DRUG EVALUATION Golimumab: a new anti-TNF agent on the horizon for infl ammatory arthritis Rheumatoid arthritis (RA), psoriatic arthritis, and ankylosing spondylitis are highly prevalent infl ammatory arthritides. Various conventional therapies are currently in use, and biologic therapies have also been introduced into the treatment armamentarium. Despite the remarkable effi cacy of the anti-tumor necrosis factor (TNF) agents, there still remains an unmet need for newer anti-TNF agents. A substantial number of patients do not respond to an initial anti-TNF agent, but may respond to a second one. The modes of administration of currently marketed anti-TNF agents are not particularly convenient and risk-free for all patients. An anti-TNF agent with a better safety profi le is also highly desirable. Golimumab (CNTO-148) is a high affi nity, human monoclonal antibody to TNF-α. The various ongoing trials for golimumab have shown promising results in terms of effi cacy and safety in methotrexate-naive and -resistant patients with RA, as well as in patients with RA who were previously treated with other anti-TNF agents. In addition, the effi cacy of golimumab in psoriatic arthritis and ankylosing spondylitis has also been demonstrated. KEYWORDS: golimumab, human monoclonal antibody, new anti-TNF Shweta Bhagat1, Bhaskar Dasgupta2† & Mahboob U Rahman3,4 Rheumatoid arthritis (RA), psoriatic arthritis refractory RA if one anti-TNF agent has failed, †Author for correspondence: (PsA) and ankylosing spondylitis (AS) form the while abatacept and anakinra have not been rec- 1Southend Hospital, Essex, UK majority of the infl ammatory arthritides causing ommended. Etanercept and adalimumab have 2Essex University, Westcliff e- long-term morbidity and need protracted treat- been recommended for PsA if an anti-TNF agent on-sea, Essex, SS0 0RY, UK ment. In the UK, RA affects approximately 1% is needed, and infl iximab should be used only Tel.: +44 170 248 5353 of the population [1] . There is a signifi cant differ- if there are problems with the other two anti- Fax: +44 170 248 5909 ence in prevalence estimates between northern TNF agents. NICE recommends adalimumab bhaskar.dasgupta@ European and American countries and devel- or etanercept as possible treatment for people southend.nhs.uk oping countries [2]. There is a wide variation of with severe AS who have active spinal disease 3University of Pennsylvania annual incidence of PsA (median: 6.4, range: 0.1– as assessed on two separate occasions, 12 weeks School of Medicine, PA, USA 23.1 cases per 105 inhabitants) according to a apart, and who have tried at least two NSAIDs 4Centocor R&D, Inc., PA, USA recently published systematic review of studies without success. from around the world. The prevalence esti- Etanercept is a recombinant, dimeric fusion mates vary from one case per 105 individuals in protein composed of two extracellular domains a Japanese study to 420 cases per 105 population of the human p75 TNF receptor linked to the Fc in an Italian study (median: 180) [3]. NICE esti- portion of human immunoglobulin G1 (IgG1) mated the prevalence of clinically signifi cant AS that binds to soluble and transmembrane forms of at 0.15% of the population, and an annual inci- TNF-α and lymphotoxin (TNF-β). Adalimumab dence of 6.9 per 100,000 [4]. Thus, infl ammatory is a human IgG1 monoclonal antibody (mAb) arthritides constitute a huge disease burden. directed against TNF-α that binds to soluble and Existing nonbiologic treatments have transmembrane forms of TNF-α. Infl iximab is included analgesics, corticosteroids, NSAIDs a chimeric mAb, composed of human constant and DMARDs. Biologic therapies, specifi cally regions of IgG and murine hypervariable regions. tumor necrosis factor-α (TNF-α) inhibitors, have It binds to both soluble and transmembrane been used in a wide variety of immune-mediated TNF-α. The hypervariable region segments of infl ammatory diseases and have been approved by infl iximab and adalimumab can lead to the devel- the US FDA and EMEA. Adalimumab, etaner- opment of human anti- adalimumab and anti- cept and infl iximab have been approved to treat infl iximab anti bodies, which in some patients RA, PsA and AS. Current NICE guidlines have leads to decreased effi cacy and increased chances approved the use of infl iximab, etanercept and of infusion and injection site reaction. However, adalimumab for the treatment of RA, and other the majority of patients with antibodies do not biologics like rituximab have been approved for have any clinical consequences [5,6]. 