Atrasentan

Last updated

Atrasentan
Atrasentan structure.svg
Clinical data
ATC code
  • none
Identifiers
  • (2R,3R,4S)-4-(1,3-Benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
ECHA InfoCard 100.206.784 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C29H38N2O6
Molar mass 510.631 g·mol−1
3D model (JSmol)
  • O=C(O)[C@H]4[C@H](c1ccc(OC)cc1)N(CC(=O)N(CCCC)CCCC)C[C@@H]4c2ccc3OCOc3c2
  • InChI=1S/C29H38N2O6/c1-4-6-14-30(15-7-5-2)26(32)18-31-17-23(21-10-13-24-25(16-21)37-19-36-24)27(29(33)34)28(31)20-8-11-22(35-3)12-9-20/h8-13,16,23,27-28H,4-7,14-15,17-19H2,1-3H3,(H,33,34)/t23-,27-,28+/m1/s1 Yes check.svgY
  • Key:MOTJMGVDPWRKOC-QPVYNBJUSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Atrasentan is an experimental drug that is being studied for the treatment of various types of cancer, [1] including non-small cell lung cancer. [2] It is also being investigated as a therapy for diabetic kidney disease. [3]

It is an endothelin receptor antagonist selective for subtype A (ETA). While other drugs of this type (sitaxentan, ambrisentan) exploit the vasoconstrictive properties of endothelin and are mainly used for the treatment of pulmonary arterial hypertension, atrasentan blocks endothelin induced cell proliferation.[ citation needed ]

Clinical trials

Atrasentan failed a phase 3 trial for prostate cancer in patients unresponsive to hormone therapy. [4] A second trial confirmed this finding. [5]

In April 2014, de Zeeuw et al. showed that 0.75 mg and 1.25 mg of atrasentan reduced urinary albumin by 35 and 38% respectively with modest side effects. Patients also had decreased home blood pressures (but no change in office readings) decrease total cholesterol and LDL. Patients in the 1.25 mg dose group had increased weight gain which was presumably due to increased edema and had to withdraw from the study more than the placebo or 0.75 mg dose group. [6] Reductions in proteinuria have been associated with beneficial patient outcomes in diabetic kidney disease with other interventions but is not an accepted end-point by the FDA.[ citation needed ]

In 2013, SONAR trial [7] was initiated to determine if atrasentan reduces kidney failure in diabetic kidney disease. [8]

In 2024, the phase 3 ALIGN trial found atrasentan to be effective in reducing proteinuria in patients with IgA nephropathy. [9]

Related Research Articles

Albuminuria is a pathological condition wherein the protein albumin is abnormally present in the urine. It is a type of proteinuria. Albumin is a major plasma protein ; in healthy people, only trace amounts of it are present in urine, whereas larger amounts occur in the urine of patients with kidney disease. For a number of reasons, clinical terminology is changing to focus on albuminuria more than proteinuria.

<span class="mw-page-title-main">Proteinuria</span> Presence of an excess of serum proteins in the urine

Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy. Severe proteinuria can cause nephrotic syndrome in which there is worsening swelling of the body.

<span class="mw-page-title-main">Angiotensin II receptor blocker</span> Group of pharmaceuticals that modulate the renin–angiotensin system

Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals that bind to and inhibit the angiotensin II receptor type 1 (AT1) and thereby block the arteriolar contraction and sodium retention effects of renin–angiotensin system.

<span class="mw-page-title-main">Diabetic nephropathy</span> Chronic loss of kidney function

Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. The triad of protein leaking into the urine, rising blood pressure with hypertension and then falling renal function is common to many forms of CKD. Protein loss in the urine due to damage of the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) so called nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2 to less than 15, at which point the patient is said to have end-stage renal disease. It usually is slowly progressive over years.

<span class="mw-page-title-main">Gonadotropin-releasing hormone antagonist</span> Class of medications

Gonadotropin-releasing hormone antagonists are a class of medications that antagonize the gonadotropin-releasing hormone receptor and thus the action of gonadotropin-releasing hormone (GnRH). They are used in the treatment of prostate cancer, endometriosis, uterine fibroids, female infertility in assisted reproduction, and for other indications.

<span class="mw-page-title-main">Perindopril</span> High blood pressure medication

Perindopril is a medication used to treat high blood pressure, heart failure, or stable coronary artery disease. As a long-acting ACE inhibitor, it works by relaxing blood vessels and decreasing blood volume. As a prodrug, perindopril is hydrolyzed in the liver to its active metabolite, perindoprilat. It was patented in 1980 and approved for medical use in 1988.

<span class="mw-page-title-main">Dapagliflozin</span> Diabetes medication

Dapagliflozin, sold under the brand names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat type 2 diabetes. It is also used to treat adults with heart failure and chronic kidney disease. It reversibly inhibits sodium-glucose co-transporter 2 (SGLT-2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion.

Ramucirumab, sold under the brand name Cyramza, is a fully human monoclonal antibody (IgG1) used for the treatment of cancer. Ramucirumab is a human vascular endothelial growth factor receptor 2 (VEGFR2) antagonist. Ramucirumab was developed by ImClone Systems. It was isolated from a native phage display library from Dyax.

<span class="mw-page-title-main">Cabazitaxel</span> Chemical compound

Cabazitaxel, sold under the brand name Jevtana, is a semi-synthetic derivative of a natural taxoid. It is a microtubule inhibitor, and the fourth taxane to be approved as a cancer therapy.

<span class="mw-page-title-main">Zibotentan</span> Chemical compound

Zibotentan is an experimental anti-cancer drug candidate in development by AstraZeneca. It is an endothelin receptor antagonist.

