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.

On April 10, 2024 BioLineRx Ltd. (NASDAQ/TASE: BLRX), a commercial stage biopharmaceutical company pursuing life-changing therapies in oncology and rare diseases, reported that it has drawn-down the second tranche of $20 million under its previously announced $40 million non-dilutive debt financing agreement with funds and accounts managed by BlackRock (Press release, BioLineRx, APR 10, 2024, View Source [SID1234641977]).

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The agreement with BlackRock EMEA Venture and Growth Lending (previously Kreos Capital) was originally announced in September 2022.

"We are very pleased to be able to access this second tranche of non-dilutive funding at terms that we believe are very favorable to our company," stated Philip Serlin, Chief Executive Officer of BioLineRx. "These funds should allow us to meaningfully advance the commercialization of APHEXDA in stem cell mobilization for multiple myeloma, accelerate APHEXDA life-cycle programs in sickle cell disease and other areas, and support development of motixafortide in metastatic pancreatic cancer."

Per the terms of the original agreement, the first tranche of $10 million was made available to BioLineRx upon execution of the definitive agreement. The remaining $30 million was made available in two additional tranches of $20 million and $10 million, respectively, subject to the achievement of pre-specified milestones. The remaining tranche of $10 million may be available for drawdown through October 1, 2024.

Each tranche carries a pre-defined interest-only payment period, followed by a loan principal amortization period of up to 36 months subsequent to the interest-only period. Borrowings under the financing bear interest at a fixed rate of 9.5% per annum (~11.0%, including associated cash fees). In addition, funds and accounts managed by BlackRock are entitled to mid-to-high single-digit royalties on APHEXDA (motixafortide) sales, up to a pre-defined cap. No warrants were issued by BioLineRx in connection with this financing.

As of December 31, 2023, BioLineRx reported cash, cash equivalents, and short-term bank deposits of $43.0 million. In addition to the $20 million drawdown of the loan tranche reported herein, the company recently completed a registered direct equity offering which raised an additional $6 million.

Upcoming milestones:

Concurrent with this announcement, BioLineRx today also reiterated its expected upcoming milestones:

Continued commercial ramp-up of APHEXDA in the US
Commercial expansion in Asia with collaboration partner Gloria BioSciences
Initiation of bridging study by Gloria Biosciences in the second half of this year to support approval of APHEXDA in stem cell mobilization for multiple myeloma in China
Completion of recruitment in the Phase 1 pilot study of motixafortide for hematopoietic stem cell mobilization for gene therapies in sickle cell disease led by Washington University School of Medicine, with initial data expected in the second half of this year
Continued recruitment in the Chemo4MetPanc Phase 2b randomized clinical trial in first-line metastatic pancreatic cancer sponsored by Columbia University
Preparation activities with Gloria Biosciences on a randomized Phase 2b clinical trial evaluating motixafortide in combination with the PD-1 inhibitor zimberelimab and standard of care chemotherapy in first-line pancreatic cancer

On April 10, 2024 Bexion Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company developing a novel class of biologic therapy to treat solid tumor cancers and chemotherapy-induced peripheral neuropathy (CIPN), reported that the Company presented a poster on BXQ-350 during the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 which took place April 5-10, 2024, in San Diego, CA. Poster details are included below (Press release, Bexion, APR 10, 2024, View Source [SID1234641976]).

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Poster Details:

Abstract Title: BXQ-350: A novel biologic that allosterically activates glucosylcerebrosidase and demonstrates signs of activity in cancer patients
Abstract Number: 3072
Poster Board Number: 12
Session Title: Signaling Pathways That Regulate Metabolism 1
Session Date: Monday Apr 8, 2024
Presenter: Gilles Tapolsky, PhD, Vice President of Pharmacology & Translational Sciences, Bexion Pharmaceuticals

The abstracts were posted to the AACR (Free AACR Whitepaper) Online Program Planner at 4:30 PM ET on Tuesday, March 5.

About AACR (Free AACR Whitepaper)
The American Association for Cancer Research (AACR) (Free AACR Whitepaper) is the first and largest cancer research organization dedicated to accelerating the conquest of cancer. The AACR (Free AACR Whitepaper) Annual Meeting program covers the latest discoveries across the spectrum of cancer research—from population science and prevention; to cancer biology, translational, and clinical studies; to survivorship and advocacy—and highlights the work of the best minds in research and medicine from institutions all over the world.

About BXQ-350
Bexion’s lead drug candidate is BXQ-350, a first-in-class biologic containing the multifunctional, sphingolipid activator protein, Saposin C, and a phospholipid. Clinically, two Phase 1 clinical trials, one in adults and one in pediatric DIPG patients, have demonstrated a robust safety profile for BXQ-350 with evidence of single agent activity across multiple solid tumor types. Additionally, other clinical and non-clinical data suggest BXQ-350 has activity in chemotherapy-induced peripheral neuropathy, an area of high unmet medical need in solid tumor patients treated with oxaliplatin and other chemotoxic agents.

