Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Biotest Pharma GmbH, Landsteinerstraße 5, 63303 Dreieich, Germany, Tel.: +49 6103 801-0, Telefax: +49 6103 801-150, Email: mail@biotest.com
Pharmacotherapeutic group: immune sera and immunoglobulins, specific immunoglobulins
ATC code: J06BB09
Cytotect CP Biotest is an immunoglobulin preparation from plasma of donors with a high antibody titer against the CMV. It has a defined and high titer of high avidity anti-CMV antibodies. It also contains IgG antibodies against other pathogens representative of the large number of normal persons who contributed to the plasma pools from which the product was derived. It has a distribution of IgG subclasses closely proportional to that in native human plasma.
Cytotect CP Biotest is a CMV-specific polyclonal immunoglobulin preparation that binds to CMV surface antigens thereby neutralizing the potential of CMV from entering host cells and presenting the CMV particle for phagocytosis. Cytotect CP Biotest antibodies also modulate and interact with immune cells (dendritic cells, monocytes, B- and T-cells) exerting a positive immunological balance in addition to the virostatic inhibition of CMV replication.
The primary mode of action of Cytotect CP Biotest is the binding of circulating virus. These CMV-specific antibodies block the infection of different cell types including all CMV genotypes and of virus variants that are resistant to virostatics. Furthermore, Cytotect CP Biotest can activate CMV-reactive immune cells for long-lasting CMV-specific immune responses. It also has additional immunomodulating properties independent of CMV that have been implicated with a reduction of organ rejection.
The clinical efficacy of CMVIG was investigated in different settings, including patients who received solid organ and stem cell transplants. In renal transplantation, CMVIG reduced the incidence of CMV infection from 41.7% (control group) to 21.1% (Cytotect group). Other examples include lung transplantation, where the incidence of CMV disease was reduced from 43.3% (control group) to 13.2% (Cytotect group), and bone marrow transplantation, where the incidence of interstitial pneumonitis was reduced from 26.1% to 3.8%.
A prospective, randomized controlled study investigated the efficacy of hyperimmunoglobulin prophylaxis for CMV infection in renal transplant patients. 74 patients were enrolled who received a cadaveric kidney for the first time. The mean follow-up was 45 months. Patients received immunosuppressive regimen consisting of methylprednisolone and cyclosporin A. In the treatment group 38 patients received a dose of 2 ml/kg Cytotect i.v. just before transplantation and then on days 1, 2, 4, 18, 32, 46, 60, 74 and 88 after transplantation. The control group consisted of 36 patients who did not receive Cytotect. In the treatment group overall 8/38 patients (21.1%) had CMV infection and 5/38 patients (13.2%) had CMV disease, whereas in the control group overall 15/36 patients (41.7%) had CMV infection and 6/36 patients (16.7%) had CMV disease.
A retrospective study investigated the efficacy and safety of acyclovir plus Cytotect prophylaxis and early therapy with ganciclovir in CMV high-risk renal transplant paediatric patients (79 patients with a mean age of 14.1 ± 4.9 years, range 2.5 – 20). The minimum follow-up period was 12 months. The immunosuppressive regimen included cyclosporin A and steroids, with the addition of azathioprine in 4 patients who received a living donor-related kidney. Acute rejection episodes were treated with i.v. methylprednisolone pulses. 39 R- patients received 150 mg/kg Cytotect on the first postoperative day, 100 mg/kg on days 15 and 30 and 50 mg/kg on days 45, 60 and 120 after transplantation and oral acyclovir. 40 R+ patients received only oral acyclovir at the same dosage as R- patients. In the presence of CMV infection, 10 mg/kg body weight per day i.v. ganciclovir was administered for at least 2 weeks, or until negative antigenemia was obtained. In the R- group receiving Cytotect treatment, of the 33 CMV seronegative recipients (R-) who received the graft from a CMV seropositive donor (D+) 18 (54.5 %) experienced a CMV infection and in 6 CMV seronegative recipients (R-) who received the graft from a CMV negative donor no infection occurred. In the R+ group only receiving acyclovir, of the 28 CMV R , who received a graft from a CMV D, 11 (39.3 ) experienced CMV infection and of the 12 R +, who received a graft from a CMV D- donor one recipient experienced a CMV infection (8.3).
