Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: AOP Orphan Pharmaceuticals GmbH, Leopold-Ungar-Platz 2, 1190 Vienna, Austria
Pharmacotherapeutic group: Immunostimulants, interferons
ATC code: L03AB15
Ropeginterferon alfa-2b is a recombinant interferon alfa-2b conjugated with a two-arm mPEG at a degree of substitution of 1 mole of polymer/mole of protein. The average molecular mass is approximately 60 kDa, of which the PEG moiety constitutes approximately 40 kDa.
Interferon alfa belongs to the class of type I interferons which exhibit their cellular effects by binding to a transmembrane receptor termed interferon alfa receptor (IFNAR). Binding to IFNAR initiates a downstream signalling cascade through the activation of kinases, particularly Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2) and signal transducer and activator of transcription (STAT) proteins. Nuclear translocation of STAT proteins controls distinct gene-expression programs and exhibits various cellular effects. Interferon alfa was shown to have an inhibitory effect on the proliferation of hematopoietic and bone marrow fibroblast progenitor cells and antagonised the action of growth factors and other cytokines that have a role in the development of myelofibrosis. These actions may be involved in the therapeutic effects of interferon alfa in polycythaemia vera.
Further, it was demonstrated that interferon alfa is able to decrease the mutated JAK2V617F allele burden in patients with polycythaemia vera (a V617F point mutation in the JAK2 kinase is a hallmark of polycythaemia vera and is present in approximately 95% of patients).
An open label, randomised phase III study (PROUD-PV) evaluated the efficacy and safety of ropeginterferon alfa-2b in comparison to hydroxycarbamide in 254 adult polycythaemia vera patients (randomisation 1:1). Patients were stratified by previous exposure to hydroxycarbamide, age at screening (≤60 or >60 years) and presence of thromboembolic events in the past. Characteristics of the study population are presented in Table 2.
Table 2. Patient characteristics at screening in the PROUD-PV tudy:
| Ropeginterferon alfa-2b treatment arm (n=127) | Control treatment arm (n=127) | |
|---|---|---|
| Age | ||
| Years* | 58.5 ± 10.81 | 57.9 ± 13.10 |
| Gender | ||
| Female n (%) | 68 (53.5) | 67 (52.8) |
| Male n (%) | 59 (46.5) | 60 (47.2) |
| Race | ||
| White n (%) | 127 (100.0) | 127 (100.0) |
| Duration of PV (months)* | 12.6 ± 24.70 | 15.7 ± 25.65 |
| JAK2V617F allele burden (%)* | 41.9 ± 23.49 | 42.8 ± 24.14 |
| Haematological parameters | ||
| Haematocrit (%)* | 47.8 ± 5.22 | 48.6 ± 5.39 |
| Platelets (109/L)* | 537.7 ± 273.08 | 516.8 ± 254.43 |
| Leukocytes (109/L)* | 11.5 ± 4.76 | 11.9 ± 4.88 |
| Presence of splenomegaly | ||
| No n (%) | 115 (90.6) | 112 (88.2) |
| Yes n (%) | 12 (9.4) | 15 (11.8) |
* values are mean ± SD.
Hydroxycarbamide treatment-naïve (n=160) or hydroxycarbamide treated (n=94) patients were randomised to receive ropeginterferon alfa-2b or hydroxycarbamide. The dose was gradually increased depending on disease response and tolerability (for ropeginterferon alfa-2b, from 50 to 500 micrograms administered subcutaneously every two weeks). The mean dose after 12 months of treatment was 382 (±141) micrograms for ropeginterferon alfa-2b.
The disease response (defined as haematocrit <45% without phlebotomy [at least 3 months since last phlebotomy], platelets <400 × 109/L and leukocytes <10 × 109/L after 12 months of treatment) was 43.1% [53/123 of patients] in the ropeginterferon alfa-2b arm after 12 months of treatment.
An open-label, phase IIIb extension study (CONTINUATION-PV) enrolled 169 adult polycythaemia vera patients who previously completed the PROUD-PV Study to evaluate the long-term efficacy and safety of ropeginterferon alfa-2b. Ninety-five patients continued to receive ropeginterferon alfa-2b (from 50 to 500 micrograms administered subcutaneously every two, three or four weeks). The mean doses after 36 and 72 months of treatment (12-month treatment duration in the PROUD-PV study and 24- and 60-month treatment duration in the extension study) was 363 (±149) micrograms and 356 (±144) micrograms for ropeginterferon alfa-2b, respectively.
