Over the past decades, healthcare systems face significant challenges to meet the needs of an aging population due to progressive debility, functional decline and chronic diseases development. While there is a growing appreciation of the potential impact of mTOR inhibitors on slowing aging processes, preventing chronic disease and prolonging healthy lifespan, a major challenge in developing clinical trials to establish the clinical efficacy of mTOR inhibitors is the absence of pharmacokinetics (PK) and pharmacodynamics (PD) data in older adults. The proposed study will provide the foundation for future clinical trials assessing the role of mTOR inhibitors on aging related indications

Start Date01 May 2025

Sponsor / Collaborator

The University of Texas Southwestern Medical Center

[+2]

NCT04199026 / Not yet recruitingEarly Phase 1IIT

Pilot Trial of an Implantable Microdevice for In Vivo Drug Sensitivity Testing in Patients With Sarcomas

This early phase I trial studies the side effects of implanting and removing a microdevice in patients with sarcomas that have spread to other places in the body (metastatic) or have come back (recurrent). Microdevices are rice-sized devices that are implanted into tumor tissue and are loaded with 10 different drugs that are delivered at very small doses, or "microdoses," which may only affect a very small, local area inside the tumor. The purpose of this study is to determine which drugs delivered in the microdevice affect tumor tissue in patients with sarcomas.

Start Date31 Jan 2025

Sponsor / Collaborator

The University of Texas MD Anderson Cancer Center

[+1]

NCT06658093 / Not yet recruitingEarly Phase 1IIT

RESTOR [Rapamycin and Everolimus Study Towards Older Rejuvenation]: An Exploratory PK/PD Study of mTOR Inhibition in Older Human Subjects

As people get older, there are changes in their cells and tissues that may affect their ability to function. This can lead to increased death and age-associated disorders, like heart disease, cancer, and Alzheimer's disease. Studies in animal models have been able to identify drugs that slow the aging process, leading to a longer, healthier life. This study is focused on one such family of drugs, called mTOR inhibitors, and the investigators' goal is to test two of these drugs, Rapamycin (Sirolimus) and Everolimus (Afinitor), in healthy older adults to find a dose and dose timing that can be used to safely inhibit mTOR to the levels seen in young healthy persons. The investigators expect that the dose that works well in women may differ from the one that is best in men, so it is important to include both sexes in this research.

Start Date01 Jan 2025

Sponsor / Collaborator

University of Texas Health Science Center At San Antonio

[+1]

100 Clinical Results associated with Everolimus

100 Translational Medicine associated with Everolimus

100 Patents (Medical) associated with Everolimus

8,542

Literatures (Medical) associated with Everolimus

01 Feb 2025·CURRENT CANCER DRUG TARGETS

Screening miRNAs to Hinder the Tumorigenesis of Renal Clear Cell Carcinoma Associated with KDR Expression

Article

Author: Suseela, Rangaraj ; Miji, Thandaserry Vasudevan ; Bharathi, Muruganantham ; Muthusami, Sridhar ; Almoallim, Hesham S. ; Kaviyaprabha, Rangaraj ; Thangaleela, Subramanian ; Sivakumar, Priyadarshini

Introduction::

This study delved into the role of Kinase Insert Domain Receptor (KDR) and its associated miRNAs in renal cell carcinoma through an extensive computational analysis. The potential of our findings to guide future research in this area is significant.

Methods::

Our methods, which included the use of UALCAN and GEPIA2 databases, as well as miRDB, MirDIP, miRNet v2.0, miRTargetLink, MiEAA v2.1, TarBase v8.0, INTERNET, and miRTarBass, were instrumental in identifying the regulation of miRNA associated with KDR expression. The predicted miRNA was validated with the TCGA-KIRC patients’ samples by implementing CancerMIRNome. The TargetScanHuman v8.0 was implemented to identify the associations between human miRNAs and KDR. A Patch Dock server analyzed the interactions between hsa-miR-200b-3p-KDR and hsa-miR-200b-3p with KDR.

Results::

The KDR expression rate was investigated in the Kidney Renal Cell Carcinoma (KIRC) samples, and adjacent normal tissues revealed that the expression rate was significantly higher than the normal samples, which was evident from the strong statistical significance (P = 1.63e-12). Likely, the KDR ex-pression rate was estimated as high at tumor grade 1 and gradually decreased till the metastasis grade, reducing the survival rate of the KIRC patients. To identify these signals early, we predicted a miRNA that could trigger the expression of KDR. Furthermore, we uncovered the potential associations between miR-200c-3p expressions by regulating KDR towards the progression of KIRC.

Discussion::

Upon examining the outcome, it became evident that miR-200c-3p was significantly down-regulated in KIRC compared to the normal samples. Moreover, the negative correlation was obtained for hsa-miR-200c-3p (R = - 0.276) along with the KDR expression describing that the increased rate of hsa-miR-200c-3p might reduce the KDR expression rate, which may suppress the KIRC initiation or progres-sion.

Conclusion::

The in-silico analysis indicated that the significant increase in KDR expression during the initiation of KIRC could serve as an early diagnostic marker. Moreover, KDR could be utilized to identify advancements in KIRC stages. Additionally, hsa-miR-200c-3p was identified as a potential regulator capable of downregulating and upregulating KDR expression among the 24 miRNAs screened. This find-ing holds promise for future research endeavors. Concurrent administration of the FDA-approved 5-fluor-ouracil with KIRC drugs, such as sorafenib, zidovudine, and everolimus, may have the potential to en-hance the therapeutic efficacy in downregulating hsa-miR-200c-3p. However, further in vitro studies are imperative to validate these findings and gain a comprehensive understanding of the intricate regulatory interplay involving hsa-miR-200c-3p, KDR, 5-fluorouracil, and other FDA-approved drugs for the treat-ment of KIRC. This will facilitate the identification of KIRC stage progression and its underlying pre-ventative mechanisms.

