On June 22, 2020 Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematologic and oncologic diseases, reported findings on the investigational cyclin-dependent kinase 9 (CDK9) inhibitor alvocidib and TP-1287, an oral prodrug of alvocidib (Press release, Tolero Pharmaceuticals, JUN 22, 2020, View Source [SID1234561362]). These data, highlighting a novel biomarker detection method for CDK9 inhibition and evaluating the anti-tumor activity of alvocidib and TP-1287 in hematologic cancer cells, are being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Meeting II, taking place June 22-24, 2020.

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The virtual poster presents a novel biomarker detection method to assess CDK9 inhibition through reduction of myeloid cell leukemia-1 (MCL-1) expression and of phosphorylation of RNA polymerase II (p-RPB1). Using peripheral blood mononuclear cells (PBMCs) as a surrogate tissue, this method was able to identify CDK9 inhibition in healthy donor PBMCs treated with alvocidib, the active form of TP-1287, ex vivo. This was also identified in a Phase 1 study participant receiving TP-1287 in an ongoing trial in patients with refractory solid tumors. These data may suggest a novel clinical biomarker approach for assessing overall CDK9 inhibition in patients.1

In preclinical studies, TP-1287 and alvocidib also showed potent cell-based activity in vitro and tumor growth inhibition in vivo across multiple hematologic cell lines, including acute myeloid leukemia (AML) and multiple myeloma (MM). Alvocidib was found to suppress p-RPB1 and the transcription of MCL-1, both downstream effectors of CDK9 activation, across cell lines and in normal PBMCs. Separately in a MM xenograft model, TP-1287 was shown to inhibit tumor growth, suppress p-RPB1 and the transcription MCL-1, and induce apoptosis.1

"Together, the results presented at AACR (Free AACR Whitepaper) show the inhibitory downstream effects of TP-1287 and its active form, alvocidib, across multiple AML and MM cell lines and in in vivo mouse models, which can be measured by a novel biomarker detection method," said David J. Bearss, Ph.D., Chief Executive Officer, Tolero Pharmaceuticals, and Chief Scientific Officer and Global Head of Research, Global Oncology. "Given the identification of this novel biomarker detection method to assess CDK9 inhibition, and the ability of TP-1287 to deliver alvocidib in the clinic, these findings support continued evaluation of the potential of CDK9 inhibition and the use of surrogate biomarkers in the ongoing study of TP-1287."

Below are the details for the presentation:

Abstract Title

Details

Author

Pharmacodynamic biomarker strategies
for CDK9 inhibition

Abstract# 5813

June 22, 2020

9 a.m. ET

Poster Presentation

Yuta Matsumura, Tolero
Pharmaceuticals

About TP-1287

TP-1287 is an investigational oral cyclin-dependent kinase 9 (CDK9) inhibitor under evaluation in a Phase 1 study in patients with advanced solid tumors (NCT03604783). TP-1287 has shown favorable oral bioavailability in preclinical models.

About Alvocidib

Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in the ongoing Phase 2 Zella 202 study in patients with acute myeloid leukemia (AML) who have either relapsed on or are refractory to venetoclax in combination with azacitidine or decitabine (NCT03969420). Alvocidib is also being evaluated in Zella 102, a Phase 1b/2 study in patients with myelodysplastic syndromes (MDS) in combination with azacitidine or decitabine (NCT03593915), and in a Phase 1 study in patients with relapsed or refractory AML in combination with venetoclax (NCT03441555).

About CDK9 Inhibition and MCL-1

MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.2 In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.3 MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse or resistance to treatment.2,4 The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).5,6 Because of the short half-life of MCL-1 (2-4 hours), the effects of targeting upstream pathways are expected to reduce MCL-1 levels rapidly.5 Inhibition of CDK9 has been shown to block MCL-1 transcription, resulting in the rapid downregulation of MCL-1 protein, thus restoring the normal apoptotic regulation.2

on June 22, 2020 twoXAR Pharmaceuticals, a drug discovery and development company focused on bringing first-in-class small molecules to market, reported that preclinical data for its investigational treatment TXR-311 with a novel MOA demonstrated significant efficacy and good tolerability in in vivo studies for the potential treatment of hepatocellular carcinoma (HCC), with results comparable to sorafenib, today’s standard-of-care (Press release, TwoXAR, JUN 22, 2020, View Source [SID1234561361]). The data was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II. The full poster and accompanying audio of the data is available at www.twoxar.com.

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"We are pleased that our TRX-311 in vivo data was selected for presentation at AACR (Free AACR Whitepaper). This study is another demonstration that our approach to drug discovery is effective in identifying novel molecules that have high likelihood of showing positive safety and efficacy signals in preclinical studies," stated Andrew A. Radin, co-founder and CEO of twoXAR. "We are thrilled with the progress of our HCC clinical program thus far and look forward to advancing additional drug candidates in disease areas with similar unmet needs."