On April 10, 2024 Aprea Therapeutics, Inc. (Nasdaq: APRE) ("Aprea", or the "Company"), a clinical-stage biopharmaceutical company focused on precision oncology through synthetic lethality, reported details about four poster presentations at the ongoing American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 5 to 10, 2024 in San Diego, CA (Press release, Aprea, APR 10, 2024, View Source [SID1234641975]). The posters feature APR-1051, Aprea’s next-generation inhibitor of WEE1 kinase, as well as a clinical update on ATRN-119, its novel macrocyclic ATR inhibitor. The Company also presented a poster highlighting a new set of preclinical data in glioblastoma with a next-generation macrocyclic ATR inhibitor, ATRN-333.

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"The four poster presentations at this prestigious conference highlight our growing pipeline and commitment to help cancer patients in need," said Dr. Oren Gilad, President and CEO of Aprea. "We are pleased to share the strong pre-clinical data and future clinical strategy for our promising next-generation WEE1 kinase inhibitor, APR-1051. We are also very excited to provide an encouraging update on the ongoing clinical study of our novel macrocyclic ATR inhibitor, ATRN-119."

Copies of the posters will be available on the Aprea corporate website here, at the conclusion of the AACR (Free AACR Whitepaper) meeting.

APR-1051

The novel WEE1i, APR-1051, is a potentially well tolerated and effective treatment for cyclin E-overexpressing cancers

Lead Author and Presenter: Molly Hansbarger
Abstract Number: 7121

This poster summarizes the pre-clinical data of APR-1051
APR-1051 exhibits high potency for WEE1 inhibition in vitro
Selectivity is key for success. APR-1051 shows low off-target inhibition of the PLK family of kinases.
To measure the potential for off-target inhibition of the PLK family of enzymes, in vitro experiments were conducted to determine the IC50s of APR-1051 vs ZN-c3 (Zentalis Pharmaceuticals)
The results showed significantly lower off-targeting of PLK1, PLK2 and PLK3 as indicated by higher IC50 values for APR-1051 compared to ZN-c3.
IC50 of APR-1051 over IC50 of ZN-c3
• PLK1: > 150-fold
• PLK2: > 50-fold
• PLK3: > 600-fold
• Off-targeting of PLK1 by other WEE1 inhibitors may compromise the efficacy of these drugs.
• Off-targeting of the PLK family may increase the risk of producing PLKi-associated adverse effects.

Cyclin E as a potential biomarker for APR-1051 treatment
APR-1051 demonstrated effectiveness in suppressing the growth of Cyclin E-overexpressing breast and ovarian cancer cell lines.
The dose and scheduling of APR-1051 that causes significant suppression of CCNE1-amplified high-grade serous ovarian cancer tumors in mice is well tolerated.
Red blood cell and platelet counts remained within non-pathogenic ranges after a 28-day treatment period, consistent with proposed minimal off target PLK1 inhibition
APR-1051 will potentially exhibit low cardiotoxicity.
Inhibition WEE1 by APR-1051 occurs at an IC50 that is 200-fold lower on average than the IC50 of hERG potassium channel inhibition.
Strong evidence for combination therapy
APR-1051 was evaluated in combination with Aprea’s second-generation ATR inhibitors (ATRN-330 and ATRN-354) in xenografted tumors. The results showed higher anti-tumor activity for the combinations, compared with vehicle or monotherapy.
APR-1051 received U.S. FDA clearance for a clinical trial, now with plans to dose the first patient in June 2024
ASECOT-1051: First-in-human phase 1 study of WEE1 inhibitor APR-1051 in patients with advanced solid tumors harboring cancer-associated gene alterations.

Presenter: Nadeem Q. Mirza, M.D., MPH
Lead author: Timothy Yap, M.D.
Abstract Number: CT196

