On April 10, 2021 iTeos Therapeutics, Inc. (Nasdaq: ITOS), clinical-stage biopharmaceutical company pioneering the discovery and development of a new generation of highly differentiated immuno-oncology therapeutics for patients, reported a presentation featuring preliminary clinical data from 22 adult patients in the ongoing Phase 1/2a trial of its anti-TIGIT antibody, EOS-448, at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021, taking place virtually April 10-15 (Press release, iTeos Therapeutics, APR 10, 2021, View Source [SID1234577846]). The presentation highlights initial findings from the completed dose escalation monotherapy portion of the trial, indicating a favorable tolerability profile and early signs of clinical activity in advanced cancers.

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"We are pleased to share these data showing promising preliminary signs of clinical activity and a favorable tolerability profile with our anti-TIGIT antibody, EOS-448, in patients with advanced cancers," said Joanne Jenkins Lager, M.D., chief medical officer of iTeos Therapeutics. "The results support our excitement around TIGIT as a therapeutic target capable of harnessing the immune system to treat patients with advanced, difficult to treat cancers. We believe the depletion of TIGIT+ suppressive and exhausted cells shown at even the lowest tested dose provides evidence of engagement of the FcγR, and therefore the potential of EOS-448 to activate multiple immune mechanisms. Based on these encouraging results, we are enrolling a total of 40 patients in this study to evaluate the effects of EOS-448 within the tumor. We are advancing EOS-448 into the next stage of clinical development as both a monotherapy and in combination for the treatment of multiple indications, with the goal of improving outcomes for people with advanced cancers."

Summary of the Data Presented

The objective of the dose escalation portion of the ongoing EOS-448 trial, presented at AACR (Free AACR Whitepaper), is to evaluate primary objectives of safety and tolerability, and secondary objectives of pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of EOS-448 as a monotherapy in patients with advanced solid tumor cancers. As of the data cut-off (December 31, 2020), the trial had enrolled 22 advanced cancer patients with solid tumors for whom no standard treatment was available. The patients received EOS-448 intravenously (IV) once every two weeks (Q2W) or once every four weeks (Q4W) according to their dose and schedule allocation. Doses of 20, 70, 200, 700 mg Q2W and 1400 mg Q4W were evaluated. Since the data cut-off for the AACR (Free AACR Whitepaper) poster, as of March 9, 2021, an additional 11 patients have received single agent EOS-448. In addition to the five dose levels which were described at AACR (Free AACR Whitepaper), patients have also received doses of 400mg Q4w and 700mg Q4w.

EOS-448 was generally well-tolerated at all tested doses in patients with advanced cancer. Preliminary evidence of clinical activity as a monotherapy, including a confirmed partial response in one pembrolizumab-refractory melanoma patient and disease stabilization in nine patients, was also observed. The most common treatment related adverse events were itching, infusion-related reactions, fatigue, rash and fever, and one treatment related serious adverse event, a grade 2 systemic inflammatory response, was observed. As of March 9, 2020, two additional treatment-related serious events have been reported: Grade 2 Systemic Inflammatory Response and Grade 3 infusion-related reaction.

PK assessments indicated a linear and dose-proportional response and PD assessments showed complete target engagement. Biomarker analyses showed evidence of FcγR engagement, as demonstrated by a reduction in suppressive immune cells and immune cells considered to be exhausted in the blood, including TIGIT+ regulatory T cells (Tregs) and TIGIT+ CD8 T cells, with only a slight reduction in the total CD8+ T cell count. A shift towards a more functional immune response was observed, with a two-fold increase in the ratio of CD8+ T cells to Treg and a four-fold increase in the ratio of CD8+ TIGIT- T cells to CD8+ TIGIT+ T cells.

"I am highly encouraged by these initial results from the EOS-448 trial, particularly the clinically meaningful response to treatment in the pembrolizumab-refractory melanoma patient," said Mario Sznol, M.D., professor of medicine and leader, Melanoma/RCC Disease-Associated Research Team, at Yale University. "The treatment of patients who develop resistance to checkpoint inhibitors is challenging in a number of tumor types, and these data give us hope that EOS-448 could provide benefit in adult solid tumor patients who don’t respond to or who progress on current checkpoint inhibitors."

