On October 9, 2024 Harbour BioMed (the "Company"; HKEX: 02142), a global biopharmaceutical company committed to the discovery, development, and commercialization of novel antibody therapeutics focusing on oncology and immunology, reported the online publication of the results from its phase I clinical trial of porustobart (HBM4003), the Company’s first-in-class fully human heavy chain antibody targeting CTLA-4 (Press release, Harbour BioMed, OCT 9, 2024, View Source [SID1234647111]). The trial evaluated porustobart in combination with the anti-PD-1 antibody toripalimab for the treatment of advanced solid tumors, with a particular focus on melanoma. These results were published in the Journal for ImmunoTherapy of Cancer (IF=10.3, 2023).

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This multicenter, open-label phase I trial was led by Dr. Jun Guo, Chief Physician of the Department of Melanoma and Soft Tissue Sarcoma at Beijing Cancer Hospital. The data demonstrated that the combination of porustobart and toripalimab had a manageable safety profile with no new safety signals in the treatment of solid tumors. Initial results also indicated promising antitumor activity, particularly in PD-1 treatment-naïve mucosal melanoma.

Dual immunotherapy combining anti-CTLA-4 and anti-PD-1 antibodies is currently approved as a frontline treatment for several solid tumors, including melanoma, renal cell carcinoma, and non-small cell lung cancer. However, the high toxicity associated with anti-CTLA-4 antibodies has limited their broader use. Porustobart, a next-generation fully human anti-CTLA-4 antibody developed using the HCAb Harbour Mice platform, is the first of its kind to enter clinical development globally. Its unique properties offer the potential to overcome the efficacy and toxicity challenges of conventional anti-CTLA-4 therapies, making it a promising candidate in the field of cancer immunotherapy.

The phase I trial was conducted in two stages: a dose-escalation phase (Part 1) and a dose-expansion phase (Part 2). A total of 40 patients received treatment aimed at evaluating the safety, pharmacokinetics, immunogenicity, and preliminary efficacy of the combination therapy for the treatment of solid tumors, with a particular focus on melanoma.

Safety Results

Among the 40 patients who received study treatment, 10 (25.0%) patients reported grade ≥3 treatment-related adverse events (TRAEs). The commonly reported TRAEs were rash (30.0%), abnormal liver function (30.0%), leukopenia (25.0%), and fever (20.0%). Additionally, 5 (12.5%) patients experienced immune-related adverse events (irAEs) with maximum severity of Grade 3. No Grade 4 or 5 irAEs occurred.

Efficacy Results

Efficacy was evaluated in 32 melanoma patients treated with the recommended phase II dose (RP2D) of porustobart 0.3 mg/kg combined with toripalimab 240 mg every three weeks (Q3W), and who had available post-baseline imaging data. The objective response rate (ORR) was 33.3% in the anti-PD-1/PD-L1 treatment-naïve subgroup. For patients with mucosal melanoma, the ORR in this anti-PD-1/PD-L1 treatment-naïve subgroup was 40.0%. A high baseline Treg/CD4+ ratio in the tumor was identified as an independent predictive factor for immunotherapy efficacy.

In summary, the combination of porustobart 0.3 mg/kg with toripalimab 240 mg Q3W demonstrated promising antitumor activity and manageable safety in patients with advanced melanoma, including the difficult-to-treat mucosal subtypes. Further studies are needed to confirm these findings, particularly in patients with mucosal melanoma.

"We are encouraged by the positive results from our phase I study of porustobart in combination with an anti-PD-1 antibody, which has shown a favorable safety profile and early signs of clinical activity," said Dr. Jingsong Wang, Founder, Chairman and CEO of Harbour BioMed. "Porustobart is the first internally developed molecule generated from our HCAb Harbour Mice platform. We look forward to moving forward with further studies to fully explore the potential of this combination in addressing unmet medical needs and ultimately making a meaningful difference in patients’ lives."

