Rheumatology-Rhumatologie

Tocilizumab was safe and effective for RA patients in comparison to tocilizumab plus DMARD therapy.

Abstract

Participants: 

Participants were 94 postmenopausal women with osteoporosis.

Outcome Measures: 

Lumbar spine, femoral neck, total hip, and distal radius BMD and serum markers of bone turnover were measured.

Results: 

At 24 months, lumbar spine BMD increased more in the combination group (12.9 ± 5.0%) than in either the teriparatide (9.5 ± 5.9%, P = .01) or denosumab (8.3 ± 3.4%, P = .008) groups. Femoral neck BMD also increased more in the combination group (6.8 ± 3.6%) than in either the teriparatide (2.8 ± 3.9%, P = .003) or denosumab (4.1 ± 3.8%, P = .008) groups. Similarly, total hip BMD increased more in the combination group (6.3 ± 2.6%) than in the teriparatide (2.0 ± 3.0%) or denosumab (3.2 ± 2.5%) groups (P < .001 for both). Although spine and hip BMD continued to increase in the second year in all groups, these year 2 increases did not differ among groups. Serum C-telopeptide and N-terminal propeptide of type 1 procollagen were equally suppressed in the denosumab and combination groups, whereas osteocalcin decreased more in the denosumab group than in the combination group, a difference that persisted, but lessened, in the second year of therapy.

Conclusions: 

Two years of concomitant teriparatide and denosumab therapy increases BMD more than therapy with either medication alone and more than has been reported with any current therapy. The combination of these agents may prove to be an important treatment option in patients at high risk of fracture.

A combination of old drugs is not inferior to biologics for rheumatoid arthritis • Tumor necrosis factor inhibitors are safe and effective therapies for patients with rheumatoid arthritis resistant to methotrexate and other disease modifying drugs,...

The European Medicines Agency’s (EMA) Management Board unanimously adopted a new policy on the publication of clinical reports that underpin the decision-making on medicines. The policy will enter into force on 1 January 2015 and will apply to clinical reports supporting all applications for centralised marketing authorisations submitted after that date. Please see separate press release for further information.

Mid-year report: supporting the development of innovative medicines

The Management Board discussed the Agency’s mid-year report for 2014.

Innovative medicines hold the potential to bring significant benefits to patients. Supporting the development of such medicines is a priority for the Agency. In the first half of 2014, interaction and dialogue with medicines developers increased. The number of requests for scientific advice and protocol assistance increased by 16% compared to the same period last year. 

The number of requests for joint scientific advice with health technology assessment (HTA) bodies has considerably increased (six in the first half of 2014 compared with one in the first half of 2013). HTA bodies provide recommendations on medicines that can be paid for or reimbursed by the healthcare system in a particular Member State. 

The EMA has selected eight development programmes for in-depth discussion with the applicant as part of its adaptive licensing pilot project, which was launched in March 2014. The project is intended to explore the progressive licensing of medicines, a prospectively planned process, which starts with an early authorisation in a restricted patient population, followed by iterative phases of evidence gathering and adaptations of the marketing authorisation to expand access to the medicine for increasingly broader patient populations.

In the first half of 2014, the overall number of applications for marketing authorisationremained stable.

Steady increase in medicines for rare diseases

Bruno Sepodes, the Chair of the EMA’s Committee for Orphan Medicinal Products(COMP), highlighted the steady increase in the number of medicines authorised for the treatment of rare diseases. So far, 93 medicines are available for patients.

The number of requests for the orphan designation of medicines for rare diseases, a status which offers a range of incentives to companies developing these medicines, is also increasing. In 2014, the COMP expects more than 300 requests for orphan medicines designations, a 50% increase compared to 2013 and the highest figure since the creation of the Committee.

In September 2014, the EMA started a pilot project to involve patients in the assessment of the benefits and risks of medicines in the EMA’s Committee for Medicinal Products for Human Use (CHMP).

Since 2013, a formal Healthcare Professionals’ Working Party (HCPWP) has supported the participation of doctors, pharmacists and other healthcare professionals in the work of the EMA.

Continued focus on replacement, reduction and refinement of animal testing

The Management Board renewed for the second time the mandate of the joint ad hoc expert group on the application of the so-called 3Rs principles. This group aims to promote best practice in relation to the replacement, reduction and refinement of the use of animals in the tests required by regulatory authorities. The group comprises experts from working parties of both the Committee for Medicinal Products for Veterinary Use (CVMP) and the CHMP.

Among other activities, the group has worked on opening up a route for the approval of alternative testing methods by the EMA. A guideline describing this route and the key principles underlying regulatory acceptance was adopted by the CHMP and the CVMP in September 2014 and is available on the EMA website.

