On July 23, 2023 Exelixis, Inc. (Nasdaq: EXEL) reported that it has entered into a Settlement and License Agreement (Agreement) with Teva Pharmaceuticals Development, Inc. and Teva Pharmaceuticals USA, Inc. (collectively Teva) (Press release, Exelixis, JUL 23, 2023, View Source [SID1234633374]). This settlement resolves patent litigation brought by Exelixis in response to Teva’s Abbreviated New Drug Application (ANDA) seeking approval to market a generic version of CABOMETYX (cabozantinib) tablets prior to the expiration of the applicable patents.

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Pursuant to the terms of the Agreement, Exelixis will grant Teva a license to market its generic version of CABOMETYX in the United States beginning on January 1, 2031, if approved by the U.S. Food and Drug Administration and subject to conditions and exceptions common to agreements of this type.

Additionally, in accordance with the Agreement, the parties will terminate all ongoing Hatch-Waxman litigation between Exelixis and Teva regarding CABOMETYX patents pending in the U.S. District Court for the District of Delaware.

The Agreement is confidential and subject to review by the U.S. Federal Trade Commission and the U.S. Department of Justice.

On July 21, 2023 Alpha Fusion Inc. (CEO: Nao Fujioka, Kita-ku, Osaka City, Osaka Prefecture) reported the company has signed a joint research agreement with a group led by Director Zhang Mingrong of the Department of Advanced Nuclear Medicine Foundation Research, Institute of Quantum Medicine, Quantum Life and Medicine Division, National Institutes for Quantum and Radiological Science and Technology (President: Shigeo Koyasu, hereinafter referred to as "QST"), to research and develop multiple new astatine therapeutic drugs targeting proteins (undisclosed) that are highly expressed in tumors (Press release, Alpha Fusion, JUL 21, 2023, View Source [SID1234647192]).

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For Alpha Fusion, this will be its second joint research partner in Japan, following Osaka University, a national university corporation.

Targeted Alpha Therapy (TAT), which physically kills cancer cells by binding radioisotopes that emit alpha rays (alpha-emitting nuclides) to compounds that accumulate in cancer cells and injecting them intravenously into cancer patients, is currently attracting worldwide attention. Astatine is one of the alpha-emitting nuclides, and since its clinical usefulness has begun to be demonstrated in basic research and mass production technology is being established, it is expected to be put to practical use.

QST, which has multiple cyclotrons, is one of the world’s leading research institutes in nuclear medicine research, taking advantage of its strength in producing radioisotopes in-house. Director Zhang Ming-rong and his team have a track record of developing and manufacturing numerous nuclear medicine diagnostic and therapeutic drugs, and providing them for clinical research. In recent years, they have also been focusing on TAT drug discovery research using astatine, and have published many research results.

Through this joint research project, AlphaFusion will combine the strengths of QST’s basic research in TAT drug discovery with the strengths of its own TAT drug discovery research and development, further accelerating the development of original therapeutic drugs in the currently rapidly developing field of TAT.

Alpha Fusion will continue to collaborate with a wide range of research institutes and companies both in Japan and overseas, and continue to lead the world in astatine drug discovery.

On July 18, 2023 ENB Therapeutics, Inc., a biotechnology company pioneering a new and differentiated class of therapeutics targeting the endothelin B receptor (ETBR) inhibitor, reported that the company has completed enrollment of its international Phase 1 ENBOLDEN-101 trial investigating the safety and efficacy of lead product ENB-003 in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy (Press release, ENB Therapeutics, JUL 21, 2023, View Source [SID1234634070]). The Phase ½a study is a multicenter, open-label study conducted in the US and Australia and is comprised of two parts. Part 1 recruited 46 patients and was a dose-escalation study to determine the recommended dose for the Part 2 expansion phase of the study. The results of this study will be presented by ENB Therapeutics in a poster titled, "ENB-003, an ETBR antagonist, in combination with pembrolizumab for refractory advanced solid tumors: Topline data from the ENBolden-101 Phase 1B study" at the Immuno-oncology Summit which is being held August 7-9, 2023 in Boston, Massachusetts.

