On September 16, 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 that it received approval from the Israeli Ministry of Health (MoH) to conduct Phase IIa clinical trial with orally-administered Namodenoson in the treatment of pancreatic carcinoma (Press release, Can-Fite BioPharma, SEP 16, 2024, View Source [SID1234646645]).

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"We are very much encouraged by the excellent data in the pre-clinical studies demonstrating the impressive anti-cancer effect of namodenoson and definitive molecular mechanism of action against pancreatic carcinoma," stated Dr. Fishman, Can-Fite’s Chief Scientific Officer and Executive Chairman. "We are very keen to initiate the study in this devastating disease and are pleased with the regulatory approval of the Israeli MOH. We do hope that as we have shown efficacy in patients with advanced liver cancer studies, we will be able to demonstrate safety and efficacy in the pancreatic cancer patient population."

The Phase IIa is 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).

The study will be conducted by Dr. Stemmer, a leading key opinion leader, at the Institute of Oncology, Rabin Medical Center, Israel and by Dr. Al Mutar from the UT Southwestern Medical Center in the US.

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 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.

On September 16, 2024 Ribometrix, a biotechnology company developing small molecule therapeutics that modulate RNA biology, reported the latest data from its eIF4E program at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, taking place in Barcelona, Spain, September 13-17 (Press release, Ribometrix, SEP 16, 2024, View Source [SID1234646662]). The poster presentation reviews in vitro and in vivo studies of a small molecule eIF4E inhibitor, RBX-6610, as a potential treatment for KRASG12C mutant non-small cell lung cancer (NSCLC). Acquired resistance is observed in most patients treated with the two approved therapies for KRASG12C mutant NSCLC, creating a significant opportunity for a therapy that re-sensitizes tumors to KRAS inhibition. Ribometrix’s data supports RBX-6610’s ability to deliver this mechanism in combination with the approved therapies.

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"In less than three years, Ribometrix has advanced its eIF4E program from concept to a lead molecule that has just completed non-GLP toxicology studies," stated Michael Solomon, CEO of Ribometrix, Inc. "The program is a testament to Ribometrix drug discovery capabilities, and the commitment and professionalism of the Ribometrix team. We look forward to moving this program forward into the clinic in collaboration with a partner who shares our vision of its potential to benefit patients, via its novel mechanism of action."

"These data further evidence the broad potential of eIF4E inhibition in multiple tumor types, particularly in combination as a re-sensitizing agent. We have further validated the mechanism of action and characterized the synergistic benefit of RBX-6610, our most advanced eIF4E inhibitor," said Jessica Sorrentino, Ph.D., SVP of Translational Medicine. "RBX-6610 is progressing towards the clinic and we see significant promise for its inclusion with the standard-of-care for both naïve and treatment resistant NSCLC patients, especially whose tumors have KRAS mutations."

Key highlights:

RBX-6610 demonstrated consistent anti-proliferative effects in KRASG12C mutant tumor cell lines, in both treatment-naïve lines and those with acquired resistance.
Additionally, the combined in vitro effects of co-treatment of RBX-6610 with KRAS inhibitors were synergistic, such that the proliferative inhibitory effects were greater than the sum of either treatment alone. Mechanistically, this was due to an induction of apoptosis, specific to co-treatment in treatment-naïve tumor cells as well as cells resistant to KRAS inhibitors. This synergistic phenotype was observed with both approved KRAS inhibitors, as well as investigational RAS inhibitors.
Daily oral RBX-6610 monotherapy led to substantial tumor growth inhibition in both treatment naïve and resistant KRASG12C NSCLC xenograft model (75% vs 71% TGI, respectively), corroborating the anti-proliferative effects seen in vitro.
In combination with sotorasib, an approved KRAS inhibitor, daily oral treatment with RBX-6610 led to significant tumor regression and improved survival in both the treatment-naïve and sotorasib resistant setting (34% and 49% mean tumor regression respectively). No toxicity was observed in up to 35 days of daily oral treatment across all cohorts.
In vitro data demonstrated improved selectivity of cap dependent translation inhibition by RBX-6610 relative to other translation inhibitors including zotatifin, an eIF4A inhibitor.
Ribometrix continues to generate data demonstrating the multi-tumor therapeutic potential of eIF4E inhibition. Studies in melanoma and breast cancer were presented at the Society for Melanoma Research and the San Antonio Breast Cancer Symposium in 2023, and data across melanoma, colorectal, breast, and non-small cell lung cancer were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in 2024. Data have repeatedly included support for both monotherapy and combination regimens as well as the potential to re-sensitize to standard-of-care treatments.

