On April 10, 2024 Moleculin Biotech, Inc., (Nasdaq: MBRX) (Moleculin or the Company), a clinical stage pharmaceutical company with a broad portfolio of drug candidates targeting hard-to-treat tumors and viruses, reported positive preclinical data regarding the Company’s next-generation anthracycline, Annamycin, was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 5-10, 2024 in San Diego, CA (Press release, Moleculin, APR 10, 2024, View Source [SID1234641983]).

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The poster titled, Non-cardiotoxic Properties of Annamycin, a Clinically Evaluated Anthracycline and Potent Topoisomerase 2β Poison, was presented in the "Late-Breaking Research: Experimental and Molecular Therapeutics 2" session held on Monday, April 8th. The presented poster outlined results from the assessment and comparison of the potency of doxorubicin (a commonly prescribed anthracycline) and Annamycin, Moleculin’s next-generation anthracycline, against topoisomerase II-alpha and II-beta and determine their impact on physiology of human cardiomyocytes demonstrating no pathologic changes in mice hearts following chronic in vivo exposure.

"Cardiotoxicity continues to be a significant side effect limiting the clinical use of anthracyclines, despite anthracyclines representing some of the most important treatments available for AML and Advanced STS. These data, documenting lack of cardiotoxicity of Annamycin and aligned with the data demonstrated to date in our ongoing clinical trials, bolster our confidence in Annamycin potential to offer patients a safe and effective treatment option. Interestingly, the presented data demonstrates that Annamycin appears to be a significantly more potent inhibitor of topoisomerase II-beta than doxorubicin providing validation for additional studies to reevaluate the role of topoisomerase II-beta in anthracycline induced cardiotoxicity," commented Walter Klemp, Chairman and Chief Executive Officer of Moleculin.

"Additionally, with our recently issued patent, which covers composition of matter protection across all indications, we have the potential to expand the development of Annamycin into greater patient populations in indications where cardiotoxicity remains a significant unmet need. We remain highly encouraged by Annamycin and committed to advancing its development," concluded Mr. Klemp.

As part of the presented data, the potency of Annamycin and doxorubicin to inhibit topoisomerase II was tested in DNA relaxation assays using recombinant topoisomerase II-alpha and II-beta with kinetoplast as the DNA substrate. Annamycin and doxorubicin cytotoxicity was assessed in a panel of cancer cell lines cardiomyocytes (murine and human). In addition, the effects on cardiomyocyte physiology (beating rate, contraction, electric potential,) were assessed in human cardiomyocytes using the xCELLigence RTCA CardioECR. The pathophysiology of the heart after chronic exposure to the drugs was also evaluated in mice models.

Key Data Highlights:

Annamycin demonstrated to be a more potent topoisomerase II-alpha and II-beta poison than doxorubicin.
In contrast to doxorubicin:
Annamycin does not affect viability of established culture of human iPSCc cardiomyocytes (tested up to 1.5 μM)
Annamycin does not affect contractility or the electric potential of the cardiomyocytes
Rat cardiomyocytes (H9c2) appear to be resistant to ANN while sensitive to DOX
Annamycin is well tolerated by the animals even at schedules exceeding the therapeutic dosage while ex vivo pathology examination of the mice confirmed no toxicity to the heart/myocardium.
These data are clearly aligned with the lack of drug-related cardiotoxic events in Annamycin-treated patients in ongoing clinical trials
The role of topoisomerase II-beta in cardiotoxicity of anthracyclines should be further investigated
A video on the comparison of cardiotoxic effects of Annamycin and doxorubicin on human cardiomyocytes can be accessed here
The Company also announced that the United States Patent and Trademark Office (USPTO) formally issued U.S. Patent number 11,951,118 titled, "Preparation of Preliposomal Annamycin Lyophilizate" (the ‘118 patent’) to Moleculin and The University of Texas System Board of Regents.

Annamycin is currently being evaluated in ongoing clinical trials for the treatment of relapsed or refractory acute myeloid leukemia (AML) and soft tissue sarcoma (STS) lung metastases. For more information about the ongoing trials, please visit clinicaltrialsregister.eu: EudraCT 2020-005493-10 or clinicaltrials.gov: NCT05319587; and clinicaltrials.gov: NCT04887298, respectively.

