SLC35A2

Updated data from the Phase 3 MAGNITUDE study of niraparib in combination with abiraterone acetate plus prednisone in patients with metastatic castration-resistant prostate cancer will be featured RARITAN, N.J., Feb. 13, 2023 /PRNewswire/ -- The Janssen Pharmaceutical Companies of Johnson & Johnson today announced plans to present more than 20 abstracts featuring seven oncology therapies from its robust portfolio and pipeline at the annual American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium, taking place in San Francisco on February 16-18. Building on more than a decade of leadership in the development of medicines for people diagnosed with GU cancers, Janssen will present data demonstrating its ambition to advance patient-centered treatment through precision medicine, real-world evidence and innovative development approaches across all stages of prostate and bladder cancer. "At Janssen, we are focused on early intervention in prostate and bladder cancer and optimizing outcomes through treatment approaches based on the genetic profiles of tumors," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Janssen Research & Development, LLC. "Data featured at this year's ASCO GU reflect the cutting-edge therapies in our portfolio and pipeline and illustrate how Janssen's science is advancing our vision to eliminate cancer." "Despite advances in treatment over the past decade, we continue to see unmet needs across genitourinary cancers, especially for tumors with certain genetic mutations," said Luca Dezzani, M.D., U.S. Vice President, Medical Affairs, Solid Tumor, Janssen Scientific Affairs, LLC. "Presentations at this year's ASCO GU underscore our continuing commitment to addressing the needs of patients living with prostate and bladder cancer at all stages of their disease." Further information about these data and efforts across Janssen to advance the science of prostate and bladder cancer will be made available throughout ASCO GU via the Janssen Oncology Virtual Newsroom. Key highlights from Janssen-sponsored studies to be presented at ASCO GU include: Updated Data from the Phase 3 MAGNITUDE Study of Niraparib in Combination with Abiraterone Acetate Plus Prednisone (AAP) for the Treatment of Patients with BRCA-Positive Metastatic Castration-Resistant Prostate Cancer (mCRPC) Rapid Oral Presentation: A presentation will highlight data from the second interim analysis of the Phase 3 MAGNITUDE study evaluating niraparib in combination with AAP for the treatment of patients with mCRPC with specific homologous recombination repair (HRR) gene alterations, in particular BRCA mutations (Abstract #170).1 Poster Presentation: An additional analysis from MAGNITUDE will review the impact of run-in treatment with AAP on the safety and efficacy of niraparib in combination with AAP to determine if the combination improved outcomes in patients with HRR genetic alterations, in particular BRCA mutations (Abstract #172).2 Latest ERLEADA® (apalutamide) Data Includes Results from the Phase 3 PRESTO Study in High-Risk Biochemically Relapsed Prostate Cancer, a Post-Hoc Analysis from the Phase 3 SPARTAN Study Evaluating Treatment Sequencing in People with Advanced Disease and Multiple Real-World Evidence Presentations Poster Presentation: New data from the collaborative Phase 3 PRESTO study will evaluate baseline factors associated with improved prostate-specific antigen (PSA) progression-free survival (PFS) when intensifying treatment beyond androgen deprivation therapy (ADT) with the addition of ERLEADA®, with or without AAP in patients with high-risk biochemically relapsed prostate cancer (Abstract #208).3 Poster Presentation: A post-hoc analysis from the Phase 3 SPARTAN study will report the efficacy of subsequent therapies for mCRPC in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with ERLEADA® (Abstract #157).4 Poster Presentations: Multiple real-world evidence data studies will evaluate the benefit of ERLEADA® in patients across the prostate cancer spectrum including: Real-world evidence data in patients with nmCRPC treated with ERLEADA® assessed for PSA response and metastasis-free survival (MFS) (Abstract #69).5 A study describing time-to-castration resistance based on real-world evidence data for patients with metastatic castration-sensitive prostate cancer (mCSPC) who were treated with ERLEADA®, abiraterone acetate or enzalutamide (Abstract #65).6 A retrospective study will examine real-world evidence data in patients with high-risk localized or locally advanced prostate cancer treated with external beam radiation therapy (Abstract # 330).7 Data from the Phase 1 TAR-200-102 Study Evaluating Safety and Efficacy of TAR-200, Real-World Evidence Data Evaluating Treatment Patterns and Adherence to Standard of Care in Patients with Non-Muscle Invasive Bladder Cancer (NMIBC), and a Trial-In-Progress Update from SunRISe-4 in Some Patients with Muscle-Invasive Bladder Cancer (MIBC) Poster Presentation: New findings from the Phase 1 TAR-200-102 study will assess the safety and tolerability of TAR-200, a novel intravesical drug delivery system designed to provide a continuous, slow release of gemcitabine within the bladder, in patients with intermediate-risk NMIBC (Abstract #505).8 Poster Presentation: Real-world treatment patterns and adherence to Bacillus Calmette-Guerin (BCG) in the context of guideline recommendations for patients with NMIBC will help to emphasize the need for additional available treatment options that are safe, effective and tolerable (Abstract #470).9 Poster Presentation: Researchers will share a trial-in-progress update from the SunRISe-4 study of TAR-200 in combination with cetrelimab, an investigational programmed cell death receptor-1 (PD-1) monoclonal antibody, or cetrelimab alone in patients with MIBC who are ineligible or refuse neoadjuvant