General Information

Nplate (romiplostim), is an antihemorrhagic. This member of the thrombopoietin (TPO) mimetic class is an Fc-peptide fusion protein (peptibody) that activates intracellular transcriptional pathways leading to increased platelet production via the TPO receptor (also known as cMpl), a mechanism analogous to endogenous TPO.

Nplate is specifically indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy.

Nplate is supplied as sterile solution (250 mcg and 500 mcg) designed for subcutaneous administration. Nplate must be reconstituted with preservative-free Sterile Water for Injection. The recommended initial dose of the drug is 1 mcg/kg once weekly based on actual body weight, as a subcutaneous injection.

Dose adjustments
Use the actual body weight at initiation of therapy, then adjust the weekly dose of Nplate by increments of 1 mcg/kg until the patient achieves a platelet count of greater than or equal to 50 x 109/L as necessary to reduce the risk for bleeding; do not exceed a maximum weekly dose of 10 mcg/kg.

Adjust as follows:
If the platelet count is < 50 x 109/L, increase the dose by 1 mcg/kg.
If platelet count is > 200 x 109/L for 2 consecutive weeks, reduce the dose by 1 mcg/kg.
If platelet count is > 400 x 109/L, do not dose. Continue to assess the platelet count weekly. After the platelet count has fallen to < 200 x 109/L, resume Nplate at a dose reduced by 1 mcg/kg.

If platelet count does not increase after 4 weeks at the maximum weekly dose of 10 mcg/kg, Nplate should be discontinued.

Clinical Results

FDA Approval
FDA approval of Nplate was based on the results of two double-blind, placebo-controlled clinical studies and an open-label extension study.

Studies One and Two
These studies enrolled subjects with chronic ITP who had completed at least one prior treatment and had a platelet count of less than or equal to 30 x 109/L prior to study entry. The subjects were randomized to 24 weeks of single weekly SC injections of Nplate (1 mcg/kg subcutaneous [SC]) or placebo. Individual dose adjustments were made to maintain platelet counts (50 x 109/L to 200 x 109/L). Subjects already receiving ITP medical therapies at a constant dosing schedule were allowed to continue receiving these medical treatments throughout the studies.

Study One
This study evaluated subjects who had not undergone a splenectomy. Overall, the median platelet count was 19 x 109/L at study entry. During the study, the median weekly Nplate dose was 2 mcg/kg.

Study Two
This study evaluated subjects who had undergone a splenectomy. Overall, the median platelet count was 14 x 109/L at study entry. During the study, the median weekly Nplate dose was 3 mcg/kg.

Results
A durable platelet response was the achievement of a weekly platelet count greater than or equal to 50 x 109/L for any 6 of the last 8 weeks of the 24-week treatment period in the absence of rescue medication at any time. A transient platelet response was the achievement of any weekly platelet counts greater than or equal to 50 x 109/L for any 4 weeks during the treatment period without a durable platelet response. An overall platelet response was the achievement of either a durable or a transient platelet response.

Results from Study One

Results from Study Two

In both studies, nine subjects reported a serious bleeding event. Bleeding events that were grade 2 severity or higher occurred in 15% of subjects treated with Nplate and 34% of those treated with placebo.

Extension Study
Subjects who had participated in either Study 1 or Study 2 were withdrawn from study medications. If platelet counts subsequently decreased to less than or equal to 50 x 109/L, the patients were allowed to receive Nplate in an open-label extension study with weekly dosing based on platelet counts. Following Nplate discontinuation in Studies 1 and 2, seven patients maintained platelet counts of greater than 50 x 109/L. Among 100 subjects who subsequently entered the extension study, platelet counts were increased and sustained regardless of whether they had received Nplate or placebo in the prior placebo-controlled studies. The majority of subjects reached a median platelet count of 50 x 109/L after receiving one to three doses of Nplate, and these platelet counts were maintained throughout the remainder of the study with a median duration of Nplate treatment of 60 weeks and a maximum duration of 96 weeks.

