On March 26, 2024 Aptamer Sciences Inc. (KOSDAQ, 291650) reported the filing of an Investigational New Drug (IND) application for the phase 1 clinical trial of AST-201 with the Korean Ministry of Food and Drug Safety on March 12th, 2024 (Press release, Aptamer Sciences, MAR 26, 2024, View Source [SID1234641473]).

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AST-201, the company’s pioneering candidate in its pipeline, is an ApDCTM (Aptamer-Drug Conjugate) designed to target GPC3 protein, which exhibits high expression levels in specific cancer cells, notably liver cancer. It comprises gemcitabine as the payload and an aptamer that selectively binds to GPC3 protein. Gemcitabine, a proven systemic anticancer agent, is widely utilized in treating various cancers, including ovarian, breast, non-small cell lung, and pancreatic cancer. The choice of gemcitabine as the payload was deliberate, owing to its moderate toxicity profile, particularly suitable for liver targeting, given the organ’s susceptibility to drug toxicity. Additionally, gemcitabine’s nature as a DNA analogue facilitates its synthesis within the aptamer DNA sequence. The company’s strategic focus on liver cancer addresses significant unmet medical needs, as evidenced by AST-201’s superior efficacy over sorafenib in animal models and its synergistic effect when co-administered with anti-PD-1 therapy.

Liver cancer poses a significant health challenge, particularly in East Asia, with a dismal survival rate. While combination therapies such as atezolizumab and bevacizumab have emerged as standard treatments for advanced liver cancer, recent findings published in Nature Medicine suggest their limited efficacy in certain liver cancer populations with high GPC3 expression levels, highlighting substantial unmet medical needs. In this context, AST-201 offers a promising therapeutic approach by specifically targeting GPC3.

The planned phase 1 trial seeks to evaluate the safety, pharmacokinetic profile, and preliminary efficacy of AST-201 in patients with GPC3-positive advanced solid tumors. Notably, Dr. Hong Jae Chon from CHA Bundang Medical Center, a prominent medical oncologist in South Korea, will serve as the coordinating investigator. The trial will be conducted across four hospitals, including CHA Bundang Medical Center, Samsung Medical Center, Severance Hospital, and the National Cancer Center in South Korea.

Dr. Chon remarked, "GPC3 has garnered considerable attention in liver cancer therapeutic development among biopharmaceutical companies," expressing optimism that "AST-201 may emerge as a novel treatment option for liver cancer patients."

Aptamer Sciences Inc. aims to showcase the clinical benefits of AST-201 and the technological value of its ApDCTM platform through this trial. Moreover, the company anticipates that this milestone will propel its research and development efforts, enhancing the competitiveness of its subsequent hemato-oncology pipeline products, including AST-202 targeting CD25, ApRC (Aptamer Radioligand Conjugate), ApIS (Aptamer Immune Stimulator Conjugate), and so on.

Dr. Dong-il Han, CEO of Aptamer Sciences Inc., emphasized, "Since the second aptamer drug Izervay approved by FDA last year, aptamer technology has garnered significant attention in the pharmaceutical market," highlighting, "The AST-201 clinical trial will showcase the technological capabilities of the ApDCTM platform and expedite ongoing technology transfer discussion with multiple partners. This milestone underscores Aptamer Sciences Inc.’s commitment to advancing innovative therapies and addressing critical unmet needs in oncology."

Fig 1. AST-201 structure (Among the sequence of GPC3 aptamer, the payload of gemcitabine is conjugated as the part of sequence.)

Fig 2. AST-201 mechanism of action

1. AST-201 targets and binds to the GPC3 protein located on the surface of cancer cells.

2. The drug undergoes internalization into the cancer cell by endocytosis.

3. After the lysosomal degradation, gemcitabine monophosphate (dFdCMP), the active form of gemcitabine, is released within the cell leading to programmed cell death of the tumor cell (apoptosis).

On March 26, 2024 Ubiquigent Limited (Ubiquigent), a drug discovery and development company harnessing novel deubiquitinase (DUB) modulators as new therapeutics for areas of high unmet medical need, reported an agreement with Debiopharm, a biopharmaceutical company aiming to develop tomorrow’s standard-of-care treatments to cure cancer and infectious diseases (Press release, Debiopharm, MAR 26, 2024, View Source [SID1234641472]). The agreement will support the development of Debiopharm’s USP1 inhibitor programme, Debio 0432.

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Under the terms of the agreement, Ubiquigent will deploy its DUB-focused platform, combined with its deep understanding of the DUB field, to develop novel target engagement assays to support Debio-0432 as it approaches the clinic.