The response to ropeginterferon alfa-2b treatment is presented in Table 3 and Table 4. After 72 months of treatment, disease response defined as complete haematological response only was 54.5% and 39.8% of patients showed a complete haematological response with an improvement in disease burden. Patients showed a statistically significant difference in the JAK2V617F allele burden (16.6%) and JAK2V617F allele change from baseline (-25.4%).
Table 3. Disease response after 12 to 72 months of ropeginterferon alfa-2b:
| Disease response | Patients with of ropeginterferon alfa-2b treatment Responder N (%) | |||
|---|---|---|---|---|
| 12 months | 24 months1 | 36 months2 | 72 months3 | |
| Complete haematological responsea | 59 (62.1) | 67 (70.5) | 67 (70.5) | 48 (54.5) |
| Complete haematological responsea and improvement in disease burdenb | 44 (46.32) | 48 (50.53) | 51 (53.68) | 35 (39.77) |
a defined as haematocrit <45% without phlebotomy (at least 3 months since last phlebotomy), platelets <400 × 109/L and leukocytes <10 × 109/L.
b defined as the improvement of disease-related signs (clinically significant splenomegaly) and disease-related symptoms (microvascular disturbances, pruritus, headache).
1 12-month treatment duration in the PROUD-PV Study and 12-month treatment duration in the extension study
2 12-month treatment duration in the PROUD-PV Study and 24-month treatment duration in the extension study
3 12-month treatment duration in the PROUD-PV Study and 60-month treatment duration in the extension study
The mean JAK2V617F allele burden continuously declined throughout the 6-year ropeginterferon alfa-2b treatment, from 42.8% at baseline (before treatment in PROUD-PV) to 15.5% at 72 months.
Table 4. JAK2V617F allele burden [%] absolute values and changes from baseline in the CONTINUATION-PV extension study:
| Study month | n | Mean (±SD) | Change from baseline |
|---|---|---|---|
| Baseline | 94 | 42.8 (±23.40) | - |
| M12 | 92 | 30.1 (±23.03) | -12.13 (±17.04) |
| M241 | 73 | 18.5 (±17.09) | -24.59 (±22.07) |
| M362 | 71 | 16.6 (±18.22) | -25.43 (±24.39) |
| M723 | 51 | 15.5 (±20.38) | -25.97 (±27.29) |
1 12-month treatment duration in the PROUD-PV Study and 12-month treatment duration in the extension study
2 12-month treatment duration in the PROUD-PV Study and 24-month treatment duration in the extension study
3 12-month treatment duration in the PROUD-PV Study and 60-month treatment duration in the extension study
The European Medicines Agency has waived the obligation to submit the results of studies with Besremi in all subsets of the paediatric population in the treatment of polycythaemia vera (see section 4.2 for information on paediatric use).
The absorption of ropeginterferon alfa-2b is sustained in patients with peak serum concentrations reached after 3 to 6 days.
The absolute bioavailability of subcutaneous administered ropeginterferon alfa-2b was not investigated in humans. Thus, no valid estimation of the absolute bioavailability could be done. Based on data in monkeys, it is approx. 80%, similar to that seen for pegylated interferon alfa-2a.
Ropeginterferon alfa-2b is found mainly in the bloodstream and extracellular fluid as seen by the volume of distribution at steady-state (Vd) of 6.6 to 17 litres in patients after subcutaneous administration (dose range 50–450 micrograms). Mean Cmax was 2.4 ng/mL (with a dose of 50–80 micrograms) to 49 ng/mL (with a dose of 450 micrograms) and AUC0-t ranged from 28.5 ng*h/mL (with a dose of 50-80 micrograms) to 552.6 ng*h/mL (with a dose of 450 micrograms) in patients after subcutaneous multiple dose administration. Inter-subject variability was observed with 25% and 35% for AUC and Cmax, respectively, in healthy volunteers.
In patients who received ropeginterferon alfa-2b at 2-weeks interval (400–500 micrograms, PK Group 1) or at 4-weeks interval (100-500 [mean 350] micrograms, PK Group 2) at steady-state, mean Vdss was 10.7 L in PK Group 1 and 18.3 L in PK Group 2. In PK Group 1 mean Cmax,ss was 28.26 ng/mL, AUCtau,ss was 7504.0 ng*h/mL and Cmin was 14.52 ng/mL. In PK Group 2 mean Cmax,ss was 18.82 ng/mL, AUCtau,ss was 6021.3 ng*h/mL and Cmin was 2.10 ng/mL.
