[From orthoclone to denosumab, the fast growing market of monoclonal antibodies]. / D'orthoclone au dénosumab : l'expansion des anticorps monoclonaux à des fins thérapeutiques.

Monoclonal antibodies are a specific medicinal category within the current therapeutic armamentarium. Their market share is growing fast as they are often the only therapeutic option at some stages of certain diseases, due to their targeted action in the body and to an acceptable tolerance. The budget impact of monoclonal antibodies is increasing, leading payers and health authorities to growing attention and pressure when they have to decide on the reimbursement, coverage and pricing of these products. The launch of biosimilars after patent expiry of some of these drugs will take time in view of the complexity of these molecules, and is not likely to significantly impact the cost of these therapies.

Muromonab CD3: a reappraisal of its pharmacology and use as prophylaxis of solid organ transplant rejection.

The murine monoclonal antibody muromonab CD3 (OKT3) is directed against the CD3 antigen on peripheral human T cells and effectively blocks all T cell function. Prophylaxis with muromonab CD3 (5mg intravenously once daily for 10 to 14 days) as induction therapy together with corticosteroids, azathioprine and delayed cyclosporin (sequential therapy) optimises early graft function by delaying the potentially nephrotoxic and hepatotoxic effects of cyclosporin until graft function is established. Although clinical data are limited (by inconsistencies in trial design and trial size), prophylactic muromonab CD3-based sequential therapy is significantly more effective than standard triple therapy in the prophylaxis of allograft rejection in renal and hepatic, but not cardiac, transplant recipients. Benefits are particularly notable in patients with delayed graft function. No significant between-treatment differences in patient survival have been observed. The overall efficacy of muromonab CD3- and polyclonal-based prophylactic regimens appears to be similar, although results vary between investigators and confirmation is needed. An anti-interleukin-2 monoclonal antibody-based prophylactic regimen improved graft and patient survival compared with muromonab CD3-based prophylaxis in hepatic transplant recipients. Antimuromonab CD3 antibodies may develop; however, muromonab CD3 may be successfully reused in patients with low titres. Preliminary pharmacoeconomic data suggest that mean drug costs are greater with quadruple immunosuppressive regimens containing muromonab CD3, antithymocyte globulin (ATG) or antilymphocyte globulin (ALG) than with triple therapy. Drug costs with prophylactic muromonab CD3-based regimens were similar or greater than those with polyclonal-based protocols. The first doses of muromonab CD3 are associated with the 'cytokine-release syndrome'. More severe first-dose events include aseptic meningitis, intragraft thromboses, seizures and potentially fatal pulmonary oedema. The incidence and/or severity of cytomegalovirus infection with prophylactic muromonab CD3 based immunosuppression is similar to or greater than that with triple therapy and ATG- or ALG-based regimens. However, the risk of infection and also the observed increase in lymphoproliferative disorders appears to be related to the degree of immunosuppression rather than to the drug itself Thus, sequential muromonab CD3-based therapy is more effective than standard triple therapy (in renal and hepatic transplant recipients) and appears to be similar to that of polyclonal-based regimens in the prophylaxis of transplant rejection. Although the routine use of prophylactic muromonab CD3 in low-risk patients with primary graft function does not appear to be justified, prophylactic muromonab CD3-based therapy has a role in patients at high risk of rejection.

Two approaches to comparing hospital charges between cadaveric renal transplant patients who received orthoclone OKT 3 sterile solution or Atgam sterile solution for induction therapy.

