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DESCRIPTION
Gammaplex is a ready to use sterile solution of polyclonal human Immunoglobulin G for IV administration that contains sorbitol, glycine and polysorbate 80 as stabilizers. Specifically, Gammaplex contains approximately 5 g normal human immunoglobulin and 5 g D-sorbitol in 100 mL of buffer solution containing: 0.6 g glycine, 0.2 g sodium acetate, 0.3 g sodium chloride, and ~5 mg polysorbate 80. Immunoglobulin G purity is > 95%, the pH is in the range of 4.8 to 5.1, and osmolality is not less than 240 mOsmol/kg (typically 420 to 500 mOsmol/kg). The distribution of the four IgG subclasses is approximately 64% IgG1, 30% IgG2, 5% IgG3, and 1% IgG4. The content of IgA is lower than 10 µg/mL. The anti-D and anti-A/anti-B hemagglutinin content of the drug product is strictly controlled to specification. Gammaplex contains no reducing carbohydrate stabilizers (e.g. sucrose, maltose) and no preservative.
Gammaplex is prepared from large pools of human plasma by a combination of cold ethanol fractionation and ion exchange chromatography. Fab functions tested include antigen binding activity, and Fc functions tested include complement activation and rubella antibody-mediated hemolysis.
Gammaplex is manufactured from plasma, obtained from healthy US donors, that have passed viral screening tests. All donors are subjected to medical examinations, laboratory tests, and a review of their medical history before being allowed to donate blood or plasma. There are several stages within this manufacturing process that contribute to viral reduction, including management of donors, screening of donations and specific virus removal steps during manufacturing.
All plasma donations are screened for antibody to HIV-1/2 and HCV, and hepatitis B surface antigen (HBsAg). Furthermore, plasma mini-pools (512 donations per pool) undergo nucleic acid amplification testing (NAT) for HIV, hepatitis B virus (HBV), HCV, hepatitis A virus (HAV) and Parvovirus B19. Further testing is carried out on the manufacturing pools for HBsAg, and antibody to HIV-1/2; HCV and Parvovirus B19 are also tested by NAT, with the limit for B19 set to not exceed 104 IU B19 DNA per mL plasma.
There are three processing steps specifically designed to remove or inactivate viruses:
1) Solvent/Detergent treatment is targeted to enveloped viruses;
2) A virus filtration step using Pall Ultipor DV20 is designed to remove small viruses including non-enveloped viruses, on a size exclusion basis; and
3) The terminal low pH incubation step is identified as contributing to the overall viral clearance capacity for enveloped and non-enveloped viruses.
The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model. Overall virus reduction was calculated only from steps that were mechanistically independent from each other. In addition, each step was validated to provide robust virus reduction. The table below presents the contribution of each process step to virus reduction and the overall process reduction.
Table 3: Viral Reduction by Process Step
| Virus |
Type (Envelope/Genome) |
Size
(nm) |
Process Log10 Reduction of Virus (LRV) over manufacturing step |
Total LRV |
| Solvent Detergent |
20 nm filtration |
Terminal low pH/elevated temperature incubation |
HIV: Human immunodeficiency virus
SIN: Sindbis virus, model for hepatitis C virus (HCV)
WNV: West Nile Virus
BVDV: Bovine viral diarrhea virus, model for HCV
IBR: Infectious bovine rhinotracheitis, bovine herpesvirus model for enveloped DNA viruses including hepatitis B
HAV: Hepatitis A virus
EMC: Encephalomyocarditis, model for HAV
NA: Not applicable, solvent detergent step is limited to the inactivation of enveloped viruses
I: Inactivation by the product intermediate precluded the accurate estimation of the removal of these viruses by the filtration step
NT: Not tested
B19: Viral clearance of Human Parvovirus B19 was investigated experimentally at the 20 nm filtration step. The estimated Log reduction Factor obtained was 6.0 |
| HIV |
Env/RNA |
80-100 |
>6.8 |
I |
>6.1 |
>12.9 |
| SIN |
Env/RNA |
70 |
>6.7 |
6.2 |
>7.3 |
>20.2 |
| WNV |
Env/RNA |
50 |
>6.4 |
I |
NT |
>6.4 |
| BVDV |
Env/RNA |
40-60 |
>5.6 |
I |
>6.1 |
>11.7 |
| IBR |
Env/DNA |
200 |
>5.0 |
I |
>6.3 |
>11.3 |
| HAV |
Non-Env/RNA |
30 |
NA |
>4.8 |
1.1 |
>5.9 |
| EMC |
Non-Env/RNA |
30 |
NA |
>4.8 |
2.7 |
>7.5 |
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CLINICAL PHARMACOLOGY
Mechanism of Action
Gammaplex is a replacement therapy for primary humoral immunodeficiency. It acts through a broad spectrum of opsonic and neutralizing IgG antibodies against pathogens and their toxins involving antigen binding and effector functions15,16. However, the mechanism of action in PI has not been fully elucidated.