Currently, in late-stage preclinical development, Debio 0432 is a small molecule with best-in-class potential that could be deployed to combat multiple tumour types. Through its potent and selective inhibition of USP1, a critical player in the DNA damage repair (DDR) pathway, Debio 0432 has the potential to induce synthetic lethality in tumour types with underlying defects of DNA repair genes.

"We are delighted to enter this agreement with Debiopharm, supporting the development of its advanced USP1 inhibitor programme. Following our successful collaborations with other clinical stage companies, this latest agreement further demonstrates the capability of Ubiquigent’s platform to address all aspects of DUB drug discovery and development, encompassing target validation, hit-to-lead, candidate selection, translational research, and the development of assays to support clinical evaluation." Jason Mundin, CEO of Ubiquigent, said: "With multiple assets now reaching clinical stage, we look forward to seeing the continued progression and expansion of the DUB field over the coming years as more companies enter the space and new therapeutics enter the clinic."

Bertrand Ducrey, CEO, Debiopharm, commented: "Ubiquigent’s specialised drug discovery platform is uniquely positioned to support our USP1 inhibitor programme as it approaches the clinic, enabling the development of novel target engagement assays. Selective inhibition of USP1 to interrupt DNA damage repair pathway is an exciting approach to cancer treatment."

On March 26, 2024 MEI Pharma, Inc. (Nasdaq: MEIP), a clinical-stage pharmaceutical company evaluating novel drug candidates to address known resistance mechanisms to standard-of-care cancer therapies, reported initiation of enrollment in a 12-patient expansion cohort in the ongoing Phase 1 study evaluating voruciclib, an investigational selective oral cyclin-dependent kinase 9 ("CDK9") inhibitor, in combination with venetoclax (Venclexta), a B-cell lymphoma 2 ("BCL2") inhibitor, in relapsed and refractory ("R/R") acute myeloid leukemia ("AML") patients (Press release, MEI Pharma, MAR 26, 2024, View Source [SID1234641471]). The Safety Review Committee recommended initiating the expansion cohort after observing anti-leukemic activity in multiple heavily pretreated patients in the dose escalation cohorts, including responses, anticipated decreases in myeloid leukemia cell differentiation protein ("Mcl-1") in available patient samples, no overlapping toxicity or dose limiting toxicities, and favorable safety results to date.

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"MCL-1 overexpression has been associated with a poor prognosis and development of resistance to BCL-2 inhibition by venetoclax in patients with AML and CLL. Voruciclib is a potent, oral CDK9 inhibitor that indirectly also suppresses MCL-1. We are participating in the ongoing multicenter phase 1 study, where preliminary results are demonstrating good treatment tolerance and safety to date," said Yesid Alvarado-Valero, M.D., Associate Professor, Department of Leukemia, University of Texas MD Anderson Cancer Center and study chair of the combination therapy stage of the Phase 1 study. "When Voruciclib is used in combination with venetoclax, the combination appears to have no added toxicity, in addition there is evidence of synergistic, early clinical activity, with disease responses, in a group of heavily pretreated acute myeloid leukemia patients."

"Increasingly, venetoclax is being used as a standard treatment in patients with AML, but resistance to salvage therapy after venetoclax use is common and yields limited benefit upon relapse; only about 10% of patients respond to salvage therapy after venetoclax failure, representing a significant need for patients with AML," said Richard Ghalie, M.D., chief medical officer of MEI Pharma. "We see the voruciclib data to date demonstrating anti-leukemic activity as promising, particularly alongside the consistent reductions of Mcl-1 that provide evidence we are eliciting the anticipated biological response in patients, and we are excited to share additional updates as appropriate in the second half of 2024."

Dr. Ghalie continued: "As we enroll the expansion cohort evaluating the potential of voruciclib in combination with venetoclax among a larger group of patients, I would like to thank and recognize the continued engagement of our investigators, and the participation of the patients enrolling in this study."

Phase 1 Study Details

The Phase 1 study is a multiple stage, open-label, 3+3 dose escalation and expansion study evaluating voruciclib, an oral CDK9 inhibitor, as a monotherapy and in combination with venetoclax, a BCL2 inhibitor. The first stage of the study evaluated the dose and schedule of voruciclib as a single-agent in patients with AML or B-cell malignances after failure of standard therapies. This stage is complete.

The second stage of the study, evaluating voruciclib in combination with standard dose venetoclax in patients with R/R AML, has completed enrollment in the dose escalation cohorts evaluating seven voruciclib dose levels from 50 mg every other day to 300 mg daily for two weeks in a four-week cycle. The study is currently enrolling a 12-patient expansion cohort evaluating voruciclib administered at 300 mg daily for two weeks in a four-week cycle in combination with venetoclax. Considering the tolerability results for the combination to date, another arm of the study will evaluate escalating doses of voruciclib administered over three weeks in a four-week cycle in combination with venetoclax to increase dose intensity and potentially optimize patient response.

