On January 27, 2025 AstraZeneca and Daiichi Sankyo reported that Enhertu (trastuzumab deruxtecan) has been approved in the US for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by a Food and Drug Administration (FDA)-approved test, that has progressed on one or more endocrine therapies in the metastatic setting (Press release, AstraZeneca, JAN 27, 2025, View Source [SID1234649894]).

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The approval was granted by the FDA after securing Priority Review and Breakthrough Therapy Designation and was based on results from the DESTINY-Breast06 Phase III trial, which were presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Meeting and published in The New England Journal of Medicine.

Aditya Bardia, MD, MPH, Program Director of Breast Oncology and Director of Translational Research Integration, UCLA Health Jonsson Comprehensive Cancer Center, US, and investigator in the DESTINY-Breast06 trial, said: "Endocrine therapy is typically used in the initial treatment of HR-positive metastatic breast cancer and following progression, subsequent chemotherapy is associated with poor outcomes. With a median progression-free survival exceeding one year and a response rate of more than 60 per cent, trastuzumab deruxtecan offers a potential new standard of care for patients with HR-positive, HER2-low or HER2-ultralow metastatic breast cancer following endocrine therapy."

Dave Fredrickson, Executive Vice President, Oncology Haematology Business Unit, AstraZeneca, said: "Building on the practice-changing previous approvals for Enhertu, this new approval brings this important medicine to an earlier treatment setting and a broader patient population with HER2-expressing metastatic breast cancer. The approval also highlights the importance of testing metastatic breast cancer tumours for detectable staining with a standard IHC test to identify those who may be eligible for treatment with Enhertu following endocrine therapy."

Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, said: "Enhertu continues to redefine the classification and treatment of HR-positive metastatic breast cancer with important new data across the spectrum of HER2 expression. Today’s approval underscores our ongoing commitment to realising the full potential of this innovative antibody drug conjugate and represents another paradigm shift in how certain breast cancers can be treated."

Krissa Smith, Vice President, Education, Susan G. Komen, said: "We are excited to see more treatment options for these patients which enable more personalised care. It is critical for patients to understand the HER2 status of their metastatic breast cancer to help them make informed treatment decisions. Patients with tumours that are HER2-low or HER2-ultralow now have more options to consider with their healthcare team."

In the trial, Enhertu showed a 36% reduction in the risk of disease progression or death versus chemotherapy (hazard ratio [HR] 0.64; 95% confidence interval [CI]: 0.54-0.76; p<0.0001) in the overall trial population of patients with chemotherapy-naïve HER2-low or HER2-ultralow metastatic breast cancer. A median progression-free survival (PFS) of 13.2 months was seen in patients randomised to Enhertu compared to 8.1 months in those randomised to chemotherapy. The confirmed objective response rate (ORR) in the overall trial population was 62.6% for Enhertu versus 34.4% for chemotherapy.

In an exploratory analysis of patients with HER2-ultralow expression, results were seen to be consistent between patients with HER2-low expression and HER2-ultralow expression.

HER2 status in the trial was confirmed by a central laboratory and was performed on a tumour sample obtained at the time of initial metastatic diagnosis or later. Approximately 85-90% of patients with HR-positive, HER2-negative metastatic breast cancer were determined to have actionable levels of HER2-expression.1 Further, nearly two-thirds of patients previously assessed as IHC 0 at a local laboratory were classified as HER2-low or HER2-ultralow upon central analysis of the tumour sample.1

The safety profile of Enhertu in DESTINY-Breast06 was consistent with previous clinical trials of Enhertu in breast cancer with no new safety concerns identified.

Enhertu is a specifically engineered HER2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

Enhertu is already approved in more than 70 countries, including the US, for patients with HER2-low metastatic breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial. Regulatory applications are under review in the EU, Japan and several other countries based on the DESTINY-Breast06 results.

Financial considerations
Following this approval for Enhertu in the US, an amount of $175m is due from AstraZeneca to Daiichi Sankyo as a milestone payment for the HER2-low and HER2-ultralow chemotherapy-naïve breast cancer indication. The milestone will be capitalised as an addition to the upfront payment made by AstraZeneca to Daiichi Sankyo in 2019 and subsequent capitalised milestones and will be amortised through the profit and loss statement.

Sales of Enhertu in the US are recognised by Daiichi Sankyo. AstraZeneca reports its share of gross profit margin from Enhertu sales in the US as Alliance Revenue in the Company’s financial statements.

Further details on the financial arrangements were set out in the March 2019 announcement of the collaboration.

