On December 22, 2023 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global biotechnology company, reported the U.S. Food and Drug Administration (FDA) has approved a label update for BRUKINSA (zanubrutinib) to include superior progression-free survival (PFS) results from the Phase 3 ALPINE trial comparing BRUKINSA against IMBRUVICA (ibrutinib) in previously treated patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) (Press release, BeiGene, DEC 22, 2023, View Source [SID1234638776]).

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"The ALPINE trial is the first and only study to demonstrate PFS superiority in a head-to-head comparison versus ibrutinib in CLL," said Mehrdad Mobasher, M.D., M.P.H., Chief Medical Officer, Hematology at BeiGene. "BRUKINSA was approved in the U.S. for CLL at the beginning of 2023, and we submitted additional data from the ALPINE PFS analysis supporting it as the BTK inhibitor of choice in CLL, solidifying it as an important treatment option for patients. When making treatment decisions, it is critical that physicians and patients understand the totality of data supporting BRUKINSA’s robust efficacy and differentiated safety in CLL."

The updated label is based on a prespecified analysis of the ALPINE trial, which demonstrated superior efficacy and a favorable cardiac safety profile for BRUKINSA versus ibrutinib in patients with R/R CLL and was presented in a late-breaking session at the 64th Annual American Society for Hematology (ASH) (Free ASH Whitepaper) Meeting and Exposition and published simultaneously in The New England Journal of Medicine. The updated label includes data at a median follow-up of 31 months, in which BRUKINSA demonstrated superior PFS compared with ibrutinib in patients with R/R CLL (HR: 0.65 [95% CI, 0.49-0.86] P=.0024, for both investigator and independent review committee). Additionally, BRUKINSA demonstrated a favorable cardiac safety profile with significantly lower rates of atrial fibrillation/flutter (5.2% vs. 13.3%) and zero deaths due to cardiac disorders with BRUKINSA versus six with ibrutinib (0% vs. 1.9%).

Please see Important Safety Information below.

At the recent 65th Annual ASH (Free ASH Whitepaper) Meeting and Exposition, BeiGene presented extended follow-up data from the ALPINE trial at a median follow-up of 39 months. The data demonstrate that BRUKINSA continues to show sustained PFS benefit versus ibrutinib (HR: 0.68 [95% CI, 0.53-0.86] P=0.0011) among R/R CLL patients receiving more than three years of treatment, with durable PFS benefits observed across subgroups, including patients with 17p deletion or TP53 mutation (HR: 0.52 [95% CI, 0.33-0.83] P=0.0047). PFS benefit is consistent across multiple sensitivity analyses, demonstrating that PFS advantage with BRUKINSA was primarily driven by efficacy and not tolerability. The overall safety and tolerability profile was consistent with previous ALPINE analyses, including persistently lower rates of cardiovascular events reported with BRUKINSA. The most commonly reported treatment emergent adverse events (≥20%) with BRUKINSA were COVID-19-related, neutropenia, hypertension, and upper respiratory tract infection.

BRUKINSA is approved in more than 65 countries, including the U.S., China, EU, Great Britain, Canada, Australia, South Korea, and Switzerland, in selected indications and under development for additional indications globally. In the U.S., BRUKINSA is approved for the treatment of adult patients with CLL or small lymphocytic lymphoma, Waldenström’s macroglobulinemia, mantle cell lymphoma who have received at least one prior therapy, and relapsed or refractory marginal zone lymphoma who have received at least one anti-CD20-based regimen. The global BRUKINSA development program includes more than 5,000 subjects enrolled to date in 29 countries and regions.

About Chronic Lymphocytic Leukemia (CLL)
A life-threatening cancer of adults, CLL is a type of mature B-cell malignancy in which abnormal leukemic B lymphocytes (a type of white blood cells) arise from the bone marrow and flood peripheral blood, bone marrow, and lymphoid tissues.i,ii CLL is the most common type of leukemia in adults, accounting for about one-quarter of new cases of leukemia.ii,iii Approximately 18,740 new cases of CLL will be diagnosed in the United States in 2023.iii

About BRUKINSA (zanubrutinib)
BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared with other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease relevant tissues.

U.S. Indications and Important Safety Information for BRUKINSA (zanubrutinib)

INDICATIONS
BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with:

Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
Waldenström’s macroglobulinemia (WM)
Mantle cell lymphoma (MCL) who have received at least one prior therapy
Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen
The MCL and MZL indications are approved under accelerated approval based on overall response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Hemorrhage
Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher hemorrhage, including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 3.6% of patients treated with BRUKINSA monotherapy in clinical trials, with fatalities occurring in 0.3% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 30% of patients.

Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Coadministration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections
Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 24% of patients, most commonly pneumonia (11%), with fatal infections occurring in 2.9% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia, and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias
Grade 3 or 4 cytopenias, including neutropenia (22%), thrombocytopenia (8%) and anemia (7%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy. Grade 4 neutropenia occurred in 11% of patients, and Grade 4 thrombocytopenia occurred in 2.8% of patients.

Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted. Treat using growth factor or transfusions, as needed.

Second Primary Malignancies
Second primary malignancies, including non-skin carcinoma, have occurred in 13% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer reported in 7% of patients. Other second primary malignancies included malignant solid tumors (5%), melanoma (1.2%), and hematologic malignancies (0.5%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

Cardiac Arrhythmias
Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 3.7% of 1550 patients treated with BRUKINSA monotherapy, including Grade 3 or higher cases in 1.7% of patients. Patients with cardiac risk factors, hypertension and acute infections may be at increased risk. Grade 3 or higher ventricular arrhythmias were reported in 0.2% of patients.

Monitor for signs and symptoms of cardiac arrhythmias (e.g. palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately, and consider the risks and benefits of continued BRUKINSA treatment.

Embryo-Fetal Toxicity
Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse Reactions
In this pooled safety population, the most common adverse reactions, including laboratory abnormalities, in ≥30% of patients who received BRUKINSA (N=1550) included decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), and musculoskeletal pain (30%).

Drug Interactions
CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For coadministration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers: Avoid coadministration with strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate CYP3A inducers.

Specific Populations
Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

Please see full U.S. Prescribing Information and U.S. Patient Information.

On December 22, 2023 Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, "Astellas") reported that it has completed the acquisition of Propella Therapeutics, Inc. (President and CEO: William Moore, "Propella"), and has become a wholly owned subsidiary of Astellas as of U.S. Eastern Time December 21, 2023 (Press release, Astellas, DEC 22, 2023, View Source [SID1234638743]).

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Through the acquisition of Propella, Astellas has acquired PRL-02 (abiraterone decanoate), a next-generation androgen biosynthesis inhibitor being developed by Propella to treat prostate cancer. PRL-02 is a novel, long-acting prodrug* of abiraterone that, following intramuscular injection, is expected to achieve high concentrations in target tissues where the active moiety, abiraterone, is continuously released. PRL-02 may provide improved efficacy and safety compared to existing treatment options by high CYP17 lyase inhibition selectivity. PRL-02 is currently in a Phase 1 clinical trial and is expected to enter Phase 2a clinical trials in 2024.

Under the agreement, Astellas paid approximately US $175 million to acquire all of the outstanding common stock and equity interests in Propella.

The impact of this transaction on Astellas’ financial results in the fiscal year ending March 31, 2024, will be limited.

On December 21, 2023 Exscientia plc (Nasdaq: EXAI) reported that Sanofi is adding a new discovery stage programme identified and initially advanced by Exscientia into the current collaboration (Press release, Exscientia, DEC 21, 2023, View Source [SID1234638770]). In this programme, Exscientia has designed a novel lead series with a potential best in class profile, with preliminary data showing good potency and selectivity towards the target and differentiated molecular properties.

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"Sanofi adding an Exscientia discovery stage programme into the collaboration speaks to the strengths of our AI-driven platform to solve complex drug discovery problems," said Professor Andrew Hopkins FRS FMedSci, founder and Chief Executive Officer of Exscientia. "The growth of our collaboration is a testament to our strong relationship with Sanofi and our shared vision for AI-enabled drug discovery. As we enter 2024, we expect to continue working with partners to apply our platform capabilities across therapeutic areas while maintaining our internal pipeline focus on high value oncology targets."

Under the terms of the amended agreement, Exscientia is eligible for up to $45 million in upfront and preclinical milestone payments. Exscientia will also be eligible for additional development, regulatory and sales-based milestone payments of over $300 million and tiered royalties on product sales ranging from high-single-digits to mid-teens, as described in the original collaboration agreement. The upfront payment is expected to be reflected in the first quarter 2024 results for Exscientia as cash inflows from collaborations and recognised as revenue over the duration of the agreement.

On December 21, 2023 Natera, Inc. (NASDAQ: NTRA), a global leader in cell-free DNA testing, reported a new study published in Molecular Oncology comparing the performance of mean tumor molecules per milliliter (MTM/mL) against mean variant allele frequency (mVAF) for measuring circulating tumor DNA (ctDNA), using Signatera, Natera’s personalized and tumor-informed molecular residual disease (MRD) test (Press release, Natera, DEC 21, 2023, View Source [SID1234638769]). The full study can be found here.

