Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Immunostimulants, interferons, ATC code: L03AB11 
Mechanism of action

The conjugation of PEG reagent (bis-monomethoxypolyethylene glycol) to interferon alfa-2a forms a pegylated interferon alfa-2a (Pegasys). Pegasys possesses the in vitro antiviral and antiproliferative activities that are characteristic of interferon alfa-2a.



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PEGASYS                                                       MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                  December 2015 Interferon alfa-2a is conjugated with bis-[monomethoxy polyethylene glycol] at a degree of substitution of one mole of polymer/mole of protein. The average molecular mass is approximately 60,000 of which the protein moiety constitutes approximately 20,000.

Pharmacodynamic effects

HCV RNA levels decline in a biphasic manner in responding patients with hepatitis C who have received treatment with 180 micrograms Pegasys. The first phase of decline occurs 24 to 36 hours after the first dose of Pegasys and is followed by and the second phase of decline which continues over the next 4 to 16 weeks in patients who achieve a sustained response. Ribavirin had no significant effect on the initial viral kinetics over the first 4 to 6 weeks in patients treated with the combination of ribavirin and pegylated interferon alfa-2a or interferon alfa.

Clinical efficacy and safety

Chronic hepatitis B
All clinical trials recruited patients with chronic hepatitis B who had active viral replication measured by HBV DNA, elevated levels of ALT and a liver biopsy consistent with chronic hepatitis. Study WV16240 recruited patients who were positive for HBeAg, while study WV16241 recruited patients who were negative for HBeAg and positive for anti-HBe. In both studies the treatment duration was 48 weeks, with 24 weeks of treatment-free follow-up. Both studies compared Pegasys plus placebo vs Pegasys plus lamivudine vs lamivudine alone.
No HBV-HIV co-infected patients were included in these clinical trials.

Response rates at the end of follow-up for the two studies are presented in Table 5. In study WV16240, the primary efficacy endpoints were HBeAg seroconversion and HBV-DNA below 105 copies/ml. In study WV16241, the primary efficacy endpoints were ALT normalisation and HBV-DNA below 2 x 104 copies/ml. HBV-DNA was measured by the COBAS AMPLICOR HBV MONITOR Assay (limit of detection 200 copies/ml).

A total of 283/1351 (21%) of patients had advanced fibrosis or cirrhosis, 85/1351 (6%) had cirrhosis. There was no difference in response rate between these patients and those without advanced fibrosis or cirrhosis.



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PEGASYS                                                                 MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                            December 2015 Table 5: Serological, virological and biochemical responses in chronic hepatitis B HBeAg positive                         HBeAg negative / anti-HBe positive Study WV16240                                  Study WV16241

Response          Pegasys         Pegasys          Lamivudin         Pegasys       Pegasys       Lamivudin Parameter         180 mcg         180 mcg              e             180 mcg       180 mcg           e &               &              100 mg              &             &           100 mg Placebo        Lamivudine                          Placebo      Lamivudine 100 mg                                           100 mg

(N=271)          (N=271)          (N=272)          (N=177)       (N=179)       (N=181) #
HBeAg               32%               27%              19%              N/A           N/A           N/A Sero- conversion
#                                                   #
HBV DNA             32%               34%              22%             43%            44%           29% response *
#                                                   #
ALT Normal-         41%               39%              28%             59%            60%           44% isation

HBsAg Sero-          3% #              3%               0%              3%            2%             0% conversion
5
* For HBeAg-positive patients: HBV DNA < 10 copies/ml
4
For HBeAg-negative/anti-HBe-positive patients: HBV DNA < 2 x 10 copies/ml 
# p-value (vs. lamivudine) < 0.01 (stratified Cochran-Mantel-Haenszel test) 
Histological response was similar across the three treatment groups in each study; however, patients showing a sustained response 24 weeks after the end of treatment were significantly more likely to also show histological improvement.
All patients who completed the phase III studies were eligible for entry into a long-term follow-up study (WV16866). Among patients from study WV16240, who received Pegasys monotherapy and entered the long-term follow-up study, the rate of sustained HBeAg seroconversion 12 months after the end of therapy was 48% (73/153). In patients receiving Pegasys monotherapy in study WV16241, the rate of HBV DNA response and ALT normalisation 12 months after end of treatment were 42% (41/97) and 59% (58/99), respectively.