The objectives of this study were: (1) to compare total hospital charges for a sample of cadaveric renal transplant patients categorized according to the type of induction therapy used (Orthoclone OKT3 Sterile Solution or Atgam Sterile Solution); (2) to compare specific charge categories between the two groups; and (3) to examine the relationship between charges and a set of independent variables. A retrospective review was conducted of hospital charges associated with a sample of renal transplant patients. The overall sample for this study comprised 510 patient discharges from 22 hospitals in the United States. Comparisons between the OKT3 and Atgam groups were made for total and specific charge categories using two different approaches to help control variations in charges that were not related to the type of induction therapy used. The first approach consisted of t test or chi-square comparisons between the groups for subsets of observations that had been identified in a stepwise fashion. These judgment samples were defined to remove sources of variation in charges other than those resulting from the type of induction therapy selected. The second approach used multiple linear regression analysis to help statistically control variation in charges from other sources. The results showed that higher drug charges in the Atgam group were offset by lower charges in other categories (P < 0.05). These findings suggest that hospital formulary committees should consider all relevant costs, not just drug acquisition costs, when selecting products. However, further investigation is warranted to explore differences in charges due to: (1) between-hospital variation; (2) patients' severity of illness before receiving induction therapy; and (3) differences in side-effect profiles for the two induction therapies.

Induction immunosuppression in kidney transplant recipients older than 60 years of age : safety and efficacy of ATGAM, OKT3 and Simulect.

BACKGROUND: The choice of induction immunosuppression for kidney transplantation in elderly recipients is dictated by the consideration of the risk of infection as well as efficacy in the prevention of acute rejection, thus allowing a reduction in subsequent maintenance immunosuppression and its attendant long-term adverse effects. OBJECTIVE: To compare the efficacy and safety of the antibody induction immunosuppression strategies in elderly recipients of kidney transplants. PATIENTS AND METHODS: We present retrospective data analysis on 183 kidney transplant recipients > or = 60 years of age at Hahnemann University Hospital (Philadelphia, PA, USA) over a 12-year period. We compared four consecutive cohorts of kidney transplant recipients receiving lymphocyte immune globulin, equine antithymocyte globulin (ATGAM) [n = 29]; muromonab CD3 (OKT3) [n = 45]; basiliximab (Simulect) with corticosteroid maintenance [n = 40]; and Simulect without corticosteroid maintenance (n = 69). RESULTS: Delayed graft function (DGF) was observed in 48% of patients receiving ATGAM, 35.6% in the OKT3 group and 35% in the Simulect group with corticosteroid maintenance and 36.2% in the Simulect group without corticosteroid maintenance. The rejection rate within the first 3 months was 31% in the ATGAM and OKT3 groups, 17.5% in the Simulect group with corticosteroid maintenance and 14.5% in the Simulect group without corticosteroid maintenance. These differences for DGF and acute rejection were statistically significant between patients receiving ATGAM and OKT3, ATGAM or OKT3 and both groups of Simulect (all p < 0.05). Patients receiving Simulect were free of adverse effects typically encountered by patients receiving polyclonal and monoclonal antibodies for induction. Patients receiving Simulect had much shorter hospital stays and benefited from significant reduction of costs compared with other groups. CONCLUSION: Our data indicate that kidney transplant recipients > or = 60 years of age benefit from induction therapy with Simulect followed by corticosteroid-free maintenance immunosuppression.

Randomized double-blind study of standard versus low-dose OKT3 induction therapy in renal allograft recipients.

A double-blind, randomized, prospective study was undertaken to determine if the dose of OKT3 used for induction immunosuppression following kidney and kidney-pancreas transplantation affected clinical outcomes. Twenty-five patients were randomized in each group. Five patients in each group received a combined kidney/pancreas transplant. All patients received sequential quadruple immune suppression (azathioprine and methylprednisolone, followed by oral prednisone and cyclosporine A), regardless of randomization to the standard (5 mg) or low-dose (2 mg) OKT3 group. OKT3 was administered for 7 to 14 days. The dose of OKT3 was adjusted to ascertain the clearance of peripheral positive CD3 lymphocytes. The mean cumulative OKT3 dose for the standard dose group was 52.0 mg versus 23.4 mg for the low-dose group (P < 0.00001). Dosage increases were necessary for 29% of the standard dose and 32% of the low-dose patients. The side effect score for the standard versus low-dose group was not statistically different (0.79 +/- 0.58 v 0.84 +/- 0.68), except for chills, which occurred more frequently in the low-dose-treated patients (P = 0.003). Anti-OKT3 antibodies developed with similar frequency in both dosage groups, with 8% exhibiting titers of 1:500 or greater at the end of treatment. Kidney graft survival was 96% for the standard dose and 92% for the low-dose group. The overall incidence of rejection was similar in both groups; however the low-dose group did experience an increase in early rejection episodes. The incidence of major and minor viral and bacterial infections was also similar for both dosage groups.(ABSTRACT TRUNCATED AT 250 WORDS)