An open-label, comparative, retrospective study investigated the combined prophylaxis of Cytotect plus ganciclovir versus Cytotect alone in 207 adult high-risk heart transplant recipients (mean age 52.2 years) receiving an allograft from seropositive donors (D+/R-). All patients received polyclonal rabbit antithymocyte globulin as induction therapy. Cyclosporin A, azathioprine, and prednisone were used as maintenance immunosuppressive therapy. Acute allograft rejection episodes were treated with a daily bolus of prednisone for 3 consecutive days. In group A 96 patients received Cytotect Biotest alone and in group B 111 patients received Cytotect with ganciclovir. 100 mg/kg Cytotect were administered i.v. before transplantation and on postoperative days 1, 7, 14, 21 and 28. Patients with CMV disease were treated with ganciclovir for 21 days in combination with a reduction of the immunosuppressive therapy. Additional Cytotect was administered at weekly intervals. In group A 53.1% had CMV infection and 32.3% (31/96 patients) had CMV disease. In group B 65.8% had CMV infection and 11.7% (13/111 patients) had CMV disease. Four CMV-associated deaths were observed in group A; 3 patients died of severe CMV sepsis, and 1 patient died of CMV encephalitis. There were no CMV-associated deaths observed in group B, which reflects a statistically significant benefit of combined Cytotect and ganciclovir versus sole Cytotect prophylaxis (P=0.0326).
An open-label, single center study investigated the passive immunisation against CMV in adult allograft recipients (146 patients who underwent heart transplantation between 1984 and 1991 with a median age of 47 years). The follow-up period ranged from 13 to 73 months (median 43 months). Maintenance immunosuppression consisted of cyclosporin A and prednisone. Azathioprine was added to this regimen in 11 patients because of recurrent rejection within the first year. In the treatment group 65 CMV (R-) patients received 150 mg/kg Cytotect during the operation and 100 mg/kg Cytotect at days 2, 7, 14, 28, 42, 56 and 72 after transplantation, whereas the control group consisted of 81 CMV (R+) patients who did not receive CMV prophylaxis. In the treatment group 21/65 (R-) patients (32.3%) had CMV infection and 11/65 (R-) patients (16.9%) had CMV disease. In the control group 40/81 (R+) patients (49.4%) had CMV infection and 10/81 (R+) patients (12.3%) had CMV disease.
A retrospective, single center study investigated CMV immunoglobulin for prophylaxis and treatment of CMV infection (156 adult patients who received a lung transplant between 2007 and 2011 with a mean age of 52 years (range 17-67 years) were analyzed). The median duration of follow-up was 19.2 months. All patients received basiliximab induction, and a triple immunosuppression (tacrolimus, mycophenolate mofetil, methylprednisolone followed by prednisolone). Ganciclovir i.v. was initiated in all at-risk patients (D+/R– or R+) during the first week post-transplant. In the treatment group 23 D+/R– patients received 2 ml/kg Cytotect on days 1, 4, 8, 15, and 30 post-transplant, then monthly for a further year and valganciclovir for 6 months. In the control group 133 R+ patients received valganciclovir for 3 months. In the treatment group 14/23 (D+/R-) patients (61%) had CMV infection and 4/23 (D+/R-) patients (17.4%) had CMV disease, whereas in the control group 46/133 (R+) patients (35%) had CMV infection and 6/133 (R+) patients (4%) had CMV disease. The mortality was 4/23 (D+R-) patients (17.4%) in the treatment group and 40/133 (R+) patients (30%) in the control group.
A comparative, retrospective study investigated the combined CMV prophylaxis after lung transplantation in 68 adult lung-transplant patients (mean age 55.8 years in the treatment group and 49.2 years in the control group) with CMV seropositive allograft. The median follow-up period was 16.5 months in the control group (5.3 to 69.5 months) and 23.8 months in the study group (11.9 to 35 months). In the control group 30 patients (transplanted from 1994 to 2000) received ganciclovir alone for the first 3 postoperative months, in the treatment group 38 patients (transplanted from 2000 to 2004) received additional treatment with 1 ml/kg Cytotect in 7 doses within the first post-transplant month.
