Nplate

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

Studies 1 (NCT00102336) and 2 (NCT00102323)

• In Studies 1 and 2, patients with ITP who had completed at least one prior treatment and had a platelet count of ≤30x10⁹/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 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 (50x10⁹/L to 200x10⁹/L).
• Study 1 evaluated patients who had not undergone a splenectomy. 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. During the study, the median weekly Nplate dose was 3 mcg/kg (25th–75th percentile: 2– 7 mcg/kg).
• A durable platelet response was the achievement of a weekly platelet count ≥50x10⁹/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 ≥50x10⁹/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 of the study showed that the durable platelet response was observed in 61% of patients in Study 1 (nonsplenectomized) and 38% of patients in Study 2 (splenectomized). Moreover, the overall platelet response in patients who still retained their spleens had a higher Nplate response (88%) rate than those who underwent a splenectomy (79%).

Study 3 (NCT01143038) 

Study 3 (n=75) was a single-arm, open-label study designed to assess the safety and efficacy of Nplate in adult patients who had an insufficient response (platelet count ≤30x10⁹/L) to first-line therapy. Patients received single weekly SC injections of Nplate over a 12-month treatment period, with individual dose adjustments to maintain platelet counts (50x10⁹/L to 200x10⁹/L). During the study, the median weekly Nplate dose was 3 mcg/kg (25th-75th percentile: 2-4 mcg/kg). 

Of the 75 patients enrolled in Study 3, 70 (93%) had a platelet response ≥50x10⁹/L during the 12-month treatment period. The mean number of months with platelet response during the 12-month treatment period was 9.2 (95% CI: 8.3, 10.1) months; the median was 11 (95% CI: 10, 11) months. The Kaplan-Meier estimate of the median time to first platelet response was 2.1 weeks (95% CI: 1.1, 3.0). Twenty-four (32%) patients maintained every platelet count ≥50x10⁹/L for at least 6 months in the absence of Nplate and any medication for ITP (concomitant or rescue); the median time to onset of maintaining every platelet count ≥50x10⁹/L for at least 6 months was 27 weeks (range 6 to 57). 

Study 4 (NCT00116688) Extension Study 

Patients who had completed a prior Nplate study (including Study 1 and Study 2) were allowed to enroll in a long term open-label extension study. After Nplate discontinuation in Studies 1 and 2, seven patients maintained platelet counts of ≥50x10⁹/L. Among 291 patients who subsequently entered the extension study and received Nplate, 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 50x10⁹/L after receiving 1 to 3 doses of Nplate; platelet counts were maintained throughout the remainder of the study with a median duration of Nplate treatment of 78 weeks and a maximum duration of 277 weeks. 

Pediatric Patients with ITP 

The safety and efficacy of Nplate in pediatric patients ≥1 year with ITP for at least 6 months were assessed in two double-blind, placebo-controlled clinical trials. 

Study 5 (NCT01444417) 

In Study 5, patients refractory or relapsed after at least one prior ITP therapy with a platelet count ≤30x10⁹/L were stratified by age and randomized (2:1) to receive Nplate (n=42) or placebo (n=20). The starting dose for all ages was 1 mcg/kg weekly. Over a 24-week treatment period, dose was titrated up to a maximum of 10 mcg/kg weekly of either Nplate or placebo to maintain a target platelet count of ≥50x10⁹/L to 200x10⁹/L. 

The results of the study showed durable platelet response (≥6 weekly platelet counts ≥50x10⁹/L during weeks 18-25) was seen in 22 (52%) patients in the romiplostim arm vs 2 (10%) patients in the placebo arm. Overall platelet response was observed in 30 (71%) patients in the romiplostim arm vs 4 (20%) patients in the placebo arm. In addition, romiplostim-treated patients had platelet counts ≥50x10⁹/L for median 12 weeks vs 1 week in placebo-treated patients. All endpoints were statistically significant (all P <.05). 

Study 6 (NCT00515203) 

In study 6, patients diagnosed with ITP at least 6 months prior to enrollment with a platelet count ≤30x10⁹/L were stratified by age and randomized (3:1) to receive Nplate (n=17) or placebo (n=5). The starting dose for all ages was 1 mcg/kg weekly. Over a 12-week treatment period dose was titrated up to a maximum of 10 mcg/kg weekly of either Nplate or placebo in an effort to maintain a target platelet count of ≥50x10⁹/L to 250x10⁹/L.  

The efficacy of Nplate in this trial was measured by the proportion of patients who achieved a platelet count of ≥50x10⁹/L for 2 consecutive weeks and by the proportion of patients who achieved an increase in platelet count of ≥20x10⁹/L above baseline for 2 consecutive weeks. 

Of the 17 patients who received romiplostim, 15 achieved a platelet count of ≥50x10⁹/L for 2 consecutive weeks (88.2%, 95% CI: 63.6%, 98.5%). The same 15 patients also achieved an increase in platelet count of ≥20x10⁹/L above baseline for 2 consecutive weeks during the treatment period (88.2%, 95% CI: 63.6%, 98.5%). None of the patients treated with placebo achieved either endpoint. 

Patients with Hematopoietic Syndrome of Acute Radiation Syndrome 

Efficacy studies of Nplate could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Approval for this indication was based on efficacy studies conducted in animals, Nplate’s effect on platelet count in healthy human volunteers and on data supporting Nplate’s effect on thrombocytopenia in patients with ITP and insufficient response to corticosteroids, immunoglobulins, or splenectomy.  

The efficacy of Nplate was studied in a randomized, blinded, placebo-controlled study in a non-human primate model of radiation injury. Rhesus monkeys were randomized to either a control (n=40) or treated (n=40) cohort. Animals were exposed to total body irradiation (TBI) of 6.8 Gy from a Cobalt⁶⁰ gamma ray source, representing a dose that would be lethal in 70% of animals by 60 days of follow-up (LD70/60). Animals were given a single subcutaneous dose of blinded treatment (control article [sterile saline] or Nplate [5mg/kg]) 24 hours post-irradiation. The primary efficacy endpoint was survival.

Nplate significantly (one-sided P =0.0002) increased 60-day survival in the irradiated animals: 72.5% survival (29/40) in the Nplate group vs 32.5% survival (13/40) in the control group. In the same study, an exploratory cohort of n=40 animals received Nplate (5mg/kg) on day 1 and pegfilgrastim (0.3mg/kg) on days 1 and 8 post-irradiation. Survival in this combined treatment group was 87.5% (95% CI: 73.2%, 95.8%).