DeBeurs.nl

harvester 10 mei 2018 15:25

1

quote:
harvester schreef op 10 mei 2018 15:17:
MOR 106 in conference call Morphosys (transcript from 8 May Source Finance.yahoo:

The next compound from our Proprietary Development segment, where we have seen great progress, is MOR106. This potential first-in-class antibody targeting IL-17C is currently in co-development with Galapagos for the treatment of atopic dermatitis. In February of this year, we presented results of the AAD meeting in San Diego from our Phase I study of MOR106 in patients suffering from moderate-to-severe atopic dermatitis.

In the study, MOR106 was shown to be generally well tolerated and we saw first signs of clinical activity. Although efficacy was just an exploratory endpoint of the trial and treatment duration of 4 weeks was relatively short, at the highest dose level, 5 out of 6 patients reached an improvement of at least 50% of their atopic dermatitis symptoms, the so-called EASI-50 score. We also observed a durable effect of the antibody lasting for more than 2 months after the last administration of the antibody. Based on these Phase I findings, we have decided together with Galapagos to move the program into Phase II and just 2 days ago, we reported the enrollment of the first patient. The so-called IGUANA trial will evaluate 3 different intravenous doses of MOR106 and 2 different dosing schemes in 180 patients with moderate-to-severe atopic dermatitis over a 12-week treatment period.

This is an area of major unmet medical need in which we expect to be transformed by biologic therapies, in the way other inflammatory indications such as psoriasis have been transformed in the last 2 decades. We also see potential for MOR106 in other indications.

Zoe Karamanoli, RBC Capital Markets, LLC, Research Division - Analyst [28]

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No problem. And on MOR106, if you could comment on the progress of the subcu formulation or when do you think that we can have an update on that?

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Simon E. Moroney, MorphoSys AG - Chairman of Management Board and CEO [29]

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Yes. That's progressing well. For an indication like this having a subcu formulation is basically a must. The molecules will behave in terms of the solubility and our ability to concentrate it for a subcu formulation, so that is on track. And we will, in the course of the clinical development plan, introduce a subcu formulation into clinical testing at some point in the future that's been integrated into the overall plan. And as and when we're ready to start that, we'll update you. But we don't see that as being a limiting factor in the overall development plan.

Lingus 10 mei 2018 22:25

1

RHB-104: bedreiging voor, of aanwinst naast de studie van filgotinib voor de ziekte van Crohn?
Ik zou zeggen aanwinst, als de hypothese van RedHill Biopharma (Israël) hout snijdt, dat "de ziekte van Crohn wordt veroorzaakt door Mycobacterium avium subspecies paratuberculosis (MAP) -infectie bij gevoelige patiënten." Een antibiotische benadering dus. De toekomst zal het leren. Overigens, misschien geen toeval dat een Israëlisch bedrijf onderzoek doet naar de ziekte van Crohn. Mensen die van Joodse afkomst zijn hebben twee tot vier keer meer kans om de ziekte te krijgen.

Bericht van 3 dagen geleden: RedHill Biopharma maakt laatste patiënt bekend voor primair eindpunt in RHB-104 Fase III-onderzoek voor de ziekte van Crohn
Top-line resultaten van de Fase III studie met RHB-104 voor de ziekte van Crohn worden verwacht binnen ongeveer drie maanden te worden aangekondigd.

Een paar stukken uit het persbericht, automatisch vertaald:
RHB-104 is een potentieel baanbrekende, door eigendomsrechten beschermde, oraal toegediende antibioticum-combinatietherapie met krachtige intracellulaire, antimycobacteriële en ontstekingsremmende eigenschappen. RHB-104 is gebaseerd op de hypothese dat de ziekte van Crohn wordt veroorzaakt door Mycobacterium avium subspecies paratuberculosis (MAP) -infectie bij gevoelige patiënten.

Bovendien loopt een open-label extensie Fase III studie (MAP US2 studie) om de veiligheid en werkzaamheid van RHB-104 te evalueren bij patiënten die aan actieve ziekte van Crohn blijven (CDAI = 150) na 26 weken geblindeerde onderzoekstherapie in de lopende Fase III MAP-studie in de VS.

Er zijn waarschijnlijk aanvullende klinische onderzoeken nodig om een ??Amerikaanse New Drug Application (NDA) voor RHB-104 te ondersteunen, indien ingediend. Als de studieresultaten van MAP US positief zijn, zal RedHill een ontmoeting hebben met belangrijke opinieleiders en de Amerikaanse Food and Drug Administration (FDA) om het gegevenspakket te presenteren en het voorkeurspad naar mogelijke goedkeuring te bespreken.

Bronnen:
finance.yahoo.com/news/redhill-biopha...
nl.wikipedia.org/wiki/Ziekte_van_Crohn
www.redhillbio.com/crohns-disease

Rekyus 11 mei 2018 08:06

1

De nieuwe trend: bestaande antibiotica in een vaste verhouding combineren met het oog op grotere werkzaamheid. Zo zijn de samenstellende actieve bestanddelen van RHB-104 eerder afzonderlijk gebruikt tegen door Mycobacteriën veroorzaakte ziektes. Het gaat bij RHB-104 om de combi clarithromycine, clofazimine en rifabutine in de verhouding 63-7-30.

NielsjeB 14 mei 2018 16:06

3

EULAR 2018, 12-15 juni Amsterdam

EFFICACY OF THE HIGHLY SELECTIVE ADAMTS-5 INHIBITOR GLPG1972 IN THE RAT MENISCECTOMY MODEL

web.eular.org/EULAR_Production/2018_A...

NielsjeB 14 mei 2018 16:31

0

Ik had trouwens ook een update van de DARWIN3 extension safety/efficacy data verwacht, ik zie helemaal geen enkele abstract over filgotinib. Vreemd.

NielsjeB 14 mei 2018 17:49

4

Met dank aan een behulpzaam iemand.

SAT0200

LONG TERM SAFETY OF FILGOTINIB IN THE TREATMENT OF RHEUMATOID ARTHRITIS: WEEK 108 DATA FROM A PHASE 2B OPEN-LABEL EXTENSION STUDY

R. Westhovens1,*, R. Alten2, K. Winthrop3, M. Greenwald4, L. Ponce5, F. Enriquez-Sosa6, M. Stanislavchuk7, M. Mazur8, A. Spindler9, R. Cseuz10, N. Nikulenkova11, M. Glowacka-Kulesz12, I. Szombati13, A. Dudek14, N. Mozaffarian15, J. Greer15, R. Kunder15, D. An15, P. Harrison16, A. Van der Aa16, A. Kavanaugh17, M. Genovese18

1University Hospitals, Leuven, Belgium, 2Schlosspark Klinik, University Medicine, Berlin, Germany, 3Oregon Health and Science University, Portland, 4Desert Medical Advances, Palm Springs, United States, 5Cons. Priv, Temuco, Chile, 6Clinstile SA de CV , Col Roma, Mexico, 7Vinnitsya Reg Clin Hosp, Vinnitsya, Ukraine, 8IMSP Inst. de Cardiologie, Chisinau, Moldova, Republic of, 9Centro Méd. Priv. Reum, Tucumau, Argentina, 10Revita Reumatológiai Kft, Budapest, Hungary, 11Vladimir Reg Clin Hosp, Shosse, Russian Federation, 12Silesiana Centrum Medyczne, Wroclawska, Poland, 13Qualiclinic Kft, Budapest, Hungary, 14AMED Medical Center, Warsaw, Poland, 15Gilead Sciences, Inc, Foster City, United States, 16Galapagos NV, Mechelen, Belgium, 17University of California, San Diego, La Jolla, 18Stanford University School of Medicine, Palo Alto, United States

Background: Filgotinib (FIL) is an orally administered, selective inhibitor of Janus Kinase 1 (JAK1) in Phase 3 development for the treatment of rheumatoid arthritis (RA).

Objectives: Assess the long-term safety and efficacy of FIL in the DARWIN 3 open-label extension study.

Methods: Two 24-week Phase 2b studies were completed in patients (pts) with moderately to severely active RA (DARWIN 1, DARWIN 2; Ref 1, 2). Following study completion, pts were offered FIL in the ongoing DARWIN 3 extension study: 100 mg QD (US males), 200 mg QD, or 100 mg BID. This report summarizes safety data from the first dose of FIL in the DARWIN program to 11 Oct 2017 and efficacy data from the DARWIN 3 baseline visit to Week 108, which all ongoing pts have completed.

Results: Of 877 pts, 790 (90%) completed DARWIN 1/2, and 739 (84%) enrolled in DARWIN 3; 603 (82%) were female, mean age 53 years. At analysis, 491/739 (66%) were on study. Cumulative patient years of exposure (PYE) was 1931, median time on study drug was 1072 days. Key data are summarized in Table 1. 87%, 68%, and 48% of pts achieved ACR20/50/70, respectively, and 72% achieved DAS28-CRP =3.2 (by observed case analysis).

Conclusions: Filgotinib long-term RA data demonstrates an acceptable safety and durable efficacy profile.

References: 1. Westhovens R, et al. Ann Rheum Dis 2017;76:998-1008; 2. Kavanaugh A, et al. Ann Rheum Dis 2017;76:1009-1019.

Disclosure of Interest: R. Westhovens Grant/research support from: Galapagos and Celltrion, Roche and BMS, Consultant for: Galapagos and Celltrion, Roche and BMS, R. Alten Grant/research support from: Galapagos/Gilead, K. Winthrop Consultant for: Pfizer, Lilly, Galapagos, Gilead, AbbVie, M. Greenwald Grant/research support from: Gilead, L. Ponce: None declared, F. Enriquez-Sosa: None declared, M. Stanislavchuk: None declared, M. Mazur: None declared, A. Spindler: None declared, R. Cseuz: None declared, N. Nikulenkova: None declared, M. Glowacka-Kulesz: None declared, I. Szombati: None declared, A. Dudek: None declared, N. Mozaffarian Shareholder of: Gilead, Employee of: Gilead, J. Greer Shareholder of: Gilead, Employee of: Gilead, R. Kunder Shareholder of: Gilead, Employee of: Gilead, D. An Shareholder of: Gilead, Employee of: Gilead, P. Harrison Shareholder of: Galapagos, Employee of: Galapagos, A. Van der Aa Shareholder of: Galapagos, Employee of: Galapagos, A. Kavanaugh Consultant for: Galapagos, M. Genovese Consultant for: Gilead, Galapagos, Abbvie, Lilly, Pfizer

DOI: 10.1136/annrheumdis-2018-eular.1947

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Bijlage:

seren 14 mei 2018 17:54

1

Dank NielsjeB en degene die behulpzaam was

[verwijderd] 14 mei 2018 18:00

0

'Conclusions: Filgotinib long-term RA data demonstrates an acceptable safety and durable efficacy profile.

Hoe interpreteer je in dit kader 'acceptable'? Klinkt als voldoende maar niet als uitstekend.

NielsjeB 14 mei 2018 18:00

2

SAT0231

EFFECTS OF THE JAK1-SELECTIVE INHIBITOR FILGOTINIB ON GENE EXPRESSION PROFILE IN BLOOD OF PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS

P. C. Taylor1, J. Tarrant2,*, L. Zhao2, Y. Gindin2, A. Mirza2, P. Harrison3, C. Tasset3, R. Galien4, A. Van der Aa3, B. Downie2

1Botnar Research Centre, Nuffield Dept Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom, 2Gilead Sciences, Inc., Foster City, United States, 3Galapagos NV, Mechelen, Belgium, 4Galapagos SASU, Romainville, France

Background: Filgotinib (FIL), an oral selective JAK1 inhibitor, has shown good safety and efficacy in two phase 2b studies (background methotrexate (MTX, DARWIN 1) and as monotherapy (DARWIN 2)) in active rheumatoid arthritis (RA) patients with inadequate response to MTX1,2. We conducted a large-scale RNA sequencing study of genes expressed in blood samples from these studies.

Objectives: Identify RA-associated gene transcripts that are altered in response to FIL treatment.

Methods: PAXgene blood samples from 242 RA patients receiving either a stable dose of MTX and placebo (PBO) or FIL 200mg once daily (QD, DARWIN 1); or PBO, FIL 100mg, or 200mg monotherapy QD (DARWIN 2), were collected and analyzed at baseline, week 1 and/or week 12. RNA in whole blood was sequenced (Illumina HiSeq 2500) after globin depletion. Differential gene expression analysis was performed on all time-paired data after subtracting gene expression changes in the PBO group. Spearman’s rank correlation of gene expression to time, dose, and disease activity score (DAS28) were calculated on samples without missing values. A false-discovery rate (FDR) of 10% was applied for all analyses

Results: Top-ranked gene sets positively associated with DAS28 disease activity at baseline over both studies included interferon alpha (IFN-a) and IFN gamma (IFN-?) response, IL6/JAK/STAT3 signaling, and toll-like receptor signaling pathways (FDR<10%). Of 197 genes that positively correlated with disease score (increased gene expression with increased DAS28, FDR<10%), 117 (59%) trended toward reduced expression at 12 weeks with FIL in both studies. These genes were enriched in pathways which included granulocyte and macrophage activation. Conversely, of 256 genes negatively correlated with disease score (FDR<10%), 169 (66%) trended toward increased expression post-FIL (Figure 1). Of 14724 genes expressed at >1CPM in at least 5% of the samples, 607 were differentially expressed following FIL treatment in either DARWIN1 or DARWIN2 with 48 genes significant in both studies (FDR<10%). Genes reaching significance in at least one study showed consistent magnitude and direction of change in both studies and were enriched in JAK/STAT, innate and adaptive immunity, and autoimmune associated pathways. CISH, SOCS2, SOCS3, VWA5a, APCDD1, DNASE1L3, and PIM3 correlated with both duration of treatment and FIL dose (FDR<10%). CISH and SOCS confirm JAK pathway modulation.

Figure 1. Heatmap of 453 DAS28-correlated genes and the corresponding change in gene expression with 12 wk FIL in Phase2b RA studies

Conclusions: RA patients treated with FIL show reproducible changes in gene expression consistent with modulation of JAK/STAT signaling and innate and adaptive immunity. FIL was shown to partially reverse the dysregulated gene expression profile associated with baseline DAS28 score, consistent with the efficacy observed in RA patients.

References: 1. Kavanaugh A, et al. Ann Rheum Dis 2017;76:1009–19; 2. Westhovens R, et al. Ann Rheum Dis 2017;76:998-1008

Disclosure of Interest: P. Taylor Consultant for: AbbVie, Biogen, BMS, Galapagos, GSK, Janssen, Lilly, MSD, Novartis, Sandoz, UCB;, J. Tarrant Employee of: GSI Employee, L. Zhao Employee of: GSI Employee, Y. Gindin Employee of: GSI Employee, A. Mirza Employee of: GSI Employee, P. Harrison Employee of: GLPG Employee, C. Tasset Employee of: GLPG Employee, R. Galien Employee of: GLPG Employee, A. Van der Aa Employee of: GLPG Employee, B. Downie Employee of: GSI Employee

DOI: 10.1136/annrheumdis-2018-eular.3759

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NielsjeB 14 mei 2018 18:02

1

AB0484

MONOTHERAPY WITH FILGOTINIB, A JAK1-SELECTIVE INHIBITOR, REDUCES DISEASE SEVERITY AND ALTERS IMMUNE CELL SUBSETS IN THE NZB/W F1 MURINE MODEL OF LUPUS

C. Pohlmeyer1,*, Z.-H. Cui1, P. Han1, A. S. Clarke1, R. M. Jones1, N. Mollova1, I. Mikaelian1, S. Zaboli1, A. Shauf1, J. A. Di Paolo1

1Gilead Sciences, Inc, Foster City, United States

Background: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by immune system hyperactivation leading to the production of autoantibodies and immune attack on multiple organs including the skin and kidneys. High levels of type I interferons (IFNa/b) alter the activation state of immune cell populations and have been identified as a risk factor for SLE. Antibody blockade of the interferon alpha receptor (IFNAR) has demonstrated clinical efficacy in a Phase 2b study in SLE, and validates targeting this pathway in SLE1. Janus kinase 1 (JAK1) is critical for mediating downstream signaling of type I IFNs. Inhibition of JAK1, therefore, is anticipated to reduce IFN signaling, activation of immune cell subsets, and SLE disease activity. The JAK1 selective inhibitor filgotinib (FIL) is currently being evaluated in three proof-of-concept Phase 2 studies in SLE-like diseases.

Objectives: To characterize the efficacy and mechanism-of-action of FIL in the NZB/W F1 spontaneous mouse model of lupus in a therapeutic setting.

Methods: FIL was tested in the NZB/W F1 model of lupus at two concentrations (0.05% and 0.1%) formulated in chow and administered ad libitum from weeks 28-40. Cyclophosphamide (CP) was used as a positive control at 5 mg/kg, once daily, i.p. Efficacy was determined by changes in proteinuria, renal histopathology, and survival. Splenic cell populations were analyzed by flow cytometry at study termination at week 40 to measure changes in immune cell subsets in diseased versus non-diseased mice and following FIL treatment. An in vitro murine whole blood pSTAT1 assay and PK exposure data were used to assess target coverage in the model.

Results: In the NZB/W model, FIL showed a dose-dependent decrease in proteinurea with a concomitant reduction in BUN levels, renal inflammation, improved glomerular morphology, and increased survival (Table 1). Diseased mouse spleens had decreased frequencies of naive T cells, increased frequencies of CD11+ dendritic cells (DCs), and an increased ratio of memory:naive T cells versus non-diseased mice. FIL treatment showed a dose-responsive reversal of these populations toward non-diseased levels. FIL inhibited in vitro IFNa-stimulated pSTAT1 signaling in T cells. Calculated JAK target coverage of pSTAT1 inhibition was similar to that observed in human studies at clinical doses.

Table 1: Efficacy scores in the NZB/W F1 model

a Urine score AUC (week 28-40)

b Includes: glomerular diameter, protein casts, interstitial inflammation, and vasculitis

p-values comparing % changes between treatment and placebo groups: *p<0.05

Conclusions: FIL demonstrated efficacy in the NZB/W F1 murine model of lupus with an alteration of splenic immune cell subsets affected by type I IFNs toward non-diseased levels. This data provides the basis for the evaluation of FIL as monotherapy in the currently ongoing Phase 2 studies in lupus-related diseases.

References: 1Furie R, et al. Arthritis Rheumatol 2017; 69: 376-386.

Disclosure of Interest: C. Pohlmeyer Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, Z.-H. Cui Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, P. Han Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, A. Clarke Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, R. Jones Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, N. Mollova Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, I. Mikaelian Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, S. Zaboli Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, A. Shauf Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc, J. Di Paolo Shareholder of: Gilead Sciences, Inc, Employee of: Gilead Sciences, Inc

DOI: 10.1136/annrheumdis-2018-eular.3367

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NielsjeB 14 mei 2018 18:02

1

AB0492

JAK-INHIBITION WITH PEFICITINIB AND FILGOTINIB IN FIBROBLAST-LIKE SYNOVIOCYTES IN RHEUMATOID ARTHRITIS.

M. Diller1,*, M.-L. Hülser1, R. Hasseli1, S. Rehart2, U. Müller-Ladner1, E. Neumann1

1Dept. of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus-Liebig-University, Gießen, 2Dept. of Orthopaedics and Trauma Surgery, Agaplesion Markus Hospital, Frankfurt, Germany

Background: With the approval of the Janus kinase inhibitors (JAKi) Tofacitinib and Baricitinib for the treatment of rheumatoid arthritis (RA) in the European Union (EU), the opportunities for a successful therapy were extended by a new substance class. Other JAKi like Peficitinib and Filgotinib are currently examined in clinical trials. Peficitinib is a pan-JAKi, whereas the other substances differ clearly in the capability to block the four members of the Janus kinase family. It is unclear, if the new substances offer an additional benefit in RA treatment in comparison to the approved JAKi.

Objectives: This study characterized the effect of the different JAKi on inflammatory response of activated fibroblast-like synoviocytes from patients with RA (RA-FLS).

Methods: RA-FLS were isolated from synovial tissue of patients with RA undergoing joint replacement surgery. The cells were pretreated for 2 h with different concentrations of JAKi or vehicle control and then stimulated with IL1-ß (10 or 20 ng/ml) or Oncostatin M (OSM, 100 ng/ml). After the indicated time (17-24 h), the supernatants were collected and the concentrations of IL-6 and MMP-3 were measured by ELISA. An assay combining the measurement of cell viability, cytotoxicity and apoptosis was performed to exclude effects of JAKi caused by cell toxicity.

Results: To detect the most effective JAKi in blocking the inflammatory response induced by IL1-ß, RA-FLS were first pretreated with different JAKi for 2 h with concentrations of 1 µM and 10 µM and then additionally stimulated with IL1-ß (20 ng/ml) for 18 h. Even at the highest concentration of 10 µM Tofacitinib and Baricitinib did not change the IL-6 levels, whereas Peficitinib and Filgotinib reduced the IL-6 release at 10 µM. Tofacitinib and Baricitinib reduced the cytokine release if the RA-FLS were stimulated with OSM, a factor directly inducing the JAK-dependent IL-6-pathway (n=3).

To obtain a dose-response curve for the clinically relevant range of concentrations between 0.01 µM and 5 µM, RA-FLS were pretreated with Filgotinib and Peficitinib for 2 h and then stimulated with IL1-ß (10 ng/ml) for 17 h. In contrast to Filgotinib, Peficitinib at 5 µM caused a reduction of IL-6 levels of 66% compared to control with IL1-ß (p<0.01, n=5). The MMP-3 release was decreased by both substances at 5 µM: In comparison to the control with IL1-ß, Peficitinib caused a reduction of 92% (p<0.0001, n=5) whereas Filgotinib only reduced the levels by 43% (p<0.05, n=3). Furthermore, Peficitinib at 1 µM decreased the MMP-3 release by 46% (p<0.01).

The treatment with Peficitinib did not affect the viability, cytotoxicity or apoptosis of RA-FLS (n=3). Therefore, the effects of Peficitinib on the inflammatory response were not caused by cell death.

Conclusions: Peficitinib reduced the release of proinflammatory cytokines and of matrix metalloproteinases after activation of RA-FLS with IL1-ß and appeared to be superior to Tofacitinib and Baricitinib in targeting the pro-inflammatory and matrix destructive properties of RA-FLS.

Disclosure of Interest: None declared

DOI: 10.1136/annrheumdis-2018-eular.2182

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NielsjeB 14 mei 2018 18:03

1

quote:
Lechajiem schreef op 14 mei 2018 18:00:
'Conclusions: Filgotinib long-term RA data demonstrates an acceptable safety and durable efficacy profile.

Hoe interpreteer je in dit kader 'acceptable'? Klinkt als voldoende maar niet als uitstekend.

Dit is een gebruikelijke term in wetenschappelijke publicaties. Zoek maar even in bijv. de ABT-494/upa publicaties.

NielsjeB 14 mei 2018 18:04

0

FRI0539

A SAFETY, TOLERABILITY, PHARMACOKINETICS (PK) AND PHARMACODYNAMICS (PD) STUDY WITH INCREASING ORAL DOSES OF GLPG1972 ADMINISTERED DAILY FOR 29 DAYS SHOWS A STRONG BIOMARKER EFFECT IN PATIENTS WITH KNEE AND/OR HIP OA

H. M. Deckx1,*, S. Hatch1, M. Robberechts1, S. Dupont2, J. Desrivot3, H. Coleman4, S. Larsson5, A. Struglics5, E. M. van der Aar1, A. Fiew1

1Clinical Development, Galapagos NV, Mechelen, Belgium, 2Translational Science, 3Galapagos SASU, Romainville, France, 4CRU, Covance, Daytona Beach, United States, 5Clinical Sciences , Lund University, Lund, Sweden

Background: Osteoarthritis (OA) is characterized by structural changes of the joint, of which degradation of articular cartilage is one of the major signs1. The main proteoglycan component of the extracellular matrix of articular cartilage is aggrecan. GLPG1972 as a potent and selective inhibitor of ADAMTS-5, a key aggrecan-cleaving enzyme involved in cartilage degradation, is being developed as a potential disease-modifying OA drug (DMOAD). Aggrecan cleavage by ADAMTS-5 results in release of N-terminal ARGS neo-epitope fragments of which serum levels significantly decreased in healthy subjects treated with GLPG1972 during 14 days in a previous study².

Objectives: To assess safety, tolerability, PK and PD (serum ARGS-aggrecan levels) during and following administration of GLPG1972 in patients with knee and/or hip OA.

Methods: This was a single center, randomized, double-blind, placebo-controlled, age and gender stratified, ascending dose Phase Ib study, with three semi-sequential cohorts of 10 patients each, randomized to active drug or placebo in a 4:1 ratio. Doses tested were once daily 100, 200 and 300 mg. Treatment duration was 29 days. Patients had follow-up visits 14 and 21 days after last dosing for additional PD assessments. Methods for PD have been described previously³.

Results: Thirty patients were included. Of these, 24 patients (M/F rate 8/16, 14 aged 50-64 and 10 aged 65-75) received active medication.

All adverse events (AE) were mild and transient. No serious AEs were reported during the study; one female patient in the 300-mg group was discontinued after 15 days of treatment due to drug-related elevated transaminase values which returned to normal 9 days later while her bilirubin levels remained normal. There were no overall trends in lab abnormalities over time or significant changes in vital signs, ECG and Holter parameters.

Steady state in plasma exposure was reached after 3 days of dosing. Exposure increased dose-proportionally. Mean serum ARGS levels (SEM) decreased steadily over time in all patients receiving GLPG1972: -40% (2.9), -46% (4.5) and -53% (2.8) at day 15 compared to baseline in the 100, 200 and 300 mg group respectively. These levels remained stable until last dose on day 29, then consistently returned to pre-dose levels for all groups 14 and 21 days after last dose. Placebo group levels remained unchanged.

Conclusions: When administered daily for 29 days in patients with knee and/or hip OA, GLPG1972 at oral doses of 100, 200 and 300 mg q.d. was generally well tolerated and safe. Serum ARGS levels, as a marker for target engagement and potential proxy of cartilage degradation, showed a dose-dependent decrease over time up to 53% below baseline in the 300 mg group. These PK-PD findings are consistent with what we observed in a previous study in healthy subjects² and reinforce the rationale for developing GLPG1972 as a DMOAD.

References:

1. Hunter, D. J., et al. Curr. Opin. Rheumatol. 2009, 21, 110–117

2. van der Aar E, et al. Arthritis Rheumatol. 2017; 69 (suppl 10).

3. Larsson et al. Osteoarthritis Cartilage 2014, 22(2):242-9

Disclosure of Interest: H. Deckx Employee of: Galapagos NV, Belgium, S. Hatch Consultant for: Galapagos NV, Belgium, M. Robberechts Employee of: Galapagos NV, Belgium, S. Dupont Employee of: Galapagos SASU, France, J. Desrivot Employee of: has been employee of Galapagos SASU, France, H. Coleman Paid instructor for: Covance has been contracted by Galapagos NV to conduct the study, S. Larsson: None declared, A. Struglics: None declared, E. van der Aar Employee of: Galapagos NV, Belgium, A. Fiew Employee of: Galapagos NV, Belgium

DOI: 10.1136/annrheumdis-2018-eular.3101

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NielsjeB 14 mei 2018 18:10

0

SAT0236

LONG-TERM SAFETY AND EFFICACY OF UPADACITINIB (ABT-494), AN ORAL JAK-1 INHIBITOR IN PATIENTS WITH RHEUMATOID ARTHRITIS IN AN OPEN LABEL EXTENSION STUDY

M. C. Genovese1,*, J. Kremer2, S. Zhong3, A. Friedman3

1Stanford Univ, Palo Alto, 2Albany Medical College, Albany, 3AbbVie Inc., North Chicago, United States

Background: Upadacitinib (UPA, ABT-494) is a selective, oral JAK-1 inhibitor studied in two phase 2 randomized controlled trials (RCTs) in patients (pts) with rheumatoid arthritis (RA).

Objectives: We assessed UPA safety and efficacy in BALANCE-EXTEND, an ongoing, combined open-label extension (OLE) of the phase 2 RCTs.

Methods: Pts completing the two 12-week RCTs (in TNF-IR and (MTX-IR pts)1,2 could enter the OLE. Pts switched to 6 mg UPA from their RCT dose of UPA 3, 6, 12, 18 mg twice daily (BID), 24 mg once daily (QD) or Placebo. A dose increase to 12 mg BID was required for pts with <20% improvement in both SJC and TJC on 6 mg BID (at wk 6 or 12), and permitted for pts not meeting CDAI LDA. Pts without 20% improvement in SJC and TJC 6 wks after escalation, or at any 2 consecutive visits, were discontinued. The dose was decreased to 6 mg BID only in pts with a safety concern or intolerability. Pts are grouped as: Never-titrated (on 6 mg BID throughout); Titrated-up (from 6 to 12 mg BID); Titrated-up and back down (to 6 mg BID). After Jan 2017, the 6 and 12 mg BID doses were replaced by 15 and 30 mg QD extended-release equivalents currently being studied in phase 3. Data up to Jan 13 2017 are reported. Adverse events (AE) per 100 yrs of pt exposure (PY) are summarized starting from day 1 of OLE. Efficacy is assessed by ACR20/50/70 and LDA (by DAS28-CRP and CDAI), and observed data are presented up to Wk 72 of OLE due to sample size consideration.

Results: Out of 516 pts who completed the 2 RCTs, 494 entered the OLE, 493 were dosed, 328 (66.5 %) were never-titrated, 150 (30.4%) were titrated-up, and 15 (3%) were titrated-up and back down; 150 pts (30.4%) were discontinued [42 (8.5%) withdrew consent, 37 (7.5%) due to AE and 24 (4.9%) due to lack of efficacy]. Mean exposure to UPA was 525.4 ± 221.4 days (range 1-961 days), and cumulative exposure was 725.1 PY (Table). The E/100PY for any AE in the OLE (170.5) were lower than for the RCTs in the TNF-IR (697.9, 48 PY) and MTX-IR (408.4, 54.6 PY) study populations. The E/100PY were 2.3 for serious infection, 3.7 for herpes zoster, 0.8 for malignancies excluding non-melanoma skin cancer, and 0.7 for adjudicated cardiovascular events. There were 2 deaths: one sudden death (adjudicated as undetermined or unknown cause of death) and one death due to Hodgkin’s lymphoma. Changes from baseline in laboratory parameters were consistent with observations from phase 2 RCTs. For those pts completing Wk 72, efficacy was maintained in pts on 6 mg BID UPA from day 1 of OLE (never-titrated); 55% pts met ACR70 and 83% were in LDA by DAS28-CRP and CDAI based on as observed data (Table).

Conclusions: The safety profile of UPA remained consistent with that expected for an RA population treated with JAKi. Efficacy responses were maintained up to 72 wks in pts on 6 mg BID UPA in the OLE.

References: 1. Kremer et al. 2016, Arth & Rheum;68:2867

2. Genovese et al. 2016, Arth & Rheum;68:2857

Acknowledgements: AbbVie and the authors thank the patients, study sites and investigators who participated in this clinical trial. AbbVie Inc was the study sponsor, contributed to study design, data collection, analysis & interpretation, and to writing, reviewing, and approval of final version. Medical writing support was provided by Naina Barretto, PhD, of AbbVie, Inc.

