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eFFECTOR’s Zotatifin (eFT226) Inhibited Tumor Growth and Caused Tumor Regression Across Diverse Receptor Tyrosine Kinase-Driven Tumor Types in Preclinical Models of Disease

On April 27, 2020 eFFECTOR Therapeutics, Inc., a leader in the development of selective translation regulator inhibitors (STRIs) for the treatment of cancer, reported that data presented today in a virtual session at the AACR (Free AACR Whitepaper) Annual Meeting, showed the anti-tumor activity of the company’s product candidate, zotatifin, in preclinical models of FGFR1, FGFR2 and HER2 driven cancers, demonstrating the potential of zotatifin in receptor tyrosine kinase (RTK)-driven cancers (Press release, eFFECTOR Therapeutics, APR 27, 2020, View Source [SID1234556626]).

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Peggy A. Thompson, Ph.D., executive director, translational medicine at eFFECTOR, gave a presentation entitled, "Preclinical evaluation of eFT226, a potent and selective eIF4A inhibitor with anti-tumor activity in FGFR1, FGFR2 and HER2 driven cancers" which showed that zotatifin significantly inhibited tumor growth and caused tumor regression across diverse RTK-driven tumor types. Zotatifin has been shown to downregulate RTK protein levels and associated AKT and MAPK signaling, resulting in anti-tumor activity in FGFR1, FGFR2 and HER2 driven models. In a HER2+ breast cancer model, tumor regression was sustained long after cessation of therapy. Further evaluation of predictive markers of sensitivity or resistance showed that RTK tumor models with mTOR mediated activation of eIF4A are most sensitive to zotatifin.

"These promising preclinical studies demonstrated that the association of zotatifin activity in RTK tumor models with mTOR pathway activation provides an opportunity to further enrich for sensitive patient subsets during clinical development," said Steve Worland, Ph.D., president and chief executive officer of eFFECTOR. "This selection strategy will complement our selection of KRAS-mutant tumors based on zotatifin’s down-regulation of KRAS protein in preclinical studies."

A Phase 1/2 clinical trial of zotatifin in patients with KRAS- or RTK-mutant solid tumors is ongoing [NCT04092673]. The trial is enrolling patients with activating mutations, amplifications or fusions in HER2, ERBB3, FGFR1, or FGFR2 receptor tyrosine kinases, or any KRAS mutation subtype. The primary objectives of the trial include safety and tolerability of zotatifin as monotherapy. Secondary objectives include antitumor activity and survival, as well as pharmacokinetics of the drug. Exploratory objectives include pharmacodynamics of zotatifin.

About Zotatifin
Zotatifin is a potent and sequence selective inhibitor of eukaryotic translation initiation factor 4A (eIF4A) mediated translation. Zotatifin is designed to inhibit the translation of mRNAs encoding several important oncogenes and survival factors, including several RTKS, KRAS, Cyclin D, CDK4/6, MYC, MCL1 and BCL-2 resulting in potent in vivo tumor regression in multiple tumor models dependent on these factors, including colorectal cancer, non-small cell lung cancer, breast cancer, hepatocellular carcinoma and B cell lymphomas. Since zotatifin inhibits the translation of mRNA encoding KRAS and RTK, it is not limited to any mutation subtypes. The product candidate is currently being evaluated in a Phase 1/2 clinical trial in patients with solid tumors.

About eIF4A
eIF4A is an RNA helicase that catalyzes the ATP-dependent translation of highly structured mRNA. eIF4A helicase activity is tightly controlled by the PI3K and RAS signaling pathways. Activation of eIF4A results in the selective upregulation of oncogenes with highly structured 5’-UTRs (untranslated regions) that are involved in cell proliferation, survival and metastasis. Inhibition of eIF4A selectively regulates the translation of a set of target mRNAs distinct from those regulated by MNK1/2 and eIF4E. Targeting these selective translational regulators may expand the potential patient population that benefits from translation regulation therapy.

Corcept Therapeutics to Announce First Quarter Financial Results, Provide Corporate Update and Host Conference Call

On April 27, 2020 Corcept Therapeutics Incorporated (NASDAQ: CORT) reported it will report first quarter financial results and provide a corporate update on May 4, 2020 (Press release, Corcept Therapeutics, APR 27, 2020, https://ir.corcept.com/news-releases/news-release-details/corcept-therapeutics-announce-first-quarter-financial-results-5 [SID1234556625]). The company will also host a conference call that day at 5:00 p.m. Eastern Time (2:00 p.m. Pacific Time).

Conference Call Information
To participate, dial 1-800-458-4121 from the United States or 1-323-794-2093 internationally approximately ten minutes before the start of the call. The passcode will be 2827359.

A replay will be available through May 18, 2020 at 1-888-203-1112 from the United States and 1-719-457-0820 internationally. The passcode will be 2827359.