Notes

Breast cancer and HER2 expression
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.2 More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally.2 In the US, more than 300,000 cases of breast cancer are diagnosed annually.3 While survival rates are high for those diagnosed with early breast cancer, only about 30% of patients diagnosed with or who progress to metastatic disease are expected to live five years following diagnosis.4

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including breast cancer.5 Patients with high levels of HER2 expression (IHC 3+ or 2+/ISH+) are classified as HER2-positive and treated with HER2-directed therapies, representing approximately 15-20% of all breast cancers.6 Historically, tumours that were not classified as HER2-positive were classified as HER2-negative.7

HR-positive, HER2-negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers.4 Endocrine therapies are widely given consecutively in the early lines of treatment for HR-positive metastatic breast cancer. However, after initial treatment, further efficacy from endocrine therapy is often limited.8 The current standard of care following endocrine therapy is chemotherapy, which is associated with poor response rates and outcomes.8-11

Despite being classified as HER2-negative, many of these tumours may still carry some level of HER2 expression.7 Prior to the approvals of Enhertu in HER2-low or HER2-ultralow metastatic breast cancer based on the DESTINY-Breast04 and DESTINY-Breast06 trials, there were no targeted therapies specifically approved for these patient populations.12,13

DESTINY-Breast06
DESTINY-Breast06 is a global, randomised, open-label, Phase III trial evaluating the efficacy and safety of Enhertu (5.4mg/kg) versus investigator’s choice of chemotherapy (capecitabine, paclitaxel or nab-paclitaxel) in patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) advanced or metastatic breast cancer. Patients in the trial had no prior chemotherapy for advanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastatic setting. Patients were also eligible if they had received one prior line of endocrine therapy combined with a CDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of starting 1st-line treatment or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months.

The primary endpoint is PFS in the HR-positive, HER2-low patient population as measured by blinded independent central review (BICR). Key secondary endpoints include PFS by BICR in the overall trial population (HER2-low and HER2-ultralow), overall survival (OS) in the HER2-low patient population and OS in the overall trial population. Other secondary endpoints include ORR, duration of response, time to first subsequent treatment or death, time to second subsequent treatment or death and safety.

DESTINY-Breast06 enrolled 866 patients (n=713 for HER2-low and n=153 for HER2-ultralow) in Asia, Europe, Australia, North America and South America. For more information about the trial, visit ClinicalTrials.gov.

Enhertu
Enhertu is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Enhertu (5.4mg/kg) is approved in more than 75 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC 3+ or in-situ hybridisation [ISH]+) breast cancer who have received a (or one or more) prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial.

Enhertu (5.4mg/kg) is approved in more than 75 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.

Enhertu (5.4 mg/kg) is approved in the US for adult patients with unresectable or metastatic HR-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting based on the results from the DESTINY-Breast06 trial.

Enhertu (5.4mg/kg) is approved in more than 50 countries worldwide for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumours have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in China and the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Continued approval in China for this indication will depend on whether a randomised controlled confirmatory clinical trial can demonstrate clinical benefit in this population.

Enhertu (5.4mg/kg) is approved in the US, Russia, Israel and Brazil for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumours who have received prior systemic treatment and have no satisfactory alternative treatment options based on the results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication in the US may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu development programme
A comprehensive global clinical development programme is underway evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers. Trials in combination with other anti-cancer treatments, such as immunotherapy, also are underway.

On January 27, 2025 Lantern Pharma Inc. (NASDAQ: LTRN), an artificial intelligence (AI) company dedicated to developing cancer therapies and transforming the cost, pace, and timeline of oncology drug discovery and development, reported advancements in the application of its RADR AI platform to accelerate and optimize the development of antibody-drug conjugates (ADCs) (Press release, Lantern Pharma, JAN 27, 2025, View Source [SID1234649893]). The global ADC market is projected to reach $30.4 billion by 2028, growing at a CAGR of 41.7%, with several recently approved ADCs achieving blockbuster status with annual sales exceeding $1 billion. Major biotech and pharmaceutical companies have recently completed ADC-focused acquisitions valued at over $10 billion, highlighting the sector’s growing strategic importance. Lantern Pharma is actively advancing multiple ADC candidates through preclinical development, including a promising collaboration with the prestigious MAGICBULLET::Reloaded Initiative at the University of Bielefeld in Germany.

