作者: Vekaria, Hemendra ; Sullivan, Patrick ; Joshi, Smita ; Whiteheart, Sidney W ; Lykins, Joshua ; Prakhya, Kanakanagavalli Shravani ; Coenen, Daniёlle M ; Omali, Linda ; Wang, Qing Jun ; Alfar, Hammodah R

Although the presence of glycogen in platelets was established in the 1960s, its importance to specific functions (i.e., activation, secretion, aggregation, and clot contraction) remains unclear. Patients with glycogen storage disease often present with increased bleeding and glycogen phosphorylase (GP) inhibitors, when used as treatments for diabetes, induce bleeding in preclinical studies suggesting some role for this form of glucose in hemostasis. In the present work, we examined how glycogen mobilization affects platelet function using GP inhibitors (CP316819 and CP91149) and a battery of ex vivo assays. Blocking GP activity increased glycogen levels in resting and thrombin-activated platelets and inhibited platelet secretion and clot contraction, with minimal effects on aggregation. Seahorse energy flux analysis and metabolite supplementation experiments suggested that glycogen is an important metabolic fuel whose role is affected by platelet activation and the availability of external glucose and other metabolic fuels. Our data shed light on the bleeding diathesis in glycogen storage disease patients and offer insights into the potential effects of hyperglycemia on platelets.

2023-03-28·Molecules (Basel, Switzerland)

Design and Synthesis of 3-(β-d-Glucopyranosyl)-4-amino/4-guanidino Pyrazole Derivatives and Analysis of Their Glycogen Phosphorylase Inhibitory Potential.

Article

作者: Docsa, Tibor ; Somsak, Laszlo ; Kun, Sandor ; Hayes, Joseph M. ; Mathomes, Rachel T.

Glycogen phosphorylase (GP) is a key regulator of glucose levels and, with that, an important target for the discovery of novel treatments against type 2 diabetes. β-d-Glucopyranosyl derivatives have provided some of the most potent GP inhibitors discovered to date. In this regard, C-β-d-glucopyranosyl azole type inhibitors proved to be particularly effective, with 2- and 4-β-d-glucopyranosyl imidazoles among the most potent designed to date. His377 backbone C=O hydrogen bonding and ion-ion interactions of the protonated imidazole with Asp283 from the 280s loop, stabilizing the inactive state, were proposed as crucial to the observed potencies. Towards further exploring these features, 4-amino-3-(β-d-glucopyranosyl)-5-phenyl-1H-pyrazole (3) and 3-(β-d-glucopyranosyl)-4-guanidino-5-phenyl-1H-pyrazole (4) were designed and synthesized with the potential to exploit similar interactions. Binding assay experiments against rabbit muscle GPb revealed 3 as a moderate inhibitor (IC₅₀ = 565 µM), but 4 displayed no inhibition at 625 µM concentration. Towards understanding the observed inhibitions, docking and post-docking molecular mechanics-generalized Born surface area (MM-GBSA) binding free energy calculations were performed, together with Monte Carlo and density functional theory (DFT) calculations on the free unbound ligands. The computations revealed that while 3 was predicted to hydrogen bond with His377 C=O in its favoured tautomeric state, the interactions with Asp283 were not direct and there were no ion-ion interactions; for 4, the most stable tautomer did not have the His377 backbone C=O interaction and while ion-ion interactions and direct hydrogen bonding with Asp283 were predicted, the conformational strain and entropy loss of the ligand in the bound state was significant. The importance of consideration of tautomeric states and ligand strain for glucose analogues in the confined space of the catalytic site with the 280s loop in the closed position was highlighted.

2022-12-01·Bioorganic Chemistry

Discovery of novel heterocyclic derivatives as potential glycogen phosphorylase inhibitors with a cardioprotective effect

Article

作者: Yan, Zhiwei ; Li, Jing ; Ma, Can ; Li, Shuai ; Wang, Youde ; Zhang, Liying ; Guo, Yachun

The purpose of this study was to evaluate the effect of GP inhibitor as a potential pharmaceutical target on MI/R injury. Four different structural types of novel compounds (I, II, III, and IV) were designed and synthesized, obtaining 31 novel GP inhibitors. SAR studies revealed that the conjugates of 5-chloroindole with benzo six-membered heterocyclic were found to elevate the activity. In particular, compound IIIh (IC₅₀ = 0.21 ± 0.03 µM) emerged as a potent derivative against RMGPa, being approximately 2-fold less potent than that of PSN-357. In order to screen out a compound for in vivo activity test, we further conducted an experiment of inhibition against three different subtypes of GPa (HLGPa, HMGPa and HBGPa) and the corresponding affinity experiment. As a result, compound IIIh showed strong inhibitory activity against the above three subtypes of GP, especially on HBGPa (IC₅₀ = 0.09 ± 0.002 µM), which was relatively close to that of positive control ingliforib (IC₅₀ = 0.16 ± 0.02 µM). The affinity of compound IIIh to HBGPa was 4.3 times higher than that of HLGPa, and 1.1 times higher than that of HMGPa. This fact further proved that compound IIIh has a higher inhibitory effect on HMGPa than the other two subtypes. Besides, in vivo activity evaluation demonstrated that compound IIIh exhibited obviously cardioprotective effect on MI/R injury mice. The discovery of compound IIIh provides a new strategy for developing novel GP inhibitors with myocardial ischemia protection.