01 Feb 2025·Clinical Genitourinary Cancer

Cost-Effectiveness Analysis of Lenvatinib plus Pembrolizumab or Everolimus as First-Line Treatment for Advanced Renal Cell Carcinoma

Article

Author: Zheng, Huanrui ; Zhang, Jinhua ; Zhou, Jin ; Tong, Yao

BACKGROUND:

Recently, due to its promising efficacy against advanced renal cell carcinoma (RCC), the combination therapy with lenvatinib and pembrolizumab or everolimus has been approved as a first-line treatment for patients with advanced RCC in China and the United States. However, the high costs of combination therapies, especially of those new drugs, may limit their viability as clinical treatment options. Thus, our study aimed to evaluate the cost-effectiveness of using lenvatinib plus pembrolizumab or everolimus as a first-line treatment for patients with advanced RCC from the perspective of the Chinese healthcare system and US third-party payers.

METHODS:

We established a Markov model using TreeAge Pro 2022 software to estimate and compare the cost and effectiveness of the therapy with lenvatinib plus pembrolizumab or everolimus with those of sunitinib therapy for treating advanced RCC based on the clinical data derived from a phase III randomized controlled trial (CLEAR, ClinicalTrials.gov number NCT02811861). Transition probabilities and other data were calculated and obtained by using parametric survival modeling. The direct medical costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were used as economic indicators in this analysis. The robustness of the model was assessed by performing one-way and probability sensitivity analyses (PSA).

RESULTS:

Among the 3 treatment strategies, the sunitinib 1 was the least expensive option. All ICERs were far higher than the thresholds of $38,024 and $100,000 selected for China and the United States, respectively. The ICERs of the therapy with lenvatinib plus pembrolizumab versus sunitinib therapy were 106,749.06 US$/QALY and $414,672.19 US$/QALY in China and the United States, respectively. Thus, among these 2, the former strategy was less cost-effective than the latter. In addition, the ICERs of the lenvatinib plus everolimus treatment vs. sunitinib treatment were $44,353.18 US$/QALY and $292,653.10 US$/QALY in China and the United States, respectively. Thus, among these 2 strategies, the former was less cost-effective than the latter. The total cost of the lenvatinib plus everolimus treatment strategy was lower than that of lenvatinib plus pembrolizumab; however, the former treatment was less effective than the latter.

CONCLUSION:

The treatment with lenvatinib plus pembrolizumab or everolimus is less cost-effective than the sunitinib treatment for patients with advanced RCC in China and the United States.

01 Jan 2025·NEUROPHARMACOLOGY

Abnormal increased mTOR signaling regulates seizure threshold in Dravet syndrome

Article

Author: Ho, Shih-Yin ; Chang, Kai-Chieh ; Tsai, Che-Wen ; Chen, I Chun ; Chen, Hou-Jen ; Liou, Horng-Huei ; Tsai, Feng-Chiao

Excessive activation of mTOR has been observed in the brains of mouse models for Dravet syndrome. We aim to confirm whether that the overactivation of mTOR contributes to the neuropathological changes leading to epileptogenesis and neurobehavior deficits to support a novel pharmacological therapeutic approach for Dravet syndrome. The mTOR inhibitor everolimus, as a clinical antiseizure medication, was utilized to investigate whether mTOR is involved in hyperthermia-induced seizures, anxiety-like, and autism-like behaviors, as well as to explore potential pathogenic mechanisms in Scn1a^E1099X/+ mice, a model of Dravet syndrome. First, we found that mTOR signaling was upregulated in hippocampus tissues and neural cultures derived from Scn1a^E1099X/+ mice prior to seizure onset. Behaviorally, everolimus increased the seizure threshold and improved anxiety-like and autism-like behaviors in Scn1a^E1099X/+ mice. Electrophysiologically, everolimus reduced the frequency of spontaneous excitatory postsynaptic currents in dentate granule neurons from Scn1a^E1099X/+ mice. Biochemically, everolimus prevented hyperthermia-induced phosphorylation of hippocampal S6 ribosome in hippocampus, and it delayed hyperthermia-induced increase of cytosolic Ca²⁺ level in primary neuronal cultures derived from Scn1a^E1099X/+ mice. Our results provide the evidence that overactivated mTOR as an important neuropathological change which regulates seizure threshold, impairments of neurobehavior, neuronal glutamatergic transmission and intracellular Ca²⁺ levels in Scn1a^E1099X/+ mice. Inhibition of mTOR is a potential pharmacological therapeutic approach.

211

News (Medical) associated with Everolimus

13 Dec 2024

·www.businesswire.com

Merck Receives Positive EU CHMP Opinion for WELIREG® (belzutifan) as Treatment for Adult Patients With Certain Types of Von Hippel-Lindau Disease-Associated Tumors and for Certain Previously Treated Adult Patients With Advanced Renal Cell Carcinoma