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In a peer-reviewed study published in PLOS ONE, Lantern Pharma researchers demonstrated how their AI-driven approach successfully identified 82 promising ADC targets and 290 target-indication combinations, while also validating 729 potential payload molecules from a screening of over 50,000 compounds. Notably, 22 of these targets have already been validated in clinical or preclinical settings, demonstrating the platform’s ability to identify clinically relevant targets. The remaining 60 novel targets represent significant potential for new intellectual property, portfolio development of ADC candidates at Lantern Pharma and licensing opportunities with other biotech and pharma companies. The ADC module helped to characterize payload molecules with exceptional potency, exhibiting GI50 values from picomolar to 10 nM (nanomolar) ranges. These payload molecules can be further optimized by leveraging RADR’s comprehensive molecular features database by mapping drug-response relationships with biochemical and molecular structure characteristics. This AI-driven optimization capability could potentially enhance both the selective targeting and therapeutic window of these ADC payload candidates. Lantern Pharma continues to advance the methods and automations outlined in the paper as part of it’s RADR AI platform and further enhance the data and computational precision of the module.

"This breakthrough demonstrates how AI can transform the traditionally costly and time-consuming process of ADC development," said Panna Sharma, CEO & President of Lantern Pharma. "By simultaneously analyzing multiple data types and integrating mutation profiles with target expression, our team was able to identify optimal therapeutic combinations that have the potential to be more effective and safer for specific patient populations. We believe that our data-driven and machine-learning ready approach could reduce ADC development timelines by 30 to 50% and cut associated costs by up to 60% compared to traditional methods of ADC development."

The research leverages Lantern’s proprietary RADR platform to analyze complex datasets including transcriptomics, proteomics, and mutation profiles across 22 tumor types. The platform’s ability to predict mutation-specific responses could enable more precise patient stratification in clinical trials, potentially increasing success rates and reducing development costs. This precision approach to ADC development could be valuable for biotech and pharmaceutical companies looking to advance their ADC portfolio in more targeted indications and is also being actively used by Lantern in the development and modeling of their ADC candidates in preclinical testing and optimization.

"The implications of this research extend far beyond just expanding the repertoire of potential ADC targets," said Kishor Bhatia, Ph.D., Chief Scientific Officer at Lantern Pharma. "By leveraging our RADR platform’s advanced AI capabilities, we’ve created a systematic approach that could dramatically reduce both the time and cost of ADC development while increasing the probability of clinical success. Our platform is particularly well-suited for partnership opportunities with pharmaceutical companies looking to accelerate their ADC programs or expand their pipeline with novel targets."

Key Highlights of the AI-powered ADC module include:

Demonstrated platform validation through the successful identification of 22 clinically proven targets with established therapeutic potential
Discovered 60 novel targets that present significant opportunities for new intellectual property development, portfolio expansion, and strategic licensing partnerships
Developed proprietary mutation-specific targeting capabilities that enable improved clinical trial design, enhanced precision in indication selection, and more accurate patient response predictions
Established a framework that could reduce ADC development costs by up to 60% and accelerate development timelines by 30-50% for both Lantern Pharma and its collaborators
Created a highly scalable, machine-learning ready approach that leverages the RADR AI platform to systematically evaluate thousands of potential tumor sub-types and indications
Designed a clear pathway to commercialization through strategic industry partnerships and collaborative development programs
The complete research paper, titled "Expanding the repertoire of Antibody Drug Conjugate (ADC) targets with improved tumor selectivity and range of potent payloads through in-silico analysis," is available in PLOS ONE at View Source The paper outlines the approach and initial data-sets used in the development of the AI-powered ADC development module which continues to be enhanced, and is being further validated by Lantern Pharma.

On January 27, 2025 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported that management will participate in the following investor conferences in February (Press release, ORIC Pharmaceuticals, JAN 27, 2025, View Source [SID1234649891]):

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Jones Research Precision Medicine Day – Participating in a fireside chat on Monday, February 3, 2025, at 12:30 p.m. ET

Guggenheim Securities SMID Cap Biotech Conference – Participating in a fireside chat on Wednesday, February 5, 2025, at 1:30 p.m. ET

Oppenheimer 35th Annual Healthcare Life Sciences Conference – Participating in a fireside chat on Tuesday, February 11, 2025, at 12:00 p.m. ET
Live webcasts of the discussions will be available through the investor section of the company’s website at www.oricpharma.com. Replays of the webcasts will be available for 90 days following the event.

On January 27, 2025 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported the U.S. Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) seeking approval of WELIREG (belzutifan), Merck’s oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, for the treatment of adult and pediatric patients (12 years and older) with advanced, unresectable, or metastatic pheochromocytoma and paraganglioma (PPGL) (Press release, Merck & Co, JAN 27, 2025, View Source [SID1234649890]). The sNDA is based on objective response rate (ORR) and duration of response (DOR) data from the Phase 2 LITESPARK-015 trial, which will be presented at an upcoming medical meeting. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of May 26, 2025.

