On September 19, 2023 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global biotechnology company, reported that it has entered into an agreement with Novartis to regain worldwide rights to develop, manufacture, and commercialize TEVIMBRA (tislelizumab) (Press release, BeiGene, SEP 19, 2023, View Source [SID1234635240]).

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"We are excited to regain the global rights to TEVIMBRA, which enables us to build out our in-house solid tumor commercial capabilities and complements our deep pipeline presented at our recent R&D Day. With more than 12,000 patients enrolled in our TEVIMBRA global clinical trial program, we plan to rapidly accelerate our regulatory and development plans across a wider range of tumor types," said John V. Oyler, Co-Founder, Chairman and CEO of BeiGene. "BeiGene will continue to work with Novartis on development, regulatory and manufacturing priorities. Novartis will manufacture TEVIMBRA for many markets worldwide and explore its potential in combination with their oncology assets."

BeiGene has launched more than 20 potentially registration-enabling trials with TEVIMBRA, of which 10 Phase 3 randomized trials and four Phase 2 trials have already had positive readouts. Through these trials, TEVIMBRA has demonstrated its ability to safely deliver clinically meaningful improvements in survival benefits and quality of life for hundreds of thousands of cancer patients across a range of tumor types – in many cases, regardless of PD-L1 status – both as a monotherapy and in combination with other regimens. More than 750,000 patients have been prescribed TEVIMBRA to-date.

"TEVIMBRA is the backbone of our diverse solid tumor development pipeline focused on developing novel combination regimens with precision medicine targets – such as OX40, HPK1, and LAG3 – in our next wave immuno-oncology portfolio. It also nicely complements our diversified research portfolio, which includes additional modalities such as antibody drug conjugates and bispecific antibodies, many of which have blockbuster potential," said Mark Lanasa, M.D., Ph.D., Chief Medical Officer, Solid Tumors at BeiGene. "We are eager to continue to explore TEVIMBRA’s full potential to address unmet clinical needs around the world, including in combination with our deep and diverse solid tumor pipeline, which has over 20 immuno-oncology and targeted molecules that could be paired with TEVIMBRA to help more patients."

Terms of the Agreement
The parties mutually agreed to terminate the previous collaboration and license agreement entered into on January 11, 2021, and, pursuant to the new agreement, BeiGene regained full global rights to TEVIMBRA with no royalty payments due to Novartis. In addition, Novartis will provide transition services and support to BeiGene to enable key aspects of the TEVIMBRA development and commercialization plan to proceed without disruption, including manufacturing, regulatory, safety and clinical support. BeiGene has agreed to provide Novartis with ongoing clinical supply of TEVIMBRA to support its clinical trials.

Under the previous agreement, BeiGene and Novartis were jointly developing TEVIMBRA 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 was responsible for regulatory submissions and had the right to commercialize in these licensed countries following regulatory approval.

About TEVIMBRA (tislelizumab)
TEVIMBRA 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.

TEVIMBRA is currently under review by the U.S. Food and Drug Administration and the European Medicines Agency (EMA) for advanced or metastatic ESCC after prior chemotherapy. The EMA is reviewing a marketing authorization application for TEVIMBRA 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 TEVIMBRA are also under review by authorities in the U.K., Australia, China, New Zealand, Brazil, Korea, Switzerland, Israel and Indonesia. Tislelizumab is approved as a treatment in 11 indications in China and is the leading PD-1 inhibitor in the country.

The tislelizumab development program 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 September 19, 2023 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global biotechnology company, reported that the European Commission (EC) has approved TEVIMBRA (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 (Press release, BeiGene, SEP 19, 2023, View Source [SID1234635239]). Additionally, the U.S. Food and Drug Administration (FDA) accepted for review a Biologics License Application (BLA) for tislelizumab as a first-line treatment for patients with unresectable, recurrent, locally advanced, or metastatic ESCC.

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"We are excited to announce the European Commission approval and the FDA filing acceptance for tislelizumab, having recently regained full global rights to this important medicine. These are significant milestones for people with advanced or metastatic ESCC, as tislelizumab has been shown to deliver clinically meaningful survival benefit as monotherapy and in combination with chemotherapy in patients worldwide," said Mark Lanasa, M.D., Ph.D., Chief Medical Officer, Solid Tumors at BeiGene. "We are proud to bring this therapy to European patients and potentially to American patients and will continue to focus on ensuring that we develop tislelizumab to its full potential to address unmet clinical needs around the world."