About Porustobart

Porustobart (HBM4003) is a fully human anti-CTLA-4 monoclonal heavy chain only antibody (HCAb) generated from Harbour Mice. It is the first fully human heavy-chain-only monoclonal antibody entered into clinical stage globally. By enhancing antibody-dependent cell cytotoxicity (ADCC) killing activity, porustobart has demonstrated significantly improved depletion specific to high CTLA-4 expressing Treg cells in tumor tissues. The potent anti-tumor efficacy and differentiated pharmacokinetics with durable pharmacodynamic effect present a favorable product profile. This novel and differentiated mechanism of action has the potential to improve efficacy while significantly reducing the toxicity of the drug in monotherapy and combination therapy.

On October 9, 2024 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported that the company will present a poster at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics to be held October 23-25, 2024, in Barcelona, Spain (Press release, ORIC Pharmaceuticals, OCT 9, 2024, View Source [SID1234647110]).

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Poster presentation details:

Title: ORIC-114, a highly selective, brain penetrant EGFR and HER2 inhibitor, demonstrates best-in-class properties against exon 20 insertions and other atypical EGFR mutations
Poster #: PB050
Poster Session: Molecular Targeted Agents
Date & Time: Wednesday, October 23, 2024, 9:00 – 11:00 a.m. CEST
Location: Exhibition Hall

Abstract highlights:
ORIC-114 is a highly selective, brain penetrant, orally bioavailable, irreversible inhibitor that selectively targets EGFR and HER2 with high potency against exon 20 insertion mutations and other atypical EGFR mutations. It has previously demonstrated systemic and intracranial clinical responses in patients with EGFR and HER2 exon 20 insertion mutations. In an expanded preclinical comparative analysis, ORIC-114 demonstrated best-in-class properties including brain penetrance, superior kinome selectivity, potent activity across EGFR PACC mutations and exon 20 insertion mutations, relative to firmonertinib, zipalertinib, and BDTX-1535. Additionally, evidence of molecular response in ctDNA from patients whose tumors harbored PACC mutations and exon 20 insertion mutations was observed with ORIC-114 treatment. ORIC-114 is a promising potential therapy for patients with non-small cell lung cancer harboring atypical mutations in EGFR, including those presenting with active CNS metastases, and is being evaluated in a global clinical trial (NCT05315700).

Full abstracts are available for viewing on the symposium website here.

On October 9, 2024 Nimbus Therapeutics, LLC ("Nimbus Therapeutics" or "Nimbus"), a biotechnology company that designs and develops breakthrough medicines for patients through its powerful computational drug discovery engine, reported that it will present the first preclinical data on its novel Werner syndrome helicase (WRN) inhibitor in a poster presentation at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics, being held October 23-25, 2024 in Barcelona, Spain (Press release, Nimbus Therapeutics, OCT 9, 2024, View Source [SID1234647109]).

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WRN is a helicase required for DNA replication and DNA repair and is a validated target for tumors with microsatellite instability (MSI). Nimbus will present preclinical data on NTX-452, a novel WRN inhibitor developed using the company’s computational drug discovery platform.

Details of the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium presentation are as follows:

Abstract Title: Preclinical Characterization of NTX-452, a Potent, Selective and Highly Efficacious WRN Inhibitor for the Treatment of MSI-H Tumors

Date: Friday, October 25, 2024

Time: 9:00 a.m. – 3:00 p.m. CEST

Session Title: DNA Repair Modulation (e.g. PARP, CHK, ATR, ATM)

Abstract Number: 356

On October 9, 2024 Boehringer Ingelheim and Circle Pharma (Circle) reported a new research collaboration and license agreement with the shared goal to develop a first-in-class cyclin inhibitor that can halt the growth of cancer cells potentially offering hope to those living with hard-to-treat cancers (Press release, Circle Pharma, OCT 9, 2024, View Source;utm_medium=rss&utm_campaign=boehringer-ingelheim-and-circle-pharma-announce-new-research-collaboration-to-develop-a-novel-precision-cancer-treatment [SID1234647107]).