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"Pheochromocytoma and paraganglioma are rare tumors that form in and around the adrenal glands, and currently, there are no approved therapies available in the U.S. for patients with this rare disease," said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. "Today’s U.S. filing acceptance demonstrates our commitment to advancing novel therapies, such as WELIREG, to help treat patients with certain rare oncologic diseases. We look forward to working with the FDA to potentially provide this critical option to these patients who urgently need new innovative therapies."

WELIREG is the first and only HIF-2α inhibitor therapy approved in the U.S. for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors (pNETs) not requiring immediate surgery, based on results from the Phase 2 LITESPARK-004 trial. WELIREG is also approved for certain adult patients with VHL disease-associated tumors in China and 16 additional countries around the world.

WELIREG is also approved in the U.S. and Canada for the treatment of adult patients with advanced RCC following a PD-1/PD-L1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI), based on results from the Phase 3 LITESPARK-005 trial.

Merck is investigating WELIREG in rare oncologic diseases, RCC and other tumor types through a broad clinical development program, including in Phase 2 and 3 trials evaluating WELIREG as monotherapy and in combination with other medicines.

About LITESPARK-015

LITESPARK-015 is an open-label, single-arm, multi-cohort Phase 2 trial (NCT04924075) evaluating the efficacy and safety of WELIREG monotherapy in patients with advanced PPGL (Cohort A1), pNETs (Cohort A2), VHL disease-associated tumors (Cohort B1), advanced gastrointestinal stromal tumors (Cohort C), or advanced solid tumors with HIF-2α-related genetic alterations (Cohort D). The primary endpoint is ORR per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by blinded independent central review (BICR). Secondary endpoints include DOR, time to response, disease control, progression-free survival, overall survival and safety. The trial enrolled an estimated 322 patients who received WELIREG 120 mg orally once daily.

About pheochromocytoma and paraganglioma

Pheochromocytoma and paraganglioma (PPGL) are rare adrenal tumors that can be caused by certain genetic syndromes or mutations. It is estimated that up to 2,000 new cases of PPGL are diagnosed each year in the U.S., and up to 52,800 new cases are diagnosed each year worldwide. Pheochromocytoma occur in the center of the adrenal gland, whereas paraganglioma occur in nerve tissue in the adrenal glands and near certain blood vessels and nerves. Up to 25% of PPGL cases are metastatic at diagnosis.

About WELIREG (belzutifan) 40 mg tablets, for oral use

Indications in the U.S.

Certain von Hippel-Lindau (VHL) disease-associated tumors

WELIREG (belzutifan) is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.

Advanced Renal Cell Carcinoma (RCC)

WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI).

Selected Safety Information for WELIREG

Warning: Embryo-Fetal Toxicity

Exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective.

Anemia

WELIREG can cause severe anemia that can require blood transfusion. Monitor for anemia before initiation of, and periodically throughout, treatment. Transfuse patients as clinically indicated. For patients with hemoglobin <8 g/dL, withhold WELIREG until ≥8 g/dL, then resume at the same or reduced dose or permanently discontinue WELIREG, depending on the severity of anemia. For life-threatening anemia or when urgent intervention is indicated, withhold WELIREG until hemoglobin ≥8 g/dL, then resume at a reduced dose or permanently discontinue WELIREG.

In LITESPARK-004 (N=61), decreased hemoglobin occurred in 93% of patients with VHL disease and 7% had Grade 3 events. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months).

The safety of erythropoiesis-stimulating agents (ESAs) for treatment of anemia in patients with VHL disease treated with WELIREG has not been established.

In LITESPARK-005 (n=372), decreased hemoglobin occurred in 88% of patients with advanced RCC and 29% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 16.6 months). Of the patients with anemia, 22% received transfusions only, 20% received ESAs only, and 12% received both transfusion and ESAs.

Hypoxia

WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization.

Monitor oxygen saturation before initiation of, and periodically throughout, treatment. For decreased oxygen saturation with exercise (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same or a reduced dose. For decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg) or when urgent intervention is indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening or recurrent symptomatic hypoxia, permanently discontinue WELIREG. Advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider.

In LITESPARK-004, hypoxia occurred in 1.6% of patients.

In LITESPARK-005, hypoxia occurred in 15% of patients and 10% had Grade 3 events. Of the patients with hypoxia, 69% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 months).

Embryo-Fetal Toxicity

Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman.

Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. WELIREG can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.

Adverse Reactions

In LITESPARK-004, serious adverse reactions occurred in 15% of patients, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each).