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ENB-003 in combination with pembrolizumab was well tolerated in the dose escalation study and demonstrated no DLTs across the 6 dosing cohorts. The most common treatment emergent adverse events irrespective of grade or causality included fatigue (28.2%), constipation (26.1%), abdominal pain (26.1%), nausea (23.9%), anemia 17.4%, diarrhea (17.4%). Serious adverse events, grade 3 and above considered possibly related to study treatment included fatigue (n=4), diarrhea (n=3), dyspnea (n=3) constipation (n=2), rash (n=2). 15 patients with evaluable disease were enrolled in cohorts 1-5 (ENB-003 dose range 150ug-1000ug) and 15 patients with evaluable disease were enrolled in the 6th cohort (ENB-003 dose 2000ug). The dosing frequency for cohort 6 was doubled to 6 doses every 3 weeks from 6 doses every 6 weeks in cohort 1-5. The DCR across all cohorts irrespective of ETBR status was 33% (1 PR, 9 SD, 20 PD). The DCR in ETBR-Hi patients was 33% in cohorts 1-5 (4 SD, 1 PR, 10 PD) and 83% in cohort 6 (5 SD, 1 PD). The DCR for ETBR-Lo patients in cohort 6 was 0% (9 PD). ETBR-Lo patients were not enrolled in cohorts 1-5. For microsatellite stable (MSS) platinum refractory/ resistant ovarian cancer there was an 80% DCR across all cohorts (1 PR, 3 SD, 1 PD) with a trend for durable responses at higher doses of ENB-003. A platinum refractory MSS ovarian cancer patient experienced a 95% PR of 12-month duration. The sample size was not powered for statistical significance.

"The completion of enrollment of the Phase 1 ENBOLDEN-101 first-in-man study is a significant milestone for our Company. We are extremely encouraged by the results in heavily treated cancer patients refractory to standard of care treatment," stated Sumayah Jamal, MD-PhD, President, Chief Scientific Officer and Co-Founder of ENB Therapeutics. "Our data suggest potential efficacy in patients that do not historically respond to immunotherapy and support further clinical development. We are grateful to our patients and their families for their participation in our study. "

Part 2 is a dose expansion study at the recommended dose designed to evaluate the safety, tolerability and efficacy of ENB-003 in combination with pembrolizumab in cancers refractory to standard of care including MSS R/R ovarian cancer, MSS pancreatic cancer, anti-PD1 refractory HNSCC, anti-PD1 refractory melanoma and anti-PD1 refractory TNBC. For more information on this Phase 1/2a study, see NCT04205227.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

About ENB-003

ENB-003 is a selective endothelin B receptor (ETBR) inhibitor that, in preclinical studies, enhances efficacy of CAR-T and anti-PD-1 in solid tumors across multiple cancer types in preclinical studies. In an ongoing multi-center Phase 1/2 clinical trial, early efficacy signals suggest that ENB-003 overcomes resistance to the anti-PD-1 therapy KEYTRUDA (pembrolizumab) in heavily pre-treated drug resistant cancer patients. The Phase 2 portion of the ENB-003 + pembrolizumab combination study is expected to start in the first half of 2024. The trial will enroll microsatellite stable platinum refractory and primary platinum resistant ovarian cancer patients, as well as microsatellite stable pancreatic cancer patients that have failed standard of care.

On July 21, 2023 BeiGene (Nasdaq: BGNE; HKEX: 06160; SSE: 688235), a global biotechnology company, reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending approval for tislelizumab as monotherapy for the treatment of adult patients with unresectable, locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) after prior platinum-based chemotherapy.

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"Tislelizumab is the first medicine to come from BeiGene’s immuno-oncology research program and our team partnered with patients, caregivers, and clinical researchers across the world to generate the evidence supporting this CHMP recommendation," said Lai Wang, Ph.D., Global Head of R&D at BeiGene. "We continue to make progress in our mission to bring the highest quality therapies to more people around the world and look forward to working with Novartis and health authorities on regulatory filings for tislelizumab."

The Marketing Authorization Application (MAA) for ESCC is based on results from BeiGene’s RATIONALE 302, a global, randomized, open-label, Phase 3 study (NCT03430843) to investigate the efficacy and safety of tislelizumab when compared with investigator’s choice chemotherapy as a second-line treatment for patients with unresectable, locally advanced or metastatic ESCC. The study enrolled 513 patients from 132 research sites in 11 countries in Asia, Europe, and North America. The study met its primary endpoint with a statistically significant and clinically meaningful survival benefit for tislelizumab compared with chemotherapy (HR 0.70 [95%CI 0.57 – 0.85]; one-sided P=.0001; median overall survival 8.6 vs 6.3 months). The safety profile for tislelizumab was consistent with previous trials.i The MAA included safety data for 1,972 patients who received tislelizumab monotherapy in seven clinical trials.

Tislelizumab is not currently authorized for use in Europe.

About ESCCii
Globally, esophageal cancer (EC) is the sixth most common cause of cancer-related deaths and ESCC is the most common histologic subtype, accounting for more than 85% of ECs. An estimated 957,000 new EC cases are projected in 2040, an increase of nearly 60% from 2020 that underscores the need for additional effective treatments.

About Tislelizumab

Tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody specifically designed to minimize binding to Fc-gamma (Fcγ) receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors. In pre-clinical studies, binding to Fcγ receptors on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells.

