Efficacy and Safety of Cytotect®CP, Hyperimmune Anti-CMV IVIg as CMV Prophylaxis in Patients Developing Acute Grade II-IV GVHD After Allogeneic Hematopoietic Cell Transplantation: A Prospective, Open-label, Phase II Study

Many risk factors are known to be associated with high risk of developing CMV infection in positive CMV-serostatus patients: negative CMV-serostatus donor, unrelated or mismatched donor, use of antithymocyte globulin (ATG), and development of GVHD. Acute GVHD occurs during the first hundred days after transplantation. In spite of systematic GVHD prophylactic using immunosuppressive agents, approximately 50% of transplantation recipients develop GVHD. The first-line treatment of acute GVHD is methylprednisolone 2 mg/kg/day. Probably because of the use corticosteroids but also due to the GVHD itself, approximately 46% of CMV seropositive patients develop CMV infection (report from the national database of the SFGM-TC, data unpublished yet).
CMV infection leads to longer duration of hospitalization and increases the risk of mortality, particularly in cases of CMV disease. Available antiviral agents used to prevent CMV infections are generally reputed to cause significant side effects. These agents can prevent full immunological post-transplant reconstitution and cause profound cytopenia. Some agents may be responsible for renal impairment, which prevents continuation of immunosuppressive treatment; this is especially the case with calcineurin inhibitors in allo-HCT patients. Indeed, compared to placebo, intravenous ganciclovir has been shown to reduce the risk of CMV infection and disease, although it did not appear to improve overall survival. However, it was responsible for 30% of cases of severe neutropenia in allo-HCT patients, increasing the risk of bacterial and fungal coinfections. CMV infection treatment is commonly based on ganciclovir and foscavir and, to a lesser extent, on other drugs, including cidofovir. However, these drugs cause high levels of toxicity, resulting in myelotoxicity in the case of ganciclovir, or, in the case of foscavir and cidofovir, potential renal failure, incurring treatment discontinuation.
CMV prophylaxis using drugs with fewer side-effects is necessary in patients at high risk of CMV infection.
With its safety profile, Cytotect®CP offers an alternative option for CMV prophylaxis with avoidance of renal and bone marrow impairment.
Considering the high risk of developing CMV infection, we decided to investigate the efficacy and safety of Cytotect®CP in patients requiring systematic corticosteroids (≥ 1 mg/kg/day) for an initial episode of grade II-IV acute GVHD following a first allo-HCT.

Start Date13 Sep 2022

Sponsor / Collaborator

Centre Hospitalier Universitaire de Lille

[+1]

NCT05170269 / Active, not recruitingPhase 3

Prevention of Maternal-fetal Cytomegalovirus Transmission After Primary Maternal Infection With Gestational Age ≤ 14 Weeks - an Open-label, Single-arm, Prospective Trial Investigating Efficacy and Safety of Cytotect CP Biotest

A phase 3, open-label, single-arm, prospective, multi-center trial of Cytotect CP Biotest (BT097) for prevention of maternal-fetal CMV transmission after primary maternal CMV infection. The main purpose of the trial is to demonstrate efficacy and safety of Cytotect CP Biotest in preventing maternal-fetal transmission of cytomegalovirus (CMV).

Start Date17 Nov 2021

Sponsor / Collaborator

Biotest AG

NCT04934527 / RecruitingPhase 2IIT

Evaluating a Therapeutic Association Between CMV-specific Immunoglobulin Infusion and Pre-transplant CD16-expressing Gamma Delta Vdelta 2 Negative T-cells in CMV-positive Patients for Preventive Treatment of CMV Infection in Renal Transplantation