A total of 29 patients with R/R AML, median age 67 years (range 34-89), enrolled in the dose escalation stage of the study evaluating voruciclib in combination with venetoclax. These patients were generally heavily pretreated; the median number of prior therapies was 3 (range 1-7), and 15 (52%) patients had ≥3 prior lines. Almost all patients (28/29) were treated with venetoclax in an earlier line of therapy. Additionally, 21 (72%) patients were noted as being in an adverse 2017 ELN Risk Category due to adverse cytogenetics and molecular mutations.

The primary objectives of the study are to determine the safety and biologic effective dose of voruciclib monotherapy or voruciclib in combination with venetoclax. Secondary objectives of the study include assessing the preliminary efficacy, pharmacokinetics, pharmacodynamics, and biomarkers of voruciclib monotherapy or voruciclib in combination with venetoclax.

Voruciclib Plus Venetoclax Combination: Initial Safety and Tolerability Data

Voruciclib at doses up to 300 mg administered on 14 consecutive days in a 28-day cycle in combination with standard dose venetoclax was well tolerated with no dose limiting toxicities observed. The maximum tolerated dose of voruciclib administered on this schedule with venetoclax has not been established. There were no discontinuations due to drug-related adverse events. No evidence of overlapping toxicity has been observed to date. The most common (≥5% of patients) grade 3 adverse events were myelosuppression associated with AML. Only 1 patient was observed as having a non-hematologic grade 3 drug-related adverse event (diarrhea).

Voruciclib Plus Venetoclax Combination: Initial Efficacy Data

In the 20 patients administered voruciclib at a dose of 100 mg or more, three patients achieved a response, including two patients that achieved a complete response with incomplete hematologic recovery (CRi) and one patient that achieved a morphologic leukemia-free state (MLFS), in each case having received venetoclax in an earlier line of treatment. Responses lasted 7 months in one patient, 5 months and ongoing in the second patient, and the third patient was referred to stem cell transplant. Further, an additional 14 patients had stable disease which lasted more than 90 days in 5 patients.

In the patients administered voruciclib at a dose of 100 mg or more, initial results from correlative biomarker assay studies of available samples from patients treated with the combination demonstrate the anticipated decrease of Mcl-1. Further, the available assays from the dose escalation cohorts demonstrated dose proportional decreases in Mcl-1. Reductions in Mcl-1 are consistent with the known mechanism of action of CDK9, which regulates Mcl-1.

About Voruciclib

Voruciclib is an investigational orally administered cyclin-dependent kinase 9 ("CDK9") inhibitor with potential to treat both hematological malignancies and solid tumors. It is in clinical development for acute myeloid leukemia and B-cell malignancies. Applications in solid tumors are also being considered.

The CDK family of proteins are important cell cycle regulators responsible for the control of cell proliferation, differentiation, apoptosis, and DNA repair. CDK9, one of several members of the CDK family of proteins, functions as a gene transcription controller and is also involved in regulating protein degradation. Specifically, CDK9 is a promising target to treat a range of cancers because of its role in controlling two other proteins often dysregulated in cancerous cells: myeloid leukemia cell differentiation protein ("Mcl-1") and the MYC proto-oncogene protein ("MYC").

Mcl-1 is 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 Mcl-1, which is an established resistance mechanism to the B-cell lymphoma 2 ("BCL2") inhibitor venetoclax (marketed as Venclexta).

MYC 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.

On March 26, 2024 Avenzo Therapeutics, Inc. ("Avenzo"), a clinical-stage biotechnology company developing next generation oncology therapeutics, reported the closing of an oversubscribed $150 million Series A-1 financing (Press release, Avenzo Therapeutics, MAR 26, 2024, View Source [SID1234641470]). The total capital raised since the company’s founding in August 2022 is $347 million. The financing round includes nine new investors and was led by New Enterprise Associates (NEA), Deep Track Capital, Sofinnova Investments, and Sands Capital, with participation from additional new investors, including INCE Capital, TF Capital, Delos Capital, and Quan Capital. In conjunction with the announcement, Jakob Dupont, M.D., Executive Partner, Private Equity, Sofinnova Investments, will join the Avenzo Board of Directors.

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Proceeds from the financing will be used to advance Avenzo’s emerging oncology pipeline which is led by AVZO-021, a potentially best-in-class cyclin-dependent kinase 2 (CDK2) selective inhibitor being studied in an ongoing U.S.-based Phase 1 clinical study for the treatment of HR+/HER2- metastatic breast cancer and other advanced solid tumors.