Chronic hepatitis C

Predictability of response
Please refer to section 4.2, in Table 2.
Dose-response in monotherapy
In a direct comparison with 90 micrograms, the 180 micrograms-dose was associated with superior sustained virological response in patients with cirrhosis, but in a study in non- cirrhotic patients very similar results were obtained with doses of 135 micrograms and 180 micrograms.

Confirmatory clinical trials in treatment-naïve patients
All clinical trials recruited interferon-naïve patients with chronic hepatitis C confirmed by detectable levels of serum HCV RNA, elevated levels of ALT (with the exception of study NR16071) and a liver biopsy consistent with chronic hepatitis. Study NV15495 specifically recruited patients with a histological diagnosis of cirrhosis (about 80%) or transition to cirrhosis (about 20%). Only HIV-HCV co-infected patients were included in the study NR15961 (see Table 14). These patients had stable HIV disease and mean CD4 T-cell count was about 500 cells/µl.
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PEGASYS                                                                MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                           December 2015 For HCV monoinfected patients and HIV-HCV co-infected patients, for treatment regimens, duration of therapy and study outcome see Tables 6, 7, 8 and Table 14, respectively.
Virological response was defined as undetectable HCV RNA as measured by the COBAS AMPLICOR HCV Test, version 2.0 (limit of detection 100 copies/ml equivalent to 50 International Units/ml) and sustained response as one negative sample approximately 6 months after end of therapy.

Table 6: Virological response in HCV patients
Pegasys monotherapy                      Pegasys combination therapy non-cirrhotic and                  cirrhotic               non-cirrhotic and cirrhotic cirrhotic
Study NV15496 +               Study NV15495             Study            Study NV15801 NV15497 + NV15801                                       NV15942
Pegasys     Interferon      Pegasy       Interferon      Pegasys       Pegasys       Interferon alfa-2a          s           alfa-2a       180 mcg       180 mcg         alfa-2b 180 mcg    6 MIU/3 MI       180 mcg        3 MIU                                        3 MIU U                                          &             &               & &                                       Ribavirin     Ribavirin      Ribavirin 3 MIU                                      1000/120      1000/120      1000/1200 0             0              mg mg            mg

(N=701)       (N=478)       (N=87)        (N=88)         (N=436)       (N=453)       (N=444)                 48 weeks      48 weeks         48         48 weeks       48 weeks      48 weeks      48 weeks weeks

Response at End of       55 - 69%      22 - 28%        44%           14%            68%            69%           52% Treatment

Overall
Sustained       28 - 39%      11 - 19%        30%*              8%*        63%           54%**         45%** Response
* 95% CI for difference: 11% to 33%      p-value (stratified Cochran-Mantel-Haenszel test) = 0.001 ** 95% CI for difference: 3% to 16%      p-value (stratified Cochran-Mantel-Haenszel test) = 0.003 
The virological responses of HCV monoinfected patients treated with Pegasys and ribavirin combination therapy in relation to genotype and pre-treatment viral load and in relation to genotype, pre-treatment viral load and rapid virological response at week 4 are summarised in Table 7 and Table 8, respectively. The results of study NV15942 provide the rationale for recommending treatment regimens based on genotype, baseline viral load and virological response at week 4 (see Tables 1, 7 and 8).
The difference between treatment regimens was in general not influenced by presence/absence of cirrhosis; therefore treatment recommendations for genotype 1, 2 or 3 are independent of this baseline characteristic.