The ESMO (Free ESMO Whitepaper) poster is now available to view on the "Publications" page of Ribometrix’s website.

About eIF4E

Eukaryotic translation initiation factor 4E (eIF4E) is a crucial regulatory component of mRNA translation and well-documented driver of oncogenesis. Clinically, eIF4E activity is elevated in many tumor indications and it is typically associated with poor prognosis. Targeting eIF4E has the potential to enhance anti-cancer activity when given in combination with standard-of-care. Additionally, eIF4E inhibition has the potential to overcome drug resistance and re-sensitize tumors to anti-cancer therapies. Based on substantial external and in-house data, Ribometrix is developing eIF4E inhibitors as a promising combination therapy approach and treatment for treatment-resistant tumors.

On September 16, 2024 Akeso (9926.HK) reported the phase 2 results from its ivonescimab in combination with chemotherapy as a first-line (1L) treatment for triple-negative breast cancer (TNBC) at the 2024 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Conference (Press release, Akeso Biopharma, SEP 16, 2024, View Source [SID1234646678]). The preliminary data, with only a 10-month median follow-up, revealed that the ivonescimab combination regimen demonstrated excellent efficacy and a favorable safety profile in 1L TNBC. Professor Wang Xiaojia from Zhejiang Provincial Cancer Hospital, a co-primary investigator of the study, presented the findings orally at the conference.

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As of May 31, 2024, a total of 30 patients with locally advanced unresectable or metastatic TNBC were enrolled. 80% of patients had a PD-L1 combined positive score (CPS) <10, and 60% of patients had previously received taxane-based neoadjuvant or adjuvant therapy (a proportion higher than that observed in similar studies involving targeted drugs).

Although the follow-up period is relatively short and the data are not yet mature, the study still demonstrates that the ivonescimab combination regimen demonstrates excellent progression-free survival (PFS) benefits for TNBC patients, with safety consistent with previous ivonescimab-related studies.

Ivonescimab combination regimen demonstrated high efficacy in tumor response and disease control, with an objective response rate (ORR) of 72.4% and a disease control rate (DCR) of 100%, including a complete response (CR) rate of 6.9%.
As of the latest update, five additional patients have achieved partial response (PR) (Among them, four newly evaluable patients all achieved a PR, and one patient who previouly had stable disease also achieved a PR ), leading to an adjusted ORR of approximately 78.8% and DCR of 100%.
Ivonescimab combination regimen showed a promising trend towards improved long-term survival benefits, with a median progression-free survival (PFS) of 9.3 months (6.24 months -NE), and a 6-month PFS rate of 73.3%.
In the PD-L1 CPS≥10 population, the ORR was 83.3%, and the median PFS was not yet reached.
In the PD-L1 CPS <1 population, the ORR was 86.7%, with a median PFS of 9.3 months (5.26 months-NE).
As of the latest update, two additional patients in the PD-L1 CPS <1 group have achieved PR, resulting in an adjusted ORR of 88.2%.
In the PD-L1 CPS <10 population, the ORR was 69.6%, with a median PFS of 9.3 months (5.55 months-NE).
As of the latest update, five additional patients in this group have achieved PR, leading to an adjusted ORR of approximately 77.8%.
Ivonescimab combined with chemotherapy as a first-line treatment for TNBC exhibited an acceptable safety profile. The most common treatment-related adverse events (TRAEs) were predominantly grade 1-2 and manageable, consistent with previous studies. There were no TRAEs that led to permanent treatment discontinuation or death.

