On July 1, 2024 Can-Fite BioPharma Ltd., a biotechnology company with a pipeline of proprietary small molecule drugs that address oncological and inflammatory diseases, reported that a patient with liver decompensated cirrhosis who was treated with Namodenoson at the Soroka Medical Center in Israel under compassionate use showed an improvement in liver indices (Press release, Can-Fite BioPharma, JUL 1, 2024, View Source [SID1234644621]). This drug candidate is currently used in a pivotal Phase III study for patients with advanced liver cancer and a Phase IIb study for MASH (metabolic dysfunction-associated steatohepatitis).

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Decompensated cirrhosis is defined as an acute deterioration in liver function in a patient with cirrhosis and is characterized by jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome, or variceal hemorrhage. While some drugs can treat symptoms, there is no therapeutic approach that has shown efficacy in slowing disease progression.

In the past year Can-Fite has initiated a compassionate use program at the Soroka Medical Center, Beersheva, Israel, for the treatment of decompensated patients with Namodenoson. The first patient, a 63-year-old female with a history of decompensated primary biliary cirrhosis is now treated for one year with Namodenoson. Prior to the treatment with Namodenoson and despite best medical care for her underlying disease, she developed ascites and was admitted to the hospital with acute variceal bleeding. Currently, the patient shows improvement in liver function tests hematological parameters and FibroScan values and has not experienced any event of decompensation since starting treatment with Namodenoson. Namodenoson is known to induce liver protective effects in other liver pathologies, and Phase IIa data in patients suffering from MASH (metabolic dysfunction-associated steatohepatitis), responded positively to the drug, showing anti-inflammatory, anti-steatotic, and antifibrotic effects with a very favorable safety profile.

Ohad Etzion, MD, Director, Department of Gastroenterology and Liver Diseases at the Soroka Medical Center, Beer Sheva, Israel, the Investigator and Initiator of this study commented, "We were very much encouraged by the response of the first patient with decompensated liver cirrhosis who showed a rapid and sustained response to the drug with an improvement with liver indices. We plan to treat more patients and hopefully see an improvement of liver function in this devastating disease.

Decompensated cirrhosis is defined as an acute deterioration in liver function, with cirrhosis and is characterized by jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome, or variceal hemorrhage. While some drugs can treat symptoms, there is no therapeutic approach that has shown efficacy in slowing disease progression. An estimated 10.6 million people globally had decompensated cirrhosis in 2017, with few treatment options available aside from liver transplants if the decompensated cirrhosis has reached an advanced stage. Underscoring the need for an effective treatment, the American Liver Foundation states there are more people who need a liver than supply available, and some people can be on the wait list for a liver transplant for more than 5 years. The treatment of liver cirrhosis globally is estimated to become an approximately $29.2 billion market by 2031.

About Namodenoson

Namodenoson is a small orally bioavailable drug that binds with high affinity and selectivity to the A3 adenosine receptor (A3AR). Namodenoson was evaluated in Phase II trials for two indications, as a second line treatment for hepatocellular carcinoma, and as a treatment for Metabolic Dysfunction-Associated Steatohepatitis (MASH). 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.

On July 1, 2024 Signet Therapeutics, a biotech company using organoid disease models and AI to advance targeted cancer therapy, reported that the FDA has granted its IND application for sigx1094 as a potential treatment for diffuse gastric cancer (DGC) (Press release, Signet Therapeutics, JUL 1, 2024, View Source [SID1234644637]). This marks a significant milestone as sigx1094 is the first targeted drug candidate for DGC, a disease currently lacking effective treatments. The company is poised to commence a Phase I clinical trial to assess the safety and efficacy of sigx1094 in patients with DGC and other advanced solid tumors.

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"The FDA’s IND approval for sigx1094 marks a significant step forward in addressing the critical unmet medical needs in DGC. This milestone fuels our optimism for a new era where AI and organoid disease models become the catalysts for more fruitful drug discovery efforts, propelling the transformation of biological discoveries into innovative, life-saving treatments," said Dr. Haisheng Zhang, Founder and CEO of Signet Therapeutics.

Accelerating Drug Discovery with Organoid Disease Models and AI

In leveraging its proprietary organoid disease model platform and through a strategic collaboration with XtalPi, XtalPi (2228.HK), a leading drug R&D platform company driven by artificial intelligence (AI) and robotics, Signet nominated pre-clinical candidate sigx1094 in just over six months, and received FDA’s IND approval in under four years, significantly accelerating the drug discovery and design process. For efficacy evaluation, Signet used its proprietary organoid disease models developed from real-world cancer genomics data to simulate drug effects in 3D tissues that resemble human biology, allowing for more accurate predictions of patient responses. Sigx1094 is the first of a series of pipeline projects that was discovered by AI and validated by organoid disease models. By designing and evaluating candidate molecules using data of higher clinical relevance, the company hopes such innovative R&D approach will increase the likelihood of clinical trial success. The company’s novel organoid disease model platform not only supports its own drug pipeline but also provides external services, including drug efficacy evaluation, target screening, and model animal experiments, ensuring a consistent revenue stream.

