On September 19, 2023 Heidelberg Pharma AG (FSE: HPHA) reported that the clinical Phase I/IIa study with the lead development candidate HDP-101 has already started to recruit patients for the fifth patient cohort with a dosing of 100 µg/kg (Press release, Heidelberg Pharma, SEP 19, 2023, View Source [SID1234635242]). The Safety Review Committee’s (SRC) evaluation of patient data concluded that no dose-limiting toxicities have occurred to date. The first four dose levels have shown to be safe and well tolerated. So far 12 patients have been treated in the trial.

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With the expansion of study sites this summer, patient enrollment has significantly accelerated. One patient from the third cohort has now been on HDP-101 monotherapy for over nine months and has been treated with eleven doses.

Dr. András Strassz, Chief Medical Officer of Heidelberg Pharma, commented: "We are delighted that our first Amanitin-based antibody drug conjugate HDP-101 is well tolerated and does not show any dose-limiting toxicities to date. The dose escalation will continue as planned with the fifth cohort."

The BCMA antibody Amanitin conjugate HDP-101 is being tested in an open-label, multicenter study for the treatment of relapsed or refractory multiple myeloma, a cancer of the bone marrow.

About the Phase I/IIa study with HDP-101

The first part of the study is a Phase I dose escalation study to determine the maximum tolerated dose of HDP-101. These findings will be used to determine the dose for the Phase IIa part, the primary objective of which is to initially evaluate the anti-tumor activity of HDP-101.

The open-label, multicenter Phase I/IIa trial is expected to enroll up to 36 patients in the first part and up to 30 patients in the second part. Patients in Phase IIa will be stratified based on 17p deletion status. Preclinical data show that Amanitin has the potential to work particularly well on those tumors that have been genetically altered by a so-called 17p deletion to bypass a particular protective mechanism of cells. Patients with such a deletion generally respond less well to standard therapies and have a significantly poorer prognosis. Phase IIa will not only validate the efficacy of HDP-101 in patients with multiple myeloma, but also the clinical relevance of the 17p deletion.

On September 19, 2023 BioLineRx Ltd. (NASDAQ: BLRX) (TASE: BLRX), a commercial stage biopharmaceutical company pursuing life-changing therapies in oncology and rare diseases, reported that pilot phase data from an investigator-initiated, open-label, multicenter Phase 2 clinical trial with motixafortide in first-line pancreatic ductal adenocarcinoma (PDAC) will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Special Conference on Pancreatic Cancer taking place in Boston, Massachusetts, September 27-30, 2023 (Press release, BioLineRx, SEP 19, 2023, View Source [SID1234635241]). The Phase 2 clinical trial is designed to evaluate the company’s CXCR4 inhibitor motixafortide in combination with PD-1 inhibitor cemiplimab and standard of care chemotherapies gemcitabine and nab-paclitaxel, versus gemcitabine and nab-paclitaxel alone, in first-line pancreatic cancer (PDAC).

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Sponsored by Columbia University, the single-arm pilot phase of the Phase 2 trial focused on the safety of the drug combination. Additionally, based on the original protocol, if ≥3 of the planned 10 patients within the pilot phase experienced a partial response (PR) by RECIST criteria within 16 weeks, the combination would be considered promising and an expansion cohort of an additional 30 patients would be initiated for enrollment. Earlier this year, following a review of the pilot phase data, the trial was amended to become a randomized study, with planned enrollment increasing from 30 to 102 patients. A poster of the amended clinical trial design was presented at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, held June 2-6 in Chicago, Illinois (see abstract).

Presentation at AACR (Free AACR Whitepaper) Special Conference in Cancer Research: Pancreatic Cancer

Westin Copley Place, Boston Massachusetts

Plenary Session Details

Title: CheMo4METPANC: Combination Chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) Motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) in METastatic treatment-naïve PANCreatic adenocarcinoma

Presenter: Gulam A. Manji, MD, PhD, Columbia University Irving Medical Center/New York Presbyterian, New York, N.Y.

Session: Plenary Session 3: Clinical Updates

Date: Thursday, September 28, 2023

Time: 2:30-4:40 pm EDT

About Pancreatic Cancer

Pancreatic cancer has a low rate of early diagnosis and a poor prognosis. In the United States in 2023, an estimated 64,000 adults will be diagnosed with the disease, which accounts for approximately 3% of all cancers in the U.S. and about 7% of all cancer deaths. Worldwide, an estimated 496,000 people were diagnosed with the disease in 2020. In the U.S., if the cancer is detected at an early stage when surgical removal of the tumor is possible, the 5-year relative survival rate is 44%. About 12% of people are initially diagnosed at this stage. If the cancer has spread to surrounding tissues or organs, the 5-year relative survival rate is 15%. For the 52% of people who are initially diagnosed with metastatic cancer, the 5-year relative survival rate is 3%.[i] These data highlight the need for the development of new therapeutic options.

About Motixafortide in Cancer Immunotherapy

Motixafortide inhibits CXCR4, a chemokine receptor and a well validated therapeutic target that is over-expressed in many human cancers including pancreatic ductal adenocarcinoma (PDAC). Motixafortide leverages the expression of the CXCR4 receptor on different immune cells and potentiates the immune system against the tumor. Among CXCR4-expressing immune cells, some exhibit anti-tumoral activity, such as effector T cells and some exhibit pro-tumoral activity and support tumor growth. By blocking the CXCR4 receptor, motixafortide was shown in a Phase 2 study in pancreatic cancer patients to enhance anti-tumoral activity and to ameliorate the pro-tumoral activities by modulating the effector/suppressor cell ratio towards a proinflammatory profile.

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.