From mass balance, tissue distribution and whole body autoradioluminography studies performed in rats, it was shown that a similar interferon alfa medicinal product (pegylated interferon alfa-2a) was distributed to the liver, kidney and bone marrow in addition to being highly concentrated in the blood.
The metabolism of ropeginterferon alfa-2b is not fully characterised. The attachment of interferon alfa-2b to a high molecular weight (40 kDa) branched polyethylene glycol moiety is considered as the main reason for the differences in the elimination compared to unpegylated interferons. Studies in rats with a similar interferon alfa medicinal product (pegylated interferon alfa-2a) showed a primarily elimination via hepatic metabolism. The same elimination route is considered for ropeginterferon alfa-2b.
Pharmacokinetic interaction studies in humans with pegylated interferon alfa-2a indicated a moderate inhibitory effect on substrates metabolised by CYP1A2 and CYP2D6 (see section 4.5).
The elimination of ropeginterferon alfa-2b is not fully characterised. Studies with a similar interferon alfa medicinal product (pegylated interferon alfa-2a) indicated that the kidney is a major organ for excretion of radiolabelled metabolic products (study in rats) and that the systemic clearance of pegylated interferon alfa-2a in humans is about 100-fold lower compared to the native, unpegylated interferon alfa-2a.
After subcutaneous multiple dose administration (dose range 50–500 micrograms), the terminal halflife of ropeginterferon alfa-2b in patients is approximately 6 to 10 days and the clearance of ropeginterferon alfa-2b is 0.023 to 0.066 L/h.
The involvement of transport proteins in absorption, distribution, and elimination of ropeginterferon alfa-2b is not known.
Over a dose range of 24 to 270 micrograms, ropeginterferon alfa-2b Cmax increased proportionally with dose in a pharmacokinetic study with healthy subjects. A higher than proportional increase in exposure was observed. Inter-subject variability for ropeginterferon alfa-2b was 35% (Cmax) and 25% (AUC).
Comparable exposure and pharmacokinetic profile were reported for another interferon alfa medicinal product (pegylated interferon alfa-2a) in cirrhotic (Child-Pugh A) and non-cirrhotic patients. Pharmacokinetics were not evaluated in patients with increased severity of hepatic impairment.
The pharmacokinetic profile in patients with moderate or severe renal impairment and in patients with end stage renal disease (ESRD) has been evaluated only for other pegylated interferon alfa medicinal products.
Patients with moderate or severe renal impairment receiving 180 micrograms of pegylated interferon alfa-2a once weekly showed a comparable or 60% higher drug plasma exposure, respectively, compared to subjects with normal renal function.
In 13 patients with ESRD requiring chronic haemodialysis, administration of 135 micrograms pegylated interferon alfa-2a once weekly resulted in a 34% lower drug exposure than in patients with normal renal function.
Patients with renal impairment receiving a single dose of 1.0 micrograms/kg pegylated interferon alfa-2b showed an increased relation of Cmax, AUC, and half-life to the degree of renal impairment. Following multiple dosing of pegylated interferon alfa-2b (1.0 micrograms/kg subcutaneously administered every week for four weeks), the clearance of pegylated interferon alfa-2b was reduced by a mean of 17% and 44% in patients with moderate or severe renal impairment, respectively, compared to subjects with normal renal function. Based on single dose data, clearance was similar in patients with severe renal impairment not on haemodialysis and in patients who received haemodialysis.
Only limited pharmacokinetic data are available from the use of ropeginterferon alfa-2b in the elderly. Based on the results from the PROUD-PV and CONTINUATION-PV Study on drug exposure, pharmacodynamic response and tolerability, a dose adjustment for ropeginterferon alfa-2b is not considered necessary in the elderly population.
The pharmacokinetic profile of ropeginterferon alfa-2b has not been determined in obese and underweight patients.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Reproductive and developmental studies were not performed with ropeginterferon alfa-2b. Interferon alfa was shown to be abortifacient in primates and ropeginterferon alfa-2b is expected to have a similar effect. Effects on fertility was not assessed.
It is unknown if the active substance of the medicinal product is excreted into experimental animal or human milk (see section 4.6).
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