RAHWAY, N.J.--( BUSINESS WIRE )--Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending the conditional approval of WELIREG ® (belzutifan), Merck’s oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, as monotherapy for: The treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated, localized renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), and for whom localized procedures are unsuitable; The treatment of adult patients with advanced clear cell renal cell carcinoma (RCC) that progressed following two or more lines of therapy that included a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and at least two vascular endothelial growth factor (VEGF) targeted therapies. The CHMP’s recommendation will now be reviewed by the European Commission for marketing authorization in the European Union (EU), and a final decision is expected in the first quarter of 2025. “ Today’s positive CHMP opinion brings us closer to offering WELIREG, a first-in-class HIF-2α inhibitor, to certain patients in the European Union, in order to help address critical gaps in care for these patients,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “ We are committed to providing innovative treatment options that address serious unmet needs for patients globally and look forward to the European Commission’s decision.” The CHMP recommendation in VHL disease-associated tumors is based on objective response rate (ORR) and duration of response (DOR) results from the LITESPARK-004 trial. If approved, WELIREG would be the first and only systemic treatment for patients with VHL disease-associated tumors in the EU. In August 2021 , WELIREG was approved in the U.S. for the treatment of adult patients with VHL disease who require therapy for associated RCC, CNS hemangioblastomas or pNET not requiring immediate surgery based on the results from LITESPARK-004, an open-label clinical trial in 61 patients with VHL-associated RCC. In the LITESPARK-004 trial, WELIREG showed an ORR of 49% (95% CI, 36-62) in patients with VHL-associated RCC (n=30/61); all responses were partial responses (PR). Median DOR for these patients was not reached, with ongoing responses ranging from 2.8+ to 22+ months; among responders, 56% (n=17/30) maintained a response for at least 12 months. Patients enrolled in LITESPARK-004 had other VHL-associated tumors, including CNS hemangioblastomas and pNET. In patients with VHL-associated CNS hemangioblastomas (n=24) in this trial, WELIREG showed an ORR of 63% (95% CI, 41-81) (n=15/24), with a complete response (CR) rate of 4% (n=1/24) and a PR rate of 58% (n=14/24). Median DOR for these patients was not reached, with ongoing responses ranging from 3.7+ to 22+ months; among responders, 73% (n=11/15) maintained a response for at least 12 months. In patients with VHL-associated pNET (n=12) in this trial, WELIREG showed an ORR of 83% (95% CI, 52-98) (n=10/12), with a CR rate of 17% (n=2/12) and a PR rate of 67% (n=8/12). Median DOR for these patients was not reached, with ongoing responses ranging from 11+ to 19+ months; among responders, 50% (n=5/10) maintained a response for at least 12 months. The CHMP recommendation in advanced clear cell RCC that progressed following two or more lines of therapy that included a PD-(L)1 inhibitor and at least two VEGF targeted therapies, is based on PFS and ORR results from the LITESPARK-005 trial, the first positive Phase 3 trial in these patients. In December 2023 , WELIREG was approved in the U.S. for the treatment of adult patients with advanced RCC following a PD-1 or PD-L1 inhibitor and a VEGF-TKI based on the results from LITESPARK-005, an open-label clinical trial in 746 patients with unresectable, locally advanced or metastatic clear cell RCC that progressed following PD-1 or PD-L1 checkpoint inhibitor and VEGF receptor targeted therapies either in sequence or in combination. In the trial, WELIREG reduced the risk of disease progression or death by 25% (HR=0.75 [95% CI, 0.63-0.90]; p=0.0008) versus everolimus in these patients. Median PFS was 5.6 months (95% CI, 3.9-7.0) for WELIREG versus 5.6 months (95% CI, 4.8-5.8) for everolimus. The ORR for WELIREG was 22% (n=82) (95% CI, 18-27), with a CR rate of 3% (n=10) and a PR rate of 19% (n=72), and the ORR for everolimus was 4% (n=13) (95% CI, 2-6), with no patients achieving a CR and a PR rate of 4% (n=13). About von Hippel-Lindau disease Von Hippel-Lindau disease is a rare genetic disease, which impacts an estimated 200,000 people worldwide and an estimated 10,000 to 15,000 people in Europe. Patients with VHL are at risk for recurrent, benign blood vessel tumors as well as some cancerous ones. The most commonly occurring tumor is RCC, a form of kidney cancer, which occurs in about 70% of patients with VHL disease. About renal cell carcinoma Renal cell carcinoma is by far the most common type of kidney cancer. In 2020, more than 130,000 new cases of RCC were diagnosed in Europe. Renal cell carcinoma is about twice as common in men than in women. Approximately 30% of patients with kidney cancer are diagnosed at an advanced stage. About WELIREG ® (belzutifan) 40 mg tablets, for oral use Indications in the U.S. Certain von Hippel-Lindau (VHL) disease-associated tumors WELIREG (belzutifan) is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. Advanced Renal Cell Carcinoma (RCC) WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). Selected Safety Information for WELIREG Warning: Embryo-Fetal Toxicity Exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective. Anemia WELIREG can cause severe anemia that can require blood transfusion. Monitor for anemia before initiation of, and periodically throughout, treatment. Transfuse patients as clinically indicated. For patients with hemoglobin <8 g/dL, withhold WELIREG until ≥8 g/dL, then resume at the same or reduced dose or permanently discontinue WELIREG, depending on the severity of anemia. For life-threatening anemia or when urgent intervention is indicated, withhold WELIREG until hemoglobin ≥8 g/dL, then resume at a reduced dose or permanently discontinue WELIREG. In LITESPARK-004 (N=61), decreased hemoglobin occurred in 93% of patients with VHL disease and 7% had Grade 3 events. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months). The safety of erythropoiesis-stimulating agents (ESAs) for treatment of anemia in patients with VHL disease treated with WELIREG has not been established. In LITESPARK-005 (n=372), decreased hemoglobin occurred in 88% of patients with advanced RCC and 29% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 16.6 months). Of the patients with anemia, 22% received transfusions only, 20% received ESAs only, and 12% received both transfusion and ESAs. Hypoxia WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization. Monitor oxygen saturation before initiation of, and periodically throughout, treatment. For decreased oxygen saturation with exercise (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same or a reduced dose. For decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg) or when urgent intervention is indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening or recurrent symptomatic hypoxia, permanently discontinue WELIREG. Advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider. In LITESPARK-004, hypoxia occurred in 1.6% of patients. In LITESPARK-005, hypoxia occurred in 15% of patients and 10% had Grade 3 events. Of the patients with hypoxia, 69% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 months). Embryo-Fetal Toxicity Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. WELIREG can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose. Adverse Reactions In LITESPARK-004, serious adverse reactions occurred in 15% of patients, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each). WELIREG was permanently discontinued due to adverse reactions in 3.3% of patients for dizziness and opioid overdose (1.6% each). Dosage interruptions due to an adverse reaction occurred in 39% of patients. Those which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness. Dose reductions due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reaction which required dose reduction was fatigue (7%). The most common adverse reactions (≥25%), including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin (93%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%). In LITESPARK-005, serious adverse reactions occurred in 38% of patients. The most frequently reported serious adverse reactions were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis (0.5%) and hemorrhage (0.5%). WELIREG was permanently discontinued due to adverse reactions in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) were hypoxia (1.1%) and hemorrhage (0.5%). Dosage interruptions due to an adverse reaction occurred in 39% of patients. Of the patients who received WELIREG, 28% were 65 to 74 years, and 10% were 75 years and over. Dose interruptions occurred in 48% of patients ≥65 years of age and in 34% of younger patients. Adverse reactions which required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%), and hemorrhage (2.2%). Dose reductions due to an adverse reaction occurred in 13% of patients. Dose reductions occurred in 18% of patients ≥65 years of age and in 10% of younger patients. The most frequently reported adverse reactions which required dose reduction (≥1.0%) were hypoxia (5%) and anemia (3.2%). The most common (≥25%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (88%), fatigue (43%), musculoskeletal pain (33%), increased creatinine (34%), decreased lymphocytes (34%), increased alanine aminotransferase (32%), decreased sodium (31%), increased potassium (29%), and increased aspartate aminotransferase (27%). Drug Interactions Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended. Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A4 substrates, which may reduce the efficacy of these substrates or lead to therapeutic failures. Avoid coadministration with sensitive CYP3A4 substrates. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding. Lactation Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with WELIREG and for 1 week after the last dose. Females and Males of Reproductive Potential WELIREG can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating treatment with WELIREG. Use of WELIREG may reduce the efficacy of hormonal contraceptives. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose. Based on findings in animals, WELIREG may impair fertility in males and females of reproductive potential and the reversibility of this effect is unknown. Pediatric Use Safety and effectiveness of WELIREG in pediatric patients under 18 years of age have not been established. Merck’s focus on cancer Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www.merck.com/research/oncology/ . About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us X (formerly Twitter) , Facebook , Instagram , YouTube and LinkedIn . Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovation products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site ( www.sec.gov ). Please see Prescribing Information, including information for the Boxed Warning about embryo-fetal toxicity, for WELIREG (belzutifan) at https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_pi.pdf and Medication Guide for WELIREG at https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_mg.pdf .