Bio-Path Holdings Presents at 2020 American Association for Cancer Research Annual Meeting

On April 27 , 2020 Bio-Path Holdings, Inc., (NASDAQ: BPTH), a biotechnology company leveraging its proprietary DNAbilize antisense RNAi nanoparticle technology to develop a portfolio of targeted nucleic acid cancer drugs, reported the presentation of a poster highlighting the clinical trial design of its Phase 1 study of BP1002 at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held virtually from April 27-28, 2020 (Press release, Bio-Path Holdings, APR 27, 2020, View Source [SID1234556624]).

The poster, titled, "A Phase I Clinical Trial to Study the Safety, Pharmacokinetics, and Efficacy of BP1002 (L-Bcl-2) Antisense Oligonucleotide in Patients with Advanced Lymphoid Malignancies," was presented virtually by Dr. Ana Tari Ashizawa, Senior Vice President of Research, Development and Clinical Design at Bio-Path Holdings.

"We are particularly pleased to have our Phase 1 clinical development program for BP1002 as a potential therapy for lymphoma and chronic lymphocytic leukemia patients highlighted in a poster at this important scientific meeting," stated Peter Nielsen, President and Chief Executive Officer of Bio-Path Holdings. "We believe this poster will enhance visibility for our Bcl-2 program among an audience of world-leading oncologists and cancer researchers."

The Phase 1 clinical trial is expected to be conducted at several leading cancer centers, including The University of Texas MD Anderson Cancer Center, the Georgia Cancer Center and the Sarah Canon Research Institute. Initially, a total of six evaluable patients will be treated with BP1002 monotherapy in a standard 3+3 design, with a starting dose of 20 mg/m2. The approved treatment cycle is two doses per week over four weeks, resulting in eight doses administered over 28 days. The primary objective of the study is to evaluate the safety and tolerability of escalating doses of BP1002.

BP1002 targets the protein Bcl-2, which is responsible for driving cell survival in up to 60% of all cancers. High expression of Bcl-2 has been correlated with adverse prognosis for patients diagnosed with relapsed, aggressive non-Hodgkin’s lymphoma. Preclinical studies have shown BP1002 to be a potent inhibitor against the Bcl-2 target, and Bio-Path believes that its benign safety profile should enable BP1002 combination therapy with approved agents.

Aptose Presents Preliminary Clinical Data on CG-806 at AACR Virtual Annual Meeting 2020

On April 27, 2020 Aptose Biosciences Inc. (Nasdaq: APTO; TSX: APS), a clinical-stage company developing highly differentiated therapeutics that target the underlying mechanisms of cancer, reported the early clinical data on CG-806, the company’s oral, first-in-class FLT3/BTK cluster selective kinase inhibitor, at the AACR (Free AACR Whitepaper) Virtual Annual Meeting I (April 27-28), in lieu of the live oral presentation originally planned (Press release, Aptose Biosciences, APR 27, 2020, View Source [SID1234556623]).

Rafael Bejar M.D., Ph.D., Aptose’s Chief Medical Officer, presented a video summary of Abstract # 9967 – Early clinical findings from a phase 1a/b dose escalation trial to evaluate the safety and tolerability of CG-806 in patients with relapsed or refractory CLL/SLL or non-Hodgkin’s lymphomas [link].

The first-in-human tests of CG-806 are being carried out in a Phase 1a/b clinical study. The target population in the study includes patients with significant unmet needs including patients with relapsed or refractory chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL) or non-Hodgkin lymphoma (NHL) who have failed or been intolerant to two lines of established therapy. CG-806 is administered as oral capsules dosed twice daily in 28-day cycles. The study design includes an accelerated titration followed by a 3+3 dose escalation to establish the recommended Phase 2 dose for planned expansion cohorts and future studies.

The first patient, treated with 150 mg BID of CG-806, was heavily pretreated, carried a TP53 mutation, and had severe thrombocytopenia prior to study entry. This patient currently is in the eleventh cycle of therapy without having experienced a dose-limiting toxicity (DLT) and has been dose escalated to the 450 mg BID dose level.

The second patient, treated at the 300 mg BID dose level, had significant marrow involvement with neutropenia and thrombocytopenia at study entry, and developed a brisk lymphocytosis, but did not experience a DLT through four cycles of therapy including no worsening of their thrombocytopenia or neutropenia.

The study has now completed three dose levels without observing any drug-related severe adverse events (SAE) and has not reached a dose-limiting toxicity. Three patients completed the safety evaluation period at the third dose level, 450 mg BID, and as a result, the fourth dose level was opened. The first patient, previously dosed at 150 mg BID was dose escalated to dose level 3 at 450 mg BID. Enrollment is open and dosing is ongoing at the 600 mg BID dose level with no drug-related SAEs or DLTs encountered to date.