项与 GL-GP inhibitors(Boehringer Ingelheim) 相关的新闻（医药）

2023-05-25

·Business Wire

EMD Serono Highlights Commitment to Improving Cancer Outcomes at ASCO 2023

ROCKLAND, Mass.--( BUSINESS WIRE )--EMD Serono, the Healthcare business of Merck KGaA, Darmstadt, Germany in the US and Canada, today announced that 43 abstracts covering several modalities and mechanisms will be presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, June 2-6, Chicago. New data for the medicines BAVENCIO ® (avelumab) and TEPMETKO ® (tepotinib) and pipeline assets including the first-in-class investigational IAP (inhibitor of apoptosis protein) inhibitor xevinapant demonstrate the Company’s efforts to pioneer novel medicines intended to improve the lives of people living with cancer. “The research we will present at ASCO 2023 demonstrates that we are not only maximizing the impact of our standard-of-care treatments but also advancing development programs focused on synergistic approaches targeting key cancer pathways and mechanisms,” said Victoria Zazulina, M.D., Head of Development Unit, Oncology, for the Healthcare business of Merck KGaA, Darmstadt, Germany. Key presentations include: BAVENCIO (Abstracts: 4515, 4516) clinical data reinforce its role as a standard of care in first-line maintenance for advanced urothelial carcinoma (UC): Poster discussions, including long-term safety analyses and an analysis of quality-adjusted survival from the Phase III JAVELIN Bladder 100 study, confirm the acceptable long-term benefit-risk profile as well as the net benefit estimate of BAVENCIO first-line (1L) maintenance and further support its use as a standard of care for advanced UC. As part of the JAVELIN Bladder regimen, BAVENCIO first-line maintenance has demonstrated the longest survival benefit seen to date in a global, randomized Phase III trial in advanced UC. Xevinapant (Abstracts: TPS6101, 6027) preclinical data supporting dosing rationale for this investigational IAP inhibitor as well as a trial-in-progress poster outlining design of the recently initiated Phase III XRay Vision ® study in locally advanced squamous cell carcinoma of the head and neck (LA SCCHN): Preclinical data demonstrate the benefit of extended xevinapant treatment beyond the completion of xevinapant plus radiotherapy (RT) and support the rationale for administration of six cycles of xevinapant in the ongoing Phase III studies, while also indicating that restoring sensitivity to apoptosis may address some unmet treatment needs in LA SCCHN. The trial design of the ongoing randomized Phase III XRay Vision study also will be featured. This study is assessing xevinapant plus RT in patients with resected, high-risk LA SCCHN who are not eligible for cisplatin. TEPMETKO (Abstracts: 9021, 9060, 9070, 9074) data continue to demonstrate durable efficacy for first-line treatment of MET ex14 advanced non-small cell lung cancer (NSCLC): Long-term outcomes from the VISION study, the largest study of a MET inhibitor in patients with MET ex14-skipping advanced NSCLC (N=313), demonstrate the robust and durable clinical activity of TEPMETKO, particularly in the first-line setting, detected by liquid and/or tissue biopsy: with median follow-up of 32.6 months, in 164 first-line patients, overall response rate was 57.3% (95% CI: 49.4, 65.0) and median duration of response was 46.4 months (13.8, not estimable). A manageable safety profile further supports its use in clinical practice. Additional presentations for TEPMETKO include analyses from the INSIGHT 2 study in EGFR m MET amp NSCLC for patients treated with TEPMETKO plus osimertinib. Additional company-sponsored activity at ASCO: CME Live Symposium & Webcast, “After More Than a Decade: Can We Now Enhance Treatment of Patients With LA SCCHN?” with course director Kevin Harrington, PhD, FRCR, FRCP, The Institute of Cancer Research, The Royal Marsden Hospital, London, UK, on June 3, 7:00-8:00 PM CDT, Hilton Chicago (720 South Michigan Ave.), room Continental A. In addition to the data being presented at ASCO 2023, EMD Serono will launch a new educational initiative for oncology professionals on the unmet medical need in LA SCCHN, cancer’s resistance to apoptosis, and the role of apoptosis proteins. More information on the initiative can be found at www.TheWallinSCCHN.com . Select EMD Serono-related abstracts accepted for presentation at ASCO 2023 include (all times in CDT): Title Lead Author Abstract Session Information BAVENCIO (avelumab) Advanced Urothelial Carcinoma Long-term safety of avelumab first-line (1L) maintenance for advanced urothelial carcinoma (aUC) in the JAVELIN Bladder 100 trial Bellmunt J 4516 Genitourinary Cancer: Kidney and Bladder Saturday, June 3, 2023 8:00AM-11:00AM Poster Discussion Time: 3:00PM-4:30PM Estimated net benefit of avelumab (AVE) + best supportive care (BSC) vs BSC alone for patients (pts) with advanced urothelial carcinoma (aUC) using a quality-adjusted time without cancer symptoms or toxicity (Q-TWiST) analysis Powles T 4515 Genitourinary Cancer: Kidney and Bladder Saturday, June 3, 2023 8:00AM-11:00AM Poster Discussion Time: 3:00PM-4:30PM Real-world response (rwR) rates and clinical outcomes of patients treated with first-line (1L) platinum-based chemotherapy (PBC) for advanced urothelial cancer (aUC) Moon HH 4567 Genitourinary Cancer: Kidney and Bladder Saturday, June 3, 2023 8:00 AM-11:00 AM Metastatic Merkel Cell Carcinoma Avelumab as second-line or later (2L+) treatment in patients (pts) with metastatic Merkel cell carcinoma (mMCC): analysis of real-world outcomes in France using the CARADERM registry and the French national healthcare database Blom A 9537 Melanoma/Skin Cancers Saturday, June 3, 2023 1:15PM-4:15PM Metastatic Colorectal Cancer Modified FOLFOXIRI plus cetuximab and avelumab as initial therapy in RAS wild-type unresectable metastatic colorectal cancer: results of the phase II AVETRIC trial by GONO Conca V 3575 Gastrointestinal Cancer: Colorectal and Anal Monday, June 5, 2023 8:00AM-11:00AM Xevinapant Phase 3 study of xevinapant plus radiotherapy (RT) for high-risk, cisplatin-ineligible patients with resected, locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) Ferris RL TPS6101 Head and Neck Cancer Monday, June 5, 2023 1:15PM-4:15PM Effect of extended treatment with IAP inhibitor xevinapant post radiotherapy (RT) on efficacy and the tumor microenvironment (TME) in preclinical models Yeung TL 6027 Head and Neck Cancer Monday, June 5, 2023 1:15PM-4:15PM TEPMETKO (tepotinib) Long-term outcomes of tepotinib in patients with MET exon 14 skipping NSCLC from the VISION study Paik P 9060 Lung Cancer: Non-Small Cell Metastatic Sunday, June 4, 2023 8:00AM-11:00AM Tepotinib + osimertinib for EGFR mutant (EGFRm) NSCLC with MET amplification (METamp) after first-line (1L) osimertinib Tan D 9021 Lung Cancer: Non-Small Cell Metastatic Sunday, June 4, 2023 8:00AM-11:00AM Poster Discussion Time: 4:30PM-6:00PM Detection of MET amplification (METamp) in patients with EGFR mutant (m) NSCLC after first-line (1L) osimertinib Yu H 9074 Lung Cancer: Non-Small Cell Metastatic Sunday, June 4, 2023 8:00AM-11:00AM Patients with EGFR-mutant (m) MET-altered NSCLC receiving tepotinib with an EGFR tyrosine kinase inhibitor (TKI): a case series Le X 9070 Lung Cancer: Non-Small Cell Metastatic Sunday, June 4, 2023 8:00 AM-11:00 AM Advancing the Future of Cancer Care At EMD Serono, we strive every day to improve the futures of people living with cancer. Our research explores the full potential of promising mechanisms in cancer research, focused on synergistic approaches designed to hit cancer at its core. We are determined to maximize the impact of our standard-of-care treatments and to continue pioneering novel medicines. Our vision is to create a world where more cancer patients will become cancer survivors. Learn more at www.emdseronooncology.com . About BAVENCIO ® (avelumab) BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, BAVENCIO has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models. The Merck KGaA, Darmstadt, Germany-Pfizer strategic alliance regarding BAVENCIO was mutually terminated, with an effective date of June 30, 2023, with Merck KGaA, Darmstadt, Germany regaining exclusive worldwide rights for BAVENCIO. BAVENCIO Approved Indications BAVENCIO ® (avelumab) is indicated in the US for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. BAVENCIO is also indicated for the treatment of patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. BAVENCIO in combination with INLYTA (axitinib) is indicated in the US for the first-line treatment of patients with advanced renal cell carcinoma (RCC). In the US, the FDA granted accelerated approval for BAVENCIO for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials. BAVENCIO is currently approved for at least one indication for patients in more than 50 countries. BAVENCIO Important Safety Information from the US FDA-Approved Label BAVENCIO can cause severe and fatal immune-mediated adverse reactions in any organ system or tissue and at any time after starting treatment with a PD-1/PD-L1 blocking antibody, including after discontinuation of treatment. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. No dose reduction for BAVENCIO is recommended. For immune-mediated adverse reactions, withhold or permanently discontinue BAVENCIO depending on severity. In general, withhold BAVENCIO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue BAVENCIO for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids. In general, if BAVENCIO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic corticosteroids (eg, endocrinopathies and dermatologic reactions) are discussed in subsequent sections. BAVENCIO can cause immune-mediated pneumonitis , including fatal cases. Monitor patients for signs and symptoms of pneumonitis and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for Grade 2 and permanently discontinue for Grade 3 or Grade 4 pneumonitis. Immune-mediated pneumonitis occurred in 1.2% (21/1738) of patients, including fatal (0.1%), Grade 4 (0.1%), Grade 3 (0.3%) and Grade 2 (0.6%) adverse reactions. Systemic corticosteroids were required in all (21/21) patients with pneumonitis. BAVENCIO can cause immune-mediated colitis . The primary component of immune-mediated colitis consisted of diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Withhold BAVENCIO for Grade 2 or Grade 3, and permanently discontinue for Grade 4 colitis. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including Grade 3 (0.4%) and Grade 2 (0.7%) adverse reactions. Systemic corticosteroids were required in all (26/26) patients with colitis. BAVENCIO can cause hepatotoxicity and immune-mediated hepatitis . Withhold or permanently discontinue BAVENCIO based on tumor involvement of the liver and severity of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin elevation. Immune-mediated hepatitis occurred with BAVENCIO as a single agent in 0.9% (16/1738) of patients, including fatal (0.1%), Grade 3 (0.6%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in all (16/16) patients with hepatitis. BAVENCIO in combination with INLYTA can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 ALT and AST elevation compared to BAVENCIO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy. Withhold or permanently discontinue both BAVENCIO and INLYTA based on severity of AST, ALT, or total bilirubin elevation, and consider administering corticosteroids as needed. Consider rechallenge with BAVENCIO or INLYTA, or sequential rechallenge with both BAVENCIO and INLYTA, after recovery. In patients treated with BAVENCIO in combination with INLYTA in the advanced RCC trials, increased ALT and increased AST were reported in 9% (Grade 3) and 7% (Grade 4) of patients. Immune-mediated hepatitis was reported in 7% of patients including 4.9% with Grade 3 or 4 immune-mediated hepatitis. Thirty-four patients were treated with corticosteroids and one patient was treated with a non-steroidal immunosuppressant. BAVENCIO can cause primary or secondary immune-mediated adrenal insufficiency . For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement, as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Immune-mediated adrenal insufficiency occurred in 0.5% (8/1738) of patients, including Grade 3 (0.1%) and Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in all (8/8) patients with adrenal insufficiency. BAVENCIO can cause immune-mediated hypophysitis . Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement, as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Immune-mediated pituitary disorders occurred in 0.1% (1/1738) of patients, which was a Grade 2 (0.1%) adverse reaction. BAVENCIO can cause immune-mediated thyroid disorders . Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism, as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Thyroiditis occurred in 0.2% (4/1738) of patients, including Grade 2 (0.1%) adverse reactions. Hyperthyroidism occurred in 0.4% (7/1738) of patients, including Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in 29% (2/7) of patients with hyperthyroidism. Hypothyroidism occurred in 5% (90/1738) of patients, including Grade 3 (0.2%) and Grade 2 (3.7%) adverse reactions. Systemic corticosteroids were required in 7% (6/90) of patients with hypothyroidism. BAVENCIO can cause immune-mediated type I diabetes mellitus , which can present with diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Immune-mediated type I diabetes mellitus occurred in 0.1% (2/1738) of patients, including Grade 3 (0.1%) adverse reactions. BAVENCIO can cause immune-mediated nephritis with renal dysfunction . Withhold BAVENCIO for Grade 2 or Grade 3, and permanently discontinue for Grade 4 increased blood creatinine. Immune-mediated nephritis with renal dysfunction occurred in 0.1% (1/1738) of patients, which was a Grade 2 (0.1%) adverse reaction. Systemic corticosteroids were required