Atrasentan Explained

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.

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

It is an endothelin receptor antagonist selective for subtype A (ET_A). 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.

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.^[5] 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.

In 2013, SONAR trial was initiated to determine if atrasentan reduces kidney failure in diabetic kidney disease.^[6]

Notes and References

1. Web site: 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, Lush R, Padilla B, Burton M, Williams C, Simon G, Antonia S, Sullivan DM, Bepler G . 6 . 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 . March 2008 . 18316570 . 10.1158/1078-0432.CCR-07-1508 .
3. Addition of experimental drug to standard chemotherapy for advanced prostate cancer shows no benefit in phase 3 clinical trial . National Cancer Institute . April 21, 2011 . October 18, 2014.
4. Quinn DI, Tangen CM, Hussain M, Lara PN, Goldkorn A, Moinpour CM, Garzotto MG, Mack PC, Carducci MA, Monk JP, Twardowski PW, Van Veldhuizen PJ, Agarwal N, Higano CS, Vogelzang NJ, Thompson IM . 6 . 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 . August 2013 . 23871417 . 4277263 . 10.1016/S1470-2045(13)70294-8 .
5. de Zeeuw D, Coll B, Andress D, Brennan JJ, Tang H, Houser M, Correa-Rotter R, Kohan D, Lambers Heerspink HJ, Makino H, Perkovic V, Pritchett Y, Remuzzi G, Tobe SW, Toto R, Viberti G, Parving HH . 6 . 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 . May 2014 . 24722445 . 4005314 . 10.1681/ASN.2013080830 .
6. Heerspink HJ, Parving HH, Andress DL, Bakris G, Correa-Rotter R, Hou FF, Kitzman DW, Kohan D, Makino H, McMurray JJ, Melnick JZ, Miller MG, Pergola PE, Perkovic V, Tobe S, Yi T, Wigderson M, de Zeeuw D . 6 . Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial . Lancet . 393 . 10184 . 1937–1947 . May 2019 . 30995972 . 10.1016/S0140-6736(19)30772-X . 113407761 .