Thrombopoietic Growth Factors: A Story of Never Giving Up
By Ashley Smith

If at first you don’t succeed, try, try again. This slogan, which is used often by parents to teach children the importance of never giving up, must have been the mantra for researchers focused on developing a drug form of thrombopoietin (TPO) — the principal growth factor that stimulates platelet production. The session “Growth Factors as Drugs: Thrombopoietin” (9117-S)—a joint ASH/AABB program—provided an overview of the development of TPO as a growth factor, the first generation of clinical trails, recent successes with the second-generation product and what the future may hold for this drug. 

Discovering TPO

TPO is naturally found in humans, and it binds to receptors on the cell membrane, activating the pathways that stimulate the production of platelets. “TPO is the main regulator of the platelet count,” said David J. Kuter, MD, DPhil, from Harvard Medical School and Massachusetts General Hospital.

The concept that something may exist to stimulate the growth and development of platelets began around 1956, and over the course of the next several decades, researchers vied to discover the compound. In 1994, the Wall Street Journal announced that multiple companies had identified the compound — thrombopoietin — and trials focused on using this compound to increase platelet counts in humans ensued.

A First-Generation Product

The first generation of TPO was based on two compounds: rhTPO — a glycosylated, full-length version — and PEG-rhuMGDF — a truncated, nonglycosylated version. Each was used in a variety of clinical trials from 1994 until 1999. In trials of patients receiving nonmyeloablative chemotherapy, researchers were able to demonstrate that TPO helped reduce the need for platelet transfusions, and when TPO was given to patients with idiopathic thrombocytopenic purpura (ITP) or myelodysplastic syndrome (MDS) or to donors of apheresis platelets, there was a marked increase in the platelet production. “Eighty percent of donors who received TPO had an increased platelet yield,” Kuter said.

Not all trials with first-generation products were successful, however. In two trials where TPO was given to patients undergoing myeloablative treatments, researchers found no effect on platelet recovery and only a slight reduction in the need for transfusions. According to Kuter, the real problems emerged when TPO was given to healthy subjects. “This is where we saw antibody formation occur, and this is what ended the use of the first-generation TPOs,” he said.

Round Two: A Second Generation

Researchers recognized that although their first attempt did not succeed, the value of a TPO growth factor agent was evident, and they pursued the development of a second-generation product. “These second-generation products consist of three types — TPO peptide mimetics, TPO nonpeptide mimetics and TPO agonist antibodies,” Kuter explained. Romiplostim, which is a TPO peptide mimetic, has been shown to stimulate platelet production the same way TPO does. “It is a potent drug, and one study has shown that after five days, you begin to see an increase in the platelet count of healthy humans,” Kuter said. “This increase peaks around day 12 to 14.”

Eltrombopag, a TPO nonpeptide mimetic, has been studied extensively, and Kuter told the audience that its approval by the Food and Drug Administration is expected soon. It is a very small molecule that can be delivered orally. Eltrombopag stimulates megakaryocyte proliferation and differentiation and increases platelet counts. “It is unique, though, because it is species dependent, and a single amino acid regulates whether it will work in a given species or not,” Kuter stated. In a Phase I trial, healthy males received a range of doses of eltrombopag once a day for 10 days, and those who received 30 mg, 50 mg or 75 mg had increased platelet counts at the end of the trial.  

Clinical trials of second-generation thrombopoietic growth factors mostly have been conducted with patients suffering from chemotherapy-induced thrombocytopenia, hepatitis C thrombocytopenia, ITP and MDS.  “The trials have been successful in demonstrating that both romiplostim and eltrombopag are effective in treating ITP, and there have been no major adverse effects,” Kuter said. Romiplostim recently received its FDA approval and is indicated for the treatment of thrombocytopenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy.

The Real Deal

James B. Bussel, MD, from Cornell University, informed the audience that the use of thrombopoietic growth factors has demonstrated that thrombopoietic agonists that stimulate the TPO-receptor in patients are the “real deal” for increasing platelet counts.

Patients with ITP emerged as potential recipients of TPO because of their low platelet count with no known cause. “In 75% of ITP patients, TPO levels are not increased, and two-thirds of patients have either reduced or normal levels of platelet production,” Bussel explained. “This is caused by autoantibody inhibition of megakaryocyte growth and the induction of early apoptosis.”

Bussel posed the question, why did researchers focus on ITP patients as those who could benefit from TPO agonists when facing low platelet counts? “This was a result of the imperfect outcomes seen in the canine idiopathic thrombocytopenia trials and the suboptimal platelet production of ITP patients,” he said. One recent study of romiplostim demonstrated that once treatment with the growth factor drug began, platelet production in patients increased as well as the overall platelet count.

Two six-week trials that used eltrombopag to treat ITP that proved to be pivotal studies also were highlighted. The trials included over 100 patients with chronic ITP. “After two weeks, those patients who achieved platelet counts of greater than 50,000/µL were considered responsive, and any patient who achieved a count greater than 200,000/µL was released from the study and considered responsive to the therapy,” Bussel said. Patients receiving the highest doses of eltrombopag showed the greatest response in the shortest time, but there were no data before day eight. “The increase in platelet counts remained stable throughout the study in the groups with the highest doses,” Bussel noted. “This is a good drug for stable, long-term use.”

Risks and Consequences

Even with the advances in TPO, there still are potential and real adverse consequences of TPO growth factors. In animal studies, the subjects developed cataracts, and Bussel stated that although this has not been seen in humans, more data are needed. Other potential consequences include thrombosis, the stimulation of leukemia cell growth and a reduction in the threshold for platelet activation.

An adverse consequence that has been noted, but only infrequently, is abnormal liver function tests in some patients. “Some patients also have experienced worsening of their thrombocytopenia,” Bussel said. A main adverse consequence that has been recorded is the increase in marrow reticulin and collagen. “We need more studies in this area,” Bussel noted, “because we still do not know what will happen to patients with these consequences or the real incidence.”

What Lies Ahead and New Applications

Even with the positive results from recent studies, Bussel told the audience there are questions that remain regarding the use of TPO agents for patients with ITP in the future:

·          How fast can one increase platelet counts?

·          If a high enough dose is used, what is the true rate of response?

·          Do the different agents work the same in all patients or are responses different?

·          Do you give these agents indefinitely or may improvements be seen?

·          Is there synergy with other treatments?

Researchers also are beginning to explore novel approaches for using TPO agents to manage low platelet counts associated with chronic liver disease, such as hepatitis C virus (HCV). “The worldwide burden of chronic HCV infection is estimated to be approximately 170 million individuals, and many of these people are unaware of their infections because they are asymptomatic,” Bussel said. In a study of HCV patients who could not start traditional therapy because of low platelet counts, a TPO agent was given over a four-week period, and a dramatic increase in platelet counts was noted. “When traditional HCV therapy was initiated, some patients experienced a decrease in their platelet count, but two-thirds of those patients receiving 75 mg were able to complete 12 weeks of therapy despite their initial low platelet count,” Bussel stated.

In summarizing the status of TPO-like agents, Bussel said, “there are limitations such as reticulin fibrosis in marrow, but there also is the promise that the agents may revolutionize the care of many types of thrombocytopenia.”