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Attacking a platelet-depleting autoimmune disease in a whole new way, an experimental drug is helping patients with immune thrombocytopenic purpura (ITP) once again produce healthy amounts of platelets – with no major side effects.

That's the conclusion of a new, multicenter study led by Dr. James B. Bussel, professor of pediatrics at Weill Cornell Medical College, attending pediatrician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, and director of the Hospital's Program for Platelet Disorders.

His team's findings appear in The New England Journal of Medicine.

The new drug, a novel protein called AMG 531, successfully boosted platelet production in patents with chronic ITP, a serious autoimmune disorder that affects more than 16,000 adult Americans, and perhaps as many children, each year.

In ITP, immune system antibodies mysteriously begin to attack and destroy blood platelet cells. In some cases, the disease goes into spontaneous remission, but for many patients it remains a chronic condition. Impaired clotting leaves many patients, especially the elderly, vulnerable to serious or fatal hemorrhage.

Up till now, ITP patients have typically turned to powerful drugs such as corticosteroids or intravenous immune globulin, which work by inhibiting platelet destruction. These drug therapies can have limited success, but they also have serious side effects. For some ITP patients splenectomy (surgical removal of the spleen) is another treatment option.

AMG 531 fights ITP in a totally different way.

"Experts have long realized that ITP not only destroys platelets, it also inhibits platelet production in the marrow," explains Dr. Bussel.

In fact, prior work in the 1990s had focused on a type of recombinant thrombopoietin, called PEG-MGDF, that researchers hoped would stimulate platelet production.

The drug did have success. "However, Dr. David Kuter at Massachusetts General Hospital showed that some patients – and even healthy volunteers – developed antibodies to the drug, and these antibodies cross-reacted with their own natural thrombopoietin. The result was chronic low platelet counts in people who, in many cases, had never had such problems before," Dr. Bussel says.

The trick, then, was to find a platelet-stimulating agent that avoided this dangerous immune-system response.

"Luckily, Amgen, the company that has funded this research, didn't throw in the towel," Dr. Bussel says.

The company, under the guidance of the study's senior author, Dr. Janet Nichol, eventually developed AMG 531 – a novel protein with no structural similarity to human thrombopoietin. This dissimilarity and other features mean AMG 531 is largely ignored by the immune system.

The new, two-phase trial was led by Dr. Bussel and conducted at nine centers across the United States.

In the Phase 1 part of the study, doctors first gave six groups of four ITP patients (24 total) two subcutaneous injections of AMG 531 delivered at least two weeks apart. Depending on the group they were in, patients received anywhere from 0.2 to 10 micrograms of the drug per kilogram of body weight.

In the Phase 2 part of the trial, 21 patients were randomized to receive six weekly injections of either a harmless placebo, or AMG 531 at doses of 1, 3, or 6 micrograms per kilogram of body weight.

The Phase 1 results showed the drug to be safe, with no major adverse events attributed to AMG 531 during the treatment period. Four of a total of 41 patients did show some temporary post-treatment lowering of their platelet counts, but this later resolved.

The drug's efficacy impressed the researchers.

"We were very pleased," says Dr. Bussel. Hoping to boost platelet counts to between 50,000 to 450,000 per cubic millimeter, the researchers report that seven of 12 patients given higher doses of AMG 531 (3, 6 or 10 micrograms/kilogram) fell within that range after six weeks on the therapy.

"In fact, three of these patients saw their counts rise to over 450,000 per cubic millimeter," Dr. Bussel notes.

Platelet counts increased in treated patients in a dose-dependent fashion, with mean peak counts of 163,000, 309,000 and 746,000 per cubic millimeter for doses of 3, 6 and 10 micrograms/kilogram, respectively.

"This was a relatively small trial, so more study is needed. However, the results point to a new, effective and safe way of letting people receive an injection once a week that stimulates them to increase their platelets," Dr. Bussel says.

How does AMG 531 work? According to the researchers, the drug acts much like natural thrombopoietin, stimulating the production of platelets from their earliest stages of development within the marrow, straight through to their appearance in the bloodstream.

Based on the findings, Dr. Bussel is optimistic that ITP patients everywhere will soon have a potent new weapon against the disease.

"Further clinical trials in AMG 531 are well under way," he says, "and the next step, we hope, will be to license the compound. Then, maybe, we can begin to broaden its use to other illnesses, where boosting platelets might help the many other patients with low platelets fight disease."

Co-researchers include Dr. David J. Kuter of Massachusetts General Hospital, Boston; Dr. James N. George of the University of Oklahoma Medical Center, Oklahoma City; Drs. Robert MacMillan and Jorge Nieva, of Scripps Cancer Center, La Jolla, Calif; Dr. Louis M. Aledort of Mount Sinai Medical Center, New York City; Dr. George T. Conklin of the Diagnostic Clinic of Houston; Dr. Alan E. Lichtin, of the Cleveland Clinic Foundation; Dr. Roger M. Lyons of Hematology-Oncology Associates of South Texas, San Antonio; Dr. Jeffrey S. Wasser of DeQuattro Community Cancer Center, Manchester, Conn; Dr. Israel Wiznitzer of the Broward General Medical Center, Fort Lauderdale, Fla; and Reggie Kelly and Dr. Chien-Feng Chen, of Amgen, Thousand Oaks, Calif.