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To date, mVAF and MTM/mL are the two main metrics that have been used to quantify ctDNA levels in the blood. Unlike mVAF, which is a fraction that can be confounded by changes in total background cfDNA, MTM/mL takes into account total cfDNA as well as plasma volume. The premise is that MTM/mL is therefore more representative of a patient’s true disease burden, a hypothesis that was validated in this study.

The study analyzed ctDNA data generated in 55,183 ctDNA-positive samples from 23,543 patients who underwent testing with Signatera for various cancer diagnoses, and it reported the correlation between MTM/mL and mVAF, as well as the correlations of each with patient outcomes.

Key findings include:

Among the 18,426 patients with longitudinal ctDNA measurements, 13.3% had discordant ctDNA trajectories (increase/decrease) when calculated using MTM/mL versus mVAF.
In patients with stage IV disease receiving immunotherapy (N=51), ctDNA dynamics measured in MTM/mL were more predictive of therapy response than those measured in mVAF, with a hazard ratio (HR) nearly 2x higher (MTM/mL HR 16, p<0.0001; mVAF HR 8.8, p<0.0001).
In a case study of a patient with metastatic triple-negative breast cancer, disease progression during systemic therapy was reflected in increasing MTM/mL values, while mVAF levels remained stable.
"We are pleased to see the publication of these important findings, in which MTM/mL provided a more accurate measure of ctDNA than mVAF, particularly for patients undergoing active therapy which can impact the levels of background cfDNA," said Minetta Liu, M.D., chief medical officer of oncology at Natera. "Clinicians need tools to enable reliable predictions of therapy response and clinical outcomes. As the only MRD test that uses MTM/mL, this study supports the utility of Signatera for ctDNA quantification, to measure treatment response at critical time points and inform decisions on how patients are managed."

About Signatera

Signatera is a personalized, tumor-informed, molecular residual disease test for patients previously diagnosed with cancer. Custom-built for each individual, Signatera uses circulating tumor DNA to detect and quantify cancer left in the body, identify recurrence earlier than standard of care tools, and help optimize treatment decisions. The test is available for clinical and research use and is covered by Medicare for patients with colorectal cancer, breast cancer (stage IIb and higher) and muscle invasive bladder cancer, as well as for immunotherapy monitoring of any solid tumor. Signatera has been clinically validated across multiple cancer types and indications, with published evidence in more than 50 peer-reviewed papers.

On December 21, 2023 ImmunoScape, a biotechnology company focused on next-generation T Cell receptor (TCR)-based immunotherapies, reported a partnership with the Experimental Drug Development Centre (EDDC), Singapore’s national platform for drug discovery and development hosted by the Agency for Science, Technology and Research (A*STAR) (Press release, immunoSCAPE, DEC 21, 2023, View Source [SID1234638768]).

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ImmunoScape’s core antigen-specific T cell immune profiling technology was developed at A*STAR’s Singapore Immunology Network and is exclusively licensed from A*STAR. Since its spinout from A*STAR in 2016, ImmunoScape has developed a cutting-edge, high-throughput, TCR discovery platform that produces a broad and emerging portfolio of novel, safe, and efficacious TCRs against solid tumors.

In this new partnership, ImmunoScape will leverage its catalog of highly potent tumor-specific TCR candidates for the joint development of innovative off-the-shelf TCR-based bispecific molecules with EDDC. These molecules contain two distinct binding sites and are engineered to bind and activate T cells, redirecting them towards tumor sites for interaction with cells expressing the unique tumor-specific antigen through the TCR. This approach enables the patient’s own T cell repertoire to selectively eliminate cancer cells. EDDC will apply its expertise in therapeutic protein design and antibody engineering to develop these novel TCR-based bispecific molecules.

"The benefit of off-the-shelf TCR molecules is that they do not require engineering and manufacturing of the patients’ own T cells, which can make them accessible to a much broader patient population and further results in much lower production costs and shorter timelines for the patients to receive the drug," said Choon-Peng Ng, CEO of ImmunoScape. "By combining the power of our machine learning-augmented TCR discovery platform with EDDC’s broad expertise in the design of multifunctional constructs, we will aim to rapidly develop novel off-the-shelf TCR-based bispecific molecules that could overcome widespread challenges in cell therapy approaches against solid tumors."

"We are thrilled to join forces with ImmunoScape to design and produce TCR-based bispecific constructs that could lead to more effective treatments for solid tumors," said Damian O’Connell, CEO of EDDC. "Our deep expertise in progressing projects from discovery and production of antibodies to the design of multifunctional constructs, paired with ImmunoScape’s TCR discovery platform and library of tumor-specific TCRs, will allow us to jointly develop molecules for sensitive and effective tumor targeting in a T cell-independent manner."

The collaboration is set to commence in early 2024.