January 1, 2005 (Vol. 25, No. 1)

Leukemia Drugs In Development Highlighted at Meeting

Wall Street analysts crowded the “46th Annual American Society of Hematology” (ASH) meeting in San Diego in December intent on learning about drugs in late-stage trials for treating various forms of leukemia.

Results from clinical studies of anticancer therapies for treating multiple myeloma (MM), myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) were of particular interest.

Analysts focus on clinical trial results as part of formulating their opinions on investing in companies that have drugs in the late stages of clinical development and are about to file a new drug application (NDA) with the FDA.

The power of biotechnology and the industry’s innovative approach to drug development is well reflected by the experimental therapies now being developed in hematology. Alan List, M.D., of the H. Lee Moffitt Cancer and Research Institute (Tampa, FL) noted that novel therapeutics were now being studied to treat MDS, once considered an orphan disease.

MDS, a stem cell malignancy, evolves into acute leukemia, mostly in the elderly. However, patients with MDS usually succumb to complications of bone marrow failure before the disease progresses to AML.

Thalidomide is one of the drugs emerging in a promising new class of therapeutics for MDS. The recently discovered uses of thalidomide have conferred upon the once derided drug the moniker “wonder drug.” Hematologists are working to discover novel molecular pathways in which the drug and its derivatives can be used in a combination regimen to treat various forms of leukemia.

In the 1970s, thalidomide was found to be an effective anti-inflammatory agent for treating certain forms of leprosy, particularly in those patients with erythema nodosum leprosum (ENL). Interest in the drug was renewed, and eventually it was approved for use in Europe as chemotherapeutic for leprosy.

During the 1990s an Israel physician administered thalidomide to a leprosy patient who also had multiple myeloma. Following thalidomide therapy, the patient was cured of his cancer.


In 1998, Celgene (Warren, NJ) received FDA approval to treat ENL with thalidomide. The company’s strategy involved plans to eventually market the drug to clinical oncologists.

Thalidomide was also found to be an immunosuppressant and was used in cancer patients receiving bone marrow transplants. With these findings and the surprising results in treating multiple myeloma, Celgene reaped considerable benefits from the off-label use of thalidomide.

In 2003, Celgene reported $223.7 million net product sales; that figure is projected to be over $300 million in 2004 for Thalomid, the company’s branded thalidomide. In December 2003, the company filed a supplemental NDA with the FDA for Thalomid in the treatment of multiple myeloma.

Thalidomide is considered an immunomodulatory agent that inhibits the activity of cytokines, such as TNF and TGF, and also anti-angiogenic properties by inhibiting the activity of VEGF. In a 207-patient Phase III study, thalidomide used in combination with a corticosteroid and dexamethasone demonstrated (in newly diagnosed patients with multiple myeloma) a 63% response rate compared to a 41% response rate with only dexamethasone, according to Celgene.

Celgene has also developed a more potent analog of thalidomide, Revlimid. Clinical data from a 31-patient study with newly diagnosed MM patients, were presented at ASH. Revlimid in combination with dexamethasone reportedly showed an even greater efficacy profile.

Also in Celgene’s pipeline is another thalidomide derivate, Actimid, which induces apoptosis, disrupts cell adhesion, and enhances natural killer T cell activity. In relapsed/refractory MM patients the drug demonstrated a 50% response rate, the company reported.

Millennium Pharmaceuticals (Cambridge, MA) is already marketing Velcade (bortezomib) for the treatment of relapsing multiple myeloma. At ASH, clinical investigators reported Phase II data with previously untreated MM patients treated with Velcade. According to the company, Velcade demonstrated efficacy as a front-line therapy.

In three separate ongoing Phase II studies, Velcade also reportedly demonstrated efficacy in treating both follicular and mantle cell non-Hodgkin’s lymphoma. Mantle cell lymphoma is an insidious incurable disease where the median survival rate is 34 years.


Recently, rumors have surfaced about an increase in deaths among MDS patients treated with Revlimid. During ASH, Celgene held a meeting for analysts where the company presented data from two recent studies.

A subset of patients with a 5q chromosomal deletion had the more benign form of MDS. Since MDS is a bone marrow disease and patients become anemic, Revlimid’s activity was measured by a 50% decrease in transfusions or an increase in blood hemoglobin concentration (demonstrating that the body produces its own red blood cells).

The major erythroid response to transfusion dependence was 61% in the drug-treated arm of the study, according to the company. However, a number of deaths occurred in both studies, which, the company noted, were mostly not drug-related. The majority of deaths, the company’s investigators concluded, were from secondary causes such as pneumonia.

Celgene reported that it would file an NDA in the first quarter of this year. The short-sellers of the stock, however, believe that the FDA will reject Revlimid’s application for MDS because of its toxicity and that the pneumonia-associated deaths were a result of the drug. The bears also noted that the FDA will probably reject Celgene’s application since the studies were not randomized and placebo controlled.

On the other hand, investors who are bullish on Celgene, anticipate that the real play in Revlimid is an anticipated approval for multiple myeloma, which will skyrocket Celgene’s stock price.

Biotech analyst, Derek Taller, Ph.D., from Tradition-Asiel Securities (New York City), who is following Celgene, seemed less disturbed about Revlimid’s drug-related deaths and more concerned about the efficacy of the drug and the durability of the response to the drug treatment in both patient populations.

Dr. Taller was concerned about Celgene’s business strategy of trying to have Revlimid approved for MDS and also have the drug used off-label to treat MM (where there seems to be the real clinical benefit).

Other players in MDS arena are Pharmion (Boulder, CO), which is already marketing its drug Vidaza (azacitidine), and SuperGen (Dublin, CA), which reported on its Phase III study with Dacogen (decitabine) at ASH.

Both drugs are hypomethylation agents with a unique mechanism of action that recognizes that cells involved in this particular form of cancer have aberrant methylation patterns. By inactivating DNA methyltransferases with cytosine analogues, the aberrant cancer cells should inactivate.

Another interesting drug is Maxim Pharmaceuticals’ (San Diego) Celpene for AML. Celpene is a histamine dihydrochloride that acts as a protectant to anti-cancer T cells that could be suppressed by blood phagocytes.

Maxim’s investigators presented data from a Phase III trial demonstrating a leukemia-free survival benefit in AML patients in complete remission when treated with Celpene and Interleukin-2.

Diseases of the blood and cancer appear to be the power zone for biotech-based drug products. Wall Street’s focus on clinical data emanating from the scientific conferences, such as ASH, reinforces the power of developing novel therapeutics to treat diseases that were once thought to be an exercise in futility for drug developers focused on these small disease markets.

Thalidomide reflects how understanding underlying disease mechanisms can lead to new clinical indications for drugs once considered niche market products.

It is conceivable that in the not too distant future we will have biotech products that not only delay disease onset or death, but also actually cure diseases.

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