BeiGene has launched more than 20 potentially registration-enabling trials with TEVIMBRA, of which 10 Phase 3 randomized trials and four Phase 2 trials have already had positive readouts. Through these trials, TEVIMBRA has demonstrated its ability to safely deliver clinically meaningful improvements in survival benefits and quality of life for hundreds of thousands of cancer patients across a range of tumor types – in many cases, regardless of PD-L1 status – both as a monotherapy and in combination with other regimens. More than 750,000 patients have been prescribed TEVIMBRA to-date.

"TEVIMBRA is the cornerstone of BeiGene’s solid tumor portfolio. We believe having full control of the development and commercialization of TEVIMBRA will allow us to rapidly accelerate our plans and reach more patients worldwide," said Josh Neiman, Chief Commercial Officer for North America and Europe at BeiGene. "We look forward to bringing TEVIMBRA to people living with advanced or metastatic ESCC, an aggressive disease with limited treatment options."

TEVIMBRA Receives European Commission Approval for the Treatment of Advanced or Metastatic ESCC

The EC approval follows the positive opinion of the Committee for Medicinal Products for Human Use and is based on positive results from BeiGene’s RATIONALE 302 study.

"The global RATIONALE 302 trial demonstrated the anti-PD-1 antibody tislelizumab prolonged the survival of patients with locally advanced or metastatic ESCC who had received prior systemic treatment, with no new safety signals identified," said Prof. Florian Lordick, Director and Professor of Oncology of the University Cancer Center Leipzig, Germany. "The approval of tislelizumab in Europe is a noteworthy moment for patients, their caregivers and their physicians, due to the existing unmet need for new treatment options."

RATIONALE 302 is a global, randomized, open-label, Phase 3 study (NCT03430843) designed to investigate the efficacy and safety of TEVIMBRA 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 Europe, Asia and North America.

RATIONALE 302 met its primary endpoint in the intention-to-treat population with a statistically significant and clinically meaningful survival benefit for TEVIMBRA compared with chemotherapy (HR 0.70 [95% CI: 0.57 – 0.85]; one-sided P=0.0001; median overall survival 8.6 vs 6.3 months). The safety profile for TEVIMBRA was consistent with previous trials.i The marketing authorization application included safety data for 1,972 patients who received TEVIMBRA monotherapy across seven clinical trials.

U.S. FDA Accepts Biologics License Application in First-Line Advanced ESCC

The FDA has assigned a target action date in the second half of 2024, under the Prescription Drug User Fee Act. The FDA application is supported by previously announced results from RATIONALE 306 (NCT03783442), a randomized, placebo-controlled, double-blind, global Phase 3 trial evaluating the efficacy and safety of tislelizumab in combination with chemotherapy as a first-line treatment in patients with advanced or metastatic ESCC.

The FDA also granted tislelizumab Orphan Drug Designation (ODD) for the treatment of previously untreated advanced or metastatic ESCC. The FDA’s ODD is granted to investigational therapies intended for the treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the U.S.ii

About ESCC
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.iii EC is a rapidly fatal disease, and more than two-thirds of the patients have advanced or metastatic disease at the time of diagnosis, with a median survival of eight to 10 months and an expected five-year survival rate of less than five percent.iv

About TEVIMBRA (tislelizumab)
TEVIMBRA 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.

TEVIMBRA is currently under review by the U.S. Food and Drug Administration (FDA) and received approval by the European Commission (EC) for advanced or metastatic esophageal squamous cell carcinoma (ESCC) after prior chemotherapy. The EMA is reviewing a marketing authorization application for TEVIMBRA 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 TEVIMBRA are also under review by authorities in the U.K., Australia, China, New Zealand, Brazil, Korea, Switzerland, Israel and Indonesia. Tislelizumab is approved as a treatment in 11 indications in China and is the leading PD-1 inhibitor in the country.

