The Road to Romiplostim Approval and Beyond

Romiplostim (Nplate) was the first thrombopoietin (TPO) receptor agonist to receive regulatory approval by the US Food and Drug Administration (FDA) for treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The effects of TPO are mediated through the TPO receptor on megakaryocytes and platelets, with TPO levels regulated primarily by the amount of receptors available for binding, which is generally increased in patients with thrombocytopenia due to decreased production.[1] Following experience with a first-generation recombinant product where cross-reacting antibodies developed, resulting in severe thrombocytopenia, alternative TPO agonists have been sought that lack any sequence homology with endogenous TPO. These new agents include TPO peptide mimetics, nonpeptide mimetics, and agonist antibodies.[2]

The peptide mimetic, romiplostim, is a recombinant fusion protein with two identical subunits consisting of a peptide with two TPO-binding domains covalently bound to the Fc domain of a human IgG molecule.[3] The rationale for the use of TPO agonists in ITP is based on the observation that serum TPO levels are inappropriately normal or low in the majority of patients with an apparent defect in platelet production due to immune destruction of platelet precursors.[4]

Clinical and Regulatory Background

The recent clinical development and regulatory history of romiplostim are summarized by Pazdur et al in the accompanying article. Their report summarizes both the clinical data and some of the challenges in critically appraising therapeutic trial results in this disease setting. The FDA approved romiplostim for use in patients with chronic ITP based on a durable platelet response in two phase III multicenter, double-blind, randomized placebo-controlled trials in splenectomized and nonsplenectomized patients receiving at least one prior treatment for ITP. Both studies were agreed to by the FDA in the framework of a special protocol assessment process. Most adverse events were mild to moderate, and there was no significant increase in serious adverse events reported in the romiplostim arm.[5] Pooled data from these trials have also demonstrated that romiplostim therapy is associated with significant improvements in health-related quality of life.[6] Data from an extension study of prolonged romiplostim administration and a pilot study of romiplostim in patients with myelodysplastic syndrome (MDS) were also reviewed during the regulatory review.

FDA approval of romiplostim followed a unanimous recommendation of the Oncology Drug Advisory Committee and was based on the favorable risk-to-benefit profile in patients with chronic ITP. Overall, safety data on romiplostim were substantial given the orphan status of the disease, with a total of 308 ITP subjects included in clinical trials, and 114 patients receiving romiplostim for 1 year or more. No neutralizing antibodies to TPO were observed despite careful monitoring. Nevertheless, approval was accompanied by substantial pharmacovigilance efforts including a Risk Evaluation and Mitigation Strategy (REMS).

Overall, two identified risks with supporting clinical data are included in the risk management plan and the product information label. Reticulin formation was observed in 10 patients, although progression to marrow fibrosis was not observed in the two phase III studies. Severe thrombocytopenia following discontinuation of romiplostim was reported in four patients, resolving within 2 weeks. Possible risks without signals from clinical study data were also included, the most notable of which was disease progression observed in patients with MDS who received romiplostim. However, no control group was included in this exploratory study and no increased risk of hematologic malignancies was observed in the phase III studies.

Postmarketing Requirement

Four postmarketing requirements have also been agreed to, including an antibody registry, a pregnancy registry, a lactation study, and a bone marrow study. Studies currently or soon to be underway include (1) the Nplate US Patient Safety Registry (US PSR); (2) the Registry of Immunogenicity Based on Spontaneously Submitted Requests for Post Marketing Blood Tests (RI-PMBT) among Nplate Treated Patients; (3) Nplate Pregnancy Exposure Registy (NPER); (4) Study to Detect the Presence of Nplate in the Breast Milk of Lactating Female Subjects with Chronic Immune Thrombocytopenic Purpura; and (5) Prospective, Phase IV, Open-Label, Multi-Center Study Evaluating Changes in Bone Marrow Morphology in Adult Subjects Receiving Romiplostim for the Treatment of Thrombocytopenia Associated with Immune Thrombocytopenia Purpura. Safety registries have also been included in approvals in Canada by the Canadian Health Authority and in Europe by the European Medicines Agency.

Overall, this arguably represents one of the most aggressive and extensive risk management strategies and postmarketing requirements yet developed around the approval of a new agent under the FDA Amendment Act. Only time will tell whether this monitoring strategy was entirely necessary or sufficient to address the safety concerns raised. What is clear is that there will be increasing attention in the approval process to safety signals raised in both the pivotal trials and supporting clinical studies. In more common disease settings, clinical trials of sufficient size and duration are needed to identify important efficacy and safety issues with reasonable confidence. Targeting less common clinical disorders, as in the orphan disease setting, will continue to pose challenges to new drug evaluation. However, accelerated approval of effective agents will be increasingly accompanied by comprehensive and extended postmarketing requirements.

Possible Additional Indications

Additional safety and efficacy clinical development studies for romiplostim are underway. These studies are exploring additional indications including adults with chemotherapy-induced thrombocytopenia, for whom current therapeutic options are very limited. Studies in cancer patients receiving chemotherapy include a phase I/II, multicenter, open-label, sequential dose- and schedule-finding study in subjects with lymphoma experiencing severe thrombocytopenia due to multicycle chemotherapy and a phase II, randomized, double-blind, placebo-controlled dose- and schedule-finding study of romiplostim for treatment of chemotherapy-induced thrombocytopenia in subjects with advanced non–small-cell lung cancer receiving gemcitabine and platinum.

Future indications in patients receiving cancer chemotherapy are likely to be limited to high-risk settings such as those with current or recent severe thrombocytopenia. The potential impact of less severe thrombocytopenia on delivered chemotherapy dose intensity has yet to be fully explored. Clinical risk models for thrombocytopenia may be useful for the identification of cancer patients at particularly high risk of thrombocytopenic complications for entry into clinical trials of preemptive or prophylactic use of these agents.

Financial Disclosure:Dr. Lyman is principal investigator on a research grant to Duke University from Amgen Inc and serves on Amgen’s speakers bureau.

Dr. Lyman is a member of the FDA Oncology Drug Advisory Committee (ODAC) but did not participate in the ODAC review and recommendations related to romiplostim.

References:

1. Nurden AT, Viallard JF, Nurden P: New-generation drugs that stimulate platelet production in chronic immune thrombocytopenic purpura. Lancet 373:1562-1569, 2009.
2. Wright J, Vadhan-Raj S: Thrombocytopenia and thrombopoietic growth factors, in Lyman GH, Crawford J (eds): Cancer Supportive Care: Advances in Therapeutic Strategies, pp 135-148. New York; Informa Healthcare USA, Inc; 2008.
3. Wang B, Nichol JL, Sullivan JT: Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther 76:628-638, 2004.
4. Bussel JB, Kuter DJ, George JN, et al: AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med 355:1672-1681, 2006.
5. Kuter DJ, Bussel JB, Lyons RM, et al: Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: A double-blind randomised controlled trial. Lancet 371:395-403, 2008.
6. George JN, Mathias SD, Go RS, et al: Improved quality of life for romiplostim-treated patients with chronic immune thrombocytopenic purpura: results from two randomized, placebo-controlled trials. Br J Haematol 144:409-415, 2009.