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PEGASYS                                                                  MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                             December 2015 Table 7: Sustained virological response based on genotype and pre-treatment viral load after Pegasys combination therapy with ribavirin in HCV patients Study NV15942                                   Study NV15801
Pegasys       Pegasys         Pegasys           Pegasys          Pegasys          Interferon 180 mcg       180 mcg         180 mcg           180 mcg          180 mcg            alfa-2b 3 MIU
&              &              &                  &                &                  & Ribavirin      Ribavirin      Ribavirin         Ribavirin         Ribavirin         Ribavirin 800 mg       1000/1200        800 mg           1000/1200        1000/1200         1000/1200 mg                               mg                mg                mg 
24 weeks       24 weeks        48 weeks          48 weeks         48 weeks          48 weeks

Genotype 1       29%          42%             41%               52%              45%                36% Low viral load   (29/101)     (49/118)*       (102/250)*        (142/271)*       (134/298)          (103/285) High viral       41%          52% (37/71)     55% (33/60)       65% (55/85)      53% (61/115)       44% (41/94) load             (21/51)      26% (12/47)     36% (69/190)      47% (87/186)     40% (73/182)       33% (62/189) 16% (8/50)
Genotype         84%          81%             79% (78/99)       80% (123/153)    71%                61% (88/145) 2/3              (81/96)      (117/144)       88% (29/33)       77% (37/48)      (100/140)          65% (34/52)
Low viral load   85%          83% (39/47)     74% (49/66)       82% (86/105)     76% (28/37)        58% (54/93) High viral       (29/34)      80% (78/97)                                        70% (72/103) load             84%
(52/62)
Genotype 4       (0/5)        (8/12)          (5/8)             (9/11)           (10/13)            (5/11) 
Low viral load = ≤ 800,000 IU/ml; High viral load = > 800,000 IU/ml *Pegasys 180 mcg & ribavirin 1000/1200 mg, 48 w vs. Pegasys 180 mcg & ribavirin 800 mg, 48 w: Odds Ratio (95% CI) = 1.52 (1.07 to 2.17), P-value (stratified Cochran-Mantel-Haenszel test) = 0.020 *Pegasys 180 mcg & ribavirin 1000/1200 mg, 48 w vs. Pegasys 180 mcg & ribavirin 1000/1200 mg, 24 w: Odds Ratio (95% CI) = 2.12 (1.30 to 3.46), P-value (stratified Cochran-Mantel-Haenszel test) = 0.002.

The possibility to consider shortening treatment duration to 24 weeks in genotype 1 and 4 patients was examined based on a sustained rapid virological response observed in patients with rapid virological response at week 4 in studies NV15942 and ML17131 (see Table 8).

Table 8: Sustained virological response based on rapid viral response at week 4 for genotype 1 and 4 after Pegasys combination therapy with ribavirin in HCV patients Study NV15942                              Study ML17131
Pegasys                   Pegasys                          Pegasys
180 mcg                   180 mcg                          180 mcg
&                         &                                &
Ribavirin                 Ribavirin                        Ribavirin
1000/1200 mg              1000/1200 mg                    1000/1200 mg 24 weeks                  48 weeks                         24 weeks
Genotype 1 RVR                 90% (28/31)               92% (47/51)                     77% (59/77) Low viral load                 93% (25/27)               96% (26/27)                     80% (52/65) High viral load                 75% (3/4)                88% (21/24)                      58% (7/12) Genotype 1 non                 24% (21/87)              43% (95/220)                           - RVR                                                                                        - Low viral load                 27% (12/44)                   50% (31/62)                       - High viral load                 21% (9/43)                  41% (64/158) Genotype 4 RVR                    (5/6)                         (5/5)                      92% (22/24) 
Genotype 4 non                     (3/6)                        (4/6)                           - RVR

Low viral load = ≤ 800,000 IU/ml; High viral load = > 800,000 IU/ml RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24 
Although limited, data indicated that shortening treatment to 24 weeks might be associated with a higher risk of relapse (see Table 9).


