ATLANTA—Interim long-term follow-up data—up to 48 weeks—suggest that the investigational compound AMG 531 continues to boost platelet production safely in patients with immune thrombocytopenic purpura (ITP).
The results of an ongoing open-label study, presented during an oral session here at the ASH Annual Meeting, showed that about 85% of patients (29 of 34) achieved a platelet response, defined as doubling of the baseline platelet count with at least 50,000 platelets per microliter of blood.
Although conventional therapies aim to reduce platelet destruction by suppressing the immune system, AMG 531 is designed to increase platelet production directly and outpace platelet destruction by the immune system, according to information from the manufacturer, Amgen.
James B. Bussel, MD, Professor of Pediatrics and Medicine, Weill Cornell Medical Center, New York, who presented the updated research, explained that although the normal platelet range for a person without ITP is 150,000 to 400,000 platelets/mcL, those with the chronic autoimmune bleeding disorder that identifies the body's normal platelets as alien and destroys them often have dangerously low counts of less than 30,000 platelets/mcL.
Approximately 200,000 Americans suffer from ITP, with three times as many women as men, according to new estimates, Dr. Bussel added. But no one knows why it develops in the first place.
James George, MD, Professor of Medicine at the University of Oklahoma Health Sciences Center, who participated in the follow-up ITP study, said that beginning with the use of steroids and followed by surgical removal of the spleen and more intensive immunosuppression, traditional therapies for ITP have focused on diminishing platelet destruction by suppressing the immune system. But these treatments may have serious side effects, and about half of patients treated do not respond in any case.
For these ITP sufferers, there are no effective therapeutic options, Dr. George said. “That's why the current long-term results of our study are so encouraging: They show that AMG 531 administered as an individualized weekly dose produced a durable platelet response.”
Fast Track Status
The Food and Drug Administration has granted Fast Track status to AMG 531, and Phase III trials are under way. “If approved, AMG 531 may well provide that very important option for ITP patients—one that enables them to taper off long-term steroid therapy.”
The researchers presented interim results for 34 patients treated with AMG 531 for up to 48 weeks. All patients were previously treated; 28 had undergone splenectomy before entering the study and eight were receiving concurrent corticosteroids for ITP.
Overall, 47% of patients (16 patients) had a durable platelet response, defined as a platelet response at six or more weeks between Weeks 18 through 25.
Dr. Bussel also noted that of the eight patients on concurrent corticosteroids, four discontinued corticosteroid treatment and two had a dose reduction of at least 50%.
“It's exciting that most patients in this study achieved platelet counts of more than 50,000 per microliter, despite how refractory they were, from a starting count of about 18,000,” he said. “It suggests that the speed with which AMG 531 may stimulate platelet production [and override platelet destruction] may also enable patients to sustain a satisfactory platelet count with ongoing therapy.”
Adverse Effects Mild
Headache, upper respiratory infection, and fatigue were the most frequently reported adverse events, while serious adverse events considered to be treatment-related included bone pain, anemia, and vaginal hemorrhage—seen in one patient each.
One case of diffuse reticulin formation in the bone marrow also was reported, but subsequent bone marrow biopsies revealed steady improvement in the reticulin, according to the follow-up data, Dr. Bussel noted.
”Clinicians should know that overall, AMG 531 is very effective and seems to have little by way of side effects. While it needs to be injected subcutaneously once a week, the plus side is that at least 75% of the so-called ‘worst’ ITP patients could have their platelets maintained at a safe count by this approach.
“When you consider that more than one million people give themselves one or two insulin shots every day to manage their diabetes, a once-per-week physician-administered shot that controls serious ITP seems like a minor inconvenience.”
The Best Dosage
The safest and most effective starting dose of AMG 531 was found to be 1 mcg/kg, by once-weekly subcutaneous injection, with dose adjustment to a maximum of 15 mcg/kg. Importantly, when patients reached a stable dose and schedule, their physician office visits were reduced from weekly to once per month. Concurrent corticosteroid treatment could be tapered when platelet counts reached 50,000 platelets/mcL.
AMG 531, the first of a class of investigational proteins called peptibodies, works similarly to thrombopoietin (TPO), a natural protein in the body. AMG 531 increases the production of platelets by activating the TPO receptor (the “on-off switch”), which is required for the growth and maturation of the megakaryocytes large bone marrow cells that play a pivotal role in platelet production.
Asked for a comment about the study, Ellis Neufeld, MD, Associate Chief of Hematology at Children's Hospital in Boston, who was not involved with the AMG 531 studies, said, “The new approach used by AMG 531—which avoids the dangerous tactic of suppressing the immune system—aims to convince the body to produce more and more platelets. This could be a very exciting option, particularly in the many cases where patients with refractory ITP fail to respond to any existing therapy. In fact, it may be their first real option.”
The excitement around AMG 531's potential has not gone unnoticed by other drug companies, he added. “Thus, early research is under way to develop a similar oral medication to boost platelet production.”
Summing up, Dr. George, said that AMG 531 may open up an entirely new era for ITP and perhaps other platelet disorders as well, introducing clinicians to a method of treatment they had never considered before. “Just being aware of an approach on the horizon that could be so helpful to their patients is very heartening,” he said.
“Patients with uncommon diseases have been as discouraged as their doctors,” he noted. “They've had so few options they believe the pharmaceutical industry neglects them.
“But now with AMG 531 we have an example of a biotech company offering them what looks like an opportunity for a longer and better life. Enhancing platelet production is a concept whose time has come,” said Dr. George.