In 2021, BeiGene and Novartis announced a collaboration agreement to jointly develop tislelizumab in the United States, Canada, Mexico, member countries of the European Union, United Kingdom, Norway, Switzerland, Iceland, Liechtenstein, Russia, and Japan. Under the agreement Novartis is responsible for regulatory submission and has the right to commercialize in these licensed countries following regulatory approval.

The EMA is reviewing a MAA for tislelizumab as a treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy, and in combination with chemotherapy for previously untreated locally advanced or metastatic NSCLC. Regulatory submissions for tislelizumab are also under review by authorities in the U.S., U.K., Australia, China, New Zealand, Brazil, Korea, and Switzerland.

More than 12,000 patients from across the world have participated in the tislelizumab development program that encompasses 21 registration-enabling clinical trials in more than 30 countries and regions. To date, BeiGene has announced positive readouts from 10 Phase 3 pivotal studies across multiple tumor types and disease settings such as NSCLC, Small Cell Lung Cancer, Gastric Cancer, ESCC, Hepatocellular Cancer, and Nasopharyngeal Cancer. More information on the clinical trial program for tislelizumab can be found at: View Source

On July 21, 2023 Novocure (NASDAQ: NVCR) reported the results of a pre-specified interim analysis for the phase 3 PANOVA-3 clinical trial evaluating the safety and efficacy of Tumor Treating Fields (TTFields) therapy together with nab-paclitaxel and gemcitabine for the treatment of patients with unresectable, locally advanced pancreatic cancer (Press release, NovoCure, JUL 21, 2023, View Source [SID1234633372]). An independent data monitoring committee (DMC) reviewed the safety and efficacy data for all patients in the fully enrolled clinical trial. The interim analysis resulted in a DMC recommendation that the clinical trial proceed to final analysis.

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"Completion of the interim analysis with the DMC’s recommendation to continue PANOVA-3 to completion marks another important step in pursuit of our mission to treat patients with difficult solid tumors of the abdomen," said Asaf Danziger, Novocure’s Chief Executive Officer. "I would like to express my thanks to our patients and investigators. We look forward to reviewing the PANOVA-3 data in 2024 and potentially extending the lives of patients diagnosed with deadly locally advanced pancreatic cancer by treating with our novel therapy, Tumor Treating Fields."

About PANOVA-3

PANOVA-3 is a randomized, open-label clinical trial designed to enroll 556 adult patients with unresectable, locally advanced pancreatic adenocarcinoma. Patients have been randomized to receive either the combination of nab-paclitaxel and gemcitabine concomitant with TTFields therapy tuned to 150 kHz until progression or the combination of nab-paclitaxel and gemcitabine alone. The primary endpoint is overall survival. Secondary endpoints include progression free survival, local progression free survival, objective response rate, one-year survival rate, quality of life, pain-free survival, puncture-free survival, resectability rate, and toxicity. Following enrollment of the final patient in February 2023, patients will be followed for a minimum of 18 months.

About Pancreatic Cancer

Pancreatic cancer is one of the most lethal cancers and is the third most frequent cause of death from cancer in the U.S. While overall cancer incidence and death rates are remaining stable or declining, the incidence and death rates for pancreatic cancer are increasing. It is estimated that approximately 53,000 patients are diagnosed with pancreatic cancer each year in the U.S. Pancreatic cancer has a five-year relative survival rate of just 10%.

Physicians use different combinations of surgery, radiation and pharmacological therapies to treat pancreatic cancer, depending on the stage of the disease. For patients with locally advanced pancreatic cancer involving encasement of arteries but no extra-pancreatic disease, the standard of care is surgery followed by chemotherapy with or without radiation. Unfortunately, the majority of locally advanced cases are diagnosed once the cancer is no longer operable, generally leaving chemotherapy with or without radiation as the only treatment option.

About Tumor Treating Fields Therapy

Tumor Treating Fields (TTFields) are electric fields that exert physical forces to kill cancer cells via a variety of mechanisms. TTFields do not significantly affect healthy cells because they have different properties (including division rate, morphology, and electrical properties) than cancer cells. The multiple, distinct mechanisms of TTFields therapy work together to selectively target and kill cancer cells. Due to its multimechanistic actions, TTFields therapy can be added to cancer treatment modalities in approved indications and demonstrates enhanced effects across solid tumor types when used with chemotherapy, radiotherapy, immune checkpoint inhibition, or PARP inhibition in preclinical models. TTFields therapy provides clinical versatility that has the potential to help address treatment challenges across a range of solid tumors. To learn more about Tumor Treating Fields therapy and its multifaceted effect on cancer cells, visit tumortreatingfields.com.