On July 17, 2024 Orion reported that the Phase III ARANOTE trial, investigating darolutamide plus ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC), has met its primary endpoint of rPFS (Press release, Orion, JUL 17, 2024, View Source [SID1234644909]). Darolutamide plus ADT significantly increased rPFS compared to placebo plus ADT. The safety data were comparable between both treatment arms and reconfirm the established tolerability profile of darolutamide in advanced prostate cancer.

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Darolutamide is already approved under the brand name Nubeqa for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC), who are at high risk of developing metastatic disease, and patients with metastatic hormone-sensitive prostate cancer (mHSPC, in combination with ADT and docetaxel).

"The results of the ARANOTE trial reconfirm that darolutamide, a compound discovered by Orion scientists, is a viable treatment option for patients with metastatic hormone-sensitive prostate cancer. In these patients, darolutamide has now shown efficacy with and without docetaxel, and thus, pending regulatory approval, can provide choices for the personalised treatment regime. I would like to thank all the patients and the investigators who participated in the ARANOTE trial," said Professor, M.D., Ph.D. Outi Vaarala, Senior Vice President of Innovative Medicines and Research & Development at Orion.

Detailed results of the ARANOTE trial are planned to be presented at a forthcoming scientific congress. Bayer plans to submit the data from the study to relevant global health authorities to support expanded use of darolutamide in men with mHSPC.

ARANOTE is part of a robust clinical development program investigating darolutamide across various stages of prostate cancer, which includes the Phase III ARASTEP trial evaluating darolutamide plus ADT versus ADT alone in hormone-sensitive high-risk biochemical recurrence (BCR) prostate cancer, who have no evidence of metastatic disease by conventional imaging and a positive PSMA PET/CT at baseline. Furthermore, darolutamide is also being investigated by Bayer in the collaborative Phase III DASL-HiCaP (ANZUP1801) trial led by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). The study evaluates darolutamide as an adjuvant treatment for localized prostate cancer with very high risk of recurrence.

About the ARANOTE trial
The ARANOTE trial is a randomized, double-blind, placebo-controlled Phase III study designed to assess the efficacy and safety of darolutamide plus ADT in patients with mHSPC. A total of 669 patients were randomized to receive 600mg of darolutamide twice daily or matching placebo in addition to ADT.

The primary endpoint of this study is rPFS, measured as time from randomization to date of first documented radiological progressive disease or death due to any cause, whichever occurs first. Secondary endpoints include overall survival (time to death from any cause), time to first castration-resistant event, time to initiation of subsequent anti-cancer therapy, time to prostate-specific antigen (PSA) progression, PSA undetectable rates, time to pain progression, and safety assessments.

About metastatic hormone-sensitive prostate cancer
Prostate cancer is the second most common cancer in men and the fifth most common cause of cancer death in men worldwide.1 In 2020, an estimated 1.4 million men were diagnosed with prostate cancer, and about 375,000 died from the disease worldwide.2

At the time of diagnosis, most men have localized prostate cancer, meaning their cancer is confined to the prostate gland and can be treated with curative surgery or radiotherapy. mHSPC is a stage in the disease where the cancer has spread outside of the prostate to other parts of the body. Up to 10% of men will already present with mHSPC when first diagnosed.3, 4, 5 For patients with mHSPC, ADT is the cornerstone of treatment, often in combination with chemotherapy docetaxel and/or an androgen receptor inhibitor (ARi). Despite treatment, most men with mHSPC will eventually progress to castration-resistant prostate cancer (CRPC), a condition with limited survival.

About darolutamide
Darolutamide is an oral ARi with a distinct chemical structure that binds to the androgen receptor with high affinity and exhibits strong antagonistic activity, thereby inhibiting the receptor function and the growth of prostate cancer cells. The low potential for blood-brain barrier penetration for darolutamide is supported by preclinical models and neuroimaging data in healthy humans. This is also supported by the overall low incidence of central nervous system (CNS)-related adverse events (AEs) compared to placebo as seen in the ARAMIS Phase III trial and the maintained verbal learning and memory observed in the darolutamide arm of the Phase II ODENZA trial.