Disclosure of Interest: M. Genovese Grant/research support from: AbbVie, Lilly, Astellas, Pfizer, Galapagos, Gilead, Consultant for: AbbVie, Lilly, Astellas, Pfizer, Galapagos, Gilead, J. Kremer Shareholder of: Corona, Grant/research support from: AbbVie, Lilly, Novartis, Pfizer, MedImmune, Sanofi, and Regeneron, Consultant for: AbbVie, Lilly, Novartis, Pfizer, MedImmune, Sanofi, and Regeneron, Employee of: Corona, S. Zhong Shareholder of: AbbVie, Employee of: AbbVie, A. Friedman Shareholder of: AbbVie, Employee of: AbbVie

DOI: 10.1136/annrheumdis-2018-eular.7021

b-com.mci-group.com/Abstract/Statisti...

Bijlage:

NielsjeB 14 mei 2018 18:15

0

Abstracts van ABT-494/upadacitinib zijn er wat veel, zelf even zoeken op 'upadacitinib' op b-com.mci-group.com/AbstractList/EULA...

NielsjeB 14 mei 2018 19:46

2

quote:
NielsjeB schreef op 14 mei 2018 16:06:
EULAR 2018, 12-15 juni Amsterdam

EFFICACY OF THE HIGHLY SELECTIVE ADAMTS-5 INHIBITOR GLPG1972 IN THE RAT MENISCECTOMY MODEL

web.eular.org/EULAR_Production/2018_A...

Voor de volledigheid.

OP0258

EFFICACY OF THE HIGHLY SELECTIVE ADAMTS-5 INHIBITOR GLPG1972 IN THE RAT MENISCECTOMY MODEL

L. Lepescheux1, P. Clement-Lacroix1, D. Merciris1, S. Meurisse1, M. Borgonovi1, C. Cottereaux1, P. Mollat1, F. Brebion1, R. Gosmini1, F. De Ceuninck2, I. Botez2, E. van der Aar3, T. Christophe3, N. Vandervoort3, R. Blanqué1, D. Comas1, P. Deprez1, D. Amantini1,*

1GALAPAGOS SASU, Romainville, 2Institut de Recherches Servier, Suresnes, France, 3Galapagos NV, Mechelen, Belgium

Background: Aggrecan cleavage is an early process in cartilage degradation observed in OA. As a result, aggrecanase inhibition is an attractive therapeutic strategy for the treatment of OA.1a,1b A disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) is an aggrecanase playing a key role in the catabolic events leading to OA.2 We previously described the pharmacological characterization of GLPG1972, a potent, selective and orally bioavailable ADAMTS-5 inhibitor showing anti-catabolic activity in cartilage explants and displaying disease-modifying OA drug (DMOAD) potential in the destabilization of the medial meniscus (DMM) model in mice.3a,3b

Objectives: In this communication we report the activity of GLPG1972 in a second model of surgery-induced OA, the rat meniscectomy (MNX) model.4

Methods: OA pathology was induced by meniscectomy in the right hind leg of each rat. On day 1 post surgery, rats were randomly assigned to a treatment group (n=20 per group) according to their body weight. GLPG1972 was administered orally over 3 weeks at dose levels of 10, 25 and 50 mg/kg b.i.d. At sacrifice, the right tibias were collected and processed for histological analysis. OA development in the tibial plateau was evaluated using the OARSI score. The following structural parameters were measured by imaging histomorphometry analysis: subchondral bone plate thickness, proteoglycan content and fibrillation index. Blood samples were collected at steady state at predose, 1, 3 and 6 h postdose for the determination of GLPG1972 plasma concentrations.

Results: Three weeks post-surgery, a significant reduction in OARSI score compared to vehicle-treated rats was observed with GLPG1972 at 25 and 50 mg/kg b.i.d. (-24% and -23%, respectively). Treatment with GLPG1972 also resulted in a significant reduction in cartilage fibrillation as of 25 mg/kg b.i.d. and prevented proteoglycan loss and subchondral bone plate thickening at all doses. At 25 mg/kg b.i.d. GLPG1972 average plasma concentration over 24 h was found to be in line with the value observed in other rat MNX experiments (385 ng/mL). GLPG1972 bio-distribution in the target tissue was also determined: the average condyle to plasma ratio was found to be 0.14.

Conclusions: Oral dosing with GLPG1972 in rat MNX model resulted in significant chondroprotection confirming the DMOAD potential of GLPG1972. A Phase 1 first-in-human study was successfully completed with GLPG1972 (NCT02612246), and a dose-escalation Phase 1b study in OA patients is ongoing (NCT03311009). GLPG1972 is a promising OA drug candidate and a Phase 2 program is currently under preparation.

References: 1) a) Little CB et al., J Clin Invest 2007, 117:1627–1636; b) Larsson S et al., Arthritis Res Ther 2009, 11:R92.

2) Fosang AJ, Osteoarthritis Cartilage 2015;23(8):1231-1232.

3) a) Clement-Lacroix P et al., OARSI congress 2017; b) Clement-Lacroix P et al., EULAR congress 2017

4) Little CB and Smith MM, Curr RheumatoloRev 2008, 4:175-182.