Blisibimod is a selective antagonist of B-cell activating factor, being developed by Anthera Pharmaceuticals as a treatment for systemic lupus erythematosus. It is currently under active investigation in clinical trials.

<span class="mw-page-title-main">Fostamatinib</span> Chemical compound

Fostamatinib, sold under the brand names Tavalisse and Tavlesse, is a tyrosine kinase inhibitor medication for the treatment of chronic immune thrombocytopenia (ITP). The drug is administered by mouth.

Darolutamide, sold under the brand name Nubeqa, is an antiandrogen medication which is used in the treatment of non-metastatic castration-resistant prostate cancer in men. It is specifically approved to treat non-metastatic castration-resistant prostate cancer (nmCRPC) in conjunction with surgical or medical castration. The medication is taken by mouth twice per day with food.

<span class="mw-page-title-main">Finerenone</span> Chemical compound

Finerenone, marketed under the brand name Kerendia 10 or 20 mg among others, is a medication used to reduce the risk of kidney function decline, kidney failure, cardiovascular death, non-fatal heart attacks, and hospitalization for heart failure in adults with chronic kidney disease associated with type 2 diabetes. Finerenone is a non-steroidal mineralocorticoid receptor antagonist (MRA). It is taken orally.

<span class="mw-page-title-main">Setanaxib</span> Chemical compound

Setanaxib is an experimental orally bioavailable dual inhibitor of NADPH oxidase isoforms NOX4 and NOX1. Setanaxib is a member of the pyrazolopyridine dione chemical series. The compound is the only specific NOX inhibitor that has entered into clinical trials.

<span class="mw-page-title-main">Custirsen</span> Chemical compound

Custirsen, with aliases including custirsen sodium, OGX-011, and CC-8490, is an investigational drug that is under clinical testing for the treatment of cancer. It is an antisense oligonucleotide (ASO) targeting clusterin expression. In metastatic prostate cancer, custirsen showed no benefit in improving overall survival.

Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) is a clinical trial investigating treatments for high risk or terminal prostate cancer. Recruitment started in 2005 and ended in 2022; as of January 2020, over 10,000 participants had joined the trial.

The Scandinavian Prostate Cancer Group (SPCG) is a group of scientific researchers who have conducted a series of clinical trials of treatments for prostate cancer. The group was founded in 1981 and the first study, SPCG-1, began in 1984.

The Early Prostate Cancer (EPC) programme was a large clinical trial programme of monotherapy with the nonsteroidal antiandrogen bicalutamide (Casodex) plus standard care versus standard care alone in men with early prostate cancer. It was started in August 1995, with the first analysis published in 2002 and the final follow-up published in 2010. The programme consisted of three large randomized, double-blind, placebo-controlled trials in which a total of 8,113 men with localized or locally advanced prostate cancer were treated with 150 mg/day bicalutamide plus standard care (n=4052) or given placebo (n=4061). It constituted the largest clinical trial of prostate cancer treatment to have ever been conducted at the time.

<span class="mw-page-title-main">Sparsentan</span> Medication

Sparsentan, sold under the brand name Filspari, is a medication used for the treatment of primary immunoglobulin A nephropathy. Sparsentan is an endothelin and angiotensin II receptor antagonist. It is taken by mouth.

References

  1. "Atrasentan". NCI Dictionary of Cancer Terms. National Institute of Cancer. 2011-02-02.
  2. Chiappori AA, Haura E, Rodriguez FA, Boulware D, Kapoor R, Neuger AM, et al. (March 2008). "Phase I/II study of atrasentan, an endothelin A receptor antagonist, in combination with paclitaxel and carboplatin as first-line therapy in advanced non-small cell lung cancer". Clinical Cancer Research. 14 (5): 1464–9. doi:10.1158/1078-0432.CCR-07-1508. PMID   18316570.
  3. "Atrasentan - Chinook Therapeutics". AdisInsight. Springer Nature Switzerland AG.
  4. "Addition of experimental drug to standard chemotherapy for advanced prostate cancer shows no benefit in phase 3 clinical trial" (Press release). National Cancer Institute. April 21, 2011. Retrieved October 18, 2014.
  5. Quinn DI, Tangen CM, Hussain M, Lara PN, Goldkorn A, Moinpour CM, et al. (August 2013). "Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial". The Lancet. Oncology. 14 (9): 893–900. doi:10.1016/S1470-2045(13)70294-8. PMC   4277263 . PMID   23871417.
  6. de Zeeuw D, Coll B, Andress D, Brennan JJ, Tang H, Houser M, et al. (May 2014). "The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy". Journal of the American Society of Nephrology. 25 (5): 1083–93. doi:10.1681/ASN.2013080830. PMC   4005314 . PMID   24722445.
  7. Clinical trial number NCT01858532 for "Study Of Diabetic Nephropathy With Atrasentan (SONAR)" at ClinicalTrials.gov
  8. Heerspink HJ, Parving HH, Andress DL, Bakris G, Correa-Rotter R, Hou FF, et al. (May 2019). "Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial" (PDF). Lancet. 393 (10184): 1937–1947. doi:10.1016/S0140-6736(19)30772-X. PMID   30995972. S2CID   113407761.
  9. Heerspink HJ, Jardine M, Kohan DE, Lafayette RA, Levin A, Liew A, et al. (October 2024). "Atrasentan in Patients with IgA Nephropathy". The New England Journal of Medicine. doi:10.1056/NEJMoa2409415. PMID   39460694.