Peginesatide as a new approach for treating anemia of CKD patient: is it like a falling star?

Abstract

Any scientific innovation needs to translate into a significant benefit. Peginesatide is noninferior to other erythropoiesis stimulating agents (ESAs) in terms of efficacy, and it shares the advantages of other long-acting ESAs: delayed administration frequency and no changes in dose needs according to the administration route. The molecular structure of peginesatide does not require the use of recombinant DNA technology during the manufacturing process, making its synthesis simpler and likely economically cheaper. During clinical development, its safety profile seemed to be safe, excepting the potential increase in the risk of safety end-point events in nondialysis CKD patients. However postmarketing serious hypersensitivity reactions have completely changed the scenario and urgently needs in-depth clarification. This promising drug seems to have prematurely finished its prospects.

Keywords::

• anemia
• chronic kidney disease
• peginesatide
• safety

1. Introduction

Erythropoiesis stimulating agents (ESAs) have transformed anemia management in patients with chronic kidney disease (CKD). They are effective in anemia correction, avoiding or minimizing blood transfusions, and possibly improving certain domains of quality of life.

In the past two decades, pharmacological research has made a great effort in finding new agents with longer half-life and reduced receptor affinity compared to recombinant human erythropoietin (rHuEPO). This has been done by modifying the EPO molecule through changes in the aminoacid sequence and increase in the glycosylation pattern through the adding of a pegylated moiety (high-molecular-weight erythropoietins) or, more recently, by creating simpler molecules not related to the EPO structure.

Holger Schmid [1] now reports in the Journal an accurate profile of peginesatide (Affymax and Takeda Pharmaceuticals), which is a small, dimeric peptide conjugated to a pegylated moiety with a sequence completely unrelated to EPO and a much smaller molecular weight. It has a highly specific binding to the EPO receptor with five-times less binding potency than epoetin or darbepoetin alfa [2]. The half-life of this drug is intermediate between that of darbepoetin alfa and methoxypolyethylene glycol-epoetin beta; similar to them, dose requirements are irrespective of the administration route.

Peginesatide was approved by the Food and Drug Administration (FDA) in March 2012 for the treatment of anemia in adults undergoing dialysis. Its phase III clinical development consisted of two correction studies (PEARL 1 and PEARL 2) [3] and two maintenance studies (EMERALD 1 and EMERALD 2) [4] enrolling over 2600 patients.

In PEARL 1 and PEARL 2, 983 ESA-naïve CKD patients not on dialysis were randomized to receive peginesatide subcutaneously (once a month, 0.025 mg or 0.04 mg/kg) or darbepoetin alfa (once in every 2 weeks, 0.75 μg/kg) with a 1:1:1 ratio and followed for a median follow-up of nearly 20 months [3]. In EMERALD 1 and EMERALD 2 studies, 1608 dialysis patients were randomized to either peginesatide (mean dose ranging between 4.8 and 5.7 mg) or to continue with epoetin (mean weekly dose 4625 – 9000 U), aiming at an Hb target range between 10 and 12 g/dl [4]. The median duration of follow-up was around 16 months.

2. Clinical efficacy

Phase II and III clinical development of peginesatide has shown efficacy in increasing Hb levels in single- and multi-dose correction studies of EPO-naïve patients, as well as conversion studies of dialysis patients previously treated with other ESAs. Both PEARL [3] and EMERALD [4] studies showed noninferiority in achieving (PEARL) and maintaining Hb levels in the Hb target range compared to the comparator. In particular, the mean changes of Hb values from the baseline were -0.24 ± 0.96 g/dl and -0.07 ± 1.01 g/dl in the peginesatide group and -0.09 ± 0.92 g/dl and in the epoetin group in the EMERALD 1 and EMERALD 2 studies, respectively. In PEARL studies, peginesatide was noninferior to darbepoetin in increasing and maintaining Hb levels in both dose groups. However, the mean difference was slightly higher in the higher dose group (0.03 g/dl for the lower starting dose and 0.26 g/dl for the higher starting dose of peginesatide in the PEARL 1; 0.14 g/dl and 0.31 g/dl for the lower and higher starting dose, respectively, in the PEARL 2).

3. Safety

In healthy subjects and in phase II and III studies, peginesatide was generally well tolerated. However, concerns about cardiovascular safety were raised by the PEARL studies [3]. A higher frequency of cardiovascular safety end-points was found in patients receiving peginesatide compared to darbepoetin with a hazard ratio of 1.32 (95% CI, 0.97 – 1.81). This was mainly due to higher incidences of death, unstable angina, and arrhythmia. The clinical meaning of this finding is unclear, also considering that the analysis of the EMERALD studies and the combined one of the four trials did not confirm an increased cardiovascular risk with peginesatide [4]. The latter analysis was the one foreseen by the study protocol; conversely, those on the two separate CKD populations were secondary ones with inadequate statistical power.