platinum-based chemotherapy (Abstract #TPS584).10 Data from the Phase 2 THOR-2 Study Evaluating the Safety and Efficacy of BALVERSA® (erdafitinib) in High-Risk NMIBC and Intermediate-Risk NMIBC; TAR-210 Trial-in-Progress Update Poster Presentation: Cohort 2 will assess patients with BCG-unresponsive high-risk NMIBC carcinoma in situ (CIS) with fibroblast growth factor receptor (FGFR) 3/2 genetic alterations. (Abstract #503).11 Poster Presentation: Cohort 3 will assess patients with intermediate-risk NMIBC and residual marker lesions with FGFR 3/2 genetic alterations. (Abstract #504).12 Poster Presentation: A trial-in-progress update from the open-label, multicenter Phase 1 TAR-210 study (Erdafitinib Intravesical Delivery System) will evaluate the safety and efficacy of TAR-210 in patients with NMIBC and MIBC harboring select FGFR genetic alterations (Abstract #TPS583).13 About Niraparib Niraparib is an orally administered, highly selective poly (ADP-ribose) polymerase (PARP) inhibitor that is currently being studied by Janssen for the treatment of patients with prostate cancer. Additional ongoing studies include the Phase 3 AMPLITUDE study evaluating the combination of niraparib and AAP in a biomarker-selected patient population with metastatic castration-sensitive prostate cancer (mCSPC).14 In April 2016, Janssen Biotech, Inc. entered a worldwide (except Japan) collaboration and license agreement with TESARO, Inc. (acquired by GlaxoSmithKline [GSK] in 2019) for exclusive rights to niraparib in prostate cancer. Niraparib is currently marketed by GSK as ZEJULA®.15 About Abiraterone Acetate Abiraterone acetate is an orally administered androgen biosynthesis inhibitor. In the United States, abiraterone acetate is indicated with prednisone for the treatment of mCRPC and high-risk mCSPC.16 About ERLEADA ® ERLEADA® (apalutamide) is an androgen receptor signaling inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and for the treatment of patients with mCSPC.17 ERLEADA® received U.S. Food and Administration (FDA) approval for nmCRPC in February 2018, and received U.S. FDA approval for mCSPC in September 2019.17 To date, more than 100,000 patients worldwide have been treated with ERLEADA®. For more information, visit . About TAR-200 TAR-200 is an investigational drug delivery system, enabling controlled release of gemcitabine into the bladder, increasing dwell time and local drug exposure. The safety and efficacy of TAR-200 are being evaluated in Phase 2 and Phase 3 studies in patients with muscle-invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC). About Cetrelimab Cetrelimab is an investigational programmed cell death receptor-1 (PD-1) monoclonal antibody being studied to treat bladder cancer, prostate cancer, melanoma and multiple myeloma as part of a combination treatment. Cetrelimab is also being evaluated in multiple other combination regimens across the Janssen Oncology portfolio. About BALVERSA® BALVERSA® (erdafitinib) is a once-daily, oral FGFR kinase inhibitor for the treatment of adults with locally advanced or metastatic urothelial carcinoma (mUC) that has susceptible FGFR3 or FGFR2 genetic alterations and has progressed during or following at least one line of platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy and received U.S. FDA approval in April 2019.18 Patients are selected for therapy based on an FDA-approved companion diagnostic for BALVERSA®. This indication is approved under accelerated approval based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.18,19 BALVERSA® is the only approved treatment option for patients with FGFR-mutated mUC. In 2008, Janssen Pharmaceutica NV entered into an exclusive worldwide license and collaboration agreement with Astex Pharmaceuticals to develop and commercialize BALVERSA®. For more information, visit . About TAR-210 TAR-210 is an intravesical drug delivery system designed to provide local, continuous release of erdafitinib within the bladder. The safety and efficacy of TAR-210 is being evaluated in a Phase 1 study in patients with muscle-invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC). ERLEADA® IMPORTANT Safety Information 17 WARNINGS AND PRECAUTIONS Cerebrovascular and Ischemic Cardiovascular Events — In a randomized study (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events occurred in 3.7% of patients treated with ERLEADA® and 2% of patients treated with placebo. In a randomized study (TITAN) in patients with mCSPC, ischemic cardiovascular events occurred in 4.4% of patients treated with ERLEADA® and 1.5% of patients treated with placebo. Across the SPARTAN and TITAN studies, 4 patients (0.3%) treated with ERLEADA® and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. Patients with history of unstable angina, myocardial infarction, congestive heart failure, stroke, or transient ischemic attack within 6 months of randomization were excluded from the SPARTAN and TITAN studies. In the SPARTAN study, cerebrovascular events occurred in 2.5% of patients treated with ERLEADA® and 1% of patients treated with placebo. In the TITAN study, cerebrovascular events occurred in 1.9% of patients treated with ERLEADA® and 2.1% of patients treated with placebo. Across the SPARTAN and TITAN studies, 3 patients (0.2%) treated with ERLEADA®, and 2 patients (0.2%) treated with placebo died from a cerebrovascular event. Cerebrovascular and ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA®. Monitor for signs and symptoms of ischemic heart disease and cerebrovascular disorders. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Consider discontinuation of ERLEADA® for Grade 3 and 4 events. Fractures — In a randomized study (SPARTAN) of patients with nmCRPC, fractures occurred in 12% of patients treated with ERLEADA® and in 7% of patients treated with placebo. In a randomized study (TITAN) of patients with mCSPC, fractures occurred in 9% of patients treated with ERLEADA® and in 6% of patients treated with placebo. Evaluate patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents. Falls — In a randomized study (SPARTAN), falls occurred in 16% of patients treated with ERLEADA® compared with 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Falls occurred in patients receiving ERLEADA® with increased frequency in the elderly. Evaluate patients for fall risk. Seizure — In two randomized studies (SPARTAN and TITAN), 5 patients (0.4%) treated with ERLEADA® and 1 patient treated with placebo (0.1%) experienced a seizure. Permanently discontinue ERLEADA® in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA®. Advise patients of the risk of developing a seizure while receiving ERLEADA® and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Severe Cutaneous Adverse Reactions — Fatal and life-threatening cases of severe cutaneous adverse reactions (SCARs), including Stevens Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) occurred in patients receiving ERLEADA®. Monitor patients for the development of SCARs. Advise patients of the signs and symptoms of SCARs (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy). If a SCAR is suspected, interrupt ERLEADA® until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, or for other Grade 4 skin reactions, permanently discontinue ERLEADA® [see Dosage and Administration (2.2)]. Embryo-Fetal Toxicity — The safety and efficacy of ERLEADA® have not been established in females. Based on findings from animals and its mechanism of action, ERLEADA® can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA® [see Use in Specific Populations (8.1, 8.3)]. ADVERSE REACTIONS The most common adverse reactions (≥10%) that occurred more frequently in the ERLEADA®-treated patients (≥2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture. Laboratory Abnormalities — All Grades (Grade 3-4) Hematology — In the TITAN study: white blood cell decreased ERLEADA® 27% (0.4%), placebo 19% (0.6%). In the SPARTAN study: anemia ERLEADA® 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA® 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA® 41% (1.8%), placebo 21% (1.6%). Chemistry — In the TITAN study: hypertriglyceridemia ERLEADA® 17% (2.5%), placebo 12% (2.3%). In the SPARTAN study: hypercholesterolemia ERLEADA® 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA® 70% (2%), placebo 59% (1.0%); hypertriglyceridemia ERLEADA® 67% (1.6%), placebo 49% (0.8%); hyperkalemia ERLEADA® 32% (1.9%), placebo 22% (0.5%). Rash — In 2 randomized studies (SPARTAN and TITAN), rash was most commonly described as macular or maculopapular. Adverse reactions of rash were 26% with ERLEADA® vs 8% with placebo. Grade 3 rashes (defined as covering >30% body surface area [BSA]) were reported with ERLEADA® treatment (6%) vs placebo (0.5%). The onset of rash occurred at a median of 83 days. Rash resolved in 78% of patients within a median of 78 days from onset of rash. Rash was commonly managed with oral antihistamines, topical corticosteroids, and 19% of patients received systemic corticosteroids. Dose reduction or dose interruption occurred in 14% and 28% of patients, respectively. Of the patients who had dose interruption, 59% experienced recurrence of rash upon reintroduction of ERLEADA®. Hypothyroidism — In 2 randomized studies (SPARTAN and TITAN), hypothyroidism was reported for 8% of patients treated with ERLEADA® and 1.5% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA® and 7% of patients treated with placebo. The median onset was at the first scheduled assessment. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose adjusted. DRUG INTERACTIONS Effect of Other Drugs on ERLEADA® — Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary; however, reduce the ERLEADA® dose based on tolerability [see Dosage and Administration (2.2)]. Effect of ERLEADA® on Other Drugs CYP3A4, CYP2C9, CYP2C19, and UGT Substrates — ERLEADA® is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA® with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of ERLEADA® with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA® and evaluate for loss of activity. P-gp, BCRP, or OATP1B1 Substrates — Apalutamide is a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA® with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP, or OATP1B1 must be co-administered with ERLEADA® and evaluate for loss of activity if medication is continued. Please see the full Prescribing Information for ERLEADA®. BALVERSA® IMPORTANT SAFETY INFORMATION18 WARNINGS AND PRECAUTIONS Ocular Disorders – BALVERSA® can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect. CSR/RPED was reported in 25% of patients treated with BALVERSA®, with a median time to first onset of 50 days. Grade 3 CSR/RPED, involving central field of vision, was reported in 3% of patients. CSR/RPED resolved in 13% of patients and was ongoing in 13% of patients at the study cutoff. CSR/RPED led to dose interruptions and reductions in 9% and 14% of patients, respectively, and 3% of patients discontinued BALVERSA®. Dry eye symptoms occurred in 28% of patients during treatment with BALVERSA® and were Grade 3 in 6% of patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed. Perform monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography. Withhold BALVERSA® when CSR occurs and permanently discontinue if it does not resolve within 4 weeks or if Grade 4 in severity. For ocular adverse reactions, follow the dose modification guidelines [see Dosage and Administration (2.3)]. Hyperphosphatemia and Soft Tissue Mineralization – BALVERSA® can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcinosis, non-uremic calciphylaxis and vascular calcification. Increases in phosphate levels are a pharmacodynamic effect of BALVERSA® [see