On April 10, 2024 Kura Oncology, Inc. (NASDAQ: KURA), a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer, reported its participation in Stifel 2024 Targeted Oncology Forum (Press release, Kura Oncology, APR 10, 2024, View Source [SID1234641982]). Troy Wilson, Ph.D., J.D., President and Chief Executive Officer, is scheduled to participate in a virtual fireside chat at 11:30 a.m. ET / 8:30 a.m. PT on April 17, 2024. A live audio webcast of the fireside chat will be available in the Investors section of Kura’s website at www.kuraoncology.com, with an archived replay following the event.

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On April 10, 2024 IGM Biosciences, Inc. (Nasdaq: IGMS), a clinical-stage biotechnology company creating and developing engineered IgM antibodies, reported that Fred Schwarzer, Chief Executive Officer, will participate in a fireside chat at the Stifel 2024 Virtual Targeted Oncology Forum on Wednesday, April 17, 2024, at 12:00 p.m. EDT (Press release, IGM Biosciences, APR 10, 2024, View Source [SID1234641980]).

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A live webcast of the event will be available on the "Events and Presentations" page in the "Investors" section of the Company’s website at View Source A replay of the webcast will be archived on the Company’s website for 90 days following the presentation.

On April 10, 2024 HOOKIPA Pharma Inc. (NASDAQ: HOOK, HOOKIPA or the Company), a company developing a new class of immunotherapeutics based on its proprietary arenavirus platform, reported that members of HOOKIPA’s Executive Team will host an investor call summarizing the Company’s constructive regulatory interactions with the U.S. Food & Drug Administration (FDA) and the European Medicines Agency (EMA) (Press release, Hookipa Biotech, APR 10, 2024, View Source [SID1234641979]). HOOKIPA and the FDA have aligned on the design and protocol of the Company’s upcoming pivotal Phase 2/3 clinical trial of HB-200 in combination with pembrolizumab. The investor call will be held on April 25, 2024, at 8:00 a.m. ET. Complete details and registration information are included below.

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The Company also announced that EMA has granted PRIME designation for the investigational product HB-200 in combination with pembrolizumab for the treatment of patients with Human Papillomavirus 16-positive (HPV16+) recurrent/metastatic PD-L1 CPS ≥ 20 oropharyngeal squamous cell carcinoma (OPSCC) in the first line setting. PRIME designation is intended to expedite development and review of drug candidates, alone or in combination with other drugs. Eligibility and approval are based on preliminary clinical evidence and indicate that the drug candidate may offer substantial improvement over existing therapies.

"There is a significant unmet need for patients with OPSCC, and we are excited to share our pivotal Phase 2/3 trial design and demonstrate how we hope to provide better treatment options for these patients," said Joern Aldag, Chief Executive Officer of HOOKIPA. "We have had positive conversations with our regulators as we have outlined our clinical trial plans for HB-200. The FDA is aligned on our clinical trial design and protocol, while EMA’s PRIME designation is additional validation for the potential of our HB-200 program. We look forward to sharing more details on our upcoming call."

Call Details:
HOOKIPA HB-200 Phase 2/3 Clinical Trial Update
Thursday, April 25, 2024, 8:00 a.m. ET
Webcast Registration
Dial-in Registration

On April 10, 2024 Blacksmith Medicines, Inc. (Blacksmith), a leading biopharma dedicated to discovering and developing medicines targeting metalloenzymes, reported preclinical data on its oncology program targeting flap endonuclease 1 (FEN1), a structure-specific metallonuclease that cleaves 5’ DNA flaps during replication and repair, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024, taking place April 5-10 at the San Diego Convention Center, San Diego CA (Press release, Blacksmith Medicines, APR 10, 2024, View Source [SID1234641978]).