Darolutamide is approved under the brand name Nubeqa in more than 85 countries around the world for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC), who are at high risk of developing metastatic disease. It is also approved in combination with ADT and docetaxel for the treatment of patients with mHSPC in over 80 markets including the U.S., Japan, EU, and China. The product is developed jointly by Orion and Bayer.

On July 16, 2024 Bayer reported that the Phase III ARANOTE trial, investigating NUBEQA (darolutamide) plus androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC), has met its primary endpoint of radiological progression-free survival (rPFS) (Press release, Bayer, JUL 16, 2024, View Source [SID1234644907]). NUBEQA plus ADT demonstrated a statistically significant and clinically meaningful increase in rPFS compared to placebo plus ADT.

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Results were consistent with NUBEQA’s established safety profile with no new signals observed. Detailed results from this randomized, double-blind, placebo-controlled trial are planned to be presented at a forthcoming scientific congress.

NUBEQA is currently indicated in the U.S. for the treatment of adult patients with mHSPC in combination with docetaxel and for the treatment of adult patients with non-metastatic castration-resistant prostate cancer (nmCRPC).1

"We are excited to share the positive results from this Phase III trial. Following potential regulatory approval, physicians will be able to tailor NUBEQA treatment plans with or without docetaxel based on individual patient’s needs," said Christian Rommel, Ph.D., Head of Research and Development at Bayer’s Pharmaceuticals Division. "Today’s results build on the established efficacy and tolerability profile of NUBEQA. We are looking forward to future outcomes of our clinical development program investigating the compound across multiple prostate cancer stages and indications."

Bayer plans to present the pivotal data at a forthcoming scientific conference and discuss these data with the U.S. FDA regarding submission for regulatory approval.

About the ARANOTE Trial

The ARANOTE trial (NCT04736199) is a randomized, double-blind, placebo-controlled Phase III study designed to assess the efficacy and safety of NUBEQA plus androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). 669 patients were randomized to receive 600mg of NUBEQA twice daily or matching placebo in addition to ADT.

The primary endpoint of this study is radiological progression-free survival (rPFS), as measured as the time from the date of randomization to the date of first documentation of radiological progressive disease or death due to any cause, whichever occurs first. Secondary endpoints include overall survival, time from randomization to the date of death from any cause, time from randomization to the date of first castration-resistant event, time to initiation of subsequent anti-cancer therapy, time to prostate-specific antigen (PSA) progression, PSA undetectable rates, time to pain progression, and safety assessments.

About NUBEQA (darolutamide)1

NUBEQA (darolutamide) is an androgen receptor inhibitor (ARi) with a distinct chemical structure that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription.

NUBEQA is being evaluated in a robust clinical development program, which includes studies across various stages of prostate cancer, including in the Phase III ARANOTE trial evaluating NUBEQA plus androgen deprivation therapy (ADT) versus ADT alone for mHSPC, the ARASTEP Phase III trial evaluating NUBEQA plus ADT versus ADT alone in HSPC patients with high-risk biochemical recurrence (BCR) and no evidence of metastatic disease by conventional imaging and a positive PSMA PET/CT at baseline, as well as in the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) led international Phase III co-operative group DASL-HiCaP (ANZUP1801) trial evaluating NUBEQA as an adjuvant treatment for localized prostate cancer with very high risk of recurrence. Information about these trials can be found at www.clinicaltrials.gov.

NUBEQA is currently indicated in the U.S. in combination with docetaxel and ADT for the treatment of adult patients with mHSPC and for the treatment of adult patients with non-metastatic castration-resistant prostate cancer (nmCRPC) with ADT.1

NUBEQA is developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company.

