On November 24, 2021 Pyrotech (Beijing) Biotechnology Co., Ltd ("Pyrotech Therapeutics"), a company dedicated to developing revolutionary innovative drugs for inflammation and cancer, reported that their independently developed small molecule innate immune agonist PTT-936, with a completely new mechanism of action, has been approved by the U.S. Food and Drug Administration (FDA) for clinical research (Press release, Pyrotech, NOV 24, 2023, View Source [SID1234643789]). This marks the company’s first innovative drug to enter clinical evaluation in the United States.

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PTT-936 is a novel alpha-protein kinase 1 (ALPK1) small molecule agonist that activates the body’s immune system to attack tumors. ALPK1, as a new innate immune receptor, can recognize the small molecule ADP-heptose derived from bacteria and activate the body’s immune response. In 2018, Dr. Feng Shao, a co-founder of Pyrotech Therapeutics, reported this discovery in the journal "Nature" (Zhou et al., Nature 2018). Preclinical studies have shown that activating ALPK1 can efficiently induce anti-tumor immunity. Based on this insight, Pyrotech Therapeutics developed the novel ALPK1 agonist PTT-936.

Preclinical studies have demonstrated that PTT-936, either as a monotherapy or in combination with immune checkpoint inhibitors, exhibits excellent anti-tumor activity. Compared to other innate immune agonists with different mechanisms, PTT-936 has a potentially larger therapeutic window. As a small molecule agonist based on a completely new target and mechanism, PTT-936 is expected to circumvent the safety and efficacy issues limiting the utility of existing innate immune agonists and thereby offer a new treatment option for cancer patients.

On November 24, 2023 Theolytics, a biotechnology company harnessing viruses to combat disease, reported pre-clinical data on its lead oncolytic adenovirus – THEO-260 at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) annual meeting, which was held from Friday October 20, 2023, to Tuesday, October 24, 2023, in Madrid, Spain (Press release, Theolytics, NOV 24, 2023, View Source [SID1234638013]).

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ASCO Abstract

Title: Development of an oncolytic virus for the treatment of high grade serous

ovarian cancer and other stromal rich tumours

LINK to abstract

The data presented supports the progression of oncolytic adenovirus THEO-260 to first in human clinical trials. The results show THEO-260 is highly efficacious in killing cancer cells and cancer associated fibroblasts in fresh ovarian cancer patient tumour samples. Cancer associated fibroblasts in stromal rich tumours are a barrier to the effectiveness of many cancer treatments. The destruction of cancer associated fibroblasts, in addition to cancer cells, is a potentially exciting and differentiating feature of Theolytics’ virotherapy. To date, neither chemotherapy, nor immunotherapeutic approaches have been able to demonstrate a similar level of clearance of cancer associated fibroblasts pre-clinically, potentially positioning THEO-260 as a breakthrough in the oncolytic virus field.

Miriam Bazan-Peregrino, VP Translational Development at Theolytics who presented the data at ESMO (Free ESMO Whitepaper) 2023 said, "In pre-clinical models THEO-260 shows antitumour efficacy, with complete responses. The therapy demonstrates high selectivity and was shown to be safe in immunocompetent mouse models. The genetic and temperature stability of THEO-260 has been confirmed and is currently being GMP manufactured at high yields. Together, these data support the development of this promising new therapy, which we hope will create a step-change in the treatment of Platinum Resistant Ovarian Cancer."

On November 24, 2023 GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, reported the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) of China has accepted the New Drug Application (NDA) for GFH925 (IBI351) and granted GFH925 with Priority Review designation, for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring KRAS G12C mutation who have received at least one systemic therapy (Press release, GenFleet Therapeutics, NOV 24, 2023, View Source [SID1234637961]). It’s the first China-developed KRAS G12C inhibitor that has its NDA submission accepted and granted with Priority Review Designation by NMPA. GFH925 also received Breakthrough Therapy Designations this year for treating advanced KRAS G12C-mutant NSCLC that have received at least one systemic therapy and colorectal carcinoma (CRC) patients who have received at least two systemic therapies.

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The Priority Review designation is based on the results from a single-arm registrational Phase II study of GFH925 monotherapy treating advanced KRAS G12C-mutant NSCLC patients who failed or was intolerant of standard-of-care treatment in China (NCT05005234). The results will be presented at the upcoming European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Asia Congress 2023.

The results of GFH925 from a Phase I trial was updated in an oral presentation at the 2023 AACR (Free AACR Whitepaper) Annual Meeting. As of data cutoff date (February 10, 2023), of the 67 evaluable NSCLC patients, 41 achieved partial response (PR), with investigator assessed ORR 61.2% and DCR 92.5%. Of 30 patients with NSCLC treated at 600mg BID (the recommended phase 2 dose), better efficacy signal was observed, with investigator assessed ORR 66.7% (confirmed ORR 53.3%) and DCR 96.7%.