Clinical ResultDrug ApprovalPhase 3

12 Dec 2024

·www.prnewswire.com

Menarini Group and MEDSIR Present the Phase III Study ADELA: A New Therapeutic Strategy for Advanced Breast Cancer

ADELA, an international phase III study being conducted across multiple countries, combines elacestrant with everolimus to treat advanced ER+/HER2- breast cancer with ESR1 mutations, aiming to delay disease progression. The study was presented by the Menarini Group and MEDSIR at the San Antonio Breast Cancer Symposium 2024 (SABCS 2024), one of the world's most prestigious events in oncology. MEDSIR's participation at SABCS 2024 solidifies its position as a global leader in oncology research and underscores its commitment to innovation and the development of more personalized and effective therapies. FLORENCE, Italy and BARCELONA, Spain, Dec. 12, 2024 /PRNewswire/ -- The Menarini Group ("Menarini"), a leading international pharmaceutical and diagnostics company, and Stemline Therapeutics, Inc. ("Stemline"), a wholly-owned subsidiary of the Menarini Group focused on bringing transformational oncology treatments to cancer patients, along with MEDSIR, a leading global independent clinical research company in oncology and part of Oncoclínicas & Co., the largest specialized oncology treatment group in Latin America, presented research on the pioneering clinical trial ADELA. This important research addresses therapeutic resistance in advanced ER+/HER2- breast cancer. Presented at the San Antonio Breast Cancer Symposium 2024 (SABCS), the study represents a key milestone in the quest for more effective and personalized treatment options for patients with disease progression. The standard first-line treatment for advanced ER+/HER2- breast cancer combines endocrine therapy with CDK4/6 inhibitors. ESR1 mutations develop as a result of prior exposure to endocrine therapy during metastatic treatment, and up to 50% of ER+, HER2- advanced or metastatic breast cancers will develop these mutations. ESR1 mutations cause the tumors to become resistant to endocrine therapy, in turn causing the cancer to progress; therefore, it is important to test for ESR1 whenever mBC progresses. Longer exposure to endocrine therapy during first-line treatment increases the chance of a patient's tumor developing an ESR1 mutation. With the goal of addressing this unmet medical need, the ADELA phase III clinical trial investigates a new therapeutic option combining elacestrant, a next generation, oral selective estrogen receptor degrader, with everolimus, an mTORC1 inhibitor. This combination is being evaluated in patients with advanced ER+/HER2- breast cancer that harbors ESR1 mutations, and who have experienced progression after standard first-line treatment. Results from the phase III EMERALD study were the basis for elacestrant's approval. Meanwhile, everolimus has shown efficacy in inhibiting other resistance mechanisms in this type of cancer. The elacestrant and everolimus combination has demonstrated preliminary efficacy with a manageable safety profile in the phase 1b/2 ELEVATE study (NCT05563220). "We at Menarini Stemline are delighted to announce the collaboration with MEDSIR to continue advancing the clinical research to explore the combination therapy with elacestrant," said Nassir Habboubi, MD, Chief Medical Officer of Stemline Therapeutics. "We are committed to driving innovation in cancer treatment by delivering transformational therapies aiming to extend the lives of people living with cancer." The primary objective of this international, randomized, double-blind trial is to evaluate whether the combination of elacestrant and everolimus offers greater efficacy in delaying disease progression compared to elacestrant monotherapy. Additionally, it investigates other crucial aspects, such as overall survival, toxicity profile, and the impact on patients' quality of life. The ADELA study represents a critical step in understanding how to overcome tumor resistance challenges in patients with ESR1 mutations, with the goal of advancing towards more effective and safer treatments. "At MEDSIR, we understand innovation not only as achieving clinical results but as the ability to transform patients' lives on a global scale. With ADELA, we take a decisive step toward accomplishing less invasive and more accessible treatments, aiming to offer new hope to those facing the most complex forms of the disease. This advancement reinforces our commitment to increasingly personalized and patient-centered medicine, a fundamental pillar in shaping the future of oncology," said Dr. Antonio Llombart-Cussac, Senior Scientific Leader at MEDSIR. The phase III study not only has significant clinical objectives, but also holds the potential to pave the way for regulatory approval of this therapeutic combination, enabling its use in a broader population of patients with advanced breast cancer. Moreover, the international scope of the study, which includes participation from multiple countries, including Spain, Italy, France, Austria, the Czech Republic, Greece, Germany, and the United Kingdom, underscores the study's global importance and relevance in the scientific community. The presentation of the ADELA study at an event as prominent as SABCS 2024 reinforces MEDSIR's leadership in excellence-driven oncology research and highlights its focus on addressing unmet needs in breast cancer treatment. The ADELA study is active and already recruiting patients. About ORSERDU (elacestrant) U.S. Indication: ORSERDU (elacestrant), 345 mg tablets, is indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Full prescribing information for the U.S. can be found at . Important Safety Information Warning and Precautions Dyslipidemia: Hypercholesterolemia and hypertriglyceridemia occurred in patients taking ORSERDU at an incidence of 30% and 27%, respectively. The incidence of Grade 3 and 4 hypercholesterolemia and hypertriglyceridemia were 0.9% and 2.2%, respectively. Monitor lipid profile prior to starting and periodically while taking ORSERDU. Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, ORSERDU can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the final dose. Adverse Reactions Serious adverse reactions occurred in 12% of patients who received ORSERDU. Serious adverse reactions in >1% of patients who received ORSERDU were musculoskeletal pain (1.7%) and nausea (1.3%). Fatal adverse reactions occurred in 1.7% of patients who received ORSERDU, including cardiac arrest, septic shock, diverticulitis, and unknown cause (one patient each). The most common adverse reactions (≥10%), including laboratory abnormalities, of ORSERDU were musculoskeletal pain (41%), nausea (35%), increased cholesterol (30%), increased AST (29%), increased triglycerides (27%), fatigue (26%), decreased hemoglobin (26%), vomiting (19%), increased ALT (17%), decreased sodium (16%), increased creatinine (16%), decreased appetite(15%), diarrhea(13%), headache (12%), constipation (12%), abdominal pain (11%), hot flush (11%), and dyspepsia (10%). Drug interactions Concomitant use with CYP3A4 Inducers and/or inhibitors: Avoid concomitant use of strong or moderate CYP3A4 inhibitors with ORSERDU. Avoid concomitant use of strong or moderate CYP3A4 inducers with ORSERDU. Use in specific populations Lactation: Advise lactating women to not breastfeed during treatment with ORSERDU and for 1 week after the last dose. Hepatic Impairment: Avoid use of ORSERDU in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of ORSERDU in patients with moderate hepatic impairment (Child-Pugh B). The safety and effectiveness of ORSERDU in pediatric patients have not been established. To report SUSPECTED ADVERSE REACTIONS, contact Stemline Therapeutics, Inc. at 1-877-332-7961 or FDA at 1-800-FDA-1088 or . About The Menarini Group The Menarini Group is a leading international pharmaceutical and diagnostics company, with a turnover of $4.7 billion and over 17,000 employees. Menarini is focused on therapeutic areas with high unmet needs with products for cardiology, oncology, pneumology, gastroenterology, infectious diseases, diabetology, inflammation, and analgesia. With 18 production sites and 9 Research and Development centers, Menarini's products are available in 140 countries worldwide. For further information, please visit . About Stemline Therapeutics Inc. Stemline Therapeutics, Inc. ("Stemline") a wholly-owned subsidiary of the Menarini Group, is a commercial-stage biopharmaceutical company focused on the development and commercialization of novel oncology therapeutics. Stemline commercializes ORSERDU® (elacestrant) in the U.S. and Europe, an oral endocrine therapy indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Stemline also commercializes ELZONRIS® (tagraxofusp-erzs), a novel targeted treatment directed to CD123 for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic cancer, in the United States and Europe, which is the only approved treatment for BPDCN in the U.S. and E.U. to date. Stemline also commercializes NEXPOVIO® (selinexor) in Europe, an XPO1 inhibitor for multiple myeloma. Stemline also has an extensive clinical pipeline of small molecules and biologics in various stages of development for a host of solid and hematologic cancers. About MEDSIR   Established in 2012, MEDSIR prides itself on working closely with its strategic partners to drive innovation in oncology research. Operating in Spain and the United States, the company provides end-to-end clinical trial management, from study design to publication, with an extensive global network of experts and integrated technology to streamline the process. The company offers proof-of-concept support and a strategic approach that enables research partners to benefit from the best of both worlds: industry clinical research and investigator-driven trials.   With the aim of promoting independent research worldwide, MEDSIR has formed a strategic alliance with Oncoclínicas, the leading oncology group in Brazil, which offers outstanding research potential in South America.  For further information:     About Oncoclínicas & CO   Oncoclínicas&Co is the largest group dedicated to cancer treatment in Latin America, with a specialized and innovative model focused on the entire oncology care journey, combining operational efficiency, humanized care, and high specialization through a medical team composed of over 2,700 specialist physicians with an emphasis on oncology. With its mission to democratize cancer treatment, it offers a comprehensive system that integrates outpatient clinics with high-complexity cancer centers. The company operates 145 units across 39 Brazilian cities, allowing high-quality access in all regions it serves, aligned with world-class standards. Focusing on technology, precision medicine, and genomics, Oncoclínicas performed approximately 635,000 treatments in 2023. It is the exclusive partner in Brazil of the Dana Farber Cancer Institute, affiliated with Harvard Medical School, one of the world's leading cancer research and treatments centers. The company also owns Boston Lighthouse Innovation, a bioinformatics firm based in Cambridge, United States, and holds shares in Medsir, a company dedicated to the development and management of clinical trials for independent cancer research, based in Barcelona, Spain. Recently, Oncoclínicas expanded its operations to Saudi Arabia through a joint venture with the Al Faisaliah Group, bringing its mission to beat cancer to a new continent and providing advanced oncology care on a global scale by combining oncological hyperspecialization with innovative treatment approaches. The company is part of the IDIVERSA index, launched by B3, highlighting companies committed to gender and racial diversity. For more information, visit: .    Logo - WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Phase 3Drug Approval