A prospective, double-blind, randomized study of high-versus low-dose OKT3 induction immunosuppression in cadaveric renal transplantation.

We undertook a prospective, double-blind study of high-(5-mg) versus low-(2-mg) dose OKT3 for induction immunosuppression (12 days) in cadaveric renal allograft transplantation. Maintenance immunosuppression was identical in both groups and consisted of azathioprine and prednisone initially, with cyclosporine beginning on the 5th postoperative day. Twenty-six patients were randomized. The groups were similar in terms of age, kidney ischemia time, peak PRA, and latest PRA. There were more diabetics and women in the high-dose group. Patient survival at 12 months was 100% in both groups. Graft survival at 12 months was 92% and 100% in the high- and low-dose groups, respectively. Infections were mostly minor and equal in frequency in the two groups. All patients receiving high- or low-dose OKT3 had manifestations of the cytokine release syndrome; these were delayed in onset in the low-dose group. Eleven patients (85%) in each group produced anti-OKT3 antibodies. Lymphocyte depletion after 1 day was major (> 98%) and identical in both groups. CD3 antigens were removed more slowly in the low-dose group but eventually at equal rates in both groups. Cost was significantly lower in the low-dose group. We conclude that while both doses of OKT3 were effective and safe for induction immunosuppression, it may be prudent to use a lower dose of OKT3 for induction immunosuppression because of its potential to reduce cytokine-mediated effects and to avoid the complications of overimmunosuppression and because of the lower costs associated with it.

Muromonab-CD3 and antithymocyte globulin in renal transplantation.

OBJECTIVE: To review the recently published medical literature for the practical and efficient use of muromonab-CD3 (OKT-3) and antithymocyte globulin (ATG) in renal transplantation. DATA SOURCES: MEDLINE and EMBASE were searched (1985-February 1996). Key words used were antithymocyte globulin (ATG, Atgam), muromonab-CD3 (OKT-3, Orthoclone), and kidney transplantation. Thereafter, the search was restricted to English-language articles, clinical trials, and human studies. STUDY SELECTION AND DATA EXTRACTION: The search was reviewed for articles of interest, and pertinent references from these articles were further reviewed to supplement the initial search. The review focused on antibody therapy as induction and/or rejection therapy in renal transplantation. DATA SYNTHESIS: Although ATG and OKT-3 are effective in delaying and reducing the occurrence of acute rejection, their impact on long-term graft survival has not been established. Improved graft survival has, however, been demonstrated in patients at high risk for rejection. These risks are described in the review. As first-line or steroid-resistant rejection therapy, ATG and OKT-3 have proven efficacious. Some studies have shown improved graft survival with OKT-3. Although serious infections may occur, OKT-3 has been shown to be effective in reversing rejections resistant to both steroids and ATG. Therefore, reserving OKT-3 for steroid- or ATG-resistant rejections may be preferred over the first-line use of OKT-3, which is limited by the development of antimurine antibodies with subsequent uses. However, the benefits of first-line antibody therapy may outweigh the risks of developing these antibodies in patients for whom high-dose steroids may not be the most appropriate treatment. Other factors that need to be considered are adverse effects, which appear to be lower with ATG, cost, and total hospital charges. The accuracy of treatment outcomes analysis among these studies is limited by variations in the immunosuppressive regimens of the study centers, doses of concomitant therapies, use of prophylactic antibiotics, and time to follow-up. CONCLUSIONS: While important benefits are realized from using antibody therapies in renal transplantation, their use is often associated with excess immunosuppression and increased treatment costs. Despite encouraging results from published trials, questions regarding the extent of their prophylactic use and impact on long-term outcomes need to be answered. The current literature contains no prospective, controlled, randomized comparisons of OKT-3 and ATG with standardized regimens of conventional immunosuppressive agents and antirejection protocols. The majority of studies use OKT-3 as part of the treatment protocol. Well-designed studies using ATG are lacking. Further research is needed to refine treatment protocols for ATG and OKT-3 to determine the optimal timing and dosing for these agents.