In combating NSCLC, the multi-center trial of GFH925 and ERBITUX (cetuximab, EGFR inhibitor) has progressed into phase II study in Europe with favorable safety and encouraging efficacy and numerous patients were observed with partial response. The trial is led by led by Professor Rafael Rosell, a world-renowned expert in particular in the field of lung cancer, and partial responses were observed among advanced KRAS G12C-mutant patients. In China, Innovent is also exploring the potential of IBI351(GFH925) in combination therapies for previously untreated advanced NSCLC patients with KRAS G12C mutation; two Phase Ib studies of IBI351（GFH925）in combination with cetuximab and sintilimab (TYVYT, PD-1 inhibitor) respectively are currently ongoing.

"GFH925 is GenFleet’s first NDA-stage product and becomes China’s first KRAS G12C inhibitor that receives NDA acceptance and Priority Review Designation. That demonstrates GFH925’s encouraging safety and efficacy in treating advanced NSCLC, and its potential in commercialization in the future. Meanwhile, GenFleet’s combination study of GFH925 and cetuximab treating NSCLC in 1st line also progressed smoothly in Europe with preliminary results of good safety and efficacy. GenFleet will promote the advancement of more multiple-regional studies in monotherapy and combination therapies and we look forward to positive progress of this study and other studies of GFH925 conducted by Innovent." stated Yu Wang, M.D.,Ph.D., Chief Medical Officer of GenFleet.

KRAS mutation as the ‘undruggable’ target for decades has become one of the most popular directions for clinical development recently. IBI351 is a novel, irreversible covalent inhibitor of KRAS G12C mutation. IBI351 monotherapy demonstrated favorable safety and promising activity in KRAS G12C mutated advanced NSCLC. We look forward to the NDA approval of this novel drug to benefit more NSCLC patients with KRAS G12C mutation soon." stated Professor Yi-Long Wu from Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital.

GFH925 is also the first domestic KRAS G12C inhibitor that received CDE Breakthrough Therapy Designation as monotherapy for previously treated KRAS G12C mutant CRC patients. According to the preliminary data of GFH925 monotherapy treating CRC at the 2023 ASCO (Free ASCO Whitepaper) Annual Meeting, favorable safety/tolerability and promising antitumor activity of GFH925 monotherapy were observed among patients. As of data cutoff date (Feb 16, 2023), a total of 54 metastatic colorectal cancer patients were included for analysis; of 42 evaluable subjects at 600mg BID, ORR was 42.9% (18/42), confirmed ORR was 31.0% (13/42), DCR was 88.1% (37/42).

About KRAS G12C Mutated Non-small Cell Lung Cancer

Lung cancer is one of the malignancies with the highest incidence and mortality worldwide, among which non-small cell lung cancer (NSCLC) is the most common pathological type, accounting for about 85% of all lung cancers. KRAS mutations are common driver gene mutations in NSCLC, most of which occur in lung adenocarcinoma. KRAS mutations rarely co-exist with driver mutations such as EGFR and ALK, and patients with advanced NSCLC with KRAS G12C mutations are often unable to benefit from the multiple drugs already on the market that target these mutations or rearrangements. After the progress of first-line standard treatment in this population, there are limited second-line treatment options with low effective rate and poor prognosis.

About GFH925（IBI351）

RAS protein family can be divided into KRAS, HRAS and NRAS categories. KRAS mutation are detected in nearly 90% of pancreatic cancer, 30-40% of colon cancer, and 15-20% lung cancer patients. The occurrence of KRAS G12C mutation subset is more frequently observed than those with ALK, ROS1, RET and TRK 1/2/3 mutations combined.

Discovered by GenFleet Therapeutics, GFH925 (Innovent R&D code: IBI351) is a novel, orally active, potent KRAS G12C inhibitor designed to effectively target the GTP/GDP exchange, an essential step in pathway activation, by modifying the cysteine residue of KRAS G12C protein covalently and irreversibly. Preclinical cysteine selectivity studies demonstrated high selectivity of GFH925 towards G12C. Subsequently, GFH925 effectively inhibits the downstream signal pathway to induce tumor cells’ apoptosis and cell cycle arrest.

In September 2021, Innovent and GenFleet Therapeutics entered into an exclusive license agreement for the development and commercialization of GFH925 in China (including mainland China, Hong Kong, Macau and Taiwan) with additional option-in rights for global development and commercialization.

On November 24, 2023 Circio Holding ASA (OSE: CRNA), a biotechnology company developing novel circular RNA and immunotherapy medicines, reported that the European Patent Office (EPO) board of appeal has moved to revoke the EU Patent 3140320 "Peptide vaccine comprising mutant RAS peptide and chemotherapeutic agent" during proceedings held on 22 November 2023 (Press release, Circio, NOV 24, 2023, View Source [SID1234637959]).

