Life Raft meets with Infinity about IPI-504

By Norman Scherzer and Jerry Call

While at the American Society of Clinical Oncology (ASCO) 2006 meeting in Atlanta, Life Raft Group members Norman Scherzer and Jerry Call had the opportunity to meet with Julian Adams, Ph.D., and David Grayzel M.D., of Infinity Pharmaceuticals. Infinity has a new drug, IPI-504, that is being tested in a phase I trial in GIST patients. Adams is the President and Chief Scientific Officer at Infinity and Grayzel is the Vice President, Clinical Development and Medical Affairs.

Prior to joining Infinity, Dr. Adams discovered and successfully brought to market two drugs, Viramune® for HIV and Velcade® for cancer. Adams received a B.S. from McGill University and a Ph.D. from the Massachusetts Institute of Technology in the field of synthetic organic chemistry. He has received many awards, including the 2001 Ribbon of Hope Award for Velcade® from the International Myeloma Foundation.

Dr. Grayzel obtained his medical degree at Harvard Medical School where, working in the Department of Genetics investigating familial inheritance of cardiovascular disease, he assisted in identifying the gene causing Holt-Oram Syndrome.

IPI-504 belongs to a new class of drugs known as heat shock protein 90 (Hsp90) inhibitors. Articles about this drug and the phase I trial have appeared in the November 2005 and January 2006 editions of this newsletter. The Hsp90 protein binds to and protects the KIT protein (Activated KIT protein is the primary driver behind the great majority of GIST tumors). Inactivating the Hsp90 protein causes degradation of the KIT protein and results in tumor cell death. In-vitro tests have shown activity of this class of drugs in GIST cells lines that have secondary mutations that are typically insensitive to Gleevec and other drugs.

IPI-504 is given intravenously twice per week for two weeks followed by one week off. As in any phase I trial the investigators primary concerns are looking for toxicities and establishing the right schedule and dose. As Hsp90 is an important protein that interacts with many other proteins besides KIT, investigators must proceed cautiously when establishing the right schedule and dose. Much of the experience with similar drugs in this class is with a schedule similar to the one used in the IPI-504 trial.

IPI-504 is not the only drug given to GIST patients in an on drug/off drug schedule. Sutent, the only drug currently approved for Gleevec-resistant GIST, is given in a four week on/two week off schedule. The on/off schedule of Sutent has been the subject of concern as some patients and some doctors feel that tumors can become “reactivated” during the off drug period. This has resulted in a phase II trial for Sutent to test whether Sutent given continuously might be safe with increased effectiveness over the on/ off schedule. The off drug period is commonly called a “washout period.”

One of the topics that we discussed at the meeting with Infinity was the washout period of IPI-504. Similar to the washout period with Sutent, some patients have reported difficulties with the washout period on IPI-504. Infinity acknowledged the concerns with the washout periods in GIST patients and had plans to discuss the IPI-504 washout with the trial investigators immediately after our meeting.

Infinity is a very promising start-up pharmaceutical company that is targeting an interesting protein, Hsp90. They seem committed to working with investigators and patients to bring their compound to patients. With Gleevecresistant GIST, it might be a case of having found the right disease for their drug rather than a much longer term process of developing a specific drug solely for GIST.