in this patient. BAVENCIO can cause immune-mediated dermatologic adverse reactions , including rash or dermatitis. Exfoliative dermatitis including Stevens Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold BAVENCIO for suspected and permanently discontinue for confirmed SJS, TEN, or DRESS. Immune-mediated dermatologic adverse reactions occurred in 5% (90/1738) of patients, including Grade 3 (0.1%) and Grade 2 (2.0%) adverse reactions. Systemic corticosteroids were required in 29% (26/90) of patients with dermatologic adverse reactions. BAVENCIO can result in other immune-mediated adverse reactions . Other clinically significant immune-mediated adverse reactions occurred at an incidence of <1% in patients who received BAVENCIO or were reported with the use of other PD-1/PD-L1 blocking antibodies. For myocarditis, permanently discontinue BAVENCIO for Grade 2, Grade 3, or Grade 4. For neurological toxicities, withhold BAVENCIO for Grade 2 and permanently discontinue for Grade 3 or Grade 4. BAVENCIO can cause severe or life-threatening infusion-related reactions . Premedicate patients with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent infusions based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 infusion-related reactions. Permanently discontinue BAVENCIO for Grade 3 or Grade 4 infusion-related reactions. Infusion-related reactions occurred in 25% of patients, including three (0.2%) Grade 4 and nine (0.5%) Grade 3 infusion-related reactions. Eleven (92%) of the 12 patients with Grade ≥3 reactions were treated with intravenous corticosteroids. Fatal and other serious complications of allogeneic hematopoietic stem cell transplantation (HSCT) can occur in patients who receive HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT. BAVENCIO in combination with INLYTA can cause major adverse cardiovascular events (MACE) including severe and fatal events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Permanently discontinue BAVENCIO and INLYTA for Grade 3-4 cardiovascular events. MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with INLYTA compared to 3.4% treated with sunitinib in a randomized trial. These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%). BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants. The most common adverse reactions (all grades, ≥20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%). Selected treatment-emergent laboratory abnormalities (all grades, ≥20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%). A fatal adverse reaction (sepsis) occurred in one (0.3%) patient with locally advanced or metastatic urothelial carcinoma (UC) receiving BAVENCIO + best supportive care (BSC) as first-line maintenance treatment. In patients with previously treated locally advanced or metastatic UC, fourteen patients (6%) who were treated with BAVENCIO experienced either pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal adverse events, which led to death. The most common adverse reactions (all grades, ≥20%) in patients with locally advanced or metastatic UC receiving BAVENCIO + BSC (vs BSC alone) as first-line maintenance treatment were fatigue (35% vs 13%), musculoskeletal pain (24% vs 15%), urinary tract infection (20% vs 11%), and rash (20% vs 2.3%). In patients with previously treated locally advanced or metastatic UC receiving BAVENCIO, the most common adverse reactions (all grades, ≥20%) were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection. Selected laboratory abnormalities (all grades, ≥20%) in patients with locally advanced or metastatic UC receiving BAVENCIO + BSC (vs BSC alone) as first-line maintenance treatment were blood triglycerides increased (34% vs 28%), alkaline phosphatase increased (30% vs 20%), blood sodium decreased (28% vs 20%), lipase increased (25% vs 16%), aspartate aminotransferase (AST) increased (24% vs 12%), blood potassium increased (24% vs 16%), alanine aminotransferase (ALT) increased (24% vs 12%), blood cholesterol increased (22% vs 16%), serum amylase increased (21% vs 12%), hemoglobin decreased (28% vs 18%), and white blood cell decreased (20% vs 10%). Fatal adverse reactions occurred in 1.8% of patients with advanced renal cell carcinoma (RCC) receiving BAVENCIO in combination with INLYTA. These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing pancreatitis (0.2%). The most common adverse reactions (all grades, ≥20%) in patients with advanced RCC receiving BAVENCIO in combination with INLYTA (vs sunitinib) were diarrhea (62% vs 48%), fatigue (53% vs 54%), hypertension (50% vs 36%), musculoskeletal pain (40% vs 33%), nausea (34% vs 39%), mucositis (34% vs 35%), palmar-plantar erythrodysesthesia (33% vs 34%), dysphonia (31% vs 3.2%), decreased appetite (26% vs 29%), hypothyroidism (25% vs 14%), rash (25% vs 16%), hepatotoxicity (24% vs 18%), cough (23% vs 19%), dyspnea (23% vs 16%), abdominal pain (22% vs 19%), and headache (21% vs 16%). Selected laboratory abnormalities (all grades, ≥20%) worsening from baseline in patients with advanced RCC receiving BAVENCIO in combination with INLYTA (vs sunitinib) were blood triglycerides increased (71% vs 48%), blood creatinine increased (62% vs 68%), blood cholesterol increased (57% vs 22%), alanine aminotransferase increased (ALT) (50% vs 46%), aspartate aminotransferase increased (AST) (47% vs 57%), blood sodium decreased (38% vs 37%), lipase increased (37% vs 25%), blood potassium increased (35% vs 28%), platelet count decreased (27% vs 80%), blood bilirubin increased (21% vs 23%), and hemoglobin decreased (21% vs 65%). Please see full US Prescribing Information and Medication Guide available at http://www.BAVENCIO.com . About TEPMETKO ® (tepotinib) TEPMETKO is a once-daily oral MET inhibitor that inhibits the oncogenic MET receptor signaling caused by MET (gene) alterations. Discovered and developed in-house at Merck KGaA, Darmstadt, Germany, TEPMETKO has a highly selective mechanism of action, with the potential to improve outcomes in aggressive tumors that have a poor prognosis and harbor these specific alterations. TEPMETKO was the first oral MET inhibitor to receive a regulatory approval anywhere in the world for the treatment of advanced NSCLC harboring MET gene alterations, with its approval in Japan in March 2020. In February 2021, the US Food and Drug Administration granted accelerated approval to TEPMETKO, making it the first and only once-daily oral MET inhibitor approved for patients in the US with metastatic NSCLC with MET ex14-skipping alterations. In February 2022, the European Commission (EC) approved once-daily oral TEPMETKO as monotherapy for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) harboring alterations leading to mesenchymal-epithelial transition factor gene exon 14 ( MET ex14) skipping, who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy. TEPMETKO is available in a number of countries. To meet an urgent clinical need, TEPMETKO is also available in a pilot zone of China in line with the government policy to drive early access for innovative medicines approved outside of China. Merck KGaA, Darmstadt, Germany is also investigating the potential role of tepotinib in treating patients with NSCLC and acquired resistance due to MET amplification in the Phase II INSIGHT 2 study of tepotinib in combination with osimertinib in MET amplified, advanced or metastatic NSCLC harboring activating EGFR mutations that has progressed following first-line treatment with osimertinib. TEPMETKO Approved Indication in the US TEPMETKO is a kinase inhibitor indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal epithelial transition (MET) exon 14 skipping alterations. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Important Safety Information from the US FDA-Approved Label TEPMETKO can cause interstitial lung disease (ILD)/pneumonitis , which can be fatal. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Immediately withhold TEPMETKO in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified. ILD/pneumonitis occurred in 2.2% of patients treated with TEPMETKO, with one patient experiencing a Grade 3 or higher event; this event resulted in death. TEPMETKO can cause hepatotoxicity , which can be fatal. Monitor liver function tests (including ALT, AST, and total bilirubin) prior to the start of TEPMETKO, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop increased transaminases or total bilirubin. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue TEPMETKO. Increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST) occurred in 13% of patients treated with TEPMETKO. Grade 3 or 4 increased ALT/AST occurred in 4.2% of patients. A fatal adverse reaction of hepatic failure occurred in one patient (0.2%). The median time-to-onset of Grade 3 or higher increased ALT/AST was 30 days (range 1 to 178). TEPMETKO can cause embryo-fetal toxicity . Based on findings in animal studies and its mechanism of action, TEPMETKO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential or males with female partners of reproductive potential to use effective contraception during treatment with TEPMETKO and for one week after the final dose. Avoid concomitant use of TEPMETKO with dual strong CYP3A inhibitors and P-gp inhibitors and strong CYP3A inducers . Avoid concomitant use of TEPMETKO with certain P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling. Fatal adverse reactions occurred in one patient (0.4%) due to pneumonitis, one patient (0.4%) due to hepatic failure, and one patient (0.4%) due to dyspnea from fluid overload. Serious adverse reactions occurred in 45% of patients who received TEPMETKO. Serious adverse reactions in >2% of patients included pleural effusion (7%), pneumonia (5%), edema (3.9%), dyspnea (3.9%), general health deterioration (3.5%), pulmonary embolism (2%), and musculoskeletal pain (2%). The most common adverse reactions (≥20%) in patients who received TEPMETKO were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea. Clinically relevant adverse reactions in <10% of patients who received TEPMETKO included ILD/pneumonitis, rash, fever, dizziness, pruritus, and headache. Selected laboratory abnormalities (≥20%) from baseline in patients receiving TEPMETKO in descending order were: decreased albumin (76%), increased creatinine (55%), increased alkaline phosphatase (ALP) (50%), decreased lymphocytes (48%), increased alanine aminotransferase (ALT) (44%), increased aspartate aminotransferase (AST) (35%), decreased sodium (31%), decreased hemoglobin (27%), increased potassium (25%), increased gamma-glutamyltransferase (GGT) (24%), increased amylase (23%), and decreased leukocytes (23%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) in descending order were: decreased lymphocytes (11%), decreased albumin (9%), decreased sodium (8%), increased GGT (5%), increased amylase (4.6%), increased ALT (4.1%), increased AST (2.5%), and decreased hemoglobin (2%). A clinically relevant laboratory abnormality in <20% of patients who received TEPMETKO was increased lipase in 18% of patients, including 3.7% Grades 3 to 4. For more information about TEPMETKO, please see full Prescribing Information , and visit www.TEPMETKO.com . About Xevinapant Xevinapant (formerly known as Debio 1143) is an investigational first-in-class potent oral small-molecule IAP (inhibitor of apoptosis protein) inhibitor for the treatment of LA SCCHN. In preclinical studies, xevinapant restored sensitivity to apoptosis in cancer cells, thereby enhancing the effects of chemotherapy and radiotherapy. Xevinapant, the most clinically advanced IAP inhibitor, improved efficacy outcomes in combination with chemoradiotherapy (CRT), including three-year progression-free survival and five-year survival, compared with placebo plus CRT in a Phase II study in patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). In March 2021, Merck KGaA, Darmstadt, Germany, gained exclusive rights from Debiopharm to develop and commercialize xevinapant worldwide. Xevinapant is not approved for any use anywhere in the world. About EMD Serono, Inc. EMD Serono - the healthcare business of Merck KGaA, Darmstadt, Germany in the U.S. and Canada -aspires to create, improve and prolong life for people living with difficult-to-treat conditions like infertility, multiple sclerosis and cancer. The business is imagining the future of healthcare by working to translate the discovery of molecules into potentially meaningful outcomes for people with serious unmet medical needs. EMD Serono’s global roots go back more than 350 years with Merck KGaA, Darmstadt, Germany. Today, the business has approximately 1,500 employees around the country with commercial, clinical and research operations in Massachusetts. www.emdserono.com . About Merck KGaA, Darmstadt, Germany Merck KGaA, Darmstadt, Germany, a leading science and technology company, operates across life science, healthcare and electronics. More than 64,000 employees work to make a positive difference to millions of people’s lives every day by creating more joyful and sustainable ways to live. From providing products and services that accelerate drug development and manufacturing as well as discovering unique ways to treat the most challenging diseases to enabling the intelligence of devices – the company is everywhere. In 2022, Merck KGaA, Darmstadt, Germany, generated sales of € 22.2 billion in 66 countries. The company holds the global rights to the name and trademark “Merck” internationally. The only exceptions are the United States and Canada, where the business sectors of Merck KGaA, Darmstadt, Germany, operate as MilliporeSigma in life science, EMD Serono in healthcare and EMD Electronics in electronics. Since its founding in 1668, scientific exploration and responsible entrepreneurship have been key to the company’s technological and scientific advances. To this day, the founding family remains the majority owner of the publicly listed company.

