TPO Receptor Agonists
Platelet Growth Factors or thrombopoietin (TPO) receptor agonists are a class of treatments that stimulate the bone marrow to produce more platelets. TPO, a protein made in everyone's liver, naturally stimulates platelet production in the bone marrow. TPO receptor agonists bind to the same receptor in the bone marrow as the TPO produced in the body. This prompts the megakaryocyte cells in the bone marrow to produce more platelets, sufficient to increase the platelet count in most people with ITP.
About 80% of people with ITP who receive these treatments respond as long as the treatments are given.2 However, a small percent of people are able to discontinue these treatments and maintain a safe platelet count.1 Note: the goal of these treatments is a platelet count of about 50,000/ml, not a normal platelet count.
There are two TPO receptor agonists approved by the FDA in the US for adults and by the regulatory agencies in some other countries: romiplostim (Nplate®) and eltrombopag (Promacta®/Revolade®). Eltrombopag was approved by the FDA for limited use in children in June, 2015. Clinical trials are ongoing for other TPO receptor agonists.
Romiplostim is a manufactured peptibody (part peptide and part antibody) liquid that is given by weekly subcutaneous (under the skin) injection. On September 4, 2008, the US FDA approved romiplostim for adults with ITP (either splenectomized or not) who have failed at least one other treatment for the disease.3 Since then other countries have approved its use, sometimes adding other criteria.
Eltrobopag is a small molecule (pill) taken daily. The drug was given FDA approval in 2008 for use in adults with ITP with the same approval criteria as romiplostim. In addition, in 2015 eltrombopag was FDA approved for treatment of ITP in children under age 18.3 Other countries have also approved its use, again, sometimes adding other criteria.
romiplostim: The dose of romiplostim, from 1ug/kg to 10 ug/kg, depends on the patient's weight and response to previous doses. The dose is reduced or discontinued if the platelet count rises too high or if the patient doesn't respond.2
eltrombopag: The pill is given as a 25, 50, or 75 mg daily dose. It must be taken on an empty stomach as other medications and food affect its absorption.2 People of Japanese heritage require a lower starting dose.7
When discontinuing these treatments, some doctors reduce the dose gradually to avoid a sharp drop in the platelet count.
romiplostim: The most common adverse reactions are joint and muscle pain, dizziness, insomnia, indigestion, and ‘pins and needles’ sensation. There is a slight potential for patients to develop reticulum (fibrous growths) in the bone marrow and also for the platelet count to drop below the pre-treatment count when the treatment is discontinued.6
eltrombopag: The most common adverse reaction is a mild to moderate headache. Other side effects include nausea, diarrhea, upper respiratory tract infection, vomiting, rash, flu, sore throat, back pain, and tingling or numbness in the skin.8 A small percent of people develop elevated liver functions which usually resolves when the treatment is discontinued.9
Because these treatments are expensive the manufacturers have established several programs to assist those people in the US who are not insured, underinsured or who cannot meet the insurance co-payments.
romiplostim/Nplate (Amgen): Financial support section on the Amgen website.
eltrombopag/Promacta (Novartis): Patient assistance program.
In December 2011 the U.S. Food and Drug Administration (FDA) approved modifications to the Risk Evaluation and Mitigation Strategies (REMS) for platelet-booster drugs Nplate (romiplostim) injection and Promacta (eltrombopag) tablets. The modifications include the removal of certain elements of the REMS, including the requirements for restricted distribution and additional safety data collection. FDA no longer requires patient participation in the NEXUS or CARES programs of the two drug companies.12
Measure thrombopoietin (TPO) Levels: Since these treatments stimulate TPO production, patients who produce a lot of TPO on their own may not benefit. In one study patients with TPO levels greater than 95pg/mL did not respond well to the TPO agents.11 Quest Diagnostics has a test to measure TPO levels (test no. 16336)
Analyze platelet lifespan: In one study, the platelets of people who were able to sustain a remission had a normal lifespan and were removed from the body in the same way as those without the disease.10
1. Ghadaki B et al. "Sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists." Transfusion. 2013 Mar 3.
2. Provan, D, “International consensus report on the investigation and management of primary immune thrombocytopenia,” Blood. 2010 Jan 14; 115(2):168-86. http://bloodjournal.hematologylibrary.org/cgi/content/full/115/2/168
4. Bussel JB et al. “A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia.” Blood. 2011 Jul 7;118(1):28-36. http://www.ncbi.nlm.nih.gov/pubmed/21502541
5. Blanchette VS et al. "Health-Related Quality of Life in Children with Chronic Immune Thrombocytopenia Treated with Eltrombopag in the PETIT Study." 2012 American Society of Hematology meeting. Abstract 2197.
7. Tomiyama Y, et al. "A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia (ITP)." J Thromb Haemost. 2012 Mar 12. http://www.ncbi.nlm.nih.gov/pubmed/22409309
8. FDA News Release https://www.cancer.gov/about-cancer/treatment/drugs/fda-eltrombopag
9. Saleh MN et al. “Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study.” Blood. 2013 Jan 17;121(3):537-45. http://www.ncbi.nlm.nih.gov/pubmed/23169778
10. Iuliano F. “Platelet Kinetic Study (PKS) May Early Identify a Subset of Patients with Immune Thrombocytopenia (ITP) Probably Cured by Romiplostim. Two Years Follow-up.” 2012 American Society of Hematology meeting. Abstract 2197.
11. Makar RS et al. “Thrombopoietin (TPO) levels in patients with disorders of platelet production: Diagnostic potential and utility in predicting response to TPO Receptor agonists.” Am J Hematol. 2013 Aug 1. http://www.ncbi.nlm.nih.gov/pubmed/23913253
12. FDA Drug Safety Communication: Modified Risk Evaluation and Mitigation Strategies (REMS) for Nplate (romiplostim) and Promacta (eltrombopag) Dec. 6, 2011. http://www.fda.gov/Drugs/DrugSafety/ucm280165.htm