On September 16, 2024 Checkpoint Therapeutics, Inc. ("Checkpoint") (Nasdaq: CKPT), a clinical-stage immunotherapy and targeted oncology company, reported the presentation of longer-term data from its pivotal trial of cosibelimab, its anti-programmed death ligand-1 ("PD-L1") antibody, in locally advanced and metastatic cutaneous squamous cell carcinoma ("cSCC") during the European Society for Medical Oncology ("ESMO") Congress 2024, which is taking place in Barcelona, Spain, from September 13 to 17, 2024 (Press release, Checkpoint Therapeutics, SEP 16, 2024, View Source [SID1234646646]).

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Poster Presentation Title: Cosibelimab in Advanced Cutaneous Squamous Cell Carcinoma (CSCC): Longer-term Efficacy and Safety Results from Pivotal Study

"These longer-term results for cosibelimab presented at the ESMO (Free ESMO Whitepaper) Congress demonstrate a deepening of response over time, with higher objective response and complete response rates than initially observed at the primary analyses, and continue to expand the evidence supporting the efficacy and safety of cosibelimab as a potential new treatment for advanced cSCC," said James Oliviero, President and Chief Executive Officer of Checkpoint. "We look forward to our upcoming December 28, 2024, Prescription Drug User Fee Act ("PDUFA") goal date for our Biologics License Application for cosibelimab, and believe, if approved, cosibelimab’s dual mechanisms of action and safety profile may position the product, over time, as the preferred immunotherapy of U.S. oncologists."

Data highlights include:

Efficacy

With 16 months of additional follow-up since the primary analysis, cosibelimab demonstrated increasing objective response rates ("ORRs") and complete response rates per independent central review in 109 patients with advanced cSCC.
ORRs of 54.8% and 50.0% achieved in locally advanced and metastatic cSCC, with median follow-up durations of 24.1 and 29.3 months, respectively.
Results demonstrate a deepening of response over time, with complete response rates of 25.8% and 12.8% in locally advanced and metastatic cSCC, respectively.
Clinically meaningful durations of response ("DOR") were observed, with median DORs not yet reached in either group.
Safety

Overall, in 192 advanced cSCC patients treated with cosibelimab, a manageable safety profile was observed, with notable low rates of treatment-emergent adverse events ("TEAEs"), severe immune-related adverse events ("irAEs"), and treatment discontinuations.
3.6% of patients experienced an irAE assessed as grade 3, with no observed grade ≥4 irAEs.
No events of grade ≥3 pneumonitis, colitis, hepatitis, nephritis, or endocrinopathies.
Treatment discontinuation due to TEAEs, regardless of attribution, was observed in 12 patients (6.3%); the most common reason was COVID-19/COVID-19 pneumonia (1.6%).
A copy of the poster can be found on the Publications page of the Checkpoint Therapeutics website.

In December 2023, the U.S. Food and Drug Administration ("FDA") issued a complete response letter ("CRL") for the cosibelimab Biologics License Application ("BLA") for the treatment of patients with metastatic or locally advanced cSCC who are not candidates or curative surgery or radiation. The CRL only cited findings that arose during a multi-sponsor inspection of Checkpoint’s third-party contract manufacturing organization ("CMO") as approvability issues to address in a resubmission. In July 2024, Checkpoint announced it had completed a resubmission of the BLA to the FDA for cosibelimab to potentially address the approvability issues cited in the CRL. The resubmission was accepted by the FDA as a complete response and the FDA has set a PDUFA goal date of December 28, 2024.

About Cutaneous Squamous Cell Carcinoma (cSCC)
Cutaneous Squamous Cell Carcinoma is the second most common type of skin cancer in the United States, with an estimated annual incidence of approximately 1.8 million cases according to the Skin Cancer Foundation. Important risk factors for cSCC include chronic ultraviolet exposure and immunosuppressive conditions. While most cases are localized tumors amenable to curative resection, approximately 40,000 cases will become advanced, and an estimated 15,000 people will die from this disease each year. In addition to being a life-threatening disease, cSCC causes significant functional morbidities and cosmetic deformities based on tumors commonly arising in the head and neck region and invading blood vessels, nerves and vital organs such as the eye or ear. The immune-suppressed population represents a challenging target in the treatment of advanced cSCC, as they present with a more aggressive disease and with a higher risk of developing immune-related toxicities from checkpoint inhibitor treatment.