Signet Therapeutics’ Origins and Vision

Before establishing the company, Dr. Haisheng Zhang was part of a team led by Dr. Adam Bass at Dana-Farber Cancer Institute at Harvard Medical School. Their groundbreaking research, published in Nature, classified gastric cancer into four distinct molecular subtypes, with diffuse gastric cancer (DGC) identified as a genomically stable cancer. This subtype is particularly challenging due to its high invasiveness and poor response to conventional treatments like chemotherapy and radiotherapy and the current targeted therapies.

Driven by these insights, Dr. Zhang established Signet Therapeutics in late 2020 and led a team dedicated to identifying novel targets and developing effective therapies for cancers. The team is driven by the urgent need for new treatments for cancers where traditional therapies have often been ineffective. They have established unique organoid disease models using transgenic mice to study DGC, leading to the discovery of potent targets such as FAK and YAP.

Broad Potential of sigx1094

Apart from treating DGC, sigx1094 has shown promise in preclinical studies for treating various cancers, including ovarian, triple-negative breast, and pancreatic cancers. The drug candidate also demonstrated potential in combination therapies, particularly with chemotherapy and targeted treatments for KRAS-mutated and EGFR-mutated cancers. As clinical studies progress, Signet hopes to further investigate and validate sigx1094’s potential as treatment in a broader range of therapeutic areas.

On July 1, 2024 Circle Pharma, a leader in macrocycle drug discovery and development, reported the submission of its first Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) for CID-078, a first-and-only-in-class cyclin A/B RxL inhibitor (Press release, Circle Pharma, JUL 1, 2024, View Source [SID1234644622]). This milestone marks a significant advancement in the development of novel drug candidates generated by Circle’s proprietary MXMO platform for difficult-to-drug targets in oncology and other serious illnesses.

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CID-078 is an orally bioavailable macrocycle that has shown preclinical efficacy across multiple tumor types characterized by high E2F expression, including small cell lung cancer, triple negative breast cancer, ER-low breast cancer, and HR-positive breast cancer following a CDK 4/6-inhibitor. The IND submission includes comprehensive data from preclinical studies which have demonstrated a safety, efficacy, and pharmacokinetic profile of CID-078 to support the proposed phase 1 trial.

CID-078 is designed to selectively inhibit key protein-to-protein interactions involving cyclins A and B, which are implicated in the proliferation and survival of cancer cells. Cyclins are a family of proteins that function as master regulators of the cell cycle. Early work in the laboratory of Nobel Laureate and Circle Pharma’s Scientific Advisory Board Chair William G. Kaelin Jr., MD, showed that disrupting the function of cyclins in certain types of cancer cells that had dysregulated cell cycle control was synthetic lethal – meaning that these cancer cells were selectively killed while the viability of normal cells was unaffected.1 The mechanism of action of CID-078 offers a novel therapeutic approach to potentially address unmet medical needs in patients with advanced solid tumors who currently have limited therapeutic choices.

"I am proud that we have reached this critical milestone in the development of CID-078," said David J. Earp, CEO of Circle Pharma. "Our team has worked diligently to advance this promising candidate from discovery through preclinical development. The IND filing represents a major step forward in our mission to harness the power of macrocycle therapies to create effective treatments for cancer and other serious illnesses."

"We believe, based on our preclinical data package, that CID-078 has the potential to provide a transformative therapeutic option for patients with cancer," said Michael Cox, PharmD, MHSc, BCOP, head of Early Development and senior vice president. "We are excited to advance CID-078 into clinical studies. This step underscores our commitment to develop innovative therapeutics that target challenging and previously undruggable proteins."

Pending regulatory approval, Circle Pharma plans to initiate a phase 1 clinical trial of CID-078 in patients with advanced solid tumor malignancies. The dose escalation and dose expansion portions of the trial will evaluate safety, tolerability, and pharmacokinetics, as well as anti-tumor activity as assessed by objective response rate and duration of response.

About CID-078, Circle Pharma’s Cyclin A/B RxL Inhibitor Program

CID-078 is an orally bioavailable macrocycle with dual cyclin A and B RxL inhibitory activity that selectively targets tumor cells with oncogenic alterations that cause cell cycle dysregulation. In biochemical and cellular studies, Circle’s cyclin A/B RxL inhibitors have been shown to potently and selectively disrupt the protein-to-protein interaction between cyclins A and B and their key substrates and modulators, including E2F (a substrate of cyclin A) and Myt1 (a modulator of cyclin B). Preclinical studies have demonstrated the ability of these cyclin A/B RxL inhibitors to cause single-agent tumor regressions in multiple xenograft models.