10 Dec 2024

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Olema Oncology Presents Updated Clinical Results for Palazestrant in Combination with Ribociclib at the San Antonio Breast Cancer Symposium

Palazestrant, in combination with ribociclib, demonstrated promising clinical activity, a safety profile consistent with ribociclib and endocrine therapy, and favorable tolerability in patients with ER+/HER2- advanced or metastatic breast cancer With a median follow-up of 12 months, median progression-free survival (PFS) has not been reached6-month PFS rate was 73% in all patients, 81% in patients with ESR1 mutations, 70% in ESR1 wild-type patients, and 68% in patients with prior CDK4/6 inhibitor treatment; data continue to mature Conference call today at 8:00 a.m. ET SAN FRANCISCO, Dec. 10, 2024 (GLOBE NEWSWIRE) -- Olema Pharmaceuticals, Inc. (“Olema” or “Olema Oncology”, Nasdaq: OLMA), a clinical-stage biopharmaceutical company focused on the discovery, development, and commercialization of targeted therapies for breast cancer and beyond, today announced updated clinical results from the ongoing Phase 1b/2 study of palazestrant in combination with CDK4/6 inhibitor, ribociclib, in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced or metastatic breast cancer. Results as of September 25, 2024, will be presented in a poster session at the San Antonio Breast Cancer Symposium (SABCS 2024) being held December 10-13 at the Henry B. Gonzalez Convention Center in San Antonio, Texas. Updated results as of November 11, 2024, are detailed below. “We believe these data, while still maturing, are compelling and highly differentiated, with robust clinical activity shown across both ESR1 wild-type and mutant patient populations after prior treatment with a CDK4/6 inhibitor in combination with endocrine therapy. Mutations in the ESR1 gene are one of the most common resistance mechanisms arising during current front-line standard of care treatment, leading to progression. Palazestrant has demonstrated its potential to work in combination with ribociclib by completely blocking estrogen receptor signaling and suppressing tumor growth to extend progression-free survival after prior progression on the current standard of care, regardless of ESR1 status,” said Sean P. Bohen, M.D., Ph.D., President and Chief Executive Officer of Olema Oncology. “These data provide the foundation to initiate OPERA-02, our planned pivotal Phase 3 trial of palazestrant in combination with ribociclib in front-line metastatic breast cancer next year. We look forward to sharing mature data from this combination in 2025 and continuing the development of palazestrant as we work to advance our goal of creating innovative therapies to improve the lives of breast cancer patients.” Interim Results from the Phase 1b/2 Study of Palazestrant in Combination with RibociclibEnrollment62 patients with advanced or metastatic ER+/HER2- breast cancer were treated with palazestrant (n=56 at the recommended Phase 2 dose (RP2D) of 120 mg once daily) plus ribociclib (600 mg once daily; three weeks on treatment followed by one week off treatment). The majority of participants (48 (77%)) were 2/3+ line patients; 48 (77%) patients received prior endocrine therapy for metastatic breast cancer, 46 (74%) patients received prior treatment of endocrine therapy with CDK4/6 inhibitors (CDK4/6i), 12 (19%) received two prior lines of treatment with CDK4/6i, and 11 (18%) patients received chemotherapy for metastatic breast cancer.36 (58%) patients had visceral disease; 42 (68%) patients had measurable disease at baseline. Of 60 patients whose circulating tumor DNA (ctDNA) was assessed, 28% had activating mutations in ESR1 at baseline. EfficacyPalazestrant combined with ribociclib showed promising clinical activity including tumor responses, prolonged disease stabilization, and progression-free survival in patients with ESR1 wild-type and ESR1 activating mutations at baseline and in those previously treated with one or two lines of CDK4/6i. Efficacy data continue to mature; 30 (48%) patients remain on treatment, and the longest duration on treatment is approximately 18 months (79 weeks) and was ongoing as of the data cutoff date of November 11, 2024. With a median follow-up of 12 months, the median PFS was not reached as of the data cutoff date. Across all patients, the 6-month PFS rate was 73%. In those who received prior treatment with a CDK4/6i plus an endocrine therapy, the 6-month PFS rate was 68%. The 6-month PFS rate in ESR1 mutant patients was 81% and in ESR1 wild-type patients it was 70%.In those who were clinical benefit rate (CBR)1-eligible, the CBR was 76% (37/49) in all patients, 81% (13/16) in patients with ESR1 mutations, and 74% (23/31) in ESR1 wild-type patients. In patients with prior CDK4/6i treatment, the CBR was 71% (25/35), 81% (12/16) in patients with ESR1 mutations, and 65% (11/17) in ESR1 wild-type patients.As of the data cutoff date, there were 11 responses (two confirmed complete responses, eight confirmed partial responses, and one unconfirmed partial response). Among 37 response-evaluable patients with measurable disease, the ORR was 27% (10/37). 