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EU Patent 3140320 is a method of use patent covering the combination of TG01 with the chemotherapeutic gemcitabine (and similar agents) in pancreatic cancer. The EPO board of appeal ruled that the patent should be revoked due to a lack of sufficient inventive step based on prior publications relating to TG01 clinical studies. Method of use patents are known to be challenging to uphold due to mandatory public disclosures surrounding trial design and treatment regimen. The EPO ruling applies only in European countries.

Dr. Lubor Gaal, Chief Financial Officer of Circio Holding ASA, said: "We are disappointed by and disagree with the EPO´s ruling to revoke our TG01/gemcitabine patent for pancreatic cancer. However, this chemotherapy combination was discontinued in 2019, and the ruling has no impact on ongoing clinical studies where TG01 is being tested with novel immunotherapies and in other cancer forms outside of this patent. Moreover, TG01 remains covered by orphan drug designations in pancreatic cancer and data protection as a biologic in both the EU and USA, which provides market protection for up to 12 years."

On November 23, 2023 Perpetual Medicines reported in preclinical studies using laboratory models, manipulating β-catenin levels or activity has demonstrated a significant impact on tumor growth. Inhibition of β-catenin signaling has been shown to suppress the growth of cancer cells, providing a solid rationale for developing drugs that specifically target this pathway.

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ß-catenin was discovered in the early 1980’s based on its roles in cytoskeleton structure and signaling. ß-catenin is evolutionarily conserved from worms to fruit flies to humans and is a pivotal factor in development and tissue homeostasis, cell renewal, and regeneration. Disruption of the pathway by germline and acquired mutations has implicated ß-catenin as a key driver of oncogenesis.

There have been over 40 licensing/collaboration deals in the WNT pathway in the last ten years, and 11 disclosed deal terms comprising an aggregate value of $3.27B. ß-catenin is a critical node and driver of the WNT pathway and is an attactive target for cancer drug discovery.

-Kerry Blanchard, M.D., Ph.D., Co-founder, President, CEO"

β-catenin, a protein crucial for cell communication and development, has emerged as a promising drug target in the battle against cancer. Significant strides have been made in understanding the role of β-catenin in cancer development. Recurring genetic mutations activate β-catenin, underscoring its pivotal role in driving tumor growth. In addition to genetic validation, several other lines of evidence support β-catenin as a compelling target for anti-cancer drugs:

1 Correlation with Tumor Aggressiveness

High levels of β-catenin activity have been correlated with more aggressive tumor behavior and poorer prognosis in multiple cancer types. This suggests that targeting β-catenin could potentially inhibit the growth and spread of cancer cells.

2 Preclinical Models

In preclinical studies using laboratory models, manipulating β-catenin levels or activity has demonstrated a significant impact on tumor growth. Inhibition of β-catenin signaling has been shown to suppress the growth of cancer cells, providing a solid rationale for developing drugs that specifically target this pathway.

3 Association with Cancer Stem Cells

β-catenin plays a crucial role in maintaining cancer stem cells, which are thought to drive tumor initiation, progression, and resistance to therapy. Targeting β-catenin may therefore disrupt these cancer stem cells, potentially improving the efficacy of anti-cancer treatments.

4 Clinical Correlations:

In some clinical studies, elevated β-catenin expression has been associated with resistance to conventional cancer therapies. Combining traditional treatments with β-catenin-targeted drugs could enhance therapeutic outcomes and overcome resistance.

The WNT pathway has been fertile ground for partnerships over the last few decades primarily based on the validation status of the target. Over the last decade, more than $3.27B of deals have been focused on the pathway. Most projects have focused on the upstream components of the WNT pathway: requisite components of WNT ligand release (porcupine), WNT ligand blockers, WNT receptor inhibitors, and intracellular WNT pathway blockers. These approaches inhibit the canonical WNT pathway as well as the non-canonical pathway leading to significant on-target toxicity. But the willingness of multinational pharmaceutical companies to still invest in approaches to inhibit the WNT pathway highlight the importance of this pathway.

Previous drug discovery efforts have laid the groundwork for potential breakthroughs, with researchers exploring compounds that can modulate β-catenin activity, however, none of these efforts have led to an approved drug targeting β-catenin. Recent advances in peptide therapeutics have made β-catenin an approachable target via blocking intracellul­­­ar protein:protein interactions.We believe the advances in peptide-based modalities for blocking essential protein:protein interactions opens a new world of opportunities in controlling WNT activation.An effective medicine that targets β-catenin would be a beacon of hope in the quest for more effective and targeted cancer therapies.

(Press release, Perpetual Medicines, NOV 23, 2023, View Source [SID1234661245])