The US Food and Drug Administration (FDA) has approved a new drug for the treatment of myelodysplastic syndrome (MDS). The drug is Vidaza, also called azacitadine or Aza C, and is manufactured by Pharmion of Boulder, CO.

MDS is a collection of bone marrow diseases that are considered to be pre-cancerous. While many cases of MDS remain in the pre-cancer stage, a sizeable proportion of cases eventually develop into outright leukemia. MDS is the disease that killed famed astronomer Carl Sagan.

When a disease is as rare as MDS (only 5,000-6,000 people are diagnosed with the condition in the US each year) there is little incentive for pharmaceutical companies to develop treatments for it. As a means of encouraging the development of new approaches for such uncommon diseases, the FDA has developed its so-called orphan drug category. By granting a drug orphan status the FDA effectively gives the manufacturer of that drug a seven-year market monopoly in that category. Vidaza was not only granted orphan drug status by the FDA, it was also given a priority review, allowing approval to go through in six months as opposed to the usual ten. Pharmion's stock jumped 48 percent on the announcement of the news.

"This new treatment will offer a much-needed option for patients suffering from this rare illness that, in some cases, has been found to progress to leukemia," said Dr. Lester M. Crawford, acting FDA commissioner. "The agency continues to make approvals of these types of remarkable treatments one of its highest priorities."

"The approval of Vidaza represents a significant milestone for Pharmion and, more importantly, represents an important new option for patients being treated for MDS," said Patrick Mahaffy, Pharmion's president and CEO, in a press release. "Until today, there have been no approved therapies for the treatment of MDS."

The company said Vidaza received approval for treatment of the five MDS subtypes - refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. All of these bone marrow disorders are characterized by production of abnormally functioning, immature blood cells.

So now there is an approved treatment for MDS, a potentially deadly precursor of cancer for which there has previously been no standard treatment. However, the question remains, how good is this treatment?

Cancer and Leukemia Group B Study

The word Vidaza doesn't come up in PubMed, the National Library of Medicine's comprehensive database of medical literature. However, under the generic name azacitidine there are 72 articles relating to MDS. Of these, 12 are reports of clinical trials, 3 of which were randomized controlled trials (the so-called "gold standard" of clinical testing). The most important of these trials was the Cancer and Leukemia Group B study, headed by Dr. Lewis Silverman and colleagues of Mt. Sinai School of Medicine, New York.

In this trial, 191 patients with high-risk MDS were randomized to receive either Vidaza or supportive care. The drug was delivered by subcutaneous injection for 7 days every 28 days. Patients in both 'arms' (sections) of the study also received transfusions and antibiotics, as required. Patients in the supportive care arm whose disease worsened were permitted to cross over to treatment with Vidaza.

Responses occurred in 60 percent of patients on the Vidaza arm: of these, 7 percent had complete responses, 16 percent had partial responses, while another 37 percent improved somewhat. This compared with just 5 percent who improved while receiving supportive care. The difference was found to be statistically significant.

The median time to transformation of the disease to leukemia, or to death, was 21 months for Vidaza versus 13 months for supportive care. This gain of eight additional months was also found to be statistically significant. However, these results were somewhat confounded by the fact that patients were allowed to switch over to the Vidaza arm if their disease worsened during the trial.

Adjusting for this effect, the median (average) survival was 18 months with the drug versus 11 months with supportive care, for a gain of seven months. There were said to be significant and major advantages in physical function, symptoms, and psychological state for patients who were initially randomized to receive the drug. Dr. Silverman and his colleagues conclude that treatment with Vidaza results in significantly higher response rates, improved quality of life, reduced risk of leukemic transformation, and improved survival compared with supportive care.

Demethylation

Vidaza is an interesting compound. On the one hand, it is a classic chemotherapy drug, an antimetabolite, which prevents cells from making genetic material, DNA and RNA. Antimetabolites are Trojan horses that fool the body into thinking they are necessary breakdown products of digestion (metabolites). But when the body tries to use them in place of real metabolites, DNA and RNA cannot be manufactured, thus stopping the growth of affected cells.

Like other forms of chemotherapy, Vidaza can lower blood counts, especially 14 to 17 days after the drug is given. This can result in an increased tendency to succumb to infection and fever. Vidaza can also cause a decrease in the platelet count, and nausea and vomiting are frequent side effects, according to the American Cancer Society (ACS).

But in addition to its classic cytotoxic effects Vidaza is also a 'hypomethylating' or 'demethylating' agent. Methylation of DNA is considered a major mechanism by which cells regulate gene expression. For example, researchers have found that an increase in the methylation of DNA can block the activity of the so-called suppressor genes that regulate cell division and differentiation. Once such suppressor gene activity is blocked, cell division becomes unregulated, allowing the rapid, chaotic growth that characterizes cancer. Vidaza, at least in the test-tube, has been shown to reverse DNA methylation, leading to the re-activation of suppressor genes, thereby allowing the orderly differentiation and maturation of cells to resume (Pharmion 2004).

Ironically, this puts Vidaza in the same category as Stanislaw R. Burzynski's antineoplastons. Dr. Burzynski is a controversial Houston practitioner, who was unsuccessfully prosecuted by the US government for health fraud. Some of his concepts are now receiving wider acceptance. According to Burzynski's latest research, "antineoplastons work as molecular switches, which regulate expression of genes p53 and p21 through demethylation of promoter sequences…" (Burzynski 2004).

Click or go here for earlier articles on Dr. Burzynski.
http://www.ralphmoss.com/html/burz.shtml

Vidaza is not a cure for MDS, and it has many of the typical unpleasant effects of chemotherapy. But it does appear to increase the length of time it takes for MDS to develop into leukemia, and can increase survival by a matter of months. This will be welcome news to people who have MDS, or who are involved in caring for those who do. It is also of considerable scientific interest for its novel way of reversing cancer's progress.

--Ralph W. Moss, Ph.D.

References:

Burzynski SR. The present state of antineoplaston research. Integr Cancer Ther. 2004 Mar;3(1):47-58.

Kornblith AB, Herndon JE 2nd, Silverman LR, et al. Impact of azacytidine onthe quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol. 2002 May 15;20(10):2441-52.

Pharmion Corp. FDA accepts Pharmion's new drug application for filing and grants priority review for Vidaza for the treatment of myelodysplastic syndromes (MDS). February 23, 2004. Retrieved May 24, 2004 from:
http://www.drugs.com/nda_vidaza_040223.html

Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J Clin Oncol. 2002 May 15;20(10):2429-40.