only 24.2% of all patients in the 3 days on 4 days off schedule experienced Grade 3 anemia, and none Grade 4 anemia.
RP-3500 monotherapy resulted in durable clinical benefit across tumor types and genomic alterations. Overall clinical benefit rate (CBR) for all patients was 43%, and 47% in patients after PARP inhibitor (PARPi) failure.
Promising results were observed particularly in patients with advanced ovarian cancer (n = 20). 90% of evaluated patients had prior PARPi failure, and 85% of evaluated patients were platinum resistant. In these patients, overall response (OR) was 25%, including one complete response (CR), three partial responses (PR) as determined by RECIST 1.1 criteria, and one durable and ongoing CA125 response. CBR was 75% and median progression-free survival (mPFS) was 35 weeks.
Clinical benefit was also observed in patients with tumors harboring BRCA1 and BRCA2 genomic alterations, as predicted by SNIPRx. In patients with BRCA1/2 mutated tumors (n = 37), ORR was 14% and included two patients with ovarian cancer, and one each with breast cancer, head and neck squamous cell carcinoma, and melanoma. CBR was 43% with a mPFS of 15 weeks in the BRCA1/2 population; in patients specifically with BRCA1 mutations, the CBR was 48%.
In patients with ATM loss-of-function (LOF) tumors (n = 34), ORR was 9% including one RECIST 1.1 confirmed/unconfirmed response, and two prostate specific antigen (cPSA) responses. CBR in patients with ATM LOF was 44%, with mPFS of 17 weeks.
New sequencing data demonstrated biallelic gene LOF, an emerging biomarker for synthetic lethal therapies, can potentially be leveraged to further enrich for patients most likely to benefit from RP-3500. CBR in patients with biallelic LOF was significantly higher (47%) compared to the CBR in patients with non-biallelic tumors (15%).
A second poster presentation titled, "Detection of biallelic loss of DNA repair genes in formalin-fixed, paraffin embedded (FFPE) tumor samples using a novel tumor-only sequencing panel with error correction" (abstract number 2801) will be presented on Tuesday, April 12, 2022. Results demonstrated the role of SNiPDx, a central next-generation sequencing assay, in determining biallelic LOF, germline status and clonal hematopoiesis of indeterminate potential (CHIP) alterations, in patients enrolling in the TRESR study.

Company Conference Call:

The Company will host a conference call with accompanying slides for analysts and investors today at 6:30 p.m. Eastern Time to further discuss the RP-3500 data presented at the 2022 AACR (Free AACR Whitepaper) Annual Meeting. Repare’s executive management team will be joined by Timothy Yap, MBBS, PhD, FRCP, Principal Investigator and Medical Director, Institute for Applied Cancer Science, Associate Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX.

To access the call, please dial (877) 870-4263 (U.S. and Canada) or (412) 317-0790 (international) at least 10 minutes prior to the start time and ask to be joined to the Repare Therapeutics call. A live video webcast will be available in the Investor section of the Company’s website at View Source A webcast replay will also be archived for at least 30 days.

About Repare Therapeutics’ SNIPRx Platform

Repare’s SNIPRx platform is a genome-wide CRISPR-based screening approach that utilizes proprietary isogenic cell lines to identify novel and known synthetic lethal gene pairs and the corresponding patients who are most likely to benefit from the Company’s therapies based on the genetic profile of their tumors. Repare’s platform enables the development of precision therapeutics in patients whose tumors contain one or more genomic alterations identified by SNIPRx screening, in order to selectively target those tumors in patients most likely to achieve clinical benefit from resulting product candidates.