INDICATIONS

NUBEQA (darolutamide) is an androgen receptor inhibitor indicated for the treatment of adult patients with:

Non-metastatic castration-resistant prostate cancer (nmCRPC)
Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel
IMPORTANT SAFETY INFORMATION

NUBEQA (darolutamide) is an androgen receptor inhibitor indicated for the treatment of adult patients with:

Non-metastatic castration-resistant prostate cancer (nmCRPC)
Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel
IMPORTANT SAFETY INFORMATION

Warnings & Precautions

Ischemic Heart Disease – In a study of patients with nmCRPC (ARAMIS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA versus 2.5% receiving placebo, including Grade 3-4 events in 1.7% vs. 0.4%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA vs. 0.2% receiving placebo. In a study of patients with mHSPC (ARASENS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA with docetaxel vs. 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% vs. 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel vs. 0% receiving placebo with docetaxel. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue NUBEQA for Grade 3-4 ischemic heart disease.

Seizure – In ARAMIS, Grade 1-2 seizure occurred in 0.2% of patients receiving NUBEQA vs. 0.2% receiving placebo. Seizure occurred 261 and 456 days after initiation of NUBEQA. In ARASENS, seizure occurred in 0.6% of patients receiving NUBEQA with docetaxel, including one Grade 3 event, vs. 0.2% receiving placebo with docetaxel. Seizure occurred 38 to 340 days after initiation of NUBEQA. It is unknown whether antiepileptic medications will prevent seizures with NUBEQA. Advise patients of the risk of developing a seizure while receiving NUBEQA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of NUBEQA in patients who develop a seizure during treatment.

Embryo-Fetal Toxicity – Safety and efficacy of NUBEQA have not been established in females. NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with NUBEQA and for 1 week after the last dose.

Adverse Reactions

In ARAMIS, serious adverse reactions occurred in 25% of patients receiving NUBEQA vs. 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA included urinary retention, pneumonia, and hematuria. Fatal adverse reactions occurred in 3.9% of patients receiving NUBEQA vs. 3.2% of patients receiving placebo. Fatal adverse reactions in patients who received NUBEQA included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%). The most common adverse reactions (>2% with a ≥2% increase over placebo), including laboratory test abnormalities, were increased AST, decreased neutrophil count, fatigue, increased bilirubin, pain in extremity and rash. Clinically relevant adverse reactions occurring in ≥2% of patients treated with NUBEQA included ischemic heart disease and heart failure.

In ARASENS, serious adverse reactions occurred in 45% of patients receiving NUBEQA with docetaxel vs. 42% of patients receiving placebo with docetaxel. Serious adverse reactions in ≥2% of patients who received NUBEQA with docetaxel included febrile neutropenia (6%), decreased neutrophil count (2.8%), musculoskeletal pain (2.6%), and pneumonia (2.6%). Fatal adverse reactions occurred in 4% of patients receiving NUBEQA with docetaxel vs. 4% of patients receiving placebo with docetaxel. Fatal adverse reactions in patients who received NUBEQA included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%). The most common adverse reactions (≥10% with a ≥2% increase over placebo with docetaxel) were constipation, rash, decreased appetite, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (≥30%) were anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST, increased ALT, and hypocalcemia. Clinically relevant adverse reactions in <10% of patients who received NUBEQA with docetaxel included fractures, ischemic heart disease, seizures, and drug-induced liver injury.

Drug Interactions

Effect of Other Drugs on NUBEQA – Combined P-gp and strong or moderate CYP3A4 inducers decrease NUBEQA exposure, which may decrease NUBEQA activity. Avoid concomitant use.

Combined P-gp and strong CYP3A4 inhibitors increase NUBEQA exposure, which may increase the risk of NUBEQA adverse reactions. Monitor more frequently and modify NUBEQA dose as needed.

Effects of NUBEQA on Other Drugs – NUBEQA inhibits breast cancer resistance protein (BCRP) transporter. Concomitant use increases exposure (AUC) and maximal concentration of BCRP substrates, which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use where possible. If used together, monitor more frequently for adverse reactions, and consider dose reduction of the BCRP substrate.

NUBEQA inhibits OATP1B1 and OATP1B3 transporters. Concomitant use may increase plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor more frequently for adverse reactions and consider dose reduction of these substrates.

Review the Prescribing Information of drugs that are BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA.

For important risk and use information about NUBEQA, please see the accompanying full Prescribing Information.