60% of the 37 had a reduction in target lesion size. Safety and TolerabilityAcross 62 treated patients, the combination of up to 120 mg of palazestrant with the approved dose for metastatic disease of 600 mg of ribociclib daily was well tolerated with no new safety signals or increase in toxicity. The overall safety profile was consistent with the established safety profile of ribociclib 600 mg plus an endocrine therapy. Treatment with palazestrant up to 120 mg combined with ribociclib (600 mg) was well tolerated with no dose-limiting toxicities.The majority of treatment-emergent adverse events (TEAEs) were Grade 1 or 2, and the severity and incidence of adverse events were consistent with the expected safety profile of ribociclib plus endocrine therapy. PharmacokineticsPalazestrant did not affect ribociclib drug exposure when compared with published exposure data for single-agent ribociclib. Steady-state trough values showed no clinically significant difference between the combination and single-agent palazestrant. ConclusionsFindings from this study support the advancement of palazestrant in combination with ribociclib into clinical development for the first-line treatment of ER+/HER2- advanced or metastatic breast cancer. “Palazestrant is not an endocrine therapy where you need to wait six months to see a patient derive benefit. We have seen impressive responses quickly and a significant reduction of disease burden. The patients I have seen feel much better than they have on other treatments available in the armamentarium today,” said Virginia Borges, M.D., Professor, Medicine-Medical Oncology at the University of Colorado, and Principal Investigator for the palazestrant plus ribociclib combination study. “The findings presented at SABCS show that the combination of palazestrant and ribociclib is well-tolerated with meaningful preliminary efficacy that I believe has the potential to outperform the current standard of care and change how metastatic breast cancer is treated. I look forward to the continued development of palazestrant.” A copy of the poster presented at SABCS reflecting a September 25, 2024 data cutoff date will be made available on the Publications page of Olema’s website in alignment with the Symposium’s embargo policy. 1CBR is the proportion of patients who remained on treatment through at least 24 weeks with a confirmed complete response or partial response, or stable disease. Conference Call InformationOlema will hold a conference call to discuss these results today with the investment community at 8:00 a.m. ET (7:00 a.m. CT). Register to join the webcast by visiting the Events and Presentations page on the Investors section of Olema’s website. About Palazestrant (OP-1250)Palazestrant (OP-1250) is a novel, orally available small molecule with dual activity as both a complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD). It is currently being investigated in patients with recurrent, locally advanced or metastatic ER-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In preclinical studies, palazestrant completely blocks ER-driven transcriptional activity in both ESR1 wild-type and mutant forms of breast cancer. In Olema’s ongoing clinical trials for advanced or metastatic ER+/HER2- breast cancer, palazestrant has demonstrated anti-tumor activity along with attractive pharmacokinetics and exposure, favorable tolerability, and combinability with CDK4/6 inhibitors. Palazestrant has been granted U.S. Food and Drug Administration (FDA) Fast Track designation for the treatment of ER+/HER2- metastatic breast cancer that has progressed following one or more lines of endocrine therapy with at least one line given in combination with a CDK4/6 inhibitor. It is being evaluated both as a single agent in an ongoing Phase 3 clinical trial, OPERA-01, and in Phase 1/2 combination studies with CDK4/6 inhibitors (palbociclib and ribociclib), a PI3Ka inhibitor (alpelisib), and an mTOR inhibitor (everolimus). For more information on OPERA-01, please visit www.opera01study.com. About Olema OncologyOlema Oncology is a clinical-stage biopharmaceutical company committed to transforming the standard of care and improving outcomes for patients living with breast cancer and beyond. Olema is advancing a pipeline of novel therapies by leveraging our deep understanding of endocrine-driven cancers, nuclear receptors, and mechanisms of acquired resistance. Our lead product candidate, palazestrant (OP-1250), is a proprietary, orally available complete estrogen receptor (ER) antagonist (CERAN) and a selective ER degrader (SERD), currently in a Phase 3 clinical trial called OPERA-01. In addition, Olema is developing a potent KAT6 inhibitor (OP-3136). Olema is headquartered in San Francisco and has operations in Cambridge, Massachusetts. For more information, please visit us at www.olema.com. Forward Looking StatementsStatements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Words such as “anticipate,” “believe,” “could,” “expect,” “goal,” “may,” “potential,” “upcoming,” “will,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These statements include those related to the potential beneficial characteristics, safety, tolerability, efficacy, and therapeutic effects of palazestrant and the development of palazestrant, in each case, including in combination with other drugs, the potential of palazestrant to work in combination with ribociclib to suppress tumor growth or extend progression-free survival, the initiation and timing of clinical trials, and Olema’s potential to transform the endocrine therapy standard of care treatments for patients living with ER+/HER2- metastatic breast cancer. Because such statements deal with future events and are based on Olema’s current expectations, they are subject to various risks and uncertainties, and actual results, performance or achievements of Olema could differ materially from those described in or implied by the statements in this press release. These forward-looking statements are subject to risks and uncertainties, including, without limitation, those discussed in the section titled “Risk Factors” in Olema’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2024, and other filings and reports that Olema makes from time to time with the U.S. Securities and Exchange Commission. Except as required by law, Olema assumes no obligation to update these forward-looking statements, including in the event that actual results differ materially from those anticipated in the forward-looking statements. Media and Investor Relations ContactCourtney O’KonekVice President, Corporate CommunicationsOlema Oncologymedia@olema.com

