On October 24, 2024 Cancer Research UK, one of the world’s largest funders of cancer research, and KisoJi Biotechnology Inc., a company focussed on the discovery and development of antibody therapeutics, reported to have signed a landmark agreement to bring KisoJi’s lead asset, KJ-103, into a first-in-human clinical trial (Press release, Cancer Research UK, OCT 24, 2024, View Source [SID1234647382]). KJ-103 is a naked anti-TROP2 antibody that has been created by KisoJi using its proprietary antibody technology.

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Under the agreement, Cancer Research UK’s Centre for Drug Development (CDD) will sponsor, design and deliver a Phase 1/2a clinical trial of KJ-103, in selected TROP2 expressing solid tumours. KisoJi will supply the antibody for the clinical trial and work with CDD to complete the preclinical package. Cancer Research Horizons, Cancer Research UK’s innovation arm, will manage the commercial relationship.

Unlike antibody drug conjugates (ADCs), KJ-103 does not require a cytotoxic payload but instead functions by recruiting immune cells to kill tumour cells. KJ-103 binds to TROP2 in a location distinct from where current TROP2 ADCs bind. It uses TROP2 as a way of directing macrophage activation and phagocytosis of the tumour cells expressing it, leading to tumour cell death.

KJ-103 may provide an alternative treatment option for TROP2-expressing cancers in which TROP2 ADCs have proven ineffective or are not suitable due to their toxicity profile. Tumour types expressing TROP2 include: colorectal, head and neck, ovarian, breast, bladder and lung cancers.

Lars Erwig, Director of the CDD, said: "We are excited to collaborate with KisoJi to bring KJ-103 into clinical development. This partnership aligns with our mission to explore innovative therapeutic approaches for hard-to-treat cancers. With KJ-103’s unique mechanism of action, which harnesses the body’s immune system without the potential toxicity of a drug conjugate, we hope to offer new treatment options for patients with TROP2-expressing solid tumours."

David Young, co-founder and CEO of KisoJi said: "We are thrilled to be advancing KJ-103 into the clinic in partnership with Cancer Research UK. As the first naked antibody to target TROP2 cancers, KJ-103 is the first of a new wave of antibodies to come from our modernised technology platform that leverages AI grounded in biology to create transformative antibody therapeutics."

On October 24, 2024 Accent Therapeutics, a biopharmaceutical company pioneering novel small molecule targeted cancer therapeutics, reported that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for ATX-559, a first-in-class DHX9 inhibitor (Press release, Accent Therapeutics, OCT 24, 2024, View Source [SID1234647381]). In addition, Accent has established a Clinical Advisory Board (CAB) to help guide the Company’s progress in the clinic.

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The ATX-559 Phase 1/2 trial (NCT06625515) is expected to begin dosing patients with a focus on BRCA1- or BRCA2-deficient breast cancer and patients with MSI-H and/or dMMR solid tumors (including certain patients with colorectal, endometrial, gastric, and other cancers) in the fourth quarter of 2024. The clinical study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ATX-559. For more information on the trial, visit the study page on ClinicalTrials.gov.

"The FDA’s IND clearance is a pivotal moment for Accent Therapeutics, propelling our lead program into the clinical arena. This milestone not only validates our scientifically rigorous approach to identifying innovative targets, but also brings us one step closer to helping cancer patients with significant unmet need," said Jason Sager, M.D., Chief Medical Officer of Accent Therapeutics. "ATX-559 has shown remarkable promise in preclinical studies, and we’re excited to now evaluate its potential to meaningfully improve outcomes for patients facing these challenging malignancies."

As Accent prepares to initiate its first clinical trial, the company has also established a Clinical Advisory Board to guide the advancement of its clinical pipeline. The Clinical Advisory Board consists of renowned clinician-scientists and leaders whose strategic insights and clinical expertise will support the Company’s efforts to advance its mission of creating life-changing therapeutics for patients living with cancer.