CMV infection in transplantation remains the most frequent infectious complication causing increased morbidity and mortality. International recommendations advocate prevention of this infection by instituting direct antiviral treatment or monitoring viral replication by PCR with the start of curative antiviral treatment when the DNAemia is positive.
The risk of CMV infection varies according to the serostatus of the donor (D) and recipient (R) at the time of transplantation. In the absence of prophylaxis, CMV infection occurs in 60-80% of D+R-, 50-60% of D+R+ and 25-50% of D-R+.
The humoral anti-CMV response is represented by the production of antibodies to envelope proteins (gB and gH) and to molecules involved in viral attachment and entry into target cells. However, the majority of CMV-specific antibodies do not have antiviral neutralising activity. The investigators have identified a new player in the specific anti-CMV response expressing the Fc RIIIa receptor (CD16), that interacts with anti-CMV immunoglobulins (Ig): the Tgamma-delta V delta 2-negative lymphocyte (LTgdVd2neg). This lymphocyte subpopulation shows persistent expansion in the peripheral blood of kidney transplant patients with CMV infection. These cells express an effector-memory phenotype (CD45RA+/CD27-). This expansion is associated with resolution of infection in patients. The investigators have shown that CD16 is specifically and constitutively expressed on the surface of CMV-induced LTgdVd2neg in healthy volunteers and kidney transplant patients. The investigators have observed that one of the antiviral activities of anti-CMV IgG lies in its binding to the Fc RIIIa receptor (CD16) on the surface of LTgdVd2neg. The anti-CMV IgGs capturing virions thus activate CD16+ LTgdVd2neg with production of IFN interferon which in turn is responsible for inhibition of CMV viral multiplication.
Anti-CMV IgG is a recommended therapeutic option, with a marketing authorisation for the prevention of CMV infection in kidney transplantation in Europe and a Temporary Authorisation for Use in France.
Thus, R+ patients expressing a significant level of LTgdVd2neg CD16+ at D0 of transplantation could be protected against CMV, in the absence of direct antiviral treatment by the addition of anti-CMV Ig.

Start Date17 Nov 2021

Sponsor / Collaborator

Centre Hospitalier Universitaire de Bordeaux

[+1]

100 Clinical Results associated with Cytomegalovirus immune globulin (Biotest)

100 Translational Medicine associated with Cytomegalovirus immune globulin (Biotest)

100 Patents (Medical) associated with Cytomegalovirus immune globulin (Biotest)

132

Literatures (Medical) associated with Cytomegalovirus immune globulin (Biotest)

01 Aug 2023·Antiviral research

New therapeutic perspective in the prevention of congenital cytomegalovirus infection.

Article

Author: Hantz, Sébastien ; Berto, Laurie ; Coste Mazeau, Perrine ; Andouard, Déborah ; Alain, Sophie ; El Hamel, Chahrazed ; Chianea, Thierry

INTRODUCTION:

Hyperimmune globulin Cytotect CP® is a candidate for cytomegalovirus congenital infection prevention. We previously demonstrated its efficacy to prevent villi infection in our first-trimester placenta explants up to day 7, but with an inefficiency at day 14 (Coste-Mazeau et al., Microorganisms, 2021). As this could impact clinical efficacy, we now study the effect of weekly administration of Cytotect CP® on the prevention of villi infection.

METHODS:

Human embryonic lung fibroblast cells were infected at confluence with the endothelial strain TB40/E. Placentae were collected from voluntary pregnancy terminations (8-14 weeks of gestation) from cytomegalovirus-seronegative women. After 5 days of infection of the cells, villi explants were simultaneously added on sponges with Cytotect CP® at various concentrations. After 7 days, Cytotect CP® was renewed in only half of the plates. Villi were collected at days 7 and 14 with or without medium renewal. We compared the viral load by duplex quantitative PCR cytomegalovirus/albumin and the toxicity by measuring β-hCG concentrations in the supernatants with and without medium renewal.

RESULTS:

We did not find any efficacy of Cytotect CP® at day 14 when Cytotect CP® is not renewed, but a regular decrease of the viral load when the immunoglobulins were renewed at day 7, with an EC50 = 0.52 U/mL. We did not observed toxicity of Cytotect CP® with or without renewal of the molecule.

CONCLUSION:

Cytotect CP® is more effective when renewed at day 7. The prevention of congenital cytomegalovirus infection could be enhanced by reducing the spacing of doses.

01 Jul 2022·American journal of obstetrics & gynecology MFM

Amniocentesis to diagnose congenital cytomegalovirus infection following maternal primary infection

Article

Author: Simhan, Hyagriv N ; Casey, Brian M ; Varner, Michael W ; Gyamfi-Bannerman, Cynthia ; Mallett, Gail ; Chien, Edward K ; Parry, Samuel ; Heyborne, Kent D ; Dinsmoor, Mara J ; Rouse, Dwight J ; Costantine, Maged M ; Macones, George A ; Allard, Donna ; Swamy, Geeta K ; Hughes, Brenna L ; El-Sayed, Yasser Y ; Goodnight, William H ; Reddy, Uma M ; Thom, Elizabeth A ; Napolitano, Peter G ; Chauhan, Suneet P ; Saade, George R ; Fette, Lida M ; Tita, Alan T N

BACKGROUND:

Congenital cytomegalovirus infection following maternal primary cytomegalovirus infection affects approximately 0.4% of newborns in the United States but may be hard to diagnose prenatally.