About Metastatic Hormone-Sensitive Prostate Cancer

Prostate cancer is the second most common cancer in men and the fifth most common cause of cancer death in men worldwide.2 In 2020, an estimated 1.4 million men were diagnosed with prostate cancer, including almost 300,000 cases in the U.S., and about 375,000 died from the disease worldwide.3,4

At the time of diagnosis, most men have localized prostate cancer, meaning their cancer is confined to the prostate gland and can be treated with curative surgery or radiotherapy. Upon relapse when the disease will metastasize or spread, androgen deprivation therapy (ADT) is the cornerstone of treatment for this hormone-sensitive disease. Approximately 10% of men will already present with mHSPC when first diagnosed.5,6,7 Men with metastatic hormone-sensitive prostate cancer (mHSPC) will start their treatment with hormone therapy, such as ADT, androgen receptor inhibitor (ARi) plus ADT or a combination of the chemotherapy docetaxel and ADT. Despite this treatment, most men with mHSPC will eventually progress to castration-resistant prostate cancer (CRPC), a condition with limited survival.

On July 16, 2024 Orum Therapeutics ("Orum" or the "Company"), a clinical-stage private biotechnology company pioneering the field of degrader-antibody conjugates (DACs), reported a global, multi-target license and option agreement whereby it granted Vertex Pharmaceuticals ("Vertex") (Nasdaq: VRTX) rights to conduct research using Orum’s Dual-Precision Targeted Protein Degradation (TPD²) technology for the discovery of novel targeted conditioning agents for use with gene editing (Press release, Orum Therapeutics, JUL 16, 2024, View Source [SID1234644906]).

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Following the research period for each target, Vertex will have the option to obtain a worldwide, exclusive license to research, develop, manufacture, and commercialize DACs developed with Orum’s TPD² technology for that target. Under the terms of this agreement, Orum will receive an upfront payment of $15 million and is eligible to receive additional option payments and milestones potentially totaling up to $310 million per target for up to three targets, as well as tiered royalties on potential future global annual net sales. Vertex is responsible for all research, development, and commercialization.

"Vertex is a leader in discovering and developing innovative medicines, including being the first to receive FDA approval of a CRISPR/Cas9 gene-edited therapy, and we are pleased they’ve selected Orum’s TPD² technology to discover novel targeted conditioning agents," said Sung Joo Lee, Ph.D., CEO and founder of Orum Therapeutics. "This agreement with Vertex creates the potential to treat patients in a novel indication space with our leading targeted protein degradation approach for an exciting new therapeutic class of degrader-antibody conjugates."

On July 16, 2024 SOTIO Biotech, a clinical-stage biopharmaceutical company owned by PPF Group, and Biocytogen (HKEX: 02315), a global biotech company focused on the discovery of novel antibody therapeutics, reported a research collaboration and exclusive option and license agreement (Press release, Biocytogen, JUL 16, 2024, View Source [SID1234644905]).

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The agreement grants SOTIO the option to license multiple fully human bispecific antibodies generated with Biocytogen’s proprietary RenLite platform, which SOTIO will use to develop next-generation antibody-drug conjugates (ADCs) targeting solid tumors. The agreement also includes an option for SOTIO to leverage Biocytogen’s proprietary ADC platform. Biocytogen will be eligible to receive upfront, development, and commercial milestones and royalties on net sales on a product-by-product basis.

"SOTIO’s powerful ADC platform brings together multiple technologies, allowing us to tailor our therapeutics to meet the needs of specific cancer types. Specifically, exploiting bispecific targeting in the context of our ADC approaches to improve precision targeting and overcome tumor heterogeneity is particularly appealing," said Martin Steegmaier, Ph.D., chief scientific officer of SOTIO. "This agreement with Biocytogen complements our existing collaborations with Synaffix, LigaChem, and NBE-Therapeutics, providing SOTIO with access to fully human antibodies from Biocytogen’s state-of-the-art in vivo discovery platform. With the first targets for a bispecific program already selected, we are well-positioned to expand our ADC pipeline and the therapeutic possibilities for patients with solid tumors."