Pharmacokinetics
In the clinical study assessing safety and efficacy in primary humoral immunodeficiency, the pharmacokinetics of Gammaplex was assessed for 28 days after administration to 24 subjects on 21- or 28-day infusion cycles. Blood samples for pharmacokinetic (PK) analysis were obtained after Infusion 9 for subjects on a 21-day schedule (9 subjects) and after Infusion 7 for subjects on a 28-day schedule (15 subjects), i.e., during the sixth month after initiation of Gammaplex treatment.
The mean dose (range) for those on the 21-day schedule was 476 mg/kg (range: 330 to 721 mg/kg), and it was 468 mg/kg (range: 324 to 799 mg/kg) for those on the 28-day schedule. Table 4 summarizes the PK parameters of Gammaplex, measured as serum concentrations of total IgG.
Assessment of the clinical relevance of half-life measurements in this study should be viewed with caution. Although half-life estimates are provided for total IgG and the specific antibodies, drug elimination half-lives should be measured over a minimum period of at least 3 half-lives. However, the short dosing intervals relative to the long half-life of IgG in this clinical trial do not permit accurate assessment of half-life.
Table 4: Pharmacokinetic Parameters of Gammaplex in Subjects with PI
| Parameter (unit) |
21-day Dosing Interval
(n=9) |
28-day Dosing Interval
(n=15) |
|
Mean ± SD
(Range) |
Mean ± SD
(Range) |
| tau = dosing interval |
| Cmax (mg/mL) |
21.6 ± 3.8
(16.3-27.3) |
21.4 ± 4.3
(15.9-31.0) |
| Tmax (hr) |
5.4 ± 7.2
(2.1-24.5) |
6.1 ± 11.6
(2.4-48.1) |
| AUC0-tau (days*mg/mL) |
289 ± 41
(214-365) |
346 ± 52
(262-455)
|
| Half-Life (days) |
42 ± 26
(22-108) |
41 ± 14
(22-70)
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| Clearance (mL/days/kg) |
0.59 ± 0.24
(0.19-1.02) |
0.58 ± 0.27
(0.24-1.28)
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CLINICAL STUDIES
In a Phase 3 multicenter, open-label study to evaluate the efficacy, safety, and pharmacokinetics of Gammaplex in primary humoral immunodeficiency, 50 subjects on regular IGIV replacement therapy for at least 3 months prior to participation were treated for 12 months at 21-day (22 subjects) or 28-day (28 subjects) dosing intervals. Out of the 50 subjects, 26 were male and 24 were female, and 46 were Caucasian. They were in the age range of 9 to 78 years.
Doses ranged from 279 mg/kg to 799 mg/kg. The mean dose (range) for the 21-day interval was 465 mg/kg (330 - 693 mg/kg); the mean dose (range) for the 28-day interval was 458 mg/kg (326 - 790 mg/kg). Subjects received a total of 703 infusions of Gammaplex. The maximum infusion rate allowed during this study was 0.08 mL/kg/min.
The primary analysis for efficacy was based on the annual rate of acute serious bacterial infections (aSBIs), defined as pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, visceral abscess, and bacterial meningitis, per subject per year17. Other important clinical analyses for efficacy were based on the annual rate of infections, antibiotic use, days out of work/school/day care or unable to perform normal activities due to illness, and days of hospitalization.
During the 12-month study period, no serious acute bacterial infections occurred in any subject with an onset date between the first infusion of Gammaplex and the first follow-up visit, inclusive. Thus, the mean event rate of serious, acute, bacterial infections per year was zero (with an upper 1-sided 99% confidence interval of 0.101).
Table 5: Summary of Efficacy Results in Subjects with PI
| Number of Subjects |
50 |
| Total Number of Subject Days |
16715 |
| Infections |
|
| Annual rate of confirmed serious acute bacterial infectionsDefined as pneumonia, bacterial meningitis, bacteremia/septicemia, osteomyelitis/septic arthritis, and visceral abscess.
|
0 /subject year Upper 1-sided 99% confidence interval: 0.101
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| Annual rate of other infections (median) |
3.07 infections/subject year |
| Antibiotic use (therapeutic) |
|
| Number of subjects (%) |
40 (80%) |
| Annual rate |
47.2 days/subject year |
| Out of work/school/day care or unable to perform normal activities due to illness |
|
| Number of subjects (%) |
23 (46%) |
| Number of days (%) |
394 (2.36%) |
| Annual rate |
8.73 days/subject year |
| Hospitalization |
|
| Number of subjects (%) |
4 (8%) |
| Number of days (%) |
29 (0.17%) |
| Annual rate |
0.75 days/subject year |
Duration of exposure in all tables relating to GMX01 was calculated as the difference between the date of the last visit (first follow-up visit) i.e. approximately 10-14 days following the last dose of Gammaplex and the date of the first Gammaplex infusion (plus one day).
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