IC50 value: 16 nM
Target: androgen receptor
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Home » Posts tagged 'Apalutamide'
The U.S. Food and Drug Administration today approved Erleada (apalutamide) for the treatment of patients with prostate cancer that has not spread (non-metastatic), but that continues to grow despite treatment with hormone therapy (castration-resistant). This is the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer. Continue reading.
February 14, 2018
The U.S. Food and Drug Administration today approved Erleada (apalutamide) for the treatment of patients with prostate cancer that has not spread (non-metastatic), but that continues to grow despite treatment with hormone therapy (castration-resistant). This is the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer.
“The FDA evaluates a variety of methods that measure a drug’s effect, called endpoints, in the approval of oncology drugs. This approval is the first to use the endpoint of metastasis-free survival, measuring the length of time that tumors did not spread to other parts of the body or that death occurred after starting treatment,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “In the trial supporting approval, Erleada had a robust effect on this endpoint. This demonstrates the agency’s commitment to using novel endpoints to expedite important therapies to the American public.”
According to the National Cancer Institute (NCI) at the National Institutes of Health, prostate cancer is the second most common form of cancer in men in the U.S.. The NCI estimates approximately 161,360 men were diagnosed with prostate cancer in 2017, and 26,730 were expected to die of the disease. Approximately 10 to 20 percent of prostate cancer cases are castration-resistant, and up to 16 percent of these patients show no evidence that the cancer has spread at the time of the castration-resistant diagnosis.
Erleada works by blocking the effect of androgens, a type of hormone, on the tumor. These androgens, such as testosterone, can promote tumor growth.
The safety and efficacy of Erleada was based on a randomized clinical trial of 1,207 patients with non-metastatic, castration-resistant prostate cancer. Patients in the trial either received Erleada or a placebo. All patients were also treated with hormone therapy, either with gonadotropin-releasing hormone (GnRH) analog therapy or with surgery to lower the amount of testosterone in their body (surgical castration). The median metastasis-free survival for patients taking Erleada was 40.5 months compared to 16.2 months for patients taking a placebo.
Common side effects of Erleada include fatigue, high blood pressure (hypertension), rash, diarrhea, nausea, weight loss, joint pain (arthralgia), falls, hot flush, decreased appetite, fractures and swelling in the limbs (peripheral edema).
Severe side effects of Erleada include falls, fractures and seizures.
This application was granted Priority Review, under which the FDA’s goal is to take action on an application within 6 months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.
The sponsor for Erleada is the first participant in the FDA’s recently-announced Clinical Data Summary Pilot Program, an effort to provide stakeholders with more usable information on the clinical evidence supporting drug product approvals and more transparency into the FDA’s decision-making process. Soon after approval, certain information from the clinical summary report will post with the Erleada entry on Drugs@FDA and on the new pilot program landing page.
The FDA granted the approval of Erleada to Janssen Pharmaceutical Companies.
//////////////fda 2018, Erleada, apalutamide, Priority Review, Janssen
ARN-509; cas 956104-40-8; ARN 509; UNII-4T36H88UA7;
ARN-509; JNJ-56021927; JNJ-927\
Phase III Prostate cancer
|Molecular Weight:||477.434713 g/mol|
|Product Name||Sponsor Only||Condition||Start Date||End Date||Phase||Last Change Date|
|ARN-509||Aragon Pharmaceuticals Inc||Hormone refractory prostate cancer||31-JUL-10||30-JUN-13||Phase 2||17-SEP-13|
|Aragon Pharmaceuticals Inc||31-MAR-13||30-JUN-13||Phase 1||17-SEP-13|
|Aragon Pharmaceuticals Inc||Hormone refractory prostate cancer||31-OCT-13||31-DEC-16||Phase 3||05-NOV-13|
|Aragon Pharmaceuticals Inc; Johnson & Johnson||Hormone refractory prostate cancer||28-FEB-13||01-FEB-14||Phase 1||07-OCT-13|
|Aragon Pharmaceuticals Inc||Hormone dependent prostate cancer||28-FEB-13||28-FEB-18||Phase 2||18-OCT-13|
Apalutamide, also known as ARN-509 and JNJ-56021927 , is an androgen receptor antagonist with potential antineoplastic activity. ARN-509 binds to AR in target tissues thereby preventing androgen-induced receptor activation and facilitating the formation of inactive complexes that cannot be translocated to the nucleus. This prevents binding to and transcription of AR-responsive genes. This ultimately inhibits the expression of genes that regulate prostate cancer cell proliferation and may lead to an inhibition of cell growth in AR-expressing tumor cells.
Apalutamide (INN) (developmental code name ARN-509, also JNJ-56021927) is a non-steroidal antiandrogen that is under development for the treatment of prostate cancer. It is similar to enzalutamide both structurally and pharmacologically, acting as a selective competitive antagonist of the androgen receptor (AR), but shows some advantages, including greater potency and reduced central nervous system permeation. Apalutamide binds weakly to the GABAA receptor similarly to enzalutamide, but due to its relatively lower central concentrations, may have a lower risk of seizures in comparison. The drug has been found to be effective and well-tolerated in clinical trials thus far, with the most common side effects reported including fatigue, nausea, abdominal pain, and diarrhea. Apalutamide is currently in phase III clinical trials for castration-resistant prostate cancer.