Table 1. Results of the study:
| Treatment group (ganciclovir + Cytotect) (N=38) | Control group (ganciclovir alone) (N=30) | |
|---|---|---|
| 1-year survival | 81.6% | 63.3% |
| 3-year survival | 71.5% | 40% |
| 1-year freedom from CMV reactivation or de novo infection | 71.5% | 51.1% |
| 3-year freedom from CMV reactivation or de novo infection | 66.4% | 30% |
| Development of CMV disease during follow–up | 13.2% | 43.3% |
| Development of CMV pneumonitis | 13.2% | 33.3% |
| Occurrence of CMV syndrome | 0% | 10% |
| 1-year freedom from bronchiolitis obliterans syndrome (BOS) | 91.0% | 69.7% |
| 3-year freedom BOS | 82% | 54.3% |
| CMV related death | 0% | 16.7% |
A randomised comparative study investigated the use of intravenous hyperimmunoglobulin in the prevention of CMV infection in 49 adult patients with leukemia who received allogenic BMT from HLA-matched siblings (mean age 22 (Cytotect) and22.5 years (control)). The follow-up was 110 days. All patients were conditioned with cyclophosphamide and total body irradiation. In the treatment group 26 patients received 1 ml/kg Cytotect, in the control group 23 patients received 2 ml/kg normal immunoglobulin on day -7, and days 13, 33, 73 and 93 after BMT. Within the first 110 days after BMT 1/26 patients (4%) developed CMV-related interstitial pneumonitis in the treatment group and in the control group 6/23 patients (26%). Two patients in the Cytotect treated group developed CMV-related interstitial pneumonitis after cessation of treatment (Days 143 and 153).
An open-label, non-comparative study investigated the reduction of CMV disease by prophylaxis with CMV hyperimmunoglobulin plus oral acyclovir in 93 adult BMT recipients (median age 22 years, years, range 1-49 years). Acute GVHD was reported for 43 (48.3%) (Grade <II), 18 (20.2%) (Grade II) and 28 (34.3%) (Grade III-IV) patients. Total body irradiation was applied in a fractionated scheme on Days -3 to -1. 100 mg/kg Cytotect was given twice before BMT and then every third week through day 100 post BMT. 11/93 patients (11.8%) showed evidence of CMV infection of these 6 patients developed CMV infection during the time they received prophylaxis with CMV hyperimmunoglobulin, and 5 patients reactivated the virus after Cytotect was stopped. Among the patients suffering from severe GVHD 10/38 patients (26.2%) developed CMV infection, in contrast to only 1/55 patients (1.8%) who experienced mild GVHD.
Meta-analyses of the literature data on clinical efficacy have been performed to analyze all published data with Cytotect in the approved indication prophylaxis, independent of their study design. The CMV infection rate was determined as analyzed parameter for the primary endpoint. One meta-analysis covers all studies irrespective of the type of transplantation and one covers only solid organ transplantations (bone marrow transplant/leukaemia not included), results see table 2.
Table 2. Results of the meta-analyses:
| Cytotect | Control Group | |
| n/N | n/N | |
| % | % | |
| 95% Clopper-Pearson CI | 95% Clopper-Pearson CI | |
| Meta-analysis (all indications) | 422/1137 | 286/637 |
| 37.1% | 44.9% | |
| 34.3%-40.0% | 41.0%-48.9% | |
| 2-sided chi-square test: p-value = 0.001 | ||
| Meta-analysis (renal, heart and lung transplantations) | 390/969 | 283/603 |
| 40.2% | 46.9% | |
| 37.1%-43.4% | 42.9%-51.0% | |
| 2-sided chi-square test: p-value = 0.009 | ||
In both analyses a significant reduction of CMV infection was observed in patients treated with Cytotect. Including all indications, the CMV infection rate was reduced from 44.9% of patients in the control group to 37.1% of patients in the Cytotect group (p=0.001). Looking only at renal, heart and lung transplantations, the reduction was from 46.9% to 40.2% of all patients (p=0.009).
Cytotect CP Biotest is immediately and completely bioavailable in the recipient’s circulation after intravenous administration. It is distributed relatively rapidly between plasma and extravascular fluid; after approximately 3-5 days an equilibrium is reached between the intra- and extravascular compartments.
Cytotect CP Biotest has a half-life of 25 days. This half-life may vary from patient to patient and depends also on the clinical condition.
IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.
Immunoglobulins are normal constituents of the human body. Repeated dose toxicity testing and embryo-foetal toxicity studies are impracticable due to induction of, and interference with antibodies.
Since clinical experience provides no hint for tumorigenic and mutagenic effects of immunoglobulins, experimental studies, particularly in heterologous species, are not considered necessary.
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