The newly formed Clinical Advisory Board includes:

Lillian L. Siu, M.D., FRCPC, medical oncologist, Director of the Phase I Program at Princess Margaret Cancer Centre, Professor of Medicine at the University of Toronto, and President-Elect of the American Association for Cancer Research (AACR) (Free AACR Whitepaper)
Josep Tabernero, M.D., Ph.D., Professor of Medicine, Head of the Medical Oncology Department at the Vall d’Hebron Barcelona Hospital Campus, and Director of the Vall d’Hebron Institute of Oncology (VHIO)
Sam Blackman, M.D., Ph.D., co-founder and Head of Research and Development of Day One Biopharmaceuticals
"We are honored to have such distinguished experts join our Clinical Advisory Board as we advance our programs into the clinic," said Shakti Narayan, Ph.D., J.D., Chief Executive Officer of Accent Therapeutics. "Their experience will be invaluable as we work to bring transformative therapies to patients."

Accent is also on track to advance its second program, targeting KIF18A in chromosomally instable tumors, into the clinic with a Phase 1 trial anticipated to begin in early 2025. This marks an exciting phase of growth for the company as it continues to build on its foundational platform technology to develop innovative cancer therapies.

About ATX-559
ATX-559 is a first-in-class DHX9 inhibitor with the potential to address high unmet need indications not adequately served by existing therapies, such as BRCA-deficient tumors (including breast, ovarian, and others), MSI-H and/or dMMR cancers (including colorectal, endometrial, gastric, and others) and additional undisclosed cancer types representing large patient populations. DHX9 is a DNA/RNA helicase that has been reported to play important roles in replication, transcription, translation, RNA splicing, RNA processing, and maintenance of genomic stability. Inhibition of DHX9 exploits key tumor vulnerabilities, resulting in cancer-specific cell death, and thus this enzyme represents a compelling novel oncology target. Accent retains full worldwide rights to ATX-559 and the DHX9 program.

About KIF18A
Accent’s second lead program is a potential best-in-class inhibitor for KIF18A which may address a large patient population across several cancer indications, including ovarian and triple negative breast cancer (TNBC). KIF18A is a mitotic kinesin motor protein critical for cell division in select tumors with chromosomal instability. A subset of tumor cells with an abnormal number of chromosomes (aneuploid) are reliant on KIF18A and show rapid cell killing in vitro and in vivo upon KIF18A inhibitor treatment, while cells with normal numbers of chromosomes (euploid) are unaffected.

On October 24, 2024 Aktis Oncology, a clinical-stage oncology company focused on unlocking the breakthrough potential of targeted radiopharmaceuticals for large patient populations not addressed by existing platform technologies, reported data presented on its potential first-in-class, Nectin-4 targeting miniprotein radiopharmaceutical, AKY-1189, in three abstracts, including one oral presentation, at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, October 23-25, 2024 (Press release, Aktis Oncology, OCT 24, 2024, View Source [SID1234647380]). AKY-1189 is designed to deliver actinium-225 to Nectin-4 expressing tumors, with potential applications in locally advanced or metastatic urothelial carcinoma (mUC) and other Nectin-4 expressing cancers, such as breast, lung, colorectal and cervical.

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Mike Sathekge, MD, Head of Nuclear Medicine Department, University of Pretoria, and Steve Biko Academic Hospital, and President and CEO, Nuclear Medicine Research Infrastructure (NuMeRI), will present an oral plenary on the human biodistribution and dosimetry data of AKY-1189. The plenary presentation (Abstract no. 10), titled "AKY-1189, a novel, first-in-class miniprotein radiopharmaceutical designed to deliver Actinium-225 (225Ac) to Nectin-4 expressing tumors with broad therapeutic applications in metastatic urothelial carcinoma (mUC) and other Nectin-4 expressing tumors," demonstrates a promising profile for AKY-1189 in patients with Nectin-4 expressing tumors. Pursuant to Section 21 guidelines of the South African Health Products Regulatory Authority (SAHPRA), 20 patients diagnosed with mUC, metastatic breast cancer, non-small cell lung cancer carcinoma, colorectal cancer and cervical cancer were imaged with [68Ga]Ga-AKY-1189 to address patient need. The resulting data were later assessed. A total of 15 patients were evaluable for biodistribution and tumor uptake analysis. Eight patients were dosed with [177Lu]Lu-AKY-1189 and were evaluable for kidney and bone marrow dosimetry. The assessment demonstrated AKY-1189 to be generally well tolerated with no treatment-emergent adverse events, and dosimetry analyses suggest a wide therapeutic index for [²²⁵Ac]Ac-AKY-1189. Significant tumor uptake of AKY-1189 was observed across primary and metastatic lesions in multiple cancer types evaluated. These data mark the first Nectin-4 targeted radiopharmaceutical to demonstrate significant tumor uptake and supports the progression of [²²⁵Ac]Ac-AKY-1189 to therapeutic clinical studies across several solid tumor types. The oral presentation is scheduled on Friday, October 25 from 1:12-1:24 p.m. CEST.

"These data provide evidence of sufficient tumor uptake of AKY-1189, not only in mUC but in other tumor types, and that AKY-1189 has promising biodistribution in normal organs and tissues," said Professor Sathekge. "This discovery marks a critical step forward in the fight against Nectin-4 expressing cancers, and sheds light on radiopharmaceuticals as a potential mainstream oncology treatment."

Aktis also showcased AKY-1189’s potential as a targeted radiopharmaceutical through two poster presentations displayed within the Exhibition Hall, which are both available online for viewing. The first poster (Abstract no. 118), titled, "Discovery and pre-clinical development of AKY-1189, a potent and selective Nectin-4 miniprotein binder optimized for use as a targeted radiopharmaceutical," highlighted AKY-1189’s preclinical data supporting advancement to clinical development.

The second poster (Abstract no. 308), titled, "Allometric scaling of preclinical dosimetry for the Nectin-4 miniprotein binders AKY-807 and AKY-1189 accurately predicts human absorbed dose to major organs," highlighted the accuracy of allometric scaling methods in predicting human organ dosimetry from preclinical data.

"The presentations at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Meeting underscores the potential of AKY-1189 in targeting Nectin-4 expressing cancers," said Matthew Roden, PhD, President and Chief Executive Officer of Aktis Oncology. "As the first therapeutic product candidate discovered from our novel miniprotein radioconjugate platform, AKY-1189 data suggest that we can achieve a favorable clinical profile and opens a new path forward in the field of radiopharmaceuticals. We look forward to advancing this promising product candidate through therapeutic clinical studies."

On October 24, 2024 Tyra Biosciences, Inc. (Nasdaq: TYRA), a clinical-stage biotechnology company focused on developing next-generation precision medicines that target large opportunities in Fibroblast Growth Factor Receptor (FGFR) biology, reported clinical proof-of-concept data for TYRA-300 in patients with metastatic urothelial (mUC) cancer from its ongoing SURF301 Phase 1/2 study (Press release, Tyra Biosciences, OCT 24, 2024, View Source [SID1234647378]). These data will be presented in a late-breaking oral presentation at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) (ENA) Symposium on Molecular Targets and Cancer Therapeutics, being held October 23-25, 2024 in Barcelona, Spain. TYRA-300 is a potential first-in-class, investigational, oral, FGFR3-selective inhibitor designed to avoid the toxicities associated with inhibition of FGFR1, FGFR2 and FGFR4, while being agnostic for the FGFR3 gatekeeper mutations.

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"FGFR3 alterations are known to drive tumor biology in a subset of urothelial cancer. While pan-FGFR inhibitors have demonstrated benefit and are approved for use in FGFR3 altered urothelial cancer, they are associated with multiple intolerable on-target toxicities that limit their clinical utility. There remains an unmet need to deliver improved precision medicine for urothelial cancer patients, that allow patients to not only live longer, but live better," said Ben Tran, M.D., Associate Professor, Peter McCallum Cancer Centre, Melbourne, Australia. "The initial results from TYRA-300 are very encouraging. I believe TYRA-300 has the potential to be a next generation targeted therapy, with high selectivity for FGFR3. These early data provide support that TYRA-300 can deliver improved anti-tumor activity and tolerability for our FGFR3 altered urothelial cancer patients. TYRA-300 has real potential to improve outcomes, and I look forward to its continued development in all FGFR3 altered cancers."

Summary of Interim Clinical Results

As of August 15, 2024, the data cutoff date, 41 patients were enrolled in the Phase 1 portion of the SURF301 Phase 1/2 study. Eligible participants were adults with advanced malignancies with or without FGFR3 alterations, including those with prior treatment with erdafitinib. The enrolled patient population was heavily pre-treated, with 44% of patients receiving ≥ 3 lines of therapy prior to receiving TYRA-300, and 76% of FGFR3+ mUC patients receiving ≥ 3 lines of therapy. Treatment with TYRA-300 was evaluated across six dose levels, ranging from 10 mg-120 mg once daily (QD).

Preliminary PK/PD analysis in 41 patients as of the data cutoff date: TYRA-300 plasma concentrations indicate adequate target coverage at ≥ 90 mg QD, with further pharmacokinetic characterization ongoing.

In patients with FGFR3+ mUC who received doses ≥ 90 mg QD, anti-tumor activity was observed in all patients:
6 out of 11 (54.5%) patients at ≥ 90 mg QD achieved a PR, 3 of which are still ongoing.
5 out of 10 (50%) patients at 90 mg QD achieved a PR.
1 out of 1 (100%) patient at 120 mg QD achieved a PR.
A 100% disease control rate (DCR) was achieved for all patients at ≥ 90 mg QD (PR + stable disease).

TYRA-300 has demonstrated favorable interim safety results as of the data cutoff date:
Preliminary data from SURF301 suggest TYRA-300 to be generally well-tolerated, with infrequent FGFR2- and FGFR1-associated toxicities.
In doses from 10 mg up to 120 mg QD, there were 4 (10%) serious adverse events related to TYRA-300, 1 dose-limiting toxicity (DLT) of grade (Gr) 3 diarrhea at 90 mg QD, and 1 treatment-related adverse event (TRAE) leading to discontinuation of treatment (Gr3 ALT, 90 mg QD).
There were no ≥ Gr4 TRAEs.
The 120 mg QD dose was the highest dose evaluated with no DLTs reported.
"The preliminary data are what we were expecting to see with TYRA-300, being generally well-tolerated with fewer toxicities, and anti-tumor activity in FGRF3+ mUC patients," said Doug Warner, M.D., Chief Medical Officer of TYRA. "The emerging profile of TYRA-300 supports further development in metastatic urothelial cancer, where an attractive opportunity exists for a more tolerable option in second line."

Dr. Warner continued, "We are grateful for the support of our study participants, their families and our global collaborators on SURF301. We remain focused on progressing TYRA-300 through dose optimization in SURF301 and toward patients in need."

"Our team set out to solve an ambitious chemistry problem that had stumped the field of precision oncology – to create an efficacious FGFR3-selective inhibitor with a favorable tolerability profile to address the limitations of pan-FGFR inhibitors. We believe that today’s interim results provide clinical support for addressing this difficult problem, and the data are in line with our expectations," said Todd Harris, CEO of TYRA. "These data give us confidence to advance TYRA-300 through Part B in SURF301 and explore larger opportunities with Phase 2 studies in metastatic urothelial cancer, non-muscle invasive bladder cancer and achondroplasia."

ENA 2024 presentation details:

Title: "Preliminary safety and anti-tumor activity of TYRA-300, a highly selective FGFR3 inhibitor, in participants with advanced solid tumors with activating FGFR3 mutations/fusions (SURF301)"

Session: Late Breaking Abstracts and Proffered Papers: Novel discoveries in drug development
Date: Friday, October 25, 2024
Time: 15:36 – 15:48 hrs CEST
Abstract #: 500LBA

Conference Call Information

TYRA is hosting a conference call and webcast on October 25, 2024, at 8am ET to review the interim clinical proof-of-concept results demonstrated with TYRA-300 in mUC. Participants may access a live webcast of the call and the associated slide presentation on the "For Investors" page of the TYRA website at View Source To participate via telephone, please register in advance at this link. Upon registration, all telephone participants will receive a confirmation email detailing how to join the conference call, including the dial-in number along with a unique passcode and registrant ID that can be used to access the call. A replay of the conference call and webcast will be archived on the Company’s website for at least 30 days.

About TYRA-300 and the SURF301 Study

TYRA-300 is TYRA’s lead precision medicine program stemming from its in-house SNÅP platform. TYRA-300 is an investigational, oral, FGFR3-selective inhibitor currently in development for the treatment of cancer and skeletal dysplasias, including achondroplasia and hypochondroplasia. In oncology, TYRA-300 is being evaluated in a multi-center, open label Phase 1/2 clinical study, SURF301 (Study in Untreated and Resistant FGFR3+ Advanced Solid Tumors) (NCT05544552). The study is designed to determine the optimal and the recommended Phase 2 dose (RP2D) of TYRA-300, as well as to evaluate the preliminary anti-tumor activity of TYRA-300. Part A of the study included patients with all solid tumors who are FGFR3 +/-, and explored doses of TYRA-300 ranging from 10mg -120mg once-daily (QD). Part A of SURF301 is complete. The Company continues to advance TYRA-300 through dose expansion in Part B, which includes patients with solid tumors who are FGFR3+, to evaluate potentially therapeutic doses in preparation for potential future Phase 2 studies in metastatic urothelial carcinoma (mUC) and non-muscle invasive bladder cancer (NMIBC).

In skeletal dysplasias, TYRA-300 has demonstrated positive preclinical results in achondroplasia and hypochondroplasia. In July 2023 and January 2024, the FDA granted Orphan Drug Designation (ODD) and Rare Pediatric Designation (RPD) to TYRA-300, respectively, for the treatment of achondroplasia.

On October 24, 2024 iTeos Therapeutics, Inc. (Nasdaq: ITOS) ("iTeos"), a clinical-stage biopharmaceutical company pioneering the discovery and development of a new generation of immuno-oncology therapeutics for patients, reported that preclinical, translational, and clinical data from inupadenant will be presented at the European Society for Medical Oncology Immuno-Oncology (ESMO-IO) Congress 2024, being held December 11-13, 2024 in Geneva, Switzerland (Press release, iTeos Therapeutics, OCT 24, 2024, View Source [SID1234647376]). The clinical and translational data from the dose escalation portion of A2A-005, the Phase 2 trial assessing inupadenant and platinum-doublet chemotherapy in post-immunotherapy metastatic non-small cell lung cancer (NSCLC) patients, will be presented as mini oral presentations. Preclinical data from inupadenant will be presented in the poster session.

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Mini Oral Presentation Details
Title: The A2AR Antagonist Inupadenant Promotes Humoral Responses in Patients
Abstract Number: 174MO
Session Title: Mini Oral Session 1
Date / Time: December 12, 2024 at 9:24 am CEST

Title: Inupadenant Combined with Chemotherapy in Patients with Non-Squamous NSCLC Progressing On or After Immune Checkpoint Inhibitor Therapy: Results from Dose-Finding Part of the A2A-005 Trial
Abstract Number: 120MO
Session Title: Mini Oral Session 2
Date / Time: December 12, 2024 at 14:55 pm CEST

Poster Presentation Details
Title: The A2AR Antagonist Inupadenant Promotes Humoral Responses in Preclinical Models
Abstract Number: 48P
Session Title: Poster Display Session
Date / Time: December 12, 2024 at 12:30 pm CEST

ESMO-IO indicates that all regular abstracts will be published on the ESMO (Free ESMO Whitepaper)-IO website on Thursday, December 5, 2024 at 00:05 am CEST.