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"FEN1 has been identified as an important therapeutic metalloenzyme involved in DNA replication and repair but previous drug discovery efforts have been hampered by chemistry limitations resulting in inhibitors lacking potency and selectivity," said Zachary Zimmerman, Ph.D. CEO of Blacksmith. "Using our metalloenzyme fragment-based drug discovery approach, we have identified a highly potent and selective inhibitor of FEN1 having synergies with multiple DDR drug classes that include inhibitors of PARP, PARG, USP1, and ATR."

The Blacksmith fragment-based drug discovery platform identified a novel metal-binding pharmacophore that binds to the two magnesium ions in the FEN1 active site. Further elaboration using fragment growth strategies resulted in highly potent and selective inhibitors. The current lead (BSM-1516) is ~65-fold more potent against FEN1 than its related enzyme Exonuclease 1 (Exo1) in biochemical assays (IC50 of 7 nM and 460 nM, respectively), an improvement of more than an order of magnitude in selectivity compared to earlier efforts. FEN1 target engagement in live cells was validated by cellular thermal shift assay (CETSA EC50 of 24 nM). Inhibition of FEN1 led to its increased association with chromatin in S-phase cells and recruitment of PARP1 enzyme.

In clonogenic assay, BRCA2-deficient DLD1 cells were ~15-fold more sensitive to FEN1 inhibition than their isogenic BRCA2-wild-type counterparts (EC50 of 350 nM and 5 µM, respectively), confirming the increased susceptibility of HR deficient cancer cells to FEN1 inhibition. Treatment of BRCA2-deficient but not wild-type DLD1 cells with BSM-1516 resulted in cell cycle arrest accompanied by DNA damage signaling and accumulation of chromatin-bound RPA32, a marker of ssDNA.

In FEN1-inhibitor-anchored CRISPR screen, it was observed that perturbations in EXO1, USP1, PARP1 and HR pathway genes sensitized cells to FEN1 inhibition. Synergistic relationships of BSM-1516 and its combination potential were further explored in viability studies with a panel of DDR inhibitors (n=25) in BRCA2-proficient and deficient cell lines. Strong synergy was identified with multiple drug classes that included inhibitors of USP1 (KSQ-4279), PARP (Olaparib, Niraparib, Talazoparib, AZD5305), PARG (PDD 00017273) and ATR (AZD6738, VE-822, Elimusertib).

In vitro ADME assays and in vivo PK studies showed that BSM-1516 has properties suitable for in vivo testing, either as a single agent or in combination with synergistic DDR inhibitors, an investigation that is currently underway.

Poster presentation details

Abstract Number: 7148
Title: "Small molecule inhibitor of FEN1 nuclease utilizing a novel metal binding pharmacophore synergizes with inhibitors of USP1, PARP, PARG and ATR"
Session Category: Experimental and Molecular Therapeutics
Session Title: Novel Antitumor Agents 6
Session Date and Time: Wednesday April 10, 2024 9:00 AM – 12:30 PM
Location: Poster Section 23
Poster Board Number: 10

About FEN1

Flap endonuclease 1 (FEN1) is a structure-specific di-magnesium metallonuclease that cleaves 5’ DNA flaps during replication and repair. FEN1 is an attractive target for development of anticancer therapeutics because it is overexpressed in many tumor types and has a large number of synthetic lethality partners including genes in Homologous Recombination (HR) pathway.

About metalloenzymes and the Blacksmith platform

Metalloenzymes utilize a metal ion cofactor in the enzyme active site to perform essential biological functions. This diverse class of targets has historically been difficult to drug due to small molecule chemistry limitations that have plagued the industry. The Blacksmith metalloenzyme platform has solved this problem by leveraging the following:

A large proprietary fragment library of metal-binding pharmacophores (MBPs);
A comprehensive database containing a full characterization of the metalloenzyme genome including functions, metal cofactors, and associations to disease;
A first-of-its-kind metallo-CRISPR library of custom single guide RNAs;
An industry-leading metalloenzyme computational toolkit for docking, modeling and structure-based drug design; and
A robust and blocking intellectual property estate covering bioinorganic, medicinal, and computational chemistry approaches for metalloenzyme-targeted medicines.