Pharmacodynamics (12.2)]. Hyperphosphatemia was reported as adverse reaction in 76% of patients treated with BALVERSA®. The median onset time for any grade event of hyperphosphatemia was 20 days (range: 8–116) after initiating BALVERSA®. Thirty-two percent of patients received phosphate binders during treatment with BALVERSA®. Cutaneous calcinosis, non-uremic calciphylaxis and vascular calcification have been observed in 0.3% of patients treated with BALVERSA®. Monitor for hyperphosphatemia throughout treatment. In all patients, restrict phosphate intake to 600–800 mg daily. If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serum phosphate level returns to <5.5 mg/dL. Withhold, dose reduce, or permanently discontinue BALVERSA® based on duration and severity of hyperphosphatemia [see Dosage and Administration (2.3), Table 2: Dose Modifications for Adverse Reactions]. Embryo-fetal Toxicity –Based on the mechanism of action and findings in animal reproduction studies, BALVERSA® can cause fetal harm when administered to a pregnant woman. In a rat embryo-fetal toxicity study, erdafitinib was embryotoxic and teratogenic at exposures less than the human exposures at all doses studied. Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with BALVERSA® and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BALVERSA® and for one month after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]. Most common adverse reactions including laboratory abnormalities ≥20%: Phosphate increased (76%), stomatitis (56%), fatigue (54%), creatinine increased (52%), diarrhea (47%), dry mouth (45%), nail disorder (45%), alanine aminotransferase increased (41%), alkaline phosphatase increased (41%), sodium decreased (40%), decreased appetite (38%), albumin decreased (37%), dysgeusia (37%), hemoglobin decreased (35%), dry skin (34%), aspartate aminotransferase increased (30%), magnesium decreased (30%), dry eye (28%), alopecia (26%), palmar-plantar erythrodysesthesia syndrome (26%), constipation (28%), phosphate decreased (24%), abdominal pain (23%), calcium increased (22%), nausea (21%), and musculoskeletal pain (20%). The most common Grade 3 or greater adverse reactions (>1%) were stomatitis (9%), nail dystrophy*, palmar-plantar erythrodysesthesia syndrome (6%), paronychia (3%), nail disorder (10%), keratitis†, and hyperphosphatemia (1%). *Included within onycholysis. †Included within dry eye. An adverse reaction with a fatal outcome in 1% of patients was acute myocardial infarction. Serious adverse reactions occurred in 41% of patients, including eye disorders (10%). Permanent discontinuation due to an adverse reaction occurred in 13% of patients. The most frequent reasons for permanent discontinuation included eye disorders (6%). Dosage interruptions occurred in 68% of patients. The most frequent adverse reactions requiring dosage interruption included hyperphosphatemia (24%), stomatitis (17%), eye disorders (17%), and palmar-plantar erythrodysesthesia syndrome (8%). Dose reductions occurred in 53% of patients. The most frequent adverse reactions for dose reductions included eye disorders (23%), stomatitis (15%), hyperphosphatemia (7%), palmar-plantar erythrodysesthesia syndrome (7%), paronychia (7%), and nail dystrophy (6%). Drug Interactions Moderate CYP2C9 or strong CYP3A4 Inhibitors: Consider alternative agents or monitor closely for adverse reactions. (7.1) Strong CYP2C9 or CYP3A4 inducers: Avoid concomitant use with BALVERSA®. (7.1) Moderate CYP2C9 or CYP3A4 inducers: Increase BALVERSA® dose up to 9 mg. (7.1) Serum phosphate level-altering agents: Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose modification period. (2.3, 7.1) CYP3A4 substrates: Avoid concomitant use with sensitive CYP3A4 substrates with narrow therapeutic indices. (7.2) OCT2 substrates: Consider alternative agents or consider reducing the dose of OCT2 substrates based on tolerability. (7.2) P-gp substrates: Separate BALVERSA® administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic indices. (7.2) Use in Specific Populations Lactation – Because of the potential for serious adverse reactions from erdafitinib in a breastfed child, advise lactating women not to breastfeed during treatment with BALVERSA® and for one month following the last dose. Please see the full Prescribing Information for BALVERSA®. About the Janssen Pharmaceutical Companies of Johnson & Johnson At Janssen, we're creating a future where disease is a thing of the past. We're the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular, Metabolism & Retina; Immunology; Infectious Diseases & Vaccines; Neuroscience; Oncology; and Pulmonary Hypertension. Learn more at . Follow us at @JanssenUS and @JanssenGlobal. Janssen Research & Development, LLC and Janssen Biotech, Inc. are part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Cautions Concerning Forward-Looking Statements This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of niraparib, abiraterone acetate + prednisone, ERLEADA® (apalutamide), TAR-200, cetrelimab, BALVERSA® (erdafitinib) and TAR-210. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC, Janssen Biotech, Inc., or any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 2, 2022, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in Johnson & Johnson's subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at , or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments. 1 Efstathiou, E e at. Niraparib (NIRA) with abiraterone acetate and prednisone (AAP) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations: second interim analysis (IA2) of MAGNITUDE. ASCO GU 2023. 2 Castro, E et al. Impact of run-in treatment with abiraterone acetate and prednisone (AAP) in the MAGNITUDE study of niraparib (NIRA) and AAP in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations. ASCO GU 2023. 