WELIREG was permanently discontinued due to adverse reactions in 3.3% of patients for dizziness and opioid overdose (1.6% each).

Dosage interruptions due to an adverse reaction occurred in 39% of patients. Those which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness.

Dose reductions due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reaction which required dose reduction was fatigue (7%).

The most common adverse reactions (≥25%), including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin (93%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%).

In LITESPARK-005, serious adverse reactions occurred in 38% of patients. The most frequently reported serious adverse reactions were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis (0.5%) and hemorrhage (0.5%).

WELIREG was permanently discontinued due to adverse reactions in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) were hypoxia (1.1%) and hemorrhage (0.5%).

Dosage interruptions due to an adverse reaction occurred in 39% of patients. Of the patients who received WELIREG, 28% were 65 to 74 years, and 10% were 75 years and over. Dose interruptions occurred in 48% of patients ≥65 years of age and in 34% of younger patients. Adverse reactions which required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%), and hemorrhage (2.2%).

Dose reductions due to an adverse reaction occurred in 13% of patients. Dose reductions occurred in 18% of patients ≥65 years of age and in 10% of younger patients. The most frequently reported adverse reactions which required dose reduction (≥1.0%) were hypoxia (5%) and anemia (3.2%).

The most common (≥25%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (88%), fatigue (43%), musculoskeletal pain (33%), increased creatinine (34%), decreased lymphocytes (34%), increased alanine aminotransferase (32%), decreased sodium (31%), increased potassium (29%), and increased aspartate aminotransferase (27%).

Drug Interactions

Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended.

Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A4 substrates, which may reduce the efficacy of these substrates or lead to therapeutic failures. Avoid coadministration with sensitive CYP3A4 substrates. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding.

Lactation

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with WELIREG and for 1 week after the last dose.

Females and Males of Reproductive Potential

WELIREG can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating treatment with WELIREG.

Use of WELIREG may reduce the efficacy of hormonal contraceptives. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.

Based on findings in animals, WELIREG may impair fertility in males and females of reproductive potential and the reversibility of this effect is unknown.

Pediatric Use

Safety and effectiveness of WELIREG in pediatric patients under 18 years of age have not been established.

On January 27, 2025 Lineage Cell Therapeutics, Inc. (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing allogeneic cell therapies for unmet medical needs, reported the closing of the second tranche of its previously announced registered direct offering of an aggregate of up to $66 million (Press release, Lineage Cell Therapeutics, JAN 27, 2025, View Source [SID1234649889]). The Company had previously received $24 million in gross proceeds at the closing of the first tranche in November 2024. Today, the Company received an additional $6 million in gross proceeds at the closing of the second tranche. In addition, the Company may receive up to an additional $36 million of gross proceeds upon the exercise in full on a cash basis of the clinical milestone-linked warrants issued in the offering.

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Lineage obtained shareholder approval of the issuance of the securities at the closing of the second tranche, in satisfaction of applicable NYSE American rules. Lineage shareholders approved the issuance of 7,894,737 common shares and accompanying warrant to purchase an aggregate of up to 7,894,737 common shares, at a combined purchase price of $0.76 per common share and accompanying warrant, to Broadwood Partners, L.P., an affiliate of Neal Bradsher, a member of Lineage’s board of directors. Such warrant is exercisable for one common share at an exercise price of $0.91 per common share commencing on May 21, 2025 and will expire on the earlier of (a) May 21, 2028 and (b) the 90th day following the date of the public disclosure of the intent to advance OpRegen (also known as RG6501) into a multi-center phase 2 or 3 clinical trial which includes a control or comparator arm, or if the date of such public disclosure occurs prior to May 21, 2025, then the 90th day following May 21, 2025.

The securities described above were offered and sold by Lineage in a registered direct offering pursuant to a "shelf" registration statement on Form S-3 (File No. 333-277758) filed with the Securities and Exchange Commission (the "SEC") on March 7, 2024, and which was declared effective by the SEC on May 14, 2024. The offering of the securities in the registered direct offering was made only by means of a base prospectus and a prospectus supplement that forms a part of the effective registration statement. A final prospectus supplement and the accompanying base prospectus relating to the offering were filed with the SEC and are available on the SEC’s website at www.sec.gov. Electronic copies of the final prospectus supplement and the accompanying base prospectus may also be obtained from H.C. Wainwright & Co., LLC, who served as the exclusive placement agent for the offering, at 430 Park Avenue, 3rd Floor, New York, NY 10022, by phone at (212) 856-5711 or e-mail at [email protected].

This press release shall not constitute an offer to sell or a solicitation of an offer to buy any of the securities described herein, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction.