Andrew M Wright

Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis

A human antibody to interleukin-17A is well tolerated and may be effective in the treatment of psoriasis, rheumatoid arthritis, and noninfectious uveitis. Stopping Inflammation in Its Tracks Inflammation—characterized by redness, swelling, and pain and derived from the Latin word inflammare (to set on fire)—is the body’s principal defense against infection and injury. Once the infection has been squelched by the immune system, the inflammatory response is usually switched off. Sometimes, however, immune cells activated during inflammation elude the “off switch,” resulting in tissue destruction and various diseases—including cancer, rheumatoid arthritis, and skin disorders such as psoriasis. Cytokines that activate immune cells are key drivers of inflammation. To address whether blocking one of these cytokines, interleukin-17A (IL-17A), might be a useful therapeutic strategy for treating inflammatory diseases, Hueber and colleagues used a human monoclonal antibody (AIN457) against IL-17A to treat patients in three small proof-of-concept trials for psoriasis, rheumatoid arthritis, and uveitis (eye inflammation). Their results demonstrate that IL-17A participates in these diseases and that the antibody against this cytokine may be an effective therapeutic agent. The proinflammatory cytokine IL-17A is produced by T helper 17 (TH17) cells and affects many different cell types including macrophages and dendritic cells of the immune system, as well as epithelial, endothelial, and skin cells. IL-17A has been implicated in psoriasis, rheumatoid arthritis, and uveitis, but its exact role is unclear. The etiologies and symptoms of these three diseases are very different. TH17 and TH1 cells have been implicated in both psoriasis (characterized by excessive turnover of skin cells resulting in scaly skin patches) and uveitis (intraocular inflammation that can lead to vision loss). In contrast, in the autoimmune disease rheumatoid arthritis, autoreactive T and B cells together with autoantibodies promote prolonged inflammation, ultimately resulting in the destruction of cartilage and bone. In their three proof-of-concept trials, Hueber and co-workers treated a total of 60 patients with the human monoclonal antibody AIN457 at different doses and observed no major adverse effects. Although the trials were small and the results were preliminary, improvements were seen in all three disease groups. Psoriasis patients receiving AIN457 showed reduced scaly skin patches, decreased production of inflammatory cytokines, and a reduction in T cells infiltrating the skin lesions compared with placebo-treated patients. After receiving infusions of AIN457, rheumatoid arthritis patients exhibited reduced inflammation of the synovial joints as shown by improvements in three different clinical scores compared with placebo-treated patients. Meanwhile, patients with uveitis treated with AIN457 showed improved visual acuity, reduced ocular inflammation, or a reduced need for steroid drugs after 8 weeks. These encouraging results warrant larger clinical trials to assess further the safety and efficacy of AIN457 for treating psoriasis, rheumatoid arthritis, and uveitis and perhaps other inflammatory diseases in which IL-17A has been implicated. Interleukin-17A (IL-17A) is elaborated by the T helper 17 (TH17) subset of TH cells and exhibits potent proinflammatory properties in animal models of autoimmunity, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental autoimmune uveitis. To determine whether IL-17A mediates human inflammatory diseases, we investigated the efficacy and safety of AIN457, a human antibody to IL-17A, in patients with psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis. Patients with chronic plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52), or chronic noninfectious uveitis (n = 16) were enrolled in clinical trials to evaluate the effects of neutralizing IL-17A by AIN457 at doses of 3 to 10 mg/kg, given intravenously. We evaluated efficacy by measuring the psoriasis area and severity index (PASI), the American College of Rheumatology 20% response (ACR20) for rheumatoid arthritis, or the number of responders for uveitis, as defined by either vision improvement or reduction in ocular inflammation or corticosteroid dose. AIN457 treatment induced clinically relevant responses of variable magnitude in patients suffering from each of these diverse immune-mediated diseases. Variable response rates may be due to heterogeneity in small patient populations, differential pathogenic roles of IL-17A in these diseases, and the different involvement or activation of IL-17A–producing cells. The rates of adverse events, including infections, were similar in the AIN457 and placebo groups. These results support a role for IL-17A in the pathophysiology of diverse inflammatory diseases including psoriasis, rheumatoid arthritis, and noninfectious uveitis.

Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial

BACKGROUND Ankylosing spondylitis is a chronic immune-mediated inflammatory disease characterised by spinal inflammation, progressive spinal rigidity, and peripheral arthritis. Interleukin 17 (IL-17) is thought to be a key inflammatory cytokine in the development of ankylosing spondylitis, the prototypical form of spondyloarthritis. We assessed the efficacy and safety of the anti-IL-17A monoclonal antibody secukinumab in treating patients with active ankylosing spondylitis. METHODS We did a randomised double-blind proof-of-concept study at eight centres in Europe (four in Germany, two in the Netherlands, and two in the UK). Patients aged 18-65 years were randomly assigned (in a 4:1 ratio) to either intravenous secukinumab (2×10 mg/kg) or placebo, given 3 weeks apart. Randomisation was done with a computer-generated block randomisation list without a stratification process. The primary efficacy endpoint was the percentage of patients with a 20% response according to the Assessment of SpondyloArthritis international Society criteria for improvement (ASAS20) at week 6 (Bayesian analysis). Safety was assessed up to week 28. This study is registered with ClinicalTrials.gov, number NCT00809159. FINDINGS 37 patients with moderate-to-severe ankylosing spondylitis were screened, and 30 were randomly assigned to receive either intravenous secukinumab (n=24) or placebo (n=6). The final efficacy analysis included 23 patients receiving secukinumab and six patients receiving placebo, and the safety analysis included all 30 patients. At week 6, ASAS20 response estimates were 59% on secukinumab versus 24% on placebo (99·8% probability that secukinumab is superior to placebo). One serious adverse event (subcutaneous abscess caused by Staphylococcus aureus) occurred in the secukinumab-treated group. INTERPRETATION Secukinumab rapidly reduced clinical or biological signs of active ankylosing spondylitis and was well tolerated. It is the first targeted therapy that we know of that is an alternative to tumour necrosis factor inhibition to reach its primary endpoint in a phase 2 trial. FUNDING Novartis.

The human anti-IL-1β monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis

IntroductionIL-1β is a proinflammatory cytokine driving joint inflammation as well as systemic signs of inflammation, such as fever and acute phase protein production.MethodsACZ885, a fully human monoclonal antibody that neutralizes the bioactivity of human IL-1β, was generated to study the potent and long-lasting neutralization of IL-1β in mechanistic animal models as well as in a proof-of-concept study in patients with rheumatoid arthritis (RA).ResultsThe mouse IL-1 receptor cross-reacts with human IL-1β, and it was demonstrated that ACZ885 can completely suppress IL-1β-mediated joint inflammation and cartilage destruction in mice. This observation prompted us to study the safety, tolerability and pharmacodynamic activity of ACZ885 in RA patients in a small proof-of-concept study – the first to be conducted in humans. Patients with active RA despite treatment with stable doses of methotrexate were enrolled in this dose escalation study. The first 32 patients were split into four cohorts of eight patients each (six were randomly assigned to active treatment and two to placebo). ACZ885 doses were 0.3, 1, 3 and 10 mg/kg, administered intravenously on days 1 and 15. To explore efficacy within 6 weeks of treatment, an additional 21 patients were randomly assigned to the 10 mg/kg cohort, resulting in a total of 20 patients dosed with 10 mg/kg and 15 patients treated with placebo. There was clinical improvement (American College of Rheumatology 20% improvement criteria) at week 6 in the 10 mg/kg treatment group; however, this did not reach statistical significance (P = 0.085). A statistically significant reduction in disease activity score was observed after 4 weeks in the 10 mg/kg group. Onset of action was rapid, because most responders exhibited improvement in their symptoms within the first 3 weeks. C-reactive protein levels decreased in patients treated with ACZ885 within 1 week. ACZ885 was well tolerated. Three patients receiving ACZ885 developed infectious episodes that required treatment. No anti-ACZ885 antibodies were detected during the study.ConclusionACZ885 administration to methotrexate-refractory patients resulted in clinical improvement in a subset of patients. Additional studies to characterize efficacy in RA and to determine the optimal dose regimen appear warranted.Trial RegistrationClinicalTrials.gov identifier NCT00619905.

Canakinumab (ACZ885, a fully human IgG1 anti-IL-1β mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS)

IntroductionCryopyrin-associated periodic syndrome (CAPS) represents a spectrum of three auto-inflammatory syndromes, familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular syndrome (NOMID/CINCA) with etiology linked to mutations in the NLRP3 gene resulting in elevated interleukin-1β (IL-1β) release. CAPS is a rare hereditary auto-inflammatory disease, which may start early in childhood and requires a life-long treatment. Canakinumab, a fully human anti-IL-1β antibody, produces sustained selective inhibition of IL-1β. This study was conducted to assess the efficacy, safety, and pharmacokinetics of canakinumab in the treatment of pediatric CAPS patients.MethodsSeven pediatric patients (five children and two adolescents) with CAPS were enrolled in a phase II, open-label study of canakinumab in patients with CAPS. Canakinumab was administered at a dose of 2 mg/kg subcutaneously (s.c.) (for patients with body weight ≤ 40 kg) or 150 mg s.c. (for patients with body weight > 40 kg) with re-dosing upon each relapse. The primary efficacy variable was time to relapse following achievement of a complete response (defined as a global assessment of no or minimal disease activity and no or minimal rash and values for serum C-reactive protein (CRP) and/or serum amyloid A (SAA) within the normal range, < 10 mg/L).ResultsAll patients achieved a complete response within seven days after the first dose of canakinumab and responses were reinduced on retreatment following relapse. Improvements in symptoms were evident within 24 hours after the first dose, according to physician assessments. The estimated median time to relapse was 49 days (95% CI 29 to 68) in children who received a dose of 2 mg/kg. Canakinumab was well tolerated. One serious adverse event, vertigo, was reported, but resolved during treatment.ConclusionsCanakinumab, 2 mg/kg or 150 mg s.c., induced rapid and sustained clinical and biochemical responses in pediatric patients with CAPS.Trial registration numberClinicalTrials.gov: NCT00487708

Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial

Summary Background Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids. Methods We did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3–9, 10–30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (<30 g per week) were permitted during weeks 1–3. The non-inferiority primary effectiveness outcome was the proportion of participants with three or fewer blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of non-inferiority. The primary safety outcome was the proportion with severe, life-threatening, or fatal (grade 3–5) treatment-related adverse events by 52 weeks. Analysis (modified intention to treat [mITT] for the superiority safety analysis and mITT and per protocol for non-inferiority effectiveness analysis) used a regression model adjusting for baseline disease severity, age, and Karnofsky score, with missing data imputed. The trial is registered at ISRCTN, number ISRCTN13704604. Findings Between March 1, 2009, and Oct 31, 2013, 132 patients were randomly assigned to doxycycline and 121 to prednisolone from 54 UK and seven German dermatology centres. Mean age was 77·7 years (SD 9·7) and 173 (68%) of 253 patients had moderate-to-severe baseline disease. For those starting doxycycline, 83 (74%) of 112 patients had three or fewer blisters at 6 weeks compared with 92 (91%) of 101 patients on prednisolone, an adjusted difference of 18·6% (90% CI 11·1–26·1) favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening, and fatal events at 52 weeks were 18% (22 of 121) for those starting doxycycline and 36% (41 of 113) for prednisolone (mITT), an adjusted difference of 19·0% (95% CI 7·9–30·1), p=0·001. Interpretation Starting patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control in bullous pemphigoid and significantly safer in the long-term. Funding NIHR Health Technology Assessment Programme.

Dermal PK/PD of a lipophilic topical drug in psoriatic patients by continuous intradermal membrane-free sampling.

BACKGROUND Methodologies for continuous sampling of lipophilic drugs and high-molecular solutes in the dermis are currently lacking. We investigated the feasibility of sampling a lipophilic topical drug and the locally released biomarker in the dermis of non-lesional and lesional skin of psoriatic patients over 25h by means of membrane-free dermal open-flow microperfusion probes (dOFM) and novel wearable multi-channel pumps. METHODS Nine psoriatic patients received a topical p-38 inhibitor (BCT194, 0.5% cream) on a lesional and a non-lesional application site once daily for 8 days. Multiple dOFM sampling was performed for 25 h from each site on day 1 and day 8. Patients were mobile as dOFM probes were operated by a novel light-weight push-pull pump. Ultrasound was used to verify intradermal probe placement, cap-LC-MS/MS for BCT194 and ELISA for TNFα analysis. RESULTS dOFM was well tolerated and demonstrated significant drug concentrations in lesional as well as non-lesional skin after 8 days, but did not show significant differences between tissues. On day 8, TNFα release following probe insertion was significantly reduced compared to day 1. CONCLUSIONS Novel membrane-free probes and wearable multi-channel pumps allowed prolonged intradermal PK/PD profiling of a lipophilic topical drug in psoriatic patients. This initial study shows that dOFM overcomes limitations of microdialysis sampling methodology, and it demonstrates the potential for PK/PD studies of topical products and formulations in a clinical setting.

LONG TERM INHIBITION OF IL-17A WITH SECUKINUMAB REDUCES SPINAL INFLAMMATION BUT HAS NO INFLUENCE ON FATTY LESIONS AS ASSESSED BY MAGNETIC RESONANCE IMAGING IN PATIENTS WITH ANKYLOSING SPONDYLITIS

Background Secukinumab (fully human IgG1k anti-IL17A monoclonal antibody) significantly improved clinical signs and symptoms of active ankylosing spondylitis (AS) patients enrolled in a recent proof-of-concept (PoC) study. Magnetic resonance images (MRI) of these patients (pts) showed reduction of spinal inflammation at week (W) 6 and W28 after initiation of treatment. Objectives To evaluate a subgroup of pts (N=13) in the open label extension study, who had MRI assessments at baseline (BL), W28 and W94. Methods In the 28W PoC study, 27/30 pts had sequential MRI studies, 22 had received secukinumab 2x10 mg/kg administered intravenously 3 Ws apart, and 5 pts had been randomised to placebo. 20 patients entered the extension study, 13 having MRI data at W94. Of these 13, ten were treated with secukinumab and 3 with placebo in the core study. In the extension study, all received secukinumab 14x3 mg/kg administered 4 Ws apart. MRIs (T1 and STIR) were rescored for this study. ASspiMRI-a scores and the occurrence of vertebral edges (VE) inflammatory and fatty lesions were evaluated by an independent blinded reader. Results All 13 pts completed this exploratory MRI substudy. In pts receiving 2x10 mg/kg secukinumab followed by 14x3 mg/kg (n=10) secukinumab, spinal inflammation was reduced compared to BL at W28 –similar to the results of the core study– and this reduction was sustained up to W94 (Fig 1). Also in 3 pts who had initially received placebo switching to secukinumab at W28, MRI inflammation at W94 was reduced. Of the 920 VEs evaluated, the proportion of VEs with inflammatory lesions was reduced from 9.9% (n=91) at BL to 3.7% (n=34) at W28 and 3.6% (n=33) at W94. In contrast, the proportion of fatty lesions at BL (13.5%, n=124) remained largely unchanged at W28 (14.3%, n=132) and W94 (13.7%, n=126). Image/graph Conclusions MRI analysis suggests that the IL-17 inhibitor secukinumab may reduce spinal inflammation and this effect may be sustained for up to 2 years, using a lower maintenance dose compared to the induction regimen. Notably, secukinumab appeared not to have any influence on fatty lesions. This observation contrasts recent reports of AS pts treated with TNF-blockers. The potential impact of these preliminary findings on radiographic progression under secukinumab therapy will be studied in larger trials. Disclosure of Interest X. Baraliakos: None Declared, J. Braun Grant/research support from: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, UCB, Consultant for: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, UCB, Speakers bureau: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB, D. Laurent Shareholder of: Novartis, Employee of: Novartis, D. Baeten Grant/research support from: Abbott, MSD, Pfizer, Centocor, Jansen, Novartis, UCB, Eli Lilly, Boehringer, Roche, BMS., Consultant for: Abbott, MSD, Pfizer, Centocor, Jansen, Novartis, UCB, Eli Lilly, Boehringer, Roche, BMS., D. van der Heijde Grant/research support from: AbbVie, Amgen, AstraZeneca, BMS, Centocor, Chugai, Daiichi, Eli-Lilly, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, Vertex, Consultant for: AbbVie, Amgen, AstraZeneca, BMS, Centocor, Chugai, Daiichi, Eli-Lilly, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, Vertex, Employee of: Director of Imaging Rheumatology bv, J. Sieper Consultant for: Novartis, P. Emery: None Declared, I. McInnes Consultant for: Novartis, J. van Laar: None Declared, R. Landewe Grant/research support from: Abbott, Amgen, Centocor, Novartis, Pfizer, Rhoche, Schering-Plough, UCB, Wyeth, Consultant for: Abbott, Ablynx, Amgen, Astra-Zeneca, Bristol Myers Squibb, Centocor, Glaxo-Smith-Kline, Novartis, Merck, Pfizer, Rhoche, Schering-Plough, UCB, Wyeth, Employee of: director of Rheumatology Consultancy BV, Speakers bureau: Abbott, Amgen, Bristol Myers Squibb, Centocor, Merck, Pfizer, Rhoche, Schering-Plough, UCB, Wyeth, P. Wordsworth: None Declared, J. Wollenhaupt: None Declared, H. Kellner: None Declared, A. Wright Shareholder of: Novartis, Employee of: Novartis, F. Vandenhende: None Declared, K. Radford Employee of: Novartis contractor, B. Borah Employee of: Novartis, W. Hueber Shareholder of: Novartis, Employee of: Novartis

AB0632 Essdai domain evaluation of primary sjÖgren’s syndrome (PSS) patients enrolled in two independent poc studies indicates differential utility of domains for trial inclusion and composite endpoints in pss trials

Background According to international consensus, disease activity in primary Sjögren’s syndrome (pSS) patients shall be scored across 12 different domains according to the European Sjögren Syndrome Disease Activity Index (ESSDAI1). Two separate phase 2 proof-of-concept (PoC) studies using either BAFF receptor inhibitor (VAY736; ianalumab) or CD40 inhibitor (CFZ533) have recently been completed in comparable pSS cohorts with ESSDAI as the primary endpoint. Objectives To evaluate contribution of individual domains to composite ESSDAI scores at baseline and after interventional treatment with either VAY736 or CFZ533, or placebo. Aggregate efficacy and safety results were presented at previous meetings. 2 3 Methods Key inclusion criteria for both studies were fulfilling revised European US consensus criteria for pSS,4 autoantibody positivity, exclusion of secondary SS and ESSDAI ≥6. Permitted background medications in both trials included stable doses of hydroxychloroquine, methotrexate and prednisone ≤10 mg/d and also azathioprine in the CFZ533 trial. The primary endpoint was change in ESSDAI at week 12. Descriptive and principal component analysis were done with the goal to identify distinct subgroups of patients based on ESSDAI involvement at baseline (BL), and the relative importance of single domain contribution to overall ESSDAI responses were explored. Results 27 patients received single i.v. dose VAY736 10 mg/kg (n=12) or 3 mg/kg (n=6) or placebo, and 44 patients received multiple doses of CFZ533 10 mg/kg i.v. (n=21) or 3 mg/kg s.c. (n=8) or placebo. ESSDAI breakdown at BL showed a predominance of the articular, glandular, biological, constitutional and lymphadenopathy domains in both trials. Activity in more than 3 domains was recorded for 12/27 (44%) and 12/44 (27%) of patients in the VAY736 and CFZ533 studies, respectively. Principal component analysis identified the articular domain as the key component describing the difference between patients in their ESSDAI domains at BL. Two other domains that explained the variability between patients were the biological and glandular domains. Treatment effects in domains with low BL scores were more difficult to assess using ESSDAI. The majority of ESSDAI domains were not amenable to quantitative analysis, due to absence or low incidence at baseline. Conclusions The most frequently observed ESSDAI domain was articular involvement. Our results provide insights into ESSDAI domain frequency and distribution in the randomised controlled trial setting that may have implication for future trial design in pSS. Reference [1] Seror R, et al. (2016)Ann Rheum Dis75:382–389. [2] Dörner Th, et al. (2016)Arthritis Rheumatol68 Suppl 10; [3] Fisher B, et al. (2017) Arthritis Rheumatol69; Suppl 10; [4] Vitali C, et al. (2002) Ann Rheum Dis61:554–558. Disclosure of Interest T. Dörner Grant/research support from: Novartis, Charite CRO, Consultant for: Novartis, B. Fisher Consultant for: Novartis, Roche, BMS and AstraZeneca/MedImmune., X. Ren Employee of: Novartis Pharmaceuticals, P. Faerber Employee of: Novartis Pharmaceuticals, P. Gergely Shareholder of: Novartis Pharmaceuticals, Employee of: Novartis Pharmaceuticals, L. Mooney Employee of: Novartis Pharmaceuticals, Y. Li Shareholder of: Novartis Pharmaceuticals, Employee of: Novartis Pharmaceuticals, S. Oliver Shareholder of: Novartis Pharmaceuticals, Employee of: Novartis Pharmaceuticals, W. Hueber Shareholder of: Novartis Pharmaceuticals, Employee of: Novartis Pharmaceuticals, A. Wright Shareholder of: Novartis Pharmaceuticals, Employee of: Novartis Pharmaceuticals