3 Aggarwal, R et al. Baseline Characteristic Associated with PSA Progression-Free Survival in Patients (pts) with High-Risk Biochemically Relapsed Prostate Cancer: Results from the Phase 3 PRESTO study (AFT-19). ASCO 2023. 4 Oudard, S et al. Efficacy of subsequent treatments in patients who progressed to mCRPC following treatment with apalutamide for nonmetastatic castration-resistant prostate cancer (nmCRPC): a post hoc analysis of the SPARTAN phase III trial. ASCO GU 2023. 5 Lowentritt, B et al. Real-world prostate-specific antigen (PSA) response and disease progression among patients with non-metastatic castration-resistant prostate cancer (nmCRPC) initiated on apalutamide (APA). ASCO GU 2023. 6 Lowentritt, B et al. Real-world time-to-castration resistance (CR) among patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) initiating apalutamide (APA), enzalutamide (ENZ), or abiraterone acetate (ABI) from an oncology database. ASCO GU 2023. 7 Karsh, L et al. Real-World Clinical Outcomes of Patients with Localized Prostate Cancer (LPC) Treated with External Beam Radiation Therapy (EBRT). ASCO GU 2023. 8 Hans van Valenberg, T et al. Safety, tolerability, and preliminary efficacy of TAR-200 in intermediate risk non-muscle invasive bladder cancer patients: a phase 1 study. ASCO GU 2023. 9 Gaylis, F et al. Study of real-world treatment patterns and adherence to Bacillus Calmette-Guerin (BCG) in the context of guideline recommendations for patients with high-risk non-muscle invasive bladder cancer (NMIBC). ASCO GU 2023. 10 Psutka, S et al. SunRISe-4: Tar-200 plus cetrelimab or cetrelimab alone as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for or refuse neoadjuvant platinum-based chemotherapy. ASCO GU 2023. 11 Catto, J et al. Phase 2 study of the efficacy and safety of erdafitinib in patients (pts) with Bacilius Calmette-Guerin (BCG)-unresponsive, high-risk non-muscle invasive bladder cancer (HR-NMIBC) with FGFR3/2 alterations (alt) in THOR-2: cohort 2 interim analysis results. ASCO GU 2023. 12 Daneshmand, S et al. Phase 2 study of the efficacy and safety of erdafitinib in patients with intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) with FGFR3/2 alterations (alt) in THOR-2: cohort 3 interim analysis results. ASCO GU 2023. 13 Vilaseca, A et al. Safety and efficacy of the erdafitinib (erda) intravesical delivery system, TAR-210, in patients (pts) with non-muscle invasive bladder cancer (NMBIC) or muscle-invasive bladder cancer (MIBC) harboring select FGFR mutations or fusions: phase 1 first-in-human study. ASCO GU 2023. 14 Clinical Trials.Gov. A Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for the Treatment of Participants With Deleterious Germline or Somatic Homologous Recombination Repair (HRR) Gene-Mutated Metastatic Castration Sensitive Prostate Cancer (mCSPC) (AMPLITUDE). Available at: . Last accessed February 2023. 15 ZEJULA® U.S. Prescribing Information, September 2022. 16 ZYTIGA® U.S. Prescribing Information, August 2021. 17 ERLEADA® U.S. Prescribing Information, November 2021. 18 BALVERSA® U.S. Prescribing Information, April 2019. 19 U.S. Food & Drug Administration. FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma. Available at: . Accessed February 2023. Media Contacts: Suzanne Frost +1 (416) 317-0304 Ania DiAntonio +1 (215) 620-9717 Investor Relations: Raychel Kruper +1 (732) 524-6164 U.S. Medical Inquiries: +1 (800) 526-7736 SOURCE Janssen Oncology

BASKING RIDGE, N.J.--(BUSINESS WIRE)-- Daiichi Sankyo (TSE: 4568) today announced that the new dosing regimen for TURALIO® (pexidartinib) is now available in the U.S. for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. A new 125 mg capsule of TURALIO is now available and the 200 mg capsule has been discontinued. TGCT is a rare, typically non-malignant tumor that affects small and large joints. The disease can cause debilitating symptoms, can be locally aggressive and can significantly impact everyday activities in a relatively young patient population.1,2,3 The new recommended dose of TURALIO is 250 mg orally twice daily (taken as two 125 mg capsules) with a low-fat meal of approximately 11 to 14 grams of total fat until disease progression or unacceptable toxicity. The previous dose was 400 mg orally twice daily on an empty stomach. Patients currently taking TURALIO 200 mg capsules can take the 125 mg capsules as the next scheduled dose once the 200 mg capsules have been finished. Patients should consult with their physicians to answer any questions they may have as they transition to the new dose. As part of post-marketing requirements with the U.S. Food and Drug Administration (FDA), Daiichi Sankyo conducted pharmacokinetic studies to evaluate the effects of food when taking TURALIO. Taking TURALIO with a high-fat meal (approximately 55 to 65 grams of total fat) was found to increase the concentration of TURALIO in the body and may increase the risk of adverse reactions, including hepatotoxicity. These studies demonstrated that lowering the dose of TURALIO and taking it with a low-fat meal helps to minimize the potential for drug overexposure in the event a patient did not carefully follow the dietary recommendations when taking the 200 mg capsule of TURALIO. Studies also showed that taking TURALIO 250 mg with a low-fat meal (11 to 14 grams of total fat) has no clinically significant difference in efficacy to taking TURALIO 400 mg on an empty stomach. “The new dose reflects study data that evaluated the impact of food on TURALIO exposure should patients not follow the previous recommended dietary requirements when taking the medication,” said Dan Switzer, Head of U.S. Oncology Business, Daiichi Sankyo, Inc. “As patient safety is our primary goal, we will continue to inform healthcare professionals about the new dosing regimen of TURALIO so that they can continue to treat appropriate patients with tenosynovial giant