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Uncontrolled cell growth is a common feature in most tumor types and is a driving force in the formation of tumors. Genetic alterations like mutations or amplifications in the genes encoding the regulatory machinery of cell division contribute to malignant growth in a significant fraction of all solid tumors. That is why Boehringer Ingelheim is targeting the proteins involved in this process, a promising strategy for new cancer treatments.

Current methods targeting cyclin-dependent kinases can be limited by low selectivity and toxicity. Circle has developed a possible solution to these challenges by creating macrocycle therapies that directly inhibit cyclins, the proteins that regulate cell division.

"We’re delighted to be joining forces with Circle’s scientists to develop an innovative cancer treatment based on their proprietary macrocycle platform molecules to achieve our goal of transforming the lives of people living with cancer," said Clive R. Wood, Ph.D., Senior Vice President and Global Head of Discovery Research at Boehringer Ingelheim. "This new collaboration complements our oncology research portfolio, and further reinforces our commitment to tackling intractable targets."

David Earp, Ph.D., JD, chief executive officer, Circle Pharma said, "With our lead program, CID-078, a Cyclin A/B RxL inhibitor, we have demonstrated the capability of our MXMOTM platform to deliver oral macrocycles against a target that was previously considered to be undruggable. We’re excited to partner with Boehringer Ingelheim to leverage the platform against another challenging cyclin target that offers the potential to address high unmet need cancer indications."

This partnership is a significant step toward Boehringer Ingelheim’s goal of transforming cancer care. It bolsters the already robust oncology pipeline of cancer cell-directed and immuno-oncology investigational therapies for smart combinations that may offer the greatest benefit for people living with cancer.

As part of the agreement, Circle Pharma will receive an upfront payment and potential development, regulatory, and sales milestone payments of up to USD $607 million.

On October 9, 2024 Can-Fite BioPharma Ltd. (NYSE American: CANF) (TASE: CANF), a biotechnology company advancing a pipeline of proprietary small molecule drugs that address oncological and inflammatory diseases, reported the Company’s oncology drug candidate, Namodenoson, has been granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) for the indication of pancreatic cancer, one of the most aggressive malignancies (Press release, Can-Fite BioPharma, OCT 9, 2024, View Source [SID1234647106]). The designation as an orphan drug will provide among others, potential for market exclusivity for seven years after approval and several and regulatory advantages (View Source)

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Can-Fite is now completing all the preparatory work for a Phase II study in patients with pancreatic cancer. The study will be a multicenter open-label trial in patients with advanced pancreatic adenocarcinoma whose disease has progressed on at least 1st-line therapy. The trial will evaluate the safety, clinical activity, and pharmacokinetics (PK) of Namodenoson in this patient population. All patients will receive oral Namodenoson 25 mg, administered twice daily for consecutive 28-day cycles. Patients will be evaluated regularly for safety. Approximately 20 evaluable patients will be enrolled. The primary objective of this trial is to characterize the safety profile of Namodenoson, and the secondary objective is to evaluate the clinical activity as determined by the Objective Response Rate (ORR) using Response Evaluation Criteria in Solid Tumors (RECIST 1.1), Progression-Free Survival (PFS), Disease Control Rate (DCR), Duration of Response (DoR), and Overall Survival (OS).

"We are advancing our plans to start our Phase 2 study in pancreatic cancer and aim to commence the study by the end of year; we are thrilled that the FDA has granted Orphan Drug Status," stated Can-Fite CEO Motti Farbstein".

About Namodenoson

Namodenoson is a small orally bioavailable drug that binds with high affinity and selectivity to the A3 adenosine receptor (A3AR), on the surface of liver and pancreatic cancer cells. Namodenoson, induces apoptosis of these cancer cell types. Namodenoson was evaluated in Phase II liver cancer trials for two indications, as a second line treatment for hepatocellular carcinoma, and as a treatment for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). A3AR is highly expressed in diseased cells whereas low expression is found in normal cells. This differential effect accounts for the excellent safety profile of the drug.