Anthracyclines are a class of drugs that are among the most commonly used agents in the treatment of cancer. Doxorubicin, the first anthracycline to gain approval, has demonstrated efficacy in a wide variety of cancers including breast cancer, lung cancer, sarcomas, and lymphomas. However, doxorubicin is associated with side effects such as myelosuppression, gastrointestinal disorders, mucositis, stomatitis, cumulative cardiotoxicity and extravasation.

INNO-206 (formerly DOXO-EMCH) is a prodrug for doxorubicin. Specifically, it is the (6-Maleimidocaproyl) hydrazone of doxorubicin. Essentially, this chemical name describes doxorubicin (DOXO) attached to an acid sensitive linker (EMCH). We believe this novel agent has attributes that improve on native doxorubicin including reduction of adverse events, improvement in efficacy and the ability to reach the tumor more quickly.

The proposed mechanism of action is as follows:

• After administration, INNO-206 rapidly binds endogenous circulating albumin through the EMCH linker
• Circulating albumin preferentially accumulates in tumors, bypassing uptake by other non-specific sites including heart, bone marrow and gastrointestinal tract
• Once albumin-bound INNO-206 reaches the tumor, the acidic environment of the tumor causes cleavage of the acid sensitive linker
• Free doxorubicin is released at the site of the tumor

In preclinical models, INNO-206 was superior to doxorubicin with regard to ability to increase dosing, antitumor efficacy and safety.

A Phase I study of INNO-206 that demonstrated safety and objective clinical responses in a variety of tumor types was completed in the beginning of 2006 and presented at the March 2006 Krebskongress meeting in Berlin. In this study, doses were administered at up to 4 times the standard dosing of doxorubicin without an increase in observed side effects over historically seen levels. Objective clinical responses were seen in patients with sarcoma, breast, and lung cancers.

CytRx licensed worldwide intellectual property rights to INNO-206 from KTB Tumorforschungs GmbH, a free-standing research institute based in Freiburg, Germany.

Bibliography

J. Drevs, N. Esser, H. Richly, M. Skorzec, M.E. Scheulen, C. Unger, F. Kratz . In vivo efficacy and pharmacokinetic study of an acid-sensitive albumin conjugate in a murine renal cell carcinoma model. Annals in Oncology, Supplement, NCI/EOTRC Amsterdam, 8-10, November 2000

Felix Kratz, André Warnecke, Karin Scheuermann, Cornelia Stockmar, Jürgen Schwab, Peter Lazar, Peter Drückes, Norbert Esser, Joachim Drevs, Didier Rognan, Caterina Bissantz, Caterina Hinderling, Gerd Folkers, Iduna Fichtner, and Clemens Unger. Probing the Cysteine-34 Position of Endogenous Serum Albumin with Thiol-Binding Doxorubicin Derivatives. Improved Efficacy of an Acid-Sensitive Doxorubicin Derivative with Specific Albumin-Binding Properties Compared to That of the Parent Compound. J. Med. Chem. 2002, 45, 5523-5533.