The tislelizumab development program 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 September 19, 2023 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leader in T-cell immunotherapy, leveraging its novel allogeneic Epstein-Barr virus (EBV) T-cell platform to develop transformative therapies for patients with cancer and autoimmune diseases, reported important progress related to the regulatory pathway for tabelecleucel (tab-cel) in the U.S (Press release, Atara Biotherapeutics, SEP 19, 2023, View Source [SID1234635237]).

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Following productive discussions between Atara and the U.S. Food and Drug Administration (FDA), the FDA and Atara are now aligned on analytical comparability between manufacturing process versions. This alignment supports Atara’s ability to pool the pivotal clinical trial data from different process versions in the Biologics License Application (BLA) submission.

Atara expects to submit the tab-cel BLA in Q2 2024, which will enable Atara to incorporate the latest tab-cel pivotal trial data from the ALLELE study into the BLA filing package.

"We are pleased with the FDA’s positive assessment and conclusion of comparability, and we look forward to progressing to the next stage of preparing our BLA submission for tab-cel," said Pascal Touchon, President and Chief Executive Officer of Atara. "Following this clarity, we can also continue to advance our U.S. partnership discussions with several parties, selecting the best possible partner to bring this potentially life-saving treatment to patients."

Tabelecleucel is an allogeneic, EBV-specific T-cell immunotherapy which targets and eliminates EBV-infected cells in an HLA-restricted manner. Epstein-Barr virus-positive post-transplant lymphoproliferative disease (EBV+ PTLD) is a rare, acute, and potentially deadly hematologic malignancy that occurs after transplantation when patient T-cell immune responses are compromised by immunosuppression. It can impact patients who have undergone solid organ transplant (SOT) or allogeneic hematopoietic cell transplant (HCT). Poor median survival of 0.7 months and 4.1 months for HCT and SOT, respectively, is reported in EBV+ PTLD patients for whom standard of care failed, underscoring the significant need for new therapeutic options.

Tabelecleucel is commercialized by Pierre Fabre in Europe as EBVALLO following European Commission marketing authorization in December 2022. In Europe, EBVALLO is indicated as a monotherapy for the treatment of adult and pediatric patients two years of age and older with relapsed or refractory EBV+ PTLD who have received at least one prior therapy. For solid organ transplant patients, prior therapy includes chemotherapy, unless chemotherapy is inappropriate.

On September 19, 2023 Otsuka Pharmaceutical Europe Ltd. (Otsuka) and Astex Pharmaceuticals, Inc. (Astex) reported that the European Commission (EC) has approved INAQOVI (oral decitabine and cedazuridine) as monotherapy for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for standard induction chemotherapy (Press release, Astex Pharmaceuticals, SEP 19, 2023, View Source [SID1234635236]). The EC decision applies to the European Economic Area (EEA), which includes the EU member states, Iceland, Liechtenstein and Norway. INAQOVI is the first and only oral hypomethylating agent licensed in the EEA in this patient population.

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The EC approval is based on the results from the Phase 3 ASCERTAIN clinical trial investigating the pharmacokinetic exposure equivalence of the novel oral fixed-dose combination versus intravenous (IV) decitabine in AML patients1. The ASCERTAIN study met its primary endpoint, with the orally administered decitabine and cedazuridine fixed-dose combination showing pharmacokinetic exposure equivalence to a standard 5-day regimen of IV decitabine using a two-cycle, cross-over study design. Safety findings for the fixed-dose combination of decitabine and cedazuridine were generally consistent with those anticipated for IV decitabine1.

The current treatment options for adults with AML range from hospital-administered IV chemotherapy infusions or, for those patients not eligible for chemotherapy, regimens based on parenterally administered hypomethylating agents, with treatment cycles typically extending for 5-7 days2. Fatigue can significantly restrict daily activities and impact a patient’s quality of life3. INAQOVI may provide both patients and physicians with an oral treatment option in this patient population.

On 10th June 2022, the European Medicines Agency (EMA) agreed to a Paediatric Investigation Plan for the oral decitabine and cedazuridine fixed-dose combination, representing an important milestone for the prospect of furthering clinical studies in children with AML.