10.2217/17584272.4.1.15 © 2009 Future Medicine Ltd Int. J. Clin. Rheumatol. (2009) 4(1), 15–23 ISSN 1758-4272 15 DREVIEWRUG EVALUATIONAuthors Bhagat, Dasgupta & Rahman Despite their effi cacy in randomized clinical Pharmacokinetics & metabolism trials, there are some limiting factors of indi- The fi rst in-human Phase I study published in vidual agents contributing to both restriction 2007 was a randomized, double-blind, placebo- in therapeutic effi cacy and treatment-limiting controlled, parallel-group, dose-escalating study adverse effects. Even in diseases where anti-TNF conducted at two sites in the USA. Six groups of treatments have been proven to be successful, adult subjects with RA were randomly assigned to more than a third of patients do not respond receive a single intravenous infusion dose of goli- adequately to treatment [7]. This may be due to mumab of 0.1, 0.3, 1, 3, 6 or 10 mg/kg. Following differing mechanisms of disease, different bind- intravenous administration, serum concentrations ing properties of each of the antagonists to TNF of golimumab declined biexponentially, with a molecules and different dissociation rates [8,9]. median t½ of 19.3 days for the 10 mg/kg group. The binding to soluble and transmembrane The median half-life appeared to increase with an TNF receptors may also activate several dif- increase in dose [11] . No dose adjustment accord- ferent cascades. Finally, the genetic makeup of ing to body weight appeared to be necessary individuals may dictate response to biological based on the fi ndings of this study. Detectable treatments. When an individual fails to respond concentrations of golimumab were observed in to one biologic treatment, a switch to another the majority of subjects through week 4, even biologic is often successful [10] . those in the lower dose groups. Estimates based Despite being highly effective and generally on a population pharmacokinetics model also well-tolerated, anti-TNF agents can lead to seri- suggest that the t½ of golimumab ranges from ous adverse reactions (serious infections including 2 to 3 weeks. sepsis), TB immunogenic reactions (lupus-like Another multicenter, randomized, double- syndromes) and hypersensitivity-type reactions blind, placebo-controlled, dose-ranging study (including infusion and injection-site reactions). reported similar results. Median trough con- The current modes of delivery of these biologic centrations increased as the dose increased, and anti-TNF agents remain extremely inconvenient attained steady state by week 12 for all goli- for patients. While oral administration of such mumab dosage groups (50 mg every 4 weeks, large protein molecules (approximately 150 kD) 50 mg every 2 weeks, 100 mg every 4 weeks does not seem to be feasible in the near future, and 100 mg every 2 weeks) [12] . However, there other modes of administration, including less was much variability between patients. A study frequent subcutaneous injections, could provide of golimumab in PsA patients identifi ed several substantial relief for patients. co-variates that affected the apparent clearance Clearly, there is a need for future research of golimumab. Of these, weight, antibody to aimed at innovations to improve and extend golimumab status, baseline C-reactive protein the therapeutic use and safety of biological (CRP) and smoking status were identifi ed as agents. Golimumab, with monthly subcutane- signifi cant co-variates [13] . ous administration, is one such newer anti-TNF agent developed for use in the infl ammatory Clinical effi cacy of golimumab in trials arthritides. Phase II trial in RA This was the fi rst study reporting the effi cacy Introduction to the compound: of golimumab in humans. This study enrolled chemistry & formulation patients with active RA despite treatment with Golimumab (CNTO-148) is a high affi nity, MTX [12] . This was a dose-fi nding study that human mAb to TNF-α. The constant regions evaluated four dosing regimens of golimumab of the heavy and light chains of golimumab are in combination with MTX, compared with identical in amino acid sequence to the corre- MTX alone. A total of 172 adult patients with sponding human constant regions of infl ixi- RA that had been active for at least 3 months mab. The antibody neutralizes both soluble and while on MTX, and were on a stable dose of membrane-bound forms of TNF-α. MTX during the 4 weeks prior to study entry, Golimumab is the fi rst anti-TNF agent with were randomly assigned to one of fi ve treatment both subcutaneous and intravenous formulations, groups: placebo plus MTX, 50 mg golimumab requiring less frequent administration compared every 4 weeks plus MTX, 50 mg every 2 weeks with current anti-TNF products. Golimumab plus MTX, 100 mg every 4 weeks plus MTX and is intended to be used as monotherapy or in 100 mg every 2 weeks plus MTX. The primary combination with metho trexate (MTX). end point of a greater proportion of patients in 16 Int. J. Clin. Rheumatol. (2009) 4(1) future science group Golimumab: a new anti-TNF agent on the horizon for infl ammatory arthritis DRUG EVALUATION the combined golimumab plus MTX groups, serum CRP concentration compared with the and at least one of the individual golimumab other three dose groups. Both the 50 and 100 mg plus MTX groups achieving ACR20 at week 16 every 4 weeks dosing demonstrated adequate compared with the placebo plus MTX group effi cacy.