About Cosibelimab
Cosibelimab is a potential differentiated, high affinity, fully-human monoclonal antibody of IgG1 subtype that directly binds to PD-L1 and blocks the PD-L1 interaction with the programmed death receptor-1 ("PD-1") and B7.1 receptors. Cosibelimab’s primary mechanism of action is based on the inhibition of the interaction between PD-L1 and its receptors PD-1 and B7.1, which removes the suppressive effects of PD-L1 on anti-tumor CD8+ T-cells to restore the cytotoxic T cell response. Cosibelimab is potentially differentiated from the currently marketed PD-1 and PD-L1 antibodies through sustained high tumor target occupancy of PD-L1 to reactivate an antitumor immune response and the additional potential benefit of a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity ("ADCC") for potential enhanced efficacy.

On September 16, 2024 UroGen Pharma Ltd. (Nasdaq: URGN), a biotech company dedicated to developing and commercializing innovative solutions that treat urothelial and specialty cancers, reported that it has received a Notice of Allowance from the United States Patent and Trademark Office (USPTO) for patent application no. 18/535,108 entitled "Material and Method for Treating Cancer (Press release, UroGen Pharma, SEP 16, 2024, View Source [SID1234646663])."

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The allowed claims relate to the combination of UroGen’s RTGel technology with medac’s licensed proprietary lyophilized mitomycin formulation and cover the use of UroGen’s UGN-103 and UGN-104 development programs in the treatment of low-grade intermediate-risk non-muscle invasive bladder cancer (LG-IR-NMIBC) and low-grade upper tract urothelial cancer (LG-UTUC), respectively. The U.S. patent, once issued, will have an expiration date in December 2041.

"Allowance of this patent application strengthens our intellectual property position for our next-generation investigational programs for patients with urothelial cancers," said Liz Barrett, President and CEO of UroGen. "We believe that the combination of UroGen’s RTGel technology with medac’s patent-protected lyophilized mitomycin has the potential to provide advantages related to production, cost, supply, and product convenience for patients. Our vision remains to develop innovative medicines that advance the care of patients, and this patent allowance is a key element of our strategy to build a long-term growth company."

In January 2024, UroGen entered into a licensing and supply agreement with medac to develop UGN-103 for LG-IR-NMIBC and UGN-104 for LG-UTUC. In April 2024, the FDA accepted UroGen’s IND application for UGN-103 and the company is currently onboarding clinical sites for the study. The company anticipates commencing a similar study for UGN-104, which is expected in early 2025.

About UGN-102

UGN-102 (mitomycin) for intravesical solution is an innovative drug formulation of mitomycin, currently in Phase 3 development for the treatment of LG-IR-NMIBC. Utilizing UroGen’s proprietary RTGel technology, a sustained release, hydrogel-based formulation, UGN-102 is designed to enable longer exposure of bladder tissue to mitomycin, thereby enabling the treatment of tumors by non-surgical means. UGN-102 is delivered to patients using a standard urinary catheter in an outpatient setting by a trained healthcare professional. UroGen completed the NDA submission for UGN-102 in August 2024, ahead of schedule. UroGen anticipates potential FDA approval in early 2025 if the NDA is accepted for filing by the FDA and priority review is granted.

About UGN-103 and UGN-104

UGN-103 and UGN-104 are innovative mitomycin formulations in development by UroGen for the treatment of LG-IR-NMIBC and LG-UTUC, respectively. UGN-103 aims to streamline manufacturing and reconstitution processes while providing intellectual property coverage until December 2041; it utilizes UroGen’s RTGel technology for prolonged mitomycin exposure. UGN-104, also leveraging RTGel technology, is designed for treating low-grade upper tract urothelial cancer and is anticipated to enter Phase 3 trials in early 2025, offering a non-surgical treatment option with similar intellectual property protection.