临床3期临床结果上市批准ASCO会议加速审批

2023-02-16

·BioSpace

Pfizer Announces Positive TALZENNA® and XTANDI® Combination Data from Phase 3 TALAPRO-2 Study

Data show 37% reduction in risk of disease progression or death in men with metastatic castration-resistant prostate cancer treated with TALZENNA plus XTANDI Supplemental new drug application for TALZENNA and XTANDI combination granted U.S. FDA Priority Review NEW YORK--(BUSINESS WIRE)-- Pfizer (NYSE: PFE) announced today positive results from the Phase 3 TALAPRO-2 study of TALZENNA® (talazoparib), an oral poly ADP-ribose polymerase (PARP) inhibitor, in combination with XTANDI® (enzalutamide), demonstrating a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) compared to placebo plus XTANDI in men with metastatic castration-resistant prostate cancer (mCRPC), with or without homologous recombination repair (HRR) gene mutations. In addition, the U.S. Food and Drug Administration (FDA) has granted Priority Review for Pfizer’s supplemental new drug application (sNDA) for TALZENNA in combination with XTANDI for the treatment of men with mCRPC. The FDA grants Priority Review to medicines that may offer significant advances in treatment or may provide a treatment where no adequate therapy exists. The FDA’s decision on the sNDA is expected in 2023. The TALAPRO-2 results will be presented today, Thursday, February 16, at 8:00 a.m. PST during the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) as a late-breaking presentation (Abstract LBA17) and will be featured in the ASCO GU official press program. In the final rPFS analysis, TALZENNA plus XTANDI reduced the risk of disease progression or death by 37% versus placebo plus XTANDI (Hazard Ratio [HR]: 0.63; 95% Confidence Interval [CI], 0.51–0.78; P< 0.001). The median rPFS for the treatment arm was not reached at the time of analysis versus 21.9 months for placebo plus XTANDI. Median rPFS is reached when 50% of trial participants have had an event of disease progression or death. “Novel hormone therapies dramatically changed outcomes for patients with mCRPC in the last decade, and the results from the TALAPRO-2 study show that the addition of talazoparib to the existing standard of care adds significant clinical benefit,” said Neeraj Agarwal, M.D., FASCO, Professor of Oncology and Presidential Endowed Chair of Cancer Research at Huntsman Cancer Institute, University of Utah, and lead investigator for TALAPRO-2. “In addition to delaying disease progression, this combination delayed prostate-specific antigen progression and time to chemotherapy without adversely impacting patient quality of life. The TALAPRO-2 results support the potential for this combination to be practice-changing, with strong, highly consistent efficacy and observations in mCRPC patients both with or without HRR gene mutations, and across clinically relevant sub-populations.” A trend in overall survival (OS) favoring TALZENNA plus XTANDI was also observed, though these data are immature. The final OS will be reported once the predefined number of survival events has been reached. TALAPRO-2 is the first Phase 3 study to combine TALZENNA with XTANDI in patients unselected for genetic alterations in DNA damage repair pathways, directly or indirectly involved with HRR. The study also showed clinically meaningful improvement in median rPFS for patients in the study treated with TALZENNA plus XTANDI across several prospectively assessed subgroups including HRR-deficient (HR, 0.46; 95% CI, 0.30–0.70; P<0.001) and HRR-non-deficient or unknown (HR, 0.70; 95% CI, 0.54–0.89; P=0.004). Objective response rates, prostate-specific antigen (PSA) response ≥50%, and time to PSA progression and use of subsequent cytotoxic chemotherapy and antineoplastic therapy were also significantly improved in patients treated with TALZENNA plus XTANDI versus placebo plus XTANDI. Median time to definitive clinically meaningful deterioration in global health status/quality of life was also longer in those treated with TALZENNA plus XTANDI (30.8 vs 25.0 months, respectively; HR, 0.78; 95% CI, 0.62–0.99; P=0.04). “Patients with mCRPC need new treatment approaches that can improve outcomes, and the rPFS results from TALAPRO-2, which appears to be the longest observed in a randomized trial in this setting, demonstrate the potential of the TALZENNA and XTANDI combination, if approved, to become a new standard of care,” said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology and Rare Disease, Pfizer Global Product Development. “We are pleased that the FDA has granted Priority Review for our application, and we look forward to working with the Agency and global regulatory authorities to bring this treatment to men with mCRPC.” In the TALAPRO-2 trial, the safety of TALZENNA plus XTANDI was generally consistent with the known safety pro each medicine. Among patients treated with TALZENNA plus XTANDI, the most common adverse events (AE) (greater than 20% of participants, all grades) included anemia (65.8%), decreased neutrophil count (35.7%), fatigue (33.7), decreased platelet count (24.6%), back pain and decreased white blood cell count (22.1% each), and decreased appetite (21.6%). The most common grade ≥3 treatment emergent adverse events (TEAEs) were anemia (46.5%), low neutrophil (18.3%), and low platelet counts (7.3%). Among patients treated with placebo plus XTANDI, the most common AEs (greater than 15%) were fatigue (29.4%), arthralgia (19.7%), back pain (18.0%), anemia (17.5%), constipation (17.0%), and decreased appetite (15.7%). The most common grade >3 AEs were hypertension (7.5%), anemia (4.2%), and fatigue (2.0%). TEAEs led to discontinuation of TALZENNA in 19.1% of patients versus 12.2% of placebo. Discontinuation rates of XTANDI were generally consistent across both study arms (10.8% vs 11.0%). Pfizer plans to submit detailed results from the trial for peer-reviewed publication. In addition to the FDA, Pfizer has also shared these data with the European Medicines Agency and other regulatory agencies to support regulatory filings and will provide further updates at the appropriate time. Neither TALZENNA nor the combination of TALZENNA plus XTANDI has been approved by any regulatory agency for the treatment of mCRPC. In addition to the TALAPRO-2 trial, the combination of TALZENNA plus XTANDI is being investigated in the TALAPRO-3 trial (NCT04821622), a global, randomized, double-blind, placebo-controlled Phase 3 study in men with HRR-deficient metastatic castration-sensitive prostate cancer (mCSPC). About Metastatic Castration-Resistant