Recently, the acquired F876L mutation of the AR identified in advanced prostate cancer cells was found to confer resistance to both enzalutamide and apalutamide. A newer antiandrogen, ODM-201, is not affected by this mutation, nor has it been found to be affected by any other tested/well-known AR mutations.
The chemical structure of ARN-509 is very similar structure to that of Enzalutamide (MDV3100) with two minor modifications: (a) two methyl groups in the 5-member ring of MDV3100 is linked by a CH2 group in ARN-509; (b) the carbon atom in the benzene ring of MDV3100 is replaced by a nitrogen atom in ARN-509. ARN-509 is considered as a Me-Too drug of Enzalutamide (MDV3100). ARN-509 was claimed to be more active than Enzalutamide (MDV3100).
ARN-509 is a novel 2nd Generation anti-androgen that is targeted to treat castration resistant prostate cancers where 1st generation anti-androgens fail. ARN-509 is unique in its action in that it inhibits both AR nuclear translocation and AR binding to androgen response elements in DNA. Importantly, and in contrast to the first-generation anti-androgen bicalutamide, it exhibits no agonist activity in prostate cancer cells that over-express AR. ARN-509 is easily synthesized, and its oral bioavailability and long half-life allow for once-daily oral dosing. In addition, its excellent preclinical safety profile makes it well suited as either a mono- or a combination therapy across the entire spectrum of prostate cancer disease states. (source: http://www.aragonpharm.com/programs/arn509.htm).
ARN-509 is a competitive AR inhibitor, which is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/day of ARN-509 , whereas the same response required 100 mg/kg/day of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer. (source: Cancer Res. 2012 Jan 20. [Epub ahead of print] )
(source: Cancer Res. 2012 Jan 20. [Epub ahead of print] )
Prostate cancer is one of the most common forms of cancer found in Western men and the second leading cause of cancer death in Western men. When prostate cancer is confined locally, the disease can usually be treated by surgery and/or radiation. Advanced disease is frequently treated with anti-androgen therapy, also known as androgen deprivation therapy. Administration of anti-androgens blocks androgen receptor (AR) function by competing for androgen binding; and therefore, anti-androgen therapy reduces AR activity. Frequently, such therapy fails after a time, and the cancer becomes hormone refractory, that is, the prostate cancer no longer responds to hormone therapy and the cancer does not require androgens to progress.
Overexpression of AR has been identified as a cause of hormone refractory prostate cancer (Nat. Med., 10:33-39, 2004; incorporated herein by reference). Overexpression of AR is sufficient to cause progression from hormone sensitive to hormone refractory prostate cancer, suggesting that better AR antagonists than the current drugs may be able to slow the progression of prostate cancer. It has been demonstrated that overexpression of AR converts anti-androgens from antagonists to agonists in hormone refractory prostate cancer. This work explains why anti-androgen therapy fails to prevent the progression of prostate cancer.
The identification of compounds that have a high potency to anatgonize AR activity would overcome the hormone refractory prostate cancer and slowdown the progression of hormone sensitive prostate cancer. Such compounds have been identified by Sayers et al. (WO 2007/126765, published Nov. 8, 2007; which is incorporated herein by reference). One compound is known as A52, a biarylthiohydantoin, and has the chemical structure
Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ (2015). “Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies”. Sci Rep 5: 12007. doi:10.1038/srep12007. PMC 4490394. PMID 26137992
11Clegg NJ, Wongvipat J, Tran C, Ouk S, Dilhas A, Joseph J, Chen Y, Grillot K, Bischoff ED, Cai L, Aparicio A, Dorow S, Arora V, Shao G, Qian J, Zhao H, Yang G, Cao C, Sensintaffar J, Wasielewska T, Herbert MR, Bonnefous C, Darimont B, Scher HI, Smith-Jones PM, Klang M, Smith ND, de Stanchina E, Wu N, Ouerfelli O, Rix P, Heyman R, Jung ME, Sawyers CL, Hager JH. ARN-509: a novel anti-androgen for prostate cancer treatment. Cancer Res. 2012 Mar 15;72(6):1494-1503. Epub 2012 Jan 20.PubMed PMID: 22266222.
. Schweizer MT, Antonarakis ES. Abiraterone and other novel androgen-directed strategies for the treatment of prostate cancer: a new era of hormonal therapies is born. Ther Adv Urol. 2012 Aug;4(4):167-78.
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|US2014296312||2014-10-02||TREATMENT OF BREAST CANCER|
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|US2014107085||2014-04-17||Bifunctional AKR1C3 Inhibitors/Androgen Receptor Modulators and Methods of Use Thereof|
|US2014088129||2014-03-27||ANTI-ANDROGENS FOR THE TREATMENT OF NON-METASTATIC CASTRATE-RESISTANT PROSTATE CANCER|
|US2013225821||2013-08-29||SYNTHESIS OF THIOHYDANTOINS|
|US2013116258||2013-05-09||ANDROGEN RECEPTOR MODULATORS AND USES THEREOF|
|US2011003839||2011-01-06||ANDROGEN RECEPTOR MODULATOR FOR THE TREATMENT OF PROSTATE CANCER AND ANDROGEN RECEPTOR-ASSOCIATED DISEASES|
|US2010190991||2010-07-29||SYNTHESIS OF THIOHYDANTOINS|
|Systematic (IUPAC) name|
|Molar mass||477.434713 g/mol|