This poster summarizes the strategy for the upcoming clinical trial of APR-1051
The aim of this first-in-human Phase 1 study (ACESOT-1051: A Multi-Center Evaluation of WEE1 Inhibitor in Patients with Advanced Solid Tumors, APR-1051) is to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent APR-1051 in advanced solid tumors harboring cancer-associated gene alterations (NCT06260514)
This biomarker-driven study will include patients with advanced/metastatic solid tumors harboring cancer-associated gene alterations, such as CCNE1 or CCNE2, FBXW7, PPP2R1A, or KRAS G12
Oral APR-1051 will be administered once daily for 28-day cycles.
The study will consist of two parts.
Part 1 will be dose escalation and is expected to enroll up to 39 patients with advanced solid tumors harboring cancer-associated gene alterations. In the dose escalation phase the first three dose levels will use accelerated titration followed by Bayesian Optimal Interval (BOIN) design for the remaining dose levels
Part 2 (up to 40 patients) is designed for dose optimization, with the goal of selecting the Recommended Phase 2 Dose (RP2D)
The primary objectives are to measure safety, dose-limiting toxicities (DLTs), maximum tolerated dose or maximum administered dose (MTD/MAD), RP2D; Secondary objectives are to evaluate pharmacokinetics, preliminary efficacy according to RECIST or PCWG3 criteria; Pharmacodynamics is an exploratory objective.
Enrollment is anticipated to begin in Q2 2024
MD Anderson Cancer Center is the lead site, and the study will be performed at between 3 and 10 sites in the U.S
ATRN-119

Nadeem Mirza, MD, MPH, Senior Medical Advisor to Aprea commented, "Enrollment of patients continues in the dose escalation portion of our Phase 1/2a clinical trial evaluating ATRN-119 in patients with advanced solid tumors having mutations in defined DDR-related genes. We are now enrolling patients in the 550 mg cohort (Cohort 5). ATRN-119 continues to be safe and well tolerated, with no dose-limiting toxicities and no signs of significant hematological toxicity reported. We are encouraged by the preliminary signs of clinical benefit. Stable disease has been reported in two patients, one of which continues to be on treatment out to Day 188. Dose escalation will proceed throughout 2024."

First-in-human phase 1/2a trial of a macrocyclic ATR inhibitor (ATRN-119) in patients with advanced solid tumors

Presenter: Nadeem Q. Mirza, M.D., MPH
Lead author: Fiona Simpkins, M.D.
Abstract Number: CT195

This poster reports on the ongoing first-in-human Phase 1 study of ATRN-119 in patients with advanced solid tumors harboring specific DDR mutations (NCT04905914)
As of March 12, 2024, 16 patients were enrolled in the first five cohorts of the dose escalation stage (50 mg/day, 100 mg/daily, 200 mg/daily, 350 mg/daily, and 550 mg/daily)
ATRN-119 is being administered daily on a continuous schedule
ATRN-119 has been found to be safe and well tolerated.
No reported DLTs and no treatment-related Grade 4 or higher AEs have been reported.
At doses up to 550 mg once daily, there have been no signs of hematological toxicity.
Pharmacokinetic studies show ATRN-119 serum concentrations are entering the expected therapeutic range at the current highest dose level (550 mg). The Company currently has FDA clearance to evaluate doses up to 800mg, with a planned protocol amendment to add doses up to 1300 mg.
Preliminary signs of clinical benefit have been observed.
Two patients have achieved stable disease (SD) – one each in the 50 mg and 200 mg cohorts.
The latter patient at 200 mg/day had SD at Days 55, 112, and 168, and continues to be on treatment as of Day 188 without significant adverse events reported. This patient is now receiving 350 mg daily, as per the trial protocol, and is tolerating treatment well.
ATRN-333

Convection-enhanced delivery of a novel ATR inhibitor synergizes with systemic lomustine for improved treatment of glioblastoma.

Presenter: Teresa Lee, Ph.D.
Lead Authors: Alexander Josowitz Ph.D., Teresa Lee Ph.D.
Abstract Number: 7117

This poster describes a combination approach using a next-generation macrocyclic ATR inhibitor, ATRN-333, to sensitize glioblastoma (GBM) tumors to lomustine, an oral DNA alkylating agent.
The DNA damage response and DNA repair mechanisms such as the ataxia telangiectasia and Rad3-related (ATR) pathway are key mediators of therapeutic responses in glioblastoma (GBM). Recent studies have shown that targeting DNA repair proteins alongside standard-of-care options is a promising anti-tumor strategy for this disease.
To overcome difficulties associated with drug delivery to the brain, a convection-enhanced delivery (CED) system in conjunction with nanoparticle (NP) technology was used for direct intracranial administration of ATRN-333 to orthotopic GBM tumors.
Both free and NP-encapsulated ATRN-333 showed high potency in inhibiting ATR function in cell-based assays.
There was a clear synergistic effect between lomustine and ATRN-333 in GBM cell lines.
ATRN-333 effectively sensitized both flank and intracranial tumors to lomustine in vivo.
When administered via CED, ATRN-333 showed favorable intracranial retention and was well tolerated in mice when combined with lomustine.
These results suggest that ATR inhibitor/lomustine combination therapy, used in conjunction with a CED platform, is a powerful avenue for GBM treatment.
The results support further investigation and potential clinical implementation of ATRN-333 and other macrocyclic ATR inhibitors as chemosensitizers for glioblastoma.