cell tumor with the only FDA-approved therapy.” TURALIO is approved with a Boxed WARNING for hepatotoxicity due to the risk of serious and potentially fatal liver injury. Hepatotoxicity with ductopenia and cholestasis has occurred in patients treated with TURALIO. Across 768 patients who received TURALIO in clinical trials, there were two irreversible cases of cholestatic liver injury. One patient died with advanced cancer and ongoing liver toxicity and one patient required a liver transplant. The mechanism of cholestatic hepatotoxicity is unknown and its occurrence cannot be predicted. It is unknown whether liver injury occurs in the absence of increased transaminases. Because of the risk of hepatotoxicity, TURALIO is available by prescription in the U.S. only through a restricted program called the TURALIO Risk Evaluation and Mitigation Strategy (REMS) Program where only certified healthcare providers may prescribe TURALIO. Patients must complete and sign an enrollment form for inclusion in a patient registry to receive treatment. Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive TURALIO. Daiichi Sankyo is committed to ensuring that patients in the U.S. who are prescribed TURALIO can access the medication and receive necessary financial support. Provider and patient support related to access, reimbursement and distribution for TURALIO in the U.S. will be accessible through Daiichi Sankyo Access Central by visiting or calling 1-866-4-DSI-NOW (1-866-437-4669). Further information is available at . For more information, please visit for full Prescribing Information, including Boxed WARNING, and for additional Important Safety Information. About TGCT (PVNS/GCT-TS) TGCT, also referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS), is a rare, typically non-malignant tumor that can be locally aggressive. TGCT affects the synovium-lined joints, bursae and tendon sheaths, resulting in reduced mobility in the affected joint or limb.1,2,3 While the exact incidence of TGCT is not known, it is estimated that the worldwide incidence of TGCT is 43 patients per million person-years.4,5,6 TGCT is subcategorized into two types: localized, which is more common and accounts for 80% to 90% of cases, and diffuse, which accounts for 10% to 20% of cases.5,6 The current standard of care for TGCT is surgical resection.1,7 However, in patients with recurrent, difficult-to-treat, or the diffuse form of TGCT, the tumor may wrap around bone, tendons, ligaments and other parts of the joint. In these cases, the tumor may be difficult to remove and/or may not be amenable to improvement with surgery. Multiple surgeries for more severe cases can lead to significant joint damage, debilitating functional impairments and reduced quality of life, and amputation may be considered.7,8,9 Recurrence rates for localized TGCT are estimated to be up to 15% following complete resection. 3,6,10,11,12 Diffuse TGCT recurrence rates are estimated to be up to 55% following complete resection.3,6,10,13 TGCT affects all age groups with the diffuse type on average occurring most often in people below the age of 40, and the localized type typically occurring in people between 30 and 50 years old.1,4,5,6 About TURALIO TURALIO (pexidartinib) is an oral small molecule that targets colony stimulating factor 1 receptor (CSF1R), KIT proto-oncogene receptor tyrosine kinase (KIT), and FMS-like tyrosine kinase 3 (FLT3) harboring an internal tandem duplication (ITD) mutation. Overexpression of the CSF1R ligand promotes cell proliferation and accumulation in the synovium. TURALIO is approved in the U.S. for the treatment of adult patients with symptomatic TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery. The medicine was granted Priority Review, Breakthrough Therapy and Orphan Drug Designation by the U.S. FDA prior to FDA approval in August 2019. Important Safety Information Indication and Usage TURALIOⓇ (pexidartinib) is indicated for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. WARNING: HEPATOTOXICITY TURALIO can cause serious and potentially fatal liver injury. Monitor liver tests prior to initiation of TURALIO and at specified intervals during treatment. Withhold and dose reduce or permanently discontinue TURALIO based on severity of hepatotoxicity. TURALIO is available only through a restricted program called the TURALIO Risk Evaluation and Mitigation Strategy (REMS) Program. Contraindications None. Warnings and Precautions Hepatotoxicity TURALIO can cause serious and potentially fatal liver injury and is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Hepatotoxicity with ductopenia and cholestasis occurred in patients treated with TURALIO. Across 768 patients who received TURALIO in clinical trials, there were two irreversible cases of cholestatic liver injury. One patient with advanced cancer and ongoing liver toxicity died and one patient required a liver transplant. The mechanism of cholestatic hepatotoxicity is unknown and its occurrence cannot be predicted. It is unknown whether liver injury occurs in the absence of increased transaminases. In ENLIVEN, 3 of 61 (5%) patients who received TURALIO developed signs of serious liver injury, defined as ALT or AST ≥3 × upper limit of normal (ULN) with total bilirubin ≥2 × ULN. In these patients, peak ALT ranged from 6 to 9 × ULN, peak total bilirubin ranged from 2.5 to 15 × ULN, and alkaline phosphatase (ALP) was ≥2 × ULN. ALT, AST and total bilirubin improved to <2 × ULN in these patients 1 to 7 months after discontinuing TURALIO. Avoid TURALIO in patients with preexisting increased serum transaminases, total bilirubin, or direct bilirubin (>ULN); or active liver or biliary tract disease, including increased ALP. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP, and gamma-glutamyl transferase (GGT), prior to initiation of TURALIO, weekly for the first 8 weeks, every 2 weeks for the next month and every 3 months thereafter. Withhold and dose reduce, or permanently discontinue TURALIO based on the severity of the hepatotoxicity. Rechallenge with a reduced dose of TURALIO may result in a recurrence of increased serum transaminases, bilirubin, or ALP. Monitor liver tests weekly for the first month after rechallenge. TURALIO REMS TURALIO is available only through a restricted program under a REMS, because of the risk of hepatotoxicity. Notable requirements of the TURALIO REMS Program include the following: Prescribers must be certified with the program by enrolling and completing training. Patients must complete and sign an enrollment form for inclusion in a patient registry. Pharmacies must be certified with the program and must dispense only to patients who are authorized (enrolled in the REMS patient registry) to receive TURALIO. Further information is available at turalioREMS.com or by calling 1-833-887-2546. Embryo-fetal toxicity Based on animal studies and its mechanism of action, TURALIO may cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective nonhormonal method of contraception, since TURALIO can render hormonal contraceptives ineffective, during treatment with TURALIO and for 1 month after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TURALIO and for 1 week after the final dose. Adverse Reactions The safety of TURALIO was evaluated in ENLIVEN, in which patients received TURALIO without food at a dose of 400 mg in the morning and 600 mg in the evening orally for 2 weeks followed by 400 mg orally twice daily until disease progression or unacceptable toxicity. Serious adverse reactions were reported in 13% of patients who received TURALIO. The most frequent serious adverse reactions (occurring in >1 patient) included abnormal liver tests (3.3%) and hepatotoxicity (3.3%). Permanent discontinuation due to adverse reactions occurred in 13% of patients who received TURALIO. The most frequent adverse reactions (occurring in >1 patient) requiring permanent discontinuation included increased ALT (4.9%), increased AST (4.9%), and hepatotoxicity (3.3%). Dose reductions or interruptions occurred in 38% of patients who received TURALIO. The most frequent adverse reactions (occurring in >1 patient) requiring a dosage reduction or interruption were increased ALT (13%), increased AST (13%), nausea (8%), increased ALP (7%), vomiting (4.9%), increased bilirubin (3.3%), increased GGT (3.3%), dizziness (3.3%), and abdominal pain (3.3%). The most common adverse reactions for all grades (>20%) were increased lactate dehydrogenase (92%), increased AST (88%), hair color changes (67%), fatigue (64%), increased ALT (64%), decreased neutrophils (44%), increased cholesterol (44%), increased ALP (39%), decreased lymphocytes (38%), eye edema (30%), decreased hemoglobin (30%), rash (28%), dysgeusia (26%), and decreased phosphate (25%). Clinically relevant adverse reactions occurring in <10% of patients were blurred vision, photophobia, diplopia, reduced visual acuity, dry mouth, stomatitis, mouth ulceration, pyrexia, cholangitis, hepatotoxicity, liver disorder, cognitive disorders (memory impairment, amnesia, confusional state, disturbance in attention, and attention deficit/hyperactivity disorder), alopecia, and skin pigment changes (hypopigmentation, depigmentation, discoloration, and hyperpigmentation). Drug Interactions Use with hepatotoxic products: TURALIO can cause hepatotoxicity. In patients with increased serum transaminases, total bilirubin, or direct bilirubin (>ULN) or active liver or biliary tract disease, avoid coadministration of TURALIO with other products known to cause hepatotoxicity. Moderate or strong CYP3A inhibitors: Concomitant use of a moderate or strong CYP3A inhibitor may increase pexidartinib concentrations. Reduce TURALIO dosage if concomitant use of moderate or strong CYP3A inhibitors cannot be avoided. Strong CYP3A inducers: Concomitant use of a strong CYP3A inducer decreases pexidartinib concentrations. Avoid concomitant use of strong CYP3A inducers. Uridine diphosphate glucuronosyltransferase (UGT) inhibitors: Concomitant use of a UGT inhibitor increases pexidartinib concentrations. Reduce TURALIO dosage if concomitant use of UGT inhibitors cannot be avoided. Acid-reducing agents: Concomitant use of a proton pump inhibitor (PPI) decreases pexidartinib concentrations. Avoid concomitant use of PPIs. Use histamine-2 receptor antagonists or antacids if needed. CYP3A substrates: TURALIO is a moderate CYP3A inducer. Concomitant use of TURALIO decreases concentrations of CYP3A substrates. Avoid coadministration of TURALIO with hormonal contraceptives and other CYP3A substrates where minimal concentration changes may lead to serious therapeutic failure. Increase the CYP3A substrate dosage in accordance with approved product labeling if concomitant use is unavoidable. Use in Specific Populations Pregnancy: TURALIO may cause embryo-fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to a fetus. Lactation: Because of the potential for serious adverse reactions in the breastfed child, advise women to not breastfeed during treatment with TURALIO and for at least 1 week after the final dose. Females and males of reproductive potential: Verify pregnancy status in females of reproductive potential prior to the initiation of TURALIO. Advise females of reproductive potential to use an effective nonhormonal method of contraception, since TURALIO can render hormonal contraceptives ineffective, during treatment with TURALIO and for 1 month after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TURALIO and for 1 week after the final dose. Renal impairment: Reduce the dose when administering TURALIO to patients with mild to severe renal impairment (CLcr 15 to 89 mL/min, estimated by Cockcroft-Gault [C-G] using actual