Key findings to date:

No drug-related SAEs or DLTs have been observed in patients to date
CG-806 demonstrates favorable steady state pharmacokinetics evidenced by stable trough plasma concentrations reached by Day 8 in the first two patients treated at dose levels 1 and 2
CG-806 has shown on-target pharmacologic activity demonstrated by plasma inhibitory assays with reporter cells exposed to patient plasma for 6 hours
Phospho-BTK is markedly reduced after exposure to plasma from the patient treated at dose level 1 and completely abrogated with plasma form the patient treated at dose level 2
Similar results are seen for the phosphorylation of PDGFR-alpha, a target of CG-806, for SYK, which lies in the same signaling pathway as BTK and for ERK
Lymphocytosis was noted at dose level 2 – pharmacologic BTK inhibition in CLL promotes exfiltration
Dr. Bejar summarized the team’s findings: "CG-806 is a novel and unique cluster selective kinase inhibitor with activity against clinically validated targets in both lymphoid and myeloid malignancies through its potent inhibition of BTK and FLT3. The ongoing Phase 1 study in relapsed/refractory B-cell malignancies has demonstrated the safety of CG-806 to date, pharmacologic activity, and predictable pharmacokinetic behavior. We look forward to presenting new data from higher dose cohorts at a future medical meeting."

The slide deck of this presentation is available on the Aptose website View Source

About CG-806

CG-806 is an oral, first-in-class FLT3/BTK cluster selective kinase inhibitor and is in Phase 1 clinical studies for the treatment of hematologic malignancies. This small molecule, demonstrates potent inhibition of wild type and all mutant forms of FLT3 (including internal tandem duplication, or ITD, and mutations of the receptor tyrosine kinase domain and gatekeeper region), cures animals of AML in the absence of toxicity in murine xenograft models, and represents a potential best-in-class therapeutic for patients with AML and other myeloid malignancies. Likewise, CG-806 demonstrates potent, non-covalent inhibition of the wild type and Cys481Ser (C481S) mutant forms of the BTK enzyme, as well as other oncogenic kinase pathways operative in B cell malignancies, suggesting CG-806 may be developed for various B cell malignancy patients (including CLL/SLL, FL, MCL, DLBCL and others) that are resistant/refractory/intolerant to covalent or other non-covalent BTK inhibitors. Because CG-806 targets key kinases/pathways operative in malignancies derived from the bone marrow, it is in development for B-cell cancers and AML.

Alpine Immune Sciences Presents Design of the ALPN-202 Phase 1 Study (NEON-1) at AACR Virtual Annual Meeting I

On April 27, 2020 Alpine Immune Sciences, Inc. (NASDAQ: ALPN), a leading clinical-stage immunotherapy company focused on developing innovative treatments for cancer and autoimmune/inflammatory diseases, reported the design of NEON-1, the first-in-human study of ALPN-202, a first-in-class, conditional CD28 costimulator and dual checkpoint inhibitor, at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting I, in the Phase I Trials in Progress Virtual Poster Session (Press release, Alpine Immune Sciences, APR 27, 2020, View Source [SID1234556622]).

Many patients treated with checkpoint inhibitors fail to achieve an objective or complete anti-tumor response. This could be due to a lack of sufficient T cell costimluation in the tumor microenvironment, such as inadequate CD28 ligands. To address this, ALPN-202 was designed to inhibit both the PD-L1 and CTLA-4 checkpoints, while also providing a CD28 costimulatory signal. Importantly, ALPN-202’s costimulatory function is designed to depend upon PD-L1, to help ensure clinical safety and tolerability.

NEON-1 includes two parts: dose escalation and expansion cohort(s). It will enroll adults with advanced solid tumors or lymphoma refractory or resistant to standard therapy, including checkpoint inhibitors when indicated. Measurable disease is required for most participants, as are an ECOG status of 0 to 2 and adequate hematological, renal, and hepatic function. Dose escalation begins with single-participant cohorts to minimize the number of participants anticipated to receive subtherapeutic doses, followed by standard 3 + 3 cohorts where two dose regimens, weekly versus every three weeks, will be studied in parallel. Expansion cohorts will explore specific tumor types and/or biomarker-selected tumors, based upon the experience during dose escalation. Safety endpoints include dose-limiting toxicities, adverse events, and circulating cytokines. Objective responses will be assessed by RECIST v1.1 for solid tumors and Lugano criteria for lymphoma. Pharmacokinetics and pharmacodynamics will also be evaluated.

"We are particularly pleased to see ALPN-202 enter the clinic," said Mitchell Gold, MD, Alpine’s Chairman and CEO. "ALPN-202 embodies the unique founding concepts of Alpine’s vIgD platform, incorporating tri-functional agonism and antagonism in a single proprietary functional domain. It is now positioned to determine the clinical relevance of localized CD28 costimulation to the immunotherapy of cancer. We look forward to opportunities to report upon its progress in appropriate future settings."

AACR has made the 2020 virtual Annual Meeting presentations freely available. Alpine’s recorded oral presentation of the NEON-1 trial design can be accessed here.

About ALPN-202

ALPN-202 is a first-in-class, conditional CD28 costimulator and dual checkpoint inhibitor with the potential to improve upon the efficacy of combined checkpoint inhibition while limiting significant toxicities. Preclinical studies of ALPN-202 have successfully demonstrated superior efficacy in tumor models compared to checkpoint inhibition alone. A phase 1 trial of ALPN-202 in advanced malignancies (NEON-1, NCT04186637) is open for enrollment.