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PEGASYS                                                                MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                           December 2015 Table 9: Relapse of virological response at the end of treatment for rapid virological response population

Study NV15942                           Study NV15801
Pegasys                          Pegasys                  Pegasys
180 mcg                         180 mcg                  180 mcg
&                               &                        &
Ribavirin                       Ribavirin                Ribavirin
1000/1200 mg                    1000/1200 mg             1000/1200 mg 24 weeks                        48 weeks                 48 weeks
Genotype 1 RVR                6.7% (2/30)                     4.3% (2/47)               0% (0/24) 
Low viral load                 3.8% (1/26)                     0% (0/25)               0% (0/17) High viral load                 25% (1/4)                     9.1% (2/22)               0% (0/7) Genotype 4 RVR                    (0/5)                          (0/5)                  0% (0/4) 

The possibility of shortening treatment duration to 16 weeks in genotype 2 or 3 patients was examined based on a sustained virological response observed in patients with rapid virological response by week 4 in study NV17317 (see Table 10).

In study NV17317 in patients infected with viral genotype 2 or 3, all patients received Pegasys 180 mcg sc qw and a ribavirin dose of 800 mg and were randomised to treatment for either 16 or 24 weeks. Overall treatment for 16 weeks resulted in lower sustained viral response (65%) than treatment for 24 weeks (76%) (p < 0.0001).

The sustained viral response achieved with 16 weeks of treatment and with 24 weeks of treatment was also examined in a retrospective subgroup analysis of patients who were HCV RNA negative by week 4 and had a LVL at baseline (see Table 10).

Table 10: Sustained virological response overall and based on rapid viral response by week 4 for genotype 2 or 3 after Pegasys combination therapy with ribavirin in HCV patients



Low viral load = ≤ 800,000 IU/ml; High viral load = > 800,000 IU/ml RVR = rapid viral response (HCV RNA undetectable) at week 4

It is presently not clear whether a higher dose of ribavirin (e.g.1000/1200 mg/day based on body weight) results in higher SVR rates than does the 800 mg/day, when treatment is shortened to 16 weeks.

The data indicated that shortening treatment to 16 weeks is associated with a higher risk of relapse (see Table 11).



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PEGASYS                                                               MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                          December 2015 Table 11: Relapse of virological response after the end of treatment in genotype 2 or 3 patients with a rapid viral response



Low viral load = ≤ 800,000 IU/ml; High viral load = > 800,000 IU/ml RVR = rapid viral response (HCV RNA undetectable) at week 4


Superior efficacy of Pegasys compared to interferon alfa-2a was demonstrated also in terms of histological response, including patients with cirrhosis and/or HIV-HCV co-infection.

Chronic hepatitis C prior treatment non-responder patients
In study MV17150, patients who were non-responders to previous therapy with pegylated interferon alfa-2b plus ribavirin were randomised to four different treatments: •     Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 60 weeks
•     Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 36 weeks
•     Pegasys 180 mcg/week for 72 weeks
•     Pegasys 180 mcg/week for 48 weeks
All patients received ribavirin (1000 or 1200 mg/day) in combination with Pegasys. All treatment arms had 24 week treatment-free follow-up.

Multiple regression and pooled group analyses evaluating the influence of treatment duration and use of induction dosing clearly identified treatment duration for 72 weeks as the primary driver for achieving a sustained virological response. Differences in sustained virological response (SVR) based on treatment duration, demographics and best responses to previous treatment are displayed in Table 12.