Disclosure of Interest: None declared

DOI: 10.1136/annrheumdis-2018-eular.2610

b-com.mci-group.com/Abstract/Statisti...

HansGarrincha 14 mei 2018 21:24

1

Peficitinib van Astellas is nieuw voor mij: zo te lezen een JAK-1, 2 en 3 inhibitor, dus minder selectief, maar het komt wel goed uit de bovenstaande abstract, JAK-INHIBITION WITH PEFICITINIB AND FILGOTINIB IN FIBROBLAST-LIKE SYNOVIOCYTES IN RHEUMATOID ARTHRITIS.

HansGarrincha 14 mei 2018 21:34

3

SAT0219

UPADACITINIB IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS AND INADEQUATE RESPONSE OR INTOLERANCE TO BIOLOGICAL DMARDS: A PHASE 3 RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY OF A SELECTIVE JAK1 INHIBITOR

M. C. Genovese1,*, R. Fleischmann2, B. Combe3, S. Hall4, Y. Zhang5, Y. Zhou5, M. F. Mohamed5, S. Meerwein6, A. L. Pangan5

1Stanford Univ, Palo Alto, 2Univ of Texas Southwestern, Dallas, United States, 3Montpellier Univ, Montpellier, France, 4Monash Univ, Cabrini Health & Emeritus Res, Malvern, Australia, 5AbbVie, N Chicago, United States, 6AbbVie Deutschland, Ludwigshafen, Germany

Background: Upadacitinib (UPA), an oral, selective JAK1 inhibitor was effective in ph 2 trials in rheumatoid arthritis (RA) pts with inadequate response (IR)/intolerance to csDMARDs and bDMARDs.

Objectives: To evaluate safety and efficacy of UPA in bDMARD-IR pts on stable background csDMARDs.

Methods: Pts with active RA (TJC=6, SJC=6; hsCRP=3 mg/L) were randomized 2:2:1:1 to receive UPA 15mg or 30mg once daily (QD) or PBO for 12 wks followed by UPA 15mg or 30mg QD starting at Wk 12. The primary endpoints were the proportion of pts achieving ACR20 (for FDA) and the proportion achieving DAS28CRP=3.2 (for EMA) at Wk 12 (NRI).

Results: Of 499 randomized pts, 498 received study drug; 451 (90.6%) and 419 (84.1%) completed Wks 12 and 24 respectively. BL disease characteristics indicated long-standing severe, refractory disease: (means) duration since diagnosis 13 yrs; DAS28CRP, 5.8; TJC68, 27.9; SJC66, 16.8; 53% experienced =2 prior bDMARDs. At Wk 12, more pts (p<.001) on UPA 15 and 30 vs PBO achieved the primary endpoints (ACR20: 64.6% and 56.4% vs 28.4%; DAS28CRP=3.2: 43.3% and 42.4% vs 14.2%) and other secondary endpoints (Table). Among pts with IR to multiple bDMARDs/MOAs, and pts with lack of efficacy for a-IL-6, the proportions achieving ACR20 on UPA vs PBO were comparable to the overall treated population. By Wk 1, more pts achieved ACR20 on UPA 15 and 30 vs PBO (27.4% and 24.8% vs 10.7%, p<.001). At Wk 12, significant improvements were observed on UPA 15 and 30 vs PBO for HAQ-DI (LSM change -0.39 and -0.42 vs -0.17, p<.001). At Wk 24, responses were similar or greater for pts originally on UPA and comparable for pts who switched to UPA after 12 wks of PBO.

Up to wk 12, the frequency of AEs was comparable for PBO and UPA 15, but higher for UPA 30 (Table). Overall AE rates (E/100 PY) through Wk 24 for UPA 30 were similar or slightly higher vs UPA 15; more AEs led to study drug discontinuation in UPA 30. Occurrence of infections was similar in all arms, but there were more serious infections and herpes zoster cases in UPA 30. Malignancies were reported in 3 pts over 12 wks with 1 additional case through Wk 24. Through Wk 12, pulmonary embolism (PE) was reported in 2 pts (1 each on UPA 15 and 30), none with DVT; through Wk 24, PE were reported in 4 more pts (UPA 15: 3, 1 of whom also had a DVT; UPA 30:1). All had risk factors for DVT/PE. 2 deaths were reported (UPA30: 1 before Wk 12; UPA 15:1 after Wk12).

Conclusions: In this treatment-refractory, bDMARD-IR RA population, rapid, significant improvements were observed with UPA at both doses vs PBO during 12 wks of treatment, and maintained through 24 wks. Overall safety was consistent with ph2 and other ph3 studies with UPA. The rates of PE and DVT observed in this study have not been reported for the other ph3 studies that have been unblinded to date. Overall data from the ph3 program will allow a comprehensive evaluation of the benefit:risk profile of UPA in RA.

Belangrijk te zien dat er hier wel een aantal serious AEs zijn waaronder een relatief hoog percentage infecties en PE en hepatic disorder, daar doelt de conclusie dan ook op neem ik aan...

Beurskingpin 14 mei 2018 22:50

0

2 deaths..

holenbeer 14 mei 2018 23:05

0

quote:
Beurskingpin schreef op 14 mei 2018 22:50:
2 deaths..

En malignancies ...
Hartelijk dank voor het delen overigens, Nielsje en Hans

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