Abstract

Objectives The safety and efficacy of sirukumab, an anti-interleukin-6 (IL-6) monoclonal antibody, were evaluated in a 2-part, placebo-controlled phase II study of patients with active rheumatoid arthritis (RA) despite methotrexate therapy.

Methods In Part A (proof-of-concept), 36 patients were randomised to placebo or sirukumab 100 mg every 2 weeks (q2w) through week 10, with crossover treatment during weeks 12–22. In Part B (dose finding), 151 patients were randomised to sirukumab (100 mg q2w, 100 mg q4w, 50 mg q4w, or 25 mg q4w) through week 24, or placebo through week 10 with crossover to sirukumab 100 mg q2w (weeks 12–24). The proportion of patients with an American College of Rheumatology 50 (ACR50) response and the change from baseline in the 28-joint count disease activity score using C-reactive protein (DAS28-CRP) were determined. Safety was evaluated through week 38 in both parts.

Results The primary endpoint (ACR50 at week 12 in Part B) was achieved only with sirukumab 100 mg q2w versus placebo (26.7% vs 3.3%; p=0.026). Greater improvements in mean DAS28-CRP at week 12 were observed with sirukumab 100 mg q2w versus placebo in Parts A (2.1 vs 0.6, p<0.001) and B (2.2 vs 1.1; p<0.001). The incidence of adverse events (AEs) was similar for sirukumab-treated and placebo-treated patients through week 12 in Part A (70.6% and 63.2%, respectively) and B (67.8% and 66.7%, respectively). Infections were the most common type of AE; one death occurred (Part B, sirukumab 100 mg q2w, brain aneurysm).

Conclusions Sirukumab-treated patients experienced improvements in the signs/symptoms of RA. Safety results through 38 weeks were consistent with other IL-6 inhibitors.

Trial registration number NCT00718718.

Rheumatoid arthritis is a condition that causes painful inflammation of several joints in the body. The joint capsule becomes swollen, and the disease can also destroy cartilage and bone as it progresses. Rheumatoid arthritis affects 0.5% to 1% of the world’s population. Up to this point, doctors have used various drugs to slow or stop the progression of the disease. But now, ETH Zurich researchers have developed a therapy that takes the treatment of rheumatoid arthritis in mice to a new level: after receiving the medication, researchers consider the animals to be fully cured.

The drug is a biotechnologically produced active substance consisting of two fused components. One component is the body’s own immune messenger interleukin 4 (IL-4); previous studies have shown that this messenger protects mice with rheumatoid arthritis against cartilage and bone damage. ETH scientists have coupled an antibody to IL-4 that, based on the key-lock principle, binds to a form of a protein that is found only in inflamed tissue in certain diseases (and in tumour tissue).

The researchers tested the new fusion molecule, which they refer to as an ‘armed antibody’, in a CTI project together with the ETH spin-off Philochem. They used a mouse model in which the animals developed swollen, inflamed toes and paws within a few days. Among other things, the researchers studied the fusion molecule in combination with dexamethasone, a cortisone-like anti-inflammatory drug that is already used to treat rheumatoid arthritis in humans. The researchers started treating each mouse as soon as they began showing signs of the disease in the form of swollen extremities.

Clinical trials in the next year

When used separately, the new fusion molecule and dexamethasone managed only to slow the progression of the disease in the affected animals. In contrast, the typical signs of arthritis, such as swollen toes and paws, disappeared completely within a few days when both medications were administered at the same time. Concentrations of a whole range of immune messengers in blood and inflamed tissue, which are changed in rheumatoid arthritis, returned to their normal levels. “In our mouse model, this combined treatment creates a long-term cure,” says Hemmerle, who, since completing her dissertation, has been working at Philochem, where she continues the project.

In 1974, in Nature, one of us has proposed a radically new idea that led to the development of anticytokine therapy which is now used around the world for the treatment of autoimmune diseases.

Introduction This randomized, double-blind, phase II study evaluated the pharmacodynamics, safety and tolerability of ISIS 329993 (ISIS-CRPRx), an antisense oligonucleotide, in patients with active rheumatoid arthritis (RA). Methods Patients with active RA of at least 6 months duration were randomized into 3 cohorts to receive ISIS-CRPRx (100 mg, 200 mg or 400 mg) or placebo (3 active:1 placebo within each cohort) via subcutaneous (SC) injection on Days 1, 3, 5 and 8 and then once weekly for the next 11 weeks. The effects of study treatment on high-sensitivity C-reactive protein (hs-CRP) level were evaluated. An exploratory analysis on disease activity was assessed via the American College of Rheumatology 20% improvement criteria (ACR20). Safety was evaluated via adverse events and laboratory measures. Results Fifty-one patients received one of the following treatments: ISIS-CRPRx 100 mg, n = 12; 200 mg, n = 13, 400 mg, n = 14; placebo n = 12. In the ISIS-CRPRx treatment groups there were dose-dependent reductions in hs-CRP. At Day 36 the mean percent change from baseline was: placebo: −14.4%; ISIS-CRPRx 100 mg: −19.5%; 200 mg: −56.6% and 400 mg: −76.7%, (p = 0.0015 placebo compared to 400 mg). There were no differences between treatment groups and placebo in the ACR20 at Day 36 or Day 92. There were no serious infections and no elevations in liver function tests, lipids, creatinine or other lab abnormalities related to ISIS-CRPRx. Conclusions In this study, ISIS-CRPRx selectively reduced hs-CRP in a dose-dependent manner, and was well-tolerated in patients with RA. Its utility as a therapy in RA remains unclear. Trial registration Clinicaltrials.gov NCT01414101. Registered July 21, 2011.