The e-poster and abstract can be accessed on the AACR (Free AACR Whitepaper) conference website. The abstract and presentation details are as follows:

Title: Preliminary data from Phase I first-in-human study of EOS884448, a novel potent anti-TIGIT antibody, monotherapy shows favorable tolerability profile and early signs of clinical activity in immune-resistant advanced cancer
Session: Phase I Clinical Trials
Poster #: CT118
Authors: Tom Van den Mooter, et al.

The Company will host a conference call and webcast to provide an overview of the data on Monday, April 12 at 8:00 a.m. EDT. Details are as follows:

Participant Dial-In: (833) 607-1661
International Dial-In: (914) 987-7874
Conference ID: 2888301
Webcast: View Source

The abstract was posted online at 12:01 a.m. EDT on Friday, April 9 and the e-poster launched at 8:30 a.m. EDT on Saturday, April 10 on the AACR (Free AACR Whitepaper) conference website.

EOS-448 Further Clinical Development Plans
Based on these preliminary results, the Company plans to advance EOS-448 using combination trials in both checkpoint-naïve and resistant patients. These Phase 1b trials will assess the safety of EOS-448 in combination with pembrolizumab and in combination with iTeos novel agent inupadenant in patients with solid tumors, and as a monotherapy and in combination with an Immunomodulatory Drug (IMiD) in patients with multiple myeloma. Subsequent disease-specific Phase 2a trials are planned in patients with non-small cell lung cancer, head and neck cancer, melanoma, and myeloma. The Company is also planning for later-stage trials of EOS-448, including in combination with pembrolizumab.

On April 10, 2021 Synthekine Inc., an engineered cytokine therapeutics company, reported preclinical data presented at the American Association of Cancer Research Annual Meeting 2021 demonstrating its alpha/beta selective IL-2 partial agonist, STK-012, induced potent anti-tumor activity while avoiding the toxicities that have hindered the development of IL-2 therapeutics, including vascular leak syndrome (VLS) (Press release, Synthekine, APR 10, 2021, View Source [SID1234577862]). Synthekine also presented new data on its orthogonal IL-2 and CD-19 CAR-T system (STK-009 and SYNCAR-001).

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"IL-2 offers a wealth of therapeutic promises and challenges. While wild-type IL-2 is a potent T-cell stimulator and has shown single agent activity in late-stage cancers, its broad and non-specific activation leads to critical, dose-limiting toxicities," said Martin Oft, M.D., chief development officer at Synthekine. "We believe that the efficacy of IL-2 is driven by the proliferation and activation of antigen activated T cells, while the toxicity of IL-2 is driven by its broad and non-specific proliferation, extravasation, and activation of all lymphocytes, including NK cells and naïve T cells. We have designed our alpha/beta IL-2 to selectively bias towards antigen activated T-cells and avoid NK cells and naïve T cells, a new approach designed to improve on both the efficacy and the toxicity of wild-type IL-2. STK-012 demonstrates improved therapeutic index compared to wild-type IL-2 and a non-alpha comparator. We look forward to advancing this program to an IND filing in 2021."

Efficacy of STK-012 was evaluated in multiple mouse models using a mouse surrogate of STK-012 (alpha/beta IL-2). In these studies, the alpha/beta IL-2 achieved superior efficacy in control of tumor growth and rate of complete responses compared to both wild-type IL-2 and a non-alpha IL-2. Synthekine’s alpha/beta IL-2 was significantly more effective than these comparators at increasing intratumoral CD8+ T-cells, including the ratio of CD8 T cells to Tregs. Importantly, studies showed the alpha/beta IL-2 did not induce lethality or VLS at therapeutic or supratherapeutic doses. Both wild-type and non-alpha IL-2 showed vascular toxicity, including VLS and lethality in mice. This finding was also supported by data from non-human primates, with the comparators resulting in significantly more infiltration of inflammatory cells in the lung relative to STK-012.

Synthekine also presented new data on its orthogonal IL-2 and CD-19 CAR-T system (STK-009 and SYNCAR-001). New analyses further demonstrate STK-009 upregulates markers for expansion and activation of SYNCAR-001 cells in a CAR refractory lymphoma model and confers a gene signature indicative of long-term memory T cell development.