OBJECTIVE:

To evaluate the current sensitivity and specificity of amniocentesis in detecting congenital cytomegalovirus infection.

STUDY DESIGN:

Secondary analysis of a multicenter randomized placebo-controlled trial designed to evaluate whether cytomegalovirus hyperimmune globulin reduces congenital cytomegalovirus infection in neonates of individuals diagnosed with primary cytomegalovirus infection before 24 weeks of gestation. At randomization, subjects had no clinical evidence of fetal infection. Eligible subjects were randomized to monthly infusions of cytomegalovirus hyperimmune globulin or placebo until delivery. Although not required by the trial protocol, amniocentesis following randomization was permitted. The fetuses and neonates were tested for the presence of cytomegalovirus at delivery. Comparisons were made between those with and without amniocentesis and between those with cytomegalovirus-positive and negative results, using chi-square or Fisher exact test for categorical variables and the Wilcoxon rank sum test or t test for continuous variables. A P value of <.05 was considered significant.

RESULTS:

From 2012 to 2018, 397 subjects were included, of whom 55 (14%) underwent amniocentesis. Cytomegalovirus results were available for 53 fetuses and neonates. Fourteen amniocenteses were positive (25%). Gestational age at amniocentesis was similar between those with and without cytomegalovirus present, as was the interval between maternal diagnosis and amniocentesis. The prevalence of fetal or neonatal infection was 26% (14/53). The neonates of all 12 subjects with a positive amniocentesis and available results had cytomegalovirus infection confirmed at delivery, as did 2 neonates from the group of 41 subjects with a negative amniocentesis, with a sensitivity of 86% (95% confidence interval, 57-98), specificity of 100% (95% confidence interval, 91-100), positive predictive value of 100% (95% confidence interval, 74-100), and negative predictive value of 95% (95% confidence interval, 83-99). Amniocentesis-positive pregnancies were delivered at an earlier gestational age (37.4 vs 39.6 weeks; P<.001) and had lower birthweights (2583±749 vs 3428±608 g, P=.004) than amniocentesis-negative pregnancies.

CONCLUSION:

Amniocentesis results are an accurate predictor of congenital cytomegalovirus infection.

01 May 2021·Annals of palliative medicineQ4 · MEDICINE

A clinical study of lyophilized intravenous human immunoglobulin containing high-titer cytomegalovirus-neutralizing antibody for the treatment of cytomegalovirus viremia after allogeneic hematopoietic stem cell transplantation

Q4 · MEDICINE

Article

Author: Han, Mingzhe ; Feng, Sizhou ; Yang, Donglin ; Jiang, Erlie ; Zhang, Ping ; Tian, Jixin

BACKGROUND:

Cytomegalovirus (CMV) infection increases the risk of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, some patients do not respond to ganciclovir (GCV) or foscarnet sodium. Lyophilized intravenous human immunoglobulin containing high-titer CMV-neutralizing antibody (CMV-IVIG) is another option to further improve treatment safety and efficacy. This study was designed to evaluate the efficacy of the combination of CMV-IVIG with traditional antiviral drugs (GCV or foscarnet sodium) at different time points for the treatment of post-allo-HSCT CMV viremia and to determine the clinical value of CMV-IVIG as a preemptive treatment strategy.

METHODS:

The clinical data of 73 patients who received allo-HSCT and concurrent CMV-IVIG to treat post-allo-HSCT CMV viremia at our hospital between January and September 2020 were retrospectively analyzed. The patients were divided into two groups based on the total dose of antithymocyte globulin (ATG) used in the pretransplant preconditioning regimen, i.e., the low-dose ATG group (rabbit ATG ≤6 mg/kg, porcine ATG ≤40 mg/kg) (n=19) and the high-dose ATG group (rabbit ATG >6 mg/kg, porcine ATG >40 mg/kg) (n=54). Real-time quantitative polymerase chain reaction (RQ-PCR) was performed to measure the peripheral CMV-DNA level. Patients with CMV viremia (CMV-DNA >1,000 copies/mL) received concurrent CMV-IVIG therapy [early (within 3 days after the diagnosis of CMV viremia) or late (after 3 days)]. The CMV-DNA conversion rate, the median time of CMV-DNA conversion, and the two-week response rate and reactivation rate were analyzed for different ATG doses and different time points of CMV-IVIG use.

RESULTS:

The overall response rate to CMV-IVIG combined with traditional anti-CMV drugs was 100%. Early use of CMV-IVIG significantly reduced the median time of CMV-DNA conversion (14 vs. 21 days, P=0.000), especially in the high-dose ATG group (14 vs. 23 days, P=0.000).