"The team at Avenzo has made great progress over the past 18 months since formation on our mission to advance the next generation of oncology therapies for patients," said Athena Countouriotis, M.D., Co-founder, President and CEO of Avenzo. "With the support of our new and existing investors, including OrbiMed, Foresite Capital, SR One, Lilly Asia Ventures and Surveyor Capital (a Citadel company), we are in a strong position to advance our potentially best-in-class CDK2 inhibitor, AVZO-021, expand our pipeline with additional assets, and continue to grow our team."

"We see significant opportunity with AVZO-021 and this team to advance potential best-in-class therapies for some of the most pressing needs in oncology today," said Jakob Dupont, M.D., Executive Partner, Private Equity, Sofinnova Investments. "I have been impressed by the progress Avenzo has made to date and look forward to supporting Athena and the Board as they advance their emerging oncology pipeline and grow their promising company."

Dr. Dupont brings more than two decades of experience in the field of oncology and other therapeutic areas, in developing therapies and programs dedicated to addressing high unmet medical needs. Prior to joining Sofinnova Investments, Dr. Dupont served in key leadership roles at Atara Biotherapeutics, Gossamer Bio, Genentech/Roche and OncoMed Pharmaceuticals, Inc.

On March 26, 2024 TriSalus Life Sciences Inc. (Nasdaq: TLSI), an oncology company integrating its novel delivery technology with immunotherapy to transform treatment for patients with liver and pancreatic tumors, reported that its technology was featured in two oral presentations at the Society of Interventional Radiology Annual Scientific Meeting (Press release, TriSalus Life Sciences, MAR 26, 2024, View Source [SID1234641469]).

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PERIO-03 Phase 1/1b Update

TriSalus is studying an investigational class C toll-like receptor-9 (TLR9) agonist, nelitolimod (formerly SD-101), delivered intravascularly using the Company’s proprietary Pressure-Enabled Drug Delivery (PEDD) method of administration in three Phase 1 trials (periotrial.com). In PERIO-03, nelitolimod is delivered via the PEDD method with the TriSalus Infusion System using a retrograde venous approach, leveraging established interventional radiology access techniques.

Early safety and feasibility data from the PERIO-03 trial for locally advanced pancreatic adenocarcinoma showed technical success in all five patients who had received eight treatment interventions at data cutoff. There were no immediate complications from the procedure, and there was no evidence of hemorrhage or thrombosis. This follows a previous report indicating evidence of encouraging immune signals such as decreases in myeloid derived suppressor cells (MDSC) in the treated pancreatic tumors with evidence of T-cell activation.

PEDD Performance in Hypovascular Solid Tumors

In a retrospective study, investigators from The University of Texas MD Anderson Cancer Center reported on a variety of tumor types, the majority of which were notable for being hypovascular metastases and for which embolization may be clinically challenging. Technical success for embolization using the TriNav microcatheter was 100%. Tumors were treated in the liver (88%), bone (9.4%), and adrenal gland (3.1%). Local tumor progression-free survival rates across organs at one month, six months, and one year were 94%, 80%, and 70%, respectively.

"The data presented at the Society of Interventional Radiology meeting provide further evidence that the Pressure Enabled Drug Delivery method has the potential to improve therapeutic uptake and clinical outcomes at multiple disease sites, including the liver and pancreas. The data, which suggest the PEDD method can address solid tumor delivery challenges, align well with the 2024 outcomes research study from Current Medical Research and Opinion, which provides support for the recently awarded Centers for Medicare & Medicaid Services reimbursement code for procedures involving the TriNav system," said Steven C. Katz, M.D., FACS, Chief Medical Officer at TriSalus.

Both TriSalus presentations from SIR are available here.

About Pressure-Enabled Regional Immuno-Oncology (PERIO) clinical trials The Pressure-Enabled Regional Immuno-Oncology (PERIO) clinical trials are studying an investigational class C toll-like receptor-9 agonist, nelitolimod, delivered intravascularly by TriSalus’ TriNav Infusion System (TriNav) using the Company’s proprietary Pressure-Enabled Drug Delivery (PEDD) method of administration in three Phase 1 trials:

The PERIO-01 Phase 1 clinical study for uveal melanoma with liver metastases (UMLM) is studying nelitolimod delivered via PEDD with TriNav in combination with intravenous checkpoint inhibitors.

The PERIO-02 Phase 1b clinical study for hepatocellular carcinoma and intrahepatic cholangiocarcinoma, is studying nelitolimod delivered via PEDD with TriNav in combination with intravenous checkpoint inhibitors.

The PERIO-03 Phase 1 clinical study for locally advanced pancreatic adenocarcinoma, is studying nelitolimod delivered via PEDD with TriNav in combination with intravenous checkpoint inhibitors.