Two low-dose OKT3 induction regimens following renal transplantation--clinical experience at a single center.

Experience with quadruple-drug induction therapy with two regimens of low-dose OKT3 in renal transplant patients was evaluated. Group I received 5.0 mg OKT3 in the operating room and on day 1, followed by 2.5 mg/d for a total dose and duration of 40 mg and 14 d, respectively, and group II received 14 d of OKT3 2.5 mg/d (a total dose of 35 mg). Rejection episodes developed in 21% of patients: 29% of group I vs. 17% of group II. In groups I and II, the mean number of days until first rejection was 134 and 119 d, respectively, and delayed graft function was observed in 24 vs. 13% of patients, respectively. Cytokine release syndrome was noted in 95% of group I patients and in 78% of group II patients. The overall incidence of infections did not differ significantly between the two groups; however, the incidence of oral candidiasis was higher in group II (30 vs. 11% in group I, p = 0.021) and the incidence of herpes simplex virus infection was higher in group I (13 vs. 1% in group II, p = 0.015). The average length of hospital stay was 6.7 d in group I and 6.2 d in group II. The current pharmacy charge for a 2.5-mg vial of OKT3 is 28% lower for a 5.0-mg vial. Our study suggests that by using either low-dose OKT3 regimen renal transplant patients can be safely treated with shortened hospital stays, lower pharmacy costs, and without increased incidence of graft loss or patient morbidity.

A cost-effectiveness analysis of OKT3 induction therapy in cadaveric kidney transplantation.

We evaluated the cost-effectiveness of a standard immunosuppressive regimen versus an OKT3 induction regimen in cadaveric kidney transplant recipients. Cost estimates were based on results from a five-center randomized trial comparing the safety and efficacy of OKT3 induction with a conventional triple-drug regimen and financial data from the National Cooperative Transplantation Study, the Medicare Provider and Analysis Review database, and other sources. Patients received OKT3 (5 mg/day) by intravenous (IV) bolus injection for 10 to 14 consecutive days in conjunction with azathioprine, prednisone, and the delayed addition of cyclosporine (CsA) on day 11 (n = 105) or a conventional immunosuppressive regimen consisting of CsA, azathioprine, and prednisone (n = 102). The following measures were used to evaluate the two regimens: costs incurred between transplantation and graft failure; the effectiveness of the two regimens as defined by length of graft survival; and cost-effectiveness ratios through 5 years of observed follow-up and modeled through the expected duration of graft survival. Results showed that OKT3 induction uniformly adds $8,219 to the cost of the transplant hospitalization. However, most of this cost is offset by a reduction in the cost of treating rejection episodes in the OKT3 group (P = 0.002). A trend toward improved graft survival was detected in the OKT3 group (P = 0.158). Through 5 years of observed follow-up, costs per year of graft survival are $30,474 with OKT3 versus $32,687 with the conventional regimen. Modeled through the expected duration of graft survival, OKT3 induction costs $8,335 for each additional year of graft survival. Results are fairly insensitive to wide variations in baseline assumptions. We conclude that OKT3 induction improves the cost-effectiveness of kidney transplantation.