Therapeutics: Biologics and Small Molecules

CTLA-4 Ig (Abatacept)

In order to effectively activate resting T cells, two molecular signals are required : (1) the interaction of the T-cell receptor with processed peptide, bound to the appropriate major histocompatibility complex molecule; and (2) interaction of CD28 on T cells with CD80/86 on the surface of the antigen-presenting cell. Another high-affinity receptor, cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), can also bind to CD80/86 with a higher avidity than CD28, thereby preventing the second signal required for T-cell activation (see Chapter 5 ). Abatacept is a fully human, soluble fusion protein comprising the extracellular domain of CTLA-4 and the Fc component of IgG1, which selectively inhibits the costimulatory signal necessary for full T-cell activation ( Fig. 14.1 ). As a selective costimulation modulator, abatacept inhibits T-cell activation by binding to CD80 and CD86, thereby blocking their interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes.

There are two preparations of abatacept, one for intravenous administration and one for subcutaneous administration. Maltose is contained in the abatacept preparation for intravenous administration and can give falsely elevated blood glucose readings with certain blood glucose monitors on the day of abatacept infusion.

In an international, multicenter prospective study of 190 subjects with polyarticular course JIA using a randomized, double-blind, placebo-controlled withdrawal design, adverse events were recorded in 37 abatacept recipients (62%) and 34 (55%) placebo recipients ( P = 0.47). Abatacept was well tolerated in this trial, and there were no serious adverse events. In the open-label extension of this study, there were 1.33 serious infections per 100 patient-years among 153 patients. Five patients developed six infections, including dengue fever, erysipelas, gastroenteritis, herpes zoster, bacterial meningitis, and pyelonephritis. Subcutaneous abatacept was tested in a 24-month open-label international trial of 219 subjects with polyarticular course JIA with age at enrollment as young as 2 years. The effectiveness of subcutaneous abatacept was comparable to what was observed with intravenous abatacept in children with JIA. Across weight groups, abatacept trough levels prior to the next injection (Cmin) were comparable to what is observed in rheumatoid arthritis (RA). Local injection-site reactions were of mild or moderate intensity and occurred in around 7% of subjects. The frequency of serious adverse events was 4.7%. There were four serious infections (upper respiratory, pneumonia, pyelonephritis, and sepsis) during the 380 patient-years of follow-up (1.1%). There was one subject found to have stage III ovarian germ cell teratoma, which was thought to be unrelated to the study drug. Systematic reviews with meta-analyses suggest that abatacept therapy is associated with few treatment emergent infections, with similar responses to therapy and reduction of flare risk in polyarticular course JIA compared with other b-DMARDs used in JIA. ^, In line with data from trials in RA, abatacept monotherapy and combination therapy with MTX yielded comparable improvement of polyarticular course JIA. In adult RA, the time to response to abatacept and TNF inhibitors were similar, ^, raising the expectation that the same might hold true for JIA. Pregnancy outcomes with abatacept exposures were reported for 161 pregnancies, 151 pregnancies after maternal exposure and 10 after paternal exposure, respectively. Seven of 86 (8.1%) live births after maternal exposure had congenital anomalies: cleft lip/cleft palate, congenital aortic anomaly, meningocele, pyloric stenosis, skull malformation, ventricular septal defect/congenital arterial malformation, and Down syndrome with premature rupture of membranes at 17 weeks that resulted in a live birth via cesarean section and subsequent infant death. In addition, 59 of 151 (39.0%) cases with maternal exposure resulted in abortions (40 spontaneous and 19 elective). Of the 10 pregnancies with paternal exposure, there were nine live births and one elective abortion; there were no congenital abnormalities identified or fetal deaths. Based on these data, there does not seem to be a specific pattern of congenital abnormalities after maternal or paternal exposure to abatacept. EULAR has recommended that abatacept be replaced before conception by other medications and only be used during pregnancy when there is no other pregnancy-compatible drug that can effectively control maternal disease. A schema for abatacept use in children with JIA is shown in Table 14.6 .

Rituximab

Rituximab is a chimeric mAb that targets the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes but not plasma cells or stem cells. Upon binding to CD20, rituximab mediates B-cell lysis. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Although the antibody-producing plasma cells are not removed, B cells that may act as antigen-presenting cells, produce cytokines, and infiltrate tissues are removed for a prolonged period. Memory B cells, which are also responsible for antibody production, may be removed as well (see Chapter 5 ). Rituximab is theoretically beneficial in diseases in which autoantibodies may be pathogenic.