Ongoing Study Commitments

• Amgen has agreed to conduct an "Antibody Registry Study" that will enroll subjects who have received romiplostim and whose blood samples contain antibodies to either romiplostim or thrombopoietin. The Antibody Registry Study will collect follow-up platelet count and 'other clinical data sufficient to assess the long term consequences of the detected antibodies. Patients will be followed until the detected antibodies resolve or stabilize in titer over a several month period of time.
  Protocol Submission: November 2008
  Study Start: May 2009
  First interim report submission: May 2010 then annually
  Final Report Submission: Within six months of FDA notification that sufficient data has been collected
• Amgen has agreed to develop and maintain a prospective, observational pregnancy exposure registry study conducted in the United States that compares the pregnancy and fetal outcomes of women exposed to romiplostim during pregnancy to an unexposed control population. The registry will detect and record major and minor congenital anomalies, spontaneous abortions, still-births, elective terminations, adverse effects on immune system development, platelet number and function, neoplasmformation, bone marrow reticulin formation, thrombotic events, and any serious adverse pregnancy outcomes. The events will also be assessed among infants through at least the first year of life.
  Protocol Submission: November 2008
  Study Start: May 2009
  First interim report submission: May 2010 then annually
  Final Report: Within six months of FDA notification that sufficient data. has been collected.
• Amgen has agreed to conduct a milk only lactation study in the subset of women enrolled in the pregnancy registry that choose to breastfeed their infants. This study will be designed to detect the presence and concentration of romiplostim in breast milk and any effects on milk production and composition.
  Protocol Submission: November 2008
  Study Start: May 2009
  First interim report submission: May 2010 then annually
  Final Report: Within six months of FDA notification that sufficient data has been collected
• Amgen has agreed to conduct trial 20080009, "A Prospective Phase iv, Open-Label, Multi-Center, Study Evaluating the Changes in Bone Marrow Morphology in Subjects Receiving Romiplostim for the Treatment of Thrombocytopenia associated with Immune (Idiopathic) Thrombocytopenia Purpura(ITP)." In this trial, at least 150 patients will receive romiplostim and undergo bone marrow, evaluations prior to, during and following the completion of romiplostim administration. A similar evaluation schedule will apply to the detection of antibody formation to romiplostim and thrombopoietin as well as the electrocardiograph (ECG) detection of cardiac conduction abnormalities.
  Protocol submission: August 22, 2008
  Trial start: July 2009
  First interim report submission: June 2012
  Second interim report submission: June 2013
  Final report submission: December 2014

Side Effects

Adverse reactions associated with the use of Nplate may include, but are not limited to, the following:

• headache
• arthralgia
• dizziness
• insomnia
• myalgia
• pain in extremity
• abdominal pain
• shoulder pain
• dyspepsia
• paresthesia

Mechanism of Action

Nplate (romiplostim), is an antihemorrhagic. This member of the thrombopoietin (TPO) mimetic class is an Fc-peptide fusion protein (peptibody) that activates intracellular transcriptional pathways leading to increased platelet production via the TPO receptor (also known as cMpl), a mechanism analogous to endogenous TPO.

Literature References

Tiu RV, Sekeres MA The role of AMG-531 in the treatment of thrombocytopenia in idiopathic thrombocytopenic purpura and myelodysplastic syndromes. Expert Opinion on Biological Therapy 2008 Jul;8(7):1021-30

Stasi R, Evangelista ML, Amadori S Novel thrombopoietic agents: a review of their use in idiopathic thrombocytopenic purpura. Drugs 2008;68(7):901-12

Kapoor S Romiplostim: an alternative treatment option besides rituximab for the management of steroid refractory idiopathic thrombocytopenic purpura. Journal of Thrombosis and Thrombolysis 2008 Apr 26

Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrère F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet 2008 Feb 2;371(9610):395-403

Additional Information

For additional information regarding Nplate or thrombocytopenia and chronic idiopathic thrombocytopenic purpura, please visit the Nplate web page.