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 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 01, 2024 Allogene Therapeutics Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) products for cancer and autoimmune disease, reported that Rocky Mountain Cancer Centers (RMCC), part of the US Oncology Network and Sarah Cannon Research Institute (SCRI); Astera Cancer Care (ACC), a multi-specialty community oncology practice and part of the OneOncology network; and Norton Cancer Institute, are open for enrollment in the pivotal Phase 2 ALPHA3 trial (Press release, Allogene, JUL 1, 2024, View Source [SID1234644620]).

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The ALPHA3 trial is evaluating the use of cemacabtagene ansegedleucel (cema-cel) as part of the first line (1L) consolidation treatment regimen for newly diagnosed and treated large B-cell lymphoma (LBCL) patients who remain positive for minimal residual disease (MRD). Detection of MRD will be done using the Foresight CLARITY Investigational Use Only (IUO) MRD test, powered by PhasED-Seq. When given as a "7th cycle" of frontline treatment to eligible patients with MRD, consolidation treatment with cema-cel has the potential to meaningfully improve 1L cure rates for patients with LBCL who are likely to relapse.

"We believe community physicians have been waiting for a trial like ALPHA3 that offers cutting-edge CAR T without the inherent complexities associated with autologous therapies," said David Chang, M.D., Ph.D., President, Chief Executive Officer and Co-Founder of Allogene. "The differentiated attributes of cema-cel eliminate many of the complex logistics that have hindered CAR T adoption in the community setting. The fact that community-based practices are the first sites to open for enrollment in the ALPHA3 trial is a significant symbolic step forward in expanding patient access to this powerful modality and will serve as a catalyst for our cema-cel development program."

RMCC is the largest multidisciplinary practice in Colorado with 19 locations across the state dedicated solely to providing care for patients with cancer and diseases of the blood. RMCC is a part of SCRI, a combination of two nationally recognized oncology research institutes – US Oncology and SCRI. This combination creates a leading oncology research organization participating in community-based clinical trials. Patients undergoing treatment for newly diagnosed LBCL throughout the RMCC network will be considered for enrollment in ALPHA3.

"Current 1L chemoimmunotherapy is effective in most patients, but the reality is that 30% will relapse," said John M. Burke, M.D., a Blood Cancer Specialist at RMCC. "The ALPHA3 trial will be answering two key questions. First, can measuring circulating tumor DNA in the blood be used to select lymphoma patients destined to relapse for early intervention? And second, does treating these high-risk lymphoma patients with cema-cel increase cure rates compared with conventional surveillance? These are critically important questions that have the potential to change the lymphoma treatment paradigm."

ACC is an independent and physician-owned multi-specialty community oncology practice serving more than 22,000 new patients annually in Central New Jersey. The practice is part of the OneOncology platform which is a partnership of over 20 independent community oncology practices nationally. Astera’s specialists practice at 13 distinct locations in Middlesex, Somerset, Bergen, Hudson, Hunterdon, Mercer and Monmouth counties in New Jersey and Langhorne, Pennsylvania and have a robust clinical trial platform for cancer therapy with one of the only community-based clinical trial programs in CAR T cell therapies in the nation. Patients undergoing treatment for newly diagnosed LBCL throughout the ACC network will be considered for enrollment in ALPHA3.

According to Edward J. Licitra, M.D., PhD, oncologist and Chairman and Chief Executive Officer at ACC, relapsed LBCL is much more difficult to treat, and physicians often consider enrollment in clinical trials to allow access to promising therapies. "I have watched with interest the acceleration of CAR T research in LBCL, but because most patients live more than two hours from the nearest treatment center, it’s not feasible for them to participate. Having access to an "off-the-shelf" CAR T product with a manageable safety profile changes that equation dramatically for me, and my patients. We are excited to help define a new treatment standard in LBCL. An approved "off-the-shelf" CAR T product would allow for greater access to cutting edge technologies for patients in their local communities and this could improve outcomes for many more cancer patients."

With more than 21 locations serving Louisville, Kentucky and Southern Indiana, Norton Cancer Institute (NCI) treats more than 4,000 newly diagnosed cancer patients each year. NCI’s network of multidisciplinary clinics offers patients the latest treatments and access to more than 100 clinical trials.

"Kentucky has one of the highest cancer death rates in the United States1 and a big contributor to this is lack of patient access to cutting-edge treatments," said Don A. Stevens, M.D., a hematologist-oncologist at Norton Cancer Institute. "Offering investigational cema-cel to our first line patients has the potential to improve cure rates for the 30% we know will relapse after chemoimmunotherapy. This could change how we treat these patients in the future."

About Cemacabtagene Ansegedleucel (cema-cel)
Cemacabtagene ansegedleucel, or cema-cel, is a next generation anti-CD19 AlloCAR T investigational product for the treatment of large B cell lymphoma (LBCL). In June 2022, the U.S. Food and Drug Administration granted Regenerative Medicine Advanced Therapy (RMAT) designation to cema-cel in third line (3L) r/r LBCL. The ALPHA3 pivotal Phase 2 trial in first line (1L) consolidation for the treatment of LBCL launched in June 2024. Allogene has oncology rights to cema-cel in the US, EU and UK with options for rights in China and Japan.

About the ALPHA3 Trial
Over 60,000 patients are expected to be treated for LBCL annually in the US, the EU and the UK. While first line (1L) R-CHOP or other chemoimmunotherapy is effective for most patients, approximately 30% will relapse and require subsequent treatment. The current standard of care (SOC) after 1L treatment has been simply to "watch and wait" to see if the disease relapses. The pivotal Phase 2 ALPHA3 study takes advantage of cema-cel as a one-time, off-the-shelf treatment that can be administered immediately upon discovery of MRD following six cycles of R-CHOP or other chemoimmunotherapy, positioning it to become the standard "7th cycle" of frontline treatment available to all eligible patients with MRD.