body weight). Hepatic impairment: Reduce the dosage of TURALIO for patients with moderate hepatic impairment (total bilirubin greater than 1.5 and up to 3 times ULN, not due to Gilbert’s syndrome, with any AST). TURALIO has not been studied in patients with severe hepatic impairment (total bilirubin greater than 3 to 10 times ULN and any AST). To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc, at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch. Please see accompanying full Prescribing Information, including Boxed WARNING, and Medication Guide. About Daiichi Sankyo Daiichi Sankyo is dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose “to contribute to the enrichment of quality of life around the world.” In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an “Innovative Global Healthcare Company Contributing to the Sustainable Development of Society.” For more information, please visit . ____________ References: 1 de Saint Aubain, et al. WHO. 2013;100-103. 2 Rao AS, et al. J Bone Joint Surg AM. 1984;66(1):76-94. 3 Ravi V, et al. Curr Opin Oncol. 2011;23:361-366. 4 Myers BW, et al. Medicine (Baltimore). 1980;59(3):223-238. 5 Mastboom MJL, et al. Acta Orthopaedica. 2017;88(6):688-694. 6 Ehrenstein V, et al. J Rheumatol. 2017; 44(10):1476-1483. 7 Verspoor FGM, et al. Future Oncol. 2013;10:1515-1531. 8 Verspoor FGM, et al. Rheumatol. 2014;53(11):2063-2070. 9 Brahmi M, et al. Curr Treat Options Oncol. 2016;17(2):10. 10 Gouin F, Noailles T. Orthop Traumatol Surg Res. 2017;103(1S):S91-S97. 11 Palmerini E, Staals EL, Maki RG, et al. Eur J Cancer. 2015;51(2):210-217. 12 Dines JS, et al. Arthroscopy. 2007;23(9):930-937. 13 Xie GP, et al. PLOS One. 2015;10(3):e0121451.

来源：药渡  撰文：星星狐    编辑：丸子近日，美国Biotech公司Blueprint在药物化学TOP期刊JMC的专栏Drug Annotation中详细介绍了当前处于美国临床I/II期的四代EGFR抑制剂BLU-945的发现过程。BLU-945的临床适应症是非小细胞肺癌（NSCLC），目前该款抑制剂已被再鼎医药引进国内。1背景在因癌症而死亡的人中，肺癌占比最多，占18%；而肺癌患者中有80%-85%是非小细胞肺癌患者。表皮生长因子受体(EGFR)激酶结构域突变是这一腺癌的致癌驱动因子。NSCLC中最常见的EGFR激活突变(EGFR+)是外显子19的缺失(ex19del)和21外显子单点突变(L858R)。酪氨酸激酶抑制剂(TKIs)在过去二十年中发展起来，以EGFR突变为靶标在治疗EGFR阳性的非小细胞肺癌患者方面已显示出优于化疗的优势，现在被认为是该领域的护理标准。然而，耐药始终是癌症治疗的难点，因而新一代EGFR抑制剂始终具有临床需求。 图1  FDA批准的第一代，第二代和第三代EGFR酪氨酸激酶抑制剂2前三代EGFR抑制剂存在的问题用于NSCLC的第一代EGFR TKIs是可逆的ATP竞争抑制剂，如吉非替尼。尽管靶向治疗显示生存期延长，但1~2年后，由于获得性耐药，患者会经历疾病复发。最常见的获得性耐药是对gatekeeper残基(T790M)形成二次突变，占耐药案例的50 ~ 70%。这种gatekeeper突变也是阿法替尼(一种不可逆共价的第二代EGFR抑制剂)获得性耐药的主要机制。除了获得性耐药，第一代和第二代EGFR抑制剂的治疗窗口有限，这可以归因于对野生型(WT) EGFR抑制引起的毒性。自从发现T790M耐药突变和wt -EGFR驱动的毒性后，已经开发了几种新的EGFR TKIs来解决这些问题。Osimertinib是一种针对EGFR活性位点C797的不可逆抑制剂，是目前唯一被广泛应用的第三代EGFR TKI，其对T790M耐药突变以及初始致敏突变具有抑制活性。虽然奥希替尼在一线二线治疗中对患者有明显的好处，但获得性耐药也会随着时间的推移而出现。使用奥希替尼治疗导致的最常见的EGFR依赖性耐药突变是C797S突变，该突变破坏了抑制剂的共价结合。 图2  针对突变的EGFR非共价抑制剂3第四代EGFR抑制剂的研发1瞄准突变的EGFR抑制剂目前，当患者二线使用奥西替尼时，产生的EGFR+/T790M/C797S突变对于目前可用的EGFR TKIs是不可治疗的。NSCLC耐药突变是众所周知的，最近的一些文献也描述了各种抑制EGFR+/T790M和EGFR+/T790M/C797S的非共价抑制剂（图2）。鉴于对下一代EGFR抑制剂的需求仍未满足，需要开发新的BIC，对WT（野生型）不抑制，且对EGFR+/T790M和EGFR+/T790M/C797S突变体有效的抑制剂。 表1  EGFR抑制剂4−6的性质2化合物筛选发现hit化合物4是从Blueprint公司的化合物库筛选出来的hit，其对EGFR突变型具有强效的酶和细胞的抑制活性，对野生型的EGFR没有抑制，表现出高选择性。（表1）。化合物4的哌啶醇羟基的邻位引入F取代，能够提高对突变型的抑制活性（2~3倍）。这个关键的改造是借鉴了基因泰克公司的改造思路。5到6是一个常见的环化改构思路，吡啶N原子保留了氢键的相互作用。 3hit的优化对6进行了SAR的研究发现了化合物24（表2）。化合物24对EGFR突变型具有优异的酶活和细胞活性，对野生型抑制弱，表现出高选择性。但是其生物利用度过低，主要的问题是吸收不行，存在外排。且大鼠的PK研究表明，静脉清除接近肝血流速率(约70 mL min−1 kg−1），使得化合物24在大鼠体内清除过快，生物利用度只有2%。。为了降低这种潜在的风险，研究人员在氮杂丁环上添加了一个甲基得到化合物25，目的是增加极性取代基周围的位阻，以减少外排，但从结果看，这仍然不够。用一个碳原子取代一个氮原子的方式来降低骨架的TPSA，从而得到异喹啉26，获得了更好的MDCK-MDR1。被动渗透的改善和外排的减少使得大鼠PK大大改善(F = 85%，Cl = 20 mL min-1kg-1)，而对细胞EGFR L858R/T790M的抑制活性几乎没有影响，化合物27进一步提高了对突变型的抑制和对WT的选择性。表2  提高生物利用度4化合物27存在的问题化合物27的药代动力学结果表明（图3），药代动力学的体内外相关性较差。体外观察到适度的微粒体内在清除率(Clint = 55 μL/min/mg)，但体内清除率较高(Cl = 31.8 mL min -1 kg−1)。这表明27可能容易发生二相代谢，II相代谢可能是体内cyno（食蟹猴）清除率高的原因。随后的实验发现，27在人的肝细胞中受ugt介导的葡萄糖醛酸化作用，但在大鼠和犬的肝细胞中不受影响，并发现葡萄糖醛酸化位点为哌啶醇的羟基。 图3  化合物27的体外/体内评价数据  5PCC的确定对化合物27的改造目的在与减少II相代谢（图4），在羟基取代的α位和β位引入取代基增加位阻得到29和28，位阻的干扰可以减缓II相代谢羟基的结合反应。28没有凑效，29取得了显著的效果，但29对EGFR+/T790M的抑制变弱了。羟基甲基化以阻断30的葡糖醛酸化位点，得到了体内结构得到改善的化合物，同时保持良好的活性和对EGFR WT的选择性。对30（BLU-945）进一步表征，确定其作为候选化合物的潜力。 图4 对27优化以减轻ugt介导的II相代谢6药效试验的验证随后，研究人员在L858R/T790M/C797S和Ba/F3 ex19del/T790M/C797S这一奥希替尼耐药的肿瘤模型中评估了30的活性(图5A,B)。在这两种模型中，100 mpk BID剂量的30产生了很强的肿瘤抑制效果，而奥西替尼没有表现出任何抗肿瘤作用。进一步分析30在患者来源的异种移植细胞系(PDX)模型中的活性。来自1例EGFR突变的NSCLC患者的样本，该患者在接受包括吉非替尼和奥希替尼在内的7种治疗方案后进展为耐药，该样本用于开发一种奥希替尼耐药的EGFR ex19del/T790M / C797S小鼠模型。在这个模型中，给小鼠注射30(75和100 mg/kg BID) 56天后，很高兴地看到该治疗对肿瘤生长有显著抑制作用(图5C)。在这些令人鼓舞的体内活性结果的支持下，30被选为开发候选药物(BLU-945)，并进入关键的非临床安全性研究。 图5  BLU-945与奥希替尼药效对比在大鼠和非人灵长类动物(NHP)的临床前28天GLP毒性研究中，BLU-945获得了适当的安全窗，以支持在剂量递增阶段以25 mg的起始剂量进入人体试验。由于在较高pH下的化合物具有较低的水溶液溶解度，因此选择了喷雾-干燥分散配方的剂型。目前，一项针对egfr突变的NSCLC患者的首次人体1期剂量递增研究正在进行中，该研究对象为之前接受过至少一次egfr靶向TKI的患者(NCT04862780)。BLU-945连续每日口服一次。图6显示了一名患者开始25mg剂量时的血浆浓度与时间PK曲线，表明BLU-945具有低清除率和长的血浆半衰期(t1/2)。图6  1例患者25 mg剂量后BLU-945的浓度与时间分布4结语几乎所有患者在EGFR-TKIs治疗后24个月内均出现疾病进展。耐药机制包括EGFR依赖性和非依赖性耐药，TKIs耐药是无法避免的。经第一、二代TKIs治疗的患者，高达50%会产生T790M突变耐药，第三代的奥希替尼在随后的二线治疗中显示出PFS获益，奥希替尼虽然对 T790M 突变有效，但其他突变（20号染色体外显子插入突变、C797S、MET扩增和HER2扩增等）仍然是治疗盲区。除了最常见的T790M耐药突变，其他耐药机制仍需继续探索。为改善EGFR突变NSCLC患者的预后，需要针对不同耐药机制研发新的抑制剂，第四代、第五代……并探索联合治疗的效果。参考文献：1，Thomas A. Dineen et al; Discovery of BLU-945, a Reversible, Potent, and Wild-Type-SparingNext-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer, https://doi.org/10.1021/acs.jmedchem.2c00704。2，https://clinicaltrials.gov/ct2/home。版权声明/免责声明本文为授权转载文章，版权归拥有者。仅供感兴趣的个人谨慎参考，非商用，非医用、非投资用。欢迎朋友们批评指正！衷心感谢！文中图片、视频为授权正版作品，或来自微信公共图片库，或取自公司官网/网络根据CC0协议使用，版权归拥有者。任何问题，请与我们联系（电话：13651980212。微信：27674131。邮箱：contact@drugtimes.cn）。衷心感谢！推荐阅读吉利德2022H1业绩：总营收128.5亿美元，肿瘤业务大涨71%，瑞德西韦神奇不再，肝病领域全面下滑...阿斯利康10亿美元购买的产品，三期临床失败，合作伙伴股价大跌，不过希望仍在...终止合作！几亿美元买来的产品，说不要就不要了？今早9点！「肝病新药联盟」成立暨首届前沿论坛！全程直播！欢迎观看！国产ADC喜讯频传！Claudin18.2开发，中国药企已领先全球，「并购」与「合作」或将成为新趋势「肝病新药联盟」成立暨首届前沿论坛！全程直播！欢迎观看！FDA又被告了，因为新药批的慢 —— 一个「藏在角落里」的条款，让药企股价跌半...股价上涨124%！猴痘疫情升为高级，Bavarian Nordic或成最大赢家？FDA、NMPA、EMA都推荐了——真实世界证据，新药「加速审批」的下一站？如果出海是一部热播连续剧，那么新剧情层出不穷，跌宕起伏，惊心动魄，扣人心弦！。。。| 药时代出海系列点击这里，欢聚药时代！