Clinical ResultPhase 3Fast TrackPhase 2

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KEGG	Wiki	ATC	Drug Bank
D02714	Everolimus	L04AA18 L01XE10	DB01590

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Epilepsy	US	Novartis Pharmaceuticals Corp.	30 Dec 2021
Epilepsies, Partial	US	Novartis Pharmaceuticals Corp.	10 Apr 2018
Renal angiomyolipoma with tuberous sclerosis complex	CN	Novartis Pharma AG	12 Dec 2016
Breast cancer recurrent	JP	Novartis Pharma AG	17 Mar 2014
Pancreatic Islet Cell Tumors	CN	Novartis Pharma AG	01 Feb 2014
Subependymal Giant Cell Astrocytoma	CN	Novartis Pharma AG	01 Feb 2014
Hormone receptor positive HER2 negative breast cancer	US	Novartis Pharmaceuticals Corp.	20 Jul 2012
Gastro-Enteropancreatic Neuroendocrine Tumor	JP	Novartis Pharma AG	22 Dec 2011
Tuberous Sclerosis	EU	Novartis Europharm Ltd.	02 Sep 2011
Tuberous Sclerosis	IS	Novartis Europharm Ltd.	02 Sep 2011
Tuberous Sclerosis	LI	Novartis Europharm Ltd.	02 Sep 2011
Tuberous Sclerosis	NO	Novartis Europharm Ltd.	02 Sep 2011
Astrocytoma	US	Novartis Pharmaceuticals Corp.	29 Oct 2010
Angiomyolipoma	CA	Novartis Pharmaceuticals Canada, Inc.	15 Mar 2010
Hormone receptor positive breast cancer	EU	Novartis Europharm Ltd.	02 Aug 2009
Hormone receptor positive breast cancer	IS	Novartis Europharm Ltd.	02 Aug 2009
Hormone receptor positive breast cancer	LI	Novartis Europharm Ltd.	02 Aug 2009
Hormone receptor positive breast cancer	NO	Novartis Europharm Ltd.	02 Aug 2009
Neuroendocrine Tumors	EU	Novartis Europharm Ltd.	02 Aug 2009
Neuroendocrine Tumors	IS	Novartis Europharm Ltd.	02 Aug 2009