Under the terms of the agreement, Biocytogen is eligible to receive upfront and potential milestone payments worth up to $325.5 million, plus low single-digit royalties on net sales. SOTIO and Biocytogen will collaborate closely during the research phase of the bispecific programs. SOTIO will be responsible for non-clinical and clinical development, manufacturing, and commercialization of the ADC products.

"We are eager to deploy Biocytogen’s cutting-edge tools for antibody discovery to support SOTIO’s exciting ADC development plans," said Yuelei Shen, Ph.D., president and chief executive officer of Biocytogen. "Our unique RenMice platforms allow us to discover fully human antibodies with high affinity, low immunogenicity, and favorable developability. We look forward to working with SOTIO to advance novel therapeutics that have the potential to improve cancer treatment."

On July 16, 2024 Tempus AI, Inc. (NASDAQ: TEM), a leader in artificial intelligence and precision medicine, reported that its multimodal immune profile score (IPS) algorithmic test is now available for research use only (RUO) (Press release, Tempus, JUL 16, 2024, View Source [SID1234644904]). IPS is the first offering of a larger immunotherapy-based portfolio being developed at Tempus to bring next-generation algorithmic diagnostics to the immuno-oncology space. Additionally, Tempus is collaborating with other partners, like Cleveland Clinic, to bring additional immunotherapy-focused algorithmic tests to this growing portfolio, leveraging clinical, laboratory, genomic, and transcriptomic data to identify patients that may respond to immunotherapy.

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Tempus’ IPS is a pan-cancer, laboratory developed test (LDT) that assesses a combination of immunotherapy-related biomarkers from prior DNA and RNA test results to calculate an IPS from 0-100 and a classification of either IPS-Low or IPS-High. IPS results can support patient stratification across pan-cancer cohorts to help inform who may or may not respond to immunotherapy. The IPS test is available today to life sciences partners for research use only, and is intended to be available as an add-on option for clinicians ordering Tempus’ xT and xR at the end of the year. Tempus is performing a retrospective, real-world study to evaluate the prognostic and the predictive utility of IPS in advanced pan-cancer patients treated with immune checkpoint inhibitors (ICI) and will be releasing data later this year.

In addition to developing and launching IPS, Tempus has licensed a machine-learning-based algorithmic test developed by Timothy A. Chan, MD, PhD, Cleveland Clinic. As described in Nature Biotechnology, the test demonstrates an ability to predict the efficacy of immune checkpoint blockade based on patient-specific biological, laboratory, genomic, and clinical factors, and adds to our expanding immunotherapy specific biomarker portfolio.

"Immune checkpoint inhibitors continue to have an incredible impact on patient outcomes, and we are excited to continue building a portfolio of AI-enabled diagnostics and tools to better equip clinicians in understanding which patients may benefit from these kinds of therapies," said Halla Nimeiri, MD, Chief Development Officer at Tempus. "The IPS test is our first multimodal algorithm to be introduced in the immunotherapy space, and we are excited to advance this field by providing critical insights that inform patient care."

"It’s a great pleasure to collaborate with Tempus on developing artificial intelligence powered models for better identification of patients who may respond to cancer immunotherapies," said Timothy A. Chan, MD, PhD, Department Chair of Immunotherapy and Precision Oncology and Professor of Medicine at Cleveland Clinic. "We look forward to working together with Tempus to bring multimodal immunotherapy response prediction assays to patients."

Tempus’ AI-enabled platform generates the type of rich multimodal data required to develop a novel class of predictive algorithms that can be introduced in the clinic to support personalized patient treatment selection. The IPS and Cleveland Clinic immune response tests joins a growing suite of algorithmic tests offered by Tempus, including Homologous Recombination Deficiency (HRD), Tumor Origin (TO), dihydropyrimidine dehydrogenase (DPYD), and PurISTSM. Each of these tests is designed to predict specific biological signals or clinical endpoints, ultimately supporting clinicians and life science partners as they seek to make more informed decisions for patients.

For more information on IPS, reach out to Tempus at tempus.com/contact-us.