Expanding the Repertoire for "Large Small Molecules": Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers

  • Mol Cancer Ther. 2021 Jun;20(6):999-1008. doi: 10.1158/1535-7163.MCT-21-0077.
Ahmed Hamed Salem  1  2 ,  Zhi-Fu Tao  1 ,  Orlando F Bueno  1 ,  Jie Chen  1 ,  Shuang Chen  1 ,  Rohinton Edalji  1 ,  Steven W Elmore  1 ,  Keith M Fournier  1 ,  Kaid C Harper  1 ,  Richard Hong  1 ,  Gary J Jenkins  1 ,  Jianguo Ji  1 ,  Russell A Judge  1 ,  John C Kalvass  1 ,  Russell C Klix  1 ,  Yi-Yin Ku  1 ,  Joel D Leverson  1 ,  Richard A Marks  1 ,  Kennan C Marsh  1 ,  Rajeev M Menon  1 ,  Chang H Park  1 ,  Darren C Phillips  1 ,  Yu-Ming Pu  1 ,  Saul H Rosenberg  1 ,  Yeshwant D Sanzgiri  1 ,  Ahmad Y Sheikh  1 ,  Yi Shi  1 ,  Deanne Stolarik  1 ,  Ahmed A Suleiman  3 ,  Xilu Wang  1 ,  Geoff G Z Zhang  1 ,  Nathaniel D Catron  1 ,  Andrew J Souers  4
Affiliations
  • 1. AbbVie, Inc., North Chicago, Illinois.
  • 2. Ain Shams University, Cairo, Egypt.
  • 3. AbbVie Deutschland GmbH & Co. KG, Ludwigshafen am Rhein, Germany.
  • 4. AbbVie, Inc., North Chicago, Illinois. [email protected].
PMID: 33785651 DOI: 10.1158/1535-7163.MCT-21-0077
Abstract

Since gaining approval for the treatment of Chronic Lymphocytic Leukemia (CLL), the Bcl-2 Inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within Bcl-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

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