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PEGASYS                                                               MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                          December 2015 Table 12: Week 12 virological response (VR) and sustained virological response (SVR) in patients with virological response at week 12 after treatment with Pegasys and ribavirin combination therapy in nonresponders to peginterferon alfa-2b plus ribavirin 


High viral load = > 800,000 IU/ml, low viral load =  800,000 IU/ml.
a
Patients who achieved viral suppression (undetectable HCV RNA, < 50 IU/ml) at week 12 were considered to have a virological response at week 12. Patients missing HCV RNA results at week 12 have been excluded from the analysis.
b
Patients who achieved viral suppression at week 12 but were missing HCV RNA results at the end of follow-up were considered to be non-responders.

In the HALT-C study, patients with chronic hepatitis C and advanced fibrosis or cirrhosis who were non-responders to previous treatment with interferon alfa or pegylated interferon alfa monotherapy or in combination therapy with ribavirin were treated with Pegasys 180 mcg/week and ribavirin 1000/1200 mg daily. Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on Pegasys plus ribavirin combination therapy for a total of 48 weeks and were then followed for 24 weeks after the end of treatment. The probability for sustained virological response varied depending upon the previous treatment regimen; see Table 13.



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PEGASYS                                                                MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                           December 2015 Table 13: Sustained virological response in HALT-C by previous treatment regimen in non-responder population
Previous Treatment                                                               Pegasys 180 mcg &
Ribavirin 1000/1200 mg
48 weeks
Interferon                                                                          27% (70/255) Pegylated interferon                                                                34% (13/38) Interferon plus ribavirin                                                           13% (90/692) Pegylated interferon plus ribavirin                                                 11% (7/61) 
HIV-HCV co-infected patients
The virological responses of patients treated with Pegasys monotherapy and with Pegasys and ribavirin combination therapy in relation to genotype and pre-treatment viral load for HIV- HCV co-infected patients are summarised below in Table 14.

Table 14: Sustained virological response based on genotype and pre-treatment viral load after Pegasys combination therapy with ribavirin in HIV-HCV co-infected patients 


Low viral load = ≤ 800,000 IU/ml; High viral load = > 800,000 IU/ml * Pegasys 180 mcg & ribavirin 800 mg vs. Interferon alfa-2a 3 MIU & ribavirin 800 mg: Odds Ratio (95% CI) = 5.40 (3.42 to 8.54), P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0001 * Pegasys 180 mcg & ribavirin 800 mg vs. Pegasys 180 mcg:
Odds Ratio (95% CI) = 2.89 (1.93 to 4.32), P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0001 * Interferon alfa-2a 3 MIU & ribavirin 800 mg vs. Pegasys 180 mcg:
Odds Ratio (95% CI) = 0.53 (0.33 to 0.85), P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0084 
A subsequent study (NV18209) in patients co-infected with HCV genotype 1 and HIV compared treatment using Pegasys 180 mcg/week and either ribavirin 800 mg or 1000 mg (<75 kg)/1200 mg (75 kg) daily for 48 weeks. The study was not powered for efficacy considerations. The safety profiles in both ribavirin groups were consistent with the known safety profile of Pegasys plus ribavirin combination treatment and not indicative of any relevant differences, with the exception of a slight increase in anaemia in the high dose ribavirin arm.

HCV patients with normal ALT
In study NR16071, HCV patients with normal ALT values were randomised to receive Pegasys 180 micrograms/week and ribavirin 800 milligrams/day for either 24 or 48 weeks followed by a 24 week treatment free follow-up period or no treatment for 72 weeks. The SVRs reported in the treatment arms of this study were similar to the corresponding treatment arms from study NV15942.


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PEGASYS                                                     MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                December 2015 Paediatric population
In the investigator sponsored CHIPS study (Chronic Hepatitis C International Paediatric Study), 65 children and adolescents (6-18 years) with chronic HCV infection were treated with Pegasys 100 mcg/m2 sc once weekly and ribavirin 15 mg/kg/day for 24 weeks (genotypes 2 and 3) or 48 weeks (all other genotypes). Preliminary and limited safety data demonstrated no obvious departure from the known safety profile of the combination in adults with chronic HCV infection, but, importantly, the potential impact on growth has not been reported. Efficacy results were similar to those reported in adults.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Following a single subcutaneous injection of Pegasys 180 micrograms in healthy subjects, serum concentrations of peginterferon alfa-2a are measurable within 3 to 6 hours. Within 24 hours, about 80% of the peak serum concentration is reached. The absorption of Pegasys is sustained with peak serum concentrations reached 72 to 96 hours after dosing. The absolute bioavailability of Pegasys is 84% and is similar to that seen with interferon alfa-2a.