An evaluation of risk factors for major adverse #cardiovascular events during #tocilizumab therapy http://t.co/EymLTiXiv1 #rheum

Objective. To explore associations of baseline and on-treatment lipid levels, inflammation, and rheumatoid arthritis (RA) disease activity with risk for major adverse cardiovascular events (MACE) in tocilizumab-treated RA patients.

Methods. In retrospective post hoc analyses, data were pooled from 3986 adults with moderate to severe RA administered ≥1 dose of tocilizumab 4 or 8 mg/kg intravenously every 4 weeks in randomized controlled trials and extension studies. Cox proportional hazards modeling was used to evaluate associations among baseline characteristics and posttreatment initiation variables (week 24) and change from baseline to week 24 disease activity and laboratory values, with risk for future MACE during extended follow-up.

Results. There were 50 independently adjudicated cases of MACE during 14,683 patient-years (PY) of follow-up (0.34 MACE/100 PY). At baseline, age, history of cardiac disorders, disease activity score using 28 joints (DAS28), and total cholesterol/high-density lipoprotein ratio were independently (P<0.05 for all) associated with MACE in multivariable models. On treatment, higher DAS28 scores and swollen and tender joint counts at week 24 were associated with future MACE. In separate models, greater reductions in DAS28 score and joint counts from baseline to week 24 were inversely associated with future MACE; changes in lipid parameters were not statistically significantly associated with risk for MACE.

Conclusion. As in the general population, an association was observed between baseline total cholesterol/high-density lipoprotein ratio and increased risk for MACE. Risk for on-treatment MACE, however, was found to be associated with control of disease activity but not lipid changes. Larger studies are needed to confirm these findings. © 2014 American College of Rheumatology.

Medscape BrCa Risk Stable With Anti-TNF Tx MedPage Today After adjustment for cancer characteristics such as nodal status, surgical approach, and use of chemotherapy, the hazard ratio for recurrence with TNF inhibitor therapy was 1.1 (95% CI...

Abstract

Objectives The aim of this 12-week Phase IIb study was to assess the efficacy and safety of olokizumab (OKZ), a humanised anti-IL6 monoclonal antibody, in patients with rheumatoid arthritis (RA) with moderate-to-severe disease activity who had previously failed tumour necrosis factor (TNF) inhibitor therapy. The dose-exposure-response relationship for OKZ was also investigated.

Methods Patients were randomised to one of nine treatment arms receiving placebo (PBO) or OKZ (60, 120 or 240 mg) every 4 weeks (Q4W) or every 2 weeks (Q2W), or 8 mg/kg tocilizumab (TCZ) Q4W. The primary endpoint was change from baseline in DAS28(C-reactive protein, CRP) at Week 12. Secondary efficacy endpoints were American College of Rheumatology 20 (ACR20), ACR50 and ACR70 response rates at Week 12. Exploratory analyses included comparisons of OKZ efficacy with TCZ.

Results Across 221 randomised patients, OKZ treatment produced significantly greater reductions in DAS28(CRP) from baseline levels at Week 12, compared to PBO (p<0.001), at all the OKZ doses tested (60 mg OKZ p=0.0001, 120 and 240 mg OKZ p<0.0001). Additionally, ACR20 and ACR50 responses were numerically higher for OKZ than PBO (ACR20: PBO=17.1–29.9%, OKZ=32.5–60.7%; ACR50: PBO=1.3–4.9%, OKZ=11.5–33.2%). OKZ treatment, at several doses, demonstrated similar efficacy to TCZ across multiple endpoints. Most adverse events were mild or moderate and comparable between OKZ and TCZ treatment groups. Pharmacokinetic/pharmacodynamic modelling demonstrated a shallow dose/exposure response relationship in terms of percentage of patients with DAS28(CRP) <2.6.

Conclusions OKZ produced significantly greater reductions in DAS28(CRP) from baseline at Week 12 compared with PBO. Reported AEs were consistent with the safety profile expected of this class of drug, with no new safety signals identified.