On April 10, 2021 Fusion Pharmaceuticals Inc. (Nasdaq: FUSN), a clinical-stage oncology company focused on developing next-generation radiopharmaceuticals as precision medicines, reported the presentation of preclinical data at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting (Press release, Fusion Pharmaceuticals, APR 10, 2021, View Source [SID1234577878]). The posters will be presented during the Preclinical Radiotherapeutics and Combination Immunotherapies sessions taking place today. The posters highlight the potential of Fusion’s targeted alpha therapies (TATs) to enable delivery of an alpha particle emitting isotope (actinium-225) as both monotherapies and combination therapies across multiple tumor types.

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"These data are the result of Fusion’s early investments in research to understand the power of combining our potent TATs with the latest generation of cancer therapies, such as checkpoint inhibitors and DNA damage response inhibitors (DDRis), and they reinforce our belief in the potential of our pipeline of TATs to redefine the utility of radiopharmaceuticals in the cancer treatment paradigm," said Fusion Chief Executive Officer John Valliant, Ph.D. "We believe we have an opportunity to advance clinical development of our product candidate FPI-1434 as monotherapy and in combination with these novel agents, leading to more treatment options for patients in earlier lines of therapy."

In one set of preclinical studies, highlighted in poster number LB130 titled, "Combination of IGF-1R Targeted Alpha Therapy with Olaparib Results in Synergistic Efficacy Against Colorectal and Lung Cancer Xenografts," results demonstrated that the delivery of alpha-particle radiation by FPI-1434 induced double-stranded DNA breaks and apoptosis in treated colorectal cancer tumor xenografts. Co-dosing with the PARP (poly ADP-ribose polymerase) inhibitor olaparib resulted in lower doses required for efficacy of FPI-1434 in lung and colorectal cancer tumor xenografts, supporting the potential clinical development of this combination.

In an additional set of preclinical studies, highlighted in poster number LB155 titled, "Combination of IGF-1R Targeted Alpha Therapy with Checkpoint Inhibitors Results in Synergistic Efficacy in Colorectal Cancer Syngeneic Model," data showed that treatment with IGF-1R TAT in combination with immune checkpoint inhibitors resulted in complete tumor eradication. Additionally, an increase in antigen-specific CD8 positive T cells and a strong "vaccine" effect were observed with the combination of IGF-1R TAT and immune checkpoint inhibitors, as noted by the prevention of tumor growth in animals that were reinoculated with the same tumor cells.

About FPI-1434
FPI-1434 is a radioimmunoconjugate designed to target and deliver alpha emitting medical isotopes to cancer cells expressing IGF-1R, a receptor that is overexpressed on many tumor types. FPI-1434 utilizes Fusion’s Fast-Clear linker to connect a human monoclonal antibody that targets IGF-1R with actinium-225, a powerful alpha-emitting isotope with desirable half-life and decay chain properties.

On April 10, 2021 MEI Pharma, Inc. (NASDAQ: MEIP), a late-stage pharmaceutical company focused on advancing new therapies for cancer, reported preclinical data demonstrating that voruciclib, an orally administered cyclin-dependent kinase (CDK) inhibitor that is potent against CDK9, has single agent activity against multiple KRAS mutant cancer cell lines and synergistically inhibits growth of KRAS mutant cancers in combination with KRAS inhibitors (Press release, MEI Pharma, APR 10, 2021, View Source [SID1234577830]). The research is featured as an E-Poster Session presentation titled, "Voruciclib, a CDK9 inhibitor, downregulates MYC and inhibits proliferation of KRAS mutant cancers in preclinical models" at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021. Voruciclib is currently in a Phase 1b clinical trial as a monotherapy in patients with relapsed and/or refractory B-cell malignancies and acute myeloid leukemia (AML).

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To view the poster and a multimedia announcement with additional media and investor resources click here.

"Collectively, the data reported today offer the opportunity to expand our current development activities with voruciclib and support its potential as a therapeutic option for KRAS mutated cancers in combination with direct inhibitors of KRAS," said Daniel P. Gold, Ph.D., president and chief executive officer of MEI Pharma. "Beyond these data, we have ongoing efforts to explore other potential synergistic combinations in various KRAS mutated cancers as we evaluate opportunities to confirm these findings in a clinical setting."