Distribution
Peginterferon alfa-2a is found predominantly in the bloodstream and extracellular fluid as seen by the volume of distribution at steady-state (Vd) of 6 to 14 litres in humans after intravenous administration. From mass balance, tissue distribution and whole body autoradioluminography studies performed in rats, peginterferon alfa-2a is distributed to the liver, kidney and bone marrow in addition to being highly concentrated in the blood.

Biotransformation
The metabolism of Pegasys is not fully characterised; however studies in rats indicate that the kidney is a major organ for excretion of radiolabelled material.

Elimination
In humans, the systemic clearance of peginterferon alfa-2a is about 100-fold lower than that of the native interferon alfa-2a. After intravenous administration, the terminal half-life of peginterferon alfa-2a in healthy subjects is approximately 60 to 80 hours compared to values of 3-4 hours for standard interferon. The terminal half-life after subcutaneous administration in patients is longer with a mean value of 160 hours (84 to 353 hours). The terminal half-life may not only reflect the elimination phase of the compound, but may also reflect the sustained absorption of Pegasys.

Linearity/non-linearity
Dose-proportional increases in exposure of Pegasys are seen in healthy subjects and in patients with chronic hepatitis B or C after once-weekly dosing.

In chronic hepatitis B or C patients, peginterferon alfa-2a serum concentrations accumulate 2 to 3 fold after 6 to 8 weeks of once weekly dosing compared to single dose values. There is no further accumulation after 8 weeks of once weekly dosing. The peak to trough ratio after 48 weeks of treatment is about 1.5 to 2. Peginterferon alfa-2a serum concentrations are sustained throughout one full week (168 hours).

Patients with renal impairment
Renal impairment is associated with slightly decreased CL/F and prolonged half-life. In patients (n=3) with CLcrea between 20 and 40 ml/min, the average CL/F is reduced by 25% compared with patients with normal renal function. In patients with end stage renal disease undergoing haemodialysis, there is a 25% to 45% reduction in the clearance, and doses of 135 micrograms result in similar exposure as 180 micrograms doses in patients with normal renal function (see section 4.2).

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PEGASYS                                                     MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                December 2015 Gender
The pharmacokinetics of Pegasys after single subcutaneous injections was comparable between male and female healthy subjects.

Older people
In subjects older than 62 years, the absorption of Pegasys after a single subcutaneous injection of 180 micrograms was delayed but still sustained compared to young healthy subjects (tmax of 115 hours vs. 82 hours, older than 62 years vs. younger, respectively). The AUC was slightly increased (1663 vs. 1295 ng·h/ml) but peak concentrations (9.1 vs.
10.3 ng/ml) were similar in subjects older than 62 years. Based on drug exposure, pharmacodynamic response and tolerability, a lower dose of Pegasys is not needed in the geriatric patient (see section 4.2).

Hepatic impairment
The pharmacokinetics of Pegasys were similar between healthy subjects and patients with hepatitis B or C. Comparable exposure and pharmacokinetic profiles were seen in cirrhotic (Child-Pugh Grade A) and non-cirrhotic patients.

Site of administration
Subcutaneous administration of Pegasys should be limited to the abdomen and thigh, as the extent of absorption based on AUC was about 20% to 30% higher upon injection in the abdomen and thigh. Exposure to Pegasys was decreased in studies following administration of Pegasys in the arm compared to administration in the abdomen and thigh.