Since launch, > 25,000 patients have received peginesatide in the US. In February, 2013 Affymax and Takeda have instituted a voluntary product recall of peginesatide following serious hypersensitivity reactions, including life-threatening and fatal events, which occurred after the commercialization in the US [5]. The FDA has received 19 reports of anaphylaxis from dialysis centers around the US, three of which resulted in death [6]. Other patients required rapid medical intervention or hospitalization. The reactions occurred within 30 minutes following the first intravenous dose. There have been no reports of such reactions following subsequent dosing. It is too early to foresee the impact of these events on the future commercialization of the drug.

4. Immunogenicity

Given that peginesatide has no sequence homology with EPO, it may have reduced potential to cause pure red cell aplasia (PRCA). However, peginesatide antibodies may reduce drug efficacy, as is the case of other agents such as insulin [7] or interferon α [8] and β [9].

Experimental studies have shown minimal immunogenicity in rats and monkeys [10,11]. Phase III studies have shown a low-degree immunogenicity in CKD patients (Figure 1).

Figure 1. Percentage of patients developing antibodies against peginesatide [3,4], recombinant human (rHu) insulin [7], interferon α [8] and β [9].

Considering that antibodies against peginesatide do not cross react with EPO and vice versa, peginesatide has been used to treat patients with anaemia due to PRCA [12]. Fourteen PRCA patients were treated with peginesatide obtaining no more need for regular blood transfusion in 13 of them.

5. Expert opinion

During scientific meetings often people ask: “Is there the need of a new ESA?”

Certainly, the development of peginesatide is fascinating from the scientific point of view, since it required the characterization of the binding activity of the EPO receptor and the evolution of methods capable of screening large numbers of peptides.

However, scientific innovation needs to translate into a significant benefit. Peginesatide is noninferior to other ESAs in terms of efficacy. From the practical point of view, it shares the advantages of other long-acting ESAs: delayed administration frequency and no changes in dose needs according to the administration route.

The molecular structure of peginesatide does not require the use of recombinant DNA technology during the manufacturing process, making its synthesis simpler compared to other EPO-based ESAs. This may be relevant from the economical point of view, considering that in 2011 the economic expenditure for ESAs in the US was nearly three thousand millions US$ [13]. In 2012, peginesatide has been sold in the US at a lower price than that of Amgen's epoetin alfa, allowing the signing of contract with some important dialysis organization for drug supply. The possibility of having a drug with the characteristics of other newer molecules but possibly cheaper than all the other ESAs implies a high theoretical potential of penetrating the market of ESAs (we do not know what would have happened in Europe if the drug had been registered).

The possible increase in cardiovascular events in CKD patients not on dialysis receiving peginesatide deserves a comment. It is difficult to accept that two ESAs acting on the same receptor and used aiming at the same Hb target in the same CKD population may have a different cardiovascular safety profile or that the same agent may have a different safety profile in two different CKD populations. Looking at the causes of deaths, the unbalance against peginesatide was due mainly to sudden deaths (2.1 vs. 0.3%) and unknown causes (2.4 vs. 1.2%). Animal studies have not shown any arrhythmic potential with peginesatide [14]. Other explanations are to be found. First, the sample size of the two trials with a 1:1:1 randomization ratio may have not ensured adequate statistical power for testing mortality and cardiovascular events, leaving open the possibility of statistical fluctuation. Second, an unbalance in baseline characteristics among groups should be considered. Patients receiving peginesatide were more likely to have diabetes compared to those randomized to darbepoetin alfa; it is well known that diabetic patients are at increased risk for sudden death [15]. Moreover, patients randomized to peginesatide had a significantly higher rate of acute renal failure compared to the darbepoetin alfa group. This, together with a higher transfusion use in the peginesatide group, may suggest an imbalance in the randomization procedure with a casual selection of patients with more comorbidities in the peginesatide group than in the darbepoetin group. Indeed, adjustment for imbalances at baseline reduced the hazard ratio (1.20; 95% CI, 0.87 – 1.64).

Another point needing a comment is immunogenicity. No PRCA cases have been reported till now with peginesatide. Patients receiving peginesatide developed neutralizing antibodies in a small percentage. This phenomenon occurs with other drugs at a higher rate, without causing adverse events excepting a loss in drug effectiveness (Figure 1). At present, exposure to peginesatide is too limited to ascertain the rate of antibody production and its clinical meaning.

To conclude, peginesatide is a new, effective ESA. Its safety profile seemed to be safe during clinical development (excepting the potential increase in the risk of safety end-point events nondialysis CKD patients). However, the voluntary recall of the drug by Affymax and Takeda following serious hypersensitivity reactions has completely changed the scenario and needs in-depth clarification. If the reasons of these serious hypersensitivity reactions are not sorted out, peginesatide will be like a falling star: a shining glitter high in the sky lasting very shortly.

Declaration of interest

L Francesco has served as an advisor for Abbott, Affymax, Amgen, Fresenius, Pharmacosmos, Fibrogen, Hoffmann-La Roche, GSK. Takeda, Janssen, Vifor and Sandoz. L Del Vecchio has received Speaker's honoraria from Amgen and Roche.