KRAS mutated cancers are frequently associated with overexpression of MYC, a transcription factor regulating cell proliferation and growth. CDK9 is a known regulator of MYC transcription and a modulator of MYC protein phosphorylation. The data reported today in preclinical models demonstrates that voruciclib:

Results in a rapid decrease in the phosphorylation of proteins that promote MYC transcription
Rapidly decreases phosphorylation of MYC protein on Ser62, a site implicated in stabilizing MYC in KRAS mutant cancers
Possesses single agent activity against multiple KRAS mutant cancer cell lines both in vitro and in vivo
Synergistically inhibits KRAS G12C mutant cancer cell lines in combination with KRAS G12C inhibitors, both in vitro and in vivo
The full video presentation is available on our website here: View Source

About Voruciclib
Voruciclib is an orally administered CDK inhibitor differentiated by its potent in vitro inhibition of CDK9 in addition to CDK6, 4 and 1. CDK9 has important functions in cell cycle regulation, including the modulation of two therapeutic targets in cancer:

CDK9 is a transcriptional regulator of the myeloid leukemia cell differentiation protein ("MCL1"), a member of the family of anti-apoptotic proteins which, when elevated, may prevent the cell from undergoing cell death. Inhibition of CDK9 blocks the production of MCL1, which is an established resistance mechanism to the B-cell lymphoma ("BCL2") inhibitor venetoclax (marketed as Venclexta).
CDK9 is a transcriptional regulator of the MYC proto-oncogene protein ("MYC") which regulates cell proliferation and growth. Upregulation of MYC is implicated in many human cancers and is frequently associated with poor prognosis and unfavorable patient survival. CDK9, in addition to being a transcription factor for MYC, also decreases phosphorylation of MYC protein that is implicated in stabilizing MYC in KRAS mutant cancers. Targeting MYC directly has historically been difficult, but CDK9 is a promising approach to target this oncogene.
Voruciclib is currently being evaluated in a Phase 1b trial evaluating dose and schedule in patients with acute myeloid leukemia ("AML") and B-cell malignancies. Applications in solid tumors are also being explored, particularly in KRAS mutated cancers.

Investor and Analyst Video Webcast
MEI will host an investor and analyst video webcast event on Tuesday, April 13, 2021 at 8:00 AM Eastern Time reviewing data from the E-Poster Session presentation at AACR (Free AACR Whitepaper), in which MEI reported data demonstrating voruciclib downregulates MYC and synergizes with KRAS inhibitors to inhibit KRAS mutant cancers in preclinical models. The event will also include additional voruciclib data as well as an overview and update of MEI’s business.

You can access the live video webcast under the investor relations section of MEI’s website on the "Events and Presentation" page at: www.meipharma.com. A replay of the video webcast will be archived for at least 30 days after the conclusion of the live event.

On April 10, 2021 Freenome, a privately held biotechnology company that has pioneered a comprehensive multiomics platform for early cancer detection using a routine blood draw, reported results of an analysis revealing the potential to use its platform for patient stratification and monitoring (Press release, Freenome, APR 10, 2021, View Source [SID1234577863]). Plasma samples from patients with kidney (n=21), melanoma (n=14) or non-small cell lung cancer (n=91) revealed signatures of immune checkpoint inhibition treatment response found to be common across all three cancer types. Whole-genome cell-free DNA (cfDNA) sequencing identified 13 transcription factors and 269 genes that reveal a potential pathway of treatment resistance and a possible epithelial mesenchymal transition signature in responders. A subsequent longitudinal analysis on a subset of lung cancer patients also identified markers for treatment response.

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"These results show the promise of our multiomics platform, which combines signatures from both tumor- and non-tumor-derived sources," commented Mike Nolan, Chief Business Officer of Freenome. "A blood-based test that can predict and monitor treatment response would help address the clear need for improved biomarkers for cancer patients undergoing immune checkpoint inhibitor treatment, where responses are highly variable."

"This work further demonstrates the many applications of our multiomics platform, and highlights our commitment to understanding the full potential of cfDNA," commented C. Jimmy Lin, M.D., Ph.D., M.H.S., Chief Scientific Officer at Freenome. "Inferring nucleosome positioning through cfDNA is yet another way we can provide more insight to answer research questions and, ultimately, apply this to clinical questions that are integral to patient care."

Data were presented in a poster presentation at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting. The poster is available online at View Source