Prostate Cancer Metastatic castration-resistant prostate cancer (mCRPC) is a cancer that has spread beyond the prostate gland and has progressed despite medical or surgical treatment to lower testosterone. Approximately 10%–20% of prostate cancer patients develop mCRPC within 5−7 years of diagnosis,1 and in the U.S., in 2020, approximately 60-90 thousand cases of the 3 million prostate cancer cases were mCRPC.2 About TALAPRO-2 The Phase 3 TALAPRO-2 trial is a two-part, two-cohort, multicenter, randomized, double-blind, placebo-controlled study that enrolled 1,106 patients with mCRPC (with no systemic treatments initiated after documentation of mCRPC) at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. The study included two patient cohorts: all-comers (n=750) and those with HRR mutations (HRRm; n=380). Patients on androgen deprivation therapy (ADT) or who had bilateral orchiectomy in the trial were randomized to receive TALZENNA 0.5 mg/day plus XTANDI 160mg/day, or placebo plus XTANDI 160 mg/day. The primary endpoint of the trial is radiographic progression-free survival (rPFS), defined as the time from the date of randomization to first objective evidence of radiographic progression by blinded independent review, or death, whichever occurs first, in both cohort 1 (all-comers) and cohort 2 (those with HRRm). The trial is still ongoing for cohort 2. Secondary endpoints include overall survival, objective response rate, duration of response, and PSA response. For more information on the TALAPRO-2 trial (NCT03395197), go to . About TALZENNA® (talazoparib) TALZENNA (talazoparib) is an oral poly ADP-ribose polymerase (PARP) inhibitor, which plays a role in DNA damage repair. Preclinical studies have demonstrated that TALZENNA blocks PARP enzyme activity and traps PARP at the site of DNA damage, leading to decreased cancer cell growth and cancer cell death. TALZENNA is approved in over 70 countries, including the U.S., as a once daily monotherapy for the treatment of adult patients with deleterious or suspected deleterious germline breast cancer susceptibility gene (BRCA)-mutated (gBRCAm) human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. TALZENNA is being investigated as a combination therapy with XTANDI® (enzalutamide) in men with advanced prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC) in the Phase 3 TALAPRO-2 clinical trial and metastatic castration-sensitive prostate cancer (mCSPC) in the Phase 3 TALAPRO-3 clinical trial. Preclinical studies have shown that the combination of a PARP inhibitor and an androgen receptor signaling inhibitor (ARSi) may result in an enhanced anti-tumor effect. Other combinations of TALZENNA with targeted therapies are also being studied in various solid tumors. TALZENNA® (talazoparib) Indication in the U.S. TALZENNA (talazoparib) is indicated for the treatment of adult patients with deleterious or suspected deleterious germline breast cancer susceptibility gene (BRCA)-mutated (gBRCAm) human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. Select patients for therapy based on an FDA-approved companion diagnostic for TALZENNA. TALZENNA® (talazoparib) Important Safety Information Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) have been reported in patients who received TALZENNA. Overall, MDS/AML has been reported in <1% (3 out of 787, 0.4%) of solid tumor patients treated with TALZENNA in clinical studies. The duration of TALZENNA treatment in these three patients prior to developing MDS/AML was 4 months, 24 months, and 60 months respectively. These patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. Myelosuppression consisting of anemia, leukopenia/neutropenia, and/or thrombocytopenia have been reported in patients treated with TALZENNA. Grade ≥3 anemia, neutropenia, and thrombocytopenia were reported, respectively, in 39%, 21%, and 15% of patients receiving TALZENNA. Discontinuation due to anemia, neutropenia, and thrombocytopenia occurred, respectively, in 0.7%, 0.3%, and 0.3% of patients. Monitor complete blood counts for cytopenia at baseline and monthly thereafter. Do not start TALZENNA until patients have adequately recovered from hematological toxicity caused by previous therapy. If hematological toxicity occurs, dose modifications (dosing interruption with or without dose reduction) are recommended. With respect to MDS/AML, for prolonged hematological toxicities, interrupt TALZENNA and monitor blood counts weekly until recovery. If the levels have not recovered after 4 weeks, refer the patient to a hematologist for further investigations. If MDS/AML is confirmed, discontinue TALZENNA. TALZENNA can cause fetal harm when administered to pregnant women. Advise women of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose. A pregnancy test is recommended for females of reproductive potential prior to initiating TALZENNA treatment. Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment with TALZENNA and for at least 4 months after receiving the last dose. Based on animal studies, TALZENNA may impair fertility in males of reproductive potential. Advise women not to breastfeed while taking TALZENNA and for at least 1 month after receiving the last dose because of the potential for serious adverse reactions in nursing infants. The most common adverse reactions (≥20%) of any grade for TALZENNA vs chemotherapy were fatigue (62% vs 50%), anemia (53% vs 18%), nausea (49% vs 47%), neutropenia (35% vs 43%), headache (33% vs 22%), thrombocytopenia (27% vs 7%), vomiting (25% vs 23%), alopecia (25% vs 28%), diarrhea (22% vs 26%), and decreased appetite (21% vs 22%). The most frequently reported Grade ≥3 adverse reactions (≥10%) for TALZENNA vs chemotherapy were anemia (39% vs 5%), neutropenia (21% vs 35%), and thrombocytopenia (15% vs 2%). The most common lab abnormalities (≥25%) for TALZENNA vs chemotherapy were decreases in hemoglobin (90% vs 77%), leukocytes (84% vs 73%), lymphocytes (76% vs 53%), neutrophils (68% vs 70%), platelets (55% vs 29%), and calcium (28% vs 16%) and increases in glucose (54% vs 51%), aspartate aminotransferase (37% vs 48%), alkaline phosphatase (36% vs 34%), and alanine aminotransferase (33% vs 37%). Coadministration with P-gp inhibitors or BCRP inhibitors may increase TALZENNA exposure. If coadministering with the P-gp inhibitors amiodarone, carvedilol, clarithromycin, itraconazole, or verapamil is unavoidable, reduce the TALZENNA dose to 0.75 mg once daily. When the P-gp inhibitor is discontinued, increase the TALZENNA dose (after 3–5 half-lives of the P-gp inhibitor) to