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Spring 2004 Volume 5, Issue 10:
Atiprimod: A New Drug Candidate in Early-Stage Development for Myeloma
By Gary S. Jacob, PhD
Callisto Pharmaceuticals
Atiprimod has a very interesting history, providing yet another example of a drug candidate that begins its story as a potential treatment for a wholly different disease indication.

These are encouraging times for patients with multiple myeloma. After three decades of clinical trial research involving thousands of patients with multiple myeloma, the last few years have seen encouraging advancements in new therapies to treat the disease. New drugs such as Velcade® (Millennium Pharmaceuticals, Inc.), the proteosome inhibitor recently approved by the FDA, and antiangiogenic agents such as Thalomid® and Revlimid® (Celgene Corp.) are providing doctors with additional ways to treat the disease. Additionally, advances in our understanding of the basic biology underlying the course of this disease are creating new targets for research scientists to explore as new potential treatments. A number of drug candidates at various stages of clinical development are currently being evaluated as both cytotoxic agents and as treatment for bone pain associated with the disease. One of these drug candidates, Atiprimod (Callisto Pharmaceuticals, Inc.), is just about to enter the clinic.

Atiprimod has a very interesting history, providing yet another example of a drug candidate that begins its story as a potential treatment for a wholly different disease indication. Other examples of this phenomenon include Thalomid®, approved for the treatment of leprosy; ViagraTM (Pfizer Inc.), originally developed as a cardiovascular drug and approved for erectile dysfunction; and even further afield, NutrasweetTM (aspartame), originally developed at G.D. Searle as a potential cardiovascular candidate before finding its present use as an artificial sweetener.

In the case of Atiprimod, the drug was originally developed by SmithKline Beecham as a treatment for rheumatoid arthritis (RA) and successfully completed three Phase l clinical trials(1) in RA patients. These trials included single-dose studies, one-month multiple-dose studies and an open-label(2) extension study in which patients were on the drug for as long as one year. The results of these studies showed the drug to be well-tolerated at the administered doses, with no observed dose-limiting toxicity. These Phase l clinical trials, along with an extensive preclinical package of data, were a significant benefit to Callisto Pharmaceuticals, Inc., providing considerable clinical and preclinical safety data which were used to facilitate the September 2003 filing of an Investigational New Drug (IND) Application for Atiprimod to treat multiple myeloma patients.

Initial animal model studies with Atiprimod by SmithKline scientists showed that the drug lowers serum levels of interleukin 6 (IL-6) and tumor necrosis factor (TNF). Because IL-6 is generally recognized as the primary growth factor in the bone marrow environment driving multiple myeloma (Figure 1), Callisto Pharmaceuticals began to further explore development of Atiprimod for treatment of this disease. These recent exploratory and preclinical studies on Atiprimod have been conducted at Dana-Farber Cancer Institute (Laboratory of Dr. Kenneth C. Anderson), at the University of Texas M.D. Anderson Cancer Center (Laboratory of Dr. Zeev Estrov), and at Callisto’s research laboratory in Princeton, New Jersey. These studies demonstrate that Atiprimod inhibits the growth of human multiple myeloma cells.

Atiprimod’s actual mechanism for inhibiting the growth of human multiple myeloma cells is unknown, although scientists have been able to show that the drug turns on programmed cellular death (apoptosis) within these cells. Scientists also know that tumors need to support their growth by stimulating formation of new blood vessels, a process referred to as angiogenesis (see Figure ). In cellular assays Atiprimod has been shown to inhibit secretion of the growth factor that promotes angiogenesis, referred to as VEGF, and to directly inhibit angiogenesis in a developmental blood vessel model performed in chicken eggs.

Finally, a separate set of experiments initially performed by SmithKline research scientists provides an additional potential benefit of Atiprimod to treat multiple myeloma. Atiprimod was found to inhibit the action of human osteoclasts (white blood cells that break down bone) from dissolving bone in in vitro cellular assays of bone resorption. This effect of Atiprimod appears to be selective against osteoclasts, with little or no effect on the bone marrow cells.

Loss of bone mass due to the effects of multiple myeloma is a common occurrence in this disease, and despite the advent of new treatments, such as more potent bisphosphonates and other methods of controlling the bone disease, the effects are not totally abated, particularly in patients who relapse or become refractory (resistant) to chemotherapy. The capability of Atiprimod to control bone resorption could potentially provide a significant additional benefit in the treatment of multiple myeloma patients.


(1) Phase I clinical studies generally involve a small group of people who take the same drug but via different methods of delivery or different dosages. The purpose of the study is to measure safety and dosage of the drug.

(2) An open label trial is a clinical study where each patient and doctor knows what each patient is receiving as the study drug.

(3) Phase l/IIa studies combine a Phase I study, testing the safety and dosage of a drug, with an early indication of drug response (efficacy) that is otherwise typically not explored until a classic Phase II study.

Atiprimod is about to enter a Phase l/lla(3) clinical trial in relapsed multiple myeloma patients in March 2004. These are patients who no longer respond to chemotherapy and are in advanced stages of the disease. The Phase l/lla trial will be performed at two sites, Dana-Farber Cancer Institute (Boston) and M.D. Anderson Cancer Center (Houston), with Principal Investigators Dr. Nikhil Munshi (Dana-Farber) and Dr. Moshe Talpaz (M.D. Anderson). The trial is an open label study, with the primary objective of assessing the safety of the drug, and the secondary objective of focusing on evaluating early indicators of efficacy (any responses in multiple myeloma patients). The duration of this clinical study will depend on how well the drug is tolerated and on drug response, with final results not available until the end of 2004.

Note: Included in this article are “forward-looking” statements. Such statements are indicated by words such as “expect,” “should,” “anticipate” and similar words indicating uncertainty in facts and figures. Although Callisto believes that the expectations reflected in such forward-looking statements are reasonable, it can give no assurance that such expectations reflected in such forward-looking statements will prove to be correct. Callisto’s actual results could differ materially from those anticipated in the forward-looking statements as a result of various factors.

Callisto is a biopharmaceutical company primarily focused on the development of drugs to treat multiple myeloma, other cancers, and osteolytic bone disease. Callisto’s lead drug candidate, Atiprimod, is a small-molecule, orally available drug with antiproliferative and antiangiogenic activity. In addition, Callisto has programs focused on the development of an analog of the human intestinal hormone, uroguanylin, to treat colon cancer, and drugs to protect against staphylococcal and streptococcal bioweapons and as a protection against the devastating effects of toxic shock syndrome.

Callisto has two operating subsidiaries, Callisto Research Labs, LLC and Synergy Pharmaceuticals Inc. For additional information, visit www.callistopharma.com.

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