Perifosine (DB06641): A Comprehensive Monograph on a Novel Akt Inhibitor from Preclinical Promise to Phase III Discontinuation

Executive Summary

Perifosine (DB06641) represents a significant and cautionary chapter in the history of targeted cancer therapy. Developed as a novel, first-in-class, orally bioavailable alkylphospholipid, it was designed to inhibit the serine/threonine kinase Akt, a central node in the PI3K/Akt/mTOR signaling pathway, which is frequently dysregulated in human cancers and is a critical mediator of cell survival, proliferation, and therapeutic resistance. The initial scientific rationale for Perifosine was compelling, targeting a high-value oncogenic driver with a unique, allosteric mechanism of action that distinguished it from conventional ATP-competitive kinase inhibitors.

Preclinical investigations revealed potent antiproliferative and pro-apoptotic activity across a broad spectrum of cancer cell lines and in vivo xenograft models. This promising laboratory data was subsequently bolstered by early-phase clinical trials. Notably, a randomized Phase II study in metastatic colorectal cancer (mCRC) demonstrated a dramatic and statistically significant improvement in both progression-free and overall survival when Perifosine was added to capecitabine. Similarly, Phase I/II trials in relapsed/refractory multiple myeloma (MM) showed impressive response rates and survival outcomes for the combination of Perifosine with bortezomib and dexamethasone. These encouraging results led to the initiation of large, pivotal Phase III registration trials for both indications, accompanied by Fast Track and Orphan Drug designations from regulatory authorities.