On July 1, 2024 Radionetics Oncology, a biotechnology company discovering and developing novel small molecule G protein coupled receptor (GPCR) targeted radiopharmaceuticals to treat a broad range of solid tumors, reported the formation of a strategic relationship with Eli Lilly and Company to take forward Radionetics’ proprietary GPCR targeting small molecule radiopharmaceuticals (Press release, Radionetics Oncology, JUL 1, 2024, View Source [SID1234644638]).

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Under the terms of the agreement, Radionetics received a $140 million upfront cash payment. As part of the strategic arrangement, Lilly obtained the exclusive right to acquire Radionetics upon conclusion of an exercise period for $1 billion. During the exercise period, Radionetics will continue to build out a proprietary pipeline of therapeutic assets. These will include small molecule radioligand therapeutics targeting GPCRs using the Radionetics proprietary discovery platform and associated intellectual property.

"We are fortunate to have entered into an agreement with Lilly given its global development capability, oncology expertise, and the radiopharmaceutical experience and capabilities Lilly is building following the acquisition of POINT Biopharma," said Paul Grayson, CEO of Radionetics Oncology.

"Furthering our commitment to radiopharmaceutical therapies, this relationship provides access to novel GPCR targets and the discovery capabilities of Radionetics Oncology," said Jacob Van Naarden, Executive Vice President and President, Lilly Oncology.

"Our platform uniquely pairs the power of radiopharmaceuticals with the precision of small molecule targeting to novel GPCRs. We have a specialized team that is focused on rapidly advancing each of our promising programs to bring these much-needed new therapies to patients," said Brett Ewald, Chief Operating Officer.

Cooley LLP is acting as legal advisor to Radionetics. Ropes & Gray LLP is acting as legal advisor to Lilly.

On July 1, 2024 Eisai reported that it has agreed to end its global strategic collaboration with Bristol Myers Squibb for the co-development and co-commercialization of farletuzumab ecteribulin (FZEC), formerly known as MORAb-202, a folate receptor alpha (FRα)-targeting antibody drug conjugate (ADC) due to ongoing portfolio prioritization efforts within Bristol Myers Squibb (Press release, Eisai, JUL 1, 2024, View Source [SID1234644623]). Based on the agreement, Eisai now owns all rights to FZEC and will solely conduct the global development and commercialization of the agent. Eisai will accelerate the development of the agent as a high priority with the hope to deliver it to patients as early as possible. Eisai plans to refund a part of the unused portion of the $200 million payment it received towards research and development expenses from Bristol Myers Squibb under the collaboration agreement and record the remaining as other income.

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FZEC is Eisai’s first ADC and is composed of Eisai’s in-house developed farletuzumab, a humanized IgG1 monoclonal antibody that binds to the FRα, and Eisai’s in-house developed anticancer agent eribulin, using an enzymatically cleavable linker. Currently, three clinical studies are ongoing: Eisai’s Phase 1/2 study for solid tumors (NCT04300556), and Bristol Myers Squibb’s Phase 2 studies for ovarian, peritoneal and fallopian tube cancers (NCT05613088(New Window)) and non-small cell lung cancer (NCT05577715(New Window)).

Eisai positions oncology as a key franchise area and aims to contribute toward the cure of cancers by exploring the depths of human biology. FZEC development for refractory cancers is a testament of our dedication to addressing the unmet medical needs of patients with cancer. Eisai will make continuous efforts to increase the benefits provided to patients with cancer and their families.

[Notes to Editors]

1. Farletuzumab ecteribulin (FZEC, formerly known as MORAb-202)
FZEC is Eisai’s first antibody drug conjugate (ADC) and that is composed of Eisai’s in-house developed farletuzumab, a humanized IgG1 monoclonal antibody that binds to the folate receptor alpha (FRα), and Eisai’s in-house developed anticancer agent eribulin, using an enzymatically cleavable linker. After FZEC enters the target FRα-positive cancer cells, it is thought that the linker is enzymatically cleaved, releasing eribulin from the antibody leading to its antitumor activity. When the anticancer agent and antibody components of an ADC are separated inside a targeted antigen-positive cancer cell, it is theorized that the released anticancer agent also has a bystander effect on neighboring antigen-negative cancer cells and the component cells of the tumor microenvironment. In pre-clinical studies, FZEC demonstrated a bystander effect*, with antitumor activity on the FRα-negative cancer cells surrounding the FRα-positive cancer cells.

The payload eribulin was the first in the halichondrin class of microtubule dynamics inhibitor. Structurally, eribulin is a simplified and synthetically produced version of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai, and functions by inhibiting the growth phase of microtubule dynamics which prevents cell division. Eribulin has been approved in countries including Japan, the United States, China, in Europe and in Asia for use in the treatment of advanced breast cancer and liposarcoma (soft tissue sarcoma in Japan).

*Bystander effect: When the anticancer agent and antibody parts of an ADC are separated inside a targeted antigen-positive cancer cell, the released anticancer agent also affects neighboring antigen-negative cancer cells and the component cells of the cancer microenvironment.