About decitabine and cedazuridine fixed-dose combination (INAQOVI)

INAQOVI is an orally administered, fixed-dose combination of the approved hypomethylating agent (HMA), decitabine (35 mg), together with cedazuridine (100 mg), an inhibitor of cytidine deaminase4-6. By inhibiting cytidine deaminase in the gut and liver, the fixed-dose combination is designed to allow for oral daily administration of decitabine over 5 days in a given cycle to achieve comparable systemic exposure to IV decitabine administered with the same dosing regimen7.

In the Phase 3 ASCERTAIN study, a total of 89 AML patients were randomised 1:1 to receive INAQOVI (35 mg decitabine and 100 mg cedazuridine) orally in Cycle 1 and decitabine (20 mg/m2) intravenously in Cycle 2 (n=44) or the reverse sequence (n=45). Both INAQOVI and IV decitabine were administered once daily on Days 1 through 5 of the 28-day cycle. Starting with Cycle 3, all patients received INAQOVI orally once daily on Days 1 through 5 of each 28-day cycle until disease progression, death, or unacceptable toxicity6.

Primary endpoint results showed that patients receiving INAQOVI achieved pharmacokinetic exposure equivalence of 99.64% (90% CI: 91.23, 108.8) to IV decitabine given at 20 mg/m2 for 5-days with a similar pharmacodynamic activity. Secondary findings showed a Median Overall Survival of 7.9 months (95% CI: 5.9, 13.0) and a Complete Response rate of 21.8% at 7.95 months median follow up1.

The most common adverse drug reaction (≥ 20%) was thrombocytopenia. The most common serious adverse reactions (≥ 20%) were febrile neutropenia and pneumonia. Permanent discontinuation occurred in 14% of patients while on treatment. The most frequent adverse reaction resulting in permanent discontinuation was pneumonia (5%)6.

About acute myeloid leukaemia (AML)

AML is the most common form of acute leukaemia in adults8. The median age at diagnosis is approximately 70 years2. Within Europe, the incidence of AML is increasing, this may be attributed to the ageing population; AML incidence in Europe has risen from 3.48 in 1976 to 5.06 patients per 100,000 population in 20132. Across Europe and all age groups, AML is notably more common in males than in females2. The outlook for patients diagnosed with AML has improved over time due to improved care and treatment, however between the years of 2000 and 2007, 5-year survival for patients was just 17%.

On September 19, 2023 Aprea Therapeutics, Inc. (Nasdaq: APRE) ("Aprea", or the "Company"), a clinical-stage biopharmaceutical company focused on precision oncology through synthetic lethality, reported two poster presentations at the upcoming 2023 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) being held on October 11-15, 2023, in Boston, MA (Press release, Aprea, SEP 19, 2023, View Source [SID1234635235]).

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Aprea is in development with two assets. Its lead program is ATRN-119, a clinical-stage small-molecule ATR inhibitor being developed for solid tumor indications. It is currently in an ongoing Phase 1/2a trial; details for which can be found here: View Source The company’s second asset, ATRN-1051, is an oral, small-molecule WEE1 inhibitor; Aprea anticipates filing an IND submission in the fourth quarter of 2023.

Details of the poster presentations are as follows:

Poster #1
Title: First in Human phase 1/2a trial of a macrocyclic ATR inhibitor (ATRN-119) in patients with advanced solid tumors
Abstract #: C034
Session: Session C; Level 2, Exhibit Hall D
Date/Time: Saturday, October 14 | 12:30pm – 4:00 pm ET
Presenter: Nadeem Q Mirza, M.D., M.P.H., Aprea Therapeutics, Inc.

Poster #2
Title: The DNA replication checkpoint inhibitors, ATRN-1051 (WEE1i) and ATRN-119 (ATRi), are potentially well-tolerated and effective cancer treatments
Abstract #: C147
Session: Session C; Level 2, Exhibit Hall D
Date/Time: Saturday, October 14 | 12:30pm – 4:00 pm ET
Presenter: Eric J. Brown, Ph.D., Perelman School of Medicine, University of Pennsylvania

In addition to the two poster presenters, Oren Gilad, Ph.D., President and Chief Executive Officer of Aprea, will be in attendance at the poster sessions and conference.