Developing

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Indication	Highest Phase	Country/Location	Organization	Date
Seizures	Phase 3	US	Novartis Pharmaceuticals Corp.	08 Jun 2017
Seizures	Phase 3	JP	Novartis Pharmaceuticals Corp.	08 Jun 2017
Seizures	Phase 3	AU	Novartis Pharmaceuticals Corp.	08 Jun 2017
Seizures	Phase 3	BE	Novartis Pharmaceuticals Corp.	08 Jun 2017
Seizures	Phase 3	CA	Novartis Pharmaceuticals Corp.	08 Jun 2017
Seizures	Phase 3	CO	Novartis Pharmaceuticals Corp.	08 Jun 2017
Seizures	Phase 3	FR	Novartis Pharmaceuticals Corp.	08 Jun 2017
Seizures	Phase 3	HU	Novartis Pharmaceuticals Corp.	08 Jun 2017
Seizures	Phase 3	IT	Novartis Pharmaceuticals Corp.	08 Jun 2017
Seizures	Phase 3	MX	Novartis Pharmaceuticals Corp.	08 Jun 2017

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03070301 (CTgov)	Phase 2	Advanced Neuroendocrine Neoplasm	21	LEE011+everolimus	icnackzutt(bavhmiluru) = rottwarwcs mwzykdpbgj (pjkabhvyhy, icpgabwvbk - udggjlorxz) View more	-	10 Oct 2024
NCT01678664 (EVACEL \| FFCD 1104-EVACEL-GTE, CTgov)	Phase 2	Liver metastases \| Endocrine Gland Neoplasms \| Neuroendocrine Tumors	74	embolization+Doxorubicin+Everolimus	vyrowwowwf(lefalbspvb) = pygngmjdbu thhpbromuv (eppmdseuik, drwhnbqbbq - zgmudhunct) View more	-	25 Sep 2024
ESMO2024	Phase 1	Advanced Neuroendocrine Neoplasm	92	Everolimus 6.1 - 10mg	xbmxdnboub(uzxhszmpnj) = hyhhmhfhma rukqxprkub (uugwqvfqdv, 3.7 - 32) View more	Positive	16 Sep 2024
				Everolimus 6mg or less	xbmxdnboub(uzxhszmpnj) = qpuyrqoqjl rukqxprkub (uugwqvfqdv, 3.9 - 27) View more
EVERGREEN (ESMO2024)	Not Applicable	ER-positive/HER2-negative Breast Cancer PIK3CA-AKT1-PTEN pathway alterations	207	Everolimus-based endocrine therapy (EVE)	jncwecjzmo(unjnqsswyp) = cqxbgjkuox bmqgugdxnr (uigoweacpj ) View more	Negative	16 Sep 2024
				Endocrine therapy alone (ETa)	jncwecjzmo(unjnqsswyp) = twqqsfguyn bmqgugdxnr (uigoweacpj ) View more
NCT02338609 (EXIST-LT, CTgov)	Phase 4	-	15	Everolimus	affseumtby(asxbmndjtr) = vcjjiqawwq inbymquaok (iushfsxxtg, ubnccninsw - upuzrtrlyu) View more	-	09 Aug 2024
NCT01120249 (EVEREST, Pubmed \| JAMA Netw Open) Manual	Phase 3	Renal Cell Carcinoma \| Papillary Renal Cell Carcinoma Adjuvant	110	Everolimus	thvxqadnqx(vyenhbxijx) = pcbxrgikek capbfdbdwo (nkrtsionfi ) View more	Negative	01 Aug 2024
				Placebo	thvxqadnqx(vyenhbxijx) = dlnwicuqpl capbfdbdwo (nkrtsionfi ) View more
NCT03154281 (CTgov)	Phase 1	Ovarian Cancer \| Breast Cancer	14	niraparib+Everolimus (Cohort 1)	qridtqgdbt(kimgknkzxj) = fsaquzgfdx aerissjfrg (nrgkdanxhu, rqpqwftvat - naqccbmgbc) View more	-	01 Aug 2024
				niraparib+Everolimus (Cohort 2)	qridtqgdbt(kimgknkzxj) = xwsjyvogcx aerissjfrg (nrgkdanxhu, itjvggxrjf - wffzawntbr) View more
NCT03312738 (BOLERO-5, Pubmed) Manual	Phase 2	ER-positive/HER2-negative Breast Cancer HER2 Negative \| ER Positive	159	Everolimus (EVE) + Exemestane (EXE)	zqzmlkygov(kpycofhkdb) = taxmpuhyku gfvhpnicha (xfvcwpmvgo, 5.5 - 9.0)	Positive	21 Jun 2024
				Placebo (PBO) + Exemestane (EXE)	zqzmlkygov(kpycofhkdb) = bgrnsysjxl gfvhpnicha (xfvcwpmvgo, 1.9 - 3.6)
AHNS2024	Not Applicable	Squamous Cell Carcinoma of Head and Neck	-	Everolimus	rrfwjpjeib(csgooywjct) = bqjpkxtwwh ycnbqnzroh (likjegandd )	-	15 May 2024
				anti-PD-1	rrfwjpjeib(csgooywjct) = qyjiepivbd ycnbqnzroh (likjegandd )
ID 427 (ESMO_BC2024)	Not Applicable	Hormone receptor positive breast cancer CDK 4/6 inhibitors	69	Everolimus + Exemestane	hvkderchgk(yncfwksqxe) = pjigntjhiy ubewsydcbf (oyhajjvidb )	Negative	14 May 2024

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