HCC is a complex and heterogenous tumor and the most common type of primary liver cancer. It is difficult to diagnose and treat, with poor survival. It is most commonly associated with underlying chronic liver disease, including hepatitis and alcoholic and non–alcoholic steatohepatitis (NASH).

"While we have some beneficial treatments for hepatocellular carcinoma, this tumor type is a growing problem worldwide and more options are needed," said Dr. Ghassan K. Abou-Alfa, MD, medical oncologist at Memorial Sloan Kettering. "These early results are interesting and exciting because they showed safety and efficacy comparability against sorafenib but with a completely novel mechanism of action."

In validation studies, TRX-311 demonstrated greater activity and selectivity in killing HCC tumor cells than standard of care, sorafenib, and significantly inhibited growth in two HCC patient-derived xenograft (PDX) tumor models. TRX-311 also demonstrated in vivo efficacy comparable to sorafenib with good tolerability.

As part of a larger oncology drug discovery program, twoXAR identified 10 novel MOAs each for HCC and pancreatic ductal adenocarcinoma (PDAC) through its AI-driven drug discovery approach that builds an in-silico disease model using multiple sets of biological, clinical and chemical data. TRX-311 showed the most promising results and was chosen to proceed into lead optimization studies for HCC. TRX-311 also showed in vitro activity at low µm concentrations in PDAC cancer cells.

About Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) occurs most often in people with chronic liver diseases, such as cirrhosis caused by hepatitis B or hepatitis C infection. HCC is a multifactorial disorder and does not cause symptoms in the early stage, which often leads to a delay in diagnosis. The exact cause of HCC is not fully understood.

On June 22, 2020 Kazia Therapeutics Limited (ASX: KZA;NASDAQ: KZIA), an Australian oncology-focused biotechnology company, reported to share poster presentations of interim data from the ongoing phase II study of paxalisib (formerly GDC-0084) in glioblastoma, the most common and most aggressive form of primary brain cancer, and from the phase I study of Cantrixil in ovarian cancer (Press release, Kazia Therapeutics, JUN 22, 2020, View Source [SID1234561360]).

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Key Points

Previous paxalisib data presented at ASCO (Free ASCO Whitepaper) was based on Stage 1 (n=9) of the ongoing phase II study in glioblastoma. This interim analysis at AACR (Free AACR Whitepaper) includes all patients in the study (n=30), and therefore provides a more robust and substantial data set
Progression-free survival (PFS) for paxalisib is 8.5 months, versus 8.4 months in the previous analysis
Paxalisib overall survival (OS) remains at 17.7 months, in line with ASCO (Free ASCO Whitepaper) data
A separate poster on the investigator-initiated study of paxalisib in combination with radiotherapy is presented by clinicians at Memorial Sloan Kettering Cancer Center in New York. It noted a ‘robust response’ in the first treated patient
Cantrixil data shows one complete response (CR) to treatment, meaning no measurable disease, and two partial responses (PR), for an overall response rate of 19% (3 / 16 evaluable patients)
Summary of Paxalisib Data in Comparison to Temozolomide (existing standard of care)

Temozolomide[1]
(FDA-approved treatment)

Paxalisib

(interim phase II data)

Progression-Free Survival (PFS)

5.3 months

8.5 months

Overall Survival (OS)

12.7 months

17.7 months

Kazia CEO, Dr James Garner, commented, "The data summarized in these posters help to strengthen our confidence in both our clinical programs. As paxalisib moves towards commencement of the GBM AGILE pivotal study in the second half of calendar 2020, these findings will be used to support set-up activities. In the meantime, the fact that the PFS has remained robust as the analysis is extended out to the full data set gives us a great deal of additional confidence in the efficacy signal it provides. For Cantrixil, the emergence of one complete responder (CR) to treatment is very positive, and these new results will help us to explore partnering opportunities over the second half of the year."

AACR Annual Meeting

The American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting is one of the leading global academic conferences for oncology research. It is typically attended by more than 20,000 clinicians, researchers, industry executives, and investors, representing over 140 countries. The conference is being conducted through a virtual format this year and has been broken into two sections. AACR (Free AACR Whitepaper) Virtual Meeting I took place 27-28 April 2020, and AACR (Free AACR Whitepaper) Virtual Meeting II is being held 22-24 June 2020.

