Author: Hertzler, Russell L ; Souers, Andrew J ; Garner, Sean M ; Henry, Rodger F ; Chen, Shuang ; Hong, Richard ; Nie, Haichen ; Sheikh, Ahmad Y ; Catron, Nathaniel D

ABBV-167, a phosphate prodrug of BCL-2 inhibitor venetoclax, was recently progressed into the clinic as an alternative means of reducing pill burden for patients in high-dose indications. The dramatically enhanced aqueous solubility of ABBV-167 allowed for high drug loading within a crystalline tablet and, when administered in phase I clinical study, conferred venetoclax exposure commensurate with the equivalent dose administered as an amorphous solid dispersion. In enabling the progression into the clinic, we performed a comprehensive evaluation of the CMC development aspects of this beyond the rule of five (bRo5) prodrug. Adding a phosphate moiety resulted in excessively complex chemical speciation and solid form landscapes with significant physical-chemical stability liabilities. A combination of experimental and computational methods including microelectron diffraction (MicroED), total scattering, tablet colorimetry, finite element, and molecular dynamics modeling were used to understand CMC developability across drug substance and product manufacture and storage. The prodrug's chemical structural characteristics and loose crystal packing were found to be responsible for the loss of crystallinity during its manufacturing, which in turn led to high solid-state chemical reactivity and poor shelf life stability. The ABBV-167 case exemplifies key CMC development challenges for complex chemical matter such as bRo5 phosphate prodrugs with significant ramifications during drug substance and drug product manufacturing and storage.

01 Jun 2021·Molecular Cancer TherapeuticsQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Salem, Ahmed Hamed ; Chen, Shuang ; Stolarik, Deanne ; Pu, Yu-Ming ; Bueno, Orlando F. ; Tao, Zhi-Fu ; Shi, Yi ; Chen, Jie ; Harper, Kaid C. ; Suleiman, Ahmed A. ; Judge, Russell A. ; Marks, Richard A. ; Klix, Russell C. ; Kalvass, John C. ; Sheikh, Ahmad Y. ; Fournier, Keith M. ; Jenkins, Gary J. ; Ku, Yi-Yin ; Sanzgiri, Yeshwant D. ; Phillips, Darren C. ; Park, Chang H. ; Marsh, Kennan C. ; Hong, Richard ; Wang, Xilu ; Souers, Andrew J. ; Ji, Jianguo ; Rosenberg, Saul H. ; Zhang, Geoff G.Z. ; Leverson, Joel D. ; Catron, Nathaniel D. ; Edalji, Rohinton ; Elmore, Steven W. ; Menon, Rajeev M.

AbstractSince 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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Indication	Highest Phase	Country/Location	Organization	Date
Hematologic Neoplasms	Phase 1	United States	AbbVie, Inc.	-
Solid tumor	Discovery	United States	AbbVie, Inc.	05 Jun 2019

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