CONCLUSIONS:

For patients with post-allo-HSCT CMV viremia, early use of CMV-IVIG effectively accelerates CMV-DNA conversion and peripheral CMV clearance, significantly improves the two-week response rate, and reduces the two-week reactivation rate. These effects are more pronounced in the high-dose ATG group.

News (Medical) associated with Cytomegalovirus immune globulin (Biotest)

09 Mar 2023

·www.pharmaceutical-technology.com

SpyBiotech reveals plans for UK-based HCMV vaccine trial in H2 2023

Image Credit: Shutterstock / Numstocker Oxford, UK-based vaccine company SpyBiotech is planning to start dosing subjects for a Phase I trial of its lead vaccine candidate against human cytomegalovirus (HCMV) infection in H2 2023, says chief scientific officer (CSO) Sumi Biswas. The preparations for the trial are moving ahead and manufacturing is already completed, says Biswas. Additionally, the company has already selected a CRO for this trial, with toxicity studies well underway, confirms CEO Mark Leuchtenberger. The study, which features a six-month dosing schedule, will be carried out in the UK, he adds. The Phase I trial will test three doses of the vaccine, says Biswas. While the trial size has not been finalised, the biotech expects to enroll 120 subjects, she adds. Sumi Biswas, CSO of SpyBiotech, Image Credit; SpyBiotech The trial will feature the company’s vaccine candidate that is based on its “protein superglue” approach, which can be used to efficiently attach different antigens to virus-like particle (VLP)-based vaccines. Designing new vaccines for different pathogens becomes much faster once this “superglue” is incorporated into a specific platform, explains Biswas. Leuchtenberger likens SpyBiotech’s approach to a car chassis. This chassis can be modified based on needs, which is more efficient than building a car up from scratch every time. SpyBiotech aims to have immunogenicity and safety data ready by the end of 2023 or the start of 2024, says Leuchtenberger. While this data will not be shared with the public at the time, it will help the company with deciding the next steps for plans related to financing and partnerships, he adds. Mark Leuchtenberger, CEO of SpyBiotech Image Credit: SpyBiotech Plans for funding and other candidates in the works Though the company remains in a financially stable position in a challenging environment, it may start considering potential partnerships and a Series B fundraise in Q1 2024, says Leuchtenberger. The company previously raised $32.5 million in a Series A round, based on a February 2021 press release. This round extended the company’s reserves until H2 2025, adds Leuchtenberger. In addition to its plans for an HCMV vaccine, the company is exploring vaccines in other indications, including cancer. SpyBiotech recently decided to go ahead with the development of a vaccine candidate for Epstein-Barr virus, says Leuchtenberger. There are no approved vaccines for this condition . Additionally, the company’s technology will be featured in an Oxford University-sponsored malaria vaccine trial, says Leuchtenberger. Further in the works, negotiation is currently underway for the development of a mosaic-8 Covid-19 vaccine, which features the company’s technology, the CEO says. While Biswas did not give concrete timelines for when these enter the clinic, she hopes it will be soon. Note: Paragraph 2 was updated to reflect new context provided on the Phase I plans after publication.

VaccinePhase 1

100 Deals associated with Cytomegalovirus immune globulin (Biotest)

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Pregnancy Complications, Infectious	Phase 3	DE	Biotest AG	17 Nov 2021
Cytomegalovirus Infections	Phase 3	AT	Biotest AG	09 Jul 2008
Cytomegalovirus Infections	Phase 3	BE	Biotest AG	09 Jul 2008
Cytomegalovirus Infections	Phase 3	HU	Biotest AG	09 Jul 2008
Acute Graft Versus Host Disease	Phase 2	FR	Biotest AG	13 Sep 2022

Clinical Result

Indication

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


P405 (EBMT2023)	Not Applicable	Cytomegalovirus Infections	61	Cytotect	aqxkmptlac(thkzigkgum) = Cytotect was safe and well tolerated - no significant adverse events were recorded wsudqukezt (wbraxdknlc )	Positive	23 Apr 2023
P531 (EBMT2018)	Not Applicable	Hematologic Neoplasms CMV copies	294	Megalotect	rrkihizvkm(mvhmrwevao) = txujzdprcw qnvkhvqlky (qtmtslmicy ) View more	Positive	19 Nov 2018
P531 (EBMT2018)	Not Applicable	Hematologic Neoplasms CMV copies	294	Foscarnet	wfnwyuhrnw(bctbyrrljr) = rwzalgosdm gtwkfvhsns (uuywjcqine )	Positive	19 Nov 2018

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