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Nplate (Romiplostim Subcutaneous) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Romiplostim, a member of the 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). The peptibody molecule contains two identical single-chain subunits, each consisting of human immunoglobulin IgG1 Fc domain, covalently linked at the C-terminus to a peptide containing two thrombopoietin receptor-binding domains. Romiplostim has no amino acid sequence homology to endogenous TPO. Romiplostim is produced by recombinant DNA technology in Escherichia coli (E coli).

Nplate is supplied as a sterile, preservative-free, lyophilized, solid white powder for subcutaneous injection. Two vial presentations are available, which contain a sufficient amount of active ingredient to provide either 250 mcg or 500 mcg of deliverable romiplostim, respectively. Each single-use 250 mcg vial of Nplate contains the following: 375 mcg romiplostim, 30 mg mannitol, 15 mg sucrose, 1.2 mg L-histidine, 0.03 mg polysorbate 20, and sufficient HCl to adjust the pH to a target of 5.0. Each single-use 500 mcg vial of Nplate contains the following: 625 mcg romiplostim, 50 mg mannitol, 25 mg sucrose, 1.9 mg L-histidine, 0.05 mg polysorbate 20, and sufficient HCl to adjust the pH to a target of 5.0 [ see Dosage and Administration (2.2) ].

CLINICAL PHARMACOLOGY

Mechanism Of Action

Nplate increases platelet production through binding and activation of the TPO receptor, a mechanism analogous to endogenous TPO.

Pharmacodynamics

In clinical studies, treatment with Nplate resulted in dose-dependent increases in platelet counts. After a single subcutaneous dose of 1 to 10 mcg/kg Nplate in patients with chronic ITP, the peak platelet count was 1.3 to 14.9 times greater than the baseline platelet count over a 2- to 3-week period. The platelet counts were above 50 x 109/L for seven out of eight patients with chronic ITP who received six weekly doses of Nplate at 1 mcg/kg.

Pharmacokinetics

In the long-term extension study in patients with ITP receiving weekly treatment of Nplate subcutaneously, the pharmacokinetics of romiplostim over the dose range of 3 to 15 mcg/kg indicated that peak serum concentrations of romiplostim were observed about 7 to 50 hours post dose (median: 14 hours) with half-life values ranging from 1 to 34 days (median: 3.5 days). The serum concentrations varied among patients and did not correlate with the dose administered. The elimination of serum romiplostim is in part dependent on the TPO receptor on platelets. As a result, for a given dose, patients with high platelet counts are associated with low serum concentrations and vice versa. In another ITP clinical study, no accumulation in serum concentrations was observed (n = 4) after six weekly doses of Nplate (3 mcg/kg). The accumulation at higher doses of romiplostim is unknown.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment Of Fertility

The carcinogenic potential of romiplostim has not been evaluated. The mutagenic potential of romiplostim has not been evaluated. Romiplostim had no effect on the fertility of rats at doses up to 37 times the MHD based on systemic exposure.

Animal Toxicology and/or Pharmacology

In a 4-week repeat-dose toxicity study in which rats were dosed subcutaneously three times per week, romiplostim caused extramedullary hematopoiesis, bone hyperostosis and marrow fibrosis at clinically equivalent and higher doses. In this study, these findings were not observed in animals after a 4-week post treatment recovery period. Studies of long-term treatment with romiplostim in rats have not been conducted; therefore, it is not known if the fibrosis of the bone marrow is reversible in rats after long-term treatment.

CLINICAL STUDIES

Chronic ITP

The safety and efficacy of Nplate were assessed in two double-blind, placebo-controlled clinical studies and in an open-label extension study.

Studies 1 and 2

In Studies 1 and 2, patients with chronic ITP who had completed at least one prior treatment and had a platelet count of ≤ 30 x 109/L prior to study entry were randomized (2:1) to 24 weeks of Nplate (1 mcg/kg subcutaneous [SC]) or placebo. Prior ITP treatments in both study groups included corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine. Patients already receiving ITP medical therapies at a constant dosing schedule were allowed to continue receiving these medical treatments throughout the studies. Rescue therapies (ie, corticosteroids, IVIG, platelet transfusions, and anti-D immunoglobulin) were permitted for bleeding, wet purpura, or if the patient was at immediate risk for hemorrhage. Patients received single weekly SC injections of Nplate, with individual dose adjustments to maintain platelet counts (50 x 109/L to 200 x 109/L).

Study 1 evaluated patients who had not undergone a splenectomy. The patients had been diagnosed with ITP for approximately 2 years and had received a median of three prior ITP treatments. 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 (25th–75th percentile: 1–3 mcg/kg).

Study 2 evaluated patients who had undergone a splenectomy. The patients had been diagnosed with ITP for approximately 8 years and had received a median of six prior ITP treatments. 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 (25th–75th percentile:
2–7 mcg/kg).

Study 1 and 2 outcomes are shown in Table 3. A durable platelet response was the achievement of a weekly platelet count ≥ 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 ≥ 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. Platelet responses were excluded for 8 weeks after receiving rescue medications.

Table 3: Results from Placebo-Controlled Studies 1
Outcomes

Study 1

Nonsplenectomized Patients

Study 2

Splenectomized Patients

Nplate

(n = 41)

Placebo

(n = 21)

Nplate

(n = 42)

Placebo

(n = 21)

Platelet Responses and Rescue Therapy
Durable Platelet Response, n (%)25 (61%)1 (5%)16 (38%)0 (0%)
Overall Platelet Response, n (%)36 (88%)3 (14%)33 (79%)0 (0%)
Number of Weeks With Platelet Counts ≥ 50 x 109/L, average151120
Requiring Rescue Therapy, n (%)8 (20%)13 (62%)11 (26%)12 (57%)
Reduction/Discontinuation of Baseline Concurrent ITP Medical Therapy
Receiving Therapy at Baseline(n = 11)(n = 10)(n = 12)(n = 6)
Patients Who Had > 25% Dose Reduction in Concurrent Therapy, n (%)

4/11

(36%)

2/10

(20%)

4/12

(33%)

1/6

(17%)

Patients Who Discontinued Baseline Therapy, n (%) 2

4/11

(36%)

3/10

(30%)

8/12

(67%)

0/6

(0%)

1 All P values < 0.05 for platelet response and rescue therapy comparisons between Nplate and placebo.
2 For multiple concomitant baseline therapies, all therapies were discontinued.

In Studies 1 and 2, nine patients reported a serious bleeding event [five (6%) Nplate, four (10%) placebo]. Bleeding events that were grade 2 severity or higher occurred in 15% of patients treated with Nplate and 34% of patients treated with placebo.

Extension Study

Patients who had participated in either Study 1 or Study 2 were withdrawn from study medications. If platelet counts subsequently decreased 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 ≥ 50 x 109/L. Among 100 patients 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 patients 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.

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