The paxalisib poster is found under number CT205 (NCT03522298), and the Cantrixil poster under CT166 (NCT02903771). Registration to the virtual meeting is free and interested parties may register via the AACR (Free AACR Whitepaper) website. The posters can be viewed on our website:

View Source

View Source

Initial Data from Memorial Sloan-Kettering Study of Paxalisib with Radiotherapy

Dr Jonathan Yang and team at Memorial Sloan Kettering Cancer Center in New York, NY, also presented a poster (number CT252) on their ongoing phase I study of paxalisib in combination with radiotherapy (NCT04192981). The poster principally reported the design of their study, but also noted a ‘robust response’ in the first patient treated. Further data is expected as the study progresses

Next Steps

The paxalisb phase II study remains ongoing with a number of patients in follow-up and approximately half of the total enrolled patient population still receiving drug at the time of analysis. Kazia expects to complete the study in 1H CY2021.

Set-up work is well underway for paxalisib’s planned entry into the GBM AGILE pivotal study, and it is expected that the first patient will be enrolled in the second half of calendar 2020.

The Cantrixil phase I study is now complete and analysis is underway, with final data expected in the second half of calendar 2020.

On June 22, 2020 ABM Therapeutics, a clinical-stage biopharmaceutical company developing a new generation of BRAF inhibitor, reported that the first cancer patient has been successfully enrolled and dosed with ABM-1310 in the Phase 1 clinical trial in the USA (Press release, ABM Therapeutics, JUN 22, 2020, View Source [SID1234561359]). ABM-1310, the company’s lead candidate, demonstrated superior properties in pre-clinical animal models, is a highly selective, highly water-soluble, orally active, and brain-penetrant small molecule BRAF inhibitor.

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Dosing the first patient in the USA represents another important milestone, both for ABM-1310 program and for patients. "We are so grateful to patients and their families, investigators and clinical study sites for their support on the study," Dr. Chen Chen, founder and CEO of ABM Therapeutics said. "Many cancer patients are affected by brain metastases, but current treatment options are limited. ABM-1310 significantly prolonged median survival time of brain metastases in preclinical models and is expected to be a new generation of BRAF inhibitors for the treatment of various malignant tumors and brain metastases. We have been at full speed conducting clinical development of ABM-1310 in the USA and hope to bring the potential therapeutic benefits to patients as soon as possible."

ABM-1310 phase 1 trial is a multi-center, open-label study to test the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of ABM-1310 in patients with BRAF mutant advanced solid tumor and BRAF mutant patients with brain metastases. The goal of the study is to determine the optimal dose for phase 1b/2 studies.

"We have designed our Phase 1 trial to move efficiently through dose escalation and to increase the chance of seeing early signs of clinical activity by focusing on the BRAF mutant patient population. We look forward to producing important early clinical data to guide our future clinical development," said Dr. Charles Zhao, Chief Medical Officer of ABM Therapeutics. "Based on the preclinical potency of ABM-1310, we believe it could provide a profound benefit for patients in urgent need of new therapies as both a single agent and in combination with other therapies."

As a clinical-stage biotechnology company, ABM Therapeutics has broad and robust proprietary pipeline to construct a brain medicine R&D platform. It will continue to focus on the small molecule research and development of novel drugs for the treatment of cancer, with an emphasis on blood–brain barrier (BBB) penetration and brain metastasis. We look forward to working with international pharmaceutical companies and biotech companies from multiple perspectives to make our drug to benefit more patients in the world.

On June 22, 2020 Castle Biosciences, Inc. (Nasdaq: CSTL), reported that it has commenced a proposed underwritten public offering of 1,500,000 shares of its common stock (Press release, Castle Biosciences, JUN 22, 2020, View Source [SID1234561358]). Castle Biosciences also intends to grant the underwriters a 30-day option to purchase up to an additional 225,000 shares of common stock at the public offering price, less the underwriting discounts and commissions. The public offering price has not yet been determined. The offering is subject to market and other conditions, and there can be no assurance as to whether or when the offering may be completed, or as to the actual size or terms of the offering.

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SVB Leerink and Baird are acting as joint book-running managers for the proposed offering and as representatives of the underwriters. Canaccord Genuity is acting as passive book-runner, and BTIG is acting as co-manager for the offering.

A registration statement on Form S-1 relating to these securities has been filed with the Securities and Exchange Commission (SEC) but has not yet become effective. These securities may not be sold, nor may offers to buy be accepted, prior to the time the registration statement becomes effective. The proposed offering will be made only by means of a prospectus.

Copies of the preliminary prospectus relating to the proposed offering may be obtained, when available, from: SVB Leerink LLC, Attention: Syndicate Department, One Federal Street, 37th Floor, Boston, MA 02110, by telephone: (800) 808‐7525, ext. 6218, or by e-mail: [email protected]; or from Robert W. Baird & Co. Incorporated, Attention: Syndicate Department, 777 East Wisconsin Ave., Milwaukee, WI 53202, by telephone: (800) 792-2473, or by email: [email protected].

This press release shall not constitute an offer to sell or a solicitation of an offer to buy, nor shall there be any offer or sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of such state or jurisdiction.