the dose used prior to the initiation of the P-gp inhibitor. When coadministering TALZENNA with other known P-gp inhibitors or BCRP inhibitors, monitor patients for potential increased adverse reactions. For patients with moderate renal impairment, the recommended dose of TALZENNA is 0.75 mg once daily. For patients with severe renal impairment, the recommended dose of TALZENNA is 0.5 mg once daily. No dose adjustment is required for patients with mild renal impairment. TALZENNA has not been studied in patients requiring hemodialysis. Please see full U.S. Prescribing Information and Patient Information for TALZENNA® (talazoparib) at . About XTANDI® (enzalutamide) and Important Safety Information XTANDI (enzalutamide) is an androgen receptor inhibitor indicated in the U.S. for the treatment of patients with castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer (mCSPC). Overall survival benefit has been observed in patients treated with XTANDI in mCRPC, nmCRPC, and mCSPC. Warnings and Precautions Seizure occurred in 0.5% of patients receiving XTANDI in seven randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment. Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder that can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES. Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in seven randomized clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions. Ischemic Heart Disease In the combined data of four randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.9% vs 1.3%). Grade 3-4 ischemic events occurred in 1.4% of patients on XTANDI versus 0.7% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease. Falls and Fractures occurred in patients receiving XTANDI. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents. In the combined data of four randomized, placebo-controlled clinical studies, falls occurred in 11% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 10% of patients treated with XTANDI and in 4% of patients treated with placebo. Embryo-Fetal Toxicity The safety and efficacy of XTANDI have not been established in females. XTANDI 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 with XTANDI and for 3 months after the last dose of XTANDI. Adverse Reactions (ARs) In the data from the four randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension. In the bicalutamide-controlled study, the most common ARs (≥ 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss. In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to adverse events (AEs) were reported for 16% of XTANDI-treated patients. In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to AEs were reported for 6% of XTANDI-treated patients. In TERRAIN, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AE as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients. In PROSPER, the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AE as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients. In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher AEs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to AEs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients. Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, and hypercalcemia. Hypertension: In the combined data from four randomized placebo-controlled clinical trials, hypertension was reported in 12% of XTANDI patients and 5% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm. Drug Interactions Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI. Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI. Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see Full Prescribing Information for additional safety information. About Pfizer Oncology At Pfizer Oncology, we are committed to advancing medicines wherever we believe we can make a meaningful difference in the lives of people living with cancer. Today, we have an industry-leading portfolio of 24 approved innovative cancer medicines and biosimilars across more than 30 indications, including breast, genitourinary, colorectal, blood, and lung cancers, as well as melanoma. About the Pfizer/Astellas Collaboration In October 2009, Medivation, Inc., which is now part of Pfizer (NYSE: PFE), and Astellas (TSE: 4503) entered into a global agreement to jointly develop and commercialize enzalutamide. The companies jointly commercialize XTANDI in the United States, and Astellas has responsibility for manufacturing and all additional regulatory filings globally, as well as commercializing XTANDI outside the United States. Disclosure Notice The information contained in this release is as of February 16, 2023. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments. This release contains forward-looking information about Pfizer Oncology, TALZENNA and XTANDI, including their potential benefits and a potential indication in men with metastatic castration-resistant prostate cancer, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; whether TALAPRO-2 trial will meet the primary endpoint for cohort 2 or the secondary endpoint for overall survival; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when applications for TALZENNA, XTANDI or a combination may be filed in particular jurisdictions for the potential indication or for any other indications; whether and when the FDA may approve the sNDA for TALZENNA in combination with XTANDI for the treatment of men with mCRPC and whether and when any such other applications for TALZENNA, XTANDI or a combination may be approved by regulatory authorities, which will depend on myriad factors, including making a determination as to whether the product’s benefits outweigh its known risks and determination of the product’s efficacy and, if approved, whether TALZENNA, XTANDI or a combination will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of TALZENNA, XTANDI or a combination; uncertainties regarding the impact of COVID-19 on our business, operations and financial results; and competitive developments. A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2021 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at and . ### 1 Kirby M, et al. (2011) Characterising the castration-resistant prostate cancer population: a systematic review. International journal of clinical practice, 65(11), 1180–1192. . 2 Scher HI, et al. (2015) Prevalence of Prostate Cancer Clinical States and Mortality in the United States: Estimates Using a Dynamic Progression Model. PLoS ONE 10(10): e0139440. .

临床3期临床结果ASCO会议上市批准优先审批

100 项与 GL-GP inhibitors(Boehringer Ingelheim) 相关的药物交易

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