Rituximab dosing is influenced by the indication of use and the stage of therapy. Higher doses are given for induction as opposed to maintenance therapy or disease relapse. Rituximab induces a profound depletion of all peripheral blood B-cell populations in patients with RA. Relapse of RA tends to occur upon the return of B cells and repopulation is accompanied by higher numbers of memory B cells. ^,

Prolonged hypogammaglobulinemia is not uncommon after rituximab. Serious (including fatal) bacterial and fungal infections can occur during and after rituximab-based therapy. The same holds true for de novo or reactivation of viral infections including cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, and hepatitis B and C virus. Supplementation with IVIG to maintain low-normal IgG levels may be needed to avoid recurrent infections in the setting of rituximab-associated hypogammaglobinemia.

Based primarily on adult data, approaches to off-label use of rituximab in children with pediatric rheumatic diseases are shown in Table 14.7 . Most pediatric studies of rituximab are in childhood-onset systemic lupus erythematosus, ^, where its use has been associated with serious infection rate at 6.6 to 12.6 per 100 patient-years of follow-up. Other reported uses are for the treatment of antiphospholipid syndrome, antineutrophil cytoplasmic antigens (ANCA)-associated vasculitis, Sjögren syndrome, Henoch–Schönlein purpura, uveitis, juvenile dermatomyositis, systemic sclerosis, and pediatric autoimmune encephalitis. HACAs may develop in one-third of patients after treatment and are associated with lower serum levels of rituximab at 2 months and less effective B-cell depletion. In a pooled analysis of placebo-controlled studies in RA, acute infusion-related reactions were experienced by 27% of rituximab-treated patients after their first infusion. Acute infusion-related reactions required dose modification (stopping, slowing, or interruption of the infusion) in 10% of the patients after the first course. Although there were no clear benefits from oral glucocorticoids, the administration of intravenous glucocorticoids prior to rituximab infusions reduced the incidence and severity of such reactions. Patients in clinical studies also received antihistamines and acetaminophen prior to rituximab infusions. Considering the experience with rituximab in 2578 RA patients, the rate of serious infections is 4.31 per 100 patient-years, mainly pneumonia, lower respiratory tract infections, cellulitis, and urinary tract infections.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system resulting from reactivation of the Creutzfeldt–Jakob virus. PML is extremely uncommon despite the high prevalence of the Creutzfeldt–Jakob virus in the general population. The U.S. Food and Drug Administration (FDA) issued an alert in December 2006 after documentation of two fatal cases of PML in patients with systemic lupus erythematosus (SLE) after rituximab treatment. In total, 26 cases of PML were identified in patients concomitantly treated with rituximab for rheumatic disease. Nevertheless, rituximab-associated PML is a rare adverse event. It occurs in less than 1 in 20,000 rituximab-treated RA patients and the risk may be higher in SLE. However, PML can occur in patients with SLE even without rituximab exposure, with the incidence ranging from 1.0 to 2.4 per 100,000 person-years. No specific treatment of PML is available, and the prognosis is poor. Baseline screening for Creutzfeldt–Jakob virus is not recommended or required. Rituximab also has been classified as a drug associated with a high risk for hepatitis B virus reactivation in hepatitis B surface antigen (HbsAg)-negative/anti-hepatitis B core (HBc) positive patients.

Using the rituximab global drug safety database, Chakravarty et al. identified 231 pregnancies associated with maternal rituximab exposure. Maternal indications included lymphoma, autoimmune cytopenias, and other autoimmune diseases. Most cases were confounded by concomitant use of potentially teratogenic medications and severe underlying disease. Of 153 pregnancies with known outcomes, 90 resulted in live births with 23 infants born prematurely, and one neonatal death at 6 weeks. Eleven neonates had hematological abnormalities; none had corresponding infections. Four neonatal infections were reported (fever, bronchiolitis, cytomegalovirus hepatitis, and chorioamnionitis). Two congenital malformations were identified: clubfoot in one twin and cardiac malformation in a singleton birth. One maternal death from preexisting autoimmune thrombocytopenia occurred. The authors concluded that, although few congenital malformations or neonatal infections were seen among exposed neonates, women should be counseled to avoid pregnancy for at least 12 months after rituximab exposure. EULAR has recommended that rituximab be replaced before conception by other pregnancy-compatible drugs whenever possible. Ofatumumab, a fully human mAb targeting CD20, is commercially available but its clinical trial program in RA has been discontinued. Potentially, given the absence of HACAs, infusion reactions from ofatumumab may be less frequent than with rituximab in rheumatic diseases.

Belimumab

Belimumab is a human IgG1 neutralizing mAb against B-lymphocyte stimulating factor (also known as B-lymphocyte stimulator [BLyS ]). BLyS, a member of the TNF ligand superfamily, exists in both a 285-amino acid membrane-bound form and a cleaved 152-amino acid soluble form. Expressed on monocytes, macrophages, and monocyte-derived dendritic cells, BLyS is upregulated in response to interferon (IFN)-γ and interleukin (IL)-10, enhancing B-cell proliferation and Ig secretion. Belimumab binds with high affinity to BLyS and inhibits binding of BLyS to its three receptors, inhibiting BLyS-induced proliferation of B cells and decreasing survival of autoreactive B cells, which are particularly dependent on soluble BLyS. ^, Treatment results in decreasing serum anti–double-stranded DNA antibody levels.

Belimumab is indicated for adult and pediatric patients with active, autoantibody-positive SLE despite receiving standard therapy. The efficacy of belimumab for the treatment of severe active lupus nephritis or severe active central nervous system lupus has recently been established, the benefit of combination therapy with other b-DMARDs or intravenous cyclophosphamide is still under investigation.

Safety data from 2133 adult SLE patients from one phase II study and two phase III studies were analyzed. The most common serious adverse events with belimumab therapy were serious infections (6.0%), most frequently pneumonia, urinary tract infection, cellulitis, and bronchitis. Infections leading to discontinuation of treatment or death occurred in less than 1.0% of patients treated with intravenous belimumab. The most commonly reported adverse events, occurring in greater than or equal to 5% of patients in clinical trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremities, depression, migraine, and pharyngitis. The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trials was 6.2% for patients receiving belimumab plus standard therapy.

The frequency of mostly mild to moderate injection-site reactions was 6.1% with subcutaneous belimumab, leading to discontinuation of the drug in 6% of those with injection-site reactions. Anti-belimumab antibodies with intravenous administration are very rare (<0.7%) and were not observed during the clinical trial of subcutaneous belimumab in 556 patients. In the controlled clinical trials of belimumab administered intravenously, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% of patients receiving belimumab, with anaphylaxis occurring in 0.6% these patients. In the controlled trials, malignancies including nonmelanoma skin cancers were similarly frequent in the belimumab and the placebo groups (0.4%).

There are only a few case reports on pregnancy outcomes with belimumab exposures, none of which supports a special pattern of birth defects. EULAR has recommended that belimumab be replaced by other medications before conception and only be used during pregnancy when there is no other pregnancy-compatible drug that can effectively control maternal disease.

A trial in childhood-onset SLE (cSLE) is under way and results are available for the 52 week endpoints. Ninety-three children with cSLE aged 5 to 17 years who continued standard of care therapy were randomized to receive IV belimumab (10 mg/kg) every 4 weeks or placebo. At week 52, there were 28/53 (52.8%) Systemic Lupus International Collaborating Clinics (SLICC) responder index 4 (SRI4) responders in the belimumab group versus 17/39 (43.6%) in the placebo group (odds Ratio [OR] 1.49 [95% CI, 0.64 to 3.46]). A greater proportion of belimumab patients were ACR/Pediatric Rheumatology International Trials Organization (PRINTO) responders (belimumab 32/53 [60.4%] vs. placebo 14/40 [35%]). The authors concluded that the benefit/risk profile of IV belimumab in the children with cSLE population is generally consistent with that of adult study populations with either intravenous or subcutaneous administration.

Current recommendations for the use of belimumab are shown in Table 14.8 .

Tumor Necrosis Factor Inhibitors

Etanercept

Etanercept is a fully human, dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) TNF receptor linked to the Fc portion of human IgG1. Etanercept is produced by recombinant DNA and is a rather large molecule consisting of 934 amino acids and an apparent molecular weight of approximately 150 kDa. Although soluble forms of the TNF receptor occur naturally, they are generally inadequate to block TNF activity in systemic inflammatory disorders. Etanercept also binds lymphotoxin (previously called TNF-β ) and the relevance of this for JIA therapy remains unknown. Because of the initial report of its effectiveness in 2000, etanercept has been used extensively in children with JIA. It is currently indicated for children age 2 and above for polyarticular course JIA in both North America and Europe. In Europe it is also approved for use in children ages 12 to 17 years with juvenile psoriatic arthritis or enthesitis-related arthritis. The placebo-controlled study showed an increase in symptoms of upper respiratory tract infection, and 7% of children with JIA treated with etanercept reported generally mild injection-site reactions during the first 3 months of treatment. A registry of nearly 600 children with JIA followed for 3 years and smaller studies of long-term continuous use for up to 10 years support the long-term safety of etanercept in JIA. In general, adverse reactions in pediatric patients are similar in frequency and type as those seen in adult patients. In open-label clinical studies of children with JIA, adverse reactions reported in those ages 2 to 4 years were similar to adverse reactions reported in older children. A recent report from the German Biologics Registry suggests that etanercept monotherapy, but not combination therapy with MTX, may be associated with an increased risk of newly developing inflammatory bowel disease and uveitis, an observation that requires further investigation. Additional information about the use of etanercept is shown in Table 14.9 .